Bicyclic pyridines and analogues as sirtuin modulators

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to a compound of formula (I), or its tautomer, or a pharmaceutically acceptable salt, where each of Z1 and Z2: N and CR, where at least, one of Z1 and Z2 represents CR, and each R: H, C1-C4 alkyl and -N(R3)(R3); W: -O-, -N(C1-C4) alkyl and -C(R6)(R6) -, and each R6: H and C1-C4 alkyl, or two R6, bound with the same carbon atom, are taken together with the formation of =O, R1: a phenyl and heterocycle, which represents a saturated or unsaturated 5-6-member monocyclic ring, containing 1-3 heteroatoms, selected from atoms N, S and O, or a 8-12-member bicyclic ring, each cycle of which is selected from a saturated, unsaturated and aromatic cycle, containing 1-2 nitrogen atoms, where R1 is optionally substituted with one or more substituents, independently selected from halogen, C1-C4 alkyl, =O, fluorosubstituted C1-C2 alkyl, -O-R3, -(C1-C4 alkyl)-N(R3)(R3), -N(R3)(R3) and -C(O)-N(R3)(R3), R2: a phenyl and heterocycle, which represents an unsaturated 5-6-member monocyclic ring, containing 1-2 heteroatoms, selected from atoms N and O, or represents dihydrobenzofuranyl, where R2 is optionally substituted with 1-2 substituents, independently selected from a halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorosubstituted alkyl, -O-R3, -(C1-C4 alkyl)-N(R3)(R3) and -N(R3)(R3); each R3: -C1-C4 alkyl; or two R3 are taken together with a nitrogen atom, which they are bound with, with the formation of a 4-8-member unsaturated heterocycle, optionally containing one additional heteroatom, selected from N and O, where in case when R3 represents an alkyl, the said alkyl is optionally substituted with two -OH groups, and when two R3 are taken together with a nitrogen atom, which they are bound with, with the formation of a 4-8-member saturated heterocycle, the said saturated heterocycle is optionally substituted with fluorine by any carbon atom; and is substituted with hydrogen by any capable of substitution nitrogen atom; p equals 1, 2 or 3; X2 is selected from -C(=O)-♣, -C(=O)-O-♣, -C(=O)-NH-♣, -S(=O)2-NH-♣ and -C(=O)-NH-CR4R5-♣, where: ♣ represents a site, by which X2 is bound with R1; and each R4 and R5 represents hydrogen. The invention also relates to compounds of formulas (IV), (V), (VI), particular the compounds, a pharmaceutical composition based on the compound of formulas (I), (IV)-(VI) and to a method of treatment, based on the application of the said compounds.

EFFECT: novel heterocyclic compounds, possessing sirtuin-modelling activity are obtained.

26 cl, 2 tbl, 40 ex

 

2420-186030RU/032

BICYCLIC PYRIDINE AND ANALOGUES AS MODULATORS of SIRTUIN

Description

Reference to related application

According to this application claims priority under provisional application U.S. No. 61/256269, filed October 29, 2009, the disclosure of which is incorporated into this description by reference.

Prior art

The family of gene regulators silent information (SIR) is a highly group of genes present in the genomes of organisms, selected from archaebacteria to eukaryotes. Coded the SIR proteins are involved in diverse processes from the regulation of silence genes to DNA repair. Proteins encoded by members of a gene family SIR, exhibit a high degree of conservation of sequence in the domain of the kernel of 250 amino acids. Well-characterized gene in this family is S. cerevisiae SIR2, which is involved in the silencing of loci NM that contains information that determines the mating type of the yeast, the telomeric position effects and cell aging. Protein of yeast Sir2 belongs to a family of histone deacetylase. Homologue of Sir2, CobB, in Salmonella typhimurium acts as NAD(nicotinamide adenine dinucleotide)-dependent ADP-ribosyltransferase.

Protein Sir2 is a class III deacetylase which uses NAD str�e cosubstrate. Unlike the other deacetylase, many of which are involved in gene silencing, Sir2 is insensitive to inhibitors of the histone deacetylase class I and II similar to trichostatin A (TSA).

Deacetylation acetylglycine under the action of Sir2 is closely linked to the hydrolysis of the ABOVE, resulting in the formation of nicotinamide and a new connection acetyl-ADP ribose. The activity of Sir2 in respect of NAD-dependent deacetylase essential for their functions, which are capable of binding their biological role and cellular metabolism in yeast. Homologues of mammalian Sir2 have activity against NAD-dependent deacetylase.

Biochemical studies have shown that Sir2 can easily deacetylate amino-terminal ends of histones H3 and H4, resulting in the formation of 1-O-acetyl-ADP-ribose and nicotinamide. Strains with extra copies of SIR2 have a keen silencing rDNA and increased by 30% lifetime. It has recently been shown that additional copies of the homologue of C. elegans SIR2, sir-2.1 gene of D. Melanogaster dSir2 significantly increase lifespan in these organisms. This means that SIR2-dependent regulatory pathway of aging appeared in the early stages of evolution and is well preserved. At the present time suggest that Sir2 genes evolved, increasing vitality and the body's resistance to stress, to increase its �ANS survival in adverse conditions.

In humans, there are seven Sir2-like genes (SIR1-SIR7) forming part of the conservative catalytic domain of Sir2. SIR1 is a nuclear protein with the highest degree of sequence similarity with Sir2. SIR1 regulates numerous cellular targets by deacetylation, including the tumor suppressor p53, a factor in the transmission of cellular signals NF-κB and the transcription factor FOXO.

SIR3 is a homologue SIR1 conserved in prokaryotes and eukaryotes. Protein SIR3 focused on mitochondrial scallops using a unique domain located at the N-end. SIR3 has NAD+-dependent protein deacetylase activity in relation to proteins, and is expressed ubiquitously, especially in metabolically active tissues. It is assumed that when you transfer into the mitochondria SIR3 split into smaller active form using a mitochondrial matrix processing peptidase (MPP).

For 70 years it is known that caloric restriction improves health and increases lifespan in mammals. The lifespan of yeast, like the lifespan of multicellular animals also increases due to effects resembling caloric restriction, for example, a low glucose. The discovery that yeast, and flies that lack the gene SIR2 not live longer when restricted�and calories proof that genes SIR2 mediate the beneficial health effects of a diet restricted in calories. Moreover, mutations that reduce the activity glucocorticoides of cyclic amp (adenosine 3',5'-monophosphate)dependent (PKA) pathways of yeast increase the lifespan of wild-type cells but not in mutant sir2 strains, showing that, apparently, SIR2 is a key downstream component of the way of calorie restriction.

Brief description of the invention

The present invention provides a number of new % -modulating compounds and methods of their use.

In one aspect of the invention provided % -modulating compounds of structural formulas (I) to(VI), described in detail below.

In another aspect of the invention provided methods of use % -modulating compounds or compositions containing % -modulating compounds. In some embodiments, % -modulating compounds that increase the level and/or activity of the protein of sirtuin, can be used for various therapeutic applications, including, for example, increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, dia�em obesity, neurodegenerative diseases, neuropathy caused by chemo, neuropathy associated with an ischemic event, ocular diseases and/or disorders, cardiovascular disease, disorders of blood clotting, inflammation and / or tides, and so on. % - Modulating compounds that increase the level and/or activity of the protein of sirtuin can also be used to treat diseases or disorders in a subject, which increase mitochondrial activity would have a beneficial effect, for enhancing muscle performance, for increasing concentrations of ATP or for treating or preventing muscle tissue damage associated with hypoxia or ischemia. In other embodiments, % -modulating compounds that increase the level and/or activity of the protein of sirtuin, you can also apply for a variety of therapeutic applications including, for example, increasing cellular sensitivity to stress, increasing apoptosis, treatment of cancer, stimulation of appetite and/or stimulation of weight gain. As further described below, these methods include the introduction to the needy in this subject a pharmaceutically effective amount % -modulating compounds.

In some respects, % -modulating compounds can be administered alone or in combination with other link�mi, including other % -modulating compounds or therapeutic agents.

Detailed description

1. Definitions

As used in this description, the following terms and expressions will have the meanings described below. If not defined otherwise, all technical and scientific terms have the same meaning as that generally understood by the person skilled in the art.

The term "agent" used in this description to refer to chemical compounds, mixtures of chemical compounds, biological macromolecules (such as nucleic acid, antibody, protein, or portion thereof, e.g., a peptide), or extract derived from biological materials such as cells or tissues of bacteria, plants, fungi, or animal (particularly mammalian). The activity of such agents may render them suitable as "therapeutic agent", which is a biologically, physiologically, or pharmacologically active substance (or substances) that acts in the subject locally or systemically.

The term "bioavailability" in respect of a connection is the definition adopted in this field, and refers to the shape of the connection, taking it into consideration, or part of the amount of compound injected, which will be absorbed, incorporated, or physiologically available subject�or at the patient, to whom it is administered.

"Biologically active portion of sirtuin" refers to a piece of protein sirtuin having biological activity, such as the ability to deacetylation. A biologically active portion of sertaline can include the domain of the kernel of sertaline. A biologically active portion of SIR1 ID GenBank No. NP_036370, including NAD+binding domain and the substrate binding domain, for example, may include, without limitation, amino acids 62-293 ID GenBank No. NP_036370, which is encoded by nucleotides with 237 at 932 ID GenBank No. NP_012238. Therefore, this region is sometimes called the domain of the kernel. Other biologically active portion SIR1, sometimes referred to as core domains, include about amino acids from 261 to 447 ID GenBank No. NP_036370, which are encoded by nucleotides 813 in 1538 ID GenBank No. NM_012238 include amino acids 242-493 ID GenBank No. NP_036370, which are encoded by nucleotides 777 at 1532 ID GenBank No. NP_012238, or comprise amino acids from about 254 to 495 ID GenBank No. NP_036370, which are encoded by nucleotides 813 in 1538 ID GenBank No. NM_012238.

The term "Pets" refers to cats and dogs. As used in the present description, the term�h "dog(dog)" means any member of the species Canis familiaris, which there are many varieties. The term "cat(cats)" refers to an animal of the family Felidae, including domestic cats and other members of the family Felidae, genus Felis.

"Diabetes" refers to high blood sugar or ketoacidosis, as well as chronic, General metabolic abnormalities arising from a prolonged state of high blood sugar levels, or reduced glucose tolerance. "Diabetes" includes forms of diabetes both type I and type II (non-insulin-dependent diabetes mellitus or NIDDM). Risk factors for diabetes include the following factors: waistline of more than 40 inches for men, or 35 inches for women, blood pressure 130/85 mmHg or higher, triglycerides over 150 mg/DL, glucose when fasting more than 100 mg/DL or HDL less than 40 mg/DL for men or 50 mg/DL for women.

The term "ED50"refers to the effective dose adopted in this area. In some embodiments, the implementation of the ED50mean dose of drug that causes 50% of its maximum response or effect, or, alternatively, the dose that causes a predefined response in 50% of test subjects or preparations. The term "LD50"applies to the determination of the lethal dose is taken in this area. In some variants� implementation of LD 50mean dose of drug that is lethal for 50% of test subjects. The term "therapeutic index" refers to the definition adopted in this area, which refers to therapeutic index of a drug defined as LD50/ED50.

The term "hyperinsulinemia" refers to the condition of the individual, wherein the level of insulin in the blood is above normal.

The term "insulin resistance" refers to the condition in which normal amounts of insulin causes an abnormal biological response compared to the biological response in a subject having insulin resistance.

"Breach of insulin resistance" discussed in the present description, refers to any disease or condition that is caused, or which contributes insulin resistance. Examples include: diabetes, obesity, metabolic syndrome, insulin resistance syndrome, syndrome X, insulin resistance, high blood pressure, high cholesterol, dyslipidemia, hyperlipidemia, atherosclerotic disease including stroke, coronary artery disease or myocardial infarction, hyperglycemia, hyperinsulinemia and/or hyperproinsulinemia, inadequate glucose tolerance, delayed insulin release,diabetic complications, including coronary heart disease, angina, congestive heart failure, stroke, cognitive factors in dementia, retinopathy, peripheral neuropathy, nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis some types of cancer (such as endometrial, breast, prostate and colon), complications of pregnancy, poor female reproductive health (such as irregularity of menstrual cycle, infertility, irregular ovulation, polycystic ovaries (PSOC)), lipodystrophy, disorders associated with cholesterol, such as gallstones, cholecystitis and cholelithiasis, gout, obstructive sleep apnea and breathing problems, osteoarthritis and bone loss, for example, in particular, osteoporosis.

The term "livestock" refers to four-legged animals, including animals raised for meat and various byproducts, e.g., livestock, including cattle and other members of the genus Bos, of pigs, including domestic swine and other members of the genus Sus, sheep, including sheep and other members of the genus Ovis, domestic goats and other members of the genus Capra, domesticated four-legged animals raised for specialized tasks such as use as a beast of burden, such as horses, including Domash�their horses and other members of the family Equidae, the genus Equus.

The term "mammal" is known in this field, and examples of mammals include humans, primates, livestock (including cows, pigs, and so on), Pets (e.g., dogs, cats and so on) and rodents (e.g. mice and rats).

"Fat" individuals, or individuals who are obese usually represent individuals with a body mass index (BMI) constituting at least 25 or more. Obesity may be associated, or not associated with insulin resistance.

The terms "parenteral administration" and "administered parenterally" are accepted in this field and refer to the route of administration different from enteral and local administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, vnutriglaznogo, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

"Patient", "subject", "individual" or "recipient" refers to either the human or to the animal than human.

The term "pharmaceutically acceptable carrier" is accepted in this field and refers to a pharmaceutically acceptable� substance, the composition or carrier, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating substance that is involved in carrying or transporting any of the composition or component. Each carrier must be "acceptable" in the sense of compatibility with the composition and its components and not injurious to the patient. Some examples of substances which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate, (4) powdered tragakant, (5) malt, (6) gelatin, (7) talc, (8) excipients, such as cocoa butter and waxes for suppositories, (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, (10) glycols, such as propylene glycol, (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol, (12) esters, such as ethyloleate and ethyl laurate, (13) agar, (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) apyrogenic water, (17) isotonic saline, (18) ringer's solution, (19) Atila�th alcohol, (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical compositions.

The term "prevention" is accepted in this field, and when used in connection with such condition, as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well known in this field, and includes administration of a composition which reduces the frequency of, or delays the onset of symptoms of the medical condition in a subject compared to a subject not receiving the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous tumors in a population of patients receiving prophylactic treatment compared with a control population not receiving treatment, and/or delaying the appearance of detectable cancerous tumors in the population who received treatment compared with a control population not receiving treatment, for example, statistically and/or clinically significant magnitude. The prevention of infectious disease includes, for example, reducing the number of diagnosing infectious diseases in the population who received treatment compared with a control population not receiving treatment, and/or delay n�interventions symptoms of infectious diseases in populations, treated compared with the control population not receiving treatment. Prevention of pain includes, for example, decreasing the amplitude, or, alternatively, delay pain sensations experienced by subjects in the population who received treatment compared with a control population not receiving treatment.

The term "prophylactic" or "therapeutic" treatment is adopted in this field and refers to the administration of the drug to the recipient. In the case when it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the animal recipient), then the treatment is prophylactic, i.e., it protects the recipient from the development of an unwanted condition, whereas if administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to reduce, improve or maintain the existing unwanted condition or going away side effects).

The term "non-pyrogenic", in respect of the composition refers to compositions that do not contain pyrogen in an amount which would lead to adverse effects (e.g., irritation, fever, inflammation, diarrhea, respiratory distress syndrome, endotoksicski shock and so on) in a subject which up�and the composition. For example, it is assumed that the term includes compositions that contain no or essentially does not contain endotoxin, such as lipopolysaccharide (LPS).

"Replication lifespan" of a cell refers to the number of daughter cells produced by a single "parent cell". On the other hand, "calendar age" or "calendar lifetime" refers to the period of time during which the population of non-proliferating cells remained viable when deprived of nutrients. "The increasing longevity of a cell or the extension of the life of the cell" as applied to cells or organisms, refers to the increase in the number of daughter cells produced by one cell; enhancing the ability of cells or organisms to withstand stress and fight the damage, for example. DNA, proteins, and/or increase the ability of cells or organisms to survive and exist in a living state for longer under a particular condition, e.g., stress (e.g., heat shock, osmotic stress, high energy radiation, chemically-induced stress, DNA damage, inadequate salt concentration, insufficient concentration of nitrogen or insufficient nutrient content). Lifespan can� increase, at least 10%, 20%, 30%, 40%, 50%, 60% or in the range of from 20% to 70%, from 30% to 60%, from 40% to 60% or more when you use the methods described here.

"%-Activating compound" refers to a compound that increases the level of protein sirtuin and/or increases at least one activity of the protein of sirtuin. In the example of implementation % -activating compound may increase at least one biological activity of the protein of sirtuin, at least 10%, 25%, 50%, 75%, 100%, or more. Illustrative biological activity of proteins sirtuin include deacetylation, e.g., of histones and p53, increased life expectancy, increased genomic stability, transcriptional silencing and regulation segregation of oxidized proteins between mother and daughter cells.

"%Protein" refers to a member of a family of proteins deacetylase of sirtuin or preferably to the sir2 family, which includes proteins of yeast Sir2 (GenBank identification number R),C. ElegansSir-2.1 (GenBank identification number NP_501912) and human SIRT1 (GenBank identification number N_012238 and NP_036370 (or AF083106)) and SIRT2 (GenBank identification number N_012237, N_030593, NP_036369, NP_085096 and AF083107). Other family members include the four additional Sir2-like genes of yeast, called "HST genes" (homologues of Sir two) HST1, HST2, HST3 and HST4, and the five other human�x homologues hSIRT3, hSIRT4, hSIRT5, hSIRT6 and hSIRT7 (Brachmann et al. (1995) Genes Dev. 9:2888 and Frye et al. (1999) BBRC 260:273). Preferred certainly are certainy having more similarities with SIRT1, that is, hSIRT1, and/or Sir2 than with SIRT2, such as members contain at least a portion of the N-terminal sequence present in SIRT1, and absent in SIRT2 such as available in SIRT3.

"SIRT1 protein" refers to a family of the sir2 deacetylase of sirtuin. In one embodiment, the implementation of SIRT1 protein includes Sir 2 yeast (GenBank identification number R), C. Elegans Sir-2 (GenBank identification number NP_501912), human SIRT1 (GenBank identification number NM_012238 or NP_036370 (or AF083106)) and its equivalents and fragments. In another embodiment of the SIRT1 protein includes a polypeptide containing a sequence comprising or essentially consisting of the amino acid sequence shown in GenBank ID numbers NP_036370, NP_501912, NP_085096, NP_036369, or R. Proteins include SIRT1 polypeptide containing all or part of the amino acid sequence shown in GenBank ID numbers NP_036370, NP_501912, NP_085096, NP_036369, or R, the amino acid sequence shown in GenBank ID numbers NP_036370, NP_501912, NP_085096, NP_036369, or R from 1 to about 2, 3, 5, 7, 10, 15, 20, 30, 50, 75 or more conservative substitutions of amino acids, the amino acid sequence that is at least 60%,70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to GenBank identification numbers NP_036370, NP_501912, NP_085096, NP_036369 or R, and its functional fragments. The polypeptides of this invention also include homologs (e.g., orthologs and paralogy), variants or fragments GenBank identification numbers NP_036370, NP_501912, NP_085096, NP_036369 or R.

As used in this description, "SIRT2 protein", "SIRT3 protein", "protein SIRT4", "SIRT5 protein", "protein SIRT6 and SIRT7 protein" refer to proteins in deacetilase of certain other mammals, e.g., humans, which are the homologues of the protein SIRT1, in particular, canned catalytic domain, consisting of approximately 275 amino acids. For example, "SIRT3 protein" refers to a member of a family of proteins deacetylase of sirtuin, which is the homologue of SIRT1 protein. In one embodiment, the implementation of SIRT3 protein includes proteins human SIRT3 (GenBank identification number AN, NP_036371 or NP_001017524) and mouse SIRT3 (GenBank identification number NP_071878) and their fragments and equivalents. In another embodiment of the SIRT3 protein includes a polypeptide containing a sequence comprising or essentially consisting of the amino acid sequence shown in GenBank ID numbers AN, NP_036371, NP_0017524 or NP_071878. SIRT3 proteins include polypeptides comprising all or part of the amino acid sequence shown under IDA�tification rooms GenBank AAN, NP_036371, NP_0017524 or NP_071878, the amino acid sequence of from 1 to approximately 2, 3, 5, 7, 10, 15, 20, 30 50, 75 or more conservative substitutions of amino acids, which, at least on 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to GenBank identification numbers AN, NP_036371, NP_0017524 or NP_071878 and its functional fragments. The polypeptides of this invention also include homologs (e.g., orthologs and paralogy), variants or fragments GenBank identification numbers AN, NP_036371, NP_0017524 or NP_071878. In one embodiment, the implementation of SIRT3 protein includes a fragment of SIRT3 protein resulting from cleavage of the mitochondrial matrix by processing peptidase (MPP) and/or a mitochondrial intermediate peptidase (MIP).

The terms "systemic administration", "administered systemically", "peripheral introduction" and "administered peripherally" are accepted in this field and refer to the introduction of the composition, therapeutic or other substance other than directly into the Central nervous system so that it enters the system of the patient and, thus, is subject to metabolism and other like processes.

Used in the present description, the term "tautomer" is accepted in this field and refers to the formal migration of a hydrogen atom, or proton, accompanied by a single shift of Saint�Zee and the neighboring double bond. When used here to describe a compound or genus of compounds that includes any tautomer of the connection part or the whole connection, such as one alternate connection, several deputies of the connection, or, for example, all link. For example, tautomer compounds containing hydroxylamine pyridine cycle (A) is a keto-enol substituted cycle (In):

The term "therapeutic agent" is accepted in this field and refers to any chemical component, which is a biologically, physiologically, or pharmacologically active substance that acts in the subject of local or systemic manner. This term also means any compound intended for use in the diagnosis, cure, relief, treatment or prevention of disease or the enhancement of desirable physical or mental development and/or conditions in an animal or human.

The term "therapeutic effect" is accepted in this field and refers to local or systemic effect in animals, particularly mammals, and more particularly humans caused by a pharmacologically active substance. The expression "terapevticheskii effective amount" means such amount of such substances, which leads to some�Oromo desired local or systemic effect at a reasonable benefit/risk in applying to any treatment. Terapevticheskii an effective amount of such substance will vary depending on the subject and the state of the disease being treated, the weight and age of the subject, the severity of the disease, the mode of administration and so on, which can be easily determined by a person skilled in the art. For example, certain compositions described herein can be administered in an amount sufficient to obtain the desired impact at an acceptable ratio of benefit/risk, applicable to such treatment.

"Treatment" of a condition or disease refers to the treatment, as well as to improve at least one symptom of a condition or disease.

The term "impairment" refers to reduced vision, which is often only partially reversible or irreversible in the treatment (e.g., surgical). In particular, severe loss of vision is called "blindness" or "vision loss", which refers to complete loss of vision, vision worse than 20/200 that cannot be corrected with corrective lenses, or a field of view with a diameter of less than 20 degrees (10 degrees).

2. Modulators of sirtuin

In one aspect, the invention provides new % -modifying compounds for the treatment and/or prevention of a wide range of diseases and disorders including, for example, diseases or disorders�Oia, associated with aging or stress, diabetes, obesity, neurodegenerative diseases, neuropathy caused by chemo, neuropathy associated with an ischemic event, ocular diseases and/or disorders, cardiovascular disease, disorders of blood clotting, inflammation and / or tides, and so on. % - Modulating compounds that increase the level and/or activity of the protein of sirtuin can also be used to treat diseases or disorders in a subject, which increase mitochondrial activity would have a beneficial effect, for enhancing muscle performance, for increasing concentrations of ATP or for treating or preventing muscle tissue damage associated with hypoxia or ischemia. Other compounds disclosed herein, may be suitable for use in pharmaceutical compositions and/or one or more of the methods disclosed in this description.

In one embodiment of the invention, there is provided a compound of structural formula (I):

it tautomer or salt, where:

each of the Z1and Z2independently selected from N and CR, where

at least one of Z1and Z2is a CR, and

each R is independently selected from hydrogen, halogen, -OH, -C≡N, fluorine-substituted C1-C2alkyl, -O-(� 1-C2)fluorine-substituted alkyl, -S-(C1-C2)fluorine-substituted alkyl, C1-C4alkyl, -O-(C1-C4)alkyl, -S-(C1-C4)alkyl, (C3-C7)cycloalkyl, (C1-C2)alkyl-N(R3)(R3), -O-CH2CH(Oh)CH2HE, -O-(C1-C3)alkyl-N(R3)(R3and-N(R3)(R3);

W is selected from-O-, -NH-, -N(C1-C4)alkyl, -S-, -S(O)-, -S(O)2and-C(R6)(R6)-, and each R6independently selected from hydrogen, C1-C4the alkyl and fluorine-substituted C1-C4alkyl, or two R6,linked to the same carbon atom, taken together with the formation of =O,

R1choose from carbocycle and heterocycle, where R1optionally substituted by one or more substituents, independently selected from halogen, -C≡N, C1-C4of alkyl, =O,3-C7cycloalkyl, fluorine-substituted C1-C2alkyl, -O-R3, -S-R3-(C1-C4alkyl)-N(R3)(R3), -N(R3)(R3), -O-(C1-C4alkyl)-N(R3)(R3), -(C1-C4alkyl)- O-(C1-C4alkyl)-N(R3)(R3), -C(O)-N(R3)(R3), and -(C1-C4alkyl)-C(O)- N(R3)(R3), and when R1represents phenyl, R1also optionally substituted-O-(saturated, heterotic�ω), -O-( fluorine-substituted saturated heterocycle), S1-C4alkyl-substituted saturated heterocycle, 3,4-methylenedioxy, fluorine-substituted 3,4-methylenedioxy, 3,4-Ethylenedioxy or fluorine-substituted 3,4-Ethylenedioxy,

R2choose from carbocycle and heterocycle, where R2optionally substituted by one or more substituents, independently selected from halogen, -C≡N, C1-C4alkyl, C3-C7cycloalkyl, S1-C2fluorine-substituted alkyl, -O-R3, -S-R3, -SO2-R3, =O, -(C1-C4alkyl)-N(R3)(R3), -N(R3)(R3), -O-(C1-C4alkyl)-N(R3)(R3), -(C1-C4alkyl)- O-(C1-C4alkyl)-N(R3)(R3), -C(O)-N(R3)(R3), -(C1-C4alkyl)-C(O)- N(R3)(R3), -O-phenyl, phenyl, and a second heterocycle, and when R2represents phenyl, R2also optionally substituted-O-(saturated heterocycle), 3,4-methylenedioxy, fluorine-substituted 3,4-methylenedioxy, 3,4-Ethylenedioxy or fluorine-substituted 3,4-Ethylenedioxy, where any phenyl, saturated heterocycle, or a second heterocyclic substituent R2optionally substituted by halogen, -C≡N, C1-C4by alkyl, fluorine-substituted C1-C2the alkyl, -O-(C1-C2) a fluorine-substituted alkyl, -O-(C1-C4) alkyl, -S-(C -C4) alkyl, -S-(C1-C2) a fluorine-substituted alkyl, -NH-(C1-C4) alkyl, and-N(C1-C4)2by alkyl;

each R3independently selected from hydrogen and-C1-C4alkyl; or

two R3taken together with the nitrogen atom to which they are bound, to form a 4-8-membered saturated heterocycle, optionally containing one additional heteroatom selected from N, S, S(=O), S(=O)2and where:

in the case where R3represents alkyl, the alkyl optionally substituted by one or more substituents selected from HE, fluorine, -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, -NH(CH2CH2OCH3) or-N(CH2CH2OCH3)2and

when two R3taken together with the nitrogen atom to which they are linked with the formation of a 4-8-membered saturated heterocycle, the saturated heterocycle optionally substituted on any carbon atom-HE, WITH1-C4by alkyl, fluorine, -NH2, -NH(C1-C4by alkyl), -N(C1-C4by alkyl)2, -NH(CH2CH2OCH3) or-N(CH2CH2OCH3)2; and optionally substituted on any subject to substitution of the nitrogen atom with hydrogen, C1-C4by alkyl, fluorine-substituted C1-C4the alkyl, or -(CH2)2-O-CH3;

p is 1, 2 or 3;

X2selected from-C(=O)-♣, -C(=O)-O-♣, -C(=O)-CR4R5-♣, -S(=O)-♣, -S(=O)2-♣, -S(=O)-CR4R5-♣,-S(=O)2-CR4R5-♣, -C(=S)-♣, -C(=S)-CR4R5-♣, -C(=O)-NH-♣, -C(=S)-NH-♣, -S(=O)-NH-♣, -S(=O)2-NH-♣, -CR4R5-NH-♣, -C(=NR4)-NH-♣, -C(=O)-NH-CR4R5-♣, -CR4R5-NH-C(=O)-♣, -CR4R5-C(=S)-NH-♣, -CR4R5-S(=O)-NH-♣, -CR4R5-S(O)2-NH-♣, -CR4R5-O-C(=O)-NH-♣, and-CR4R5-NH-C(=O)-O -♣ where:

♣ represents the point at which X2linked with R1; and

each R4and R5independently selected from hydrogen, C1-C4alkyl, -CF3and (C1-C3alkyl)-CF3.

The compound of structural formula (I) can be represented by the structural formula (II):

where

R10represents C1-C4alkyl.

The compound of structural formula (I) could also be represented by the structural formula (III):

where

R10choose from aliphatic heterocycle and carbocycle.

In one embodiment of the present invention is provided a compound represented by structural formula (IV):

it tautomer or salt, where

each of the Z1and Z2independently vybirayuthij N and CR, where

at least one of Z1and Z2represents CR; and

each R is independently selected from hydrogen, halogen, -OH, -C≡N, fluorine-substituted C1-C2alkyl, -O-(C1-C2) fluorine-substituted alkyl, -S-(C1-C2) fluorine-substituted alkyl, -C1-C4alkyl, -O-(C1-C4) alkyl, -S-(C1-C4) alkyl, C3-C7cycloalkyl, -(C1-C2) alkyl - N(R3)(R3), -O-CH2CH(Oh)CH2HE, -O-(C1-C3)alkyl-N(R3)(R3), and-N(R3)(R3);

R11selected from halogen, and R12selected from hydrogen, halogen, C1-C4the alkyl and fluorine-substituted C1-C4of alkyl,

each R6independently selected from hydrogen, C1-C4the alkyl and fluorine-substituted C1-C4alkyl, or two R6related to the same carbon atom, taken together with the formation of =O,

R1choose from carbocycle and heterocycle, where R1independently substituted by one or more substituents, independently selected from halogen, -C≡N, -C1-C4of alkyl, =O,3-C7cycloalkyl, fluorine-substituted C1-C2alkyl, -O-R3, -S-R3-(C1-C4alkyl)-N(R3)(R3), -N(R3)(R3), -O-(C1-C4)alkyl-N(R3)(R3), -(C1-C alkyl)-O-(C1-C4alkyl)-N(R3)(R3), -C(O)-N(R3)(R3and -(C1-C4alkyl)-C(O)-N(R3)(R3), and when R1represents phenyl, R1also optionally substituted-O-(saturated heterocycle), -O-( fluorine-substituted saturated heterocycle), S1-C4alkyl-substituted saturated heterocycle, 3,4-methylenedioxy, fluorine-substituted 3,4-methylenedioxy, 3,4-Ethylenedioxy or fluorine-substituted 3,4-Ethylenedioxy,

R2choose from carbocycle and heterocycle, where R2independently substituted by one or more substituents, independently selected from halogen, -C≡N, -C1-C4alkyl, C3-C7cycloalkyl, S1-C2fluorine-substituted alkyl, -O-R3, -S-R3, -S(O)2-R3, =O, -(C1-C4alkyl)-N(R3)(R3), -N(R3)(R3), -O-(C1-C4)alkyl-N(R3)(R3), -(C1-C4alkyl)-O-(C1-C4alkyl)-N(R3)(R3), -C(O)-N(R3)(R3), -(C1-C4alkyl)-C(O)-N(R3)(R3), -O-phenyl, phenyl, and a second heterocycle, and when R2represents phenyl, R2also optionally substituted-O-(saturated heterocycle), 3,4-methylenedioxy, fluorine-substituted 3,4-methylenedioxy, 3,4-Ethylenedioxy or fluorine-substituted 3,4-Ethylenedioxy, where any phenyl, saturated heterocycle, or W�Roy heterocyclic substituent R 2optionally substituted by halogen, -C≡N, -C1-C4by alkyl, fluorine-substituted C1-C2the alkyl, -O-(C1-C2) a fluorine-substituted alkyl, -O-(C1-C4) alkyl, -S-(C1-C4) alkyl, -S-(C1-C2) a fluorine-substituted alkyl, -NH-(C1-C4) alkyl and-N(C1-C4)2by alkyl;

each R3independently selected from hydrogen and-C1-C4alkyl; or

two R3taken together with the nitrogen atom to which they are bound, to form a 4-8-membered saturated heterocycle, optionally containing one additional heteroatom selected from N, S, S(=O), S(=O)2and where:

in the case where R3represents alkyl, the alkyl optionally substituted by one or more substituents selected from HE, fluorine, -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, -NH(CH2CH2OCH3and-N(CH2CH2OCH3)2and

in the case where two R3taken together with the nitrogen atom to which they are bound, to form a 4-8-membered saturated heterocycle, the saturated heterocycle optionally substituted on any carbon atom of-OH, -C1-C4by alkyl, fluorine, -NH2, -NH(C1-C4by alkyl), -N(C1-C4by alkyl)2, -NH(CH2CH2OCH3) or-N(CH2CH2 OCH3)2; and optionally substituted on any suitable for substitution of the nitrogen atom with hydrogen, -C1-C4by alkyl, fluorine-substituted C1-C4the alkyl, or -(CH2)2-O-CH3;

p is 1, 2, or 3, and

X2selected from-C(=O)-♣, -C(=O)-O-♣, -C(=O)-CR4R5-♣, -S(=O)-♣, -S(=O)2-♣, -S(=O)-CR4R5-♣,-S(=O)2-CR4R5-♣, -C(=S)-♣, -C(=S)-CR4R5-♣, -C(=O)-NH-♣, -C(=S)-NH-♣, -S(=O)-NH-♣, -S(=O)2-NH-♣, -CR4R5-NH-♣, -C(=NR4)-NH-♣, -C(=O)-NH-CR4R5-♣, -CR4R5-NH-C(=O)-♣, -CR4R5-C(=S)-NH-♣, -CR4R5-S(O)-NH-♣, -CR4R5-S(O)2-NH-♣, -CR4R5-O-C(=O)-NH-♣ and-CR4R5-NH-C(=O)-O -♣ where:

♣ represents the point at which X2linked with R1; and

each R4and R5independently selected from hydrogen, C1-C4alkyl, -CF3and (C1-C3alkyl)-CF3.

In the compound represented by structural formula (IV) each of R11and R12can be selected from halogen. For example, each of R11and R12can represent fluorine.

In another embodiment of the invention predstavljena compound represented by structural formula (V):

it tautomer or salt, where

each Z1and Z2independently chosen�up from N and CR, where

at least one of Z1and Z2represents CR; and

each R is independently selected from hydrogen, halogen, -OH, -C≡N, fluorine-substituted C1-C2alkyl, -O-(C1-C2) fluorine-substituted alkyl, -S-(C1-C2) fluorine-substituted alkyl, -C1-C4alkyl, -O-(C1-C4) alkyl, -S-(C1-C4) alkyl, C3-C7cycloalkyl, -(C1-C2) alkyl - N(R3)(R3), -O-CH2CH(Oh)CH2HE, -O-(C1-C3)alkyl-N(R3)(R3), and-N(R3)(R3);

W is selected from-O-, -NH-, -N(C1-C4alkyl), -S-, -S(O)-, -S(O)2- and-C-(R6)(R6)- and

each R6independently selected from hydrogen, halogen, C1-C4the alkyl and fluorine-substituted C1-C4alkyl, or two R6related to the same carbon atom, taken together with the formation of =O,

R1choose from carbocycle and heterocycle, where R1independently substituted by one or more substituents, optionally selected from halogen, -C≡N, -C1-C4of alkyl, =O,3-C7cycloalkyl, fluorine-substituted C1-C2alkyl, -O-R3, -S-R3-(C1-C4alkyl)-N(R3)(R3), -N(R3)(R3), -O-(C1-C4)alkyl-N(R3)(R3), -(C1-C4alkyl)-O-(C1-C4alkyl)-NR 3)(R3), -C(O)-N(R3)(R3and -(C1-C4alkyl)-C(O)-N(R3)(R3), and when R1represents phenyl, R1also optionally substituted-O-(saturated heterocycle), -O-( fluorine-substituted saturated heterocycle), S1-C4alkyl-substituted saturated heterocycle, 3,4-methylenedioxy, fluorine-substituted 3,4-methylenedioxy, 3,4-Ethylenedioxy or fluorine-substituted 3,4-Ethylenedioxy,

R2choose from carbocycle and heterocycle, where R2optionally substituted by one or more substituents, independently selected from halogen, -C≡N, -C1-C4alkyl, C3-C7cycloalkyl, S1-C2fluorine-substituted alkyl, -O-R3, -S-R3, -SO2-R3, =O, -(C1-C4alkyl)-N(R3)(R3), -N(R3)(R3), -O-(C1-C4alkyl)-N(R3)(R3), -(C1-C4alkyl)-O-(C1-C4alkyl)-N(R3)(R3), -C(O)-N(R3)(R3), -(C1-C4alkyl)-C(O)-N(R3)(R3), -O-phenyl, phenyl, and a second heterocycle, and when R2represents phenyl, R2also optionally substituted-O-(saturated heterocycle), 3,4-methylenedioxy, fluorine-substituted 3,4-methylenedioxy, 3,4-Ethylenedioxy or fluorine-substituted 3,4-Ethylenedioxy, where any phenyl, saturated heterocycle, or a second heterocyclic substituent R 2optionally substituted by halogen, -C≡N, -C1-C4by alkyl, fluorine-substituted C1-C2the alkyl, -O-(C1-C2) a fluorine-substituted alkyl, -O-(C1-C4) alkyl, -S-(C1-C4) alkyl, -S-(C1-C2) a fluorine-substituted alkyl, -NH-(C1-C4) alkyl and-N(C1-C4)2by alkyl;

each R3independently selected from hydrogen and-C1-C4alkyl; or

two R3taken together with the nitrogen atom to which they are bound, to form a 4-8-membered saturated heterocycle, optionally containing one additional heteroatom selected from N, S, S(=O), S(=O)2and where:

in the case where R3represents alkyl, the alkyl optionally substituted by one or more substituents, independently selected from HE, fluorine, -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, -NH(CH2CH2OCH3and-N(CH2CH2OCH3)2and

in the case where two R3taken together with the nitrogen atom to which they are linked, with the formation of a 4-8-membered saturated heterocycle, the saturated heterocycle optionally substituted on any carbon atom of-OH, -C1-C4by alkyl, fluorine, -NH2, -NH(C1-C4by alkyl), -N(C1-C4by alkyl)2, -NH(CH2CH2OCH3) or-N(CH 2CH2OCH3)2; and optionally substituted on any suitable for substitution of the nitrogen atom with hydrogen, -C1-C4by alkyl, fluorine-substituted C1-C4the alkyl, or -(CH2)2-O-CH3;

p is 1, 2, or 3, and

R4and R5taken together with the formation of a 3-6-membered saturated carbocycle or heterocycle.

For compounds represented by structural formula (V), R4and R5you can take along with getting carbocycle. For example, taken together, R4and R5can form a cyclopropyl ring.

In yet another variant implementation of the present invention, the compound represented by structural formula (VI):

it tautomer or salt, where

each Z1and Z2independently selected from N and CR, where

at least one of Z1and Z2represents CR; and

each R is independently selected from hydrogen, halogen, -OH, -C≡N, fluorine-substituted C1-C2alkyl, -O-(C1-C2) fluorine-substituted alkyl, -S-(C1-C2) fluorine-substituted alkyl, -C1-C4alkyl, -O-(C1-C4) alkyl, -S-(C1-C4) alkyl, C3-C7cycloalkyl, -(C1-C2) alkyl - N(R3)(R3), -O-CH2CH(Oh)CH2HE, -O-(C1-C3)alkyl-N(R3)(R3, and-N(R3)(R3);

W is selected from-O-, -NH-, -N(C1-C4alkyl), -S-, -S(O)-, -S(O)2- and-C-(R6)(R6)-, and each R6independently selected from hydrogen, halogen, C1-C4the alkyl and fluorine-substituted C1-C4alkyl, or two R6related to the same carbon atom, taken together with the formation of =O,

R1choose from carbocycle and heterocycle, where R1replaced by cerebellum and R1optionally additionally substituted by one or more substituents, independently selected from halogen, -C≡N, -C1-C4of alkyl, =O,3-C7cycloalkyl, fluorine-substituted C1-C2alkyl, -O-R3, -S-R3-(C1-C4alkyl)-N(R3)(R3), -N(R3)(R3), -O-(C1-C4)alkyl-N(R3)(R3), -(C1-C4alkyl)-O-(C1-C4alkyl)-N(R3)(R3), -C(O)-N(R3)(R3and -(C1-C4alkyl)-C(O)-N(R3)(R3), and when R1represents phenyl, R1also optionally substituted-O-(saturated heterocycle), -O-( fluorine-substituted saturated heterocycle), S1-C4alkyl-substituted saturated heterocycle, 3,4-methylenedioxy, fluorine-substituted 3,4-methylenedioxy, 3,4-Ethylenedioxy or fluorine-substituted 3,4-Ethylenedioxy,

R2choose from carbocycle and heterocycle, where R optionally substituted by one or more substituents, independently selected from halogen, -C≡N, -C1-C4alkyl, C3-C7cycloalkyl, S1-C2fluorine-substituted alkyl, -O-R3, -S-R3, -SO2-R3, =O, -(C1-C4alkyl)-N(R3)(R3), -N(R3)(R3), -O-(C1-C4alkyl)-N(R3)(R3), -(C1-C4alkyl)-O-(C1-C4alkyl)-N(R3)(R3), -C(O)-N(R3)(R3), -(C1-C4alkyl)-C(O)-N(R3)(R3), -O-phenyl, phenyl, and a second heterocycle, and when R2represents phenyl, R2also optionally substituted-O-(saturated heterocycle), 3,4-methylenedioxy, fluorine-substituted 3,4-methylenedioxy, 3,4-Ethylenedioxy or fluorine-substituted 3,4-Ethylenedioxy, where any phenyl, saturated heterocycle, or a second heterocyclic substituent R2optionally substituted by halogen, -C≡N, -C1-C4by alkyl, fluorine-substituted C1-C2the alkyl, -O-(C1-C2) a fluorine-substituted alkyl, -O-(C1-C4) alkyl, -S-(C1-C4) alkyl, -S-(C1-C2) a fluorine-substituted alkyl, -NH-(C1-C4) alkyl and-N(C1-C4)2by alkyl;

each R3independently selected from hydrogen and-C1-C4alkyl; or

two R3taken together with the nitrogen atom, to�which they are associated, with the formation of a 4-8-membered saturated heterocycle, optionally containing one additional heteroatom selected from N, S, S(=O), S(=O)2and where:

in the case where R3represents alkyl, the alkyl optionally substituted by one or more substituents selected from HE, fluorine, -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, -NH(CH2CH2OCH3and-N(CH2CH2OCH3)2and

in the case where two R3taken together with the nitrogen atom to which they are linked, with the formation of a 4-8-membered saturated heterocycle, the saturated heterocycle optionally substituted on any carbon atom of-OH, -C1-C4by alkyl, fluorine, -NH2, -NH(C1-C4by alkyl), -N(C1-C4alkyl)2, -NH(CH2CH2OCH3) or-N(CH2CH2OCH3)2; and optionally substituted on any suitable for substitution of the nitrogen atom with hydrogen, -C1-C4by alkyl, fluorine-substituted C1-C4the alkyl, or -(CH2)2-O-CH3;

p is 1, 2, or 3, and

X2selected from-C(=O)-♣, -C(=O)-O-♣, -C(=O)-CR4R5-♣, -S(=O)-♣, -S(=O)2-♣, -S(=O)-CR4R5-♣,-S(=O)2-CR4R5-♣, -C(=S)-♣, -C(=S)-CR4R5-♣, -C(=O)-NH-♣, -C(=S)-NH-♣, -S(=O)-NH-♣, -S(=O)2-NH-♣, -CR4R5-NH-♣, -C(=NR4)-H-♣, -C(=O)-NH-CR4R5-♣, -CR4R5-NH-C(=O)-♣, -CR4R5-C(=S)-NH-♣, -CR4R5-S(O)-NH-♣, -CR4R5-S(O)2-NH-♣, -CR4R5-O-C(=O)-NH-♣ and-CR4R5-NH-C(=O)-O -♣ where:

♣ represents the point at which X2linked with R1; and

each R4and R5independently selected from hydrogen, C1-C4alkyl, -CF3and (C1-C3alkyl)-CF3and when X2represents-C(=O)-NH-CR4R5-♣, R4and R5can also be rented together with the formation of a 3-6-membered saturated carbocycle or heterocycle.

In some embodiments, for compounds represented by structural formula (VI) when X2represents-C(=O)-NH-CR4R5-♣, R4and R5can also be rented together with the formation of carbocycle. For example, taken together, R4and R5can form a cyclopropyl ring.

In the case of compounds represented by structural formula (VI), spiramycin can be a 4-4 heterobicycle. In some embodiments, the 4-4 heterobicycle represented by the structure:

In some embodiments, when R1replaced by cerebellum, R1choose from

R1in the compound represented�Ohm structural formula (VI), may represent a pyridyl. In some embodiments, R1is areplaced by cerebellum. In some embodiments, R1represents pyridyl, substituted with one of:

Each of the following embodiments, unless otherwise specified or beyond these structural formulas, can be applied to any of formulas (I), (II), (III), (IV), (V) or (VI). In cases where the structure requires a specific substituent (for example, spiramycin in R1in the formula (VI)), it should be understood that the following groups are suitable fragments is associated with a specific Deputy, and therefore persist in the connection, as required in the given formula.

In some embodiments, W represents-O-, -NH-, -N(C1-C4alkyl) or-C(R6)(R6)-. In some embodiments, W is selected from-N(C1-C4alkyl)-, -S-, -S(O)-, -S(O)2- and-C(R6)(R6)-.

In some embodiments, R1choose from aliphatic heterocycle and carbocycle. In some embodiments, R1selected from aryl, different from phenyl, for example, naftel. In some embodiments, R1you�playing from heterocycle, such as heteroaryl.

In some embodiments, each of Z1and Z2represents CR, in particular, CH.

In some embodiments, R6represents-H or-CH3or two R6taken together represent =O. In specific embodiments, each R6represents-N.

In specific embodiments, W, Z1, Z2and R6chosen so that the compound is chosen from any of the following structural formula:

In some embodiments, R1choose from:

where R1optionally substituted by one or more substituents, independently selected from-C1-C4alkyl, fluorine-substituted C1-C2alkyl, -(C1-C4alkyl)-N(R3)(R3), -N(R3)(R3), -C(O)-N(R3)(R3), =O and-O-R3. In some of such embodiments, R1substituted by one or more groups independently selected from-F, -Cl, -CH3, -OCH3,

In specific embodiments, compounds of structural formula (I) R1choose from:

In even more specific embodiments, compounds of structural formula (I) R1choose from:

In some embodiments, compounds of structural formula (I) R2choose from:

where R2optionally substituted by one or more groups independently selected from halogen, -C1-C4alkyl, -(C1-C4alkyl)-N(R3)(R3), S1-C2fluorine-substituted alkyl, -O-R3, -SO2-R3, -N(R3)(R3and-O-(C1-C4alkyl)-N(R3)(R3). In some of such embodiments, R2optionally substituted by one or more groups independently selected from =O, -F, -Cl, -CN, -CH3, -OCH3, -CF2H, -N(CH3)2, -CH2N(CH3)2,-CF3-OCF3, -OCF2H,,-SO2CH3and

In specific embodiments, R2choose from

In even more specific embodiments, is�for the implementation of R 2choose from

In some embodiments, X2represents-C(=O)-NH-♣.

In some embodiments, R1, R2, W, X2, Z1and Z2chosen so that they had one, two, three, four, five or six of the specific values described above. For example, W, R6, Z1and Z2you can choose to obtain from one to six above specific structural formulas in combination with X2in the form-C(=O)-NH-♣ and any of the above specific structures R1and R2.

Described below are embodiments of apply to compounds of any of structural formulae (I) to(VI).

The compounds of this invention, including the novel compounds of the invention can also be used in ways described here.

These compounds and their salts may also be present in the form of hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate) and the solvate. Suitable solvents for obtaining solvates and hydrates, as a rule, can select an experienced specialist.

Compounds and their salts may be present in amorphous or crystalline (including co-crystalline and polymorphic) forms.

% - Modulating compounds of the invention primarily modulate the level and/or asset�spine certainly proteins in particular, deacetylase activity of protein sirtuin.

Separately or in addition to the above properties, some % -modulating compounds of the invention essentially do not possess one or more of the following activities: inhibition R-kinase, inhibition elderadostone, inhibition of tyrosine kinase inhibitors, transactivate EGFR tyrosine kinase, coronary dilation, or spasmolytic activity, at concentrations of compounds that are effective for modulating deacetylase activity of protein sirtuin (e.g., such as protein SIRT1 and/or SIRT3).

The alkyl group is a linear or branched hydrocarbon that is completely saturated. Typically linear or branched alkyl group contains from 1 to about 20 carbon atoms, preferably from 1 to about 10. Examples of the linear or branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, terbutyl, tertbutyl, pentyl, hexyl, heptyl and octyl. With1-C4linear or branched alkyl group referred to as "lower alkyl" group.

Used in the present description, the terms "carbocycle" and "carbocyclic" refers to a saturated or unsaturated cycle in which each atom of the cycle is the carbon. Carbocycle includes 5-7-membered and 8-12 membered bicyclic�Chia rings. Each cycle of the bicyclic carbocycle you can select from saturated, unsaturated and aromatic rings. In the illustrative embodiment of the aromatic cycle, for example, the phenyl can be condensed with a saturated or unsaturated cycle, for example, cyclohexane, cyclopentane or cyclohexene. In the definition of carbocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, which allows the valence. Illustrative carbocycle include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl and naphthyl.

Cycloalkyl group is carbocycle, which is fully saturated. Examples cycloalkyl groups include cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptenyl and adamantyl.

Used in the present description the terms "heterocycle" and "heterocyclic" refer to a saturated or unsaturated cycle containing one or more heteroatoms selected from the atoms N, O and S. the Heterocyclic compounds include 4 to 7-membered monocyclic and 8-12 membered bicyclic ring. Each cycle of the bicyclic heterocycle can choose from saturated, unsaturated and aromatic rings. In the illustrative embodiment of the aromatic cycle, for example, pyridyl, can be condensed with a saturated or unsaturated cycle, for example, cyclohexa�Ohm, cyclopentane or cyclohexene. The terms "heterocyclyl" and "heterocyclic" also include polycyclic cyclic system containing two or more cyclic rings in which two or more carbons are common to two adjacent cycles in which at least one of the cycles is heterocyclic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkenyl, arily, heteroaryl and/or heteroseksualci. Heterocyclic groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones and lactams.

The term "heteroaryl" includes substituted or unsubstituted aromatic monocyclic structure is preferably 5-7-membered cycles, more preferably 5-6-membered cycles, cyclic structures which include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatom. The term "heteroaryl" also includes polycyclic ring systems containing two or more cycles in which two or more carbons are common to two adjacent cycles in which at least one of the cycles is heteroaromatic, e.g., other cycles may constitute cycloalkyl, cycloalkenyl, cycloalkenyl, arily, heteroa�crystals and/or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and so on.

Monocyclic rings include 5-7-membered aryl or heteroaryl, 3-7-membered cycloalkyl and a 5-7 membered non-aromatic heterocyclyl. Examples of monocyclic groups include substituted or unsubstituted heterocycles, or carbocycle, such as thiazolyl, oxazolyl, oxazinyl, triazinyl, dithienyl, dioxane, isoxazolyl, isothiazolin, triazolyl, furanyl, tetrahydrofuranyl, dihydrofuran, pyranyl, tetrazolyl, pyrazolyl, pyrazinyl, pyridazinyl, imidazolyl, pyridinyl, pyridinyl, pyrrolyl, dihydropyrrole, pyrrolidine, piperidinyl, piperazinyl, pyrimidinyl, morpholinyl, tetrahydrothiophene, thiophenyl, cyclohexyl, cyclopentyl, cyclopropyl, cyclobutyl, cycloheptyl, azetidine, oxetane, tyranny, oxiranyl, aziridinyl and thiomorpholine.

Aromatic (aryl) groups include carbocyclic aromatic groups such as phenyl, naphthyl and antracol, and heteroaryl groups, such as imidazolyl, thienyl, furyl, pyridyl, pyrimidyl, pyranyl, pyrazolyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl and tetrazolyl.

Aromatic groups also include polycyclic aromatic cyclic system, you don carbocyclic aromatic cycle or �ethereally cycle is condensed with one or more other heteroaryl cycles. Examples include benzothiazyl, benzofuran, indole, chinoline, benzothiazol, benzoxazol, benzimidazol, chinoline, ethenolysis and isoindolyl.

"Spiramycin" refers to Bicycle in which exactly one atom is common to each cycle of this Bicycle. Each of the two periods of spirobicyclic you can choose from a 3-7-membered cycles. For example, spiramycin can have two cycles, each of which consists of 4 members, i.e. 4-4 spiramycin. Examples of structures in this category include theand. In other examples, spiramycin contains two loops with different number of members, e.g., 4-6, 5-6, 6-7. Spiramycin may include one or more heteroatoms such as O, N or S, which may be present in spirobicyclic. Spiramycin may be substituted by one or more substituting groups. Examples of the substituents include =Oh, halogen and alkyl or other substituent listed in the other groups described here. Unless otherwise specified, spiramycin is saturated.

Forsomeone includes one fluorine substituent to perversione. An example of a fluorine-substituted C1-C2alkyl includes-CFH2, -CF2H, -CF3, -CH2CH2F, -CH2CHF2, -CHFCH3and-CF2CHF2. Perversioni1-C2alkyl includes, nab�emer, -CF3and-CF2CF3.

Combinations of substituents and variables that are included in this invention are only those that result in stable compounds. As used in the present description, the term "stable" refers to compounds with sufficient stability to permit obtaining and maintaining the integrity of the compound for a time period sufficient for it to be applicable in the described herein.

Disclosed in the present description, the compounds include partially or fully deuterated variants. In some embodiments, deuterated variants can be used for kinetic studies. The person skilled in the art can choose the place, which contains deuterium atoms.

In addition, in the present invention include salts, particularly pharmaceutically acceptable salts, described here, % -modulating compounds. Compounds of the present invention having a sufficiently acidic, a sufficiently basic, or both functional groups, can interact with any number of inorganic bases, and inorganic and organic acids, to form salts. Alternatively, compounds having their own charge, such as connections with che�vertical the nitrogen atom, can form a salt with an appropriate counterion (e.g., a halide such as bromide, chloride, or fluoride, particularly bromide).

Acid, commonly used to obtain the acid-additive salts are inorganic acids such as hydrochloric acid, Hydrobromic acid, itestosterone acid, sulfuric acid, phosphoric acid, and so forth, and organic acids such as p-toluensulfonic acid, methanesulfonate, oxalic acid, p-bromophenylacetate, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and so on. Examples of such salts include the sulfate, persulfate, bisulfate, sulfite, bisulfite, phosphate, monohydratefast, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, Butin-1,4-diet, hexyn-1,4-diet, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, killshot, phenylacetate, phenylpropionate, phenylbutyrate, zyrtec, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and so on.

Basically additive salts include salts derived from inorganic bases, such as ammonia or hydroxides of alkaline or alkaline earth metals, carbonates, bicarbonates, and so on. Thus, such grounds are applicable for obtaining the salts of this invention include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate and so on.

According to another embodiment of the present invention provided methods of obtaining the above defined % -modulating compounds. These compounds can be synthesized by conventional methods. Preferably, these compounds are conveniently synthesized from readily available starting materials.

Transformations and methods of synthetic chemistry, applicable to the synthesis described here, % -modulating compounds known in this field and include, for example, the transitions and the methods described in R. Larock,Comprehensive Organic Transformations(1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed.(1991); L. Fieser and M. Fieser,Fieser and Fieser's Reagents for Organic Synthesis(1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis(1995).In the illustrative embodiment, the % -modulating compounds can pass through the plasma membrane of the cell. For example, the compound may have cell permeability, component, at least about 20%, 50% 75%, 80%, 90% or 95%.

Described here, % -modulating compounds may also have one or more of the following characteristics: the compound may be essentially non-toxic to the cell or subject, %-modulating compound may be an organic molecule or a small molecule with a molecular weight of 2000 Da or less, 1000 Da or less, the compound may have a half-life under normal atmospheric conditions, comprising at least about 30 days, 60 days, 120 days, 6 months or 1 year; the compound may have a half-life in solution, comprising, at least about 30 days, 60 days, 120 days, 6 months or 1 year, %-modulating compound may be more stable in solution than resveratrol by at least a factor of about 50%, 2 times, 5 times, 10 times, 30 times, 50 times or 100 times, %-modulating compound may promote deacetylation of the DNA repair factor Ku70, %-modulating compound may promote deacetylation RelA/p65, the connection can increase the overall speed of updates and to increase the sensitivity of cells to TNF-induced apoptosis.

In some embodiments, % -modulating compound may not have any substantial ability to inhibit the histone deacetylase (HDAC) class I, a HDAC class II, or DAC I and II when the concentration (e.g., in vivo) effective for modulating deacetylase activity sirtuin. For example, in preferred embodiments, % -modulating compound is a % -activating compound and is chosen so that its EU50relatively deacetylase activity sirtuin was at least 5 times less than the EU50relative HDAC I and/or HDAC II, and even more preferably at least 10 times, 100 times or even 1000 times less. Methods for analysis of the activity of HDAC I and/or HDAC II are known in the art, and the sets of reagents for such assays may be purchased from commercial manufacturers. See, e.g., BioVision, Inc. (Mountain View, CA; world wide web in biovision.com) and Thomas Scientific (Swedesboro, NJ, the world wide web in tomassi.com).

In some embodiments, % -modulating compound does not have any substantial ability to modulate the homologues of sirtuin. In one embodiment, the implementation of the human protein activator of sirtuin may not have any substantial ability to activate % protein from lower eukaryotes, particularly yeast or human pathogens, at concentrations (e.g., in vivo) effective for activating deacetylase activity of the human sirtuin. For example, monovibrator % -activates the connection with the value of EC 50to activate deacetylase activity of the human sirtuin, such as SIRT1 and/or SIRT3, which is at least 5 times less than the EU50to activate sirtuin yeast, such as Sir2 (such as Candida, S, cerevisiae, and so forth), and still more preferably at least 10 times, 100 times or even 1000 times less. In another embodiment of the inhibitor protein of sirtuin from lower eukaryotes, particularly yeast or pathogens of man, does not have any substantial ability to inhibit protein % of people in concentration (e.g., in vivo) effective for inhibiting deacetylase activity of protein sirtuin from a lower eukaryote. For example, you can choose % -activates the connection with the value of IC50for inhibiting deacetylase activity of the human sirtuin, such as SIRT1 and/or SIRT3, which is at least 5-fold less than the IC50for inhibition of sirtuin yeast, such as Sir2 (such as Candida, S cerevisae and so on), and still more preferably at least 10 times, 100 times or even 1000 times less.

In some embodiments, % -modulating compound may have the ability to modulate one or more homologues of protein sirtuin, for example, one or more of human SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, or SIRT7. In one of the embodiments with�rtwin-modulating compound has the ability to modulate and SIRT1, and SIRT2 protein.

In other embodiments, the SIRT1 modulator does not have any substantial ability to modulate other protein homologues of sirtuin, such as one or more of human SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, or SIRT7, at the concentration (e.g., in vivo) effective for modulating deacetylase activity of human SIRT1. For example, you can choose % -modulating compound with the value of the ED50to modulate deacetylase activity of human SIRT1, which is at least 5-fold less than the ED50for modulating one or more of human SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, or SIRT7, and even more preferably at least 10 times, 100 times or even 1000 times less. In one of the embodiments of the modulator of SIRT1 does not have any substantial ability to modulate protein SIRT3.

In other embodiments, a SIRT3 modulator does not have any substantial ability to modulate other protein homologues of sirtuin, such as one or more of human SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, or SIRT7, at the concentration (e.g., in vivo) effective for modulating deacetylase activity of human SIRT3. For example, you can choose % -modulating compound with the value of the ED50to modulate deacetylase activity of human SIRT3, Kotor�I, at least 5-fold less than the ED50for modulating one or more of human SIRT1, SIRT2, SIRT4, SIRT5, SIRT6, or SIRT7, and even more preferably at least 10 times, 100 times or even 1000 times less. In one embodiment, the implementation of a SIRT3 modulator does not have any substantial ability to modulate SIRT1 protein.

In some embodiments, % -modulating compound may have a binding affinity in respect of protein sirtuin of around 10-9M, 10-10M, 10-11M, 10-12M or less. % - Modulating compound may reduce (activator) or increase (inhibitor) apparent Km of protein sirtuin with respect to its substrate or NAD+ (or other cofactor) by a factor of at least, 2, 3, 4, 5, 10, 20, 30, 50 or 100. In some embodiments, the Km values determined using these mass spectrometric analysis. Preferred activating compounds reduce Km of sirtuin with respect to its substrate or cofactor to a greater extent than that caused by resveratrol at a similar concentration, or reducing the Km of sirtuin with respect to its substrate or cofactor of similar extent, which is caused by resveratrol at a lower concentration. % - Modulating compound may increase the Vmax of protein sirtuin on friction coefficient close to�t, constituting at least about 2, 3, 4, 5, 10, 20, 30, 50 or 100. % - Modulating compound may have an ED50 in respect of modulating deacetylase activity of the protein SIRT1 and/or SIRT3, approximately less than 1 nm, less than 10 nm, less than about 100 nm, about 1 micron, less about 10 μm, about less than 100 microns, or from about 1-10 nm, from about 10-100 nm, from about 0.1-1 μm, from about 1-10 μm, or from about 10-100 μm. % - Modulating compound may modulate deacetylase activity of the protein SIRT1 and/or SIRT3 by a factor of approximately 5, 10, 20, 30, 50 or 100, a specific cellular analysis or in the analysis on the basis of the cell. % - Activating compound may cause at least about 10%, 30%, 50%, 80%, 2-fold, 5-fold, 10-fold, 50-fold or 100-fold induction deacetylase activity of protein sirtuin relatively similar concentrations of resveratrol. % - Activating compound may have an ED50 for modulating SIRT5 that is at least about 10 times, 20 times, 30 times, 50 times greater than the ED50 for modulating SIRT1 and/or SIRT3.

Application examples

In some aspects of this invention provided methods of modulating the level and/or activity of the protein of sirtuin and the ways of its application.

In some embodiments, provided methods of using si�twin modulating compounds in which % -modulating compound activates protein%, for example, increases concentration and/or activity of the protein of sirtuin. % - Modulating compounds that increase the level and/or activity of the protein of sirtuin may be applicable for a variety of therapeutic applications including, for example, increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases and disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, disorders of blood clotting, inflammation, cancer, and/or tides, and so on. These methods include the introduction to the needy in this subject a pharmaceutically effective amount % -modulating compounds, e.g., %-activating connection.

Without wishing to be bound by theory, it is assumed that the activators of the present invention can interact with sirtuins in the same location in the protein sirtuin (e.g., active site or affecting the Km or Vmax of the active site). It is assumed that this is the reason why some classes of activators and inhibitors of sirtuins can have essentially structural similarity.

In some embodiments, the implementation described here, % -m�delirous compounds can be used individually or in combination with other compounds. In one of the embodiments of the needy in this subject, you can enter a mixture of two or more % -modulating compounds. In another embodiment, the % -modulating compound that increases the level and/or activity of the protein of sirtuin, you can enter one or more of the following compounds: resveratrol, buteena, fisetin, piceatannol or quercetin. In the illustrative embodiment, the % -modulating compound that increases the level and/or activity of the protein of sirtuin, can be administered in combination with nicotinic acid. In another embodiment, the % -modulating compound that increases the level and/or activity of the protein of sirtuin, you can enter one or more of the following compounds: nicotinamide (NAM), Surinam, NF023 (antagonist G-protein), NF279 (antagonist purinergicheskie receptor), Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), (-)-epigallocatechin (hydroxyl in positions 3,5,7,3',4',5'), (-)-epigallocatechingallate (hydroxy sites 5,7,3',4',5' and the ether may be separated in 3 position), landinggear (3,5,7,3',4'-pentahydroxyflavone chloride), deliverygeneric(3,5,7,3',4',5'-hexahydroseverely chloride), myricetin (canalisation; 3,5,7,3',4',5'-hexahydronaphthalen), 3,7,3',4',5'-pentahydroxyflavone, gossypina (3,5,7,8,3',4'-hexahydronaphthalen), sirtinol and splitomicin. In e�e one embodiment, the implementation of one or more % -modulating compounds can be entered with one or more therapeutic agents for the treatment or prevention of various diseases, including, for example, cancer, diabetes, neurodegenerative diseases, cardiovascular disease, disorders of blood clotting, inflammation, flushing, obesity, ageing, stress and so on. In various embodiments, combination therapy including % -modulating compound may refer to (1) pharmaceutical compositions containing one or more % -modulating compounds in combination with one or more therapeutic agents (e.g., one or more therapeutic agents described in the present description), and (2) co-administration of one or more % -modulating compounds with one or more therapeutic agents, where % -modulating compound and therapeutic agent have not accounted for the same compositions (but may be in the same kit or package, such as a blister pack or other multi-cell pack connected, separately sealed containers (e.g., foil pouches) that can separate a user, or set, where % is the modulating connection(s) and other therapeutic agent(s) are in separate containers). In the application of individual drugs, %-modulating compound may be administered simultaneously, fractional, step, before, after, or as a combination of this, regarding the introduction of other industries, which� therapeutic agent.

In some embodiments, the methods of reducing, preventing or treating diseases or disorders using % -modulating compounds may also include increasing the concentration of protein sirtuin, such as human SIRT1, SIRT2 and/or SIRT3, or homologs. Increase in the concentration of protein can be achieved by introducing into the cell one or more copies of a nucleic acid which encodes%. For example, the concentration of sirtuin can be increased in a cell of a mammal, introducing into the cell of a mammal a nucleic acid encoding%, for example, increasing the concentration of SIRT1 by introducing a nucleic acid that encodes the amino acid sequence provided under GenBank identification number No. NP_036370, and/or increasing the concentration of SIRT3 by introducing a nucleic acid that encodes the amino acid sequence provided under GenBank identification number No. AAN.

A nucleic acid that is inserted into the cell to increase the protein concentration of sirtuin, can encode a protein that, at least 80%, 85%, 90%, 95%, 98% or 99% identical to the sequence citrina, for example, protein SIRT1 and/or SIRT3. For example, nucleic acid that encodes a protein that may be, at least 80%, 85%, 90%, 95%, 98 % or 99% identical to the nucleic acid encoding the SIRT1 (e.g., identificat�news room GenBank No. NM_012238) and/or SIRT3 (e.g., ID GenBank No. S). Nucleic acid may also be a nucleic acid which hybridise, preferably under stringent conditions of hybridization, in nucleic acid encoding % wild-type, for example, protein SIRT1 and/or SIRT3. Stringent hybridization conditions may include hybridization and a wash in 0.2 × SSC at 65 º C. When using nucleic acid that encodes a protein which differs from the protein of sirtuin wild type, such as a protein, which is a fragment of sirtuin wild type, the protein is preferably biologically active, e.g., capable of deacetylation. It is only necessary to Express in a cell a part of sirtuin, which is biologically active. For example, a protein that differs from wild-type SIRT1, ID GenBank No. NP_036370, preferably contains the structure of its nucleus. Sometimes nuclear structure refers to amino acids 62-293 GenBank identification number No. NP_036370, which is encoded by nucleotides with 237 932 on GenBank identification number No. NM_012238 that include OVER the binding and substrate binding domains. Nuclear domain SIRT1 may also refer to amino acids from about 261 to 447 GenBank identification number No. NP_036370, which is encoded by nucleotides with 834 via 1394 GenBank identification number No. NM_012238; to am�nakilat approximately 242 493 GenBank identification number No. NP_036370, which are encoded by nucleotides 777 at 1532 GenBank identification number No. NM_012238, or amino acids from about 254 to 495 GenBank identification number No. NP_036370, which is encoded by nucleotides with 813 in 1538 GenBank identification number No. NM_012238. Does protein its biological function, for example, the ability to deacetylation can be determined by methods known in this field.

In some embodiments, methods of attenuating, preventing or treating diseases or disorders using % -modulating compounds may also include the reduction of protein level of sirtuin, such as human SIRT1, SIRT2 and/or SIRT3, or homologs. Decrease the level of protein sirtuin can be achieved by methods known in this field. For example, the cell can Express the siRNA, antisense nucleic acid, or a ribozyme, the target of which is%. You can also use a dominant-negative certainly mutant, e.g. a mutant that is not able to deacetylation. For example, you can use the mutant SIRT1 H363Y described, for example, Luo et al. (2001) Cell 107:137. Alternatively, you can use agents that inhibit transcription.

Methods of modulating the protein levels of sirtuin also include methods of modulating transcription of genes encoding circui�s, methods of stabilization/destabilization of the corresponding mRNA, and other methods known in this field.

Aging/stress

In one embodiment of the invention provides a method of increasing survival of a cell, improving the ability of cells to proliferation, slowing down the ageing of cells, stimulation of cell survival, slow down cell aging in the cell, simulating the effects of calorie restriction, increasing the resistance of cells to stress, or preventing apoptosis of a cell, due to the contact of cells with % -modulating compound of the invention that increases the level and/or activity of the protein of sirtuin. In the illustrative embodiment, the implementation of these methods include contacting the cells with a % -activating the connection.

The methods described here can be used to increase the length of time during which cells, particularly primary cells (i.e., cells obtained from an organism, e.g., humans), it is possible to keep alive in a cell culture. Embryonic stem (ES) and pluripotential cells, and differentsirovaniya cells from them, you can also handle % -modulating compound that increases the level and/or activity of the protein of sirtuin for maintaining the cells or their progeny in to�lture for longer periods of time. Such cells can also be used for transplantation to a subject, for example, after modifying theex vivo.

In one of the embodiments, the cells intended to store in a long time, you can handle % -modulating compound that increases the level and/or activity of the protein of sirtuin. These cells can be in suspension (e.g., blood cells, serum, biological environment for the cultivation and so on), or in tissues or organs. For example, blood collected from the individual for purposes of transfusion, you can handle % -modulating compound that increases the level and/or activity of the protein of sirtuin to preserve the blood cells for longer periods of time. In addition, blood intended for forensic purposes, you can also save when you use % -modulating compounds that increase the level and/or activity of the protein of sirtuin. Other cells that can be processed to increase their lifespan or prevent apoptosis include cell for consumption, for example, cells from mammals, non-human (such as meat) or plant cells (such as vegetables).

% - Modulating compounds that increase the level and/or activity of the protein of sirtuin, can also be used during the phases R�Suite and growth of mammals, plants, insects or microorganismos, for example, in order to change the deceleration or acceleration of development and/or growth.

In another embodiment of the implementation, %-modulating compounds that increase the level and/or activity of the protein of sirtuin, can also be used for treatment of cells suitable for transplantation or cell therapy, including, for example, solid tissue grafts, transplants of organs, cell suspensions, stem cells, bone marrow cells, and so on. These cells or tissues may be an autograft, allograft, engraft or xenograft. Cells or tissue can be processed % -modulating compound prior to administration/implantation, concurrently with the introduction/implantation and/or after insertion/implantation of the subject. Cells or tissue can be treated before removing cells from an individual donor,ex vivoafter removing cells from an individual donor and / or after implantation into the recipient. For example, individual donor or recipient can be treated % -modulating compound system and it can have a subpopulation of cells/tissues treated with local image % -modulating compound that increases the level and/or activity of the protein of sirtuin. In some embodiments, the cells or tissue (or and�individual donor/recipient) can be further treated with other therapeutic agent, applicable to improve the duration of survival of the graft, such as an immunosuppressant, a cytokine, an angiogenic factor, and so on.

In yet other embodiments, cells can be processed % -modulating compound that increases the level and/or activity of the protein of sirtuinin vivofor example , with the purpose of increase of their lifespan or prevent apoptosis. For example, the skin can be protected from aging (e.g., wrinkles, loss of elasticity, and so on), treating skin or epithelial cells % -modulating compound that increases the level and/or activity of the protein of sirtuin. In the illustrative embodiment of the skin contact with a pharmaceutical or cosmetic composition containing a % -modulating compound that increases the level and/or activity of the protein of sirtuin. Examples of diseases or skin conditions that can be treated according to the methods described herein include disorders or diseases related to or caused by inflammation, lesions as a result of sunburn or natural aging. For example, these compositions are used for the prevention or treatment of contact dermatitis (including irritable contact dermatitis and allergic contact dermatitis), atopic dermatitis (also known as a�lergicescoe eczema), senile keratosis, disorders associated with keratinization (including eczema), disease epidermolysis bullosa (including pemphigus), exfoliative dermatitis, seborrheic dermatitis, erythemas (including mnogoformnuû erythema and nodoso erythema), lesions caused by exposure to the sun or other light sources, discoid lupus erythematosus, dermatomyositis, psoriasis, skin cancer and the effects of natural aging. In another embodiment, the % -modulating compounds that increase the level and/or activity of the protein of sirtuin, can be used for treating wounds and/or burns to speed healing, including, for example, burns of the first, second or third degree and/or thermal, chemical go electric burns. Drugs can be entered locally on the skin or mucous membranes.

Preparations for topical application containing one or more % -modulating compounds that increase the level and/or activity of the protein of sirtuin can also be used as preventive, e.g., chemoprophylactic compositions. When used in a method of chemotherapy, sensitive skin is treated before the occurrence of any visible condition in a specific individual.

% - Modulating compounds can be delivered to a subject of local or systemic manner. In one embodiment implemented�I % -modulating compound is delivered to the tissue or organ of a subject by injection, the product for local use, and so on.

In another embodiment, the % -modulating compound that increases the level and/or activity of the protein of sirtuin, can be used for treating or preventing a disease or condition caused or exacerbated by cellular senescence in a subject; reducing the rate of aging of the subject, for example, after the beginning of aging, methods of increasing survival of a subject, methods of treating or preventing a disease or condition relating to lifespan, methods of treating or preventing a disease or condition associated with the ability of cells to proliferation, and methods of treating or preventing a disease or condition resulting from injury or cell death. In some embodiments, this method does not act by reducing the speed of the diseases that shorten the lifespan of the subject. In some embodiments, the method is not valid due to the reduction of deaths caused by disease, such as cancer.

In yet another embodiment, the % -modulating compound that increases the level and/or activity of the protein of sirtuin, you can enter the subject for the purpose of improving the lifespan of its cells and for W�shields its cells against stress and/or against apoptosis. It is assumed that the treatment of the subject compound described herein is similar to the exposure of the subject to hormesis, i.e., mild stress that is beneficial organisms and can increase their life expectancy.

% - Modulating compounds that increase the level and/or activity of the protein of sirtuin, you can enter the subject to prevent aging and aging-related consequences or diseases, such as stroke, heart disease, heart failure, high blood pressure and Alzheimer's disease. Other conditions that can be treated include ocular disorders, e.g., associated with aging eyes, such as cataracts, glaucoma and macular degeneration. % - Modulating compounds that increase the level and/or activity of the protein of sirtuin, you can also enter a subject for the treatment of diseases, e.g., chronic diseases, associated with cell death, to protect cells from cell death. Examples of diseases include diseases associated with loss of nerve cells, neuronal dysfunction or death or dysfunction of muscle cells, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis and muscular dystrophy; AIDS; fulminant hepatitis; diseases associated with degeneracies of the brain, such �AK disease Creutzfeldt-Jakob, retinitis pigmentosa and cerebellar degeneration; myelodysplasia, such as aplastic anemia; ischemic diseases such as myocardial infarction and stroke; liver disease such as alcoholic hepatitis, hepatitis b and hepatitis C; joint diseases such as osteoarthritis; atherosclerosis; alopecia; damage to the skin due to UV irradiation; lichen planus; atrophy of the skin; cataract and graft rejection. Cell death may also be caused by surgical intervention, drug therapy, exposure to chemicals or radiation.

% - Modulating compounds that increase the level and/or activity of the protein of sirtuin, can also be administered to a subject suffering from an acute illness, such as a damaged organ or tissue, for example, a subject suffering from stroke or myocardial infarction or a subject suffering from spinal cord injury. % - Modulating compounds that increase the level and/or activity of the protein of sirtuin, you can also apply for restoration of the liver of an alcoholic.

Cardiovascular disease

In the following embodiment, the invention provides a method of treatment and/or prevention of cardiovascular diseases the introduction of the needy in this subject % -modulating compounds that increase�ment level and/or activity of the protein of sirtuin.

Cardiovascular diseases that can be treated or prevented using % -modulating compounds that increase the level and/or activity of the protein of sirtuin include cardiomyopathy or myocarditis, for example, idiopathic cardiomyopathy, metabolic cardiomyopathy, alcoholic cardiomyopathy, ischemic cardiomyopathy, and hypertensive cardiomyopathy. In addition, are subjected to the treatment or prevention when using the compounds described herein or methods, atheromatous disorders of the major blood vessels (macrovascular disease) such as the aorta, carotid artery, cerebral artery, renal artery, iliac artery, femoral artery and popliteal artery. Other vascular diseases that can be treated or prevented include diseases related to platelet aggregation, the retinal arterioles, the glomerular arterioles, the vessels supplying the nerve trunks, cardiac arterioles, and associated capillary bed eyes, kidneys, heart and Central and peripheral nervous systems. % - Modulating compounds that increase the level and/or activity of the protein of sirtuin, can also be used to increase the concentration of alpha high density lipoprotein in the blood plasma of an individual.

Other disorders that can be treated PR� assistance, % -modulating compounds increase the level and/or activity of the protein of sirtuin include restenosis, e.g., following coronary intervention, and disorders relating to an abnormal level of high density cholesterol and low-density.

In one of variants of implementation % -modulating compounds that increase the level and/or activity of the protein of sirtuin, you can enter as part of a combination therapy with other cardiovascular drug. In one of variants of implementation % -modulating compounds that increase the level and/or activity of the protein of sirtuin, you can enter as part of a combination therapy with antiarrhythmic drug. In another embodiment, the % -modulating compounds that increase the level and/or activity of the protein of sirtuin, you can enter as part of a combination therapy with other cardiovascular drug.

Cell death/cancer

% - Modulating compounds that increase the level and/or activity of the protein of sirtuin, you can enter to subjects who have recently received or are likely to receive a dose of radiation or toxin. In one embodiment, the implementation of the dose of radiation or toxin receive as part of any job-related or medical procedure, for example, administered as preventive measures. In another embodiment, the implementation of Vosges�vey of radiation or toxin exposed unintentionally. In this case, the compound is preferably administered as soon as possible after the exposure to inhibit apoptosis and the subsequent development of acute radiation syndrome.

% - Modulating compounds can also be used for the treatment and/or prevention of cancer. In some embodiment of the % -modulating compounds that increase the level and/or activity of the protein of sirtuin, can be used for the treatment and/or prevention of cancer. Caloric restriction was associated with lower incidence of age-related disorders, including cancer. Accordingly, increasing the level and/or activity of the protein of sirtuin may be favorable for the treatment and/or prevention of age-related disorders, such as cancer. Examples of cancers that can be treated using % -modulating compounds include cancer of the brain and kidneys, and hormone-dependent cancers, including breast cancer, prostate cancer testicular and ovarian cancer, lymphoma and leukemia. In cancer associated with solid tumors, modulating compound can be injected directly into the tumor. Cancer of blood cells, e.g., leukemia, can be treated by introducing a modulating compound in the blood or in the bone marrow. In addition, it is possible to treat the growth of benign cells, such as warts. Other diseases that can be treated include autoimmu�related disease for example, systemic lupus erythematosus, scleroderma, and arthritis, in which you should destroy the autoimmune cells. Viral infections, such as herpes, HIV, adenovirus, and HTLV-1-associated malignant and benign disorders can also be treated by administering % -modulating compounds. Alternatively, the subject could be deleted cells, treated ex vivo to get rid of certain undesirable cells, e.g., cancer cells, and enter back to the same or another entity.

Chemotherapy drugs can be entered together with described here modulatory compounds having anticancer activity, e.g., compounds that induce apoptosis, compounds that reduce lifespan or compounds that give the cells sensitivity to stress. Chemotherapy drugs can be used by themselves as outlined here % -modulating compound that causes cell death or reducing lifespan or giving the cells sensitivity to stress and/or in combination with other chemotherapeutic agents. In addition to standard chemotherapeutic agents described here, % -modulating compounds can also be used with antisense RNA, RNA interference, or other polinal�origami for inhibiting the expression of kletochnykh components which can contribute to unwanted cell proliferation.

Combination therapy, including % -modulating compounds and standard chemotherapeutic agent may be advantageous in comparison with the combination therapy, known in this area, because this combination allows the conventional chemotherapeutic drug to achieve a greater effect with a smaller dose. In a preferred embodiment, the effective dose (ED50) chemotherapeutic drug, or a combination of standard chemotherapy drugs, when used with % -modulating compound, at least 2 times less than the ED50one chemotherapeutic drug, and even more preferably 5-fold, 10 fold or even 25 fold less. Conversely, therapeutic index (TI) for such chemotherapeutic drug, or a combination of standard chemotherapy drugs, in the application described here, % -modulating compound may be at least 2 times more than TI usually chemotherapeutic regime, and even more preferably 5 times, 10 times or even 25 times more.

Neuronal diseases/disorders

In some respects, % -modulating compounds that increase the level and/or activity of the protein of sirtuin, �can be used to treat patients suffering from neurodegenerative diseases, and traumatic or mechanical injury of Central nervous system (CNS), the spinal cord or the peripheral nervous system (PNS). Usually neurodegenerative diseases include reducing the mass and volume of the human brain, which may occur due to atrophy and/or death of brain cells, which expressed significantly stronger than atrophy and/or death of brain cells in a healthy subject, at the expense of aging.

Neurodegenerative disease can develop gradually, after a long period of normal brain function, due to progressive degeneration (e.g., dysfunction and neuronal cell death) of certain areas of the brain. Alternatively, the neurodegenerative disease may start suddenly, as in the case of diseases associated with injury or toxins. The actual onset of the degeneration of the brain may precede the clinical expression for many years. Examples of neurodegenerative diseases include, but are not limited to, Alzheimer's disease (AD), Parkinson's (PD), Huntington disease (HD), amyotrophic lateral sclerosis (ALS; disease Lou Gehrig), diffuse disease Taurus Levi, choreoathetosis, primary lateral sclerosis, ocular diseases (inflammation HL�EIT nerve), neuropathy caused by chemotherapy (for example, from receiving vincristine, formulations, bortezomib), neuropathy caused by diabetes and Friedreich's ataxia. % - Modulating compounds that increase the level and/or activity of the protein of sirtuin can be used to treat these disorders and others as described below.

AD is a violation of the Central nervous system leading to memory loss, bizarre behavior, personality changes and decreased cognitive abilities. These losses are associated with the death of certain types of brain cells and the destruction of relationships and their support structures (e.g., glial cells) between them. The earliest symptoms include loss of recent memory, the instability of judgment and personality changes. PD is a violation of the Central nervous system, leading to uncontrolled body movements, rigidity, tremor and dyskinesia, and associated with loss of brain cells in areas of the brain that produce dopamine. ALS (motor neuron disease) is a violation of the Central nervous system that affects motor neurons, components of the Central nervous system that connect the brain with the skeletal muscles.

HD is a neurodegenerative disease that causes uncontrolled movements, loss of intellectual abilities and emotional sphere. Disease Tay-Sachs and disease Sandhof is�Oh disease associated with the accumulation of glycolipids, in which GM2 of ganglioside and related glycolipids substrates of β-hexosaminidase accumulate in the nervous system and begin the process of acute neurodegeneration.

It is known that apoptosis is involved in the pathogenesis of AIDS in the immune system. However, HIV-1 also induces neurological disease that can be treated % -modulating compounds of this invention.

Loss of neurons is a prominent feature of Pranovich diseases, such as disease Creutzfeldt-Jakob in humans, BSE in cattle (mad cow disease), cistoca disease in sheep and goats, and feline spongiform encephalopathy (FSE) in cats. % - Modulating compounds that increase the level and/or activity of the protein of sirtuin, can be used for treating or preventing the loss of neurons resulting data Pranovich diseases.

In another embodiment, the % -modulating compound that increases the level and/or activity of the protein of sirtuin, can be used for the treatment or prevention of any disease or disorders, including axonopathy. Distal axonopathy is a type of peripheral neuropathy that occurs due to some metabolic or toxic disorders of the neurons of the peripheral nervous with�the system (PNS). It is the most common response of nerves to metabolic or toxic disturbances, and as such, may be caused by metabolic diseases such as diabetes, renal failure, deficiency syndromes such as malnutrition and alcoholism, or the effects of toxins or drugs. I having a distal axonopathy usually present symmetrical glove-stocking sensory disorders. In the affected areas are lost or reduced deep tendon reflexes and function of the autonomic nervous system (ANS).

Diabetic neuropathies are neuropathic disorders that are associated with diabetes. A relatively simple condition that can be associated with diabetic neuropathy include paralysis of the third nerve, mononeuropathy, multiple manometric, diabetic amyotrophy, painful polyneuropathy, autonomic neuropathy and thoracoabdominal neuropathy.

Peripheral neuropathy is the medical term for nerve damage of the peripheral nervous system, which may be caused either by diseases of the nerve or the side effects of a systemic disease. The main causes of peripheral neuropathy include epileptic seizures, lack of nutrition and HIV,although diabetes are the most likely cause.

In the illustrative embodiment, the % -modulating compounds that increase the level and/or activity of the protein of sirtuin, can be used for treating or preventing multiple sclerosis (MS), including receiveready MS and monosymptomatic MS, and other demyelinating condition, such as chronic inflammatory demyelinating polyneuropathy (CIPD) or related symptoms.

In yet another embodiment, the % -modulating compounds that increase the level and/or activity of the protein of sirtuin can be used to treat trauma to the nerves, including, trauma due to disease, injury (including surgical intervention), or injury from environmental exposure (e.g., neurotoxins, alcoholism, and so forth).

% - Modulating compounds that increase the level and/or activity of the protein of sirtuin, can be applied to prevent, treat and alleviate symptoms of various PNS disorders. The term "peripheral neuropathy" encompasses a wide range of disorders in which the affected nerves outside the brain and spinal cord - peripheral nerves. Peripheral neuropathy may also be known as peripheral neuritis, or if many nerves, you can use the terms polyneuropathy or polyneuritis.

Diseases of the PNS that can Le�'it using % -modulating compounds increase the level and/or activity of the protein of sirtuin include diabetes, leprosy, Charcot-Marie-Tooth syndrome, Guillain-Barre syndrome and brachial plexus neuropathy (disease of the cervical and first thoracic nerve roots), nerve trunks, cords and components of the peripheral nerves of the brachial plexus.

In another embodiment, the % -activating connection can be used for treating or preventing polyglutamine disease. Examples polyglutamine diseases include spinobulbar muscular atrophy (Kennedy disease), Huntington disease (HD), dentatorubral palledorous atrophy syndrome (Ho river), spinal-cerebellar ataxia type 1, spinal-cerebellar ataxia type 2, spinal-cerebellar ataxia type 3 (disease Machado-Joseph), spinal-cerebellar ataxia type 6, spinal-cerebellar ataxia 7 type and spinal-cerebellar ataxia 17 type.

In some embodiments, provided is a method of treating cells of the Central nervous system to prevent lesions in response to a reduction of blood flow in the cell. Usually the severity of the injury that is preventable, will largely depend on the extent of blood flow reduction in a cage and duration of the deduction. In one of the embodiments can prevent the death of APO�political or necrotic cells. In yet another embodiment, the implementation can be prevented ischemia-mediated lesion, such as cytotoxic edema or anoxemia tissue of the Central nervous system. In each embodiment of the cell of the Central nervous system may be a cell of the spinal cord or brain cell.

Another aspect includes the introduction of % -activating compound to a subject for treatment of an ischemic condition of the Central nervous system. The number of ischemic conditions of the Central nervous system can be treated using the described here, % -activating compounds. In one embodiment, the implementation of the ischemic condition is a stroke that lead to any type of ischemic damage to the Central nervous system, such as the death of apofaticheski or necrotic cells, cytotoxic edema or anoxemia tissue of the Central nervous system. A stroke can affect any area of the brain or to be of any etiology, which is known that it leads to the manifestation of stroke. In one variation of this implementation, a stroke is a brain stem stroke. In another embodiment, the implementation of this stroke is a cerebellar stroke. In yet another embodiment of the stroke is an embolic stroke. In yet another variant� stroke can be a hemorrhagic stroke. In the next version of the implementation of the stroke is a thrombotic stroke.

In yet another aspect, % -activating compound can be incorporated to reduce the size of the ischemic core after an ischemic condition of the Central nervous system. Furthermore, %-activating connection also can mainly be entered to reduce the size of the ischemic penumbra or transitional zone after ischemic condition of the Central nervous system.

In one embodiment, the implementation mode of combination drug therapy may include drugs or compounds for the treatment or prevention of neurodegenerative disorders or secondary conditions associated with these conditions. Thus, the mode of combination drug therapy may include one or more activators of sirtuin and one or more anti-neurodegeneration agents.

Disorders of blood coagulation

In other aspects % -modulating compounds that increase the level and/or activity of the protein of sirtuin, can be used for the treatment or prevention of blood clotting disorders (or hemostatic disorders). Used in the present description the term "hemostasis", "coagulation" and "coagulation" refers to the suppression of bleeding, including f�also properties of vasoconstriction and coagulation. Blood coagulation contributes to maintaining the integrity of mammalian circulation after injury, inflammation, disease, congenital defect, dysfunction or other disruption. In addition, the formation of blood clots not only limits the bleeding in case of injury (hemostasis), but it can cause serious organ damage and death in the context of atherosclerotic disease due to the occlusion of an important artery or vein. Thus, thrombosis is the formation of blood clots at the wrong time and the wrong place.

Accordingly, the present invention provided anticoagulate and antithrombotic treatment aimed at inhibiting the formation of blood clots to prevent or treat blood clotting disorders, such as myocardial infarction, stroke, loss of limb peripheral artery disease or pulmonary embolism.

As used in this description, in turn, modulate or modulation of hemostasis" or "regulation or regulation of hemostasis" includes the induction (e.g., stimulation or increase) hemostasis and inhibition (e.g., reduction or decrease) of hemostasis.

In one aspect of the invention provides a method of reducing or inhibiting hemostasis in a subject by introducing Sirte�n-modulating compounds increase the level and/or activity of the protein of sirtuin. Described herein compositions and methods applicable for the treatment or prevention of thrombotic diseases. Used in the present description, the term "thrombotic violation" includes any breach or condition characterized by excessive or undesirable clotting or hemostatic activity, or a hypercoagulable state. Thrombotic disorders include diseases or disorders involving platelet adhesion and thrombus formation, and may occur in the form of increased predisposition to thrombosis, for example, increased number of thrombosis, thrombosis at an early age, a familial tendency to thrombosis and thrombosis in unusual places.

In another embodiment of the mode of combination drug therapy may include drugs or compounds for the treatment or prevention of blood clotting disorders or secondary conditions associated with these conditions. Thus, the mode of combination drug therapy may include one or more % -modulating compounds that increase the level and/or activity of the protein of sirtuin, and one or more antikoaguliruyuschee and antithrombotic agents.

Fighting obesity

In another aspect, % -modular�the following compounds increase the level and/or activity of the protein of sirtuin, can be used for treating or preventing weight gain or obesity in a subject. For example, %-modulating compounds that increase the level and/or activity of the protein of sirtuin, can be used, for example, to treat or prevent hereditary obesity, dietary obesity, hormone obesity, obesity associated with the administration of the drug, to reduce the weight of the subject, or for reducing or preventing weight gain in a subject. A subject in need of such treatment may be a subject suffering from obesity, overweight, or having the likelihood to acquire excess weight. Subjects likely to suffer obesity or acquire excess weight, you can identify, for example, based on family history, genetics, nutrition, activity level, medication, or various combinations of this.

In yet another implementation options, %-modulating compounds that increase the level and/or activity of the protein of sirtuin, you can enter subjects suffering from several other diseases and conditions that can be treated or prevented by promoting weight loss in the subject. Such diseases include, for example, high blood pressure, hypertension, high level of� of cholesterol in the blood, dyslipidaemia, type 2 diabetes, insulin resistance, glucose intolerance, hyperinsulinemia, coronary heart disease, angina, congestive heart failure, stroke, gallstones, cholecystitis and cholelithiasis, gout, osteoarthritis, obstructive sleep apnea and respiratory problems, some types of cancer (such as endometrial cancer, breast, prostate and colon), complications of pregnancy, poor female reproductive health (such as irregularity of menstrual cycle, infertility, irregular ovulation), bladder control (such as incontinence), uric acid nephrolithiasis, physiological disorders (such as depression, food disorders, disorders of the form of the body and low self-esteem). Finally, in patients with AIDS may develop lipodystrophy or insulin resistance, in response to the combination therapy of AIDS.

In another embodiment, the % -modulating compounds that increase the level and/or activity of the protein of sirtuin, can be used for inhibition of lipogenesis or fat cell differentiation, in vitro or in vivo. Such methods can be used for the treatment or prevention of obesity.

In other embodiments, % -modulating compounds that increase the level and/or activity of the protein �intwine, can be used for reducing appetite and/or increasing satiety, thereby causing weight loss or avoidance of weight gain. A subject in need of such treatment, can be the subject of overweight, obese, or entity that has the probability of overweight or obesity. This method can include the introduction to the subject daily, every other day or once a week, the dose, for example, in the form of a pill. This dose can be a dose that reduces the appetite."

In the illustrative embodiment, the % -modulating compounds that increase the level and/or activity of the protein of sirtuin can be administered in combination therapy for treating or preventing weight gain or obesity. For example, one or more % -modulating compounds that increase the level and/or activity of the protein of sirtuin, you can type in combination with one or more anti-obesity drug.

In another embodiment, the % -modulating compounds that increase the level and/or activity of the protein of sirtuin, you can enter to reduce weight gain caused by medications. For example, %-modulating compound that increases the level and/or activity of the protein of sirtuin can be administered in combination therapy with drugs that can stimulate APPA�it or lead to weight gain, in particular, weight gain due to factors different from water retention.

Disorders of metabolism/diabetes

In other aspects, %-modulating compounds that increase the level and/or activity of the protein of sirtuin can be used to treat or prevent metabolic disorders such as insulin resistance, pre-diabetic state, type II diabetes and/or complications. Introduction % -modulating compounds that increase the level and/or activity of the protein of sirtuin, can improve insulin sensitivity and/or decrease the concentration of insulin in a subject. A subject in need of such treatment may be a subject having insulin resistance or another symptom is the precursor of type II diabetes suffering from type II diabetes, or having the likelihood of data States. For example, the subject may be a subject suffering from insulin resistance, e.g., having high circulating concentrations of insulin and/or concomitant conditions, such as hyperlipidemia, dyslipaemic, hypercholesterolemia, impaired glucose tolerance, high level of sugar glucose in the blood, other manifestations of syndrome X, hypertension, atherosclerosis and lipodystrophy.

In the illustrative embodiment, the % -modulating compound, on�chausee level and/or activity of the protein of sirtuin, can be administered in combination therapy for the treatment or prevention of metabolic disorders. For example, %-modulating compounds that increase the level and/or activity of the protein of sirtuin, can be administered in combination with one or more antidiabetic agents.

Inflammatory disease

In other aspects % -modulating compounds that increase the level and/or activity of the protein of sirtuin, can be used to treat or prevent diseases or disorders associated with inflammation. % - Modulating compounds that increase the level and/or activity of the protein of sirtuin, can be entered before, during, or after onset of inflammation. For prophylactic use, the compounds preferably provide prior to the occurrence of any inflammatory response or symptom. The introduction of these compounds may prevent or attenuate inflammatory responses or symptoms.

In another embodiment, the % -modulating compounds that increase the level and/or activity of the protein of sirtuin, can be used to treat or preduprejdenia allergies and respiratory conditions including asthma, bronchitis, pulmonary fibrosis, allergic rhinitis, oxygen toxicity, emphysema, chronic bronchitis, acute respiratory distress syndrome, and any chronic�e obstructive pulmonary disease (COPD). These compounds can be used to treat chronic hepatitis infection, including hepatitis b and hepatitis C.

Furthermore, %-modulating compounds that increase the level and/or activity of the protein of sirtuin, can be used for the treatment of autoimmune diseases and/or inflammation associated with autoimmune diseases, including rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, as well as organ-tissue autoimmune diseases (e.g., Raynaud's syndrome), ulcerative colitis, Crohn's disease, inflammation of the mucous membranes of the mouth, scleroderma, myasthenia gravis, reaction transplant rejection, endotoksicski shock, sepsis, psoriasis, eczema, dermatitis, multiple sclerosis, autoimmune thyroiditis, uveitis, systemic lupus erythematosus, Addison's disease, autoimmune plyuriglandulyarnaya disease (also known as autoimmune plyuriglandulyarnaya syndrome) and graves ' disease.

In some embodiments, one or more % -modulating compounds that increase the level and/or activity of the protein of sirtuin can be used individually or in combination with other compounds applicable for the treatment or prevention of inflammation.

Tides of blood

In another aspect, % -modulating compounds that increase the level and/or activity Belchertown, can be used to reduce the incidence or severity of flushing and/or hot flashes which are symptoms of the disorders. For example, the subject method includes the use of % -modulating compounds that increase the level and/or activity of the protein of sirtuin, individually or in combination with other drugs, to reduce the incidence or severity of flushing and/or hot flashes in patients with cancer. In other embodiments, the method provides the use of % -modulating compounds that increase the level and/or activity of the protein of sirtuin, to reduce the incidence or severity of flushing and/or hot flashes in women in the menopausal or post-menopausal.

In another aspect, % -modulating compounds that increase the level and/or activity of the protein of sirtuin, can be used as a therapeutic treatment to reduce the incidence or severity of flushing and/or hot flashes which are side effects of another therapeutic treatment, for example, is caused by drugs of rush of blood. In some embodiments, a method for the treatment and/or prevention caused by drugs of rush of blood includes an introduction to the needy in this patient the drug, soda�servants at least one connection, causing a rush of blood, and at least one % -modulating compound that increases the level and/or activity of the protein of sirtuin. In other embodiments, a method for the treatment caused by drugs of rush of blood includes the separate introduction of one or more compounds that cause a rush of blood, and one or more % -modulating compounds, for example, in the case where % is the modulating compound and a drug that causes a rush of blood, are not included in the same composition. When using separate compositions % -modulating compound can be entered (1) simultaneously with the introduction of the drug, causing a rush of blood, (2) intermittently with the medication, causing a rush of blood, (3) a stepped manner relative to administration of the drug, causing a rush of blood, (4) prior to administration of the medication, causing a rush of blood, (5) after the drug causing a surge of blood, and (6) and in the form of various combinations. Examples of drugs that cause a rush of blood include, for example, Niacin, raloxifene, antidepressants, antipsychotic drugs, chemotherapeutic agents, calcium channel blockers, and antibiotics.

In one of variants of implementation % -modulating compounds that increase the level and/or activity of protein C�Tuina, you can apply to reduce side effects in the form of a rush of blood caused by a vasodilator or antilipemics means (including anticholesteremic tool and a lipotropic agent). In the illustrative embodiment, the % -modulating compound that increases the level and/or activity of the protein of sirtuin, you can apply to reduce hot flashes, associated with taking Niacin.

In another embodiment, the invention provides a method of treatment and/or prevention of hyperlipidemia with reduced similar effects the tides. In yet another representative embodiment of the present method includes the use of % -modulating compounds that increase the level and/or activity of the protein of sirtuin, to reduce the side effects in the form of tides, caused by the admission of raloxifene. In yet another representative embodiment of the present method includes the use of % -modulating compounds that increase the level and/or activity of the protein of sirtuin, to reduce the side effects in the form of tides, caused by taking antidepressants or antipsychotic drug. For example, %-modulating compounds that increase the level and/or activity of the protein of sirtuin, can be used in combination (separate or co-administration) with the inhibitor re - �about takeover serotonin or antagonist of the receptor 5NT2.

In some embodiments, % -modulating compounds that increase the level and/or activity of the protein of sirtuin, can be used as part of treatment an inhibitor of the reuptake of serotonin (SRI) to reduce flushing. In yet another representative embodiment, the % -modulating compounds that increase the level and/or activity of the protein of sirtuin, you can apply to reduce the side effects in the form of tides, caused by chemotherapeutic drugs such as cyclophosphamide and tamoxifen.

In the following embodiment, the % -modulating compounds that increase the level and/or activity of the protein of sirtuin, you can apply to reduce the side effects in the form of tides, caused by taking calcium channel blockers such as amlodipine.

In the following embodiment, the % -modulating compounds that increase the level and/or activity of the protein of sirtuin, you can apply to reduce the side effects in the form of tides, caused by taking antibiotics. For example, %-modulating compounds that increase the level and/or activity of the protein of sirtuin, can be used in combination with levofloxacin.

Eye diseases

One aspect of the present invention is a method of Inga�of debugger, reduction or any other treatment of visual impairment by introducing the patient a therapeutic dose of the modulator of sirtuin selected from compounds described herein, or its pharmaceutically acceptable salt, prodrug or product of metabolism.

In some aspects of the invention, the deterioration of vision caused by damage to the optic nerve or Central nervous system. In specific embodiments, a lesion of the optic nerve due to high intraocular pressure, such as occur in glaucoma. In other specific embodiments, the defeat of the optic nerve caused by swelling of nerve that is often associated with infection or immune (or autoimmune) reaction, such as retrobulbar neuritis.

In some aspects of the invention, the deterioration of vision caused by damage to the retina. In particular embodiments, the retinal damage caused by impaired blood flow in the eye (for example, arteriosclerosis, vasculitis). In particular embodiments, the retinal damage caused by rupture of the macula (e.g., exudative or exudative macular degeneration).

Examples of retinal diseases include exudative age-related macular degeneration, nonexudative age-related macular degeneration, electronic prosthetics with�of tchatche and RPE transplantation age related macular degeneration, acute multifocal placoid pigment epitheliopathy, acute retinal necrosis, a disease of the best, embolism lateral retinal artery, embolism of the lateral vein of the retina associated with cancer and related autoimmune retinopathies, embolism of the Central retinal artery, embolism of the Central retinal vein, Central serous chorioretinopathy, disease Ilza, so-called " epimacular membrane, lattice degeneration patterns, microaneurysm, diabetic edema yellow spots, swelling yellow spots Irvine-Gass, hole in the macula, subretinal neovascular membranes, diffuse unilateral subacute neuroretinitis, nasevicius custody edema yellow spots, the syndrome of the alleged ocular histoplasmosis, exudative retinal detachment, postoperative retinal detachment, proliferative retinal detachment, rhegmatogenous retinal detachment, tractional retinal detachment, pigments retina, CMV retinitis, retinoblastoma, retinopathy pregnant, retinopathy Birdshot, background diabetic retinopathy, proliferative diabetic retinopathy, hemoglobinopathies retinopathy, retinopathy Porcher, retinopathy of Valsalva, juvenile retinoschisis, senile retinoschisis, syndrome Terson syndrome and white spot.

Examples of other diseases include ocular bacterial infections (e.g.,�injunctive, keratitis, tuberculosis, syphilis, gonorrhea), viral infections (e.g., ocular herpes simplex virus, varicella zoster virus, cytomegalovirus retinitis, human immunodeficiency virus (HIV)), and progressive necrosis of the outer retina, secondary to HIV or other HIV-associated and other related immunodeficiency disease. Moreover, ocular diseases include fungal infections (e.g. Candida chorioidea, histoplasmosis), protozoal infections (e.g., toxoplasmosis) and others, such as ocular toxocariasis and sarcoidosis.

One aspect of this invention is a method of inhibiting, reducing or treating of visual impairment in a subject undergoing treatment with chemotherapeutic drugs (e.g., a neurotoxic drug, a drug that increase intraocular pressure such as a steroid), by injection to a subject in need of such treatment, a therapeutic dose of the modulator described here sirtuin.

The next aspect of this invention is a method of inhibiting, reducing or treating of visual impairment in a subject undergoing surgery, including ocular or other surgical procedure carried out in the prone position, for example, surgery on the spinal cord, through wednesbury, in need of such treatment, a therapeutic dose of the modulator described here sirtuin. Other surgery include cataract, iridotomy and replacement lenses.

The next aspect of this invention is the treatment, including inhibition and prophylactic treatment of age-related eye diseases, including cataracts, dry eye syndrome, age-related retinal degeneration (AMD), retinal damage and so on, by introducing to a subject in need of such treatment, a therapeutic dose of the modulator described here sirtuin.

The next aspect of this invention is the prevention of eye damage caused by stress, stroke due to exposure to chemicals or radiation, by injection to a subject in need of such treatment, a therapeutic dose of the modulator described here sirtuin. Investment or electromagnetic eye involvement may include lesions caused by exposure to CRT, or exposure to sunlight or UV radiation.

In one embodiment, the implementation mode of the combined drugs may include drugs or compounds for the treatment or prevention of eye disorders or secondary conditions associated with these conditions. Thus, the mode kombinirovannykh drugs can include one or more activators of sirtuin and one or more therapeutic agents for the treatment of eye disorders.

In one of the embodiments of the modulator of sirtuin can be administered in combination with a therapeutic means to reduce intraocular pressure. In another embodiment of the modulator of sirtuin can be administered in combination with a therapeutic agent for the treatment and/or prevention of glaucoma. In yet another embodiment of the modulator of sirtuin can be administered in combination with a therapeutic agent for the treatment and/or prevention of retrobulbar neuritis. In one of the embodiments of the modulator of sirtuin can be administered in combination with a therapeutic agent for the treatment and/or prevention of CMV retinopathy. In the following embodiment of the modulator of sirtuin can be administered in combination with a therapeutic agent for the treatment and/or prevention of multiple sclerosis.

Mitochondrial diseases and disorders

In some embodiments, provided methods for the treatment of diseases and disorders that increase mitochondrial activity would have a beneficial effect. These methods include the introduction to the needy in this subject a therapeutically effective amount % -activating compounds. Increased mitochondrial activity refers to the increase in the activity of mitochondria, while maintaining observationsto mitochondria (for example, mitochondrial mass), increasing the number of mitochondria, increasing in this way mitochondrial activity (for example, by stimulating the biogenesis of mitochondria), or their combination. In some embodiments, diseases and disorders, which had a positive effect would be increased mitochondrial activity include diseases and disorders associated with mitochondrial dysfunction.

In some embodiments, methods of treating diseases and disorders, which had a positive effect would increase mitochondrial activity, may include identification of a subject suffering from mitochondrial dysfunction. Methods for diagnosing a mitochondrial dysfunction may include molecular genetic, pathologic and/or biochemical analysis. Diseases and disorders associated with mitochondrial dysfunction include diseases and disorders in which the lack of activity of mitochondrial respiratory chain contributes to the development of the pathophysiology of such diseases or disorders in a mammal. Diseases and disorders, which had a positive effect would increase mitochondrial activity, usually include, for example, diseases in which oxidative lesion, mediated by free radicals, leads to the degeneration of the tissues of the disease, when to�which cells undergo apoptosis irrelevant and diseases in which cells cannot undergo apoptosis.

In some embodiments, provided is a method of treating diseases or disorders, which had a positive effect would increase mitochondrial activity, which includes the introduction of the needy in this subject of one or more % -activating compounds in combination with other therapeutic drug, such as a drug, applicable to the treatment of mitochondrial dysfunction, or drug, applicable to reduce the symptom associated with a disease or a violation involving mitochondrial dysfunction.

In illustrative embodiments, the provided methods of treating of diseases or disorders, which had a positive effect would increase mitochondrial activity, by introducing to the subject a therapeutically effective amount % -activating compounds. Examples of diseases or disorders include, for example, neuromuscular disorders (e.g., Friedreich's ataxia, muscular dystrophy, multiple sclerosis and so on), disorders of neuronal instability (e.g., disorders associated with epileptic seizures, migraine, and so forth), developmental delay, neurodegenerative disorders (e.g. Alzheimer's, disease Park�of Nana, amyotrophic lateral sclerosis and so on), ischemia, renal tubular acidosis, age-related neurodegeneration and decline of cognitive ability, fatigue from chemotherapy, age or the chemotherapy-induced menopause or irregularity of the menstrual cycle or ovulation, mitochondrial myopathy, mitochondrial lesion (e.g., accumulation of calcium, excitotoxicity, exposure to the action of nitric oxide, hypoxia, and so forth) and deregulation of mitochondrial function.

Muscular dystrophy refers to a family of diseases involving the degradation of the neuromuscular structure and function, often resulting in atrophy of skeletal muscle and myocardial dysfunction, such as muscular dystrophy Duchenne. In some embodiments, % -activating compounds can be used to reduce the rate of degradation in muscular functional capacities and for improving muscular functional status in patients with muscular dystrophy.

In some embodiments, % -modulating compounds may be used to treat mitochondrial myopathies. The range of mitochondrial myopathies varies from small, slowly progressive weakness of the muscles outside the eye, to fatal infantile myopathy and the Multisystem encephalomyopathy. Some Sindh�ohms were identified, some of them overlap. Established syndromes affecting muscle include progressive external ophthalmoplegia syndrome, Kearns-they (with ophthalmoplegia, pigmentary retinopathy, defects of cardiac conduction system, cerebellar ataxia, and sensorineural deafness), the MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis and insulinopenia episodes), the MERFF syndrome (myoclonic epilepsy and ragged red muscle fibers), the distribution of muscle weakness in the shoulder and pelvic girdle, and infantile myopathy (benign or severe and incurable).

In some embodiments, % -activating compounds can be used to treat patients suffering from toxic damage of mitochondria, such as, toxic damage due to the unusual buildup of calcium, excitotoxicity, exposure to the action of nitric oxide, toxic lesions caused by drugs, or hypoxia.

In some embodiments, % -activating compounds can be used for the treatment of diseases or disorders associated with deregulation of mitochondrial function.

Muscle activity

In the following embodiments, provided methods of increasing muscle activity through the introduction of therapeutic�ski effective amount % -activating compounds. For example, %-activating compounds can be used for improving physical endurance (e.g., ability to perform physical activity, such as exercise, physical labor, sports activities, and so on), suppress or delay physical fatigue, increase in the concentration of oxygen in the blood, enhancing energy in healthy individuals, enhance working capacity and endurance, reducing muscle fatigue, reducing stress, improving heart and cardiovascular activity, improving sexual ability, increasing the concentration of ATP in the muscles, and/or reducing the concentration of lactic acid in the blood. In some embodiments, these methods include the introduction of a number of % -activating compound that enhances mitochondrial activity, increases mitochondrial biogenesis, and/or increase mitochondrial mass.

Sports activity refers to the ability of the muscles of the athlete to function during exercise. Increased athletic performance, strength, speed and endurance is determined by increasing the force of muscle contraction, increase the amplitude of the muscle contraction, reduce the amount of time the muscle reaction between stimulation and contraction. Athlete refers to an individual who is participating in the STRs�operational activities at every level and which aims to achieve increased power level, speed and endurance in its implementation, for example, to the bodybuilder, cyclist, long distance runners, runners for short distances and so on. Increased athletic performance are manifested by the ability to overcome muscle fatigue, ability to remain active for longer periods of time and to a more effective workout.

In the arena of sports muscle exercise activity, it is desirable to create conditions that allow you to compete or to train at higher levels of resistance of the organism for a longer period of time.

It is anticipated that the methods of the present invention will also be effective in the treatment associated with muscle pathological conditions, including acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, bed mode, the immobilization of the limb, or major thoracic, abdominal, and/or orthopedic surgery.

In some embodiments, provided new food compositions containing modulators of sirtuin, a process for their preparation, and method of use of these compositions for improvement of sports performance. Accordingly, provided therapeutic compositions, foods and drinks, having the effect of improving�of physical endurance and/or suppression of physical fatigue in people participating in physical exercises broad definition, including sports that require endurance, and occupations that require repetitive muscular effort. Such food compositions may additionally contain electrolytes, caffeine, vitamins, carbohydrates and so on.

Other applications

% - Modulating compounds that increase the level and/or activity of the protein of sirtuin, can be used for treating or preventing viral infections (such as infections caused by influenza, herpes virus, or papilloma), or as antifungal agents. In some embodiments, % -modulating compounds that increase the level and/or activity of the protein of sirtuin, you can enter as part of combination drug therapy with another therapeutic agent for the treatment of viral diseases. In another embodiment, the % -modulating compounds that increase the level and/or activity of the protein of sirtuin, you can enter as part of combination drug therapy with another anti-fungal agent.

Entities that can be subjected to the treatment described herein include eukaryotes, such as mammals, e.g., humans, sheep, cows, horses, pigs, dogs, cats not belonging to the human race primates, mice and rats. Cells that �there might be treatment, include eukaryotic cells, e.g., obtained from the above described subject, or plant cells, yeast cells, and prokaryotic cells, e.g. bacteria cells. For example, the modulating compound can introduce farm animals to improve their ability to withstand the conditions of agricultural life for a longer time.

% - Modulating compounds that increase the level and/or activity of the protein of sirtuin, can also be used to increase lifespan, resistance to stress, and resistance to apoptosis in plants. In one of the embodiments of the compound applied to the plants, for example, on a periodic basis, or mushrooms. In another embodiment, the plants are genetically modified to produce compound. In the following embodiment, the plants and fruits treated with compound prior to collection and transportation by sea, to increase resistance during sea transportation. Plant seeds can also be put in contact with the compounds described herein, for example, for their preservation.

In other embodiments, % -modulating compounds that increase the level and/or activity of the protein of sirtuin, can be used to modulate lifespan of yeast cells. With�of the situation, in which it may be desirable to increase the lifespan of yeast cells may include any process which uses yeast, for example, in the manufacture of beer, yoghurt and bakery products, e.g. bread. The use of yeast with increased life expectancy may result in using less yeast, or to receive yeast more active for a longer time. Yeast or cells of other mammals, used to obtain recombinant proteins, also can be processed as described in the present invention.

% - Modulating compounds that increase the level and/or activity of the protein of sirtuin, can also be used to increase lifespan, resilience to stress and resistance to apoptosis in insects. In this embodiment, the connection will be applied to useful insects, e.g., bees and other insects that are involved in the pollination of plants. In a particular embodiment of the compound will be applied to bees involved in the production of honey. Generally, the methods described here can be applied to any organism, for example, eukaryotes that may have commercial value. For example, they can be applied to the fish (aquaculture) and birds (e.g., chickens and poultry).

Bol�e high-dose % -modulating compounds increase the level and/or activity of the protein of sirtuin, can also be used as a pesticide if interferonovy with regulation of silent genes and the regulation of apoptosis in the development process. In this embodiment of the compound can be applied to plants using a method known in this field, ensure that the compound is bioavailable for insect larvae, and not to plants.

At least, in light of the link between reproduction and lifespan, %-modulating compounds that increase the level and/or activity of the protein of sirtuin, you can apply to influence the reproduction of organisms such as insects, animals and microorganisms.

4. Tests

Still others considered in the present description, the methods include screening methods for identifying compounds or agents that modulate%. The agent may be a nucleic acid such as an aptamer. Tests can be performed in a cellular or non-cellular format. For example, the analysis may include incubating (or contacting) sirtuin with a test agent under conditions in which % can be modulated by an agent which is known that it modulates%, and monitoring or determining the degree of modulation of sirtuin in the presence of the test�trolled agent relative to the absence of the test agent. The degree of modulation of sirtuin can be determined by determining its ability to deacetylation of the substrate. Examples of substrates are acetylated peptides, which can be obtained from BIOMOL (Plymouth Meeting, PA). Preferred substrates include p53 peptides, such as peptides containing acetylated C. A particularly preferred substrate is the Fluor de Lys-SIRT1 (BIOMOL), i.e. acetylated peptide Arg-His-Lys-Lys (SEQ ID NO:2). Other substrates are peptides from human histones H3 and H4 or acetylated amino acids. The substrates can be fluorogenic. % Can be a SIRT1, Sir2. SIRT3, or part of them. For example, from BIOMOL possible to obtain recombinant SIRT1. Interaction can be done in approximately 30 minutes and stop, for example, using nicotinamide. To determine the degree of acetylation can be used for the analysis of fluorescent HDAC activity/kit for detection of drugs (AK-500, BIOMOL Research Laboratories). Similar analyses described by Bitterman et al. (2002) J. Biol. Chem. 277:45099. The degree of modulation of sirtuin in the analysis can be compared with the degree of modulation of sirtuin in the presence of one or more (individually or simultaneously) of the compounds described herein, which may serve as positive or negative control. Sirtuin for use in the data� analyses may represent sirtuin full length, or parts of them. Since in the present description it has been shown that activating compounds appear to interact with the N-end of SIRT1, a protein for use in the assays include N-terminal part of sirtuins, e.g., about amino acids 1-176 or 1-255 of SIRT1, approximately amino acids 1-174 or 1-252 Sir2.

In one embodiment, the implementation of the screening analysis includes (i) contacting sirtuin with a test agent and an acetylated substrate under conditions appropriate for deacetylation of the substrate by sirtuins in the absence of the test agent; and (ii) the extent of acetylation of the substrate, where a lower degree of acetylation of the substrate in the presence of the test agent relative to the absence of the test agent indicates that the test agent stimulates deacetylation by using sirtuin, whereas a higher degree of acetylation of the substrate in the presence of the test agent relative to the absence of the test agent indicates that the test agent inhibits deacetylation by using sirtuin.

The identification of an agent that modulates, e.g., stimulates, sirtuinin vivomay include (i) contacting cells with a test agent and a substrate that is able to penetrate the cell in the presence of an inhibitor of HDAC class I and class II � conditions suitable for deacetylation of the substrate by sirtuins in the absence of the test agent, and (ii) the extent of acetylation of the substrate, where a lower degree of acetylation of the substrate in the presence of the test agent relative to the absence of the test agent indicates that the test agent stimulates deacetylation by using sirtuin, whereas a higher degree of acetylation of the substrate in the presence of the test agent relative to the absence of the test agent indicates that the test agent inhibits deacetylation by using sirtuin. The preferred substrate is an acetylated peptide, which is preferably fluorophenyl, as further described herein. In addition, the method may include the lysis of cells to determine the degree of acetylation of the substrate. The substrates can be added to cells at a concentration varying in the range from about 1 μm to about 10 mm, preferably from about 10 μm to 1 mm, even more preferably from about 100 μm to 1 mm, e.g. about 200 μm. The preferred substrate is an acetylated lysine, e.g., ε-acetylized (Fluor de Lys, FdL) or Fluor de Lys-SIRT1. A preferred inhibitor of HDAC class I and class II is trichostatin A (TSA), which can be used in concentrations �smenauscheesa in the range of from about 0.01 to 100 microns, preferably from about 0.1 to 10 μm, e.g. 1 μm. Incubation of cells with test compound and a substrate can be conducted for from about 10 minutes to 5 hours, preferably about 1-3 hours. Since TSA inhibits all of HDAC class I and class II, and that some substrates, e.g., Fluor de Lys, is a poor substrate for SIRT2 and even less substrate for SIRT3-7, so that the analysis can be used to identify modulators of SIRT1in vivo.

5. The pharmaceutical composition

Described here, % -modulating compounds may be drugs in the standard way by using one or more pharmaceutically acceptable carriers or excipients. For example, % -modulating compounds and their pharmaceutically acceptable salts and solvates can make preparations for the introduction of, for example, by injection (e.g. SubQ, IM, IP), inhalation or insufflation (either through the mouth or through the nose) or oral, buccal, sublingual, transdermal, nasal, parenteral or rectal administration. In one of variants of implementation % -modulating compound can be entered locally, at the site, which are the target cell, that is, in a certain tissue, organ, or fluid (e.g. blood, cerebrospinal fluid, and so on).

From % -modular�the variety of connections you can make preparations for various routes of administration, including systemic and local or localized administration. Methods and drugs can usually be found in Remington's Pharmaceutical Sciences, Meade Publishing Co., Easton, PA. In the case of parenteral administration, injection is preferred, including intramuscular, intravenous, intraperitoneal and subcutaneous. In the case of the injection of connections you can make preparations in the form of liquid solutions, preferably in physiologically compatible buffers such as Hanks solution or ringer's solution. In addition, from the data connections you can make preparations in solid form and re-dissolved or suspended before use. Also included lyophilized form.

In the case of oral administration the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules, obtained by standard methods with pharmaceutically acceptable excipients, such as binding agents (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose), fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate), lubricants (e.g. magnesium stearate, talc or silica), disintegrant (e.g., potato starch or glycolate sodium starch) or wetting agents (e.g. sodium lauryl sulphate). On tab�etki may be coated using known in the field methods. Liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for preparation with water or other suitable medium before use. Such liquid preparations can be obtained by standard methods with pharmaceutically acceptable additives such as suspendresume agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g. lecithin or Arabian gum), non-aqueous carriers (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), and preservatives (e.g. methyl or propyl-p-hydroxybenzoate or sorbic acid). The preparations can also contain buffer salts, flavoring agents, colorants and sweeteners, if necessary.

Preparations for oral administration may appropriately be to obtain the controlled release of active compounds.

For administration by inhalation (e.g., pulmonary delivery), %-modulating compounds can be conveniently delivered in the form of aerosol Spreebogen presentation from pressurized container or a nebulizer with the use of a suitable carrier gas, for example, DICHLORODIFLUOROMETHANE, trichlorofluoro�Ana, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol metered unit can be determined by providing a valve to deliver a measured quantity. For use in an inhaler or insufflator you can make the capsules and cartridges of, for example, from gelatin containing a powder mix of the compound and a suitable powder base such as lactose or starch.

From % -modulating compounds to obtain drugs for parenteral administration by injection, e.g. by bolus injection or continuous infusion. Preparations for injection can be presented in a single dosing form, e.g., in ampoules or multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous carriers, and may contain agents for the preparation of the drug, such as suspendida, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for connection with a suitable carrier, e.g., sterile apyrogenic water, before use.

From % -modulating compounds may also be obtained rectal compositions such as suppositories or derives�e enemas for example, containing the standard bases for suppositories, such as cocoa butter or other glycerides.

In addition to the previously described drugs, % -modulating compounds can also obtain drugs depot. Such long-acting drugs can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. So, for example, from % -modulating compounds can be obtained the drug with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or in the form of poorly soluble derivatives, for example, in the form of slightly soluble salts. The formula for the controlled release also includes the patches.

In some embodiments of compounds described herein can obtain the drugs for delivery to the Central nervous system (CNS) (review Begley, Pharmacology & Therapeutics 104:29-45 (2004)). Standard approaches for drug delivery to the CNS include: neurosurgical strategies (e.g., intracerebral injection or intracerebroventricular infusion), molecular manipulation of the agent (for example, obtaining a chimeric protein comprising a transport peptide that has an affinity to the molecule at the surface of endothelial cells, in combination with an agent that is itself incapable �to Rescate BBB) when you try to use one of the endogenous pathways through the BBB; pharmacological strategies designed to increase the lipid solubility of an agent (e.g., conjugation of water-soluble agents to lipid or cholesterol carriers) and temporary disturbance of the integrity of the BBB by hyperosmotic gap (resulting from the infusion of a mannitol solution into the carotid artery or by using a biologically active agent such as an angiotensin peptide).

Liposomes are another delivery system of the medicinal product that can be easily administered by injection. Accordingly, in the method of this invention the active compounds can also be administered in the form of liposome delivery systems. Liposomes are well known to specialists in this field. Liposomes can be obtained from a variety of phospholipids, such as cholesterin, stearylamine of phosphatidylcholine. Liposomes applicable for use in the method of the invention, encompass all types of liposomes, including, but not limited to, small unilamellar the vesicles, large unilamellar the vesicles and multilamellar the vesicles.

The following method of obtaining the drug in particular, a solution, a modulator of sirtuin, such as resveratrol or its derivative, is the use of cyclodextrin. Under the cyclodextrin mean α-, β - or γ-cyclodextrin. The cyclodextrins details about�isany in Pitha et al., U.S. patent No. 4727064 included in this description by reference. The cyclodextrins are cyclic oligomers of glucose; these compounds form inclusion complexes with any drug, molecules which can fit into a lipophilic-oriented cavities of the cyclodextrin molecules.

Rapidly disintegrating or dissolving dosed form apply for quick absorption, in particular, buccal and sublingual absorption of pharmaceutically active agents. Bestreplica dosed form is preferred for patients such as age and pediatricheskii patients who have difficulty swallowing conventional solid dosage forms such as capsules and tablets. In addition, bestreplica dosage forms avoid the disadvantages associated with, for example, chewing metered dose forms in which the time duration during which the active agent remains in the patient's mouth, plays an important role in determining the amount of taste masking and the extent to which the patient is able to oppose the grittiness of the active agent to the throat.

Pharmaceutical compositions (including cosmetic preparations) may contain from about 0.00001 to 100%, e.g. from 0.001 to 10% or from 0.1% to 5% by weight of one or more described here, % -mo�Wirayuda compounds. In other embodiments, the pharmaceutical composition comprises: (i) from 0.05 to 1000 mg of the compounds of the invention, or its pharmaceutically acceptable salt, and (ii) from 0.1 to 2 grams of one or more pharmaceutically acceptable excipients.

In one of the variants of the implementation described here, % -modulating compound is included in the drug-containing local action local media, which is generally suitable for local administration of medications, and includes any such substance known in this field. Local media can be chosen in such a way as to provide the composition in the desired form, for example, as an ointment, lotion, cream, microemulsion, gel, oil, solution or the like, and it can consist of substances that either exist in nature or is of synthetic origin. Preferably, the selected medium had no adverse effects on the active agent or other components of the preparation of local action. Examples of suitable carriers for use in the present invention include water, alcohols and other nontoxic organic solvents, glycerin, mineral oil, silicone, petrolatum, lanolin, fatty acids, vegetable oils, parabens, waxes and so on.

Drugs can be a colorless, having�e odor of the ointment, lotions, creams, microemulsions and gels.

% - Modulating compounds may enter into the composition of ointments, which generally are semisolid preparations that are typically based on petrolatum or other derivatives of petroleum. Concrete base for ointments, intended for use, as will be clear to the person skilled in the art, is the Foundation that will provide optimal delivery of the drug and, preferably, will provide desirable characteristics, and, for example, alleviation or the like. As for other media or environments, the basis for ointments should be inert, stable, non-irritant not sensitising.

% - Modulating compounds can be included in lotions, which generally are preparations intended for application to the skin surface without friction, and are typically liquid or semiliquid preparations in which solid particles, including the active agent, are present in a water or alcohol-based. Lotions are usually suspensions of solids, and may contain a liquid oil suspension type oil-in-water.

% - Modulating compounds can be included in creams, which generally are viscous liquid or semisolid emulsions, either oil-in-water or water-in-m�the following. Foundations creams washed with water and include an oil phase, an emulsifier and the aqueous phase. The oil phase generally consists of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessary, exceeds the oil phase in volume, and generally contains a humectant. An emulsifier in the preparation of the cream, as explained in Remington'ssuprathat is typically a nonionic, anionic, cationogenic or amphoteric surface-active agent.

% - Modulating compounds may enter into the composition of the microemulsions, which generally are thermodynamically stable, isotropically clear dispersions of two immiscible liquids such as oil and water, stabilized by a film of molecules of the surfactant on the interface (Encuclopedia of Pharmaceutical Technology (New York: Marcel Dekker, 1992), volume 9).

% - Modulating compounds may enter into the composition of the gels, which generally are semisolid systems consisting of either suspensions obtained from small inorganic particles (two-phase systems) or large organic molecules distributed essentially uniformly in the liquid media (monophasic gels). Despite the fact that the gels are commonly used aqueous liquid carrier, the liquid carrier can also apply� alcohols and oils.

In the preparations can also contain other active agents such as other anti-inflammatories, analgesics, antimicrobial agents, antifungal agents, antibiotics, vitamins, antioxidants and sunscreens usually found in sunscreen formulations including, but not limited to, anthranilate, benzophenone (particularly benzophenone-3), camphor derivatives, cinnamate (e.g., octyl methoxycinnamate), dibenzoylmethane (e.g. butylperoxybenzoate), p-aminobenzoic acid (RAV) and its derivatives, salicylates (for example, octylsalicylate).

In some local drug action active agent is present in an amount in the range from about 0.25 wt.% to 75 wt.% the drug is preferably in the range from about 0.25 wt.% to 30 wt.% of the drug, more preferably in the range from about 0.5 wt.% to 15 wt.% of the drug, and most preferably in the range from about 1.0 wt.% to 10 wt.% drug.

The eye condition can be treated or prevented, for example, by means of systemic, topical, intraocular injection, % -modulating compounds, or by the introduction of the device for prolonged release, which releases % -modulating compound. Circui�-modulating compound, increase the level and/or activity of the protein of sirtuin, can be delivered in a pharmaceutically acceptable ophthalmic carrier, so that the connection had been in contact with the ocular surface for a sufficient period of time to connect them to penetrate the corneal and internal area of the eye, for example, in the anterior chamber, posterior chamber, vitreous body, intraocular fluid, the substance of the vitreous body, cornea, iris/ciliary body, lens, choroid/retina and sclera. Pharmaceutically acceptable ophthalmic carrier, for example, may be an ointment, vegetable oil or an encapsulating material. Alternatively, the compounds of this invention can be administered by injection directly into the vitreous and intraocular fluid. In the next version of connections can introduce a systematic way, for example, by intravenous infusion or injection, for treatment of the eye.

Described here, % -modulating compounds can be stored in an environment containing oxygen. For example, resveratrol or analog can be prepared in an airtight capsule for oral administration, such as Capsugel from Pfizer, Inc.

Cells, for example, processed % -modulating compoundex vivoyou can enter the subject in �accordance with the methods of introducing a graft that may be accompanied by, for example, the introduction of immunosuppressant, for example, cyclosporin A. on the General principles of medicines refer the reader to Stem Cell Transplantation, Gene Therapy, and Cellular Immunotherapy, by G. Morstyn &W. Sheridan eds, Cambridge University Press, 1996; and Hematopoietic Stem Cell Therapy, E. D. Ball, J. Lister &P. Law, Churchill Livingstone, 2000.

Toxicity and therapeutic efficacy % -modulating compounds can be determined using standard techniques for cell cultures or experimental animals. LD50is a dose lethal for 50% of the population. ED50represents the dose therapeutically effective in 50% of the population. The ratio of doses between toxic and therapeutic effects (LD50/ED50) represents therapeutic index. Preferred are % -modulating compounds that exhibit large therapeutic indices. Although you can use % -modulating compounds that exhibit toxic side effects, should try to develop a delivery system that directs such compounds to the site of affected tissue to minimize the possible failure of uninfected cells and, thereby, reduce side effects.

The data obtained in the analysis of cell cultures and animal studies can be used as� for the preparation of the dosing interval to apply for people. Doses of such compounds can be in the range of circulating concentrations that include the ED50when small, or in the absence of toxicity. The dose may vary within this range depending on the applied dose form and used the method of administration. For any connection a therapeutically effective dose can first determine from tests on cell cultures. The dose can be in animal models to achieve a circulating plasma concentration, which includes the IC50(i.e., the concentration of the test compound that achieves a half maximal inhibition of symptoms) as determined by cell culture. Such information can be used to more accurately determine the applicable doses for humans. Concentration in plasma can be determined, for example, by using high performance liquid chromatography.

6. Sets

The present invention also provided kits, e.g., kits for therapeutic purposes or kits for modulating lifespan or modulate apoptosis. The kit can include one or more % -modulating compounds, for example, in certain doses in advance. The kit may optionally include the device for the contact of cells with compounds and sho�s to apply. Devices include syringes, stents and other devices for introducing % -modulating compounds to a subject (e.g., into a blood vessel of a subject) or applying it to the skin of the subject.

In yet another embodiment, the invention provides composition of matter containing certainly modulator of this invention and another therapeutic agent (such that are used in combination therapy and combination compositions) in separate dosage forms, but associated with each other. Used in the present description, the term "related" means that the individual dosed forms are packaged together or otherwise connected to each other, so that is certainly clear that metered data from single forms are intended for sale and introduction as part of the same regime. Agent and modulator of sirtuin preferably packaged together in a blister pack or other multiagency package, or as connected, separately closed containers (such as bags made of foil or the like) that can be divided (e.g., by tearing along the separation lines between the two containers).

In yet another embodiment, provided is a kit containing separate containers (a) modulator circui�of this invention and, and (b) another therapeutic agent, as a means described in the present description in another place.

Practical implementation of these methods will be applied, unless otherwise indicated, standard techniques of cell biology, molecular biology, transgenic biology, Microbiology, recombinant DNA and immunology, which are within the skill in this area. Such techniques are fully explained in the literature. See, for example, Molecular Cloning A Laboratory Manual, 2ndEd., ed. by Sambrook, Fritsch and Maniatis (Cold Spring Harbor Laboratory Press: 1989); DNA Cloning, Volumes I and II (D. N. Glover ed., 1985); Oligonucleotide Synthesis (M. J. Gait ed., 1984); Mullis et al. U.S. Patent No: 4,683,195; Nucleic Acid Hybridization (B. D. Hames &S. J. Higgins eds. 1984); Transcription And Translation (B. D. Hames &S. J. Higgins eds. 1984); Culture Of Animal Cells (R. I. Freshney, Alan R. Liss, Inc., 1987); Immobilized Cells And Enzymes (IRL Press, 1986); B. Perbal, A Practical Guide To Molecular Cloning (1984); the treatise, Methods In Enzymology (Academic Press, Inc., N. Y.); Gene Transfer Vectors For Mammalian Cells (J. H. Miller and M. P. Calos eds., 1987, Cold Spring Harbor Laboratory); Methods In Enzymology, Vols. 154 and 155 (Wu et al. eds.), Immunochemical Methods In Cell And Molecular Biology (Mayer and Walker, eds., Academic Press, London, 1987); Handbook Of Experimental Immunology, Volumes I-IV (D. M. Weir and C. C. Blackwell, eds., 1986); Manipulating the Mouse Embryo, (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986).

EXAMPLES

Now, being described in General terms, the present invention will be more clearly with reference to the following examples, which are included only for purposes of illustration of certain aspects and variationsummary of the present invention and are not intended to limit this invention in any way.

Example 1. GettingN-(pyridin-4-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (compound 500)

Stage 1. Synthesis of 6-bromo-2-nitropyridine-3-ol (2):

At 0 º C Br2was slowly added to a mixture of 2-nitropyridine-3-ol (1; 80,0 g, 570 mmol) and NaOCH3(30,8 g, 570 mmol) in methanol (600 ml) and stirred at this temperature for 30 min. To the mixture was added Acoh (1.5 ml) and stirred again for 10 min the crude reaction mixture was concentrated under vacuum to give a solid yellow solid, which was triturated under a mixture of petroleum ether/EtOAc, yielding 6-bromo-2-nitropyridine-3-ol (2;35.0 g, 28%). MS (ESI) calc. for C5H3BrN2O3(m/z): 217,93.

Stage 2. Synthesis of 6-bromo-3-(2-bromoethoxy)-2-nitropyridine (3):

In THF (10 ml) was dissolved PPh3(900 mg, 3.4 mmol). To this solution at 0 ° C was added dropwise diisopropylethylamine (DIAD) (688 mg, 3.4 mmol). The mixture was stirred at 0OC for 30 min. a precipitate Formed white. Then added dropwise at 0o C 2-bromatan-1-ol (427 mg, 3.4 mmol) and 6-bromo-2-nitropyridine-3-ol (2; 500 mg, to 2.29 mmol) in THF. White residue disappeared, and the resulting mixture was stirred at room temperature for 2 h. In General, the solvent was concentrated and the filter�liquid mixture by chromatography on silica gel, getting 6-bromo-3-(2-bromoethoxy)-2-nitropyridine (3; 600 mg, 80%). MS (ESI) calc. for C7H6Br2N2O3(m/z): 323,87.

Stage 3. Synthesis of 6-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (5):

Obtained in analogy to 6-bromo-4H-pyrido[3,2-b][1,4]oxazine Serie-3-one, referenced in WO2007/118130. To a solution of 6-bromo-3-(2-bromoethoxy)-2-nitropyridine (3; 560 mg, 1,73 mmol) in glacial acetic acid (6 ml) was added Fe (387 mg, 6,91 mmol) in one portion. The reaction mixture was heated at 90 ° C for 5 h, then was cooled, diluted with EtOAc and filtered through a layer of silica gel using EtOAc as eluent. After evaporation of the Acoh balance4was dissolved in DMF (5 ml), was added To the2CO3(716 mg, 5,19 mmol) and the mixture was heated at 90 ° C overnight. In General, the solvent was concentrated and the mixture was purified by chromatography on silica gel, yielding 6-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (5; 185 mg, 50%). MS (ESI) calc. for C7H7BrN2O (m/z): 213,97.

Stage 4. Synthesis of 6-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (6):

In a mixture of dioxane:H2About (45 ml:1 ml) was dissolved 6-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (5; 2.0 g, 9.30 mmol), 3-(trifluoromethyl)phenylboronic acid (2.65 g, 13,95 mmol), Pd(PPh3)4(215 mg, 0,186 mmol) and CCO 3(6.0 g, 18,6 mmol) and heated at 50 ° C over night. According to GHMC observed peak of the product, but was still a little original substance; added Bronevoy acid and stirred at 50 ° C over night. The peak of the original substance remained unchanged; cooled to room temp. and began the loss of a certain amount of sediment. Was diluted with water (40 ml), was extracted with EtOAc (3×40 ml), washed with saturated brine, dried over MgSO4, filtered, concentrated and purified on a column of silica gel ISCO (0 to 100% mixture of EtOAc/pentane), yielding mixed fractions of 6-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (6) MS (ESI) calc. for C14H11F3N2O (m/z): 290,08 found 281 [M+H].

This General methodology could be used to obtain the number of derivatives of 6-aryl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie, substituting 3-(trifluoromethyl)phenylboronic the corresponding acid Bronevoy acid.

Stage 5. Synthesis of N-(thiazol-2-yl)-6-(3-(trifluoromethyl)phenyl)- 2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (Compound 500)

Obtained according to literature methods, like Gool et alTetr Lett200849b 7171-7173. To initial substance dissolved 6-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (6;50 mg, 0.18 mmol) in CH2Cl2(approx. 3 ml) was added� triethylamine (0.06 ml, 0,43 mmol), stirred, and then added triphosgene (21,13 mg, 0,07 mmol) in 1 ml of CH2Cl2. Leave the reaction mixture to stir for approximately 10 min, then was added 2-aminothiazole (28,52 mg, 0,29 mmol) and allowed to interact for 30 min. was still a bit of original substance, so I added 1 equivalent of 2-aminothiazole and the reaction mixture was left to stir for 30 min. the Reaction mixture was diluted with CH2Cl2, washed with 10% NH4Cl, and the organic layers were extracted and subjected to column chromatography (CH2Cl2:MeOH (0-3%)). By recrystallization from MeOH received the desired N-(thiazol-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (Connection500) approximately 90% purity by UV. MS (ESI) calc. for C14H13F3N4O2S (m/z): 406,07 found 407 [M+H].

This General methodology could be used to obtain the number of derivatives of 6-aryl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide, substituting 2-aminothiazole to the corresponding amine.

Example 2. Getting 6-(3-chlorophenyl)-N-(pyridin-4-yl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (compound 541)

Stage 1. Synthesis of 6-bromo-N-(pyridin-4-yl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)carboxamide (7)

Received� according to literature methods, similar Gool et alTetr Lett2008, 49, 7171-7173.

6-Bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (54-aminopyridin was subjected to the General conditions for obtaining urea outlined here in General terms, and was purified column chromatography with the elution with a mixture of EtOAc:pentane, yielding 6-bromo-N-(pyridin-4-yl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)carboxamide (7; 62 mg, 62%). MS (ESI) calc. for C13H11BrN4O2(m/z): 335,16 found 336 [M+H].

Stage 2. Synthesis of 6-(3-chlorophenyl)-N-(pyridin-4-yl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)carboxamide (Compound 541)

According to the above General method combinations, 6-bromo-N-(pyridin-4-yl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)carboxamide (7; 275,5 mg, 0,822 mmol), 3-(trifluoromethyl)phenylboronic acid (160,2 mg, of 1.03 mmol) and CsCO3(0,725 mg, 2.1 mmol) was dissolved in a mixture of dioxane:H2About (15 ml:1.5 ml) and heated at 60 ° C over night. Reaction monitoring was performed by TLC. The crude reaction mixture was diluted with water (8 ml), was extracted with CH2Cl2(3×10 ml), washed with saturated brine, dried over Na2SO4, filtered, concentrated and was purified column chromatography with the elution with a mixture of EtOAc:pentane, yielding 6-(3-chlorophenyl)-N-(pyridin-4-yl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)carboxamide (Compound 541; 110 mg, 36%).MS (ESI) calc. for C19H15 ClN4O2(m/z): 366,8 found 368 [M+H].

Example 3. GettingN-(5-(pyrrolidin-1-ylmethyl) - thiazol-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (compound 505)

Stage 1. Synthesis tertbutyl 5-(gidroximetil) - thiazol-2-ylcarbamate (10)

A suspension of 2-aminothiazole-5-carboxylate (8; 145 g, 840 mmol), distritbution (275 g, 1260 mmol) and 4-dimethylaminopyridine (DMAP) (5 mg, catalytic amount) in THF (2175 ml) was stirred at 30 ° C for 5.5 h. the Reaction mixture was concentrated to dryness and EtOAc was added (1450 ml). The organic solvent was washed with water (2×435 ml) and saturated brine (2×145 ml), dried over MgSO4and concentrated, yielding ethyl 2-(tertbutoxycarbonyl)thiazole-5-carboxylate (9; 227 g, 99,23%) in the form of a crude product, which was used for next step without any further purification.MS (ESI) calc. for C11H16N2O4S (m/z): 272,32.

A stirred solution of ethyl 2-(tertbutoxycarbonyl)thiazole-5-carboxylate (9; 227 g, 830 mmol) in anhydrous THF (1512 ml) was cooled to-45 º C. Within 1 h was added a solution of superhybrid in THF (1.0 M, 1877 ml), and then the reaction mixture was stirred at-45 º C for 2 h, warmed to room temp. for 20 h. the Reaction mixture was quenched with a saturated solution of salt ingravalle to room temp. The mixture was concentrated, dissolved in EtOAc and washed with saturated brine, dried over Na2SO4was concentrated and was purified column chromatography on silica gel (petroleum ether/ethyl acetate=1:1), receiving tertbutyl 5-(gidroximetil) - thiazol-2-ylcarbamate (10; 95 g, 49%).MS (ESI) calc. for C9H14N2O3S (m/z): 230,28.

Stage 2. Synthesis hydrochloride salt of 5-(pyrrolidin-1-methyl) - thiazol-2-amine (12)

Solution tertbutyl 5-(gidroximetil) - thiazol-2-ylcarbamate (10; 37 g, 160 mmol), triethylamine (24.2 g, 240 mmol) in CH2Cl2(231 ml) was cooled to 0OC. Added methylchloride (23,16 g, 200 mmol) and the mixture was extracted with CH2Cl2(2×93 ml). The combined organic layers were dried over Na2SO4and concentrated under vacuum to give 2-(tertbutoxycarbonyl) - thiazol-5-yl)methylmethanesulfonate (11; 40 g, 75%).%).MS (ESI) calc. for C10H16N2O5S2(m/z): 308,37.

To a stirred solution of 2-(tertbutoxycarbonyl) - thiazol-5-yl)methylmethanesulfonate (11; 40 g, 0.13 mole) in CH2Cl2(140 ml) was added pyrrolidine (37,69 g, 530 mmol) at 0 ° C and was warmed to room temperature. The mixture was washed with saturated solution of NaHCO3and saturated salt solution (93 ml). Organic solvent was dried over Na2SO4to�have centriole and was purified column chromatography on silica gel (petroleum ether/ethyl acetate=1:1), getting 5-(pyrrolidin-1-methyl) - thiazol-2-amine (free amine) (12; 34 g, 75%).MS (ESI) calc. for C8H13N3S (m/z): 183,27.

To a stirred solution of 5-(pyrrolidin-1-methyl) - thiazol-2-amine (12; 34 g, 190 mmol) in methanol (121 ml) were barbotirovany HCl (gas) and monitored by TLC until it has consumed all matter. The solvent was removed and EtOAc was added to obtain a precipitate. The mixture was filtered and sequentially washed with the residue on the filter with EtOAc, receiving 5-(pyrrolidin-1-methyl) - thiazol-2-amine (in the form hydrochloride salt) (12; 20,6 g, 67%) in the form of white solids. MS (ESI) calc. for C8H13N3S·HCl (m/z): 219,73 found 184 [M+H].

Stage 3. Synthesis of N-(5-(pyrrolidin-1-ylmethyl) - thiazol-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)carboxamide (Compound 505)

Synthesized according to the above General method, receiving N-(5-(pyrrolidin-1-ylmethyl) - thiazol-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)carboxamide (Compound 505), which was purified column chromatography, elwira mixture (EtOAc:pentane) to give N-(5-(pyrrolidin-1-ylmethyl) - thiazol-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)carboxamide505(64.3 mg, 53%). MS (ESI) calc. for C23H22F3N5O2S (m/z): 489,51 found 491 [M+H].

Example 4. Paul�chenie triptoreline salt N-(6-morpholinopropan-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (compound 506):

Stage 1. Synthesis of 6-morpholinopropan-2-amine (14)

A mixture of 4-chloro-2-aminopyridine (13; 19,3 g, 150 mmol), K2CO3And 41.7 g, 0.30 mole) and morpholine (38,9 ml, 450 mmol) in DMSO (150 ml) was stirred at 190 ° C (oil bath) for 10 h. After cooling to room temperature was added water (300 ml) and was extracted with ethyl acetate (4×150 ml). The combined organic layers were washed with water, dried over Na2SO4and concentrated in vacuum. The residue was purified by column chromatography on silica gel (10:1 petroleum ether:ethyl acetate) to obtain 6-morpholinopropan-2-amine in the form of white solids (14; 9.0 g, 54.8 per mmol). MS (ESI) calc. for C9H13N3Oh (m/z): 179,11 found 180 [M+H].

2-(pyrrolidin-1-yl)pyridin-4-amine15had a similar sequence given above, based on 2-chloropyridin-4-amine.

Stage 2. Synthesis triptoreline saltN-(6-morpholinopropan-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)carboxamide (Compound 505)

Synthesized according to the above General method, gettingN-(6-morpholinopropan-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-�irido[3,2-b][1,4]oxazine Serie-4(3H)carboxamide ( 506), which was purified column chromatography, elwira mixture (EtOAc:pentane), the subsequent purification by HPLC in the elution MeOH and 0.1% TFA, TFA salt (68,2 mg, 32%). MS (ESI) calc. for C24H22F3N5O3·S2BUT2F3(m/z) 599,48 found 486 [M+H].

Example 5. GettingN-(6-(morpholinomethyl)pyridin-3-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (compound 507):

Stage 1. Synthesis of ethyl 5-(tertbutoxycarbonyl)picolinate (18)

To a solution of 5-aminobenzeneboronic acid (16; 8.4 g, to 60.8 mmol) in ethanol (100 ml) was added SOCl2(14.5 g, 120 mmol) at 0OC. The mixture was held at reflux for 12 hours. The solvent was removed and added to a saturated solution of Na2CO3to establish the pH=9 and filtered, obtaining a solid substance. After drying under vacuum gave ethyl 5-aminophylline (17; 7.5 g, 75%). MS (ESI) calc. for C8H10N2O2(m/z) 166,18.

To a solution of ethyl 5-aminopyridine (17; 7.5 g, 45 mmol) int-BuOH (60 ml) and acetone (20 ml) was added DMAP (0.10 g, 0.9 mmol) and di-tributilphosphat (at 19.6 g, 90 mmol). The reaction mixture was stirred at room temp. in the course of the night. The solvent was removed and hexane was added (150 ml) and cooled to-20 ° C for 2 h. the Mixture was filtered and the precipitate was dried in the vacuum�mind getting ethyl 5-(tertbutoxycarbonyl)picolinate (18; 8.9 g, 53%). MS (ESI) calc. for C13H18N2O4(m/z) 266,29.

Stage 2. Synthesis tertbutyl 6-(gidroximetil)pyridin-3-ylcarbamate (19)

To a stirred solution of ethyl 5-(tertbutoxycarbonyl)picolinate (18; 8.9 g, 24 mmol) in diethyl ether (200 ml) in a nitrogen atmosphere was added alumoweld lithium (LAH) (1.8 g, 48 mmol) in diethyl ether (100 ml) for 30 min at 0OC. The reaction mixture was stirred for 3 h, added water (1 ml) and 10% NaOH (2 ml) and the mixture was filtered and dried over Na2SO4and concentrated under reduced pressure, obtaining the connection tertbutyl 6-(gidroximetil)pyridin-3-ylcarbamate (19; 4.2 g, 78%). MS (ESI) calc. for C11H16N2O3(m/z) 224,26.

Stage 3. Synthesis tertbutyl 6-(morpholinomethyl)pyridin-3-ylcarbamate (21)

To a solution of tertbutyl 6-(gidroximetil)pyridin-3-ylcarbamate (19; 4.2 g, 18,8 mmol) and DIPEA (7.0 g, of 56.4 mmol) in THF (20 ml) was added MSCl (2.8 g, with 24.4 mmol) for 30 min at 0OC. The reaction mixture was quenched by adding saturated aqueous solution of NaHCO3and was extracted with EtOAc (3×60 ml). The combined organic layer was washed with saturated brine and dried over Na2SO4. The organic solvent was removed,obtaining the compound (5-(tertbutoxycarbonyl)pyridin-2-yl)methylmethanesulfonate ( 20; 5.5 g) without further purification for the next stage.

A mixture of (5-(tertbutoxycarbonyl)pyridin-2-yl)methylmethanesulfonate (20; 1.70 g), morpholine (1.0 g, 11.3 mmol) and K2CO3(2.30 g, to 16.9 mmol) in acetonitrile (30 ml) was stirred at room temperature for 12 h. water was Added (30 ml) and the mixture was extracted with ethyl acetate (3×30 ml) and dried over MgSO4, concentrated in vacuo and purified by chromatography on silica gel (petroleum ether/ethyl acetate = from 1:1 to 1:3), receiving tertbutyl 6-(morpholinomethyl)pyridin-3-ylcarbamate (21; 1.20 g, 71% after two steps). MS (ESI) calc. for C15H23N3O3(m/z): 293,36.

Stage 4. Synthesis of 6-(morpholinomethyl)pyridin-3-amine (22)

To a solution of tertbutyl 6-(morpholinomethyl)pyridin-3-ylcarbamate (21; 1.20 g, 4.1 mmol) in CH2Cl2(20 ml) was added TFA (6 ml). The mixture was stirred for 12 h at room temperature. The solvent was removed in vacuum and podslushivaet solid to pH=9 with saturated solution of Na2CO3. The mixture was concentrated to dryness and acidified with to pH=1, podslushivaet to pH=9 and concentrated to dryness. The residue was washed with ethyl acetate (3×25 ml), the combined organic layers were concentrated, yielding 6-(morpholinomethyl)pyridin-3-amine (22; 450 mg, 56%). MS (ESI) calc. for C10H15N3O (/z): 193,25, found 194 [M+H].

6-(Morpholinomethyl)pyridin-2-amine23had a sequence similar to that described above, based on 6-aminophylline acid.

Stage 5. Synthesis of N-(6-(morpholinomethyl)pyridin-3-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (compound 507)

Synthesized by General method described above, yielding N-(6-(morpholinomethyl)pyridin-3-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (connection 507), which was purified by column chromatography (EtOAc:pentane), the subsequent purification by HPLC in the elution MeOH and 0.1% TFA, TFA salt (at 112.3 mg, 51%). MS (ESI) calc. for C25H24F3N5O3·S2BUT2F3(m/z): 613,5 found 500 [M+H].

Example 6. Getting trifenatate saltN-(6-(azetidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (compound 512):

Stage 1. Synthesis of 2-(azetidin-1-yl)-6-chloropyridine (25):

A mixture of 2,6-dichloropyridine (24; 10.0 g, to 67.7 mmol), hydrochloride of azetidine (6.3 g, of 67.6 mmol) and K2CO3(23.3 g, 169 mmol) in DMSO (100 ml) was stirred at 110 ° C. for 12 h. water was Added (150 ml) and the mixture was extracted with ethyl acetate (100 ml ×3). United �organicheskie layers were washed with saturated brine and dried over Na 2SO4was concentrated to dryness, yielding 2-(azetidin-1-yl)-6-chloropyridin (25; 10.5 g), which was used for next step without further purification. MS (ESI) calc. for C8H9ClN2(m/z): 168,05.

Stage 2. Synthesis of 6-(azetidin-1-yl)-N-(4-methoxybenzyl)pyridin-2-amine (26):

A mixture of 2-(azetidin-1-yl)-6-chloropyridine (25; 1,68 g, 10,0 mmol), 4-methoxybenzylamine (1.35 g, 10.0 mmol), Pd2(dba)3(0.27 g, 0.29 mmol), BINAP (0,37 g, of 0.60 mmol), andt-BuONa (1.12 g, 10.0 mmol) in CH2Cl2(20 ml) was stirred at 110 ° C. in the atmosphere of N2for 12 h. the Mixture was diluted with water (100 ml), washed with water (3×50 ml), dried over Na2SO4and concentrated in vacuum. The residue was purified by chromatography on silica gel (5:1 petroleum ether:ethyl acetate) to give 6-(azetidin-1-yl)-N-(4-methoxybenzyl)pyridin-2-amine (26; 2,60 g, 9,67 mmol). MS (ESI) calc. for C16H19N3Oh (m/z): 269,15.

Stage 3. Synthesis of 6-(azetidin-1-yl)pyridin-2-amine (27):

A solution of 6-(azetidin-1-yl)-N-(4-methoxybenzyl)pyridin-2-amine (26; 2.5 g, 9.3 mmol) and TFA (20.0 ml) in the chloride methylene chloride (40 ml) was stirred at room temp. for 3 h. the pH was brought to 9 by the action of Na2CO3and was extracted with EtOAc (3×50 ml). The combined organic layers were washed with saturated brine (2×50 ml), su�or over anhydrous Na 2SO4, concentrated in vacuo and purified by chromatography on silica gel (1:1 petroleum ether:ethyl acetate) to give 6-(azetidin-1-yl)pyridin-2-amine (27; 50 mg, 0.33 mmol). MS (ESI) calc. for C8H11N3(m/z): 149,10 found 150 [M+H].

2-(Azetidin-1-yl)pyridin-4-amine28had a sequence similar to that described above, based on 2,4-dichloropyridine.

Stage 4. Synthesis trifenatate salt of N-(6-(azetidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (compound 512):

Synthesized by General method described above, yielding N-(6-(azetidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide(connection 512) which was purified by HPLC in the elution MeOH and 0.1% TCA, getting salt TFU (connection 512;47,4 mg, 47%). MS (ESI) calc. for C23H20F3N5O2·S2BUT2F3(m/z): 569,45 found 456 [M+H].

Example 7. Receiving (R)-N-(6-(2,3-dihydroxypropane)pyridin-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (compound 570):

Stage 1. Synthesis of (S)-6-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-2-amine (30):

To a solution of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol� (19,5 g 150 ml) in dioxane (250 ml) was added NaH (6.0 g, 60%) at room temperature and stirred for 30 min, then was added 2-amino-6-chloropyridin (29; 6,43 g, 50 mmol) and the mixture was stirred at reflux for 48 h. water was Added and was extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with water (6×50 ml), dried over Na2SO4, concentrated in vacuo and purified by chromatography on silica gel (20:1 methylene chloride:methanol), yielding (S)-6-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-2-amine as an oil (30; 5.7 g, and 25.4 mmol, 51%). MS (ESI) calc. for C11H16N2O3(m/z): 224,12 found 225 [M+H].

(R)-6-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-2-amine was obtained according to a sequence similar to that described above using (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol. Similarly, 6-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-2-amine was obtained according to a sequence similar to that described above, using (2,2-dimethyl-1,3-dioxolan-4-yl)methanol.

Stage 2. Synthesis of (S)-N-(6-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (31):

Synthesized by General method described above, yielding (S)-N-(6-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-2-yl)-6-(3-(trifluoromethyl)Hairdryer�l)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide ( 31). MS (ESI) calc. for C26H25F3N4O5(m/z): 530,18.

Stage 3. Synthesis of (R)-N-(6-(2,3-dihydroxypropane)pyridin-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (connection 570):

(S)-N-(6-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (31;109 mg, 0.21 mmol) was dissolved in MeOH (12 ml) together with 10 drops of concentrated HCl. The reaction mixture was stirred at room temperature for 1 h, and then concentrated under reduced pressure. As a result of purification by chromatography on silica gel was obtained (R)-N-(6-(2,3-dihydroxypropane)pyridin-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (connection 570; 75 mg, 75%). MS (ESI) calc. for C23H21F3N4O5(m/z): 490,15, found: 491 [M+H].

The use of (R)-6-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-2-amine in step 2, followed by the techniques of stage 3, resulted in obtainingconnections 571.

Example 8. GettingN-(1-(pyridin-2-yl)cyclopropyl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (compound 633):

Stage 1. Synthesis of 2-(pyridin-2-yl)cyclopropylamine (33):

Received a literary technique by analogy Bertus et al JOC2002, 67, 3965-3968.

To a stirred solution of picolinate (4.0 g, 38,42 mmol) and Ti(O-iPr)4(13 ml, 43,31 mmol) in THF (64 ml) was added EtMgBr (26 ml, 3M in THF, 78,74 mmol) at 50 ° C. The mixture was stirred for 2 h and was added BF3·Et2O (10 ml, 78,74 mmol) at 50 ° C. The mixture was stirred over night. The mixture was brought to pH=9 by the action of aqueous NaOH and was extracted with ethyl acetate (39 ml ×2). The combined organic layer was washed with water (79 ml ×2), dried over Na2SO4purified by chromatography on silica gel (CH2Cl2:methanol 10:1), obtaining oil. The oil was dissolved in CH2Cl2(79 ml). Added oxalic acid (1.4 g, 11.1 mmol) in methanol (8 ml) and stirred for 1.5 h, obtaining a solid substance. The solid was isolated by filtration and washed with CH2Cl2/MeOH (39 ml, about./about.=10:1) and diethyl ether, dried under vacuum to give 2-(pyridin-2-yl)cyclopropane(33; 1.2 g, to 13.6%). MS (ESI) calc. for C8H10N2(m/z): 134,08.

Stage 2. Synthesis of N-(1-(pyridin-2-yl)cyclopropyl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (compound 633)

Synthesized by General method described above, yielding N-(1-(pyridin-2-yl)cyclopropyl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (compound 633;126,2 mg, 43%). MS (ESI) computations�. for C23H19F3N4O2(m/z): 440,42, found: 441 [M+H].

Example 9. GettingN-(6-(2,3-dihydroxypropane)pyrazine-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (compound 696):

Stage 1. Synthesis of 6-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyrazine-2-amine (35)

To a solution of solketal with 48.7 g, 0,369 mol) in 1,4-dioxane (1500 ml) was added NaH (14,8 g, 369 mmol) at room temp. and stirred for 2 h. Then was added 6-chloropyrazine-2-amine (34; 16.0 g, 123 mmol) and the mixture was stirred at 120 ºC for 12 h. the Solvent was removed and was added ethyl acetate (1000 ml). The mixture was washed with saturated brine (1000 ml × 3), organic solvent was dried over Na2SO4, concentrated in vacuo and purified by chromatography on silica gel (methylene chloride:methanol 30:1-10:1) to give 6-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyrazine-2-amine (35;13,8 g, is 61.3 mmol, 50%) as a solid yellow color. MS (ESI) calc. for C10H15N3O3(m/z): 225,24, found: 226 [M+H].

2-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-4-amine36,

4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-2-amine37,

4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-6-methylpyran�DIN-2-amine 38,

and 2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyrimidine-4-amine39received sequence described above, based on 2-bromopyridin-4-amine, 4-chloropyridin-2-amine, 4-chloro-6-methylpyrimidin-2-amine and 2-chloropyrimidine-4-amine, respectively.

Stage 2. Synthesis of N-(6-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyrazine-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (40)

Synthesized by General method described above, yielding N-(6-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyrazine-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (40; 21,6 mg, 42%). MS (ESI) calc. for C25H24F3N5O5(m/z): 531,48, found: 532 [M+H].

Stage 3. Synthesis of N-(6-((2,3-dihydroxypropane)pyrazine-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (Connection 696)

Connection 696received using the same sequence of deprotection, which was receivedconnection 570.N-(6-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyrazine-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide was dissolved in MeOH, was added 10 drops of concentrated HCl and stirred at room temp. within 1 h, purified by HPLC, yielding N-(6-((2,3-DIH�proxyprotocol)pyrazine-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide ( Connection 696;Of 21.6 mg, 36%). MS (ESI) calc. for C22H20F3N5O5(m/z): 491,42, found: 492 [M+H].

Example 10. GettingN-(6-(1-ox-6-azaspiro[3.3]heptane-6-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (compound 823):

Stage 1. Synthesis tertbutyl 1-ox-6-azaspiro[3.3]heptane-6-carboxylate (42)

To a suspension of iodide trimethylsulfoxonium (80 g, 370 mmol) in dry tert-BuOH (1.4 l) was added at 50 ° C, trebuchet potassium (41,3 g, of 0.37 mmol), after which the mixture turned into a muddy slurry. This mixture was stirred at the same temperature for 1.5 hours, then added tertbutyl 3-oxoazetidin-1-carboxylate (41; 25 g, 150 mmol). The suspension was stirred at 50 ° C for 48 h. It was cooled to room temperature and partitioned mixture between a saturated aqueous solution of NH4Cl (30 ml) and EtOAc (50 ml). The phases were separated and the aqueous phase extracted with EtOAc (50 ml). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. Received tertbutyl 1-ox-6-azaspiro[3.3]heptane-6-carboxylate (42;8 g, 28%) after purification flash chromatography on silica gel (hexane:EtOAc gradient 2:1→0:1). MS (ESI) calc. for C24H19F3N6O2(m/z): 199,1.

Stage 2. Synthesis of TFA salt of 1-ox-6-azaspiro[3.3]heptane (43)

To a solution of tertbutyl 1-ox-6-azaspiro[3.3]heptane-6-carboxylate (42;3 g, with 15.06 mmol) in CH2Cl2(10 ml) was added at 20 ° C 2,2,2-trifluoroacetic acid (34.3 g, 301 mmol) and the mixture was stirred at 20 ° C for 30 min, then the volatiles removed in vacuum. The balance of salt TFA 1-ox-6-azaspiro[3.3]heptane was used without further purification (43; 2.5 g, 85%). MS (ESI) calc. for C5H10N-C2F3O 197,16.

Stage 3. Synthesis tertbutyl (6-(1-ox-6-azaspiro[3.3]heptane-6-yl)pyridin-2-yl)carbamate (45)

A mixture of tertbutyl 6-bromopyridin-2-ylcarbamate (44; 8,18 g, 30.0 mmol), 1-ox-6-azaspiro[3.3]heptane (43;3 g, 30.0 mmol), 1,1'-bis(diphenylphosphino)ferrocene (DPPF) (1,663 g, 3.00 mmol), Pd(OAc)2(0,34 g, 1.5 mmol) and Cs2CO3(19,5 g, for 59.9 mmol) in 50 ml of toluene was heated at 120 ° C for 5 h in a sealed tube and cooled. After evaporation of the solvent, tributyl (6-(1-ox-6-azaspiro[3.3]heptane-6-yl)pyridin-2-yl)carbamate was purified column flash chromatography (45; 2.7 g, 23%). MS (ESI) calc. for C15H21N3O3291,2.

Stage 4. Synthesis of 6-(1-ox-6-azaspiro[3.3]heptane-6-yl)pyridin-2-amine (46)

To a solution of tertbutyl 6-(1-ox-6-azaspiro[3.3]heptane-6-yl)pyridin-2-ylcarbamate (45; 2 g, 6.86 mmol) in 20 ml of methylene chloride was added 2,2,2-three�torakusu acid (7,83 g, 68,6 mmol) at room temperature. The mixture was stirred for a further 1 h and was added 50 ml saturated water. solution of Na2CO3. The organic phase was separated and concentrated. 6-(1-ox-6-azaspiro[3.3]heptane-6-yl)pyridin-2-amine was obtained column flash chromatography (46; 900 mg, 69%). MS (ESI) calc. for C10H13N3About 191,1; found 192,2.

Stage 5. SynthesisN-(6-(1-ox-6-azaspiro[3.3]heptane-6-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (Compound 823)

Synthesized by General method described above, yielding N-(6-(1-ox-6-azaspiro[3.3]heptane-6-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (Connection 823; 50 mg, 38%). MS (ESI) calc. for C25H22F3N5O3(m/z): 497,17, found: 498 [M+H].

Example 11. Synthesis triptoreline salt (2-(2,3-dihydroxypropane)pyridin-4-yl)(6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-yl)methanone (Compound 518)

Stage 1. Synthesis of 2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)isonicotinic acid (48)

To a mixture of NaH (11,95 g, 300 mmol, 60% in oil) in anhydrous THF (667 ml) was added 2,2-dimethyl-1,3-dioxolan-4-yl (solketal) (39,65 g, 300 mmol) at 0OC. The mixture was stirred for 1 hour. Was added 2-bromoisonicotinic acid (47; 20.0 g, 100 mmol) and stirred at reflux for 1.5 hours was Added water (83 ml) and the pH was adjusted to 2-3. The mixture was extracted with EtOAc (83 ml ×4). The combined organic layers were washed with water (42 ml ×3), dried over Na2SO4and concentrated under vacuum to give 2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)isonicotinoyl acid (48; 13,0 g, 52%) as a solid substance of white color.MS (ESI) calc. for C12H15NO5(m/z) 253,25.

Stage 2. Synthesis of 2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-4-yl)(6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-yl)methanone(49)

6-(3-(Trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (6; 70 mg, 0.25 mmol) was dissolved in 2 ml of DMF along with 2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)isonicotinic acid (48; 155,24 mg, 0.61 mmol), hexaflurophosphate 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylurea (HATU) (284,83 mg, 0,75 mmol) and base Janiga (0.10 ml, 0.75 mmol). The reaction mixture was stirred over night at 50 ° C. It was diluted with CH2Cl2(10 ml) and washed with water (3×5 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude reaction mixture was purified by column chromatography, elwira a mixture of EtOAc:pentane, yielding 2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-4-yl)(6-(3-(trifluoromethyl)φ�Neal)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-yl)methanon ( 49; Or 69.3 mg, 54%). MS (ESI) calc. for C26H24F3N3O5(m/z) 515,48.

Stage 3. Synthesis triptoreline salt (2-(2,3-dihydroxypropane)pyridin-4-yl)(6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-yl)methanone (Compound 518)

2-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-4-yl)(6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-yl)methanon (49; Or 69.3 mg, 0,13 mmol) was dissolved in MeOH (10 ml) together with 10 drops of concentrated HCl. The reaction mixture was stirred at room temperature for 1 h, and then concentrated in vacuo. Was purified by HPLC, elwira MeOH and 0.1% TFA, getting trifenatate salt (2-(2,3-dihydroxypropane)pyridin-4-yl)(6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-yl)methanone (Connection 518; 46,8 mg, 59%). MS (ESI) calc. for C23H20F3N3O5(m/z) 589,44 found 590 [M+H].

Example 12. Getting pyridin-4-yl 6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxylate (Compound 562)

It dissolved in 5 ml of THF 6-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (6; 100 mg, 0,357 mmol) were added triphosgene in 3 ml of THF and TEM (0,73 ml,1,43 mmol). Leave the reaction mixture to stir at room temp. within 30 min was Added 3-hydroxypyridine (84,87 mg, 0.89 mm�l) and monitored the reaction by the method IHMS; after 40 minutes not seen the original substance. The crude reaction mixture was diluted with CH2Cl2(8 ml), washed with 10% NH4Cl, the organic layer was extracted, dried over Na2SO4, filtered and concentrated under reduced pressure. As a result of purification by HPLC in the elution MeOH and 0.1% TFA was obtained pyridin-4-yl 6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxylate (The connection 562; 72,5 mg, 39%). MS (ESI) calc. for C20H14F3N3O3·S2BUT2F3(m/z) 515,36 found 402 [M+H].

Example 13. Getting 8-methyl-N-(4-thiazole-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (Compound 668)

Stage 1. Synthesis of 3-acetoxy-4-methylpyridine-1-oxide

To acetic anhydride (80 ml) portions was added 4-methylpyridine N-oxide (50; 39,0 g, 365 mmol). Upon completion of the addition (1.5 hours) the reaction mixture obtained was boiled for 30 min. then the solvent was removed in vacuo, the residue was stirred with saturated aqueous sodium bicarbonate solution. The mixture was extracted with CH2Cl2. Extracts of CH2Cl2were combined, dried and concentrated. The residue was purified by column chromatography (5:1 CH2Cl2/EtOAc) to obtain 3-acetoxy-4-methylpyridine-1-oxide (51; 15.0 g, yield 28%) in weemala pale yellow. MS (ESI) calc. for C8H9NO3(m/z): 167,16.

Stage 2. Synthesis of 4-methylpyridine-3-ol (52)

To a solution of KOH (7.0 g) in methanol (50 ml) was added 3-acetoxy-4-methylpyridine-1-oxide (51; 15.0 g, 106 mmol). The mixture was stirred at room temperature over night. The methanol was removed under vacuum and the residue was dissolved in water. The solution frustrated to pH 7 conc. HCl and was extracted with CH2Cl2and EtOAc. The extracts were combined, dried and concentrated, obtaining 4-methylpyridine-3-ol (52; 8,40 g, yield 80%) as an oil. MS (ESI) calc. for C6H7NO (m/z): 109,13.

Stage 3. Synthesis of 4-methyl-2-nitropyridine-3-ol (53)

4-Methylpyridine-3-ol (52; 8.4 g, 78.5 mmol) was added to ice-cold conc. H2SO4(42 ml). Was added dropwise fuming nitric acid (4 ml), maintaining the temperature below 10 ° C, and the mixture was stirred at 10-20ºC for 2 hours. The mixture was poured onto crushed ice and brought to pH 2 using 8h NaOH and was extracted with EtOAc. The extracts were combined, dried and concentrated. The residue was purified column chromatography, obtaining 4-methyl-2-nitropyridine-3-ol (53; 8.0 g, yield 67%). MS (ESI) calc. for C6H6N2O3(m/z): 154,12.

Stage 4. Synthesis of 6-bromo-4-methyl-2-nitropyridine-3-ol (54)

To a solution of methyl-2-nitropyridine-3-ol ( 53; 8.0 g, 52 mmol) in methanol (150 ml) was added NaOMe (10,4 ml, 28% wt./mass. the solution in MeOH). The solution was stirred at room temperature for 15 min, and then cooled in an ice bath. Was added dropwise a solution of bromine (2,64 ml) in methanol (25 ml) and stirred the reaction mixture at 0 ° C for 2 h. the Solvent was removed and the residue was purified by column chromatography (1:80 MeOH/CH2Cl2) to obtain 6-bromo-4-methyl-2-nitropyridine-3-ol (54; 7.0 g, yield 58%). MS (ESI) calc. for C6H5BrN2O3(m/z) 233,02.

Stage 5. Synthesis of ethyl 2-(6-bromo-4-methyl-2-nitropyridine-3-yloxy)acetate (55)

A solution of 6-bromo-4-methyl-2-nitropyridine-3-ol (54; 7.0 g, 30 mmol), K2CO3(12.4 g, 90 mmol) and ethylbromoacetate (4.4 ml, 39 mmol) in DMSO (80 ml) was stirred at 30 ° C for 24 h. the Mixture was poured into water and was extracted with CH2Cl2. The extracts were combined, dried and the solvent was removed in vacuum. The residue was purified by column chromatography, yielding ethyl 2-(6-bromo-4-methyl-2-nitropyridine-3-yloxy)acetate (55; 8.0 g, yield 84%). MS (ESI) calc. for C10H11BrN2O5(m/z): 319,11, found 320.

Stage 6. Synthesis of 6-bromo-8-methyl-2H-pyrido[3,2-b][1,4]oxazine Serie-3(4H)-she (56)

Ethyl 2-(6-bromo-4-methyl-2-nitropyridine-3-yloxy)acetate (55; 8.0 g, 25 mmol) was dissolved in with�art 9:2 EtOH/N 2About (120 ml) with iron (7.0 g, 125 mmol) and CaCl2(1,41 mg, 12.5 mmol). The obtained reaction mixture was held at reflux for 8 h. the Insoluble substance was filtered and the filtrate concentrated in vacuo. The residue was purified column chromatography, obtaining6-bromo-8-methyl-2H-pyrido[3,2-b][1,4]oxazine Serie-3(4H)-he (56;2.5 g, yield 41%). MS (ESI) calc. for C8H7BrN2O2(m/z): 243,06.

Stage 7. Synthesis of 6-bromo-8-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie(57)

6-Bromo-8-methyl-2H-pyrido[3,2-b][1,4]oxazine Serie-3(4H)-he (56; 2.7 g, 11.1 mmol) was dissolved in THF (40 ml) vmeste with 9.8 M BF3-Me2S (11,4 ml, 111 mmol). The obtained reaction mixture was boiled to reflux over night. After cooling, was added dropwise methanol (8 ml) and the reaction mixture was boiled to reflux for 30 min. the Solvent was removed in vacuo and the residue was purified by column chromatography (1:15 EtOAc/petroleum ether) to give 6-bromo-8-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (57; 2,24 g, yield 88%). MS (ESI) calc. for C8H9BrN2Oh (m/z): 229,07, found 230.

Stage 8. Synthesis of 8-methyl-6-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (58)

6-Bromo-8-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (57; 1.5 g, 6.55 mmol), 3-(trifluoromethyl)phenylboron�OIC acid (1,49 g, 7,86 mmol), Pd(PPh3)4(379 mg, 0.33 mmol), Na2CO3(1,67 g, 15,72 mmol) and the mixture of 4:1 dioxane/water (30 ml) was placed in a sealed vial and purged with nitrogen. The mixture was heated at 120 ºC for 12 h. Added CH2Cl2(100 ml) and the mixture was filtered through a layer of Na2SO4. The solvent was removed in vacuo and the residue was purified by column chromatography (1:15 EtOAc/petroleum ether) to give 8-methyl-6-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (58;1.64 g, yield 85%). MS (ESI) calc. for C15H13F3N2Oh (m/z): 294,27, found 295.

This General technique combinations could be used to obtain the number of derivatives of 8-methyl-6-aryl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie, substituting 3-(trifluoromethyl)phenylboronic the corresponding acid Bronevoy acid.

Stage 9. Synthesis of 8-methyl-N-(4-thiazole-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (Compound 668)

To a solution of 8-methyl-6-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (58; 80 mg, 0,272 mmol) and triethylamine (96 mg, 0,952 mmol) in CH2Cl2(4 ml) was added triphosgene (40 mg, 0,136 mmol). The reaction mixture was stirred at room temp. within 30 min, and then were added 4-thiazole-2-amine (93 mg, 0,816 mmol) and stirred the reaction mixture overnight.The solvent was removed and the residue was purified column chromatography, getting 8-methyl-N-(4-thiazole-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (Connection 668;78 mg, yield of 66.1%). MS (ESI) calc. for C20H17F3N4O2S (m/z) 434,10 found 435 [M+H].

This General methodology could be used to obtain the number of derivatives of 8-methyl-N-(substituted)-6-aryl-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide, substituting 4-methyl thiazole-2-amine to the corresponding amine. Alternatively, derivatives can also be obtained by interaction of the corresponding phenylcarbamate with 8-methyl-6-aryl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie a in the presence of DIEA at temp. from ambient to 50°C.

Example 14. Obtaining N-(4-thiazole-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrazine[2,3-b][1,4]oxazine Serie-4(3H)-carboxamide (Compound 740)

Stage 1. Synthesis of 3-bromo-6-chloropyrazine-2-amine (60)

1-Bromperidol-2,5-dione (27,5 g, 154 mmol) was added in portions during 30 minutes to a solution of 6-chloropyrazine-2-amine (59; 20 g, 154 mmol) in chloroform (200 ml), heated to reflux. Upon completion of addition the reaction mixture was allowed to cool, washed with water and concentrated. The residue was purified by column chromatography, elwira CH2Cl2getting 3-bromo-6-chloropyrazine-2-amine (60; 8 g, yield 25%). MS (ESI) calc. for C4H3BrClN3(m/z 208,44.

Stage 2. Synthesis of 6-chloro-3-methoxypyrazine-2-amine (61)

3-Bromo-6-chloro-2-pyrazinamid (60; 1.0 g), sodium methoxide (3 ml, 25% wt./mass. in MeOH) and MeOH (10 ml) was heated at reflux for 3 h. the Solvent was evaporated and the residue was dissolved in EtOAc and a saturated solution of salt. The organic layer was separated, dried (MgSO4) and concentrated. The residue was purified by column chromatography, elwira with methylene chloride, yielding 6-chloro-3-methoxypyrazine-2-amine (61; 2.0 g, yield 33%). MS (ESI) calc. for C5H6ClN3Oh (m/z) 159,57.

Stage 3. Synthesis of 3-amino-5-chloropyrazine-2-ol (62)

To a solution of 6-chloro-3-methoxypyrazine-2-amine (61; 2 g of 12.53 mmol) in CH2Cl2(300 ml) was added dropwise to tribromsalan (3,14 g, of 12.53 mmol) and the mixture was stirred over night. Was added MeOH and the mixture was dissolved in water. The solution was brought to pH 8-9 by the action of aqueous NaHCO3and then was extracted with EtOAc. The organic phase was separated and the residue was purified by chromatography on silica gel, elwira with methylene chloride, yielding 3-amino-5-chloropyrazine-2-ol (62; 0.9 g, yield 50%). MS (ESI) calc. for C4H4ClN3Oh (m/z) 145,55.

Stage 4. Synthesis of 6-chloro-3,4-dihydro-2H-pyrazine[2,3-b][1,4]oxazine Serie (63)

To a solution of 3-amino-5-Harper�in-2-ol ( 62; 0.9 g, 6.18 of mmol) in CH3CN (100 ml) was added 1,2-dibromoethane (1.16 g, 6.18 of mmol) and K2CO3(1,71 g, of 12.37 mmol). The mixture was boiled to reflux over night. After cooling to room temp. the mixture was concentrated, dissolved in water and then was extracted with EtOAc. The combined organic phase was concentrated, and the residue was purified by chromatography on silica gel, elwira with methylene chloride, yielding 6-chloro-3,4-dihydro-2H-pyrazine[2,3-b][1,4]oxazine Serie (63;0.8 g, 75% yield). MS (ESI) calc. for C6H6ClN3Oh (m/z) 171,58, found: 173 [M+H].

Stage 5. Synthesis of 6-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrazine[2,3-b][1,4]oxazine Serie (64)

To a solution of 6-chloro-3,4-dihydro-2H-pyrazine[2,3-b][1,4]oxazine Serie (63; 0.8 g, of 4.66 mmol) in a mixture of 4:1 dioxane/water was added 3-(trifluoromethyl)phenylboronic acid (886 mg, of 4.66 mmol). The mixture was deoxyribose in vacuum and re-filled with nitrogen. After stirring the mixture in a nitrogen atmosphere for 30 min, was added Pd(PPh3)4(539 mg, 0,466 mmol) and K2CO3(1.29 g, 9,32 mmol). The solution was heated to 100°C to complete the reaction. Then the reaction mixture was extracted with water and the organic layer was dried and concentrated, obtaining the crude oil, which was purified by chromatography on silica gel, yielding 6-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrazine[2,3-b][1,4]oxazine Serie 64;0.35 g, yield 27%). MS (ESI) calc. for C13H10F3N3Oh (m/z) 281,23, found: 282 [M+H].

This General methodology could be used to obtain the number of derivatives of 6-aryl-3,4-dihydro-2H-pyrazine[2,3-b][1,4]oxazine Serie, substituting 3-(trifluoromethyl)phenylboronic the corresponding acid Bronevoy acid.

Stage 6. Synthesis of N-(4-thiazole-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrazine[2,3-b][1,4]oxazine Serie-4(3H)-carboxamide (Compound 740)

To a solution of 6-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrazine[2,3-b][1,4]oxazine Serie (64; 100 mg, 0,356 mmol) and triethylamine (126 mg, 1,245 mmol) in CH2Cl2(10 ml) was added bis(trichloromethyl)carbonate (52,8 mg, 0,178 mmol). The reaction mixture was stirred at room temperature for 30 min, and then were added 4-thiazole-2-amine (122 mg, 1,067 mmol) and the mixture was stirred over night. The solvent was removed and the residue was purified column chromatography, obtaining N-(4-thiazole-2-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrazine[2,3-b][1,4]oxazine Serie-4(3H)-carboxamide (Connection 740; 40 mg, yield 27%). MS (ESI) calc. for C18H14F3N5O2S: 421,08; found 422 [M+H].

This General methodology could be used to obtain the number of derivatives of N-substituted-6-aryl-2H-pyrazine[2,3-b][1,4]oxazine Serie-4(3H)-carboxamide, substituting 4-methyl thiazole-2-amine to meet�s Amin. Alternatively, derivatives can also be obtained by interaction of the corresponding phenylcarbamate with 6-aryl-3,4-dihydro-2H-pyrazine[2,3-b][1,4]oxazine Serie a in the presence of DIEA at a temperature from ambient to 50°C.

Example 15. Obtaining N-(4-thiazole-2-yl)-2-(3-(trifluoromethyl)phenyl)-6H-pyrimido[5,4-b][1,4]oxazine Serie-8(7H)-carboxamide (Compound 709)

Stage 1. Synthesis of 2-chloro-5-methoxypyridine-4-amine (66)

To 2,4-dichloro-5-methoxypyridine (65; 9.8 g, 55 mmol) in dioxane (20 ml) was added 25% ammonium hydroxide solution (25 ml). The obtained reaction mixture was heated at 100 ° C for 21 h in a sealed ampoule. After cooling, the solvent was removed in vacuo and the residue was purified column chromatography, obtaining 2-chloro-5-methoxypyridine-4-amine (66;8,31 g, yield 95%). MS (ESI) calc. for C5H6ClN3About: 159,57.

Stage 2. Synthesis of 4-amino-2-chloropyrimidine-5-ol (67)

To a solution of 2-chloro-5-methoxypyridine-4-amine (66; 8.3 g, 52 mmol) in CH2Cl2(1.5 l) was added dropwise tribromide boron (75 ml). The mixture was stirred at room temperature over night. Carefully added MeOH until homogeneous solution. The solvent was removed in vacuo and water was added NaHCO3. The mixture was extracted with CH2Cl2and organicheskoi dried and concentrated. The residue was purified by column chromatography, yielding 4-amino-2-chloropyrimidine-5-ol (67;4.1 g, yield 54%). MS (ESI) calc. for C4H4ClN3About: 145,55.

Stage 3. Synthesis of 2-chloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Serie (68)

4-Amino-2-chloropyrimidine-5-ol (67;3.75 grams, or 25.8 mmol) was dissolved in CH2Cl2(2500 ml) with 1,2-dibromoethane (4,85 g of 25.8 mmol) and K2CO3(10,68 g, of 77.4 mmol). The reaction mixture was held at reflux for 4 h. the Precipitate from the mixture was removed by filtration. The filtrate was concentrated, and the residue was purified column chromatography, obtaining 2-chloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Serie (68; 3,18 g, yield 72%). MS (ESI) calc. for C6H6ClN3About: 171,58; found 173 [M+H].

Stage 4. Synthesis of 2-(3-(trifluoromethyl)phenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Serie (69)

2-Chloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Serie (68; 1.41 g, 8,22 mmol), 3-(trifluoromethyl)phenylboronic acid (1.87 g, was 9.86 mmol), Pd(PPh3)4(475 mg, 0,411 mmol), Na2CO3(2,09 g, of 19.7 mmol) and a mixture of dioxane/water (4:1, 35 ml) was placed in a sealed vial and filled with nitrogen. After that, the mixture was heated at 120 ° C for 12 hours. After cooling, was added CH2Cl2(100 ml) and passed the mixture through a layer of Na2SO4. The solvent was removed in vacuo and the residue was purified to�Nochnoy chromatography (1:15 EtoAc/petroleum ether), getting 2-(3-(trifluoromethyl)phenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Serie (69;1.20 g, yield 52%). MS (ESI) calc. for C13H10F3N3About: 281,23; found 282 [M+H].

This General methodology could be used to obtain the number of derivatives of 2-aryl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Serie, substituting 3-(trifluoromethyl)phenylboronic the corresponding acid Bronevoy acid.

Stage 5. Synthesis of N-(4-thiazole-2-yl)-2-(3-(trifluoromethyl)phenyl)-6H-pyrimido[5,4-b][1,4]oxazine Serie-8(7H)-carboxamide (Compound 709)

To a solution of 2-(3-(trifluoromethyl)phenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Serie (69;106 mg, 1.05 mmol) and triethylamine (84 mg, 0.3 mmol) in CH2Cl2(6 ml) was added triphosgene (44,5 mg, 0,15 mmol). The reaction mixture was stirred at room temp. within 30 min, and then were added 4-thiazole-2-amine (103 mg, 0.9 mmol) and stirred the reaction mixture overnight. The solvent was removed and the residue was purified column chromatography, obtaining N-(4-thiazole-2-yl)-2-(3-(trifluoromethyl)phenyl)-6H-pyrimido[5,4-b][1,4]oxazine Serie-8(7H)-carboxamide (Connection 709;56 mg, yield 44%). MS (ESI) calc. for C18H14F3N5O2S (m/z) 421,08 found 422 [M+H].

This General methodology could be used to obtain the number of derivatives of N-substituted-2-aryl-6H-pyrimido[5,4-b][1,4]ox�in-8(7H)-carboxamide, replacing 4-thiazole-2-amine to the corresponding amine. Alternatively, derivatives can also be obtained by interaction of the corresponding phenylcarbamate with 2-aryl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Serie a in the presence of DIEA at a temperature from ambient to 50°C.

Example 16. Getting 4-(dimethylamino)-2-(3-(fluorophenyl)-N-(pyridin-4-yl)-6H-pyrimido[5,4-b][1,4]oxazine Serie-8(7H)-carboxamide (Compound 736)

Stage 1. Synthesis of the hydrochloride of ethyl 3-formanilide (71)

A solution of 3-perbenzoate (70; 20.0 g, 165 mmol) and EtOH (50 ml) was cooled on an ice bath. To the solution was barbotirovany gaseous HCl to saturation and stirred the reaction mixture overnight. The precipitate was isolated by filtration and washed with cold ether, receivinghydrochloride ethyl 3-formanilide in the form of solids (71; 33.5 g, yield 99%). MS (ESI) calc. for C9H10FNO-HCl: 203,64.

Stage 2. Synthesis of hydrochloride of 3-formanilide (72)

The solution of hydrochloride of ethyl 3-formanilide substances (71; 33.5 g, 164 mmol) in the (150 ml) of EtOH is cooled to a temperature of from -5 to -10. Was barbotirovany gaseous ammonia until saturation of the solution and stirred the reaction mixture overnight. The precipitate was isolated by filtration and washed with cold ether, receivinghydrochloride 3-formanilide�Yes ( 72;27,2 g, yield 95%). MS (ESI) calc. for C7H17FN2-HCl: 138,14.

Stage 3. Synthesis of 2-(3-fluorophenyl)-5-methoxypyridine-4,6-diol (73)

To anhydrous methanol (60 ml) was added sodium (2.05 g, to 89.3 mmol) at 0OC. After complete dissolution of sodium to the cold solution was added the hydrochloride of 3-formanilide (72; 5.0 g, 28.8 mmol). After this dropwise added dimethyl 2-methoxymethanol (4.67 g, 28.8 mmol) over 30 min at 0OC. The obtained reaction mixture was held at reflux for 1.5 h. After cooling, the solution frustrated HCl. The solvent was removed in vacuo and the residue was purified column chromatography, obtaining 2-(3-fluorophenyl)-5-methoxypyridine-4,6-diol (73; 3.57 g, yield 53%). MS (ESI) calc. for C11H9FN2O3: 236,20.

Stage 4. Synthesis of 4,6-dichloro-2-(3-fluorophenyl)-5-methoxypyridazine (74)

A solution of 2-(3-fluorophenyl)-5-methoxypyridine-4,6-diol (73; 3.57 g, 15.1 mmol) in POCl3(20 ml) was boiled to reflux for 22 hours. The excess POCl3was removed under vacuum and partitioned the residue between water and CH2Cl2. The organic layer was dried, concentrated and the residue was purified by column chromatography, yielding 4,6-dichloro-2-(3-fluorophenyl)-5-methoxypyridazine (74; 4.10 g, yield 99%). MS (ESI) calc. for C11H7Cl2 FN2About: 273,09.

Stage 5. Synthesis of 6-chloro-2-(3-fluorophenyl)-5-methoxypyridine-4-amine (75)

4,6-Dichloro-2-(3-fluorophenyl)-5-methoxypyridazine (74; 4.1 g, 15 mmol) and 25% ammonium hydroxide (50 ml) was heated to 100 ° C for 21 h in a sealed ampoule. After cooling, the solvent was removed in vacuo and the residue was purified column chromatography, obtaining 6-chloro-2-(3-fluorophenyl)-5-methoxypyridine-4-amine (75; 2.7 g, 71% yield). MS (ESI) calc. for C11H9ClFN3About: 253,66.

Stage 6. Synthesis of 4-amino-6-chloro-2-(3-fluorophenyl)pyrimidine-5-ol (76)

To a solution of 6-chloro-2-(3-fluorophenyl)-5-methoxypyridine-4-amine (75; 2.7 g, 10.6 mmol) in CH2Cl2(50 ml) was added dropwise tribromide boron (10,2 ml). The obtained reaction mixture was stirred at room temperature for 24 h. Carefully added MeOH until homogeneous solution. The solvent was removed in vacuo and water was added NaHCO3. The mixture was extracted with CH2Cl2and the organic layer was dried and concentrated. The residue was purified by column chromatography, yielding 4-amino-6-chloro-2-(3-fluorophenyl)pyrimidine-5-ol (76;To 1.07 g, yield 42%). MS (ESI) calc. for C10H7ClFN3About: 239,63.

Stage 7. Synthesis of 4-chloro-2-(3-fluorophenyl)-6H-pyrimido[5,4-b][1,4]oxazine Serie-8(7H)-she (77)

4-Amino-6-chloro-2-(3-fluorophenyl)pyrimidine-5-ol (76; 5.3 g, 22,1 mmol) was dissolved in THF (2200 ml) together with K2CO3(15.2 g, 110 mmol). Was added dropwise 2-chloroacetanilide (2,50 g, 22,1 mmol) and stirred the reaction mixture at room temperature for 2 h. the Reaction mixture was boiled to reflux for 24 h. the Solvent was removed in vacuo, and the residue was purified by column chromatography, yielding 4-chloro-2-(3-fluorophenyl)-6H-pyrimido[5,4-b][1,4]oxazine Serie-8(7H)-he (77;3.4 g, yield 55%). MS (ESI) calc. for C12H7ClFN3O2: 279,65.

Stage 8. Synthesis of 4-chloro-2-(3-fluorophenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Serie (78)

To a solution of 4-chloro-2-(3-fluorophenyl)-6H-pyrimido[5,4-b][1,4]oxazine Serie-8(7H)-she (77; 3.4 g, 12.1 mmol) in THF (40 ml) was added 9.8 M BH3-Me2S (12,4 ml, 121 mmol). The reaction mixture was held at reflux overnight. After cooling, was added to the solution dropwise methanol (8 ml) and heated the reaction mixture for 30 min. the Solvent was removed in vacuo, and the residue was purified by column chromatography, yielding 4-chloro-2-(3-fluorophenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Serie (78;Of 2.16 g, yield 67%). MS (ESI) calc. for C12H9ClFN3About: 265,67.

Stage 9. Synthesis of 2-(3-fluorophenyl)-N,N-dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Serie-4-amine (79)

A mixture of 4-chloro-2-(3-fluorophenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Serie (79; 550 mg, 2,07 mmol), 33% solution of dimethylamine (35 ml) in dioxane (70 ml) was heated at 90 ° C for 24 h in sealed tube. The solvent was removed under vacuum, and the residue was purified column chromatography, obtaining 2-(3-fluorophenyl)-N,N-dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Serie-4-amine (80; 420 mg, yield 74%). MS (ESI) calc. for C14H15FN4About: 274,29 found 275.

Described above is a common Protocol used for the synthesis of the analogous 2-(3-fluorophenyl)-4-(pyrrolidin-1-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Serie81substituting dimethylamine for pyrrolidine, and 2-(3-fluorophenyl)-4-morpholine-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Serie82substituting dimethylamine for morpholine.

Stage 10. Synthesis of 4-(dimethylamino)-2-(3-(fluorophenyl)-N-(pyridin-4-yl)-6H-pyrimido[5,4-b][1,4]oxazine Serie-8(7H)-carboxamide (Connection 736)

To a solution of 2-(3-fluorophenyl)-N,N-dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Serie-4-amine (80; 90 mg, 0,328 mmol) and triethylamine (116 mg, 1.15 mg) in CH2Cl2(5 ml) was added triphosgene (49 mg, 0,164 mmol). The reaction mixture was stirred at room temp. within 2 h, and then was added pyridine-4-amine (93 mg, 0,984 mmol) and stirred the reaction mixture for 24 h. the Solvent was removed and the eyes�Ali the residue was separated by column chromatography, getting 4-(dimethylamino)-2-(3-(fluorophenyl)-N-(pyridin-4-yl)-6H-pyrimido[5,4-b][1,4]oxazine Serie-8(7H)-carboxamide (Connection 736;24 mg, yield 19%). MS (ESI) calc. for C20H19FN6O2: 394,16 found 395 [M+H].

This General methodology could be used to obtain the number of derivatives of 4-substituted-2-aryl-N-substituted-6H-pyrimido[5,4-b][1,4]oxazine Serie-8(7H)-carboxamide, substituting pyrimidine-4-amine to the corresponding amine. Alternatively, derivatives can also be obtained by interaction of the corresponding phenylcarbamate 2 arylamidine-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Serie-4-amine in the presence of DIEA at a temperature from ambient to 50°C.

Example 17. Obtaining 2-(3-(fluorophenyl)-4-(piperazine-1-yl)-N-(pyridin-4-yl)-6H-pyrimido[5,4-b][1,4]oxazine Serie-8(7H)-carboxamide (Compound 738)

Stage 1. Synthesis tertbutyl 4-(2-(3-(fluorophenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Serie-4-yl)piperazine-1-carboxylate (83)

4-Chloro-2-(3-fluorophenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Serie (79; 550 mg, 2,07 mmol), tertbutyl piperazine-1-carboxylate (7.7 g, up 41.4 mmol) and dioxane (100 ml) was placed in a sealed ampoule. The reaction mixture was stirred at 100 ° C for 24 h. the Solvent was removed and the residue was purified column chromatography, obtaining tertbutyl 4-(2-(3-(fluorophenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Serie-4-yl)piperazine-1-�rboxylic ( 83; 540 mg, yield 63%). MS (ESI) calc. for C21H26FN5O3: 415,46.

Stage 2. Synthesis tertbutyl 4-(2-(3-(fluorophenyl)-8-(pyridin-4-ylcarbonyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Serie-4-yl)piperazine-1-carboxylate (84)

To a solution of tertbutyl 4-(2-(3-(fluorophenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Serie-4-yl)piperazine-1-carboxylate (83; 120 mg, 0,289 mmol) and triethylamine (102 mg, 1.01 mmol) in CH2Cl2(7 ml) was added triphosgene (43 mg, 0,144 mmol). The reaction mixture was stirred at room temp. within 2 hours was Added pyridine-4-amine (82 mg, 0,867 mmol) and stirred the reaction mixture for 24 h. the Solvent was removed and the residue was purified column chromatography, obtaining tertbutyl 4-(2-(3-(fluorophenyl)-8-(pyridin-4-ylcarbonyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Serie-4-yl)piperazine-1-carboxylate (84;85 mg, yield 55%). MS (ESI) calc. for C27H30FN7O4: 535,57.

This General methodology could be used to obtain the number of derivatives of 4-aryl-8-substituted-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Serie-4-yl)substituted-1-carboxylate, substituting pyrimidine-4-amine to the corresponding amine. Alternatively, derivatives can also be obtained by interaction of the corresponding phenylcarbamate with 4-aryl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Serie-4-yl)substituted-1-carboxylate in n�outstay DIEA at a temperature from ambient to 50°C.

Stage 3. Synthesis of 2-(3-(fluorophenyl)-4-(piperazine-1-yl)-N-(pyridin-4-yl)-6H-pyrimido[5,4-b][1,4]oxazine Serie-8(7H)-carboxamide (Compound 738)

Tertbutyl 4-(2-(3-(fluorophenyl)-8-(pyridin-4-ylcarbonyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Serie-4-yl)piperazine-1-carboxylate (84; 85 mg,0,159 mmol) was added to 1N HCl (20 ml) and the mixture was stirred at room temp. in the course of the night. The solution frustrated vivid. NaHCO3and was extracted with EtOAc. The organics were combined, dried and concentrated. The residue was purified column chromatography, obtaining 2-(3-(fluorophenyl)-4-(piperazine-1-yl)-N-(pyridin-4-yl)-6H-pyrimido[5,4-b][1,4]oxazine Serie-8(7H)-carboxamide (Connection 738; 40 mg, yield 58%). MS (ESI) calc. for C22H22FN7O2: 435,18; found 436 [M+H].

Example 18. Getting 2,2-dimethyl-N-(pyridin-4-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)- carboxamide (Compound 560)

Stage 1. Synthesis of ethyl 2-((6-bromo-2-nitropyridine-3-yl)oxy)-2-methylpropanoate (86)

A mixture of 6-bromo-2-nitropyridine-3-ol (85; 3.28 g, 15 mmol), ethyl 2-bromo-2-methylpropanoate (3.51 g, 18 mmol) and K2CO3in dimethylformamide (30 ml) was stirred at room temp. for 48 h. water was Added and the mixture was extracted with EtOAc. The combined organic layers were washed with water and saturated brine, dried�, concentrated and was purified column chromatography, elwira a mixture of petroleum ether:EtOAc, yielding ethyl 2-((6-bromo-2-nitropyridine-3-yl)oxy)-2-methylpropanoate (86;1.3 g, yield 36%) as a solid yellow color. MS (ESI) calc. for C11H13BrN2O5: 333,14.

Stage 2. Synthesis of 6-bromo-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazine Serie-3(4H)-she (87)

A mixture of ethyl 2-((6-bromo-2-nitropyridine-3-yl)oxy)-2-methylpropanoate (86; 5.5 g, and 17.2 mmol) and powdered iron (5.2 g, 92 mmol) in SPLA (50 ml) was heated at 90 ° C for 2 h. the Hot solution was filtered through a layer of celite and concentrated. The residue was treated with saturated water. NaHCO3and was extracted with EtOAc. The combined organic layers were washed with saturated brine, concentrated, yielding 6-bromo-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazine Serie-3(4H)-he (87; 4.1 g, yield 92%) in the form of white solids. MS (ESI) calc. for C9H9BrN2O2: 257,08.

Stage 3. Synthesis of 6-bromo-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (88)

A solution of 6-bromo-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazine Serie-3(4H)-it (87; 4,4 g of 17.1 mmol) and BH3·Me2S (2.5 M in THF, 64 ml, 160 mmol) was heated at reflux for 24 h. After cooling portions was added to a solution of MeOH (10 ml) and boiled reactionary cm�camping for 30 min. Thereafter, the reaction mixture was concentrated, water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried (Na2SO4), filtered and concentrated and was purified column chromatography, elwira a mixture of ethyl acetate:petroleum ether, yielding 6-bromo-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (88;2.5 g, yield 57%) as a yellow oil. MS (ESI) calc. for C9H11BrN2About: 243,10; found 245 [M+H].

Stage 4. Synthesis of 2,2-dimethyl-6-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (89)

A mixture of 6-bromo-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (88; 1.0 g, 4,11 mmol), (3-(trifluoromethyl)phenyl)Bronevoy acid (1.2 g, 6,17 mmol), Pd(PPh3)4(250 mg, 0,21 mmol) and cesium carbonate (2.7 g, 8,22 mmol) in 1,2-dimethoxyethane (20 ml) and water (2 ml) was stirred at 100 ° C for 18 h. the Precipitate was filtered, and the filtrate was concentrated, obtaining a dark-colored precipitate, which was purified column chromatography, elwira a mixture of ethyl acetate:petroleum ether, yielding 2,2-dimethyl-6-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (89;1.13 g, yield 89%) as a solid almost white. MS (ESI) calc. for C16H15F3N2About: 308,30; found 309 [M+H].

This General technique can�about be used to obtain the number of derivatives of 2,2-dimethyl-6-aryl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie, replacing 3-(trifluoromethyl)phenylboronic the corresponding acid Bronevoy acid.

Stage 5. Synthesis of 2,2-dimethyl-N-(pyridin-4-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (compound 560)

To a solution of 2,2-dimethyl-6-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (89; 100 mg, 0,32 mmol) and triethylamine (0.16 ml, 1,13 mmol) in CH2Cl2(5 ml) was added triphosgene (48 mg, 0,16 mmol) and the mixture was stirred at room temp. for 30 min then was added pyridine-4-amine (92 mg, 0.97 mmol) and the mixture was stirred at room temp. in the course of the night. The reaction mixture was diluted with CH2Cl2and washed with water and saturated brine, dried (MgSO4), filtered and concentrated. The residue was purified by chromatography, yielding 2,2-dimethyl-N-(pyridin-4-yl)-6-(3-(trifluoromethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (The connection 560;40 mg, 29%). MS (ESI) calc. for C22H19F3N4O2: 428,15; found: 429 [M+H].

This General methodology could be used to obtain the number of derivatives of 2,2-dimethyl-N-substituted-6-aryl-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide, substituting pyrimidine-4-amine to the corresponding amine. Alternatively, derivatives can also be obtained by interaction of the corresponding fenil�of ramata with 2,2-dimethyl-6-aryl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie a in the presence of DIEA at a temperature from ambient to 50°C.

Example 19. The receipt (S)-6-(3-(3-ftorpirimidinu-1-yl)phenyl)-2,2-dimethyl-N-(5-methylpyridine-3-yl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (Compound 660)

Stage 1. Synthesis of (S)-1-(3-bromophenyl)-3-terpinolene (91)

To a solution of 1,3-dibromobenzene (90; 5 g, 21,20 mmol) and (S)-3-ftorpirimidinu hydrochloride (2,93 g, 23,31 mmol) in toluene (100 ml) was added BINAP (1,32 g, 2,12 mmol), Pd2(dba)3(0,97 g, 1.06 mmol) and Cs2CO3(6,93 g and 50.9 mmol). The reaction mixture was stirred at 121º for 10 h. the Mixture was concentrated and was purified column chromatography, obtaining (S)-1-(3-bromophenyl)-3-ftorpirimidinu (91; 3.5 g, 68%). MS (ESI) calc. for C10H11BrFN: 244,10.

Stage 2. Synthesis of (S)-3-(3-ftorpirimidinu-1-yl)phenylboronic acid (92)

To a solution of (S)-1-(3-bromophenyl)-3-terpinolene (91; 3.5 g, one-14.34 mmol) in THF (70 ml) was added n-BuLi (2.5 M solution in hexane, 12 ml, a 28.68 mmol) at-78º, the reaction mixture was stirred at the same temperature for 1 h and added dropwise trimethylboron (1,79 g, of 17.21 mmol). After the mixture was stirred at-78º for 30 min was added MeOH and the mixture was extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated. The residue was purified column chromatography, obtaining (S)-3-(3-ftorpirimidinu-1-yl)phenylboronic acid (92/b> ;940 mg, 31%). MS (ESI) calc. for C10H13BFN2: 209,03; found 210 [M+H].

Stage 3. Synthesis of (S)-6-(3-(3-ftorpirimidinu-1-yl)phenyl-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (93)

A mixture of compound 6-bromo-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (88; 350 mg, 1.44 mmol), (S)-3-(3-ftorpirimidinu-1-yl)phenylboronic acid (330 mg, 1,58 mmol), Pd(dppf)Cl2(60 mg, 0,072 mmol) and cesium carbonate (0,94 g, is 2.88 mmol) in 1,2-dimethoxyethane (10 ml) was stirred at 95 ° C overnight. The reaction mixture was purified by column chromatography, elwira a mixture of EtOAc:petroleum ether, yielding (S)-6-(3-(3-ftorpirimidinu-1-yl)phenyl-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (93;290 mg, yield 62%) as a solid almost white. MS (ESI) calc. for C19H22FN3About: 327,40; found 328 [M+H].

Stage 4. Synthesis of (S)-6-(3-(3-ftorpirimidinu-1-yl)phenyl)-2,2-dimethyl-N-(5-methylpyridine-3-yl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (Compound 660)

To a mixture of (S)-6-(3-(3-ftorpirimidinu-1-yl)phenyl-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (93; 65 mg, 0.2 mmol) and triethylamine (61 mg, 0.6 mmol) in THF (3 ml) was added triphosgene (24 mg, 0.08 mmol). The reaction mixture was stirred at room temperature for 1.5 hours was Added 5-methylpyridin-3-amine (43 mg, 0.4 mmol) and the reaction �rity stirred at 60 ° C for 18 h. Thereafter, the reaction mixture was washed with saturated sodium bicarbonate solution and water. The organic layer was concentrated and purified by chromatography, obtaining (S)-6-(3-(3-ftorpirimidinu-1-yl)phenyl)-2,2-dimethyl-N-(5-methylpyridine-3-yl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (Connection 660; 34 mg, 31%) as a solid yellow color. MS (ESI) calc. for C26H28FN5O2: 461,22; found: 462 [M+H].

(R)-6-(3-(3-ftorpirimidinu-1-yl)phenyl)-2,2-dimethyl-N-(5-methylpyridine-3-yl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (Compound 701)obtained by the method analogni described above for (S)-6-(3-(3-ftorpirimidinu-1-yl)phenyl)-2,2-dimethyl-N-(5-methylpyridine-3-yl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide, based on the enantiomer of the hydrochloride of (S)-3-terpinolene.

Example 20. Getting 2,2-dimethyl-N-(5-methylpyridine-3-yl)-6-(3-(pyrrolidin-1-ylmethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (Compound 629)

Stage 1. Synthesis of methyl 3-(2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie-6-yl)benzoate(94)

In a nitrogen atmosphere a mixture of compound 6-bromo-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (88; 1.5 g, 6.2 mmol), (3-(methoxycarbonyl)phenyl)Bronevoy acid (1.45 g, 8.0 mmol), Pd(dppf)Cl2(260 mg, 0,31 mmol) and cesium carbonate (4.0 g, 12,34 mmol) in dimethoxyethane (50 ml) was stirred at 90º over night. The reaction mixture was concentrated and purified by chromatography, elwira a mixture of EtOAc:petroleum ether, yielding methyl 3-(2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie-6-yl)benzoate(94;1.7 g, 92%) as a solid yellow color. MS (ESI) calc. for C17H18N2O3: 298,34.

Stage 2. Synthesis of methyl 3-(2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie-6-yl)benzoic acid(95)

To a solution of compound methyl 3-(2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie-6-yl)benzoate(94; 700 mg, 2.35 mmol) in a mixture of solvents MeOH:THF:H2About (5 ml:5 ml:3 ml) was added LiOH·H2About (200 mg, 4.7 mmol) and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated, added water (25 ml) and the pH was adjusted to 3-4 with concentrated hydrochloric acid. The precipitate was filtered and dried, yielding methyl 3-(2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie-6-yl)benzoic acid(95; 0.59 g, 84%) in the form of white solids. MS (ESI) calc. for C16H16N2O3: 284,31.

Stage 3. Synthesis of (3-(2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie-6-yl)phenyl)(pyrrolidin-1-yl)methanone (96)

Methyl 3-(2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie-6-yl)benzoic acid(95; 0.59 g, 2.1 �mol), pyrrolidine (300 mg, 4.2 mmol) and hexaflurophosphate 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylurea (HATU) (1.6 g, 4.2 mmol) was dissolved in N,N-dimethylformamide (DMF) (10 ml). Then added diisopropylethylamine (0.8 ml, 4.2 mmol) and stirred at room temp. in the course of the night. Then the reaction mixture was diluted with water and was extracted with EtOAc and the combined organic layers were washed with saturated sodium bicarbonate solution and with water and saturated brine, dried (Na2SO4) and concentrated. The residue was triturated with a mixture of EtOAc:petroleum ether, yielding (3-(2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie-6-yl)phenyl)(pyrrolidin-1-yl)methanon (96;0.49 g, 72%) as a solid yellow color. MS (ESI) calc. for C20H23N3O2: 337,42; found 338 [M+H].

Stage 4. Synthesis of 2,2-dimethyl-6-(3-(pyrrolidin-1-ylmethyl)phenyl)-)3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (97)

A mixture of (3-(2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie-6-yl)phenyl)(pyrrolidin-1-yl)methanone (96;0.49 g, 1,45 mmol) and BH3·Me2S (10 M in THF, 1.5 ml, 15 mmol) in THF (7.5 ml) was heated at reflux for 18 h. After cooling, was added to a solution of MeOH (10 ml) and kept boiling for 1 h. the Reaction mixture was concentrated and the residue was purified column chromatography, elwira a mixture of MeOH:CH2Clsub> 2getting 2,2-dimethyl-6-(3-(pyrrolidin-1-ylmethyl)phenyl)-)3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (97;0.36 g, 76%) as a semisolid substance. MS (ESI) calc. for C20H25N3About: 323,43; found: 324 [M+H].

Stage 5. Synthesis of 2,2-dimethyl-N-(5-methylpyridine-3-yl)-6-(3-(pyrrolidin-1-ylmethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (Compound 629)

To a mixture of 2,2-dimethyl-6-(3-(pyrrolidin-1-ylmethyl)phenyl)-)3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie (97;50 mg, 0,15 mmol) and triethylamine (61 mg, 0.6 mmol) in THF (3 ml) was added triphosgene (19 mg, 0,062 mmol) and stirred the reaction mixture at room temperature for 30 min. then added 5-methylpyridine-3-amine (25 mg, 0,23 mmol) and stirred the reaction mixture at 60 ° C over night. The reaction mixture was purified by chromatography, yielding 2,2-dimethyl-N-(5-methylpyridine-3-yl)-6-(3-(pyrrolidin-1-ylmethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (Connection 629;15 mg, 20%). MS (ESI) calc. for C27H31N5O2: 457,25; found: 458 [M+H].

This General methodology could be used to obtain the number of derivatives of 2,2-dimethyl-N-substituted-6-(3-(pyrrolidin-1-ylmethyl)phenyl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide, replacing 5-methylpyridine to the corresponding amine. Alternatively, derivatives can also be obtained mutually�deistvie corresponding phenylcarbamate with 2,2-dimethyl-6-(3-(pyrrolidin-1-ylmethyl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie a in the presence of DIEA at a temperature from ambient to 50°C.

Example 21. Getting 6-(3-((dimethylamino)methyl)phenyl)-2,2-dimethyl-N-(pyridin-3-yl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (Compound 677)

Stage 1. Synthesis of 3-(2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie-6-yl)-N,N-dimethylbenzamide (98)

Methyl 3-(2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie-6-yl)benzoic acid(95; 0.50 g, of 1.74 mmol), dimethylamine hydrochloride (710 mg, of 8.71 mmol) and HATU (1.3 g, of 3.42 mmol) was dissolved in DMF (10 ml). Then added diisopropylethylamine (562 mg, 4,36 mmol) and stirred at 30 ° C during the night. Then the reaction mixture was diluted with water and was extracted with EtOAc and the combined organic layers were washed with saturated sodium bicarbonate solution and with water and saturated brine, dried (Na2SO4) and concentrated. The residue was triturated with a mixture of EtOAc:petroleum ether, yielding 3-(2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie-6-yl)-N,N-dimethylbenzamide (98; 493 mg, 90%). MS (ESI) calc. for C18H21N3O2: 311,38; found 312 [M+H].

Stage 2. Synthesis of 1-(3-(2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie-6-yl)phenyl)-N,N-dimethylethanamine (99)

A mixture of 3-(2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie-6-yl)-N,N-dimethylbenzamide (98; 0.49 g, 1.56 mmol) and BH3·Me2S (10 M in THF, of 1.56 ml, 15.6 mmol) in THF (10 ml) nagrevaniya reflux for 18 h. After cooling, was added to a solution of MeOH (10 ml) and kept boiling for 1 h. the Reaction mixture was concentrated and the residue was purified column chromatography, elwira a mixture of MeOH:CH2Cl2getting 1-(3-(2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie-6-yl)phenyl)-N,N-dimethylethanamine (99;0.2 g, 43%). MS (ESI) calc. for C18H23N3About: 297,39; found: 298 [M+H].

Stage 3. Synthesis of 6-(3-((dimethylamino)methyl)phenyl)-2,2-dimethyl-N-(pyridin-3-yl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (Compound 677)

To a solution of 1-(3-(2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie-6-yl)phenyl)-N,N-dimethylethanamine (99; 50 mg, 0,15 mmol) and triethylamine (50 mg, 0.46 mmol) in THF (3 ml) was added triphosgene (18 mg, 0,062 mmol) and stirred the reaction mixture at room temperature for 30 min then was added pyridine-3-amine (42 mg, 0.46 mmol) and the mixture was stirred at 60 ° C over night. The reaction mixture was purified by chromatography, yielding 6-(3-((dimethylamino)methyl)phenyl)-2,2-dimethyl-N-(pyridin-3-yl)-2H-pyrido[3,2-b][1,4]oxazine Serie-4(3H)-carboxamide (Connection 677;15 mg, 23%). MS (ESI) calc. for C24H27N5O2: 417,22; found: 418 [M+H].

This General methodology could be used for a number of derivative 6-(3-((dimethylamino)methyl)phenyl)-2,2-dimethyl-N-substituted-2H-pyrido[,2-b][1,4]oxazine Serie-4(3H)-carboxamide, replacing pyridin-3-amine to the corresponding amine. Alternatively, derivatives can also be obtained by interaction of the corresponding phenylcarbamate with 1-(3-(2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Serie-6-yl)phenyl)-N,N-dimethylethanamine in the presence of N,N-diisopropylethylamine DIEA at a temperature from ambient to 50°C.

Example 22. Getting trifenatate salt 1-methyl-2-oxo-N-(thiazol-2-yl)-6-(3-(trifluoromethyl)phenyl)-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (Compound 520)

Stage 1. Synthesis of ethyl 2-(6-chloro-3-nitropyridine-2-ylamino)acetate (101)

Received by literary technique, similar toBioorganic and Med. Chem. Letters2006,16, 839-844. In a nitrogen atmosphere a mixture of 2,6-dichloro-3-nitropyridine (100; 50 g, 259 mmol) and ethyl 2-aminoacetate (29,34 g, 285 mmol), N,N-diisopropylethylamine (100,43 g, 777 mmol) in N,N-dimethylformamide (~0.1 M 2,6-dichloro-3-nitropyridine) was stirred at room temperature for 3 h, monitoring the reaction course was controlled by TLC. To the reaction mixture were added saturated sodium bicarbonate solution and was extracted with ethyl acetate (2 times) and the combined organic layers were washed with water and saturated brine, and then concentrated under vacuum to give a brown residue, which was purified by column chromatography, yielding ethyl 2-(6-chloro-3-�nitropyridine-2-ylamino)acetate ( 101; 42 g 50 g S. M, 66%) as a solid yellow color. MS (ESI) calc. for C9H10ClN3O4(m/z) 259,65.

Stage 2. Synthesis of ethyl 2-(3-nitro-6-(3-(trifluoromethyl)phenyl)pyridin-2-ylamino)acetate (102)

In a nitrogen atmosphere a mixture of ethyl 2-(6-chloro-3-nitropyridine-2-ylamino)acetate (101; 25 g, 93 mmol), (3-(trifluoromethyl)phenylboronic acid (19,6 g, 111,6 mmol), Pd(PPh3)4(3.8 g, 4,65 mmol) and cesium carbonate (66 g, 186 mmol) in 500 ml of 1,2-dimethoxyethane and 32 ml of water was stirred at 65 º C for 2 h. the Precipitate was filtered, and the filtrate was concentrated under vacuum to give a dark color residue, which was purified by column chromatography with the elution by the mixture ethyl acetate/petroleum ether =1:10, yielding ethyl 2-(3-nitro-6-(3-(trifluoromethyl)phenyl)pyridin-2-ylamino)acetate (102;31 g, 93.5 per cent) in the form of white solids. MS (ESI) calc. for C16H14F3N3O4: 369,30.

Stage 3. Synthesis of 6-(3-(trifluoromethyl)phenyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-she (104)

A suspension of ethyl 2-(3-nitro-6-(3-(trifluoromethyl)phenyl)pyridin-2-ylamino)acetate (102; 31 g, 9,54 mmol) and 3.0 g of wet Pd-C (wet, 50%) in 300 ml of methanol was gidrirovanie in the atmosphere of N2when the ambient temperature is within approximately 6 hours. Catalyst black filter was removed�lo g through celite, and the filtrate concentrated under vacuum to give a crude residue ethyl 2-(3-nitro-6-(3-(trifluoromethyl)phenyl)pyridin-2-ylamino)acetate (103; 35,6 g) almost white, which was used for next step without further purification.

Then ethyl 2-(3-nitro-6-(3-(trifluoromethyl)phenyl)pyridin-2-ylamino)acetate (103; 35,6 g) was dissolved in 300 ml of EtOH and stirred at reflux for 22 h. the Solvent was removed under reduced pressure, and the residue was submitted to column for flash chromatography using a mixture of ethyl acetate/petroleum ether=1:8 as eluent, yielding 6-(3-(trifluoromethyl)phenyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (104; 23 g, 83%) as a solid yellow color. MS (ESI) calc. for C14H10F3N3O(m/z) 293,24 found 294 [M+H].

Stage 4. Synthesis of 1-methyl-6-(3-(trifluoromethyl)phenyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-she (105)

To a solution of 6-(3-(trifluoromethyl)phenyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-it (104; 25,2 g, 86,0 mmol) in 400 ml of dry THF was added at 0 º Chexamethyldisilazide sodium(NaHMDS) (53,4 ml, 40% in THF, to 103.2 mmol). After addition the mixture was stirred at the same temperature for 0.5 h. To a solution of red-black colour was added CH3I and the mixture was stirred at room temperature over night. To the reaction mixture were added 100 ml of vivid�x NH 4Cl and 500 ml of water and was extracted with ethyl acetate (300 ml ×2) and combined organic layers were washed with water, saturated brine and dried, concentrated, obtaining the crude residue, which was purified column chromatography, obtaining 1-methyl-6-(3-(trifluoromethyl)phenyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he (105; 13,8 g, 52%) in the form of white solids. MS (ESI) calc. for C15H12F3N3O(m/z) 307,27 found 308[M+H].

Stage 5. Synthesis triptoreline salt 1-methyl-2-oxo-N-(thiazol-2-yl)-6-(3-(trifluoromethyl)phenyl)-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (Compound 520)

Had a similar literary technique, Gool et alTet Lett, 2008, 49, 7171-7173. 1-Methyl-6-(3-(trifluoromethyl)phenyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-he105and 2-aminothiazole were subjected to the General conditions of the formation of urea, in General terms described herein, and purified by HPLC in the elution MeOH and 0.1% TFA, yielding 1-methyl-2-oxo-N-(thiazol-2-yl)-6-(3-(trifluoromethyl)phenyl)-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide in the form of salt TFU (The connection 520; To 59.6 mg, 33%). MS (ESI) calc. for C19H14F3N5O2S·C2HO2F3(m/z) 547,43 found 434 [M+H].

This General methodology could be used to obtain the number of derivatives of 1-methyl-2-oxo-N-substituted-6-aryl-2,3-digitope�IDO[2,3-b]pyrazine-4(1H)-carboxamide, substituting 2-aminothiazole to the corresponding amine. Alternatively, derivatives can also be obtained by interaction of the corresponding phenylcarbamate with 1-methyl-6-aryl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-one in the presence of N,N-diisopropylethylamine (DIEA) at a temperature from ambient to 50°C.

Example 23. Getting trifenatate salt 1-methyl-N-(thiazol-2-yl)-6-(3-(trifluoromethyl)phenyl)-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (Compound 529)

Stage 1. Synthesis of 1-methyl-6-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (106)

A solution of 1-methyl-6-(3-(trifluoromethyl)phenyl-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-it (105;8.8 g, 28.6 mmol) and 9-BBN (32,21 g, 132 mmol) in 265 ml of THF was stirred at reflux for 4 h. the Solvent was removed under reduced pressure and the residue was purified column chromatography, obtaining an oily product (6.4 g, 81%). Then the crude product was triturated with pure petroleum ether, yielding 1-methyl-6-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (106; 2.8 g, 35%) in the form of white solids, and 3.3 g of crude oil containing the impurity of 9-BBN (42%). MS (ESI) calc. for C15H14F3N3(m/z) 293,29 found 294 [M+H].

Stage 2. Synthesis triptoreline salt 1-methyl-N-(thiazol-2-yl)-6-(3-(trifluoromethyl)phenyl)-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carb�xamiga (Compound 529)

Had a similar literary technique, Gool et alTet Lett, 2008, 49, 7171-7173. 1-Methyl-6-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine106and 2-aminothiazole were subjected to the General conditions of the formation of urea, in General terms described herein, and purified by HPLC in the elution MeOH and 0.1% TFA, yielding 1-methyl-N-(thiazol-2-yl)-6-(3-(trifluoromethyl)phenyl)-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide in the form of salt TFU (Compound 529; To 72.4 mg, 39%). MS (ESI) calc. for C19H14F3N5O2S·C2HO2F3(m/z) 547,43 found 434 [M+H].

This General methodology could be used to obtain the number of derivatives of 1-methyl-N-substituted-6-aryl-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide, substituting 2-aminothiazole to the corresponding amine. Alternatively, derivatives can also be obtained by interaction of the corresponding phenylcarbamate with 1-methyl-6-aryl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine in the presence of N,N-diisopropylethylamine (DIEA) at a temperature from ambient to 50°C.

Example 24. Obtaining N-(5-methylpyridine-3-yl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1.8-naphthiridine-1(2H)-carboxamide (Compound 585)

Stage 1. Synthesis tertbutyl 6-chloropyridin-2-ylcarbamate (108)

NaHMDS (351 ml, 0.7 mol) in THF (300 ml) was cooled to 0 ° C, probably�and a solution of 2-amino-6-chloropyridine ( 107; 40 g, 0,311 mol) in THF (300 ml), then a solution of distritbution (68 g, 0,311 mol) in THF, maintaining the internal temperature below 0OC. The resulting mixture was matured for 1 h at room temp., and then it was carefully acidified with to pH 3 by adding 1 M hydrochloric acid, was extracted with EtOAc, then the combined organic layers were successively washed with a saturated aqueous solution of NaHCO3and saturated brine, dried over Na2SO4, filtered, concentrated, obtaining the crude product. Triturated with ether, yielding the desired product tertbutyl 6-chloropyridin-2-ylcarbamate (108; 45 g, yield 63.4 per cent). MS (ESI) calc. for C10H13ClN2O2(m/z) 228,69.

Stage 2. Synthesis tertbutyl 7-chloro-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxylate (109)

To a stirred solution of tetramethylethylenediamine (TMEDA) (63,84 g, 0,549 mol) in THF (600 ml) at-20 ° C was added n-BuLi (220 ml, 0,549 mol, 2.5 M in hexane) over 10 min. the Solution was stirred at a temperature of from -20 to 10 ° C for 30 min, and then cooled to-78º. Within 15 min was added a solution of tertbutyl 6-chloropyridin-2-ylcarbamate (108; 57,0 g, 0,249 mol) in THF (300 ml). The resulting mixture was matured for 1 h, and then was added CuI (47,6 g, 0,249 mol) in one portion. The reaction mixture was allowed to warm to-10 ° C for one cha�and. Added pure 1-chloro-3-jumprope (76,5 g, 0,374 mol) for 1 min, ousted a cooling bath and let the reaction mixture to warm to temp. environment, after which it was boiled during the night. Upon completion of the reaction, the reaction mixture was cooled and quenched by adding saturated sodium bicarbonate solution. The aqueous layer was extracted with EtOAc, the combined organic layers were dried over Na2SO4was filtered through a small layer of silica gel, concentrated, obtaining the crude product. Triturated with ether, receiving tertbutyl 7-chloro-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxylate (109; 43 g, yield 67%). MS (ESI) calc. for C13H17ClN2O2(m/z) 268,74.

Stage 3. Synthesis of 7-chloro-1,2,3,4-tetrahydro-1,8-naphthiridine (110)

Tertbutyl 7-chloro-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxylate (109; 21 g, 0,078 mmol) was added to CF3COOH (100 ml) and stirred at CT during the night. The reaction mixture was concentrated and was dissolved in EA. Carefully added saturated aqueous solution of NaHCO3to pH=9. The aqueous layer was again extracted with EtOAc and the combined organic layers were dried over Na2SO4, filtered and concentrated, yielding 7-chloro-1,2,3,4-tetrahydro-1,8-naphthiridine (110; 12.9 g, yield 98%). MS (ESI) calc. for C8H9ClN2(m/z) 168,62.

Stage 4. Synthesis of 7-(3-(trifluoromethyl)�enyl)-1,2,3,4-tetrahydro-1,8-naphthiridine (111)

In a nitrogen atmosphere a mixture of 1,2,3,4-tetrahydro-1,8-naphthiridine (110; 1.2 g, 7.12 mmol) was dissolved in DME (40 ml) along with (3-(trifluoromethyl)phenylboronic acid (2,03 g, is 10.68 mmol), Cs2CO3(A 4.64 g, 14,24 mmol) and Pd(dppf)Cl2(297 mg, 0,356 mmol). The reaction mixture was stirred at 90 ° C overnight. The precipitate was filtered. Then the filtrate was diluted with N2About and was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over Na2SO4and then concentrated in vacuo. The residue was purified column chromatography, obtaining 7-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,8-naphthiridine (111;1.25 g, 63%). MS (ESI) calc. for C15H13F3N2(m/z) 278,27.

This General technique combinations could be used to obtain the number of derivatives of 7-aryl-1,2,3,4-tetrahydro-1,8-naphthiridine, substituting 3-(trifluoromethyl)phenylboronic the corresponding acid Bronevoy acid.

Stage 5. Synthesis of N-(5-methylpyridine-3-yl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxamide (Compound 585)

In a nitrogen atmosphere to a mixture of 7-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,8-naphthiridine (111;0,36 mmol, 1.0 EQ.) and TEM (0.15 ml, 1 mmol, 3.0 EQ.) in portions of anhydrous THF was added triphosgene (43 mg, 0,144 mmol, 0.4 to �sq). Then the above mixture was stirred at 30 ° C for 30 min until the disappearance of 7-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,8-naphthiridine (111) (monitoring by TLC). Added 5-methylpyridine-3-amine (0.36 mmol, 1.0 EQ.) and stirred the reaction mixture at 60 ° C for 18 hours. To the reaction mixture were added saturated sodium bicarbonate solution (5 ml) and methylene chloride (10 ml). The organic layer was washed with water (10 ml) and saturated brine, then dried over anhydrous Na2SO4and concentrated in vacuum. The crude product was purified by prep-TLC, yielding N-(5-methylpyridine-3-yl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxamide (Compound 585;40 mg, 27%). MS (ESI) calc. for C22H19F3N4Oh (m/z) 412,41.

3-(2,3-Dihydroxypropane)phenyl 7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxylate (Compound 641) and (3-(2,3-dihydroxypropane)phenyl)(7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-yl)methanon (The connection 642) was synthesized by methods described previously for theCompounds 562and518.

This General methodology could be used to obtain the number of derivatives of N-substituted-7-aryl-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxamide, replacing 5-methylpyridine-3-amine to the corresponding amine. Alternatively, derivatives can t�activate to get the cooperation of the relevant phenylcarbamate with 7-aryl-1,2,3,4-tetrahydro-1,8-naphthiridine in the presence of N,N-diisopropylethylamine (DIEA) at a temperature from ambient to 50°C.

Example 25. Getting 4-oxo-N-(pyridin-4-yl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxamide (Compound 719)

Stage 1. Synthesis tertbutyl 7-chloro-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxylate (112)

A mixture of 7-chloro-1,2,3,4-tetrahydro-1,8-naphthiridine (110; 6.0 g,3 a 5.7 mmol), BOC2About (15.6 g, 71.4 mmol) and 4-dimethylaminopyridine (DMAP) (13,1 g, 107.1 mmol) in THF (200 ml) was stirred at reflux overnight. According to TLC the reaction was completed, the mixture was poured into water. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give tertbutyl 7-chloro-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxylate (112;Is 8.74 g, 91%) in the form of white solids. MS (ESI) calc. for C13H17ClN2O2(m/z) 268,74.

Stage 2. Synthesis tertbutyl 7-(3-trifluoromethyl)phenyl-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxylate (113)

A mixture of tertbutyl 7-chloro-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxylate (112;7,74 g, 28,77 mmol), (3-(trifluoromethyl)phenylboronic acid (10,94 g 57,54 mmol), Pd(dppf)Cl2(2,35 g, is 2.88 mmol), Cs2CO3(18,72 g 57,54 mmol) and dioxane/N2About (10/1, about./about.) (165 ml) was stirred at 100 ° C overnight under an atmosphere of nitrogen. The solvent was removed and the residue was dissolved in EtOAc (200 ml). The solution was washed with nasyscennosti salt and dried over anhydrous Na 2SO4, filtered and concentrated. The residue was purified by chromatography on a column of silica gel (elwira a mixture of petroleum ether/ethyl acetate=10/1), getting tertbutyl 7-(3-trifluoromethyl)phenyl-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxylate (113;9,63 g, yield 89%) in the form of white solids. MS (ESI) calc. for C20H21F3N2O2: 378,16.

This General technique combinations could be used to obtain the number of derivatives of 7-aryl-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxylate, substituting 3-(trifluoromethyl)phenylboronic the corresponding acid Bronevoy acid.

Stage 3. Synthesis tertbutyl 4-oxo-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxylate (114)

A mixture of tertbutyl 7-(3-trifluoromethyl)phenyl-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxylate (113; 10.4 g, 27,51 mmol) and NaH2PO4(8,254 g, 68,78 mmol) in tert-BuOH (38,5 ml) and N2About (35,8 ml) was heated to 50 ° C, was then added dropwise NaMnO4/H2O (40%) (55,02 g), maintaining the temperature below 60C. Upon completion of addition of the permanganate, the reaction mixture was stirred at 50 ° C for 7 h (duration of reaction were determined using TLC plates and HRMS). Upon completion of the reaction to the cooled reaction mixture was carefully added solid Na2SO3until the disappearance of p�Burney color. The resulting suspension was filtered to remove manganese dioxide, and the filtrate was extracted with EtOAc (3×100 ml), the combined organic layers were washed with an aqueous solution of Na2CO3and saturated brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography on a column of silica gel (elwira a mixture of petroleum ether/ethyl acetate=6/1) to give tertbutyl 4-oxo-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxylate (114; 8.0 g, yield 74%). MS (ESI) calc. for C20H19F3N2O3: 392,13.

Stage 4. Synthesis of 7-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1,8-naphthiridine-1(2H)-she (115)

Tertbutyl 4-oxo-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxylate (114; 1.0 g, 2,55 mmol) was dissolved in a mixture of HCl/MeOH (10 ml, 3 N), then stirred at room temperature over night. The reaction mixture was concentrated and adjusted to pH ~ 10 by addition of aqueous Na2CO3. The resulting mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated, obtaining 7-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1,8-naphthiridine-1(2H)-he (115;0.85 g, yield 114%) in a solid yellow color. MS (ESI) calc. for C15H11F3N2About: 292,08; found: 293 [M+H].

p> Stage 5. Synthesis of 4-oxo-N-(pyridin-4-yl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxamide (Compound 719)

To a solution of 7-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1,8-naphthiridine-1(2H)-it (115;150 mg, 0,52 mmol) and triethylamine (of 0.28 ml, 2,06 mmol) in CH2Cl2(5 ml) was added triphosgene (152 mg, 0.52 mmol) and the mixture was stirred at room temperature for 30 min then was added pyridine-4-amine (144 mg, 0,15 mmol) and the mixture was stirred at room temperature over night. The reaction mixture was concentrated and purified by chromatography, yielding 4-oxo-N-(pyridin-4-yl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxamide (Connection 719; 15 mg, 7%). MS (ESI) calc. for C21H15F3N4O2: 412,11; found: 413 [M+H].

This General methodology could be used to obtain the number of derivatives of 4-oxo-N-substituted-7-aryl-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxamide, substituting 5-pyridin-4-amine to the corresponding amine. Alternatively, derivatives can also be obtained by interaction of the corresponding phenylcarbamate with 7-aryl-2,3-dihydro-1,8-naphthiridine-4(1H)-one in the presence of DIEA at a temperature from ambient to 50°C.

Example 26. 4,4-Debtor-N-(pyridin-4-yl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxamide (Compound 743)

Stage 1. Synthesis of 4,4-debtor-7-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,8-naphthiridine (116)

7-(3-(Trifluoromethyl)phenyl)-2,3-dihydro-1,8-naphthiridine-4(1H)-he (115; 1,46 g, 5 mmol) was treated with the TRIFLUORIDE diethylaminoethyl (DAST) (10 ml), then stirred at 30 ° C for 3 days. The reaction mixture was quenched with water (dropwise), was extracted with EtOAc (3×30 ml), the combined organic layers were washed with an aqueous solution of Panza3, saturated brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography on a column of silica gel (elwira a mixture of petroleum ether/ethyl acetate=10/1) to obtain 4,4-debtor-7-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,8-naphthiridine (116;759 mg, yield 50%). MS (ESI) calc. for C15H11F5N2: 314,08; found: 315 [M+H].

Stage 2. Synthesis of 4,4-debtor-N-(pyridin-4-yl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxamide (Compound 743)

Method And: To a mixture of 4,4-debtor-7-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,8-naphthiridine (116;50 mg, 0,16 mmol) in 3 ml dry THF was added in one portion, triethylamine (0,066 ml, 0.48 mmol), then triphosgene (19 mg, 0,064 mmol). The above mixture was stirred at 30 ° C for 1-2 hours and was added to the reaction mixture 4-aminopyridine (30 mg, 0.3 mmol, 2.0 EQ.) and stirred for another 20 hours. To the reaction mixture were added water and methylene chloride (10 ml); the organic layer is then washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuum. The crude product was purified by preparative TLC, yielding 4,4-debtor-N-(pyridin-4-yl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxamide (Connection 743;20 mg, 29%) as a solid pale yellow color. MS (ESI) calc. for C21H15F5N4About: 434,12; found: 435 [M+H].

Example 27. Obtaining 4,4-debtor-N-(pyridin-2-yl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxamide (Compound 814)

Method In: A mixture of 4,4-debtor-7-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,8-naphthiridine (116;50 mg, 0,16 mmol), phenyl pyridin-2-ylcarbamate (69 mg, 0,32 mmol) and 4-dimethylaminopyridine (DMAP) (23 mg, 0,192 mmol) in acetonitrile was heated in a sealed ampoule at 60 ° C for 18 h. the Crude product was purified by placing on a plate for preparative TLC, with elution by the mixture ethyl acetate/petroleum ether (1:8). There was obtained 4,4-debtor-N-(pyridin-2-yl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxamide (Connection 814) in the form of a solid pale yellow color. Yield: 60%. MS (ESI) calc. for C21H15F5 N4About: 434,12; found: 435 [M+H].

This General methodology could be used to obtain the number of derivatives of 4,4-debtor-N-substituted-7-aryl-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxamide, choosing the appropriate amine or phenylcarbamate.

Example 28. Obtaining 4,4-dimethyl-N-(pyridin-4-yl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxamide (Compound 826)

To a solution of 1,4-diaminopyridine (32,7 g, 0.3 mol, 3.0 EQ.) in dry THF (150 ml) and Et3N (35 ml, 0.25 mol, 2.5 EQ.) was added dropwise 3-methylbut-2-tailhold (12 g, 0.10 mol, 1.0 EQ.) for 10 min at 0OC. After addition, the reaction mixture was stirred at room temperature for one hour. The resulting mixture was poured in aqueous saturated sodium bicarbonate solution and was extracted with DCM (80 ml ×2). The combined organic layers were washed with water and saturated brine, and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was absorbed on silica gel and placed in a chromatographic column and suirable ethyl acetate and petroleum ether (1:5) to give N-(6-aminopyridin-2-yl)-3-methylbut-2-UNAMID in the form of white solids (10.7 g, 56%). MS (ESI) calc. for C10H13N3About: 191,23.

Stage 2. Synthesis of 7-amino-4,4-dimethyl-3,4-dihydro-1,8-nafti�idin-2(1H)-she (119)

In a nitrogen atmosphere to a solution of N-(6-aminopyridin-2-yl)-3-methylbut-2-enamide (118; Of 1.91 g, 10.0 mmol, 1.0 EQ.) in 20 ml of dry methylene chloride was added MeSO3H (2.85 g, 30.0 mmol, 3.0 EQ.), maintaining the temperature below 20ºC. The above mixture was added dropwise to a suspension of AlCl3(10.7 g, 80,0 mmol, of 8.0 EQ.) in 60 ml of dry DCM and controlled the temperature so that it was below 10 º C. After addition the reaction mixture was stirred at ambient temperature overnight. To the reaction mixture were added ice water (100 ml), stirred 10 min and podslushivaet aqueous NaOH (2n) to pH=8-10. The aqueous layer was extracted with DCM/MeOH (100:10) (2×50 ml), the combined organic layers were washed with water and saturated brine and evaporated under reduced pressure, obtaining a crude residue. The crude product was triturated with a mixture of ethyl acetate/petroleum ether=1:1, obtaining a precipitate of 7-amino-4,4-dimethyl-3,4-dihydro-1,8-naphthiridine-2(1H)-it (119; 1.25 g, 63%) of white color. MS (ESI) calc. for C10H13N3About: 191,23.

Stage 3. Synthesis of 7-chloro-4,4-dimethyl-3,4-dihydro-1,8-naphthiridine-2(1H)-she (120)

To a mixture of7-amino-4,4-dimethyl-3,4-dihydro-1,8-naphthiridine-2(1H)-it (119; 191 mg, 1.0 mmol, 1.0 EQ.) in 2 ml of concentrated hydrochloric acid at 0 ° C was added a solution of NaNO2 in water (386 mg/0.5 ml). After stirring for 30 min to the above mixture was added powdered CuCl (150 mg, 1.5 mmol) and stirred for 2 hours. To the reaction mixture were added water (5 ml) and brought to pH ~9-10 effect of NH4OH, and then was extracted with ethyl acetate (2×). The combined organic layers were washed with water, saturated brine and concentrated under vacuum to give solid yellow color. The crude product was loaded on a column for flash chromatography with silica gel using a mixture of ethyl acetate/petroleum ether=10:1 as eluent, yielding 7-chloro-4,4-dimethyl-3,4-dihydro-1,8-naphthiridine-2(1H)-he (120;105 mg, 50%) as a solid yellow color. MS (ESI) calc. for C10H11ClN2About: 210,06.

Stage 4. Synthesis of 7-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-1,8-naphthiridine (121)

In a nitrogen atmosphere to a stirred solution of 7-chloro-4,4-dimethyl-3,4-dihydro-1,8-naphthiridine-2(1H)-it (120; 1.9 g, 9,05 mmol, 1.0 EQ.) in 50 ml of dry THF was added BF3·Et2O (2.7 g, with 19.0 mmol, 2.1 EQ.) in one portion at 0 ° C. The mixture was stirred at 0 ° C for 10 min, then was added sodium borohydride (0,72 g, with 19.0 mmol, 2.1 EQ.) and stirred the reaction mixture at room temperature for 18 hours. To the reaction mixture were added ethyl acetate (20 ml), then probably�and dropwise 9 ml of 1 M HCl and the mixture was poured into saturated sodium bicarbonate solution and was extracted with ethyl acetate (2×60 ml). The combined organic layers were washed with water and saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, obtaining the crude product. The crude product was purified by trituration with petroleum ether, yielding 7-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-1,8-naphthiridine (121; 1.74 g, 98%)in the form of a solid yellow color. MS (ESI) calc. for C10H13ClN2: 196,68.

Stage 5. Synthesis of 4,4-dimethyl-7-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,8-naphthiridine (122)

In a nitrogen atmosphere a mixture of 7-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-1,8-naphthiridine (121; 1.0 g, 5.1 mmol, 1.0 EQ.), (3-(trifluoromethyl)phenylboronic acid (1.45 g, 7,65 mmol, 1.5 EQ.), Pd(dppf)Cl2(425 mg, 0,51 mmol, 0.10 equiv.) and cesium carbonate (4.1 g, of 12.75 mmol, 2.5 EQ.) in 20 ml of dimethoxyethane (DME) and 2 ml of water was stirred at 90 ° C overnight. The reaction mixture was absorbed on silica gel and purified flash chromatography with the elution by the mixture ethyl acetate/petroleum ether (1:20) to give 4,4-dimethyl-7-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,8-naphthiridine (122;Of 1.27 g, 81%). MS (ESI) calc. for C17H17F3N2: 306,33.

Stage 6. Synthesis of 4,4-dimethyl-N-(pyridin-4-yl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxamide (Compound 826)

�] And : A mixture of 4,4-dimethyl-7-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,8-naphthiridine (122;To 61.2 mg, 0.2 mmol), phenyl pyridin-4-ylcarbamate (65 mg, 0,03 mmol) and 4-dimethylaminopyridine (DMAP) (25 mg, 0.2 mmol) in acetonitrile was heated in a sealed ampoule at 60 ° C for 18 h. the Crude product was purified by placing on a plate for preparative TLC, with elution by the mixture ethyl acetate/petroleum ether (1:3). There was obtained 4,4-dimethyl-N-(pyridin-4-yl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxamide (Connection 826) in the form of white solids. The yield of 74%. MS (ESI) calc. for C23H21F3N4About: 426,17; found: 427 [M+H].

Example 29. Obtaining 4,4-dimethyl-N-(3-methylpyridine-4-yl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxamide (Connection 834)

Method In: To a mixture of 3-methylpyridine-4-amine (43,3 mg, 0.4 mmol) in 3 ml dry THF was added in one portion, triethylamine (0.3 ml), then triphosgene (47,5 mg, 0,16 mmol). The above mixture was stirred at 50 ° C for 2 hours and added to the reaction mixture of 4,4-dimethyl-7-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,8-naphthiridine (122;61,2 mg, 0,2 mmol) and stirred for 20 hours at 60'C. To the reaction mixture were added saturated sodium bicarbonate solution and methylene chloride (10 ml); the organic layer pic�we will now define was washed with water (10 ml) and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuum. The crude product was purified by preparative TLC, yielding 4,4-dimethyl-N-(3-methylpyridine-4-yl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxamide (Connection 834)in the form of a solid yellow color. The yield of 23%. MS (ESI) calc. for C24H23F3N4About: 440,18; found: 441 [M+H].

This General methodology could be used to obtain the number of derivatives of 4,4-dimethyl-N-(3-substituted-7-aryl-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxamide, choosing the appropriate amine or phenylcarbamate.

Example 30. Getting 4-methyl-N-(pyridin-4-yl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxamide (Compound 786)

Stage 1. Synthesis of 4-methyl-7-(3-(trifluoromethyl)phenyl)-1,2-dihydro-1,8-naphthiridine (124)

To a solution of tertbutyl 4-hydroxy-4-methyl-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxylate (123; 0.54 g, 1,32 mmol) in DCM (10 ml) was added trifluoroacetic acid (TFA) (10 ml). After 40 minutes, according to TLC the starting material disappeared. TFA and DCM were removed under vacuum. The residue was dissolved in EtOAc, which was washed with N2Oh, a saturated aqueous solution of Na2CO3and saturated brine, dried over anhydrous Na2SO4, filtered and concentrated, obtaining 4-methyl-7-(3-(triform�Teal)phenyl)-1,2-dihydro-1,8-naphthiridine in the form of a solid yellow color ( 124; 400 mg, quantitative yield). MS (ESI) calc. for C16H13F3N2About: 290,28.

Stage 3. Synthesis of 4-methyl-7-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,8-naphthiridine (125)

A mixture of 4-methyl-7-(3-(trifluoromethyl)phenyl)-1,2-dihydro-1,8-naphthiridine (124; 674 mg, of 2.33 mmol), Pd/C (150 mg) in THF (10 ml) was stirred under a pressure of H21 atmosphere during the night. After according to TLC the reaction was completed, the mixture was filtered and concentrated. The residue was purified by chromatography on a column of silica gel (elution with a mixture of petroleum ether/ethyl acetate=10/1) to obtain 4-methyl-7-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,8-naphthiridine in the form of white solids (125; 629 mg, yield 93%). MS (ESI) calc. for C16H15F3N2: 292,12; found: 293 [M+H].

Stage 4. Synthesis of 4-methyl-N-(pyridin-4-yl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxamide (Compound 786)

Method And: To a mixture of 4-aminopyridine (32 mg, 0.34 mmol) in 3 ml dry THF was added in one portion, triethylamine (0.5 ml), then triphosgene (33 mg, 0.11 mmol). The above mixture was stirred at room temp. for 3 h and added to the reaction mixture 4-methyl-7-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,8-naphthiridine (125; 50 mg, 0,17 mmol) and stirred even during� 18 hours at 60'C. To the reaction mixture were added water and the aqueous portion was extracted with methylene chloride (3×15 ml). The combined organic layers were washed with an aqueous solution of Na2CO3and saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative TLC, yielding 4-dimethyl-N-(pyridin-4-yl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxamide (Connection 786) in the form of white solids. MS (ESI) calc. for C22H19F3N4About: 412,15; found: 413 [M+H].

Example 31. Getting 4-methyl-N-(pyridin-2-yl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxamide (Compound 785)

Method In: A mixture of 4-methyl-7-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,8-naphthiridine (125; 40 mg, 0.14 mmol), phenyl pyridin-4-ylcarbamate (60 mg, 0.28 mmol) and DMAP (27 mg, 0,22 mmol) in acetonitrile was boiled overnight. The acetonitrile was removed by evaporation under reduced pressure. The residue was dissolved in chloride the methylene chloride and washed with an aqueous solution of Na2CO3and saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by placing on a plate for preparative TLC, yielding 4-methyl-N-(pyridin-2-yl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxamide (The connection 75 ) in the form of white solids. The yield of 21%. MS (ESI) calc. for C22H19F3N4About: 412,15; found: 413 [M+H].

This General methodology could be used to obtain the number of derivatives of 4-methyl-N-substituted-7-aryl-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxamide, choosing the appropriate amine or phenylcarbamate.

Example 32. Obtaining 2-(3-(chlorophenyl)-5-oxo-N-(pyridin-3-yl)-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxamide (Compound 747)

Stage 1. Synthesis tertbutyl 2-chloro-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxylate (127)

To a stirred solution of tetramethylethylenediamine (TMEDA) (5.6 g, 48,24 mmol) in THF (300 ml), cooled on an ice bath, was added n-BuLi (19.3 ml, 2.5 M in hexane, 48,24 mmol) within 5 min. After 20 min was added dropwise a solution of tertbutyl 6-chloropyridin-2-ylcarbamate (126; 5.0 g 21,88 mmol) over 5 min. the Reaction mixture was stirred for 1 hour and then was added CuI (4.2 g, 21,88 mmol) in one portion. The reaction mixture was allowed to warm to-20 ° C for 1 hour was Added 1-chloro-4-idbutton (7.2 g, 32,82 mmol) and the reaction mixture was left to warm to ambient temperature and then held at reflux for 18 h. then the reaction mixture was quenched by adding saturated sodium bicarbonate solution. The aqueous layer was extracted with EtOAc,then washed with water and saturated brine. The combined organic layers were concentrated, obtaining the crude product, which was triturated with petroleum ether, receiving tertbutyl 2-chloro-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxylate (127; 3.5 g, 56%)in the form of a solid pale yellow color. MS (ESI) calc. for C14H19ClN2O2: 282,77.

Stage 2. Synthesis tertbutyl 2-chloro-5-oxo-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxylate (128)

A mixture of tertbutyl 2-chloro-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxylate (127; 20.0 g, 70,92 mmol) and NaH2PO4·H2About (16.6 g, to 106.4 mmol) in tert-BuOH (300 ml) and N2(240 ml) was heated to 50 ºC. Added NaMnO4(aqueous 40%) (60 ml) and stirred the reaction mixture at 50 ° C. Monitoring of progress of the reaction was carried out by thin-layer chromatography (TLC). The reaction mixture was treated cautiously adding Na2SO3to the cooled reaction mixture until the disappearance of the purple colour, and then was extracted with EtOAc. The combined organic layers were washed with water and saturated brine, dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography, elwira a mixture of ethyl acetate:petroleum ether, receiving tertbutyl 2-chloro-5-oxo-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxylate (128;7.04 g, yield 37%) as a solid b�logo color. MS (ESI) calc. for C14H17ClN2O2: 296,75.

Stage 3. Synthesis tertbutyl 2-(3-chlorophenyl)-5-oxo-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxylate (129)

A mixture of tertbutyl 2-chloro-5-oxo-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxylate (128;7.0 g, the 23.6 mmol), 3-Chlorfenvinphos acid (9,23 g, 59,0 mmol), Pd(dppf)Cl2(1,97 g, 2.36 mmol), Cs2CO3(19.2 g, of 59.0 mmol) in a mixture of dioxane:H2Oh (10:1, by vol.:about.) (200 ml) was stirred at reflux for 18 h. Then the reaction mixture was extracted with EtOAc, washed with water and saturated brine. The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography, elwira a mixture of ethyl acetate:petroleum ether, yieldingtertbutyl 2-(3-chlorophenyl)-5-oxo-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxylate (129; 5.5 g, 63%) as a white solid. MS (ESI) calc. for C20H21ClN2O3: 372,85.

This General technique combinations could be used to obtain the number of derivatives tertbutyl 2-aryl-5-oxo-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxylate, substituting 3-Chlorfenvinphos the corresponding acid Bronevoy acid.

Stage 4. Synthesis of (3-chlorophenyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-5-she (130)

Tertbutyl 2-(3-chlorophenyl)-5-oxo-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxylate (129; 0.28 g, 0.75 mmol) was dissolved in HCl/MeOH (5 ml, 3n), then stirred at ambient temperature. The reaction mixture was concentrated, obtaining the crude (3-chlorophenyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-5-he (130; 202 mg, 87%) as an oil. MS (ESI) calc. for C15H13ClN2O: 272,73.

Stage 4.Obtaining 2-(3-(chlorophenyl)-5-oxo-N-(pyridin-3-yl)-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxamide (Compound 747)

To a solution of 3-aminopyridine (30 mg, 0,32 mmol) and triethylamine (0.3 ml, of 2.15 mmol) in THF was added triphosgene (76 mg, 0,26 mmol) in a nitrogen atmosphere and the mixture was stirred at 60 ° C for 2 h. Then was added (3-chlorophenyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-5-he (130; 50 mg, 0,16 mmol) and the mixture was stirred at 60 ° C over night. Added water and the mixture was extracted with CH2Cl2. The combined organic layers were washed with saturated brine and concentrated. The residue was purified by preparative thin layer chromatography, obtaining 2-(3-(chlorophenyl)-5-oxo-N-(pyridin-3-yl)-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxamide (Compound 747; 30 mg, 48%). MS (ESI) calc. for C21H17ClN4O2: 392,10; found: 393 [M+H].

This General methodology could be used to obtain �poison derivatives of 2-aryl-5-oxo-N-substituted-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxamide, replacing pyridin-3-amine to the corresponding amine. Alternatively, derivatives can also be obtained by interaction of the corresponding phenylcarbamate with 2-aryl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-5-one in the presence of DIEA at a temperature from ambient to 50°C.

Example 33. Obtaining 2-(3-(chlorophenyl)-6,6-dimethyl-N-(4-thiazole-2-yl)-5-oxo-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxamide (Compound 836)

Stage 1. Synthesis tertbutyl 2-(3-(chlorophenyl)-6,6-dimethyl-5-oxo-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxylate (131)

To a solution of tertbutyl 2-(3-chlorophenyl)-5-oxo-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxylate (129; 1,75 g, 4,70 mmol) in THF (63 ml) was added tert-BuOK (5,26 g, is 47.0 mmol). The mixture was stirred at-40OC for 1 h. then was added a CH3I (2,34 ml of 37.6 mmol) and the mixture was stirred at-40OC for 1 h and at room temperature for 2 hours was Added a saturated solution of NH4Cl and the aqueous layer extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography, elwira a mixture of ethyl acetate:petroleum ether, receiving tertbutyl 2-(3-(chlorophenyl)-6,6-dimethyl-5-oxo-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxylate (131; 703 mg, 37%) as a yellow oil. MS (ESI) calc. for C22H25ClN2O 3: 400,90.

Stage 2. Synthesis of 2-(3-(chlorophenyl)-6,6-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-5-she (132)

Tertbutyl 2-(3-(chlorophenyl)-6,6-dimethyl-5-oxo-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxylate (131; 1.2 g, 3.0 mmol) was dissolved in HCl/MeOH (30 ml, 3n), then stirred at room temperature over night. The reaction mixture was concentrated, then added NaHCO3to bring the pH=10. The resulting mixture was extracted with EtOAc and washed with saturated brine. The organic layers were dried (Na2SO4), filtered and concentrated, obtaining 2-(3-(chlorophenyl)-6,6-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-5-he (132;890 mg, 99%) as a solid yellow color. MS (ESI) calc. for C17H17ClN2O: 300,78; found: 301 [M+H].

Stage 3.Synthesis of 2-(3-(chlorophenyl)-N-(3-herperidin-4-yl)-6,6-dimethyl-5-oxo-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxamide (Compound 836)

To a solution of 3-herperidin-4-amine (38 mg, 0.33 mmol) and triethylamine (0.3 ml, 2,11 mmol) in THF (5 ml) was added triphosgene (40 mg, 0.13 mmol) in a nitrogen atmosphere and the mixture was stirred at 50 ° C for 2 h. Then was added 2-(3-(chlorophenyl)-6,6-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-5-he (132; 50 mg, 0,17 mmol) and the mixture was stirred at 60 ° C for 18 h. To the reaction mixture approx�ulali saturated sodium bicarbonate solution and EtOAc. The combined organic layers were washed with saturated brine and dried (Na2SO4), filtered and concentrated. The residue was purified by preparative thin layer chromatography, obtaining 2-(3-(chlorophenyl)-N-(3-herperidin-4-yl)-6,6-dimethyl-5-oxo-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxamide (Connection 837;6.3 mg, 9%)in the form of white solids. MS (ESI) calc. for C23H20ClFN4O2: 438,13; found: 439 [M+H].

This General methodology could be used to obtain the number of derivatives of 2-aryl-N-substituted-6,6-dimethyl-5-oxo-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxamide, replacing 3-herperidin-4-amine to the corresponding amine. Alternatively, derivatives can also be obtained by interaction of the corresponding phenylcarbamate with 2-aryl-6,6-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine in the presence of DIEA at a temperature from ambient to 50°C.

Example 34. Obtaining 2-(3-(chlorophenyl)-N-(pyridin-4-yl)-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxamide (Compound 728)

Stage 1. Synthesis tertbutyl 2-(3-(chlorophenyl)-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxylate (133)

A mixture of tertbutyl 2-chloro-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxylate (127;1 g, was 3.54 mmol), 3-Chlorfenvinphos acid (1.1 g, was 7.08 mmol), Pd(dppf)Cl2(295 mg, 0.35 mmol), Cs2 CO3(2.3 g, was 7.08 mmol) in a mixture of 1,4-dioxane:H2Oh (10:1, 15 ml) was heated at 110 ° C. overnight. The reaction mixture was concentrated and purified by chromatography, elwira a mixture of ethyl acetate:petroleum ether, yieldingtertbutyl 2-(3-(chlorophenyl)-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxylate (133;1.15 g, 90%) as a semisolid substance. MS (ESI) calc. for C20H23ClN2O2: 358,86.

This General technique combinations could be used to obtain the number of derivatives tertbutyl 2-aryl-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxylate, substituting 3-Chlorfenvinphos the corresponding acid Bronevoy acid.

Stage 2. Synthesis of 2-(3-chlorophenyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine (134)

Solution tertbutyl 2-(3-(chlorophenyl)-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxylate (133;790 mg, 2.2 mmol)in HCl/MeOH (3n, 10 ml) was stirred at room temperature over night. The reaction mixture was concentrated, obtaining 2-(3-chlorophenyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin (134;859 mg, 100%) in the form of white solids. MS (ESI) calc. for C15H15ClN2: 258,75.

Stage 2. Synthesis2-(3-chlorophenyl)-N-(pyridin-4-yl)-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxamide (Compound 728)

A mixture of 2-(3-chlorphen�l)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine ( 134;75 mg, 0.25 mmol), triphosgene (60 mg, 0.20 mmol) and triethylamine (0.3 ml, of 2.15 mmol) in THF (2 ml) was heated at 50 ° C for 30 min Then was added pyridine-4-amine (28 mg, 0.25 mmol) and the mixture was heated at 50 ° C for 3 h. the Mixture was concentrated and was purified preparative thin-layer chromatography, obtaining 2-(3-(chlorophenyl)-N-(pyridin-4-yl)-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxamide (Connection 728; 36,8 mg, 39%)in the form of a solid yellow color. MS (ESI) calc. for C21H19ClN4About: 378,12; found: 379 [M+H].

This General methodology could be used to obtain the number of derivatives of 2-aryl-N-substituted-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxamide, substituting pyridin-4-amine to the corresponding amine. Alternatively, derivatives can also be obtained by interaction of the corresponding phenylcarbamate with 2-aryl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine in the presence of DIEA at a temperature from ambient to 50°C.

Example 35. Obtaining 2-(3-(chlorophenyl)-5,5-debtor-N-(pyrimidine-4-yl)-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxamide (Compound 799)

Stage 1. Synthesis tertbutyl 2-(3-(chlorophenyl)-5,5-debtor-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxylate (135)

A mixture of tertbutyl 2-(3-chlorophenyl)-5-oxo-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxylate (129; 100 mg, 0.27 mmol) and the trift�the reed diethylaminoethyl (DAST) (2 ml) was stirred at room temperature for 3 days, and then when 44º for 3 days. Was slowly added water and the mixture was extracted with CH2Cl2. As a result of purification by chromatography with the elution by the mixture ethyl acetate:petroleum ether, yieldingtertbutyl 2-(3-(chlorophenyl)-5,5-debtor-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxylate (135; 75 mg, 70%). MS (ESI) calc. for C20H21ClF2N2O2: 394,84.

Stage 2. Synthesis of 2-(3-(chlorophenyl)-5,5-debtor-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine (136)

Solution tertbutyl 2-(3-(chlorophenyl)-5,5-debtor-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxylate (135; 1.16 g, to 2.94 mmol)in HCl/MeOH (3n, 25 ml) was stirred at room temperature over night. The reaction mixture was washed with a solution of NaHCO3, was extracted with EtOAc and concentrated, obtaining 2-(3-(chlorophenyl)-5,5-debtor-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin (136;808 mg, 93%). MS (ESI) calc. for C15H13ClF2N2: 294,73.

Stage 3. Synthesis2-(3-(chlorophenyl)-5,5-debtor-N-(pyrimidine-4-yl)-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxamide (Compound 799)

It chilled with ice to a solution of pyrimidine-4-amine (5.0 g, for 52.6 mmol), triethylamine (15 ml, to 107.6 mmol) in THF (100 ml) was added phenylcarbamate (10.7 g and 68.4 mmol). The reaction mixture was stirred at room temperature for 18 h. For�eat the reaction mixture was quenched with a solution of NaHCO 3and was extracted with CH2Cl2. The combined organic layers were washed with water and saturated brine, dried (Na2SO4), filtered and concentrated. The residue was triturated with petroleum ether, yielding crude phenylpyrimidine-4-ylcarbamate. Solution phenylpyrimidine-4-ylcarbamate (73 mg, 0.34 mmol), 2-(3-(chlorophenyl)-5,5-debtor-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine (136; 50 mg, 0,17 mmol) and DMAP (25 mg, 0.20 mmol) in MeCN (5 ml) was stirred at 80 ° C for 18 h. the Reaction mixture was purified by preparative thin layer chromatography, obtaining 2-(3-(chlorophenyl)-5,5-debtor-N-(pyrimidine-4-yl)-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxamide (Connection 799; 35 mg, 50%) in the form of white solids. MS (ESI) calc. for C20H16ClF2N5About: 415,10; found: 416 [M+H].

This General methodology could be used to obtain the number of derivatives of 2-aryl-5,5-debtor-N-substituted-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxamide, replacing phenylpyrimidine-4-ylcarbamate to the appropriate phenylcarbamate.

Example 36. Getting 7-(3-(chlorophenyl)-1-ethyl-2-oxo-N-(pyridin-2-yl)-3,4-dihydro-1H-pyrido[2,3-b][1,4]diazepin-5(2H)-carboxamide (Compound 765)

Stage 1. Synthesis of ethyl 3-((6-chloro-3-nitropyridine-2-yl)amino)propanoate (138)

A mixture of 2,6-dichloro-3-nitropyridine (137; 1.92 g, 10 mmol), ghidrah�orida ethyl 3-aminopropanoic (1.7 g, 11 mmol) and diisopropylethylamine (3.9 g, 30 mmol) in dimethylformamide (10 ml) was stirred at room temperature over night. Monitored the progress of the reaction by TLC. A solution of NaHCO3was added to the reaction mixture, which then was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, and then concentrated, yielding ethyl 3-((6-chloro-3-nitropyridine-2-yl)amino)propanoate (138; 2.8 g, 100%) as oil pale yellow color. MS (ESI) calc. for C10H12ClN3O4: 273,67.

Stage 2. Synthesis of 7-chloro-4,5-dihydro-1H-pyrido[2,3-b][1,4]diazepin-2(3H)-she (139)

A mixture of ethyl 3-((6-chloro-3-nitropyridine-2-yl)amino)propanoate (138; 39 g, 143 mmol) and Pd/C (3.9 g) in EtOAc (800 ml) was stirred under hydrogen atmosphere (2.5 ATM) for 16 h. the resulting mixture was filtered through a layer of celite and purified by chromatography, getting a solid dark color, which was used for next step without further purification. Solid dark color was dissolved in Acoh (1000 ml) and stirred at 130 º C during the night. Acoh was removed under reduced pressure. The residue was dissolved in EtOH, was added activated charcoal and stirred at 60 ° C for 3 h, then was filtered. The crude substance is recrystallized, yielding 7-chloro-4,5-dihydro-1H-pyrido[2,3-b][,4]diazepin-2(3H)-he ( 140; 6.8 g, 24%) as a solid gray color. MS (ESI) calc. for C8H8ClN3About: 197,62.

Stage 3. Synthesis of 7-(3-chlorophenyl)-4,5-dihydro-1H-pyrido[2,3-b][1,4]diazepin-2(3H)-she (141)

A mixture of compound 7-chloro-4,5-dihydro-1H-pyrido[2,3-b][1,4]diazepin-2(3H)-it (140; Of 1.97 g, 10 mmol), (3-chlorophenyl)Bronevoy acid (1.88 g, 12 mmol), Pd(PPh3)4(577 mg, 0.5 mmol) and cesium carbonate (6.5 g, 20 mmol) in 1,2-dimethoxyethane (50 ml) and water (3 ml) was stirred at 65 º C during the night. The precipitate was filtered, and the filtrate was concentrated, obtaining a solid dark color, which was dissolved in CH2Cl2and was extracted with water. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was triturated with methanol, obtaining 7-(3-chlorophenyl)-4,5-dihydro-1H-pyrido[2,3-b][1,4]diazepin-2(3H)-he (1.9 g, 62%)in the form of a solid yellow color. The supernatant trituration was concentrated and purified by chromatography, elwira a mixture of ethyl acetate:petroleum ether, yielding another 1.1 g of 7-(3-chlorophenyl)-4,5-dihydro-1H-pyrido[2,3-b][1,4]diazepin-2(3H)-it (141).MS (ESI) calc. for C14H12ClN3O: 273,72.

This General methodology could be used to obtain the number of derivatives of 7-aryl-4,5-dihydro-1H-pyrido[2,3-b][1,4]diazepin-2(3H)-she, substituting 3-Chlorfenvinphos acid on with�testwuide Bronevoy acid.

Stage 4. Synthesis of 7-(3-chlorophenyl)-1-ethyl-4,5-dihydro-1H-pyrido[2,3-b][1,4]diazepin-2(3H)-she (142)

To a solution of 7-(3-chlorophenyl)-4,5-dihydro-1H-pyrido[2,3-b][1,4]diazepin-2(3H)-it (141; 168 mg, 0,63 mmol) in THF (3 ml) was added tert-BuOK (84 mg, 0,75 mmol) and stirred the reaction mixture for 1 h. then was added EtI (0,055 ml of 0.68 mmol), stirred at room temperature over night. The reaction mixture was concentrated and the residue was dissolved in EtOAc. The resulting solution was filtered, and the filtrate concentrated. The residue was purified by preparative thin layer chromatography, obtaining 7-(3-chlorophenyl)-1-ethyl-4,5-dihydro-1H-pyrido[2,3-b][1,4]diazepin-2(3H)-he (142;160 mg, 86%) as a semisolid substance yellow. MS (ESI) calc. for C16H16ClN3About: 301,77.

Stage 5.Synthesis of 7-(3-(chlorophenyl)-1-ethyl-2-oxo-N-(pyridin-2-yl)-3,4-dihydro-1H-pyrido[2,3-b][1,4]diazepin-5(2H)-carboxamide (Compound 765)

Solution vinylpyridin-2-ylcarbamate (71 mg, 0.33 mmol), 7-(3-chlorophenyl)-1-ethyl-4,5-dihydro-1H-pyrido[2,3-b][1,4]diazepin-2(3H)-it (142; 50 mg, 0,17 mmol) and 4-dimethylaminopyridine (DMAP) (20 mg, 0,17 mmol) in MeCN (3 ml) was stirred at reflux overnight. The reaction mixture was concentrated and was purified preparative thin-layer chromatography, yielding 7-(3-(chlorophenyl)-1-ethyl-2-oxo-N-(p�ridin-2-yl)-3,4-dihydro-1H-pyrido[2,3-b][1,4]diazepin-5(2H)-carboxamide ( Connection 765; 31 mg, 44%)in the form of white solids. MS (ESI) calc. for C22H20ClN5O2: 421,13; found: 422 [M+H].

This General methodology could be used to obtain the number of derivatives of 7-aryl-1-ethyl-2-oxo-N-substituted - 3,4-dihydro-1H-pyrido[2,3-b][1,4]diazepin-5(2H)-carboxamide, substituting pyridine-2-ylcarbamate to the appropriate phenylcarbamate.

Example 37. Getting 7-(3-(chlorophenyl)-1-ethyl-N-(pyridin-3-yl)-3,4-dihydro-1H-pyrido[2,3-b][1,4]diazepin-5(2H)-carboxamide (Compound 789)

Stage 1. Synthesis of 7-(3-chlorophenyl)-1-ethyl-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepine (143)

To a solution of 7-(3-chlorophenyl)-1-ethyl-4,5-dihydro-1H-pyrido[2,3-b][1,4]diazepin-2(3H)-it (142; 80 mg, 0.5 mmol) in THF (3 ml) was added BH3·Me2S (1 ml, 3 mmol) at 0OC and stirred at room temperature over night. To the reaction mixture was added 1N HCl, stirred for 30 min. Then brought to pH 8 the action of a saturated solution of NaHCO3and the mixture was extracted with EtOAc. The organic layer was dried (Na2SO4), filtered, concentrated and purified preparative thin-layer chromatography, yielding 7-(3-chlorophenyl)-1-ethyl-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin (143;48 mg, 64%) as a solid. MS (ESI) calc. for C16H18ClN3: 287,79.

Stage 2. Synthesis of 7-(3-(chlorophenyl)-1-ethyl-N-(pyridin-3-yl)-3,4-dihydro-1H-pyrido[2,3-b][1,4]diazepin-5(2H)-carboxamide (Compound 789)

To a solution of pyridin-3-amine (34 mg, 0.36 mmol) and triethylamine (0.1 ml, to 0.72 mmol) in THF (3 ml) was added triphosgene (42 mg, 0.14 mmol) in a nitrogen atmosphere and the mixture was stirred at 60 ° C for approximately 4 h. Then was added 7-(3-chlorophenyl)-1-ethyl-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin (143;50 mg, 0,18 mmol) and the mixture was stirred at 60 ° C over night. To the reaction mixture were added saturated sodium bicarbonate solution and EtOAc and the aqueous layer extracted with EtOAc. The combined organic layers were washed with saturated brine and concentrated. The residue was purified by preparative thin layer chromatography, obtaining 7-(3-(chlorophenyl)-1-ethyl-N-(pyridin-3-yl)-3,4-dihydro-1H-pyrido[2,3-b][1,4]diazepin-5(2H)-carboxamide (Connection 789; 34 mg, 47%)in the form of semi-solids yellow. MS (ESI) calc. for C22H22ClN5About: 407,15; found: 408 [M+H].

This General methodology could be used to obtain the number of derivatives of 7-aryl-1-ethyl-N-substituted-3,4-dihydro-1H-pyrido[2,3-b][1,4]diazepin-5(2H)-carboxamide, replacing pyridin-3-amine to the corresponding amine. Alternatively, derivatives can also be obtained by interaction of the corresponding phenylcarbamate � 7-aryl-1-ethyl-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepine in the presence of DIEA at a temperature from ambient to 50°C.

Example 38. Obtaining N-(pyridin-4-yl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrido[3,2-b][1,4]oxazepine-5(2H)-carboxamide (Compound 558)

Stage 1. Synthesis of 6-bromo-3-(3-bromopropane)-2-nitropyridine (145)

To a cooled (0OC) solution of triphenylphosphine (3,93 g, 15 mmol) in THF (22 ml) was added dropwise DIAD (3.0 g, 15 mmol). The reaction mixture was stirred for 30 min and then added to her 6-bromo-2-nitropyridine-3-ol (2,19 g, 10 mmol) and 3-bromopropane-1-ol (2.1 g, 15 mmol) in THF (18 ml). The reaction mixture was allowed to warm to room temperature and stirred for about 2 h. then the reaction mixture was concentrated and partitioned the residue between EtOAc and water. The organic layer was washed with water and saturated brine, dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography, elwira a mixture of ethyl acetate:petroleum ether, yielding6-bromo-3-(3-bromopropane)-2-nitropyridine (1.18 g, 35%) as a yellow oil. MS (ESI) calc. for C8H8Br2N2O3: 339,97.

Stage 2. Synthesis of 6-bromo-3-(3-bromopropane)pyridin-2-amine (146)

A mixture of 6-bromo-3-(3-bromopropane)-2-nitropyridine (145; 1.18 g, 3,47 mmol) and powdered Fe (0.78 g, for 13.88 mmol) in Acoh (10 ml) was stirred at 90 ° C for 2 h. Then the reaction mixture was cooled� to room temperature, added EtOAc and the mixture was filtered. The filtrate was concentrated and purified by chromatography, elwira a mixture of ethyl acetate:petroleum ether, yielding6-bromo-3-(3-bromopropane)pyridin-2-amine (146;600 mg, 56%) in the form of white solids. MS (ESI) calc. for C8H10Br2N2O: 309,99.

Stage 3. Synthesis of 7-bromo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine (147)

To a stirred solution of 6-bromo-3-(3-bromopropane)pyridin-2-amine (146;5 g, 16,13 mmol) in DMF (500 ml) was added NaH (1.29 g, of 32.3 mmol, suspended in mineral oil) at 0OC. The reaction mixture was stirred at 100 ° C for 1 hour was Added a saturated solution of NH4Cl and water and the mixture was extracted with methylene chloride. The combined organic layers were washed with water and saturated brine, dried (Na2SO4) and concentrated. Put a second download of the same experience and cleansed the combined crude substances by chromatography, elwira a mixture of ethyl acetate:petroleum ether, yielding7-bromo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine (147; 5.9 g, 80%) in the form of white solids. MS (ESI) calc. for C8H9BrN2O: 229,07.

Stage 4. Synthesis of 7-(3-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine (148)

A mixture of 7-bromo-2,3,4,5-tetrahydro�pyrido[3,2-b][1,4]oxazepine ( 147; 1.2 g, 5,24 mmol), (3-(trifluoromethyl)phenyl)Bronevoy acid (1.5 g, 7,86 mmol), PdCl2(dppf) (218 mg, 0,26 mmol) and cesium carbonate (3.4 g, 10.5 mmol) in 1,4-dioxane (20 ml) was heated at 80 ° C in a nitrogen atmosphere for 4 h. the Reaction mixture was concentrated and purified by chromatography, elwira a mixture of ethyl acetate:petroleum ether, yielding7-(3-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine (148;1.3 g, 84%). MS (ESI) calc. for C15H13F3N2O: 294,27.

This General technique combinations could be used to obtain the number of derivatives of 7-aryl-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine, replacing (3-(trifluoromethyl)phenyl)Bronevoy the corresponding acid Bronevoy acid.

Stage 5. Synthesis of N-(pyridin-4-yl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrido[3,2-b][1,4]oxazepine-5(2H)-carboxamide (Compound 558)

To a solution of 7-(3-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine (148;100 mg, 0,34 mmol) and triethylamine (0,17 ml, 1,19 mmol) in CH2Cl2(5 ml) was added triphosgene (50 mg, 0,17 mmol) and the mixture was stirred at room temperature for 30 min Then was added pyridine-4-amine(96 mg, of 1.02 mmol) and the mixture was stirred at room temperature over night. The reaction mixture was diluted with CH2Cl2and washed with water and saturated R�the target salt, was dried (MgSO4), filtered and concentrated. The residue was purified by chromatography, yielding N-(pyridin-4-yl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrido[3,2-b][1,4]oxazepine-5(2H)-carboxamide (Compound 558; 10 mg, 7%). MS (ESI) calc. for C21H17F3N4O2: 414,13; found: 415 [M+H].

This General methodology could be used to obtain the number of derivatives of N-substituted-7-aryl-3,4-dihydropyrido[3,2-b][1,4]oxazepine-5(2H)-carboxamide, substituting pyridin-4-amine to the corresponding amine. Alternatively, derivatives can also be obtained by interaction of the corresponding phenylcarbamate with 7-aryl-2,3,4,5-tetrahydropyrido[3,2-b][1,4]diazepine in the presence of DIEA at a temperature from ambient to 50°C.

Example 39. Obtaining N-(pyridin-2-yl)-6-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-pyrrol[2,3-b]pyridine-1-carboxamide (Compound 861)

Stage 1. Synthesis of 1H-pyrrol[2,3-b]pyridine-7-oxide (150)

To a solution of 1H-pyrrol[2,3-b]pyridine (149; 20 g, 170 mmol) in CH2Cl2(300 ml) was added a suspension of m-CPBA (73 g, 430 mmol) and CH2Cl2(20 ml) for 30 min at 0OC. The reaction was warmed to room temperature and stirred for 3 h. the results of chromatography TLC plates the reaction was complete, the reaction mixture was concentrated. The residue was dissolved in MeOH (200 ml) and dobavlenny solution To 2CO3(100 ml), then stirred for 30 min and was filtered, the filtrate was concentrated and the obtained residue was triturated with CH2Cl2/MeOH (10/1), filtered and the solvent was removed. The residue was purified by chromatography on a column of silica gel (elution with a mixture of CH2Cl2/MeOH = 10/1 to 5/1) to give the crude product, which was triturated with Et2O, getting 1H-pyrrol[2,3-b]pyridine-7-oxide in the form of a solid yellow color (150; 9.5 g, purity 80%, yield 35%).MS (ESI) calc. for C7H6N2About: 134,14.

Stage 2. Synthesis of methyl 6-chloro-1H-pyrrol[2,3-b]pyridine-1-carboxylate (151)

To a solution of 1H-pyrrol[2,3-b]pyridine-7-oxide (150; 8.9 g, 66 mmol) and hexamethyldisilazane (HMDS) (10,65 ml, 66 mmol) in THF (300 ml) was added dropwise ClCO2Me (15,7 g, 166 mmol) in an atmosphere of N2at room temperature. After stirring for 1 h at the same temperature the solvent was removed and the residue was dissolved in EtOAc. EtOAc was washed with a saturated aqueous solution of NaHCO3(3×30 ml) and saturated brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by chromatography on a column of silica gel (elution with a mixture of petroleum ether/ethyl acetate=10/1), gettingmethyl 6-chloro-1H-pyrrol[2,3-b]pyridine-1-carboxylate (151;3.25 g, yield 2%). MS (ESI) calc. for C9H7ClN2O2: 210,67.

Stage 3. Synthesis of 6-(3-(trifluoromethyl)phenyl)-1H-pyrrol[2,3-b]pyridine (152)

A mixture of methyl 6-chloro-1H-pyrrol[2,3-b]pyridine-1-carboxylate (151;3.25 g, 15.5 mmol), (3-(trifluoromethyl)phenyl)Bronevoy acid (of 5.89 g, 31 mmol), Pd(dppf)Cl2(1.26 g, a 1.55 mmol), Cs2CO3(15,11 g, a 46.5 mmol) and dioxane/N2About (10/1, about./about.) (50 ml) was stirred at 100 ° C overnight in an atmosphere of N2. The solvent was removed and the residue was dissolved in EtOAc (200 ml). The solution was washed with saturated aqueous salt solution and dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography on a column of silica gel (elution with a mixture of petroleum ether/ethyl acetate=20/1) to obtain6-(3-(trifluoromethyl)phenyl)-1H-pyrrol[2,3-b]pyridine in the form of white solids (152; 3,62 g, yield 89%). MS (ESI) calc. for C14H9F3N2: 262,23.

This General technique combinations could be used to obtain the number of derivatives of 6-aryl-1H-pyrrol[2,3-b]pyridine, replacing (3-(trifluoromethyl)phenyl)Bronevoy the corresponding acid Bronevoy acid.

Stage 4. Synthesis of 6-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-pyrrol[2,3-b]pyridine (153)

To a stirred solution of 6-(3-(trifluoromethyl)phenyl)-1H-�Errol[2,3-b]pyridine ( 152; 3,62 g, at 13.84 mmol) in THF (30 ml) was added borane (at 13.84 ml, 10 M in IU2S, 138,4 mmol). After 16 h the solvent was removed and the residue was purified by chromatography on a column of silica gel (elution with a mixture of petroleum ether/ethyl acetate=10/1), getting6-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-pyrrol[2,3-b]pyridine in the form of a solid yellow color (153;886 mg, yield 24%). MS (ESI) calc. for C14H11F3N2: 264,25.

Stage 5.Synthesis of N-(pyridin-2-yl)-6-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-pyrrol[2,3-b]pyridine-1-carboxamide (Compound 861)

Method And: To a mixture of 2-aminopyridine (54 mg, 0,19 mmol) in 3 ml dry THF was added in one portion, triethylamine (0.5 ml), then triphosgene (68 mg, 0,23 mmol). The above mixture was stirred at room temperature for 3 hours and was added to the reaction mixture of 6-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-pyrrol[2,3-b]pyridine (153;50 mg, 0,19 mmol) and the mixture was stirred for 18 hours at 60'C. To the reaction mixture were added water and was extracted with water part with methylene chloride (3×15 ml). The combined organic layers were washed with saturated solution of NaHCO3and saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative TLC, yielding 4-methyl-N-(pyridin-2-yl)-7-(-(trifluoromethyl)phenyl)-3,4-dihydro-1,8-naphthiridine-1(2H)-carboxamide ( Compound 861) in the form of white solids. MS (ESI) calc. for C22H19F3N4O2: 412,15; found: 413 [M+H].

Getting 6-(2-ox-5-azaspiro[3.3]heptane-6-yl)pyridin-2-amine (160)

Stage 1. Synthesis of 6-tosyl-2-ox-6-azaspiro[3.3]heptane (155)

To a solution of KOH (33.2 g, of 0.59 mol) and p-tosylamide (37,9 g, 0.22 mole) in 600 ml of ethanol was added at room temperature 3-bromo-2,2-bis(methyl bromide)propan-1-ol (154; 60,1 g, to 0.19 mol) and heated the reaction mixture at reflux for 90 h. the Solvent was removed by evaporation, was added 500 ml of 1 M KOH and left a white suspension to stir for 2 hours at room temperature. The mixture was filtered and the residue was washed on the filter with water until neutral reaction of the wash water. The residue from the filter was dried in high vacuum to give 6-tosyl-2-ox-6-azaspiro[3.3]heptane (155; 30,55 g of a product containing 10 mol%. tosylamide in the form of white solids). Estimated total yield of pure 6-tosyl-2-ox-6-azaspiro[3.3]heptane should be (155; 27,4 g, 58%). MS (ESI) calc. for C12H15NO3S 253,3.

Stage 2. Synthesis of the oxalate of 2-ox-6-azaspiro[3.3]heptane (156)

6-Tosyl-2-ox-6-azaspiro[3.3]heptane (155; 7,30 g, 28.8 mol) and magnesium (4,9 g, 0.2 mol) was treated with ultrasound in the Techa�their one hour in methanol (500 ml). Removed almost all of the solvent from the reaction mixture grey on a rotary evaporator, yielding a viscous residue of gray. Was added diethyl ether (500 ml) and sodium sulfate (15.0 g) and vigorously stirred the mixture light grey for 30 min before filtration. The filtrate was dried over anhydrous sodium sulfate and added to the organic phase with anhydrous oxalic acid (1.3 g, 14.4 mol) dissolved in ethanol (~1 ml). Instantly formed a dense white precipitate. It was filtered and dried under vacuum to give the oxalate of 2-ox-6-azaspiro[3.3]heptane (156; 3.37 g, 81%) as amorphous white solid. MS (ESI) calc. for C10H20N2O2-C4O8376,28.

Stage 3. Synthesis of ethyl 6-(2-ox-6-azaspiro[3.3]heptane-6-yl)picolinate (157)

Oxalate 2-ox-6-azaspiro[3.3]heptane (156; 20 g, 0,23 mol), ethyl 6-bromopicolinic (44; 56,9 g, 0.25 mol) and K2CO3(62 g, 0,454 mol) was dissolved in DMSO (100 ml). The suspension was heated to 140º. After cooling to room temperature the reaction mixture was poured into water and extracted with methylene chloride. The organic layer was evaporated to dryness and the product was purified on silica gel, receiving ethyl 6-(2-ox-6-azaspiro[3.3]heptane-6-yl)picolinate (157; 7.2 g, 30%). MS (ESI) calc. for C13H16N2O3248,1.

Stage 4. Synthesis of 6-(2-ox-6-azaspiro[3.3]heptane-6-yl)picolinic acid (158)

Ethyl 6-(2-ox-6-azaspiro[3.3]heptane-6-yl)picolinate (157; 7.2 g, 0.03 mole) was dissolved in dioxane (50 ml) and added NaOH (2.3 g, 0.06 mole) in water (50 ml). The suspension was stirred at 50 ° C for approximately 2 h. the Solvent was removed and water was added (50 ml). The pH was adjusted to 5, getting 6-(2-ox-6-azaspiro[3.3]heptane-6-yl)picolinic acid (158; 4.5 g, 70%). MS (ESI) calc. for C11H12N2O3220,1; found of 221.2 [M+H].

Stage 5. Synthesis tertbutyl (6-(2-ox-6-azaspiro[3.3]heptane-6-yl)pyridin-2-yl)carbamate (159)

To a solution of 6-(2-ox-6-azaspiro[3.3]heptane-6-yl)picolinic acid (158; 4.4 g, 0.02 mole) in tert-BuOH (50 ml) was added Et3N (2.4 g, 0.02 mole) anddiphenylphosphoryl(DPPA) (6.6 g, 0,024 mol). The mixture was boiled overnight. After cooling to room temperature the solvent was evaporated and the crude product is purified column chromatography, obtainingtertbutyl (6-(2-ox-6-azaspiro[3.3]heptane-6-yl)pyridin-2-yl)carbamate (159; 4 g, 70%). MS (ESI) calc. for C15H21N3O3291,35.

Stage 6. Synthesis of 6-(2-ox-6-azaspiro[3.3]heptane-6-yl)pyridin-2-amine (160)

To a solution of tertbutyl (6-(2-ox-6-azaspiro[3.3]heptane-6-yl)pyridin-2-yl)carbamate (159;4.4 g, 0,015 mol) in CH2Cl2(50 ml) was added CF3COOH (20 ml). The mixture was stirred at room temperature for approximately 4 hours. The solvent was removed and added CH3CN (50 ml). The pH was adjusted to 7. After evaporation of volatiles 6-(2-ox-6-azaspiro[3.3]heptane-6-yl)pyridin-2-amine was obtained by purification on a column of silica gel. (160; 2.05 g, 70%). MS (ESI) calc. for C10H13N3About 191,1; found 192,2 [M+H].

Example 40

Biological activity

To identify modulators of SIRT1 activity used mass spectrometric analysis. In the mass spectrometric analysis used a peptide containing the following 20 amino acids residues: Ac-EE-K(Biotin)-GQSTSSHSK(Ac)NleSTEG-K(5TMR)-EE-NH2(SEQ ID No:1) where K(AC) is an acetylated lysine residue and Nle is norleucine. The peptide contains a fluorophore label 5TMR (excitation 540 nm/emission 580 nm) at the C-end. The sequence of the peptide substrate based on p53 with some modifications. In addition, the methionine residue normally present in the sequence, replaced by norleucine because the methionine may be susceptible to oxidation during synthesis and purification.

Mass spectrometric analysis was performed as follows: 0.5 μm peptide substrate and 120 μm βNAD+were incubated with 10 nm SIRT1 in for 25 minutes at 25 º C in �auctioncom buffer (50 mm Tris-acetate pH 8, 137 mm NaCl, 2.7 mm KCl, 1 mm MgCl2, 5 mm DTT,0,05% BSA). To the reaction mixture can be added to the test compounds described above. The SirT1 gene cloned in a T7-promoter containing vector and transformed into BL21(DE3). After 25 minutes of incubation with SIRT1 add 10 ál of 10% formic acid to stop reaction. The reaction mixture was sealed and frozen for subsequent mass spectrometric analysis. Determination of the mass of the peptide substrate can accurately determine the degree of acetylation (i.e. source material) compared to deacetylating peptide (product).

Monitoring the inhibition of the activity of sirtuin carried out by adding 1 μl of 500 nm nicotinamide as a negative control at the beginning of the reaction (for example, to determine the maximum inhibition of sirtuin). Control of the activation activity of sirtuin carried out using 10 nm of protein sirtuin, with 1 ál of DMSO instead of compound, to determine the amount of deacetylation of the substrate in a given time point within the linear interval analysis. Given time similar to the time used in the case of the tested compounds and, within the linear interval, the end time represents the change of velocity.

For the above analysis of SIRT1 protein expressional and purified following �the Braz. The SirT1 gene was cloned in a T7-promoter and transformed BL21(D3). Protein expressible by induction of 1 mm IPTG as an N-terminal His-tag hybrid protein at 18ºC during the night and was received at 30,000 × g. Cells were literally lysozyme in Lisina buffer (50 mm Tris-HCl, 2 mm Tris[2-carboxyethyl]phosphine (TSER), 10 μm ZnCl2, 200 mm NaCl) and further treated with sonication for 10 min for complete lysis. The protein was purified on a column of Ni-NTA (Amersham) and fractions containing pure protein were pooled, concentrated and passed through a fractionating column (Sephadex S200 26/60 global). The peak containing soluble protein was collected and passed through ion exchange column (MonoQ). As a result of gradient elution (200 mm-500 mm NaCl) was obtained pure protein. The protein was concentrated and dialyzed regarding dialysis buffer (20 mm Tris-HCl, 2 mm TSER) during the night. Selected aliquot of protein and frozen at-80ºC until further use.

The values of EC1.5the activating compounds of formula (I) represented by And (EC1.5<1.0 μm), (EC1.51-25 μm), (EC1.5>25 μm). The percentage of maximum fold activation represents A (fold activation >200%) or (fold activation ≤200%). The values of IC50the activating compounds of formula (I) represented by And (IC50<20 μm) or (IC50≥20 µm). "NT" means not link testing�I. "ND" means not detected. (*It should be noted that the numbers in brackets refer to the numbering of the compounds in the provisional application U.S. No. 61/256269, which in this application claimed priority).

Table 1
Compounds of formula (I)

1. The connection represented by structural formula (I):

it tautomer or pharmaceutically acceptable salt, where:
each Ζ1and Ζ2independently selected from N and CR, where
at least one of Ζ1and Ζ2is a CR, and
each R is independently selected from hydrogen, C1-C4alkyl and-N(R3)(R3);
W is selected from-O-, -N(C1-C4) alkyl and-C(R6)(R6)-, and each R6independently selected from hydrogen and C1-C4alkyl, or two R6related to the same carbon atom, taken together with the formation of =O,
R1is chosen from phenyl and heterocycle, which represents a saturated or unsaturated 5-6-membered monocyclic ring containing one, two or three heteroatom selected from the atoms N, S and O, or an 8-12-membered bicyclic ring, each cycle of which is selected from saturated, unsaturated or aromatic cycle containing one or two nitrogen atom, where R1�obazatelno substituted by one or more substituents, independently chosen from halogen, (C1-C4of alkyl, =O, fluorine-substituted C1-C2alkyl, -O-R3, -(C1-C4alkyl)-N(R3)(R3), -N(R3)(R3and-C(O)-N(R3)(R3),
R2is chosen from phenyl and heterocycle, which is an unsaturated 5-6-membered monocyclic ring containing one or two heteroatom selected from N and O atoms, or represents dihydrobenzofuranyl, where R2optionally substituted by one or two substituents, independently selected from halogen, -C≡N, C1-C4alkyl, C1-C2fluorine-substituted alkyl, -O-R3, -(C1-C4alkyl)-N(R3)(R3and-N(R3)(R3);
each R3independently selected from-C1-C4alkyl; or
two R3taken together with the nitrogen atom to which they are bound, to form a 4-8-membered saturated heterocycle, optionally containing one additional heteroatom selected from N and O, where:
in the case where R3represents alkyl, the alkyl optionally is substituted with two groups HE and
when two R3taken together with the nitrogen atom to which they are linked with the formation of a 4-8-membered saturated heterocycle, the saturated heterocycle optionally substituted on any carbon atom with fluorine; and substituted by any method�WMD to the replacement of the nitrogen atom with hydrogen;
p is 1, 2 or 3;
X2selected from-C(=O)-♣, -C(=O)-O-♣, -C(=O)-NH-♣, -S(=O)2-NH -♣- s(=O)-NH-CR4R5-♣, where:
♣ represents the point at which X2linked with R1; and
each R4and R5represents hydrogen.

2. The compound represented by structural formula (IV):

it tautomer or pharmaceutically acceptable salt, where
each Ζ1and Ζ2represents CR where
each R represents hydrogen;
R11represents a halogen, and R12represents halogen,
each R6represents hydrogen,
R1is chosen from phenyl and heterocycle, which is an unsaturated 5-6-membered monocyclic ring containing one or two heteroatom selected from the atoms N and S, where R1independently substituted with one or two substituents, independently selected from halogen, -C1-C4alkyl and-O-R3
R2represents phenyl, where R2independently substituted by one Deputy, independently selected from halogen and C1-C2fluorine-substituted alkyl;
each R3independently represents-C1-C4alkyl, substituted with two groups HE;
p is 2 or 3, and
X2represents-C(=O)-NH-♣, where ♣ is a point at which X 2linked with R1.

3. The compound represented by structural formula (V):

it tautomer or pharmaceutically acceptable salt, where
every Ζ1and Ζ2represents CR, where each R represents hydrogen;
W represents-O-,
each R6represents hydrogen,
R1represents pyridinyl,
R2represents phenyl, where R2substituted by one Deputy, independently selected from C1-C2fluorine-substituted alkyl;
p is 2 and
R4and R5taken together with the formation of a 3-6-membered saturated carbocycle.

4. The compound represented by structural formula (VI):

it tautomer or pharmaceutically acceptable salt, where
every Ζ1and Ζ2represents CR where
each R represents hydrogen;
W represents-O-;
each R6represents hydrogen,
R1represents pyridinyl, where R1replaced a 4-4 cerebellum, which includes two heteroatom such as N or O,
R2represents phenyl, where R2substituted by one Deputy, independently selected from C1-C2fluorine-substituted alkyl
p is 1 or 2, and
X2represents-C(=O)-NH-♣,
where ♣ is a place to�Oromo X 2linked with R1.

5. The compound according to any one of claims. 1-4, where R1represents pyridinyl.

6. The compound according to claim 2, where R11represents fluorine.

7. The compound according to claim 2, where R12represents fluorine.

8. The compound according to claim 3, where R4and R5taken together with the formation of the cyclopropyl ring.

9. The compound according to claim 4, where the 4-4 spirobicyclic represented by the structure:

10. The compound according to claim 4, where the 4-4 spirobicyclic represented by the structure:

11. The compound according to claim 1, wherein the compound represented by any of following structural formulas:
,,
,or.
where X corresponds to X2.

12. The compound according to claim 1, where R1choose from:



and
where R1optionally substituted by one or more substituents, independently selected from halogen, -C1-C4alkyl, fluorine-substituted C1-C2alkyl, -(C1-C4alkyl)-N(R3)(R3), -N(R3)(R3), -C(O)-N(R3)(R3and-O-R3.

13. With�according to claim unity 12, where R1substituted by one or more groups independently selected from-F, -Cl, -CH3, -OCH3,
and.

14. The compound according to claim 13, wherein R1choose from













and
.

15. The compound according to claim 14, where R1choose from





16. The compound according to any one of claims. 1, 11, 13-15, where R2choose from

and.
where R2optionally substituted with one or two groups independently selected from halogen, -C1-C4alkyl, -(C1-C4alkyl)-N(R3)(R3), S1-C2fluorine-substituted Alki�and, -O-R3and-N(R3)(R3).

17. The compound according to claim 16, where R2optionally substituted with one or two groups independently selected from =O, -F, -Cl, -CN, -CH3, -OCH3, -N(CH3)2, -CH2N(CH3)2,-CF3,.

18. The compound according to claim 17, wherein R2choose from




19. The compound according to claim 18, where R2choose from

and.

20. The compound according to any one of claims. 1, 3, or 4, where X2represents-C(=O)-ΝΗ-♣.

21. The Union representing any of the following compounds:



































22. The compound according to claim 2, where the connection is represented by any one of the following compounds:

23. The compound of claim 3 where the compound is the following compound:

24. The compound according to claim 4, where the connection is represented by any one of the following compounds:

25. Pharmaceutical composition having a % -modulating activity containing the compound according to any one of claims. 1-24, and a pharmaceutically acceptable carrier or diluent.

26. Method of treatment of a subject suffering from or prone to insulin resistance, �metabolicescomu syndrome, diabetes or its complications, or increasing insulin sensitivity in a subject, comprising administering to the needy in this subject a composition according to claim 25.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula:

double line between N and C represents double bond, X is absent, a Y stands for H; W stands for C=O; each of R1, R2, R3, R4 stands for H; R5 is selected from groups OR15, where R15 has the same determination as R; optionally R5 stands for binding group or is selected from groups: polypyrrole, polyindolyl, polyimidazolyle, polypyrrole-imidazolyle, polypyrrole-indolyl or polyimidazole-indolyl unit, optionally bound to binding groups; R6 stands for OR or optionally, R6 stands for binding group; Z is selected from groups (CH2)n, where n stands for 1, 2 or 3, CR15R16, where each of R15 and R16 independently stands for H or linear alkyl, having from 1 to 10 carbon atoms; R stands for H or linear or branched alkyl, having from 1 to 3 carbon atoms, optionally substituted with group -COR11; R11 stands for H or -OR14; and R14 stands for H or linear or branched alkyl, having from 1 to 3 carbon atoms; each of R1, R2, R3, R4, R1', R2', R3' and R4' stands for H, optionally any of R1, R2, R3, R4, R1', R2', R3' or R4' stands for binding group, Z is selected from groups (CH2)n, where n stands for 1, 2 or 3; R6 stands for OR, or optionally R6 stands for binding group; A and A′ stand for O, D and D', similar or different, and independently represent linear or branched alkyls, having from 1 to 10 carbon atoms; L is absent or stands for phenyl group, where said phenyl group representing L, is optionally substituted, where substituent is represented by binding group or is selected from OR7, NR8R9, NRCOR' or OCOR11; R and R' independently represent H or linear or branched alkyl, having from 1 to 10 carbon atoms, optionally substituted with halogen or group -COR7; R7, R8, R9 and R11 independently represent H or linear or branched alkyl, having from 1 to 10 carbon atoms, or polyethylene glycol unit (-OCH2CH2)n, where n stands for integer number from 1 to 10; on condition that said compound has not more than one binding group, which provides bond with cell-binding agent due to covalent bond, which possess anti-proliferative activity.

EFFECT: obtaining novel compounds.

24 cl, 59 dwg, 9 tbl, 40 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula (I)CE, wherein "-----" means a bond, V represents CH, and U represents CH or N, or "-----" means a bond, V represents CR6 and U represents CH, or also "-----" means a bond, V represents N and U represents CH, or "-----" is absent, V represents CH, and U represents CH2, NH or NR9; R0 represents H, or provided "-----" means a bond, can also represent C1-3alkoxygroup; R1 represents H, halogen, cyanogroup, C1-3alkyl or ethinyl; R2 represents H, acetyl or a group of formula -CH2-R3; R3 represents H, C1-3alkyl or C1-3hydroxyalkyl; R4 represents H, or provided n is other than 0, and R5 means H, can also represent OH; R5 represents H, C1-3alkyl, C1-3hydroxyalkyl, C1-3aminoalkyl, C1-3alkoxyC1-3alkyl, carboxyl group or C1-3alkoxycarbonyl; R6 represents C1-3hydroxyalkyl, carboxyl group, C1-3alkoxycarbonyl or a group -(CH2)q-NR7R8, wherein q is 1, 2 or 3 and each of R7 and R8 independently represents H or C1-3alkyl, or R7 and R8 together with a nitrogen atom to which they are attached, form a pyrrolodinyl or piperidinyl ring; R9 represents C1-3alkyl, 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl; A represents -(CH2)p-, -CH2CH2CH(OH)- or -COCH2CH(OH)-; G represents a phenyl group which is mono- or disubstituted in m- and/or n-position(s)by substitutes independently specified C1-4alkyl, C1-3alkoxygroup and halogen, or G means a group of one of formulas below G1 and G2, wherein Q means O or S, and X means CH or N; and each Y1, Y2 and Y3 represents CH, or one of Y1 and Y3 represents N, and the other one represents CH; and n is equal to 0, provided A represents -CH2CH2CH(OH)- or -COCH2CH(OH)-, and n is equal to 0, 1 or 2, provided A represents (CH2)p, wherein p is equal to 1, 2, 3 or 4, provided a sum of n and p is then equal to 2, 3 or 4; or a pharmaceutically acceptable salt of this compound.

EFFECT: compound of formula (I)CE or its pharmaceutically acceptable salt are applicable as a therapeutic agent for preventing or treating a bacterial infection.

29 cl, 2 tbl, 202 ex

FIELD: chemistry.

SUBSTANCE: invention relates to antibacterial compounds of formula

,

where R1 is an alkoxy group; R2 is H or F; each of R3, R4, R5 and R6 is independently H or D; V is CH and W is CH or N, or V is N and W is CH; Y is CH or N; Z is O, S or CH2 and A is CH2, CH2CH2 or CD2CD2; or a salt of said compound. The invention also describes a antibacterial pharmaceutical composition which contains the compound of formula (I) as a basic component, and use of the compound of formula (I).

EFFECT: obtaining novel compounds possessing useful biological properties.

25 cl, 2 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) where R1 is phenyl, imidazo[2,1-b][1,3]thiazolyl, pyridinyl, pyrazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, imidazo[2,1-b][1,3,4]thiadiazolyl, 1H-indazolyl, pyridazinyl, imidazo[1,2-b][1,2,4]triazinyl, 1H-pyrazolo[3,4-b]pyridinyl, imidazo[1,2-b]pyridazinyl, 2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl, oxadiazolyl or imidazo[1,2-a]pyridinyl; each of which is optionally substituted with 1-3 substitutes, independently selected from methyl, methoxy, cyano, cyclopropyl, -C(O)NH2 and -NHC(O)CH3; Ra in each case is hydrogen; each of Z, Z1 and Z2 is independently CH; L is a direct bond; and R2 is hydrogen, phenyl, phenoxy, pyrimidinyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, pyridinyl, oxazolyl, oxadiazolyl, pyrazolyl, pyridazinyl, triazinyl or pyrazinyl, each optionally substituted with 1-3 substitutes independently selected from methyl, trifluoromethyl, ethyl, methoxy, cyano or -C(O)NH2; or pharmaceutically acceptable salts thereof, which act as ghrelin antagonists or inverse agonists.

EFFECT: obtaining novel derivatives.

13 cl, 1 dwg, 11 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I, having cell proliferation inhibitor properties. In formula I , Y1 and Y2 each independently denote N or C(R1), but Y1 and Y2 do not simultaneously denote N or do not simultaneously denote C(R1), where R1 is selected from a group consisting of a hydrogen atom, C1-6alkyl, where R1 is substituted with 0 or 1 substitutes RR1, selected from a group consisting of -ORa; where Ra is selected from a hydrogen atom; R2 is selected from a group consisting of a hydrogen atom, C1-6alkyl; R3 is a 6-7-member monocyclic or bridge heterocycloalkyl ring containing 2 heteroatoms, selected from N and O, where the group R3 is substituted with 0-3 substitutes RR3, selected from a group consisting of -Ri, Ri is selected from C1-6alkyl; A1, A2, A3 and A4 each denote C(H); and D denotes -NR4C(O)NR5R6, where R4 is selected from a group consisting of a hydrogen atom; R5 and R6 are each independently selected from a group consisting of a hydrogen atom, C1-6alkyl, C4-6heterocycloalkyl containing one oxygen heteroatom; and where R5 and R6 are further substituted with RD, where RD is selected from -S(O)2Rm, where Rm is selected from C1-6alkyl.

EFFECT: compounds can be used to produce medicine for treating cancer.

21 cl, 1 tbl, 21 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to derivatives of oxazolopyrimidine in any of their stereoisomeric forms, or in the form of a mixture of stereoisomeric forms specified in Claim 1.

EFFECT: oxazolopyrimidine derivatives having agonistic activity in relation to Edg-1 receptor.

5 tbl, 319 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of novel pyrrolopyrazine derivatives of formula , where variables Q and R are as defined in the claim, which inhibit JAK and SYK.

EFFECT: high effectiveness when treating autoimmune and inflammatory diseases.

11 cl, 59 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) where "----" denotes a bond or is absent; R1 is a C1-4alkoxy group or halogen; R1b is H or C1-3alkyl; U and V each independently denote CH or N; W is CH or N, or, if "----" is absent, W is CH2 or NH; under the condition that at least one of U, V and W is CH or CH2; A is -CH2-CH(R2)-B-NH-* or -CH(R3)-CH2-N(R4)-[CH2]m-*; where asterisks indicate a bond which binds said fragments through a CH2-group with an oxazolidinone fragment; B is CH2 or CO; and R2 is hydrogen, OH or NH2; R3 and R4 both denote hydrogen, or R3 and R4 together form a methylene bridge; m equals 0, 1 or 2; and G is a phenyl which is monosubstituted in position 3 or 4, or disubstituted in positions 3 and 4, where each substitute is independently selected from a group comprising C1-4alkyl, C1-3alkoxy group and halogen; or G is a group selected from groups G1 and G5 where M is CH or N; Q' is S or O; Z1 is N, Z2 is CH and Z3 is CH; or Z1 is CH, Z2 is N and Z3 is CH or N; or Z1 is CH, Z2 is CR5 and Z3 is CH; or Z1 is CH, Z2 is CH and Z3 is N; and R5 is hydrogen or fluorine; or a pharmaceutically acceptable salt thereof. The compound of formula (I) or a pharmaceutically acceptable salt thereof are used as a medicinal agent for preventing or treating bacterial infections.

EFFECT: oxazolidinone derivatives used as antimicrobial agents.

15 cl, 2 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention relates to dihydrothienopyrimidinesulphoxides of formula 1, and pharmaceutically acceptable salts thereof , where X denotes SO, R1 denotes H, R2 denotes H or a residue selected from C1-C10alkyl, which is optionally substituted with one or more residues selected from OR2.1, where R2.1 denotes H or C1-C6alkyl, R2.2 and R2.3 independently denote H or C1-C6alkyl, where Het is a 6-member monocyclic, saturated heterocycle containing 1 heteroatom selected from N or O, and where the hetaryl is a 5-11-member mono- or bicyclic, optionally anellated heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, S or O, and where the cycloalkyl can be saturated, or R2 denotes a monocyclic C3-cycloalkyl, which is optionally substituted with a residue selected from a branched or linear C1-C6alkanol, C1-C3alkylene-OR2.1, or R2 denotes phenyl which is optionally substituted with a halogen, or R2 denotes a residue selected from Het and hetaryl, each optionally substituted with one or more residues selected from halogen, OH, oxo group and OR2.1, C1-C6alkyl, and where R3 denotes a bicyclic 9-11-member unsaturated or partially saturated heterocycle which is optionally substituted with one or more residues selected from a group comprising F, O, Br, CF3, CN, OH, methyl, ethyl, propyl, isopropyl, -O-methyl, -O-ethyl, phenyl, NR2.2R2.3, where the phenyl is optionally substituted with F, Cl or Br. The invention also relates to pharmaceutical compositions based on said compounds, having phosphodiesterase 4 (PDE4) inhibiting activity.

EFFECT: obtaining novel compounds and pharmaceutical compositions based thereon, which can be used in medicine to treat respiratory or gastrointestinal complaints or diseases, inflammatory diseases of joints, skin or eyes, diseases of the peripheral or central nervous system or cancers.

20 cl, 1 tbl, 156 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound, namely 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluor-1,5-naphthyridin-2(1H)-one monohydrate which possess strong antibacterial activity. This compound is highly safe and applicable in the production of pharmaceutical preparations as a parent drug. What is furthermore described is a method for preparing 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluor-1,5-naphthyridin-2(1H)-one monohydrate of formula 19 and methods for preparing intermediate compounds.

EFFECT: preparing the compounds possessing strong antibacterial activity.

8 cl, 1 tbl, 17 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new substituted aminotetrahydropyranes of structural formula or to their pharmaceutically acceptable salts , and , wherein V is specified in groups having the formulas below, Ar represents phenyl unsubstituted or substituted by one to five halogen atoms, each of R1 and R2 is independently specified in C1-C6alkyl; R3 is specified in a group consisting of C1-C6alkyl; cyano; tetrazolyl; -C(O)OC1-C6alkyl and -C(O)NH2; wherein C1-C6alkyl is substituted by 1-4 substitutes independently specified in a group consisting of OH; -C(O)NH2 and -CO2H. The declared compounds can be dipeptidylpeptidase-IV inhibitors and can be applicable in treating or preventing diseases involving the enzyme dipeptidylpeptidase-IV, such as diabetes, and especially type 2 diabetes mellitus.

EFFECT: invention also refers to a pharmaceutical composition containing the above compounds, and using the above compounds and compositions for preventing or treating the diseases involving the enzyme dipeptidylpeptidase-IV.

12 cl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new chemical compounds of general formula I wherein LA, LB, LC, cycle A, cycle B, RA, RB, RC, RD, RE and RF have the values specified in the patent claim. The compounds of formula (I) are protein kinase inhibitors.

EFFECT: invention refers to pharmaceutical compositions containing the above compounds, as well as to using the above compounds for treating and/or preventing the diseases related to aberrant protein kinase activity, particularly oncological diseases.

10 cl, 14 tbl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) such as below, or to their pharmaceutically acceptable salts, wherein R1 means H, C1-8alkyl morpholinyl, haloC1-8alkylamino, C1-8alkyloxadiazolyl, hydroxyl, halopyrrolidinyl, azetidinyl, C1-8alkylamino, amino, cyano C1-8alkylamino, halophenylC1-8alkylamino or cyanoC3-8cycloalkylamino; R2, R3, R4, R5 and R6 independently mean H, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkyloxy, halogen, hydroxyl, cyanopyrazinyloxy, halogen, hydroxyl, cyanopyrazinyloxy, pyrazolyl, C1-8alkylpyrazolyl, imidazolyl, benzimidazolyl, 6-oxo-6H-piridazinyl, C1-8alkyl-6-oxo-6H-pyridazinyl, piperazinyl, N-C1-8alkylpiperazinyl, piperidinyl, difluoropyrrolidinyl, phenylimidazolyl, oxo-pyrrolidinyl, oxo-oxazolidinyl, morpholinyl, oxo-morpholinyl, oxo-pyridinyl, 2-oxo-2H-pyrazinyl, difluoropiperidinyl, haloC1-8alkylpiperidinyl, piperidinylC1-8alkoxy, oxetanyloxy, C1-8alkylpyrazolyl, halopyridinyl, C1-8alkylpyridinyl, C3-8cycloalkyl, C3-8 cycloalkylC1-8alkyl, halophanyl, C1-8alkylcarbonylamino-C3-8-cycloalkyl-C1-8alkyl, haloC1-8alkylpiperazinyl, C1-8alkylamino, C1-8alkoxy-C1-8alkylpiperazinyl, C3-8cycloalkylpiperazinyl, hexahydropyrrolo[1,2-a]pyrazinyl, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl, C1-8alkylimidazolyl, azetidinyl, C3-8cycloalkylpiperazinyl, C1-8alkylimidazolyl, C1-8alkoxy C1-8alkoxy, imidazo[4,5-c]pyridinyl, C1-8alkylpiperazinyl, hexahydro-pyrrolo[1,2-a]pyrazinyl, haloazetidinyl, pyrimidinyl and C2-8alkenyloxy; A1 means -CH2-, carbonyl, -C(O)O- or is absence; A2 means N, CR7; A3 means N, CR8; A4 means N, CR9; R7 means H, C1-8alkyl, haloC1-8alkyl, halogen, hydroxyl, haloC1-8alkylaminocarbonyl; halophenylC1-8alkylaminocarbonyl, phenyl-C3-8-cycloalkylaminocarbonyl, haloC1-8alkylphenylC1-8alkylaminocarbonyl, halophenylC3-8 cycloalkylaminocarbonyl, halophenylC3-8cycloalkylC1-8alkylaminocarbonyl; R8 means H, C1-8alkyl, haloC1-8alkyl, halogen or hydroxyl; or R7 and R8 together with a carbon atom they are attached to, form C3-8cycloalkyl or substituted pyrrolidine, wherein substituted pyrrolidine represents pyrrolidine, N-substituted haloC1-8alkyl or formyl; R9 means H, C1-8alkyl, haloC1-8alkyl, halogen or nitro; or R8 and R9 together with a carbon atom they are attached to, form C3-8cycloalkyl; or its pharmaceutically acceptable salt

EFFECT: compounds inhibit the enzyme catepsin that enables using them in pharmaceutical compositions.

27 cl, 8 dwg, 1 tbl, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry, namely to novel hetericyclic compounds of general formula or to its tautometric form, or to its pharmaceutically acceptable salt, where 1-2 of X1, X2, X3, X4, X5, X6 is selected from N, and the remaining ones represent C, X7 is selected from N or CH; each of X8, X9, X10 and X11 is independently selected from N or CH on condition that fragment can simultaneously contain one or two nitrogen atoms; R1, R2, R3 and R4 are selected from H, 6-memberedaryl, CF3, halogen; R5, R6, R7 represent C1-alkyl on condition that X9, X10 or X11 in this case respectively equals C; "A" can represent simple bond or bridging ethyne moiety; Y can represent simple bond or is independently selected from methylene or ethylene bridging moieties; moiety Z is independently selected from no-substituted or substituted in nitrogen atom heterocycloalkyl or is non-substituted or substituted cycloalkyl on condition that N (nitrogen) equals C (carbon): , where R9 is selected from CH2OH, CON(R15, R16), where R15, R16 can independently represent H, C1-alkyl, Het represents N, n=1, n1=3; R8 is selected from H, C1-6-alkyl, C1-alkylcarbonyl, derivetives of arylacetic acid of general structure: , where methylheteroaryls of general structure: , where derivatives of alkylsulphonyls of general structure where R14=Alk, with Alk representing C1-alkyl, or to 2-methylamino-1-{3-[6-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyridin-2-ylmethyl]-1-oxa-8-azaspiro]4.5]decan-8-yl}-ethanol dihydrochloride, or to 6-(6- chloroimidazo[1,2-a]pyridin-3-yl)-1',4',5',6'-tetrahydro-2'H-[2,3']bipyridinyl-3'-carboxylic acid dihydrochloride, or to 6-(6- chloroimidazo[1,2-a]pyridin-3-yl)-1',4',5',6'-tetrahydro-2'H-[2,3']bipyridinyl-3'-carboxylic acid dimethylamine dihydrochloride. Invention also relates to pharmaceutical composition based on claimed compound and to method of Haspin kinase inhibition.

EFFECT: obtained are novel compounds, possessing useful biological properties.

5 cl, 7 tbl, 35 ex

FIELD: chemistry.

SUBSTANCE: invention relates to azoloazine salts of compounds of a fluoroquinolone line of formulae 4a-c , 5a-c , 7a-b and 8a-b , possessing antibacterial and antiviral properties. The claimed compounds can be applied for the creation of a medication for the emergency prevention and treatment of infections, caused by pathogens of both the bacterial and viral origin, including especially dangerous ones. In general formulae 4 and 5 R=CH3, R1=C2H5; R=H, R1=C2H5; R=C2H5, R1=cyclo-C3H7, in formulae 7 and 8 R=H (7a, 8a); R=CH3 (7b, 8b).

EFFECT: increased efficiency of the compound application.

8 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a citrate of a compound described by formula (II) below, and a pharmaceutical composition containing said citrate.

EFFECT: experimental results of the present inventions prove that said citrate can inhibit activity of phosphodiesterase type 5 and can be used for treating erectile dysfunction, for inhibiting thrombocyte aggregation and treating thrombosis, for reducing pulmonary hypertension and treating cardiovascular diseases, asthma and diabetic gastroparesis.

2 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: in general formulas R1 represents substituted phenyl, substituted or unsubstituted heterocyclyl, which represents an aromatic cycloalkyl containing 6 to 10 atoms in the cycle and wherein one to two carbon atoms in the cycle are independently substituted by N, wherein the above substitutes are specified in C1-8alkyl, triazolyl, halogen, aminocarbonyl, cyano or hydroxyalkyl; R2 represents H, substituted or unsubstituted C1-8alkyl, substituted C3-6cycloalkyl, unsubstituted heterocyclyl, which represents non-aromatic cycloalkyl containing 5 to 6 atoms in the cycle and wherein one to two carbon atoms in the cycle are independently substituted by N or O; unsubstituted heteroyclylalkyl, wherein heterocyclyl represents non-aromatic cycloalkyl containing 5 to 6 atoms in the cycle and wherein one to two carbon atoms in the cycle are independently substituted by N and O; substituted or unsubstituted phenylalkyl or substituted or unsubstituted C3-6cycloalkylalkyl, wherein the above substitutes are specified in C1-4alkyl, CF3, OR and NR2, wherein R represents H or C1-4alkyl; each R3 and R4 independently represents H, unsubstituted C1-8 alkyl, or R3 and R4 together with the atom to which they are attached form C3-6cycloalkyl; or R2 and one of R3 and R4 together with the atom to which they are attached form substituted or unsubstituted heterocyclyl containing 5 to 6 atoms in the cycle and which can contain additional heteroatom specified in O; wherein the substitutes are specified in -C(O)CH2OCH3, -CH2CH2OCH3, OCH3 or CH3.

EFFECT: invention refers to compounds of formula

and ,

a based pharmaceutical composition and to a method of treating or preventing cancer, immunological conditions, diabetes, obesity, neurological disturbances and age-related diseases, a method for mTOR kinase inhibition in a cell, a method of treating or preventing the condition, which can be treated or prevented by mTOR kinase metabolic path inhibition.

53 cl, 1 tbl, 20 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a chemical compound of formula wherein R=benzyl and to an antituberculous therapeutic agent representing a composition of imidazo[1,2-b][1,2,4,5]tetrazine derivative of formula I, wherein R=benzyl, isopropyl or phenyl and the known antituberculous preparation pyrazinamide with the ingredients in mole ratio 1:1.

EFFECT: there are prepared new antituberculous therapeutic agents.

2 cl, 2 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining cyclic guanidine, which can be applied in coating compositions, in particular in electrically precipitated coating compositions. Method includes reaction of (i) cyanamide, (ii) polyamine and (iii) weak acid with 5.0<pKa<13.5. Invention also relates to method of obtaining polymer resin and method of obtaining cyclic guanidine, containing 6-membered ring.

EFFECT: claimed method makes it possible to reduce amount of wastes in production of cyclic guanidines.

18 cl, 1 tbl, 15 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of structural formula (I), which possesses phosphodiesterase 10 inhibitory activity. In formula (I), R1 represents hydrogen, halogen or lower alkyl; the ring A represents optionally substituted 6-10-merous monocyclic or bicyclic heteroaryl containing 1 to 3 nitrogen atoms as heteroatoms, or a group containing a cycloaliphatic 6-merous ring condensed with the above heteroaryl, which is specified in 6-merous cycloalkane and aliphatic 6-merous heterocyclic ring containing an oxygen atom; the ring B represents optionally substituted 4-6-merous monocyclic nitrogen-containing group, which can additionally contain an oxygen atom or a 3-6-merous monocyclic hydrocarbonic group, which can be optionally saturated; R3 represents hydrogen; lower alkyl optionally substituted by a substitute specified in lower alkoxy; or lower cycloalky. The R2,Y radicals, as well as substitutes of the rings A and B are presented in the patent claim.

EFFECT: invention refers to the pharmaceutical composition containing the above compound, to a method of treating or preventing schizophrenia, anxiety disorders, drug addiction, disorders with a symptom of cognition deficiency, affective disorder or mood episode, each of which is mediated by phosphodiesterase 10 activity.

20 cl, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 5,6-dihydropyrrolo[2,1-a]isoquinoline derivatives 1-4 having the general structural formula: , where 1 - R=CH3, 2 - R=CH2CH3, 3 - R=CH2CF3, 4 - R=CH(CH3)2, characterised by that 6,7-diethoxy-3,4-dihydro-1-(3,4-diethoxybenzoyl)isoquinoline is mixed with methyl propiolate and methane, or ethanol, or 2,2,2-trifluoroethanol, or isopropanol and stirred at temperature of +50°C, the precipitate obtained at the end of the reaction and after removing reagents, is crystallised in ether.

EFFECT: method of producing derivatives which can be used as intermediate compounds when producing biologically active compounds.

4 ex

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