Cyclic inhibitors of 11beta-hydroxysteroid-dehydrogenase 1

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula (Ip1) or (Ip3) or its pharmaceutically acceptable salt, where G1 represents (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)halogenalkyl, (C1-C4)halogenalkoxy, halogen, cyano or nitro; n equals 0; G2a represents (C3-C4)cycloalkyl or (C3-C4)cycloalkyl(C1-C2)alkyl; G2b represents hydrogen; R1 represents methyl or ethyl; R2 represents phenyl or fluorophenyl; and R3 represents 2-hydroxy-2-methylpropyl or 2-methyl-2-cyanopropyl.

EFFECT: invention relates to application of compound of formula (Ip1 and Ip3) for manufacturing medication or pharmaceutical composition, intended for treating a person with disease or state, selected from type II diabetes mellitus, obesity, glucose intolerance, hyperglycemias, hyperlipidemis, insulin resistance, decrease of cognitive functions and dyslipidemia.

5 cl, 6 tbl, 107 ex

 

The SCOPE of the INVENTION

The present invention relates to inhibitors of 11β-hydroxysteroid-dehydrogenase type 1 (11β-HSD), their drugs and their primeneniyu.

The LEVEL of TECHNOLOGY

Glucocorticoids (such as cortisol (hydrocortisone)) are steroid hormones, which provides adjustment of the metabolism, functioning and fat distribution, as well as participating in the metabolism of carbohydrates, proteins and fats. It is also known that glucocorticoids exert physiological effects on development, neuroscience, inflammation, blood pressure, metabolism, and apoptosis. Cortisol and other corticosteroids are associated with glucocorticoid receptors (GR) and mineralocorticoid receptors (Mr), which are members of the same superfamily of nuclear hormone receptors and determine the action of cortisol in vivo. These receptors directly modulate transcription by DNA-binding domain of "zinc fingers", as well as causing transcription domains.

Until recently it was believed that the action of glucocorticoids is determined by three main factors: (1) the level of circulating glucocorticoids (defined mainly the hypothalamic-pituitary-adrenal (HPA) axis); (2) the level of binding of glucocorticoids with protein in blood; and t is the train (3) the number of intracellular receptors in target tissues. However, it was recently discovered fourth factor that determines the action of glucocorticoids: tissue-specific metabolism activating and inactivating glucocorticoids enzymes on praeceptorum level. These enzymes controlling the action of 11-hydroxysteroid-dehydrogenase (11β-HSD) on praeceptorum level, modulate the activation of GR and Mr by regulating glucocorticoid hormones. At the present time was carried out cloning and compiled a complete characterization of two different isozymes of 11-β-HSD: 11-HSD (also known as 11-β-HSD type 1, 11β1, GSDV, HDL (high-density lipoprotein), and 11L) and 11-HSD. 11-HSD is a bilateral oxidoreductase, providing regeneration of active cortisol from inactive 11-keto forms, while 11-HSD is a unilateral dehydrogenases that ensures inactivation of biologically active cortisol by converting it into cortisone.

Both isoforms are expressed in a certain tissue-specific manner, in accordance with differences in their physiological roles. 11-HSD widely distributed in tissues of the rat and human rights; signs of the presence of enzymes and relevant information RNA were detected in human liver, adipose tissue, lung, male sex glands, bones and ciliated epithelium. In W the global tissue, increased concentrations of cortisol stimulates the differentiation of adipocytes and may play a role in the stimulation of visceral adiposity. 11-HSD can provide control of intraocular pressure, as well as to promote the development of glaucoma; some evidence suggests that inhibition of 11-HSD can cause reduction of intraocular pressure in patients with ocular hypertension (Kotelevstev et al. (1997), Proc. Natl. Acad, Sci. USA 94(26): 14924-9). Despite the fact that 11-HSD stimulates the 11-beta-dehydrogenization, as well as the reverse reaction of 11-exorable, 11-HSD acts mainly as a NADPH-dependent oxireductases in healthy cells and tissues, stimulating the formation of active cortisol from inert cortisone (Low et al. (1994) J. Mol. Endocrin. 13: 167-174). However, the expression of 11-HSD mostly found in target tissues of mineralocorticoids, such as kidney (cortex and cerebral layer), placenta, sigmoid and rectum, salivary gland and cell lines the rectum. 11-HSD acts as OVER-dependent dehydrogenase, which activates the conversion of cortisol to cortisone (Albiston et al. (1994) Mol. Cell. Endocrin. 105: R11-R17), and also protects Mr from excess glucocorticoid (for example, when a high level is active with respect to cortisol receptors) (Blum et al. (2003) Prog. Nucl. Acid Res. Mol. Biol. 75:173-216).

Mutations in the genes 11-HSD or 11-HSD lead to human pathology. For example, in selected patients with mutations in 11-HSD deficit was observed activity on inactivation of cortisol, which in turn led to the development of the syndrome of apparent excess mineralocorticoids (also referred to as "SKY"), accompanied by hypertension, hypokalemia, and sodium retention (Edwards et al. (1988) Lancet 2: 986-989; Wilson et al. (1998) Proc. Natl. Acad. Sci. 95: 10200-10205). Similarly, mutations in the 11-HSD, as well as in the gene, encoding colocalization of NADPH-producing enzyme, glucose 6-phosphate-dehydrogenase (GDH), can cause failure cortisone-reductase (NCR); patients with these mutations observed excess androgenic hormone due to adrenocorticotropic hormone (hirsutism, irregular menstrual cycles, hyperandrogenism), and polycystic ovary syndrome (PCOS) is similar phenotype (Draper et al. (2003) Nat. Genet. 34: 434-439).

Largely violation of homeostasis in HPA-axis due to insufficient or excessive secretion or action leads to the development of Itsenko-Cushing syndrome and Addison disease, respectively (Miller and Chrousos (2001) Endocrinology and Metabolism, eds. Felig and Frohman (McGraw-Hill, New York), 4thEd.: 387-524). In patients with syndrome Itsenko-Cushing syndrome, and in patients taking glucocorticoids may develop reversible visceral adiposity. The phenotype of patients suffering from the syndrome Itsenko-Cushing syndrome, has significant similarity to the phenotype of the metabolic syndrome Raven (also known as syndrome X or insulin resistance syndrome), symptoms of which include visceral obesity, impaired cholera is in the surrounding area to glucose, insulin resistance, hypertension, type 2 diabetes and hyperlipidemia (Reaven (1993) Ann. Rev. Med. 44: 121-131). Despite the lack of full characterization of the role of glucocorticoids in obesity person, an increasing amount of data indicates that the activity of 11-HSD plays an important role in obesity and the metabolic syndrome (Bujalska et al. (1997) Lancet 349: 1210-1213); (Livingstone et al. (2000) Endocrinology 131: 560-563; Rask et al. (2001) J. Clin. Endocrinol. Metab. 86: 1418-1421; Lindsay et al. (2003) J. Clin. Endocrinol. Metab. 88: 2738-2744; Wake et al. (2003) J. Clin. Endocrinol. Metab. 88: 3983-3988).

Data obtained during testing models of transgenic mice support the hypothesis that the activity of 11-HSD in respect of adipocytes plays a major role in the process of visceral obesity and the metabolic syndrome (Alberts et al. (2002) Diabetologia. 45(11); 1526-32). Overexpression of 11-HSD in adipose tissue under the control of the promoter or in transgenic mice caused the formation of a phenotype remarkably similar to the phenotype of the metabolic syndrome person (Masuzaki et al. (2001) Science 294: 2166-2170; Masuzaki et al. (2003) J. Clinical Invest. 112: 83-90). Moreover, increased activity of 11-HSD in these mice has significant similarities with the activity observed in the obese person (Rask et al. (2001) J. Clin. Endocrinol. Metab. 86: 1418-1421), in Addition, the data obtained in tests on mice with deficiency of 11-HSD caused by homologous recombination, evidence of the comfort about the lack of 11-HSD causes decreased insulin sensitivity and impaired glucose tolerance due to tissue-specific reduction of the level of active glucocorticoid (Kotelevstev et al. (1997) Proc. Natl. Acad. Sci. 94: 14924-14929; Morton et al. (2001) J. Biol. Chem. 276: 41293-41300; Morton et al. (2004) Diabetes 53: 931-938).

Published data support the hypothesis that increased expression of 11-HSD increases the conversion of cortisone to cortisol in adipose tissue, resulting in 11-HSD plays a role in the pathogenesis of Central type of obesity, as well as in the development of the metabolic syndrome in humans (Engeli et al., (2004) Obes. Res. 12: 9-17). Consequently, from a pharmaceutical point of view 11-HSD is a promising target in the treatment of metabolic syndrome (Masuzaki et al., (2003) Curr. Drug Targets Immune Endocr. Metabol. Disord. 3: 255-62). In addition, inhibition of the activity of 11-HSD may be favorable in the treatment of numerous associated with glucocorticoids violations. For example, inhibitors of 11-HSD can be effective in the treatment of obesity and / or aspects of the cluster of metabolic syndrome, including impaired glucose tolerance, insulin resistance, hyperglycemia, hypertension and / or hyperlipidemia (Kotelevstev et al. (1997) Proc. Natl. Acad. Sci. 94: 14924-14929; Morton et al. (2001) J. Biol. Chem. 276: 41293-41300; Morton et al. (2004) Diabetes 53: 931-938). Inhibition of the activity of 11-HSD can okazyvat the beneficial effects on the pancreas, including increased insulin secretion stimulated by glucose (Billaudel and Sutter (1979) Horm. Metab. Res. 11: 555-560; Ogawa et al. (1992) J. Clin. Invest. 90: 497-504; Davani et al. (2000) J. Biol. Chem. 275: 34841-34844).

In addition, given the relationship of interpersonal differences in General cognitive function with different duration of exposure to glucocorticoids (Lupien et al. (1998) Nat. Neurosci. 1: 69-73), and that the dysregulation of the HPA-axis, which causes a chronic excess of glucocorticoids in certain sub-regions of the brain, in theory, contributes to impaired cognitive functions (McEwen and Sapolsky (1995) Curr. Opin. Neurobiol. 5: 205-216), it can be assumed that inhibition of 11-HSD will reduce the impact of glucocorticoids on the brain and, consequently, to protect neuronal activity from the harmful effects of glucocorticoids, causing impaired cognitive function, dementia and / or depression. In particular, it is known that stress and glucocorticoids affect cognitive function (de Quervain et al. (1998) Nature 394: 787-790); also observations showed that 11-HSD by controlling the actions of glucocorticoids on the brain can also affect the neurotoxicity (Rajan et al. (1996) Neuroscience 16: 65-70; Seckl (2000) Neuroendocrinol. 18:49-99).

In addition, there are data supporting the involvement of glucocorticoids and 11-HSD a change in the level of intraocular pressure (IOP) (Stokes et al. (2000) Invest. Ophthalmol. Vis. Sci. 41: 1629-1683; Rauz et al. (2001) Invet. Ophthalmol. Vis. Sci. 42: 2037-2042); if untreated, increased IOP may lead to a partial scotoma and subsequent blindness. Thus, inhibition of eye 11-HSD can cause a decrease in the local concentration of glucocorticoids and IOP. Therefore, 11-HSD can theoretically be used to treat glaucoma and other eye disorders.

In transgenic mice with ar-11-HSD high blood pressure, and increased sensitivity to dietary salt. In addition, transgenic mice was marked by elevated levels of angiotensin, angiotensin II and aldosterone in plasma, treatment of mice using antagonists of angiotensin II contributes to reduction in hypertension (Masuzaki et al. (2003) J. Clinical Invest. 112: 83-90). This effect suggests that the activity of 11-HSD can cause or exacerbate hypertension. Therefore, inhibitors of 11-HSD can be useful in the treatment of hypertension, and is also associated with hypertension, cardiovascular disorders, Inhibition of 11-HSD in Mature adipocytes, presumably, also may reduce the secretion of an inhibitor of plasminogen activator 1 (IAP-1), which is an independent factor of cardiovascular risk (Halleux et al. (1999) J. Clin. Endocrinol. Metabl. 84: 4097-4105).

Glucocorticoids can have undesirable effects on the tissues of the skeleton; prolonged exposure to glucocorticoids Yes the e in moderate doses can cause osteoporosis (Cannalis (1996) J. Clin. Endocrinol. Metab. 81: 3441-3447). In addition, 11-GST was detected in primary cultures of human osteoblasts, and bone cells adult patients (Cooper et al. (2000) Bone 27: 375-381), while the inhibitor of 11-HSD, carbenoxolone, according to the obtained data, reduces the adverse effects of glucocorticoids on the formation of Islands of ossification (Bellows et al. (1998) Bone 23: 119-125). Thus, inhibition of 11-HSD presumably causes a decrease in the local concentration of glucocorticoids in osteoblasts and osteoclasts, thereby having a positive effect on various forms of bone disease, including osteoporosis.

Inhibitors of 11-HSD can also be useful for immunomodulation. It is believed that glucocorticoids exert immunosuppressive effects, actually between the HPA axis and the immune system there is a complex dynamic interaction (Rook (1999) Baillier's Clin. Endocrinol. Metabl. 13: 576-581). Glucocorticoids may participate in modulating the balance between cellular immune response and humoral immune response. The high activity of glucocorticoids, usually associated with the humoral response. Therefore, inhibition of 11-HSD can be used as a means to bias the immune response towards the cellular immune response. Certain painful conditions, Lucaya tuberculosis, leprosy (Hansen's disease) and psoriasis cause immune response biased towards a humoral response, however, the most effective immune response may be a cellular immune response. Thus, inhibitors of 11-HSD can also be useful in the treatment of such diseases.

According to reports glucocorticoids inhibit wound healing, especially in patients with diabetic ulcers (Bitar et al. (1999) J. Surg. Res. 82: 234-243; Bitar et al. (1999) Surgery 125: 594-601; Bitar (2000) Surgery 127: 687-695; Bitar (1998) Am. J. Pathol. 152: 547-554). Among patients with impaired glucose tolerance or type 2 diabetes also often observed impaired wound healing. Glucocorticoids also increase the risk of disease and delay wound healing (Anstead (1998) Adv. Wound Care 11:277-285). In addition, the correlation between increased cortisol levels in wound fluid and non-healing wounds (EP Patent App.No, 0902288). The last published patent application contain the assumption of a beneficial effect of specific inhibitors of 11-HSD promoting the healing of wounds (PCT/US 2006/043,951).

Presented in this invention information indicates a growing need to develop new and more effective drugs, inhibiting 11-HSD. New compounds presented in this invention, are effective the inhibitors of 11-HSD.

The INVENTION

At the moment it is established that the compounds of Formula Im1or their pharmaceutically acceptability salts are effective inhibitors of 11-HSD. The invention is a compound of Formula (Im1)

;

or its pharmaceutically acceptable salt, enantiomer or diastereoisomer.

In the first embodiment of the present invention of the Formula Im1and its components specified in this document in accordance with the following definitions:

R1- (a) absent or (b) selected from (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)quinil, (C1-C3)alkoxy (C1-C3) alkoxy, or (C1-C3) alkoxy (C1-C3)alkyl, possible substituents include up to four groups independently selected from fluorine, cyano, oxo, R4, R4O-; (R4)2N-, R4O2C-, R4S, R4S(=O)-, R4S(=O)2-, R4S(=O)NR4-, (R4)2NC(=O)-, (R4)2NC(=O)O-, (R4)2NC(=O)NR4-, R4OC(=O)NR4-, (R4)2NC(=NCN)NR4-, (R4O)2P(=O)O-, (R4O)2P(=O)NR4-, R4OS(=O)2NR4-, (R4)2NS(=O)2O-, (R4)2NS(=O)2NR4-, R4S(=O)2NR4-, R4S(=O)NHC(=O)-, R4S(=O)NHC(O)O-, R4S(=O)2NHC(=O)NR4-, R4OS(=O)2NHC(=O)-, R4OS(=O)2NHC(=O)O-, R4OS(=O)2NHC(=O)NR4-, (R4)2NS(=O)2NHC(=O)-, (R4)2NS(=O)2NHC(=O)O-, (R4)2NS(=O)2NHC(=O)NR4-, R4C(=O)NHS(=O)2-, R4C(=O)NHS(=O)2O-, R4C(=O)NHS(=O)2NR4-, R4OC(=O)NHS(=O)2-, R4OC(=O)NHS(=O)2O-, R4OC(=O)NHS(=O)2NR4-, (R4)2NC(=O)NHS(=O)2-, (R4)2NC(=O)NHS(=O)2O-, (R4)2NC(=O)NHS(=O)2NR4-, heterocyclyl, heteroaryl, arylamino, heteroallyl;

And1represents (a) a bond or (b) (C1-C3)alkylene, CH2CH2O, in which the oxygen is attached to su1or CH2C(=O), in which the carbonyl carbon is attached to su1;

Su1represents aryl, heteroaryl, monocyclic cycloalkyl or monocyclic heterocyclyl, possible substituents which include from 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkenyl, (C2-C6)alkenyl, halo, (C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (the 2-C6)quinil, (C3-C6)cycloalkyl(C2-C4)quinil, halo, (C1-C6)alkyl, halo(C3-C6)cycloalkyl, halo, (C4-C7)cycloalkenyl, (C1-C6)alkoxy, (C3-C6)cycloalkane, (C4-C7)cycloalkylcarbonyl, halo, (C1-C6)alkoxy, halo(C3-C6)cycloalkane, halo, (C4-C7)cycloalkylcarbonyl, (C1-C6)alkylthio, (C3-C6)cycloalkyl, (C4-C7)cycloalkylation, halo, (C1-C6)alkylthio, halo, (C3-C6)cycloalkyl, halo, (C4-C7)cycloalkylation, (C1-C6)alkanesulfonyl, (C3-C6)cycloalkylcarbonyl, (C4-C7)cycloalkylcarbonyl, halo, (C1-C6)alkanesulfonyl, halo, (C3-C6)cycloalkylcarbonyl, halo, (C4-C7)cycloalkylcarbonyl, (C1-C6)alkanesulfonyl, (C3-C6)cycloalkylcarbonyl, (C4-C7)cycloalkylcarbonyl, halo, (C1-C6)alkanesulfonyl, halo, (C3-C6)cycloalkylcarbonyl, halo, (C4-C7)cyclo-alkylaminocarbonyl, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy(C1-C6)alkoxy, halo(C1-C6)alkoxy(C -C6)alkoxy, (C1-C6)alkoxycarbonyl, H2NCO, H2NSO2, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, (C1-C3)alkoxy(C1-C3)alkylaminocarbonyl, geterotsiklicheskikh, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, heterocyclization, (C1-C6)alkylcarboxylic, (C2-C6)alkylcarboxylic(C1-C6)alkyl, (C1-C6)alkylsulfonyl, (C1-C6)alkyl-sulfonylamino(C1-C6)alkyl, (C1-C6)alkoxycarbonyl(C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkoxy, heteroaryl, oxo, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl amino(C1-C6)alkoxy, (C1-C6)alkylamino(C1-C6)alkoxy, di(C1-C6)alkylamino(C2-C6)alkoxy, (C1-C6)alkylsulphonyl, (C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylcarbonyl, {(C3-C6)cycloalkyl}{(C1-C6)alkyl}aminocarbonyl, di(C3/sub> -C6)cycloalkylcarbonyl, (C3-C6)cycloalkylcarbonyl, {(C3-C6)cycloalkyl}{(C1-C6)alkyl}aminosulfonyl, di(C3-C6)cycloalkylcarbonyl, cyano(C1-C6)alkyl, aminocarbonyl(C1-C6)alkyl, (C1-C6)alkylaminocarbonyl(C1-With6)alkyl, di(C1-C6)alkylaminocarbonyl(C1-C6)alkyl, (C3-C6)cycloalkylcarbonyl(C1-C6)alkyl, {(C3-C6)cycloalkyl}{(C1-C6)alkyl}aminocarbonyl(C1-C6)alkyl and di(C3-C6)cycloalkylcarbonyl(C1-C6)alkyl.

Possible substituents oxodegradable ring of the Formula Im1include from 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkenyl, (C1-C6)alkenyl, halo, (C1-C6)alkenyl, hydroxy(C1-C6)alkenyl, (C2-C6)quinil, (C3-C6)cycloalkyl(C2-C4)quinil, halo, (C1-C6)alkyl, halo(C3-C6)cycloalkyl, halo, (C4-C7)cycloalkyl is the alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkane, (C4-C7)cycloalkylcarbonyl, halo, (C1-C6)alkoxy, halo(C3-C6)cycloalkane, halo, (C4-C7)cycloalkylcarbonyl, (C1-C6)alkylthio, (C3-C6)cycloalkyl, (C4-C7)cycloalkylation, halo, (C1-C6)alkylthio, halo, (C3-C6)cycloalkyl, halo, (C4-C7)Cycloalkylation, (C1-C6)alkanesulfonyl, (C3-C6)cycloalkylcarbonyl, (C4-C7)cycloalkylcarbonyl, halo, (C1-C6)alkanesulfonyl, halo, (C3-C6)cycloalkylcarbonyl, halo, (C4-C7)cycloalkylcarbonyl, (C1-C6)alkanesulfonyl, (C3-C6)cycloalkylcarbonyl, (C4-C7)cycloalkylcarbonyl, halo, (C1-C6)alkanesulfonyl, halo, (C3-C6)cycloalkylcarbonyl, halo, (C4-C7)cyclo-alkylaminocarbonyl, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy(C1-C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, H2NCO, H2NSO2, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, (C1-C3)alkoxy(C1- 3)alkylaminocarbonyl, geterotsiklicheskikh, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, heterocyclization, (C1-C6)alkylcarboxylic, (C1-C6)alkylcarboxylic(C1-C6)alkyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonyl(C1-C6)alkyl, (C1-C6)alkoxycarbonyl(C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkoxy, heteroaryl, oxo, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl amino(C2-C6)alkoxy, (C1-C6)alkylamino(C2-C6)alkoxy, di(C1-C6)alkylamino(C1-C6)alkoxy, (C1-C6)alkylsulphonyl, (C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylcarbonyl, {(C3-C6)cycloalkyl}{(C1-C6)alkyl}aminocarbonyl, di(C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylcarbonyl, {(C3-C6)cycloalkyl}{(C1-C6)alkyl}aminosulfonyl, di(C3-C6)cycloalkylation the Nile, cyano(C1-C6)alkyl, aminocarbonyl(C1-C6)alkyl, (C1-C6)alkylaminocarbonyl(C1-C6)alkyl, di(C1-C6)alkylaminocarbonyl(C1-C6)alkyl, (C3-C6)cycloalkylcarbonyl(C1-C6)alkyl, {(C3-C6)cycloalkyl}{(C1-C6)alkyl}aminocarbonyl(C1-C6)alkyl and di(C3-C6)cycloalkylcarbonyl(C1-C6)alkyl;

E represents (a) a bond or (b) (C1-C3)alkylene or (C1-C2)alkylenedioxy where attached to R2possible substituents each of which include from 1 to 4 groups independently selected from methyl, ethyl, trifloromethyl or oxo;

R2is a (C1-C6)alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl, possible substituents include from 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkenyl, (C2-C6)alkenyl, halo, (C2-C6)alkenyl, hydroxy(C1-C6)alkenyl, (C1-C6)quinil, (C3-C6)cycloalkyl(C2-C4 )quinil, halo, (C1-C6)alkyl, halo(C3-C6)cycloalkyl, halo, (C4-C7)cycloalkenyl, (C1-C6)alkoxy, (C3-C6)cycloalkane, (C4-C7)cycloalkylcarbonyl, halo, (C1-C6)alkoxy, halo(C3-C6)cycloalkane, halo, (C4-C7)cycloalkylcarbonyl, (C1-C6)alkylthio, (C3-C6)cycloalkyl, (C4-C7)cycloalkylation, halo, (C1-C6)alkylthio, halo, (C3-C6)cycloalkyl, halo, (C4-C7)cycloalkylation, (C1-C6)alkanesulfonyl, (C3-C6)cycloalkylcarbonyl, (C4-C7)cycloalkylcarbonyl, halo, (C1-C6)alkanesulfonyl, halo, (C3-C6)cycloalkylcarbonyl, halo, (C4-C7)cycloalkylcarbonyl, (C1-C6)alkanesulfonyl, (C3-C6)cycloalkylcarbonyl, (C4-C7)cycloalkylcarbonyl, halo, (C1-C6)alkanesulfonyl, halo, (C3-C6)cycloalkylcarbonyl, halo, (C4-C7)cyclo-alkylaminocarbonyl, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy(C1-C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, H2NCO, H2NO 2, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, (C1-C3)alkoxy(C1-C3)alkylaminocarbonyl, geterotsiklicheskikh, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, heterocyclization, (C1-C6)alkylcarboxylic, (C1-C6)alkylcarboxylic(C1-C6)alkyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonyl(C1-C6)alkyl, (C1-C6)alkoxycarbonyl(C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkoxy, heteroaryl, oxo, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl amino(C2-C6)alkoxy, (C1-C6)alkylamino(C2-C6)alkoxy, di(C1-C6)alkylamino(C2-C6)alkoxy, (C1-C6)alkylsulphonyl, (C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylcarbonyl, {(C3-C6)cycloalkyl}{(C1-C6)alkyl}aminocarbonyl, di(C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylation is sulfonyl, {(C3-C6)cycloalkyl}{(C1-C6)alkyl}aminosulfonyl, di(C3-C6)cycloalkylcarbonyl, cyano(C1-C6)alkyl, aminocarbonyl(C1-C6)alkyl, (C1-C6)alkylaminocarbonyl(C1-C6)alkyl, di(C1-C6)alkylaminocarbonyl(C1-C6)alkyl, (C3-C6)cycloalkylcarbonyl(C1-C6)alkyl, {(C3-C6)cycloalkyl}{(C1-C6)alkyl}aminocarbonyl(C1-C6)alkyl and di(C3-C6)cycloalkylcarbonyl(C1-C6)alkyl;

R3selected from (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)quinil, (C3-C5)cycloalkyl(C1-C4)alkyl, (C1-C3)alkoxy(C1-C3)alkoxy or (C1-C3)alkoxy(C1-C3)alkyl, possible substituents include up to four groups independently selected from fluorine, cyano, oxo, R4, R4O-, (R4)2N-, R4O2C-, R4C(=O)O-, R4S, R4S(=O)-, R4S(=O)2-, R4C(=O)NR4-, (R4)2NC(=O)-, (R4)2NC(=O)O-, (R4)2NC(=O)NR4-, R4OC(=O)NR4-, (R4)2NC(=NCN)NR4-, (R4O)2P(=O)O-, (R4O)2P(=O)NR4-, R4OS(=O)2NR4-, (R4)2NS(=O)2/sub> O-, (R4)2NS(=O)2NR4-, R4S(=O)2NR4-, R4S(=O)2NHC(=O)-, R4S(=O)2NHC(=O)O-, R4S(=O)2NHC(=O)NR4-, R4OS(=O)2NHC(=O)-, R4OS(=O)2NHC(=O)O-, R4OS(=O)2NHC(=O)NR4-, (R4)2NS(=O)2NHC(=O)-, (R4)2NS(=O)2NHC(=O)O-, (R4)2NS(=O)2NHC(=O)NR4-, R4C(=O)NHS(=O)2-, R4C(=O)NHS(=O)2O-, R4C(=O)NHS(=O)2NR4-, R4OC(=O)NHS(=O)2-, R4OC(=O)NHS(=O)2O-, R4OC(=O)NHS(=O)2NR4-, (R4)2NC(=O)NHS(=O)2-, (R4)NC(=O)NHS(=O)2O-, (R4)2NC(=O)NHS(=O)2NR4- spirocyclohexane; heterocyclyl (possible substituents which, in turn, include alkyl, haloalkyl, halogen or oxo), heteroaryl (possible substituents which, in turn, include alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2N-monoalkyl-substituted amido, N,N-dialkyl - substituted amido, or oxo), arylamino (possible substituents which, in turn, include alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2N-monoalkyl - substituted amido and N,N-dialkyl - substituted amido) and heteroarenes (possible substituents which, in turn, include lcil, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N-monoalkyl-substituted amido, N,N-dialkyl - substituted amido, or oxo); and

R4independently selected from H, (C1-C6)alkyl, halo(C1-C6)alkyl amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl, hydroxy(C1-C6)alkyl and (C1-C6)alkoxy(C1-C6)alkyl.

Alternatively, the first variant of implementation of the present invention, described above, does not include compounds with the structural Formula PR-221 and PR-313 or their pharmaceutically acceptable salt, enantiomer or diastereoisomer.

The following variant of implementation of the present invention is a pharmaceutical composition comprising i) a pharmaceutically acceptable carrier or solvent, and (ii) a compound of Formulas Ik, 11, Im2, Im5In1In2In5Io1Io2Io5Ip1Ip3or its pharmaceutically acceptable salt, enantiomer or diastereoisomer.

The following variant of implementation of the present invention is a method of inhibiting the activity of 11β-HSD comprising the step of introducing a mammal, the needs of the targets of such treatment, an effective amount of a compound of Formulas Ik, Im1, Im2, Im5In1In2In5Io1Io2Io5Ip1Ip3or its pharmaceutically acceptable salt, enantiomer or diastereoisomer.

The following variant of implementation of the present invention is a method of treatment of a patient suffering from a disease associated with the activity or expression of 11β-HSD comprising the step of accepting a patient an effective amount of a compound of Formulas Ik, Im1, Im2, Im5, 1P1In2In5Io1Io2Io5Ip1Ip3or its pharmaceutically acceptable salt, enantiomer or diastereoisomer

The following variant of implementation of the present invention is a method of using compounds of Formulas Ik, Im1, Im2, Im5In1In2In5Io1Io2Io5Ip1Ip3or its pharmaceutically acceptable salt, enantiomer or diastereoisomer in the manufacture of medicaments intended for the inhibition of the activity of 11β-HSD in mammals in need of such treatment,

The following variant of implementation of the present invention is a method of using compounds of Formulas Ik, Im1, Im2, Im5In1In2In5Io Io2Io5Ip1Ip3or its pharmaceutically acceptable salt, enantiomer or diastereoisomer in the manufacture of medicinal products intended to treat patients suffering from diseases associated with the activity or expression of 11β-HSD.

The following variant of implementation of the present invention is a compound of Formulas Ik, Im1, Im2, lm5In1In2In5Io1Io2Io5Ip1Ip3or its pharmaceutically acceptable salt, enantiomer or diastereoisomer intended for inhibiting the activity R-HSD in mammals in need of such treatment,

The following variant of implementation of the present invention is a compound of Formulas Ik, lm1, lm2, lm5In1In2In5Io1Io2Io5Ip1Ip3or its pharmaceutically acceptable salt, enantiomer or diastereoisomer, designed to treat patients suffering from diseases associated with the activity or expression of 11β-HSD.

DETAILED DESCRIPTION of the PRESENT INVENTION

The present invention is a compound of Formula Ik:

;

or its pharmaceutically acceptable salt, enantiomer or diastereoisomer; where

R1aUTS is tstuat or represents methyl or ethyl;

Su2represents a 2-oxo-1,2-dihydropyridin, possible substituents include from 1 to 4 groups independently selected from halo, hydroxy, methoxy, hydroxymethyl, methoxycarbonyl, amino, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, (2-methoxyethyl)aminocarbonyl, acetamidomethyl, methylsulfonyl, methylsulfonylamino, methylaminomethyl, isopropylaminocarbonyl, dimethylaminomethyl, pyrrolidin-1-sulfonyl, methylsulfonylmethyl, tetrazolyl, methyl, trifloromethyl, acetyl, 2-hydroxyethyl and 1-aminoethyl;

R2represents phenyl, thienyl, pyridyl or isopropyl, possible substituents each of which include halo, methyl, methylthio or (4-morpholino)methyl; and

R3represents methyl, ethyl, propyl, butyl, vinyl, allyl or ethoxyethyl, possible substituents each of which include up to two groups independently selected from methyl, BUT-, MeO-, H2N-, MeC(=O)NH-, MeS(=O)2NH-, H2NC(=O)-, MeNHC(=O)-, HO2C-, (HO)2P(=O)O-, H2NS(=O)2O, H2NS(=O)2NH-, MeNHC(=O)NH-, MeNHC(=O)O-, oxo, cyano, BUT2With-, HOCH2CH2NH-, 4-morpholino, HOCH2C(=O)NH-, H2NCH2C(=O)NH-, EtNHC(=O)NH, MeOC(=O)NH-, MeNHC(=NC=N)NH-, Me-, MeS-, MeSO2-MeSO2N(Me)-, MeS(=O)2NHC(=O)-, imidazolinone, imidazolyl, tetrazolyl, H2NCONH-, H2NCO2- NON2CH2 O-, MeNH-, Me2N - and MeCONMe.

The following variant of implementation of the present invention is a compound of any of Formula Im1, Im2and Im5or its pharmaceutically acceptable salt, enantiomer or diastereoisomer;:

.

Possible substituents oxodegradable rings (including the replacement of carbon atoms in the ring attached to atoms of hydrogen, and nitrogen atoms in the ring attached to the hydrogen atoms, i.e., including substituted nitrogen atom in the ring") in the Formula Im1, Im2and Im5include up to four substituents as described above. Suitable substituents oxodegradable ring, and suitable values of R1, R2, R3And1Su1and E above in the first embodiment of the present invention. Alternatively, suitable substituents su1and oxodegradable rings in Formulas Im1, Im2and Im5can be independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkenyl, (C1-C6)alkenyl, ha what about(C 2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)quinil, (C3-C6)cycloalkyl(C2-C4)quinil, halo, (C1-C6)alkyl, halo(C3-C6)cycloalkyl, halo, (C4-C7)cycloalkenyl, (C1-C6)alkoxy, (C3-C6)cycloalkane, (C4-C7)cycloalkylcarbonyl, halo, (C1-C6)alkoxy, halo(C3-C6)cycloalkane, halo, (C4-C7)cycloalkylcarbonyl, (C1-C6)alkylthio, (C3-C6)cycloalkyl, (C4-C7)cycloalkylation, halo, (C1-C6)alkylthio, halo, (C3-C6)cycloalkyl, halo, (C4-C7)cycloalkylation, (C1-C6)alkanesulfonyl, (C3-C6)cycloalkylcarbonyl, (C4-C7)cycloalkylcarbonyl, halo, (C1-C6)alkanesulfonyl, halo, (C3-C6)cycloalkylcarbonyl, halo, (C4-C7)cycloalkylcarbonyl, (C1-C6)alkanesulfonyl, (C3-C6)cycloalkylcarbonyl, (C4-C7)cycloalkylcarbonyl, halo, (C1-C6)alkanesulfonyl, halo, (C3-C6)cycloalkylcarbonyl, halo, (C4-C7)cyclo-alkylaminocarbonyl, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)ALCO is C(C 1-C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, H2NCO, HaNSO2, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, (C1-C3)alkoxy(C1-C3)alkylaminocarbonyl, geterotsiklicheskikh, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, heterocyclization, (C1-C6)alkylcarboxylic, (C1-C6)alkylcarboxylic(C1-C6)alkyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonyl(C1-C6)alkyl, (C1-C6)alkoxycarbonyl(C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkoxy, heteroaryl, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, di(C2-C6)alkylamino(C1-C6)alkyl amino(C1-C6)alkoxy, (C1-C6)alkylamino(C2-C6)alkoxy, di(C1-C6)alkylamino(C2-C6)alkoxy, (C1-C6)alkylsulphonyl, (C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylcarbonyl, {(C3-C6)cycle is alkyl}{(C 1-C6)alkyl}aminocarbonyl, di(C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylcarbonyl, {(C3-C6)cycloalkyl}{(C1-C6)alkyl}aminosulfonyl, di(C3-C6)cycloalkylcarbonyl, cyano(C1-C6)alkyl, aminocarbonyl(C1-C6)alkyl, (C1-C6)alkylaminocarbonyl(C1-C6)alkyl, di(C1-C6)alkylaminocarbonyl(C1-C6)alkyl, (C3-C6)cycloalkylcarbonyl(C1-C6)alkyl, {(C3-C6)cycloalkyl}{(C1-With6)alkyl}aminocarbonyl(C1-C6)alkyl and di(C3-C6)cycloalkylcarbonyl(C1-C6)alkyl; podhodila values of R1, R2, R3And1Su1and E above in the first embodiment of the present invention. Alternatively, suitable substituents su1may include (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, halogen, cyano and nitro; suitable substituents for a substitutable nitrogen atom in oxopiperidine ring in the Formula Im1, Im2and Im5include (C1-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4) cycloalkyl(C1-C2)Ala is l and (C 1-C4)haloalkyl; suitable substituents for a substitutable carbon atom in oxopiperidine ring in the Formula Im1, Im2and Im5include fluorine, chlorine, cyano, hydroxy, amino, (C1-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, CONH2, (C1-C4)alkylaminocarbonyl, di(C1-C4)alkylaminocarbonyl and (C1-C4)alkylcarboxylic; suitable values of R1, R2R3And, su1and E above in the first embodiment of the present invention.

Alternatively, the options presented in this section do not include the following connections:

(R)-6-(3-hydroxypropyl)-3-((3)-1-(4-(6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-it.

; and

(R)-6-(3-hydroxypropyl)-3-((8)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-he

;

or its pharmaceutically acceptable salt, enantiomer or diastereoisomer.

For each of the options described in the previous section, R1preferably represents methyl or ethyl.

For each of the options described in this section, the bar is dstone after Formula Im 1, Im2and Im5, R1preferably represents methyl or ethyl; and R3represents a MeSO2NHCH2CH2CH2N2NC(=O)CH2CH2N2NC(=O)CME2CH2, 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the options described in this section directly after the Formula Im1, Im2and Im5, R1preferably represents methyl or ethyl; and R3represents H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the options described in this section directly after the Formula Im1, Im2and Im5, R1preferably represents methyl or ethyl; R2represents phenyl substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH2, (C1-C4)alkyl, (C1-C4)haloalkyl, and SO2Me; a R3represents a MeSO2NHCH2CH2CH2H2NC(=O)CH2CH2H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the options described in this section directly to the public after Formula Im 1, Im2and Im5, R1preferably represents methyl or ethyl; R2represents phenyl substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH2, (C1-C4)alkyl, (C1-C4)haloalkyl, and SO2Me; a R3represents H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the options described in this section directly after the Formula Im1, Im2and Im5, R1preferably represents methyl or ethyl; and R3represents a 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the options described in this section directly after the Formula Im1, Im2and Im5, R1preferably represents methyl or ethyl; R2represents phenyl or forfinal; and R3represents a 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the options described in this section directly after the Formula Im1, Im2and Im5, R1preferably represents methyl or ethyl; R2represents phenyl or forfinal; and R3represents a 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; the substituents of the substituted is on the nitrogen atom in oxopiperidine ring in the Formula Im 1, Im2and Im5include (C1-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2)alkyl or (C1-C2)haloalkyl; and the possible substituents of one or two carbon atoms in oxopiperidine ring in the Formula Im1, Im2and Im5include methyl or ethyl.

The following variant of implementation of the present invention is a compound of any of Formulas In1In2and In5or its pharmaceutically acceptable salt, enantiomer or diastereoisomer:

.

Possible substituents oxodegradable rings (including the replacement of carbon atoms in the ring attached to atoms of hydrogen, and nitrogen atoms in the ring attached to the hydrogen atoms, i.e., including substituted nitrogen atom in the ring") in the Formulas In1In2and In5include up to four substituents as described above for su2. Suitable substituents oxodegradable ring, and suitable values of R1, R2, R3and su1presented above in the first embodiment of the present invention. Alternatively, suitable substituents su1and oxodegradable rings in Formulas In1In and In5can be independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkenyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)quinil, (C3-C6)cycloalkyl(C2-C4)quinil, rano(C1-C6)alkyl, halo(C3-C6)cycloalkyl, halo, (C4-C7)cycloalkenyl, (C1-C6)alkoxy, (C3-C6)cycloalkane, (C4-C7)cycloalkylcarbonyl, halo, (C1-C6)alkoxy, halo(C3-C6)cycloalkane, halo, (C4-C7)cycloalkylcarbonyl, (C1-C6)alkylthio, (C3-C6)cycloalkyl, (C4-C7)cycloalkylation, halo, (C1-C6)alkylthio, halo, (C3-C6)cycloalkyl, halo, (C4-C7)cycloalkylation, (C1-C6)alkanesulfonyl, (C3-C6)cycloalkylcarbonyl, (C4-C7)cycloalkylcarbonyl, halo, (C1-C6)alkanesulfonyl, halo, (C3-C6)cycloalkylcarbonyl, halo, (C4-C7)cycloalkylcarbonyl, (C1-C6)alkanesulfonyl, (C3-C 6)cycloalkylcarbonyl, (C4-C7)cycloalkylcarbonyl, halo, (C1-C6)alkanesulfonyl, halo, (C3-C6)cycloalkylcarbonyl, halo, (C4-C7)cycloalkylcarbonyl, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy(C1-C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, H2NCO, H2NSO2, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, (C1-C3)alkoxy(C1-C3)alkylaminocarbonyl, geterotsiklicheskikh, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, heterocyclization, (C1-C6)alkylcarboxylic, (C1-C6)alkylcarboxylic(C1-C6)alkyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonyl(C1-C6)alkyl, (C1-C6)alkoxycarbonyl(C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkoxy, heteroaryl, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1 -C6)alkyl amino(C2-C6)alkoxy, (C1-C6)alkylamino(C2-C6)alkoxy, di(C1-C6)alkylamino(C2-C6)alkoxy, (C1-C6)alkylsulphonyl, (C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylcarbonyl, {(C3-C6)cycloalkyl}{(C1-C6)alkyl}aminocarbonyl, di(C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylcarbonyl, {(C3-C6)cycloalkyl}{(C1-C6)alkyl}aminosulfonyl, di(C3-C6)cycloalkylcarbonyl, cyano(C1-C6)alkyl, aminocarbonyl(C1-C6)alkyl, (C1-C6)alkylaminocarbonyl(C1-C6)alkyl, di(C1-C6)alkylaminocarbonyl(C1-C6)alkyl, (C3-C6)cycloalkylcarbonyl(C1-C6)alkyl, {(C3-C6)cycloalkyl}{(C1-C6)alkyl}aminocarbonyl(C1-C6)alkyl and di(C3-C6)cycloalkylcarbonyl(C1-With6)alkyl; with the appropriate values of R1, R2, R3and su1presented above in the first embodiment of the present invention. Alternatively, suitable substituents su1may include (C1-C4)alkyl, (C1-C4) alkoxy, (C1-C4)ha is alkyl, (C1-C4)haloalkoxy, halogen, cyano and nitro; suitable substituents for a substitutable nitrogen atom in oxopiperidine ring in Formulas In1In2and In5include (C1-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4) cycloalkyl (C1-C4)alkyl and (C1-C4)haloalkyl; suitable substituents for a substitutable carbon atom in oxopiperidine ring in Formulas In1In2and In5include fluorine, chlorine, cyano, hydroxy, amino, (C1-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C6)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, CONH2, (C1-C4)alkylaminocarbonyl, di(C1-C4) alkylaminocarbonyl and (C1-C4)alkylcarboxylic; suitable values of R1, R2, R3and su1presented above in the first embodiment of the present invention. Alternatively, the options presented in this section do not include compounds PR-221 and PR-313 or their pharmaceutically acceptable salt, enantiomer or diastereoisomer

For each of the options described in the previous section, R1preferably represents methyl or ethyl.

For each of the options described what's in this section directly after the Formulas In 1In2and In5, R1preferably represents methyl or ethyl; and R3represents a MeSO2NHCH2CH2CH2H2NC(=O)CH2CH2N2NC(=O)CME2CH2, 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the options described in this section directly after the Formulas In1In2and In5, R1preferably represents methyl or ethyl; and R3represents H2NC(=O)CME2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the options described in this section directly after the Formulas In1In2and In5, R1preferably represents methyl or ethyl; R2represents phenyl substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH2, (C1-C4)alkyl, (C1-C4)haloalkyl, and SO2Me; a R3represents a MeSO1NHCH2CH2CH2N2NC(=O)CH2CH2H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the options described in this section C is directly after the Formulas In 1In2and In5, R1preferably represents methyl or ethyl; R2represents phenyl substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH2, (C1-C4)alkyl, (C1-C4)haloalkyl, and SO2Me; a R3represents H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl..

For each of the options described in this section directly after the Formulas In1In2and In6, R1preferably represents methyl or ethyl; and R3represents a 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the options described in this section directly after the Formulas In1In2and In5, R1preferably represents methyl or ethyl; R2represents phenyl or forfinal; and R3represents a 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the options described in this section directly after the Formulas In1In2and In5, R1preferably represents methyl or ethyl; R2represents phenyl or forfinal; and R3represents a 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; the substituents of the substituted is on the nitrogen atom in oxopiperidine ring in Formulas In 1In2and In5include (C1-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2)alkyl or (C1-C2)haloalkyl; and the possible substituents of one or two carbon atoms in oxopiperidine ring in Formulas In1In2and In5include methyl or ethyl.

The following variant of implementation of the present invention is a compound of any of Formula Io1Io2and Io5or its pharmaceutically acceptable salt:

.

Possible substituents oxodegradable rings (including the replacement of carbon atoms in the ring attached to atoms of hydrogen, and nitrogen atoms in the ring attached to the hydrogen atoms, i.e., including substituted nitrogen atom in the ring") in Formulas Io1Io2and Io5include up to four substituents as described above for the first variant implementation of the present invention; suitable values for G1include fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkenyl, (C2-C6)alkenyl, ha what about(C 2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)quinil, (C3-C6)cycloalkyl(C2-C4)quinil, halo, (C1-C6)alkyl, halo(C3-C6)cycloalkyl, halo, (C4-C7)cycloalkenyl, (C1-C6)alkoxy, (C3-C6)cycloalkane, [C4-C7)cycloalkylcarbonyl, halo, (C1-C6)alkoxy, halo(C3-C6)cykolhki, halo, (C4-C7)cycloalkylcarbonyl, (C1-C6)alkylthio, (C3-C6)cycloalkyl, (C4-C7)cycloalkylation, halo, (C1-C6)alkylthio, halo, (C3-C6)cycloalkyl, halo, (C4-C7)cycloalkylation, (C1-C6)alkanesulfonyl, (C3-C6)cycloalkylcarbonyl, (C4-C7)cycloalkylcarbonyl, halo, (C1-C6)alkanesulfonyl, halo, (C3-C6)cycloalkylcarbonyl, halo, (C4-C7)cycloalkylcarbonyl, (C1-C6)alkanesulfonyl, (C3-C6)cycloalkylcarbonyl, (C4-C7)zicoellences.html, halo, (C1-C6)alkanesulfonyl, halo, (C3-C6)cycloalkylcarbonyl, halo, (C4-C7)cycloalkylcarbonyl, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy(C1-C6)and is coxi, halo(C1-C6)alkoxy(C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, H2NCO, H2NSO2, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, (C1-C3)alkoxy(C1-C3)alkylaminocarbonyl, heterocalixarenes, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, heterocyclization, (C1-C6)alkylcarboxylic, (C1-C6)alkylcarboxylic(C1-C6)alkyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonyl(C1-C6)alkyl, (C1-C6)alkoxycarbonyl(C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkoxy, heteroaryl, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl, amino(C2-C6)alkoxy, (C1-C6)alkylamino(C2-C6)alkoxy, di(C1-C6)alkylamino(C2-C6)alkoxy, (C1-C6)alkylsulphonyl, (C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylcarbonyl, {(C3-C6)cycloalkyl}{(C1-C6)alkyl}am noncarbonyl, di(C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylcarbonyl, {(C3-C6)cycloalkyl}{(C1-C6)alkyl}aminosulfonyl, di(C3-C6)cycloalkylcarbonyl, cyano(C1-C6)alkyl, aminocarbonyl(C1-C6)alkyl, (C1-C6)alkylaminocarbonyl(C1-C6)alkyl, di(C1-C6)alkylaminocarbonyl(C1-C6)alkyl, (C3-C6)cycloalkylcarbonyl(C1-C6)alkyl, {(C3-C6)cycloalkyl}{(C1-C6)alkyl}aminocarbonyl(C1-C6)alkyl and di(C3-C6)cycloalkylcarbonyl(C1-C6)alkyl; n is 0, 1, 2 or 3, and suitable substituents for oxodegradable rings and the appropriate values for R1, R2and R3presented in the description of the first variant implementation of the present invention. Alternatively, n is 0, 1, 2 or 3; suitable values for G1and the substituents for oxodegradable rings in Formulas Io1Io2and Io5independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cyclo is kilakila, (C2-C6)alkenyl, halo, (C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)quinil, (C3-C6)cycloalkyl(C2-C4)quinil, halo, (C1-C6)alkyl, halo(C3-C6)cycloalkyl, halo, (C4-C7)cycloalkenyl, (C2-C6)alkoxy, (C3-C6)cycloalkane, (C4-C7)cycloalkylcarbonyl, halo, (C1-C6)alkoxy, halo(C3-C6)cycloalkane, halo, (C4-C7)cycloalkylcarbonyl, (C1-C6)alkylthio, (C3-C6)cycloalkyl, (C4-C7)cycloalkylation, halo, (C1-C6)alkylthio, halo, (C3-C6)cycloalkyl, halo, (C4-C7)cycloalkylation, (C1-C6)alkanesulfonyl, (C3-C6)cycloalkylcarbonyl, (C4-C7)cycloalkylcarbonyl, halo, (C1-C6)alkanesulfonyl, halo, (C3-C6)cycloalkylcarbonyl, halo, (C4-C7)cycloalkylcarbonyl, (C1-C6)alkanesulfonyl, (C3-C6)cycloalkylcarbonyl, (C4-C7)cycloalkylcarbonyl, halo, (C1-C6)alkanesulfonyl, halo, (C3-C6)cycloalkylcarbonyl, halo, (C4-C7)cyclo-alkylaminocarbonyl, (C1-C6)alkylamino, di(C1-C6)alkyl is Ino, (C1-C6)alkoxy(C1-C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, H2NCO, H2NSO2, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, (C1-C3)alkoxy(C1-C3)alkylaminocarbonyl, geterotsiklicheskikh, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, heterocyclization, (C1-C6)alkylcarboxylic, (C1-C6)alkylcarboxylic(C1-C6)alkyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonyl(C1-C6)alkyl, (C1-C6)alkoxycarbonyl(C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkoxy, heteroaryl, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-With6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl amino(C1-C6)alkoxy, (C1-C6)alkylamino(C2-C6)alkoxy, di(C1-C6)alkylamino(C2-C6)alkoxy and (C1-C6)alkylsulphonyl, values for R1, R2and R3correspond to those specified in the description of the research Institute of the first variant implementation of the present invention. Alternatively, n is 0, 1, 2 or 3; suitable values for G1include (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, halogen, cyano and nitro; suitable substituents for the nitrogen atom in oxopiperidine ring in Formulas Io1Io2and Io5include C1-C4alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C3)alkyl and C1-C4haloalkyl; suitable substituents for a carbon atom in oxidehydrogenation ring in Formulas Io1Io2and Oo5include fluorine, chlorine, cyano, hydroxy, amino, (C1-C4)alkyl, (C3-With4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, CONH2, (C1-C4)alkylaminocarbonyl, di(C1-C4)alkylaminocarbonyl and (C1-C4)alkylcarboxylic; suitable values for R1, R2and R3match those presented in the description of the first variant implementation of the present invention. Alternatively, the options presented in this section do not include compounds PR-221 and PR-313 or their pharmaceutically acceptable salt, enantiomer or diastereoisomer.

For each of the options described in the previous section, R1preferably represents methyl or ethyl.

For each of the options described in this section directly after Formula Io1Io2and Io5, R1preferably represents methyl or ethyl; and R3represents a MeSO2NHCH2CH2CH2H2NC(=O)CH2CH2H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl

For each of the options described in this section directly after Formula Io1Io2and Io5, R1preferably represents methyl or ethyl; and R3represents H2NC(=O)CME2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the options described in this section directly after Formula Io1Io2and Io5, R1preferably represents methyl or ethyl; R2represents phenyl substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH2, (C1-C4)alkyl, (C1-C4)haloalkyl, and SO2Me; a R3represents a MeSO2NHCH2CH2CH2H2NC(=O)CH2C 2H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2 - hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the options described in this section directly after Formula Io1Io2and Io5, R1preferably represents methyl or ethyl; R2represents phenyl substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH2, (C1-C4)alkyl, (C1-C4)haloalkyl, and SO2Me; and R3represents H2NC(=O)CME2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the options described in this section directly after Formula Io1Io2and Io5, R1preferably represents methyl or ethyl; R3represents a 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the options described in this section directly after Formula Io1Io2and Io5, R1preferably represents methyl or ethyl; R2represents phenyl or forfinal; and R3represents a 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the options described in this section directly after Formula Io1 Io2and Io5, R1preferably represents methyl or ethyl; R2represents phenyl or forfinal; and R3represents a 2 - hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; the substituents of the substituted nitrogen atom in oxopiperidine ring in Formulas Io1Io2and Io5include (C1-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2)alkyl or (C1-C2)haloalkyl; and the possible substituents of one or two carbon atoms in oxopiperidine ring in Formulas Io1Io2and Io5include methyl or ethyl.

The following variant of implementation of the present invention (referred to herein as the "First alternative implementation of the present invention") is a compound having structural Formula Io1Io2and Io5in which: n is 0 or 1, preferably 0; each G1independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, halogen, cyano or nitro; the nitrogen atom is substituted in oxopiperidine ring hydroxy(C1-C6)alkyl, (C1-C6)alkylcarboxylic(C1-C6)alkyl, (C1-C6)alkyls is phenylamino(C 1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl, cyano(C1-C6)alkyl, aminocarbonyl(C1-C6)alkyl, (C1-C6)alkylaminocarbonyl(C1-C6)alkyl, di(C1-C6)alkylaminocarbonyl(C1-C6)alkyl, (C3-C6)cycloalkylcarbonyl(C1-C6)alkyl, {(C3-C6)cycloalkyl}{(C1-C6)alkyl}aminocarbonyl(C1-C6)alkyl or di(C3-C6)cycloalkylcarbonyl(C1-C6)alkyl; one or more carbon atom of the optional replaced in oxopiperidine ring group independently selected from fluorine, chlorine, cyano, hydroxy, amino, (C1-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2) alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, CONH2, (C1-C4)alkylaminocarbonyl, di(C1-C4) alkylaminocarbonyl and (C1-C4)alkylcarboxylic; R1represents methyl or ethyl; R2represents phenyl, thienyl, pyridyl or isopropyl, possible C is mstiteli each of which include up to three groups independently selected from halo, methyl, methylthio, (4 morpholino)bromide or cyclopropyl; R3represents methyl, ethyl, propyl, butyl, vinyl, allyl or ethoxyethyl, possible substituents each of which include up to two groups independently selected from methyl, BUT-, MeO-, N2N, MeC(=O)NH-, MeS(=O)2NH-, H2NC(=O)-, MeNHC(=O)-, HO2C-, (HO)2P(=O)O, H2NS(=O)2O, H2NS(=O)2NH-, MeNHC(=O)NH-, MeNHC(=O)O-, oxo, cyano, BUT2With-, HOCH2CH2NH-, 4-morpholino, HOCH2C(=O)NH-, H2NCH2C(=O)NH-, EtNHC(=O)NH, MeOC(=O)NH-, MeNHC(=NC=N)NH-, Me-, MeS-, MeSO2 - MeSC>2N(Me)-, MeS(=O)2NHC(=O)-, imidazolinone, imidazolyl, tetrazolyl, H2NCONH-, H2NCO2-, HOCH2CH2O-, MeNH-, Me2N - and MeCONMe,

Alternatively for Structural formulas Io1Io2and Io5R2represents phenyl which may be substituted with 1, 2 or 3 zamestitelyami, independently selected from halo, cyano, CONH2, (C1-C4)alkyl, (C1-C4)haloalkyl and SO2Me; R3represents a MeSO2NHCH2CH2CH2H2NC(=O)CH2CH2H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the other variables correspond to the data presented in the description of the First alternative implementation is tvline of the present invention.

Alternatively for Structural formulas Io1Io2and Io5R3represents H2NC(=O)CME2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the other variables correspond to the data presented in the description of the First alternative implementation of the present invention.

Alternatively for Structural formulas Io1Io2and Io5R2represents phenyl which may be substituted with 1, 2 or 3 possible zamestitelyami, independently selected from halo, cyano, CONH2, (C1-C4)alkyl, (C1-C4)haloalkyl and SO2Me; R3represents H2NC(=O)CME2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the other variables correspond to the data presented in the description of the First alternative implementation of the present invention.

Alternatively for Structural formulas Io1Io2and Io5R3represents a 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the other variables correspond to the data presented in the description of the First alternative implementation of the present invention.

Alternatively for Structural formulas Io1Io2The Io 5R2represents phenyl or forfinal; R3represents a 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the other variables correspond to the data presented in the description of the First alternative implementation of the present invention.

Alternatively for Structural formulas Io1Io2and Io5R2represents phenyl or forfinal; R3represents a 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; one or two substitutable carbon atom in oxopiperidine the ring may be replaced by fluorine, stands or ethyl; and the other variables correspond to the data presented in the description of the First alternative implementation of the present invention.

For option presented in the previous seven sections, n is 0, all substitutable carbon atoms in oxopiperidine ring, preferably should remain unsubstituted.

The following variant of implementation of the present invention is a compound of any of Formula IP1and Ip3or its pharmaceutically acceptable salt:

In Formulas IP1and Ip3G1is a (C1-C4alkyl, (C1-C4)alkoxy, (C1-C 4)haloalkyl, (C1-C4)haloalkoxy, halogen, cyano or nitro; n is 0, 1 or 2; G2ais a (C1-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2)alkyl or (C1-C4)haloalkyl; G2brepresents hydrogen, fluorine, chlorine, cyano, hydroxy, amino, (C1-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2)alkyl, halo(C1-C4)alkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, DOUBT2, (C1-C4)alkylaminocarbonyl, di(C1-C4)alkylaminocarbonyl or (C1-C4)alkylcarboxylic; suitable values for R1, R2and R3meet in the description of the first variant implementation of the present invention. In alternative embodiments of the present invention, presented in this section do not include compounds PR-221 and PR-313 or their pharmaceutically acceptable salt, enantiomer or diastereoisomer.

For each of the options described in the previous section, R1preferably represents methyl or ethyl.

For each of the options described in this section directly after Formula IP1and Ip3, R1preferably, represents the Wallpaper methyl or ethyl; a R3represents a MeSO2NHCH2CH2CH2H2NC(=O)CH2CH2H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the options described in this section directly after Formula Ip1and Ip3, R1preferably represents methyl or ethyl; and R3represents H2NC(=O)CME2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the options described in this section directly after Formula Ip1and Ip3, R1preferably represents methyl or ethyl; R2represents phenyl substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH2, (C1-C4)alkyl, (C1-C4)haloalkyl, and SO2Me; a R3represents a MeSO2NHCH2CH2CH2H2NC(=O)CH2CH2H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2 - hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the options described in this section directly after Formula Ip1and Ip3, R1preferably represents methyl or ethyl; R2 represents phenyl substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH2, (C1-C4)alkyl, (C1-C4)haloalkyl, and SO2Me; a R3represents H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl,

For each of the options described in this section directly after Formula Ip1and Ip3, R1preferably represents methyl or ethyl; and R3represents a 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the options described in this section directly after Formula Ip1and Ip3, R1preferably represents methyl or ethyl; R2represents phenyl or forfinal; and R3represents a 2 - hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the options described in this section directly after Formula Ip1and Ip3, R1preferably represents methyl or ethyl; R2represents phenyl or forfinal; and R3represents a 2 - hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; Deputy G2aselected from (C1-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2)alkyl and(C 1-C2)haloalkyl; a G2bcan be selected from hydrogen, methyl or ethyl.

For each of the options described in this section directly after Formula Ip1and Ip3, R1preferably represents methyl or ethyl; R2represents phenyl or forfinal; and R3represents a 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; Deputy G2aselected from haloalkyl, (C1-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C3)alkyl and (C1-C2)haloalkyl; a G2bcan be selected from hydrogen, methyl or ethyl.

For each of the options described in this section directly after Formula IP1and Ip3, R1preferably represents methyl or ethyl; R2represents phenyl or forfinal; and R3represents a 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; Deputy G2aselected from diformate, ethyl, substituted by 1-3 fluorine atoms (preferably, 2-veratile or 2,2,2-veratile), (C1-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2)alkyl and (C1-C2)haloalkyl; a G2bcan be selected from hydrogen, methyl or ethyl.

The following variant of the implementation of us who Otsego of the invention (referred to in this document as "the Second alternative implementation of the present invention") is a compound, having the Structural formula Ip1and Ip3in which: n is 0 or 1, preferably 0; each G1independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, halogen, cyano or nitro; G2arepresents a hydroxy(C1-C6)alkyl, (C1-C4)alkylcarboxylic(C1-C6)alkyl, (C1-C6)alkylsulfonyl(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl, cyano(C1-C6)alkyl, aminocarbonyl(C1-C6)alkyl, (C1-C6)alkylaminocarbonyl(C1-C6)alkyl, di(C1-C6)alkylaminocarbonyl(C1-C6)alkyl, (C3-C6)cycloalkylcarbonyl(C1-C6)alkyl, {(C3-C6)cycloalkyl}{(C1-C6)alkyl}aminocarbonyl(C1-C6)alkyl or di(C3-C6)cycloalkylcarbonyl(C1-C6)alkyl; With2brepresents hydrogen, fluorine, chlorine, cyano, hydroxy, amino, (C1-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2)alkyl, halo(C1 -C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, CONH2, (C1-C4)alkylaminocarbonyl, di(C1-C4)alkylaminocarbonyl or (C1-C4)alkylcarboxylic; R1represents methyl or ethyl; R2represents phenyl, thienyl, pyridyl or isopropyl, possible substituents each of which include up to three groups independently selected from halo, methyl, methylthio or (4-morpholino)methyl; R3represents methyl, ethyl, propyl, butyl, vinyl, allyl or ethoxyethyl, possible substituents each of which include up to two groups independently selected from methyl, BUT-, MeO-, H2N, Month(=O)MN-, MeS(=O)2NH-, H2NC(=O)-, MeNHC(=O)-, HO2C-, (HO)2P(=O)O, H2NS(=O)2O, H2NS(=O)2NH-, MeNHC(=O)NH-, MeNHC(=O)O-, oxo, cyano, HO2C-, HOCH2CH2NH-, 4-morpholino, NON2C(=O)NH-, H2NCH2C(=O)NH-, EtNHC(=O)NH, MeOC(=O)NH-, MeNHC(=NC=N)NH-, Me-, MeS-, MeSO2- MeSO2N(Me)-, MeS(=O)2NHC(=O)-, imidazolinone, imidazolyl, tetrazolyl, H2NCONH-, H2NCO2-, HOCH2CH2O-, MeNH-, Me2N - and MeCONMe.

Alternatively for Structural formulas IP1and Ip3R2represents phenyl which may be substituted with 1, 2 or 3 substituents, independently selected from halo, cyano, CONH2, (C1-C4)al the sludge, (C1-SD4)haloalkyl and SO2Me; R3represents a MeSO2NHCH2CH2CH2H2NC(=O)CH2CH2H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the other variables correspond to the data presented in the description of the Second alternative implementation of the present invention.

Alternatively for Structural formulas Ip1and Ip3R3represents H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the other variables correspond to the data presented in the description of the Second alternative implementation of the present invention.

Alternatively for Structural formulas Ip1and Ip3R2represents phenyl which may be substituted with 1, 2 or 3 substituents, independently selected from halo, cyano, CONH2, (C1-C4)alkyl, (C1-C4)haloalkyl and SO2Me; R3represents H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the other variables correspond to the data presented in the description of the Second alternative domestic the present invention.

Alternatively for Structural formulas Ip1and Ip3R3represents a 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the other variables correspond to the data presented in the description of the Second alternative implementation of the present invention.

Alternatively for Structural formulas Ip1and Ip3R2represents phenyl or forfinal; R3represents a 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the other variables correspond to the data presented in the description of the Second alternative implementation of the present invention.

Alternatively for Structural formulas Ip1and Ip3R2represents phenyl or forfinal; R3represents a 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; one or two substitutable carbon atom in oxopiperidine ring can alternatively be replaced by fluorine, stands or ethyl; and the other variables correspond to the data presented in the description of the Second alternative implementation of the present invention.

For option presented in the previous seven sections, n is 0, a G2bpreferably represents-N.

The following variant of the implementation of this image the shadow is an anhydrate or monohydrate (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6 - dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-it, (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-it 3-{(S)-1-[4-(1-cyclopropyl-2-oxo-1,2-dihydro-pyridine-4-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazine-2-she and their pharmaceutically acceptable salts, including both forms of the anhydrate and monohydrate, as a neutral form, and, preferably, pharmaceutically acceptable salt form.

The description of the compounds of the present invention is also contained in the following documents: CYCLIC INHIBITORS of 11β-HYDROXYSTEROID-DEHYDROGENASE I, provisional application U.S. No. 61/61/135,933, filed on July 25, 2008 (Attorney Docket No. 4370.1000-000); Cyclic inhibitors of 11β-hydroxysteroid-dehydrogenase 1, provisional application U.S. No. 61/135,933, filed may 1, 2008; cyclic inhibitors of 11β-hydroxysteroid-dehydrogenase 1, provisional application U.S. No. 61/137,148, filed on July 25, 2008; and Cyclic inhibitors of 11β-hydroxysteroid-dehydrogenase 1, international application number PCT/US2008/009017, filed July 25, 2008; listed applications are provided here as a reference.

DEFINITION

The term "alkyl" refers to groups with both unbranched and branched hydrocarbon radicals having 1-10 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-g is Phil, n-octyl, n-nonyl, n-decyl and the like.

The term "cycloalkyl" refers to monocyclic, bicyclic or tricyclic saturated hydrocarbon ring having 3-10 carbon atoms, and includes, for example, cyclopropyl (C-Pr), cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, bicyclo [2.2.2]octyl, bicyclo [2.2.1]Gentil, Spiro[4.4]nonan, substituted and the like.

The term "aryl" refers to aromatic radical, represents phenyl or naftalina group, indenolol or tetrahydronaphthalene group. The aryl group can have 1-4 possible substitute. Representatives of the substituents are alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2N-monoalkyl-substituted amido and N,N-dialkyl - substituted amido.

The terms "heteroaryl" refers to 5 - and 6-membered heteroaromatic the radical, which alternatively may be fused with a saturated or unsaturated ring containing 0-4 heteroatoms selected from N, O and S, and may contain, for example, a heteroaromatic radical, which represents a 2 - or 3-thienyl, 2 - or 3-furanyl, 2 - or 3 - pyrrolyl, 2-, 3-, or 4-pyridyl, 2-pyrazinyl, 2-, 4-,or 5-pyrimidyl, 3 - or 4-pyridazinyl, 1H-indol-6-yl, 1H-indol-5-yl, 1H-benzimidazole-6-yl, 1H - benzimidazole - 5-yl, 2-, 4-, 5-, 6-, 7- or 8-hintline, 2-, 3-,5-, 6-, 7 - or 8-honokalani, 2-, 3-, 4-, 5-, 6-, 7- or 8-chinoline, 1-, 3-, 4-, 5-, 6-, 7- or 8-ethenolysis, 2-, 4-, or 5-thiazolyl, 2-, 3-, 4-, or 5-pyrazolyl, 2-, 3-, 4-, or 5-imidazolyl. Heteroaryl may be substituted. Possible substituents of heteroaryl include alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2N-monoalkyl-substituted amido and N,N-dialkyl - substituted amido, or oxo, with the subsequent formation of the N-oxyl.

The term "heterocyclyl" refers to 4-, 5-, 6 - and 7-membered saturated or partially unsaturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S. Representatives heterocyclyl are pyrrolidine, pyrrolidin-2-it, 1-methylpyrrolidine-2-it, piperidine, piperidine-2-it, dihydropyridines, tetrahydropyridine, piperazine, 1-(2,2,2-triptorelin)piperazine,

1.2-dihydro-2-oxopyridine, 1,4-dihydro-4-oxopyridine, piperazine-2-it, 3,4,5,6-tetrahydro-4-oxopyrimidine, 3,4-dihydro-4-oxopyrimidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, isoxazolidine, 1,3-dioxolane, 1,3-ditiolan, 1,3-dioxane, 1,4-dioxane, 1,3-dition, 1,4-dition, oxazolidin-2-it, imidazolidin-2-it, imidazolidin-2,4-dione, tetrahydropyrimidin-2(1H)-he morpholine, N-methylmorpholine, morpholine-3-one, 1,3-oxazine-2-it, thiomorpholine, thiomorpholine 1,1-dioxide, tetrahydro-1,2,5-tiok the azole 1,1-dioxide, tetrahydro-2H-1,2-thiazin 1,1-dioxide, hexahydro-1,2,6-thiadiazine 1,1-dioxide, tetrahydro-1,2,5-thiadiazole 1,1-dioxide isothiazolin 1,1-dioxide, 6-oxo-1,6-dihydropyridin-3-yl, 6-oxo-1,6-dihydropyridin-4-yl, 5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-yl and 5-oxo-4,5-dihydro-1H-imidazol-2-yl. Heterocyclyl has 1-4 possible substituent includes alkyl, haloalkyl, halogen and oxo.

The term "spirocyclic" refers to cycloalkyl group having in the ring one common carbon atom with another alkyl or cycloalkyl group.

The terms "patient" or "patient" as used herein, are interchangeable and refer to a mammal to be treated, including domestic animal (e.g. cat, dog and so on), agricultural animal (e.g. cow, pig, horse, sheep, goat and so on), as well as laboratory animal (e.g., rat, mouse, Guinea pig, and so on). As a rule, the term "patient" refers to a person in need of treatment.

It is assumed that at the mention or graphic representation of the present compounds or pharmaceutically acceptable salts also covered a solvate or hydrate of the compound or its pharmaceutically acceptable salts. The term "solvate" refers to crystalline forms, into the crystal lattice during crystallization entered molecules of the solvent. The solvate may include water or nonaqueous solvents, such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate. The solvate formed in case of using water as solvent molecules included in the crystal lattice, usually referred to as "hydrates". It hydrates are stoichiometric compounds, and compositions containing various amounts of water. Some of the compounds described as examples, may be anhydrous form.

The term "compound" also encompasses the deuterium-labeled in one or more positions of the connection. "Deuterium-labeled at position" means that the amount of deuterium at that position is higher than in natural conditions. In some cases, the number of deuterium at each position "connection" corresponds with that observed in nature.

Some of the compounds described herein can exist in different stereoisomeric forms. The stereoisomers are called compounds, differing only in the spatial arrangement of the individual atoms in the same order them together. The enantiomers is called a pair of stereoisomers are mirror images which do not superimpose on each other, mainly because asimmetricheskii substituted carbon atom acting as a chiral center. The term "enantiomer" refers codroy of two molecules, which analoguely mirror images. Diastereoisomers are stereoisomers that are not mirror images of each other, mainly due to two or more asymmetric carbon atoms, acting as chiral centres. The symbol "*", presented in the Structural formula indicates the presence of carbon atom acting as a chiral center. The symbols "R" and "S" indicate the configuration of substituents around one or more chiral centers of the carbon atoms. Thus, the designation "R*" and "S*" indicate the relative configuration of the substituents around one or more chiral centers of the carbon atoms.

The term "racemate" or "racemic mixture" refers to the connection equimolar amounts of the two enantiomers with no optical activity, i.e., not calling a rotation of the plane of polarization of light.

The term "geometric isomer" refers to isomers that differ from each other in different spatial arrangement of the atoms of the substituents relative to the plane of the double bond of carbon-carbon, cycloalkene ring or bridged bicyclic system. Atoms (in addition to N) on each side of the double bond carbon-carbon can be configured as E (the substituents are on opposite sides of the double bond carbon-carbon) is whether the Z substituents are located on one side of the link).

The symbol "R," "S," "S*," "R*," "E," "Z," "CIS" and "TRANS" refer to the configuration of the substituents relative to the skeleton of the molecule.

Compounds of the present invention can be prepared as individual isomers by isomer-specific synthesis or secretion of a mixture of isomers. Standard methods of isolation of the isomers include the formation of a salt of the free base of each isomer isomer pairs using an optically active acid followed by fractional crystallization or restoration of free base); the formation of a salt of the acid form of each isomer isomer pairs using optically active amine (followed by fractional crystallization or by recovery of the free acid); the formation of ester or amide of each isomer isomer pairs using optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary element); or the selection of a mixture of isomers of the starting material or of the finished product with the help of widely used chromatographic techniques.

At the mention or graphic stereochemical properties of this connection it is assumed that mentioned or depicted stereoisomer has a mass of pure substance not less 60%, 70%, 80%, 90%, 99% or 99.9% against the other stereoisomers. At the mention or graphic representation of an individual enantiomer, it is assumed that the mentioned or depicted enantiomer has a purity optical isomer by weight not less 60%, 70%, 80%, 90%, 99% or 99.9%. The percentage of optical purity by weight is the ratio of the mass enantiomer to the total mass enantiomer and its optical isomer.

At the mention or graphic representation of this connection without specifying its stereochemical properties, and subject to the availability of the connection, at least one chiral center, it is assumed that the reference or graphic image encompasses one enantiomer of a compound that does not contain the corresponding optical isomer, a racemic mixture of compounds, and mixtures enriched in one enantiomer relative to its corresponding optical enantiomer of this compound.

At the mention or graphic representation of this connection without specifying its stereochemical properties, and subject to the availability of the connection, at least two chiral centers, it is assumed that the reference or graphic image covers the diastereoisomer with no other diastereomers, or a pair of diastereomers, not containing other pairs of diastereomers, mixtures of diastereomers, mixtures of pairs of diastereoisomers, and also mixtures and diastereomers, enriched one diastereoisomer in relation to other diastereoisomer (s), and mixtures of pairs of diastereomers, enriched one pair of diastereoisomers with respect to the other/the other pair (s) diastereomers.

Compounds of the present invention can be in the form of pharmaceutically acceptable salts. Used in pharmaceuticals salts of the compounds of the present invention relate to non-toxic "pharmaceutically acceptable salts". Form pharmaceutically acceptable salts include pharmaceutically acceptable acidic/anionic or basic/cationic salts.

Pharmaceutically acceptable basic/cationic salts include: sodium, potassium, calcium, magnesium, diethanolamine, p-methyl-O-glutamine, L-lysine, L-arginine, ammonium, ethanolamine, piperazine and triethanolamine.

Pharmaceutically acceptable acidic/anionic salts include the following: acetate, bansilalpet, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, Eilat, fumarate, glycerate, glutamate, picolylamine, hexylresorcinol, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isetionate, lactate, lactobionate, malate, maleate, malonate, mandelate, mesilate, methyl sulfate, mukat, napsylate, nitrate, pamoate, Pantothenate, phosphate/diphosphate, polygalacturonate, is alicial, stearate, subacetate, succinate, sulfate, gidrogensulfat, tannat, tartrate, teoclate, tosylate and triethiodide.

The table below shows the abbreviations and their meanings:

ReductionValue
And%The percentage area
Vostert-butoxy carbonyl or t-butoxy carbonyl
(BOC)2Odi-tert-butyl dicarbonate
CbzBenzyloxycarbonyl
CbzCIBenzyl chloroformate
c-PrCyclopropyl
DASTDiethylaminomethyl TRIFLUORIDE
DBU1,8-diazabicyclo[5.4.0]undec-7-EN
DCCN,N'-dicyclohexylcarbodiimide
DCUN,N'-dicyclohexylmethane
DIADAminobutiramida azodicarboxylate
DIBAL-H Diisobutylaluminium hydride
DIEAN,N-diisopropylethylamine
DMAP4-(dimethylamino)pyridine
DMFN,N-dimethylformamide
DMPU1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
2,4-DNP2,4-dinitrophenylhydrazine
Dppf1,1'-bis(diphenylphosphino)ferrocene
DPTBSDiphenyl+butylphenyl
DMThe ratio of diastereomers
The EDC.HCI, EDCI1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
Equiv.Equivalents
EtOAcEthyl acetate
Fmoc1-[[(N-fluoren-9 ylethoxy)carbonyl]oxy]-
Fmoc-OSu1-[[(N-fluoren-9 ylethoxy)carbonyl]oxy]-2.5-pyrrolidinedione
hhour(s)
HOBt 1-hydroxybenzotriazole
HATU2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-hexaphosphate
HBTU2-(1H-benzotriazol-1-l)-1,1,3,3 - tetramethyluronium-hexaphosphate
KHMDSPotassium, hexamethyldisilazane
'lah or LJAIH4Sociallyengaged
LC-MSLiquid chromatography-mass spectroscopy
LHMDSlithium hexamethyldisilazane
m-CPBAmeta-chloroperoxybenzoic acid
Memethyl
MsCIMethanesulfonanilide
minminutes
MCMass spectrum
NaHSodium hydride
NaHCO3Sodium bicarbonate
NaN3Sodium azide
NaOHSodium hydroxide
Na2SO4The sodium sulfate
NMMN-methylmorpholin
NMPN-methylpyrrolidinone
Pd2(dba)3Tris(dibenzylideneacetone)dipalladium(0)
PEPetroleum ether
Quantity.outputQuantitative output
EXT.the pace.Room temperature
The feast upon.Rich
SOCl2Thionyl chloride
SICHSupercritical liquid chromatography
CACScintillation analysis of convergence
TPVSolid-phase extraction
TBAFTetrabutylammonium fluoride
TBSt-butyldimethylsilyl
TBDPS t-butyldiphenylsilyl
TBSCIt-butyldimethylsilyl chloride
TBDPSCIt-butyldiphenylsilyl chloride
TEAthe triethylamine or Et3N
TEMPONot containing 2,2,6,6-tetramethyl-1-piperidinyloxy radical
Theos1-[2-(trimethylsilyl)ethoxycarbonyl]-
Teoc-OSu1-[2-(trimethylsilyl)ethoxycarbonyl]pyrrolidin-2,5-dione
TunesThe outside temperature
TvotrThe internal temperature
TFATriperoxonane acid
thoseThin-layer chromatography
TMSTrimethylsilyl
TMSCIChlorotrimethylsilane or Trimethylsilyl chloride
tRRetention time
TsOHp-toluensulfonate the acid

GENERAL DESCRIPTION of METHODS for OBTAINING COMPOUNDS

The compounds of Formula I can be obtained in several ways. The following material And1Su1E , R1, R2, R3, Y and n have the meanings given above unless otherwise stated. Su2represents alternatively, the substituted 2-oxo-1,2-digidropiridinove group. In the cases described below if the intermediate and final products of Formula I* contain potentially reactive functional groups, which are groups of amino, hydroxyl, thiol and carboxylic acid, preventing the target reaction, the use of a protected form of intermediate compounds may be more effective. Selection methods, the introduction and subsequent removal of the protective groups are well known to experts in the art (T. W. Greene and P. G. M. Wuts "Protective Groups in Organic Synthesis" John Wiley & Sons, Inc., New York 1999). The use of such protective groups is taken into account in the following material, however, is not described in detail. Typically, the reagents specified in the schemes of reactions are used in equimolar amounts; however, in some cases it may be desirable to use an excess quantity of one of the reagents to complete the reaction. This measure is particularly relevant in cases where the excess is CNY the reagent can be easily removed by evaporation or extraction. Foundation, designed to neutralize the HCl in the reaction mixture, generally used in excess amounts (from 1.05 to 5 equivalents),

During the first process, the compound of the Formula I can be obtained by the reaction of intermediate amerosport Formula II and the reagent of Formula III, where Z1and Z2represent a leaving group such as chloride, 1-imidazolyl or aryloxides, in an inert solvent such as tetrahydrofuran, CH2Cl2, toluene or MeCN, usually in the presence of organic or inorganic bases, similar triethylamine or NaHCO3accordingly, at temperatures from -10°C to 120°C:

Certain types of reagent III is particularly suitable for use due to their availability in the market. For example, if Z1and Z2are chlorides, III represents the phosgene. If Z1and Z2represent 1-imidazolyl, III is carbonyldiimidazole. If Z1represents chloride, and Z2- p-nitrophenoxide, III is a p-nitrophenyl chloroformiate. If Z1and Z2are l3III is triphosgene and can be used in the amount of one third of the equivalent.

The intermediate amino is the pirates of the Formula II can be obtained by reducing the number of amides in the Formula IV using a hydride reagent, similar to the Bis. to a solution of tetrahydrofuran, NR3.IU2S or LiAlH4, in an inert ether solvent such as tetrahydrofuran or DME, at a temperature from 20°C to 100°C over a period of from 1 h to 48 hours

Intermediate compounds of Formula IV can be obtained by linking the hydroxy acid of Formula V and an amine of Formula VI using standard peptide binders, such EDC in the presence of HOBt and N,N-diisopropylethylamine in an inert solvent, similar to the CH2CL2at a temperature from 0°C to 30°C over a period of from 1 h to 24 h

The intermediate amines of Formula VI, where a1=CH2, a R1no, can be obtained by reducing the number of amides in the Formula VII using a hydride reagent, similar NR3. to a solution of tetrahydrofuran, NR3.IU2S or LiAlH4, in an inert ether solvent such as tetrahydrofuran or DME, at a temperature from 20°C to 100°C over a period of from 1 h to 48 hours

The intermediate amines of Formula VI, where a1is associated, R1no, and su1not an aromatic or heteroaromatic ring, can be obtained from ketones of Formula VIII by Klimov Formula IX or by reductive amination of the ketone of Formula VIII using ammonia:

Methods for conversion of ketones in the oximes described in the publication Smith, M. C. and March, J. "March''s Advanced Organic Chemistry", pp. 1194-1195, 5thEdition, Wiley, New York, NY, 2001. Recovery methods Asimov to primary amines described in Smith, M. C. and March, J. "March''s Advanced Organic Chemistry" p.1555, 5thEdition, Wiley, New York, NY, 2001. Methods reductive amination of ketones represented in publications Baxter, E. W. and Reitz, A. C. "Organic Reactions", Volume 59, Ed. Overman, L. E., Wiley Interscience, 2002.

Similarly can be obtained intermediate amines of Formula VI, where a1represents CH, and R1is methyl or ethyl, by restoring t-butylmethylamine Formula VIIIb, which in turn, can be obtained from ketones of Formula Villa and t-butylsulfonyl, or by the addition of ORGANOMETALLIC reagents of Formula R1M, where R1represents Me or Et, a M is Li, MgCl, MgBr or Mgl, t-butylsulfonyl Formula VIIId, which can be obtained from aldehydes of Formula VIIIc.

In the course of such reactions using chiral t-butylmethylamine often achieved high stereoselectivity.

Intermediate compounds of Formula II where n=0, can be obtained by the reaction of oxiteno Formula X and amines of the Formula VI are described in the publication Smith, M. C. and March, J. "March''s Advanced Organic Chemistry" p505, 5thEdition, Wiley, New York, NY, 2001:

Intermediate compounds of Formula II can also be obtained by reductive amination of hydroxyaldehyde Formula Ha with amines of Formula VI. Methods reductive amination of aldehydes is described in the publication Baxter, E. W. and Reitz, A. C. "Organic Reactions", Volume 59, Ed. Overman, L. E., Wiley Interscience, 2002.

Aldehydes of Formula XA can be obtained from gomoallilnymi alcohols of the Formula XXI by treatment OsO4and NalO4.

Intermediate compounds of Formula II, where a1=CH2, a R1no, can be obtained by reducing the number of intermediate amides of Formula XI using a hydride reagent, similar NR3. to a solution of tetrahydrofuran, BH3.Me2S or LiAlH4, in an inert ether solvent such as tetrahydrofuran or DME, at a temperature from 20°C to 100°C over a period of from 1 h to 48 hours

Intermediate amides of Formula XI can be obtained by reaction of the intermediate aminoalcohols of Formula XII and the activated carboxylic acid of Formula XIII, where Z3=chloride or activated ester, such ether N-hydroxysuccinimide:

Intermediate aminoalcohols of Formula XII, where n=0, can be the result of the reaction of the epoxides of Formula XIV and the cyanide ion followed by reduction of the obtained hydroxynitrile Formula XV using gaseous hydrogen in the presence of a catalyst or a hydride source, such LiAlH4:

Epoxy compounds of Formula XIV, in turn, can be obtained in several ways, including the ones described in the publication Aube, J. "Epoxidation and Related Processes" Chapter 3.2 in Volume 1 of "Comprehensive Organic Synthesis" Edited by B. M. Trost, I. Fleming and Stuart L. Schreiber, Pergamon Press, New York, 1992.

Intermediate hydroxynitrile Formula XV can be obtained by treating the ketone of Formula XVI with the anion of acetonitrile, obtained by treatment with n-BuLi or LDA, in an inert, anhydrous solvent such as tetrahydrofuran at low temperatures:

Intermediate aminoalcohols of Formula XII, where the value of n is 0, can be obtained by processing the intermediate sulfonates of the Formula XVII, where R represents, for example, methyl, trifluoromethyl or p-were using ammonia:

Intermediate aminoalcohols of Formula XII can be obtained by processing the intermediate sulfonates of the Formula XVII sodium azide to obtain the azide intermediate of Formula XVIII with subsequent catalytic hydrogenation or recovery by the reaction of Staudinger with PPh3in wet tetrahydrofuran:

Intermediate sulfonates of the Formula XVII can be obtained from the intermediate diols of Formula XIX using the Sul is the IMT chloride R ASO2Cl:

Intermediate diols of Formula XIX can be obtained through hydroporinae allyl alcohols of the Formula XX:

Intermediate diols of Formula XIX can be obtained by ozonolysis and recovery gomoallilnymi alcohols of the Formula XXI:

Intermediate aminoalcohols of Formula II, where a1is associated, R1no, and su1represents a heteroaryl group, or aryl group containing at least one strong electron-withdrawing group, such CF3can be obtained by the reaction of intermediate aminoalcohols of Formula XII with the compound of the formula XXII, where su1represents a heteroaryl group, or aryl group containing at least one strong electron-withdrawing group, such CF3, a R3represents a leaving group, for example, fluorescent, chloro, bromo or iodine:

Intermediate aminoalcohols of Formula II, where a1is a (C1)alkylen can be obtained by the reaction of amerosport Formula XII with aldehyde or methyl ketone of Formula XII in the presence of a reducing agent, such NaCNBH3or Na(OAc)3BH:

Methods reductive amination of aldehydes and ketones is described in the publication Baxter, E. W. and Reitz, A. C. "Organic Reactions", Volume 59, Ed. Overman, L. E., Wiley Interscience, 2002.

During the second process, a compound of the Formula I can be obtained by the reaction of metacarbonate Formula XXIV, where RDrepresents an alkyl or arylalkyl a group similar to the stands, t-butile or benzyl, with ORGANOMETALLIC reagents of Formula XXV, where M includes, among other things, MgCl, MgBr, Mgl or Li:

In some cases ORGANOMETALLIC reagent XXV is a bromide Allemagne, bromide allicance(II) chloride (2-methylallyl)or magnesium bromide (2-methoxy-2-oxoethyl)zinc(II). In some cases, if M is a MgCI, MgBr or Mgl, it is recommended to add Cess in the reaction mixture.

Metacarbonate Formula XXIV can be obtained by the reaction of aminoketones Formula XXVI with intermediate compounds of Formula XXVII, where RErepresents a leaving group such as chloride, succinylate, imidazolyl or t-butoxycarbonylamino:

Aminoketone Formula XXVI, where n=0, can be obtained by the reaction of unsaturated ketones of Formula XXVIII with amines of Formula VI:

Aminoketone Formula XXVI, where n=0, can be obtained in accordance with the ATA response dialkylaminomethyl Formula XXVIII, where RFrepresents lower alkyl, especially methyl, with amines of Formula VI:

- dialkylaminomethyl Formula XXVIII, in turn, can be obtained by the reaction of unsaturated ketones of Formula XXVII with dialkylamines Formula RFOtherF.

In the third process, the compound of the Formula I can be obtained by the reaction of compounds of Formula XVII with an isocyanate of Formula XXIX in the presence of a base;

The isocyanates of Formula XXIX can be obtained from the amines of Formula VI by treatment with phosgene, diphosgene or triphosgene. This third process is described in more detail in the provisional application U.S. serial number 61/137,013, filed on July 25, 2008, entitled SYNTHESIS INHIBITORS BETA-HYDROXYSTEROID-DEHYDROGENASE TYPE 1 (ID. No. Pat. the PWA. 4370.1001-000). This application is provided here as a reference.

In the fourth process, the compound of the Formula I can be obtained by reaction of the halogen compounds of the Formula where Hal represents chlorine or bromine, with an isocyanate of Formula XXIX in the presence of a base:

The halogen compounds of Formula XXX can be obtained by the reaction of haloketones Formula XXXI with ORGANOMETALLIC reagents of Formula XXV, where M represents metallosoderzhashhie radical, including MgCl, MgBr, Mgl, or Li. The reaction may optionally be conducted in the presence of anhydrous cerium trichloride:

In the fifth process, the compound of Formula I*, where a1represents CH2or CH2CH2, a R1no, can be obtained by the reaction of compounds of Formula XXXII and the compounds of Formula XXXIII, where a1represents CH2or CH2CH2, a RGare leaving group, such Br, I, OSO2Me OSO2CF3or OSO2Ph, in the presence of a base, similar NaH or K2CO3:

The compounds of Formula XXXII can be obtained by treating compounds of Formula XII various reagents of Formula III, where Z1and Z2are leaving groups such as chloride, 1-imidazolyl or aryloxides in an inert solvent, similar tetrahydrofuran, CH2CL2, toluene or MeCN, usually in the presence of organic or inorganic bases such as triethylamine or NaHCOs, respectively, at temperatures from -10°C to 120°C:

In the sixth process, the compound of Formula I*, where a1is connected, a R1no, can be obtained by the reaction of compounds of Formula XXXII and is soedineniya Formula XXII, where RBrepresents a leaving group similar to chloro, bromo, iodide or OSO2CF3in the presence of a base, such 4-(dimethylamino)pyridineK2CO3and also copper or palladium catalyst in an inert solvent such as dioxane, DMF or NMP at elevated temperature:

During the seventh process, the compound of the Formula I can be obtained by the reaction of a combination of Suzuki for the compounds of Formula XXXIV, where su1represents aryl or heteroaryl, and Rxrepresents bromine, iodine or tripterocalyx, and porinovoi acid (RYrepresents hydrogen or brunatnego ether of Formula XXXV (RYis a (C1-C6)alkyl, and two groups of RYtogether form the group (C1-C12)alkylene).

In the eighth process of the compounds of Formula XXXIV, where su1represents aryl or heteroaryl, and Rxrepresents bromine, iodine or tripterocalyx, by reaction with bis(pinacolato)diboron in the presence of palladium catalyst receive brunatny ether of Formula XXXVI, which, in turn, by reaction with a heterocyclic compound of Formula XXXVII, where Rxrepresents bromo, yo what about or tripterocalyx, in the presence of palladium catalyst, to obtain a compound of Formula I*.

During the ninth process, the compound of Formula I* can be obtained from other compounds of Formula I*. For example:

(1) compound of Formula I*, where R1or R3is a-hydroxy(C2-C6)alkyl, with the help of Jones reagent can be oxidized to compounds of Formula I*, where R1or R3represents a carboxy(C1-C6)alkyl.

(2) the compound of Formula I*, where R1or R3represents a carboxy(C1-C6)alkyl, may be associated with ammonia or (C1-C6)alkylamino using standard peptide binders similar to the EDC to obtain the compounds of Formula I*, where R1or R3represents-N2NC(=O)(C1-C6)alkyl or -{(C1-C6)N(=O)}(C1-C6)alkyl.

(3) the compound of Formula I*, where R1or R3is a-hydroxy(C1-C6)alkyl, can be converted to its methanesulfonate or triftorbyenzola by treatment with sodium azide, followed by reduction to obtain the compounds of Formula I*, where R1or R3is a-amino(C1-C6)alkyl.

(4) from the compounds of Formula I*, where R 1or R3represents amino(C1-C6)alkyl, by reaction with acetic anhydride or acetylchloride get compound of Formula I*, where R1or R3represents a {acetylamino}(C1-C6)alkyl.

(5) from the compounds of Formula I*, where R1or R3represents amino(C1-C6)alkyl, by reaction with methanesulfonyl chloride to obtain the compound of Formula I*, where R1or R3represents a {methanesulfonamido}(C1-C6)alkyl.

(6) the compound of Formula I*, where R1is a (C2-C6)alkenyl, when hydroporini form a compound of Formula I*, where R1represents a hydroxy(C2-C6)alkyl.

(7) the compound of Formula I*, where R3is a (C2-C6)alkenyl, when hydroporini form a compound of Formula I*, where R3represents a hydroxy(C2-C6)alkyl.

(8) from the compounds of Formula I*, where R1is a (C2-C6)alkenyl, by reaction with osmium-tetroxide and N-methylmorpholine-N-oxide receive the compound of Formula I*, where R1is a vicinal dihydroxy(C2-C6)alkyl.

(9) from the compounds of Formula I*, where R3is a (C2-C6)alkenyl, by reaction with osmium of tetr the oxide and N-methylmorpholin-N-oxide receive vicinal diol of the Formula I*, where R3is a vicinal dihydroxy(C2-C6)alkyl.

(10) from the compounds of Formula I*, where R1is a (C2-C6)alkenyl, by reaction with ozone, and then NaBH4get the compound of Formula I*, where R1is a-hydroxy(C1-C5)alkyl.

(11) from the compounds of Formula I*, where R3is a (C2-C6)alkenyl, by reaction with ozone, and then NaBH4get the compound of Formula I*, where R1is a-hydroxy(C1-C5)alkyl

(12) from the compounds of Formula I*, where R1or R3represents amino(C1-C6)alkyl, by reaction with (C1-C6)alkyl-isocyanate get compound of Formula I*, where R1or R3is a (C1-C6)alkylaminocarbonyl(C1-C6)alkyl.

(13) from the compounds of Formula I*, where R1or R3represents amino(C1-C6)alkyl, by reaction with (C1-C6)alkyl-chloroformiate get compound of Formula I*, where R1or R3is a (C1-C6) alkylaminocarbonyl (C1-C6)alkyl.

(14) from the compounds of Formula I*, where R1or R3represents amino(C1-C6)alkyl, by reaction with chlorosulfonylisocyanate is or sulphonamide get the compound of Formula I*, where R1or R3represents aminosulfonyl(C1-C6)alkyl.

(15) from the compounds of Formula I*, where R1or R3represents amino(C1-C6)alkyl, by reaction with (C1-C6)alkylsulfonyl chloride to obtain the compound of Formula I*, where R1or R3represents (Sgsb)alkylaminocarbonyl(C1-C6)alkyl.

(16) from the compounds of Formula I*, where R1or R3represents a hydroxy(C1-C6)alkyl, by reaction with chlorosulfonylisocyanate get compound of Formula I*, where R1or R3represents aminosulfonic(C1-C6)alkyl.

(17) from the compounds of Formula I*, where R1or R3represents a hydroxy(C1-C6)alkyl, by reaction with p-nitrophenylphosphate, pentecostalcharismatic or carbonyl diimidazol and subsequent reaction with ammonia, (C1-C6)alkylamino or di(C1-C6)alkylamino get compound of Formula I*, where R1or R3represents aminocarboxyl(C1-C6)alkyl, (C1-C6)alkyl, aminocarbonyl(C1-C6)alkyl or di(C1-C6)alkyl, aminocarbonyl(C1-C6)alkyl.

(18) from the compounds of Formula I*, where R1or R3represents g is droxi(C 1-C6)alkyl, by reaction with l3get the compound of Formula I*, where R1or R3represents (BUT)2P(=O)O(C1-C6)alkyl.

(19) from the compounds of Formula I*, where R3represents allyl or Gamaliel, by reaction with oxygen in the presence of PdCl2and CuCl get compound of Formula I*, where R3is a 2-oxopropyl or 3-oxobutyl respectively.

(20) from the compounds of Formula I*, where R3is a 2-oxopropyl or 3-oxobutyl, by reaction with MeMgX, where X represents Cl, Br or I get a connection Formula I*, where R3represents a 2-hydroxy-2-methylpropyl or 3-hydroxy-3-methylpropyl respectively.

(21) the compound of Formula I*, where R3represents-CH2CO2Me, can be processed MeMgX, where X represents Cl, Br or I, to obtain the compounds of Formula I*, where R3represents a 2-hydroxy-2-methylpropyl.

(22) from the compounds of Formula I*, where R3represents allyl or-CH2With(Me)=CH2by hydrocyanide with TsCN in the presence of triphenylsilane and various cobalt catalysts can be obtained the compounds of Formula I*, where R3represents-CH2CH(CN)IU or-CH2CMe2CN, respectively.

(23) the compound of Formula I*, where R3before the hat is CH 2C(Me)2CN, can be processed by ndimethylacetamide in the presence of PdCl2to obtain the compounds of Formula I*, where R3represents CH2CMe2CONH2.

(24) the compound of Formula I*, where R3represents-CH2With(Me)=CH2can be processed m-SRV, and then triethylborohydride lithium to obtain a compound of Formula I*, where R3represents a 2-hydroxy-2-methylpropyl.

During the tenth process, certain compounds of the invention Formula I** are as follows:

The halogen compounds of Formula LIII can be obtained by treating β-haloketones Formula XXXI ORGANOMETALLIC reagents of Formula LII, where M denotes MgCl, MgBr, Mgl, ZnBr or Znl. The reaction may optionally be conducted in the presence of anhydrous cerium trichloride in an inert anhydrous solvent such as tetrahydrofuran, at temperatures from -25 to 0°C for 0.5 hours

Cyclic carbamates of Formula LIV can be obtained by the reaction between p-galopante Formula LIII, where Hal represents a chloride, with isocyanates of Formula XXXIX in the presence of a base, such, among other things, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), in reverse condensate inert solvent, similar to, among other things, the tetrahydrofuran.

Tertiary alcohols Form the crystals LVII can be obtained from trehzameshchenny alkenes of Formula LIV by pre-alkene epoxidation using epoxidised substances, such m-SRV (3-chloroperbenzoic acid), in an inert solvent, similar dichloromethane, to obtain the corresponding epoxides of Formula LV. The obtained epoxide then undergoes reduction with ring opening to obtain the corresponding tertiary alcohol I* by processing the concentrated hydride reagent, such triethylborohydride, in an anhydrous inert solvent, similar to tetrahydrofuran.

During one of the variants of the tenth process, the compound of Formula I*** of the present invention is obtained by the reaction of a combination of Suzuki for brunatnego ether of the Formula LIX using halogenosilanes the compounds of Formula LX.

Brunatny ether of the Formula LIX get in the reaction of the bromide of Formula LVIII with bis(pinacolato)diboron. LVIII obtained by epoxidation of alkene LVII, followed by reduction with opening of epoxy rings in accordance with the above information, as 2-methyl-2-hydroxypropyl group get through epoxidation and disclosure of hybrid rings in accordance with the above-described conversion LIV in I**.

The tenth process described in more detail in the provisional application U.S. serial number 61/137,013, filed on July 25, 2008, entitled SYNTHESIS INHIBITORS BETA-G IS TOXICAROL-DEHYDROGENASE TYPE 1 (ID. no Pat, surface. 4370.1001-000). This application is provided here as a reference.

METHODS LC-MS

Method 1 [LC-MS (3 min method)]

Column: Chromolith SpeedRod RP-18e, 50 x 4.6 mm; Mobile phase: a: 0.01%TRA/water: 0,01%TRA/CH3CN; flow Rate: 1 ml/min; Gradient:

Time (min)And%In%
0,09010
2,01090
2,41090
2,59010
3,09010

Method 2 (10-80)

ColumnYMC-PACK ODS-AQ 50×2.0 mm, 5 µm
Mobile phasesA: water (4 l)+TFA (1.5 ml)
In: acetonitrile (4 l)+TFA (0.75 ml)
Time (min)And%In%
09010
2,22080
2,52080
The speed of the stream1 ml/min
WavelengthUV 220 nm
Temperature thermostat50°C
MS ionizationElectrospray ionization

Method 3 (30-90)

ColumnYMC-PACK ODS-AQ 50×2.0 mm, 5 µm
The mobile phaseA: water (4 l)+TFA (1.5 ml)
In: acetonitrile (4 l)+TFA (0.75 ml)
Time (min)And%In%
07030
2,21090
2,5 1090
The flow velocity1 ml/min
WavelengthUV 220 nm
Temperature thermostat50°C
MS ionizationElectrospray ionization

METHOD 4

ColumnWaters Xbridge C18, 30×4.6 mm 2.5 µm
The mobile phaseA: water + 0.1% F3CO2H
In: acetonitrile
Time (min)And%In%
09010
0.159010
3.151090
4.501090
4.7520 10
5.002010
The flow velocity1.2 ml/min
WavelengthUV 220, 230 or 254 nm

METHOD 5

ColumnMerck Cromolith Speed ROD, RP18e, 50×4.6 mm
The mobile phaseA: water + 0.1% HCO2H
In: acetonitrile + 0.1% HCO2H
Time (min)And%In%
0.009010
4.501090
5.001090
5.509010
The flow velocity1.5 mL/min
WavelengthUV 220, 230 or 254 nm

The METHOD ACCORDING to THE TEACHINGS 1

(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-he

Method 1

Step 1: (S)-1-bromo-4-(1-isocyanatomethyl)benzene.

To a solution of (S)-1-(4-bromophenyl)ethanamine (240 g, 1.2 mol) in methylene chloride (3 l) and saturated aqueous NaHCO3(3 l) was added triphosgene (118 g, 0,396 mol) at 0°C. the Mixture was mixed for 15 minutes. Then was separated organic phase, which was then dried over Na2SO4and boiled away to obtain 1-bromo-4-(1-isocyanatomethyl)-benzene (170 g, 63%).

Step 2: 1-chloro-3-sinergix-5-EN-3-ol

To a solution of 3-chloro-1-phenylpropane-1-she (170 g, 1.01 mol) in anhydrous tetrahydrofuran (1200 ml) was added bromide Allemagne (1.2 l, 1 mol/l) at -78°C in a nitrogen environment. The resulting mixture was stirred for 30 minutes at -78°C. the Reaction was stopped using aqueous NaHCO3. Was separated organic phase, which was then dried over Na2SO4and evaporated to obtain the crude product, later cleared during column chromatography (petroleum ether /EtOAc=100:1) to obtain 1-chloro-3-phenylhexa-5-EN-3-ol (180 g, 86%).1H NMR (CDCl3): of 2.27 (m, 2H), of 2.51 (m, 1H), 2,74 (m, 1H), up 3.22 (m, 1H), to 3.58 (m, 1H), 5,16 (m, 2H), of 5.53 (m, 1H), 7.23 percent (m, 1H), 7,39 (m, 4H).

Step 3: (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazine-2-he

SMEs-chloro-3-phenyl-Gex-5-EN-3-ol (105 g, 0,050 mmol), (S)-(-)-1-(-bromophenyl)ethyl isocyanate (170 g, 0,752 mol) and DBU (228 g, 1.5 mol) in tetrahydrofuran (1700 ml) overnight was heated to reverse the condensation. Then the mixture was diluted with EtOAc and washed with 1N HCl solution in water, followed by extraction of the aqueous phase using EtOAc (3×). The combined organic phase was dried over Na2SO4. After evaporation of the solvents the crude product was purified during column chromatography (petroleum ether/EtOAc = 20:1 to 5:1) to obtain (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazine-2-it (100 g, 34%).1H NMR (CDCl3): of 1.39 (d, 3H), and 2.14 (m, 1H), 2,24 (m, 2H), 2,48-2,61 (m, 3H), 2,82 (m, 2H), free 5.01 (m, 2H), 5,52 (q, 1H), 5,73 (m, 1H), 6,62 (d, 2H), 7,12 (m, 2H), 7,28 (m, 2H).

Step 4: (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazine-2-it 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propanal

To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazine-2-it (31 g, 78 mmol) and CuCl (19.3 g, 195 mmol) in anhydrous DMF (150 ml) was added H2O (50 ml) and PdCl2(4,10 g, 23 mmol) at room temperature. After adding the mixture during the night stirred in an oxygen atmosphere. After using TLC confirmed the disappearance of the starting material, the solid was subjected to filtration. Then were added water (200 ml) and EtOAc (200 ml), the organic layers were separated, and the command layer was subjected to extraction using EtOAc (3×40 ml). The combined organic layers were washed with brine, dried over Na2SO4subject to filtration and evaporation to obtain a precipitate, which was then purified during column chromatography (petroleum ether/EtOAc = 5:1 to 1:1) to obtain a mixture of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazine-2-it 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propanal, (26 g, 81%).

Step 5: (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazine-2-he

In the mixture of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazine-2-it 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propanal (20 g, 48.2 mmol) in t-BuOH (250 ml) and 2-methyl-2-butene (50 ml) was added a solution of NaClO2(19.3 g, 0,213 mol) and NaH2PO4(28 g, 0,179 mol) in H2O (300 ml) at 0°C. the resulting mixture was stirred for 1 h at 0°C. Then the mixture was treated with water (100 ml) and was subjected to extraction using CH2Cl2. The combined organic layers were dried over Na2SO4subject to filtration and evaporation to obtain a precipitate, and later cleared during column chromatography (petroleum ether/EtOAc = 5:1 to 2.5:1) to obtain (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazine-2-she (10.0 g, 83%).1H NMR (CDCl3): for 1.49 (d, 3H), 2,12 (s, 3H), 2,33 (m, 2H), 2.63 in (m, 1H), 2,86 to 3.0 (m, 3H), 5,57 (q, 1H), 6,66 (d, 2H), 7,19 (m, 2H), 7,33 (m, 5H).

Step 6: (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-he

To a solution of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazine-2-it (20 g, of 46.4 mmol) in anhydrous tetrahydrofuran (200 ml) was added drop by drop bromide Metalmania (31 ml, 144 mmol) at -78°C in a nitrogen environment. The mixture is then stirred at room temperature for 1 h the Reaction mixture was stopped with a solution of NaHCO3in water (50 ml) under a water bath with ice. The organic layers were separated, and the aqueous layer was subjected to extraction using EtOAc (150 ml). The combined organic layers were washed, dried over Na2SO4and evaporated in vacuo to obtain the crude product, later cleared during column chromatography (petroleum ether/EtOAc = 5:1 to 2:1) to obtain (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-it (13 g, 65%). After re-crystallization from EtOH was obtained 4 g of pure compound.1H NMR (CDCl3): of 1.06 (s, 3H), of 1.12 (s, 3H), of 1.44 (d, 3H), and 2.14 (m, 3H), of 2.21 (m, 1H), 2,33 (m, 1H), was 2.76 (m, 1H), 5,54 (q, 1H), 6,74 (d, 2H), 7,16 (d, 2H), 7,28 (m, 5H).

An alternative procedure for 2 of stage 1 of the method

A solution of 3-chloro-1-phenylpropane-1-it (100 g, 0,595 IOL) in tetrahydrofuran (280 ml) were added drop by drop into the thoroughly stirred mixture of zinc the CSOs powder (non-activated) (40 g, 1,231 mol, feast upon. aqueous solution of NH4Cl (1500 ml) and tetrahydrofuran (400 ml). The allyl bromide (143 g, 1,19 mol) was dissolved in tetrahydrofuran (200 ml) and slowly added to the reaction mixture. The reaction occurred with slight evolution of heat and unexpected reverse or. After the termination of the reverse of the condensation of the mixture stirred for 1 h Then the mixture was subjected to extraction using EtOAc was dried over anhydrous Na2SO4and evaporated to obtain 1-chloro-3-phenylhexa-5-EN-3-ol (122 g, 97%).1H NMR: (400 MHz, CDCl3): δ=2,24(s, 1H), 2,34 (m, 2H), 2,53 (m, 1H), 2,75 (m, 1H), 3,20 (m, 1H), to 3.58 (m, 1H), 5,18 (t, 1H), 5,51 (m, 1H), 7,26 (m, 1H), 7,26-7,39 (m, 3H).

(R)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-phenyl-1,3-oxazine-2-it was obtained from (S)-1-(4-bromophenyl)propan-1-amine by a procedure identical to that described within 1-3 stages 1 method 1 method of obtaining.

(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazine-2-it was obtained from (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-1,3-oxazine-2-through procedures similar to that described in part 4 and 6 stages 1 method 1 method of obtaining.

Method 2

Step 1. 1-chloro-5-methyl-3-phenyl-Gex-5-EN-3-ol

In stirred suspension of magnesium turnings (46,7 g, 1.94 mol) in 1500 ml of tetrahydrofuran (H2O<100 ppm during the titration by the method of the Arla Fisher) under nitrogen atmosphere at room temperature was added to 53.0 ml of 1 M DIBAL-H in hexane. Then in the mixture, the internal temperature was maintained below 30°C., was added 3-chloro-2-methylprop-1-ene (160 g, 1.77 mol). The resulting solution was shaken for 2 h at room temperature, and then was titrated in the presence of 1,1'-bipyridine to obtain 0.8 M of the corresponding Grignard reagent. In a dry flask containing 307,0 g anhydrous CeCl3(1.25 mol), under nitrogen atmosphere at room temperature was added 1556,8 ml of Grignard reagent (0.8 M, 1.25 mol). The resulting suspension was cooled to -10°C and were shaken for 0.5 h In a suspension, the internal temperature was maintained below 0°C, was added a solution of 200 g of 3-chloro-1-phenylpropane-1-it (1,19 mol) in 200 ml of tetrahydrofuran, after which the resulting mixture was stirred for 0.5 hours Then in the mixture, the internal temperature was maintained below 30°C, was added 1200 ml of an aqueous solution of 1 M HCl to obtain a clear solution. After separation of the phases was carried out extraction of the aqueous layer using EtOAc (500 ml). The combined organic layers were washed with brine and dried over sodium sulfate. After removal of the solvent using a vacuum was obtained crude 1-chloro-5-methyl-3-phenyl-Gex-5-EN-3-ol, which was dissolved in tetrahydrofuran to obtain H2About<500 prom is the during the titration Karl Fischer. The crude product (306 g, mass concentration in% - 83%, yield - 95%) was used directly in the course of 3 stages.1H-NMR spectroscopy (500 MHz, CDCl3) δ 7,38-7,37 (d. J=7.8 Hz, 2H), 7,33 (t, J=7.9 Hz, 2H), 7,24 (t, J=7,4 Hz, 1H), 4,91 (s, 1H), amounts to 4.76 (s, 1H), only 3.57 (ddd, J=5.6, to 10.7, and 10.7, 1H), 3.13 (ddd, J=4,7, to 10.7 and 10.7 Hz, 1H), 2,66 (d, J=13.3 Hz, 1H), 2,54 (d, J=11.3 Hz, 1H), 2,53 (s, 1H), a 2.36 (ddd, J=5,4, 10,6 and 13.9 Hz. 1H), to 2.29 (ddd, J=5,6, to 11.3 and 13.3 Hz, 1H), 1,29 (s, 3H),13C-NMR spectroscopy (125 MHz, CDCl3) δ 144,3, 141,4, 128,0, 126,6, 124,8, 116,1, 74,2, 51,2, 46,0, 39,9, 23,9.

Step 2. 1-Bromo-4-((S)-1-isocyanato-ethyl)-benzene

In jacketed reactors with a capacity of 10 l was placed 241 g of sodium bicarbonate (2,87 mol, 2,30 equiv.) and 5 l of deionized water. The resulting solution was shaken for 10-20 min until dissolved and a homogeneous solution. In a clear solution was then added 250 g (1.25 mol, of 1.00 equiv.) (S)-(-)-1-(4-bromophenyl)ethylamine in the form of a solution in a 1.00 l of dichloromethane. After that, the reactor was additionally placed 4 l of dichloromethane. The obtained two-phase solution was shaken and cooled to Tbeg=2-3°C. Triphosgene (126 g, 424 mmol, 0,340 equiv.) was added to the reactor in two approximately equal portions with an interval of 6 minutes, it Should be noted that when adding triphosgene there was a slight evolution of heat. The obtained turbid solution was shaken at Tbeg=2-5°C for 30 min, after which HPLC analysis is provided transform > 99% (220 nm). The dichloromethane layer was separated and dried using anhydrous sulfate. The resulting solution was passed through the tube from celite and evaporated to ~1.5 l with the subsequent formation of small solid particles of white. The solution was subjected to filtration and evaporation in vacuo before the formation of thick oil to obtain 239 g of 1-bromo-4-((S)-1-isocyanato-ethyl)-benzene (mass concentration in% - 93.7% of the output is 79.4%).1H-NMR spectroscopy (400 MHz, CD2Cl2) δ 7,53 (d, J=11,4 Hz, 2H), 7,26 (d, J=8,2 Hz, 2H), 4,80 (q, J=6,7 Hz, 1H), 1,59 (d, J=6,7 Hz, 3H). The material was used during the 3 stage without additional purification.

Step 3. (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazine-2-he

In the dried jacketed reactors with a capacity of 10 liters of nitrogen were placed 1-chloro-5-methyl-3-phenyl-Gex-5-EN-3-ol (167 g, mass concentration in percent to 81.7%, 610 mmol, 1.00 m equiv.), 1-bromo-4-((S)-1-isocyanato-ethyl)-benzene (219 g, mass concentration in percent - 93,7%, 911 mmol, 1.50 equiv.), anhydrous tetrahydrofuran (3,00 l) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 409 ml, 2,73 mol, 4.50 equiv.). The resulting solution was shaken and subjected to reverse or (Tint=67-69°C, TEXT=75°C.) for 19 hours, after which HPLC analysis showed the conversion of ~ 1% (220 nm) remaining 1-chloro-5-methyl-3-phenyl-Gex-5-EN-3-ol. The resulting dark colored solution was cooling is up to T int=20-25°C. Two liters of tetrahydrofuran were extracted from the solution by vacuum distillation. The remaining dark colored solution was diluted with the help of 4.0 l of ethyl acetate and 1.0 l of hexanol. The resulting solution was washed with 4.0 l of 1.0 M aqueous solution of hydrogen chloride (note: when washing, there is a slight evolution of heat). The aqueous solution was then separated and the remaining organic solution was dried using anhydrous sodium sulfate, were filtered and evaporated in vacuum before the formation of a thick oil. Thus obtained material was subjected to purification with flash chromatography on silicon (5-30% ethyl acetate/hexanol, 1,74 kg silica) to obtain 137,8 g of material (mass concentration in percent and 59 percent, the ratio of diastereomers of 3:1:1 in favor of the target diastereoisomer (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazine-2-it, the output is 32.3%). The material was used in the 4th stage without additional purification.

Data analysis (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazine-2-it:1H-NMR spectroscopy (500 MHz, CD2Cl2) δ 7,42-7,35 (m, 3H), 7,33-7,31 (m, 2H), 7,25-of 7.23 (m, 2H), 6,80-6,74 (m, 2), of 5.55 (q, J=7,1 Hz, 1H), lower than the 5.37 and 5.36 (m, 1H), 4,89 (s, 1H), 4,69 (s, 1H), 2,96-of 2.93 (m, 1H), 2,61 (dd, J=13.8 and 26,4 Hz, 2H), 2,37 was 2.25 (m, 3H), by 1.68 (s, 3H), 1,50 (d, J=7,1 Hz, 3H).13C-NMR spectroscopy (125 MHz, CD2Cl2) δ 152,5, 141,5, 140,1, 138,3, 130,6, 128,1, 128,, 126,9, 124,4, 120,2, 115,3, 82,4, 52,1, 50,1, 35,6, 29,8, 23,4, 14,5.

Data analysis (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazine-2-it:1H-NMR spectroscopy (400 MHz, CD2Cl2) δ 7,50-of 7.48 (m, 2H), 7,43-7,39 (m, 2H), 7,35-to 7.32 (m, 3H), 7,20-to 7.18 (m, 2H), ceiling of 5.60 (q, J=7,1 Hz, 1H), around 4.85 (s, 1H), 4,66 (s, 1H), 2,73-to 2.67 (m, 2H), 2,60 (dd, J=13,9 and to 19.4 Hz, 2H), 2,28 (dt, J=3.3V and 13.7 Hz, 1H), 2,14-2,05 (m, 1H), of 1.66 (s, 3H), 1,24 (d, J=7.2 Hz, 3H).13C-NMR spectroscopy (100 MHz, CD2Cl2) δ 153,4, 142,5, 141,0, 140,1, 131,8, 129,3, 128,9, 127,8, 125,3, 121,5, 116,3, 83,9, 53,2, 51,0, 36,6, 31,3, 24,3, 15,4.

Step 4. (6S)-3-((S)-1-(4-bromophenyl)ethyl)-6-((2-methyloxiran-2-yl)methyl)-6-phenyl-1,3-oxazine-2-he

In a round bottom flask with two necks capacity 1.0 l were placed (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazine-2-he (br135.8 g mass concentration in percent and 59 percent, the ratio of diastereomers of 3:1:1, 193 mmol, 1.00 m equiv.), dichloromethane (700 ml) and then 3-chloroperbenzoic acid (m-SRVA, 70%, to 95.3 g, 386 mmol, 2.0 equiv,). The resulting solution was shaken at room temperature (Tbeg=20-25°C) for 1 h, after which HPLC analysis showed a conversion of >99% (220 nm). The resulting solution was diluted with 700 ml of methyl tert-butyl ether (MTBE) and washed with 1×500 ml of sodium thiosulfate solution (mass concentration in percent - 30%) and 1×500 ml of saturated aqueous sodium bicarbonate solution. The lavage was repeated in the same sequence up until the peak organic is astora, defined by trace analysis, HPLC, i.e., the peak corresponding to the sample m-SRVA for HPLC, will not be <2.5 a% (220 nm). In this case, to obtain the specified result had to repeat the rinsing three times. Thus obtained organic layer was dried using anhydrous sodium sulfate, were filtered and evaporated in vacuum before the formation of a thick oil. The resulting material was diluted with 200 ml of anhydrous tetrahydrofuran, and then evaporated in vacuum to the formation of the thick oil to obtain the (6S)-3-((S)-1-(4-bromophenyl)ethyl)-6-((2-methyloxiran-2-yl)methyl)-6-phenyl-1,3-oxazine-2-it, which was used during the 5 stage without additional purification.

Step 5. (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-he

In a round bottom flask with three necks with a capacity of 2.0 liters, dried in a drying Cabinet, were placed the crude (6S)-3-((S)-1-(4-bromophenyl)ethyl)-6-((2-methyloxiran-2-yl)methyl)-6-phenyl-1,3-oxazine-2-he and 750 ml of anhydrous tetrahydrofuran. The resulting solution was shaken and cooled to Tbeg=2-3°C. After this clear solution was added 1.0 M solution of triethylborohydride in tetrahydrofuran (Superseded, 348 ml, 348 mmol, 1.8 equiv.) During the addition was observed heat, so the temperature of the added solution was maintained at Tbeg =<8°C. the resulting solution was shaken at Tbeg=2-3°C for 1.5 h, then was left to 2.5 h for heating up to Tbeg=10-13°C. When HPLC analysis showed the conversion of ~94% (220 nm). Then to the resulting solution was added a solution of hydrogen peroxide (95,7 ml of an aqueous solution with a mass concentration in percent 35%, diluted with 400 ml of water, a 1.08 mol, the ceiling of 5.60 equiv.). Adding significant heat, so the temperature of the added solution was maintained at Tbeg=<25°C. the resulting solution was diluted to 1.00 l of methyl-tert-butyl ether (MTBE) and washed first to 1.00 l of water, and then 500 ml of sodium thiosulfate solution with a mass concentration in% ~30%. The organic solution was dried using anhydrous sodium sulfate, were filtered and evaporated in vacuum. Thus obtained material was subjected to purification with flash chromatography on silicon (10-60% ethyl acetate, 600 g silica) to obtain 68 g of material, consisting of both diastereomers (ratio of diastereomers of 1.98:1) and 41 g of the target diastereoisomer (the ratio of diastereomers >99:1). The material, consisting of mixed fractions, was recrystallisation of 250 ml of isopropyl acetate (IPAC) and 200 ml of heptane (antibacterial) to obtain, after filtration of 31.3 g of the product (95,7% at 220 nm, the ratio of dust is remeron 74:1). Two samples were combined together to obtain 72,3 g (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-it (exit during a two-step procedure was 83.6%).1H-NMR spectroscopy (400 MHz, CDCl3) δ 7,37-7,29 (m, 5H), 7,25-7,21 (m, 2H), 6,82-6,79 (m, 2H), 5,61 (q, J=6,9 Hz, 1H), 2,83 (add, J=2,5, 5,4 and the 11.6 Hz, 1H), 2,39 (ddd, J=5,7, and 14.1 12.0 Hz, 1H), and 2.27 (ddd, J=2,6, 4,8 and 14.0 Hz, 1H), 2.21 are to 2.14 (m, 3H), of 2.08 (s, 1H), 1,49 (d, J=7,0 Hz, 3H), of 1.18 (s, 3H), of 1.13 (s, 3H).13C-NMR spectroscopy (100 MHz, CDCl3) δ 153,2, 142,6, 138,5, 131,6, 129,13, 129,10, 128,0, 125,3, 121,6, 84,2, 71,4, 54,1, 53,3, 36,4, 33,6, 32,1, 30,8, 15,6.

The METHOD of OBTAINING 2

(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-EN-2-yl)phenyl)ethyl)-1,3-oxazine-2-he

To a solution of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-she (6.6 g, of 15.2 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane (6,1 g, a 24.3 mmol) in dry DMSO (20 ml) was added COAs (4.8 g, to 48.6 mmol) and Pd(dppf)cl2(372 mg, 0.46 mmol). After the addition the mixture was left for 20 hours to heat up to 100°C. the results of the TLC showed the disappearance of starting material. The solid was filtered, then added water (60 ml) and EtOAc (20 ml). Were split layers with subsequent extraction of the aqueous layer using EtOAc (3×15 ml). The combined organic layer was washed with brine and dried over Na2SO 4, and then was subjected to filtration and evaporation to obtain a precipitate, which was then purified by column chromatography to obtain (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-EN-2-yl)phenyl)ethyl)-1,3-oxazine-2-she (4.4 g, 60%).

(S)-6-(4-forfinal)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it was obtained from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-(4-forfinal)-1,3-oxazine-2-it is the result of the same procedure.

(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazine-2-it was obtained from (S)-3-((S)-1-(4-bromophenyl)propyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-it is the result of the same procedure.

(R)-6-Methoxymethyl-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-[1,3]oxazine-2-it was obtained from 3-[1-(4-bromo-phenyl)-ethyl]-6-methoxymethyl-6-phenyl-[1,3]oxazine-2-it is the result of the same procedure.

The METHOD of OBTAINING 3

3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)-2,2-dimethylpropanoyl

Obtaining a complex of cobalt(II)

In a flask with a capacity of 50 ml were placed N,N'-bis(3,5-di-tert-butylchloride)-1,1,2,2-tetramethylaniline (0,430 g, 0.78 mmol, 1.0 equiv.), EtOH (17 ml) and Co(OAc)2(0,139 g ,78 mmol, 1.0 equiv.). The mixture was degassed, then heated under nitrogen atmosphere for 3 h for the reverse of condensation and cooled to room temperature. The precipitate was subjected to filtration, and then the purple solid was washed with EtOH (10 ml) and dried in high vacuum to obtain 0,353 g (75%) of a complex of cobalt(II).

A mixture of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazine-2-it (490 mg, 1.18 mmol), cobalt(II) (description retrieval method presented in the previous paragraph) (8 mg, 0.01 equiv.), TsCN (257 mg, 1.2 equiv.) and PhSiH3(137 mg, 157 μl, of 1.07 equiv.) in ethanol (10 ml) was stirred for 4 h at room temperature. After removing the vacuum of the solvent the residue mixture was purified by column chromatography using 40 g of silica gel and subjected to elution with 25-80% gradient of EtOAc in hexane to obtain 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)-2,2-dimethylpropanamide (267 mg, yield - 51%). Method LC-MS (3 min method) tR=1,89 minutes, the mass/charge (m/z 441, 443 (M+1).

The METHOD of OBTAINING 4

2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-6-yl)propanenitrile

3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)-2,2-dimethylpropanoate (467 mg, 1.06 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(,3,2-dioxaborolan) (538 mg, 2 equiv.), COAs (333 mg, 3.2 equiv.), PdCl2(dppf)CH2Cl2(27 mg, 0,033 equiv.) were mixed with dry DMSO (6 ml). The mixture was subjected to degassing re-saturation of the gaseous N2three times. Then the mixture during the night was heated at a temperature of 90°C. using as a protective gas gaseous N2. After cooling to room temperature the mixture was diluted with EtOAc (30 ml) and washed with water (20 ml), after which the aqueous layer was subjected to extraction using EtOAc (2×15 ml). The combined organic layer was washed with water (15 ml), brine (2×10 ml) and dried over Na2SO4, and then was subjected to filtration and evaporation to obtain a precipitate, which was then purified by column chromatography to obtain 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-6-yl)propanenitrile (393 mg, yield - 76%).

The METHOD of OBTAINING 5

3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-2-oxo-1,3-oxazine-6-yl)-2-methylpropionitrile

Method 1

Step 1. 1-chloro-3-(4-forfinal)Gex-5-EN-3-ol

In a flask with a capacity of 250 ml were placed anhydrous CeCl3(5,58 g, and 22.6 mmol) and tetrahydrofuran (40 ml). The mixture was thoroughly stirred for 3.5 h at room temperature the Suspension was cooled to -78°C, after which it was added a solution of br is foreign Allemagne (1.0 M in tetrahydrofuran, 21 ml, or 21.0 mmol). After stirring for 2 h at -78°C in suspension via cannula was added a solution of 3-chloro-1-(4-forfinal)propane-1-it (2,522 g, 13.5 mmol) in tetrahydrofuran (30 ml). The reaction mixture was left overnight (18 h) for slow cooling to 8°C by constant stirring. Then the reaction was stopped by adding a saturated aqueous solution of NaHCO3with the subsequent extraction of the aqueous phase with the aid of EtOAc and dried over Na2SO4. After evaporation of the solvents the residue was purified by chromatography using silica gel and subjected to elution with a mixture of hexanol/EtOAc to obtain 1-chloro-3-(4-forfinal)Gex-5-EN-3-ol (3,0049 g, 97%) as oil. Method LC-MS 1 tR=1,79 min, the mass/charge 213, 211 (M-OH)+;1H NMR (400 MHz, CDCl3) 7,37-to 7.32 (m, 2H), 7,07-7,02 (m, 2H), 5,57-vs. 5.47 (m, 1H), 5,20-5,19 (m, 1H), 5,16 (m, 1H), 3,59-to 3.52 (m, 1H), 3,24-3,18 (m, 1H), 2,70 (dd, J=13,8 and 5.9 Hz, 1H), 2,50 (dd, J=13,8, 8.5 Hz, 1H), to 2.29 (t, J=7.9 Hz, 2H), 2,22 (s, 1H);19F NMR (376 MHz, CDCl3) -116,52 (m).

Step 2. (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-1,3-oxazine-2-he and (S)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-1,3-oxazine-2-it.

A mixture of 1-chloro-3-(4-forfinal)Gex-5-EN-3-ol (0,4129 g, 1.8 mmol, 1.0 equiv.), (S)-(-)-1-(-bromophenyl)ethyl isocyanate (0,5005 g, 2.2 mmol, 1.2 equiv.), and DBU (0,7375 g, 4.8 mmol, 2.7 equiv.) in tetrahydrofuran (10 ml) was heated to arr is private condensation within 25 PM The mixture was diluted with EtOAc and washed with 1 N aqueous HCl solution, followed by extraction of the aqueous phase with the aid of EtOAc (2×). The combined organic phase was dried over Na2SO4. Obtained after evaporation of the solvents the crude product was used in the next step without additional purification.

An analytical sample was purified by chromatography using silica gel and subjected to elution with a mixture of hexanol/EtOAc to obtain two diastereomers of 6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-1,3-oxazine-2-it.

Isomer 1: (S)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-1,3-oxazine-2-it. LC-MS method 1 tR=2,03 min, the mass/charge 420, 418 (MH+);1H NMR (400 MHz, CDCl3) 7,46 (d, J=8,2 Hz, 2H), 7,31-7,28 (m, 2H), 7,17 (d, J=8,2 Hz, 2H), 7,07 (t, J=8.5 Hz, 2H), 5,76-to 5.66 (m, 2H), 5,10-4,99 (m, 2H), 2,75-2,52 (m, 4H), 2.23 to-2,19 (m, 1H), 2,08 is 2.00 (m, 1H), 1,24 (d, J=7,0 Hz, 3H);19F NMR (376 MHz, CDCl3) -115,07 (m).

Isomer 2: (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-1,3-oxazine-2-it. LC-MS method 1 tR=1,98 min, the mass/charge 420, 418 (MN+);1H NMR (400 MHz, CDCl3) 7,25-7,20 (m, 4H), 7,05-7,01 (m, 2H), of 6.71 (d, J=8.5 Hz, 2H), 5,74-5,64 (m, 1H), 5,58 (q, J=7,0 Hz, 1H), 5,09-4,99 (m, 2H), 2,92-2,87 (m, 1H), 2,63-of 2.50 (m, 2H), 2,33-of 2.16 (m, 3H), 1,47 (d, J=7,0 Hz, 3H);19F NMR (376 MHz, CDCl3) -114,91 (m).

Stage 3

A mixture of (R)-6-allyl-3-((S)-1 -(4-bromophenyl)ethyl)-6-(4-forfinal)-1.3-oxazine-2-it (1,067 g, 2.55 mmol, 1.0 equiv.), described in the procedure of preparation 3 catalyst of cobalt(II) (0,016 g, 0,0264 mmol, 0,010 equiv.), TsCN (0,555 g, a 3.06 mmol, 1.2 equiv.) and PhSiH3(0,294 g of 2.72 mmol, of 1.07 equiv.) in EtOH (5 ml) stirred at room temperature for 4 h resulting from removal under vacuum of the solvent the residue was purified by chromatography using silica gel and subjected to elution with a mixture of hexanol/ethyl acetate to obtain 1,0130 g (89%) of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-2-oxo-1,3-oxazine-6-yl)-2-methylpropionitrile in the form of solids. LC-MS tR=1,83, to 1.86 min, duration 3 min chromatography, mass/charge 445, 447 (MH+);1H NMR (400 MHz, CDCl3) 7,32-7,22 (m, 4H), 7,13-7,05 (m, 2H), 6,80-of 6.73 (m, 2H), ceiling of 5.60-to 5.56 (m, 1H), 3.00 and-of 1.94 (m, 7H), 1,51-1,49 (m, 3H), 1,35-1,32 (m, 1.5 H), 1,27-1,24 (m, 1,5 H);19F NMR (376 MHz, CDCl3) -113,08 (m), -113,69 (m).

Stage 4

To a solution of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-2-oxo-1,3-oxazine-6-yl)-2-methylpropionitrile (of 0.332 g, 0,746 mmol) and Mel (1.40 g, 13 equiv.) in tetrahydrofuran (12 ml) at -78°C were added 2.4 ml (2.4 mmol, 3.2 equiv.) 1.0 M solution of LiHMDS in tetrahydrofuran. The resulting mixture was stirred overnight with slow temperature rise to ambient temperature. The reaction of the reaction mixture was stopped with saline (1 ml), razbavlenie CH2Cl2and dried over Na2SO4. After evaporation of the solvent the obtained residue was purified by brato-phase HPLC (column SunFire™ Prep C 18OBD™ 5 μm 19×50 mm, 10% →90% CH3CN/H2O, 0.1% of CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% of CF3COOH over 2 min, flow rate 20 ml/min) to obtain 0,255 g (74%) of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-2-oxo-1,3-oxazine-6-yl)-2,2-dimethylpropanamide. Method LC-MS 1 tR=1,89 min, the mass/charge 459, 461 (MH+);1H NMR (400 MHz, CD3OD) 7,31-7,27 (m, 2H), 7,22-to 7.18 (m, 2H),? 7.04 baby mortality-of 6.99 (m, 2H), 6,83 (d, J=8,2 Hz, 2H), 5,41 (q, J=7,0 Hz, 1H), 3,02-of 2.97 (m, 1H), 2,42-of 2.36 (m, 1H), 2,29-of 2.08 (m, 4H), of 1.42 (d, J=7,0 Hz, 3H), of 1.30 (s, 3H), to 1.22 (s, 3H);19F NMR (376 MHz, CD3OD) -116,50 (m).

Method 2

Stage 1

A solution of 3-chloro-1-(4-forfinal)-propane-1-it (18.6 g, 0.1 mol) in tetrahydrofuran (50 ml) was added to a thoroughly stirred suspension of zinc powder (13 g, 0.2 mol) in a mixture of aqueous saturated solution of NH4Cl (260 ml) and tetrahydrofuran (65 ml). Then one drop was added to a solution of 3-iodine-2-methylprop-1-ene (36,4 g, 0.2 mol) in tetrahydrofuran (50 ml). During the reaction there was a slight evolution of heat and sudden reverse condensation. After reverse condensing the mixture was mixed for 1 h TLC showed incomplete reaction of 3-chloro-1-(4-forfinal)propane-1-it. To the mixture was added a solution of 3-iodine-2-methylprop-1-ene (18.2 g, 0.1 mol) in tetrahydrofuran (30 ml), after which the mixture is stirred at room temperature for the eyes. Then the mixture was subjected to extraction using EtOAc (2×500 ml). The combined organic layer was dried and evaporated. The obtained residue was purified by column chromatography using silica gel, and then subjected to elution with a mixture of petroleum ether/ EtOAc 50:1→30:1→5;1, to obtain 1-chloro-3-(4-forfinal)-5-metrex-5-EN-3-ol (17 g, yield - 76%) as oil.

Stage 2

A mixture of 1-chloro-3-(4-forfinal)-5-methox-5-EN-3-ol (3.15 g, 13 mmol), (S)-(-)-1-(-bromophenyl)ethyl isocyanate (3.5 g, 16 mmol) and DBU (8 g, 33 mmol) in tetrahydrofuran (80 ml) was heated to reverse condensation within 25 hours the Mixture was diluted with EtOAc and washed with 1N aqueous solution of HCl. Then was extracted using EtOAc (3×). The combined organic phase was dried over Na2SO4. After evaporation of the solvents the crude product was subjected to purification by means of column chromatography to obtain (R)-3-((S)-1-(4-bromophenyl)-ethyl)-6-(4-forfinal)-6-(2-methylallyl)-1,3-oxazine-2-it (2,13 g, yield - 38%).

Stage 3

A mixture of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-6-(2-methylallyl)-1,3-oxazine-2-it (2,13 g, 4.9 mmol) described in preparation method 3 catalyst of cobalt(II) (0,032 g, 0,053 mmol), TsCN (1,11 g, 6.12 mmol) and PhSiH3(0.6 g, 5,54 mmol) in EtOH (10 ml) stirred at room temperature for 8 hours resulting from removal in the Aquum of the solvent the residue was purified by column chromatography to obtain 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-2-oxo-1,3-oxazine-6-yl)-2,2-dimethylpropanamide (1.84 g, 81,1%).

The METHOD of OBTAINING 6

3-((R)-6-(4-forfinal)-2-oxo-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-6-yl)-2,2-dimethylpropanoyl

To a solution of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-2-oxo-1,3-oxazine-6-yl)-2,2-dimethylpropanamide (730 mg, of 1.59 mmol) in DMSO (8 ml) were added bis(pinacolato)diboron (480 mg, 1,89 mmol), COAs (480 mg, 4,89 mmol) and Pd(dppf)Cl2(45 mg, 0,042 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 90°C for 20 hours the Reaction was stopped with water, after which the mixture was subjected to extraction using EtOAc. The combined organic phase was dried over Na2SO4and evaporated to obtain the crude product, which was then purified by column chromatography to obtain 3-((R)-6-(4-forfinal)-2-oxo-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-6-yl)-2,2-dimethylpropanamide (191 mg, 23.7 per cent).

The METHOD of OBTAINING 7

(R)-6-allyl-6-(4-forfinal)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-he

A mixture of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-1,3-oxazine-2-it (0,4910 g at 1.17 mmol, 1.0 equiv.), bis(pinacolato)diboron (0,3925 g, 1.55 mmol, 1.3 equiv.), COAs (0,3696 g, 3,76 mmol, 3.2 equiv.) and PdCl2(dppf)·CH2Cl2(0,0316 g, 0,0386 mmol 0,033 equiv.) in DMSO (6 ml) was heated at 90°C in N 2the medium for 20 h, after cooling, the reaction mixture was partitioned between EtOAc and water. The organic phase was washed with brine and dried over Na2SO4. The resulting evaporation of the solvents the residue was purified by chromatography using silica gel and subjected to elution with a mixture of hexanol/ethyl acetate to obtain 0,4776 g (87%) of (R)-6-allyl-6-(4-forfinal)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it is in the form of a solid white color.

The WAY to OBTAIN 8

(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazine-2-he

To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazine - 2-it (5 g, 12.5 mmol) in tetrahydrofuran (60 ml) was added to the complex, NR3and tetrahydrofuran (25 ml, 1 mol/l, 25 mmol) at 0°C in an atmosphere of nitrogen. The resulting mixture was mixed for 2 hours the Reaction was stopped with water. Then the above mixture was added NaOH (3 mol/l, 10 ml) and H2O2(15 ml). After the reaction was carried out extraction of the mixture with the aid of EtOAc. The combined organic phase was evaporated to obtain the crude product, which was then purified by column chromatography to obtain (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydro is dipropyl)-6-phenyl-l-1,3-oxazine-2-she (2.5 g, 40%).1H NMR: (400 MHz, CDCl3): δ=1,48 (t, 3H), of 1.53 (m, 1H), 1,73 (m, 1H), 1.93 and-to 1.98(m, 2H), 2,17-of 2.28 (m, 3H), of 3.57 (t, 2H), 5,59 (m, 1H), 6,72 (m, 2H), 7,20 (m, 2H), 7,25-7,37 (m, 5H).

(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-6-(3-hydroxypropyl)-1,3-oxazine-2-it was obtained from (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-1,3-oxazine-2-it is the result of the same procedure.

(R)-3-((S)-1-(4-bromophenyl)propyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazine-2-it was obtained from (R)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-phenyl-1,3-oxazine-2-it is the result of the same procedure.

The METHOD of OBTAINING 9

(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-he

To a solution of ((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6 - phenyl-1,3-oxazine-2-she (2 g, 4.8 mmol) in DMSO (30 ml) were added bis(pinacolato)diboron (1,58 g, 6.3 mmol), COAs (1.51 g, to 15.4 mmol) and PdCl2(130 mg, 0.16 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 90°C for 20 hours the Reaction was stopped with water and subjected to extraction using EtOAc. The combined organic phase was evaporated to obtain the crude product, which was then purified by column chromatography to obtain (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-she (1.7 g, 77%).1 H NMR: (400 MHz, CDCl3): δ=1,18 (t, 1H), 1,33 (S, 11H), USD 1.43 (m, 2H), 1,48 (m, 3H), 1,71(m, 1H), of 1.88(m, 2H), 2,1-2,3 (t, 3H), and 2.7 (m, 1H), 3,5 (m, 2H), and 5.5 (m, 1H), 6,72 (m, 2H), 7,25-7,37 (m, 5H), of 7.48 (m, 2H).

(R)-6-(4-forfinal)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it was obtained from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-6-(3-hydroxypropyl)-1,3-oxazine-2-it is the result of the same procedure.

(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazine-2-it was obtained from (R)-3-((S)-1-(4-bromophenyl)propyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazine-2-it is the result of the same procedure.

(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazine-2-it was obtained from (R)-3-((S)-1-(4-bromophenyl)propyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazine-2-it is the result of the same procedure.

The METHOD of OBTAINING 10

(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(methoxymethyl)-6-phenyl-1,3-oxazine-2-he

Step 1. 1-Methoxy-2-phenyl-Penta-4-EN-2-ol

2-Methoxy-1-phenyl-Etalon (of 5.00 g) was dissolved in tetrahydrofuran (50 ml), Then at room temperature the resulting solution was added a 2 M solution Allemagne chloride in tetrahydrofuran (21 ml). The solution was mixed at room temperature for 3 h, after which it was added 10% aqueous solution of NH4Cl (50 is l). The resulting mixture was subjected to extraction with tert-butyl methyl ether (3×50 ml) then the combined extracts were washed with water (50 ml) and brine (50 ml). Then the solvent was evaporated to obtain the title compound as a colourless oil. Output: 6,40 g (quantitative indicator). Mass spectrum (electrospray ionization+): the mass/charge = 175 [M+H-H2On]+.

Step 2. 5-methoxy-4-phenyl-pentane-1,2,4-triol

OsO4(4% solution in water, 2 ml; alternatively, can be used K2OsO4), and then N-methyl-morpholine-N-oxide (5.20 g) was added to a solution of 1-methoxy-2-phenyl-Penta-4-EN-2-ol (1.10 g) in tetrahydrofuran (10 ml), cooled in an ice bath. After removing from the bath solution during the night stirred at room temperature. Then was added 10% aqueous solution of Na2S2O5(10 ml), after which the resulting mixture was again stirred at room temperature for 1.5 hours After removal in vacuo of the organic solvent remaining mixture was subjected to extraction using ethyl acetate. The combined extracts were washed with brine and dried (MgSO4). The solvent was evaporated to obtain the title compounds of high purity (approximately 95%). Output - 1.20 g (96% of theoretical value). Mass spectrum (ionizate what elektrorazpredelenie -): the mass/charge = 225 [M-N]-.

Step 3. 3-hydroxy-4-methoxy-3-phenyl-Butyraldehyde

NalO4(5.20 g) was added to a mixture of 5-methoxy-4-phenyl-pentane-1,2,4-triol (1.10 g), dichloromethane (10 ml) and water (5 ml), cooled in an ice bath. The mixture was thoroughly stirred in the cooling bath to warm to ambient temperature and then stirred overnight at the same temperature. Then to the mixture were added water (20 ml) and dichloromethane (50 ml), separated the organic layer and the aqueous layer was subjected to extraction with dichloromethane (2×25 ml). The combined organic phases were washed with water and dried (MgSO4). After removal of the solvent there was obtained the title compound, which was used in the next phase of the reaction (cleavage of glycols) without additional purification. Output: 0,94 g (quantitative indicator).

Step 4. 4-[(S)-1-(4-bromo-phenyl)-ethylamino]-1-methoxy-2-phenyl-butane-2-ol

(S)-1-(4-bromo-phenyl)-ethylamine (0,93 g), NaB(OAc)3(0,98 g) and acetic acid (0,27 ml) were added in that order to the solution of 3-hydroxy-4-methoxy-3-phenyl-Butyraldehyde (0,90 g) in tetrahydrofuran (20 ml) at a temperature of about 10-15°C. After removal of the cooling bath and the mixture was mixed at room temperature for 2 hours Then the mixture were added water (50 ml) and 1 M aqueous NaOH solution (20 ml), after che is about the resulting solution was again stirred for 30 minutes The mixture was subjected to extraction using ethyl acetate, then the combined extracts were washed with water and brine. After drying (MgSO4) the solvent was removed to obtain the title compound that was used in the next step reaction without further purification. Yield: 1.80 g (quantitative indicator). Mass spectrum (electrospray ionization+): the mass/charge = 378/380 (Br) [M+H]+

Step 5. 3-[(S)-1-(4-bromo-phenyl)-ethyl]-(R)-6-methoxymethyl-6-phenyl-[1,3]oxazine-2-it 3-[(S)-1-(4-bromo-phenyl)-ethyl]-(S)-6-methoxymethyl-6-phenyl-[1,3]oxazine-2-it.

Triphosgene (157 mg) was added to ice-cold solution of 4-[(S)-1-(4-bromo-phenyl)-ethylamino]-1-methoxy-2-phenyl-butane-2-ol (mixture of diastereomers in a ratio of 1:1, 200 mg) and EtN/Pr2(91 μl) in dichloromethane (5 ml), the resulting solution was mixed simultaneously with cooling for 2 h and at room temperature over night. Then the solution was evaporated in vacuo, the resulting residue was purified by inverse-phase HPLC (MeCN/H2O/NH3) to obtain the title compounds in the composition of the individual fractions.

Isomer 1: 3-[(S)-1-(4-bromo-phenyl)-ethyl]-(R)-6-methoxymethyl-6-phenyl-[1,3]oxazine-2-it. Yield: 45 mg (21% of theoretical value). Mass spectrum (electrospray ionization+): the mass/charge = 404 [M+H]+1H NMR (400 MHz, DMSO-d6) δ of 1.41 (d, J7,1 Hz, 3H), 2,19 (fd, J=11,2, 5,2 Hz, 1H), 2,24-of 2.34 (m, 1H), 2,34-to 2.41 (m, 1H), 3,02-to 3.09 (m, 1H), 3.27 to (s, 3H), 3,49 (d, part of the signal AB, J=a 10.6 Hz, 1H), 3,53 (d, a part of the signal AB, J=a 10.6 Hz, 1H), of 5.34 (q, J=7,0 Hz, 1H), 6,80 (dm, J=8,4 Hz, 2H), 7,27 (dm, J=8,4 Hz, 2H), 7,32-7,42 (m, 5H).

Isomer 2: 3-[(S)-1-(4-bromo-phenyl)-ethyl]-(S)-6-methoxymethyl-6-phenyl-[1,3]oxazine-2-it. Yield: 45 mg (21% of theoretical value). Mass spectrum (electrospray ionization+): mass/charge = 404 [M+H]+1H NMR (400 MHz, DMSO-d6) δ of 1.20 (d, J=7.2 Hz, 3H), 2,13-of 2.23 (m, 1H), 2,32-to 2.40 (m, 1H), 2,63-of 2.72 (m, 1H), 2,73-of 2.81 (m, 1H), 3,26 (s, 3H), 3,48 (d, part of the signal AB, J=a 10.6 Hz, 1H), 3,55 (d, a part of the signal AB, J=a 10.6 Hz, 1H), 5,35 (q, J=7.2 Hz, 1H), 7,19 (dm, J=8,4 Hz, 2H), 7,32 was 7.45 (m, 5H), 7,53 (dm, J=8,4 Hz, 2H).

The METHOD of OBTAINING 11

N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propyl)-N-methylacetamide

Stage 1

To a solution of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazine-2-he (200 mg, 0.48 mmol) in CH2Cl2(5 ml) was added Et3N (240 mg, 2.4 mmol) and methanesulfonyl chloride (164 mg, 1.4 mmol) at 0°C. the Reaction mixture was stirred at room temperature for 1 h the Reaction was stopped using H2O, after which the mixture was subjected to extraction with CH2Cl2. The organic phase was evaporated to obtain 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propyl of methansulfonate (234 mg, 98%) which was used in the ode of the next stage without additional purification.

Stage 2

To a solution of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propyl of methansulfonate (234 mg, 0.24 mmol) in CH2Cl2(3 ml) was added NaH (82 mg, 3.4 mmol) at 0°C. the Mixture is stirred at room temperature for 30 minutes Then the mixture was added N-methylacetamide (204 mg, 2.8 mmol). After that, the mixture was mixed at a temperature of 80°C for 5 hours After stopping the reaction with water, the mixture was subjected to extraction using EtOAc. The combined organic phase was evaporated to obtain the crude product, which was then purified by preparative TLC to obtain N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propyl)-N-methylacetamide (150 mg, 68%). Method LC-MS: 2 tR=1,50 min, the mass/charge= 497, 495, 475, 473.1H NMR (400 MHz, CDCl3): δ=1.41 for (m, 1H), 1,48 (t, 3H), at 1.73 (m, 1H), 1,83-of 1.95 (m, 2H), 2,01 (m, 3H), to 2.1-2.3 (m, 3H), 2,71 (m, 1H), 2,81 (s, 3H), 3,1 (m, 1H), 3,2 (m, 1H), 5,5 (m, 1H), 6,72 (m, 2H), 7,10 (m, 2H), 7,20 (m, 2H), 7,37 (m, 3H).

(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-(2-oxopyrrolidin-1-yl)propyl)-6-phenyl-1,3-oxazine-2-it was obtained from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazine-2-it is after carrying out a similar procedure using pyrrolidin-2-it is during phase 2.

The METHOD of OBTAINING 12

(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(1,-dioxo-isothiazolin-2-yl)ethyl)-6-phenyl-1,3-oxazine-2-he

A solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazine-2-she (3 g, 7.5 mmol) in CH2Cl2(50 ml) was treated with O3at -78°C before staining mixture in blue color. Then to the solution were added NaBH4(285 mg, 75 mmol) at 0°C, after which the reaction mixture is stirred at room temperature for 3 hours. The reaction was stopped using H2O followed by extraction using EtOAc. The combined organic phase was evaporated to obtain the crude product, which was then purified by preparative TLC to obtain (S)-3-((S)-1-(4-bromo-phenyl)ethyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazine-2-she (2.5 g, 84%).1H NMR (CDCl3): to 1.48 (t, 3H), 2.05 is-is 2.41 (m, 4H), 2,71 of 2.92 (m, 2H), 3,51 (m, 1H), 3,71 (m, 1H), 5,58 (m, 1H), 6.73 x (d, 2H), 7,12 (m, 2H), 7.23 percent was 7.45 (m, 6H).

(S)-3-((S)-1-(4-bromophenyl)propyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazine-2-it was obtained from (R)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-phenyl-1,3-oxazine-2-it is after the procedure, similar to that described in the previous paragraph.

The METHOD of OBTAINING 13

(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(1,1-dioxo-isothiazolin-2-yl)ethyl)-6-phenyl-1,3-oxazine-2-he

Stage 1

To a solution of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazine-2-she (300 mg, 0.75 mmol) in dichloromethane (20 ml) was added Et3N (390 mg, 3.75 mmol) and IU insulter chloride (256 mg, 2.25 mmol) at 0°C. Then the reaction mixture was stirred at room temperature for 1 h the Reaction was stopped using H2Oh, after which the mixture was subjected to extraction with dichloromethane. The organic phase was evaporated to obtain 2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)ethyl-methanesulfonate (of 352.8 mg, 98%) which was used in the next step without additional purification.

Stage 2

To a solution of 2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)ethyl-methanesulfonate (360 mg, 0.75 mmol) and K2CO3(207 mg, 1.5 mmol) in acetonitrile (10 ml) was added isothiazolin 1,1-dioxide (121 mg, 4.6 mmol), after which the mixture was subjected to reverse or. Then the mixture was subjected to filtration. The obtained filtrate was evaporated to obtain the crude product, which was purified by preparative HPLC to obtain compound (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(1,1-dioxo-isothiazolin-2-yl)ethyl)-6-phenyl-1,3-oxazine-2-it (2,43 mg, 1%). Method LC-MS 2 tR=1,37 min, the mass/charge = 509, 507.1H NMR (CDCl3): to 1.48 (t, 3H), 2.05 is-is 2.41 (m, 7H), 2,71 of 2.92 (m, 2H), 3,11 (m, 3H), 3,21 (m, 2H), 5,58 (m, 1H), 6.73 x (d, 2H), 7,18 (m, 1H), 7.23 percent (m, 3H); 7,35 (m, 3H).

(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-(1,1-dioxo-isothiazolin-2-yl)propyl)-6-phenyl-1,3-oxazine-2-it was obtained from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazin is n-2-it is after carrying out a similar procedure:

The METHOD of OBTAINING 14

(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-6-((1-hydroxyisopropyl)methyl)-1,3-oxazine-2-he

Stage 1

To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-1,3 oxazine-2-she (450 mg, 1.01 mmol) in acetone (10 ml) was added a solution of KMnO4(190 mg, 1.2 mmol) and NalO4(1.5 g, 7.2 mmol) in water (10 ml). The mixture was mixed for 2 h at 0°C. the Mixture was subjected to filtration, after which the pH of the resulting filtrate was adjusted to 5-6 with 1 N aqueous HCl, the Mixture was subjected to extraction using EtOAc. The organic phase was washed with brine, dried over anhydrous Na2SO4and evaporated to obtain 2-((S)-3-((S)-1-(4-bromphen-yl)ethyl)-6(4-forfinal)-2-oxo-1,3-oxazine-6-yl)acetic acid (540 mg, crude), which was used in the next step without additional purification.

Stage 2

To a solution of 2-((S)-3-((S)-1-(4-bromphen-yl)ethyl)-6-(4-forfinal)-2-oxo-1,3-oxazine-6-yl)acetic acid (540 mg, 1,24 mol) in Meon (20 ml) was added SOCl2(5 ml) at 0°C, after which the reaction mixture is stirred at room temperature for 2 h Then the reaction mixture was evaporated, followed by purification of the precipitate by preparative TLC to obtain methyl 2-((S)-6-(4-forfinal)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-the l)phenyl)-ethyl)-2-oxo-1,3-oxazine-6-yl)acetate (150 mg, 27%).1H NMR (CDCl3): δ=1,49 (d, 3H), 2,19 (m, 1H), 2,44 (m, 1H), 2,60 (m, 1H), 2.77-to is 3.08 (m, 3H), 3,51 (s, 3H), 5,52 (m, 2H), 6,62 (d, 2H), 6,98 (t, 2H), 7.23 percent (t, 2H), 7,28 (m, 2H).

Stage 3

To a solution of methyl 2-((S)-6-(4-forfinal)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)-ethyl)-2-oxo-1,3-oxazine-6-yl)acetate (150 mg, 0.33 mmol) and tetraisopropoxide (189 mg, 0.66 mmol) in tetrahydrofuran (20 ml) at room temperature under nitrogen atmosphere was added a 3.0 M etimani bromide (4 ml, 12 mmol). The mixture is then stirred for 2 hours the Reaction was stopped by using aqueous solution of NH4Cl, after which the mixture was subjected to filtration, and the obtained filtrate extraction using EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4and evaporated to obtain the crude product, which was then purified by preparative HPLC to obtain (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-6-((1-hydroxyisopropyl)methyl)-1,3-oxazine-2-it (2.51 mg, 2%).1H NMR (CDCl3): 0,03 (m, 1H), 0,18 (m, 1H), 0,49 (m, 1H), 0,60 (m, 1H), USD 1.43 (m, 3H), 2,08 (s, 2H), and 2.26 (m, 1H), 2,37 (m, 2H), 2,88 (m, 1H), of 5.53 (m, 1H), 6,66 (d, 2H), 6,97 (t, 2H), 7,16 (m, 2H), 7,26 (m, 2H).

The METHOD of OBTAINING 15

N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propyl)-N-methylmethanesulfonamide

To a solution of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propyl to means hanata (180 mg, 0.36 mmol) in DMF (5 ml) was added NaH (14.6 mg, 0.36 mmol) at 0°C. the Mixture is stirred at room temperature for 30 minutes Then the mixture was added iodomethane (153 mg, 1.1 mmol). The mixture was mixed at 40°C for 3 hours After the reaction was stopped with a solution of NH4Cl, then the mixture was subjected to extraction using EtOAc. The combined organic phase was evaporated to obtain the crude product, which was then purified by preparative TLC to obtain N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propyl)-N-methylmethanesulfonamide (100 mg, 55%). Method LC-MS 2 tR=1,41 min, the mass/charge = 511, 509.1H NMR (400 MHz, CDCl3): δ=1,45 (m, 1H), 1,48 (t, 3H), 1,83-of 1.97 (m, 3H), 2,1-2,2 (m, 3H), 2,61 (s, 3H), 2,71 (s, 3H), 2.91 in (m, 1H), 3.0 a (m, 2H), and 5.5 (m, 1H), 6,72 (m, 2H), 7,10 (m, 2H), 7,20 (m, 2H), 7,37 (m, 3H).

EXAMPLE 1

(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-he

To a solution of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-she (112 mg, 0,259 mmol) in 1,4-dioxane (3 ml) were added 6-oxo-1,6-dihydropyridines-3-albanova acid (55 mg, 0.40 mmol), then Pd(dppf)Cl2(11 mg, 0.015 mmol) and an aqueous solution of Cs2CO3(of 0.48 ml, 2M solution in H2O) After you install the reverse of the capacitor was produced in the den of the degassing device and three-time washing with N 2. The reaction mixture was heated to 90°C for 24 hours After cooling to room temperature the mixture was diluted with water and was subjected to three times of extraction with the aid of EtOAc. The organic layers were washed with brine, dried over Na2SO4, was subjected to filtration and evaporation. The obtained residue was purified by preparative HPLC to obtain the title compound (21,6 mg) as a thick oil. Method LC-MS 1 tR=1,25 min, the mass/charge = 447, 389;1H NMR (CD3OD) of 0.96 (s, 3H), of 1.28 (s, 3H), of 1.57 (d, 3H), of 2.16 (s, 2H), of 2.21 (m, 1H), 2,46 (m, 2H), 3,03 (m, 1H), 5,57 (q, 1H), 6,66 (d, 1H), 7,02 (d, 2H), 7,25-7,40 (7H), 7,66 (s,1H), of 7.90 (d, 1H).

EXAMPLE 2

(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-he

The title compound was obtained from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-EN-2-yl)phenyl)ethyl)-1,3-oxazine-2-it 4-iodopyridine-2(1H)-it is the result of a procedure similar to that described in Example 1. Method LC-MS 1tR=1,23 min, the mass/charge = 389, 447 (M+1);1H NMR (CD3OD) 7,40 (d, J=6,7 Hz, 1H), 7,31 (d, J=8,2 Hz, 2H), 7,29-7,20 (m, 5H), of 6.96 (d, J=8,2 Hz, 2H), 6,57-of 6.52 (m, 2H), 5,49 (q, J=7,0 Hz, 1H), 2,98-of 2.93 (m, 1H), 2,47-of 2.34 (m, 2H), 2,16-of 2.09 (m, 1H), 2,07 (s, 2H), 1,45 (d, J=7,0 Hz, 3H), 1,19 (s, 3H), of 0.87 (s, 3H).

EXAMPLE 3

(S)-3-((S)-1-(4-(1-cyclopropyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-Hairdryer is l-1,3-oxazine-2-he

Step 1. 5-bromo-1-cyclopropylmethyl-2(1H)-he

A mixture of 5-bromo-2-hydroxypyridine (0,8300 g, 4.77 mmol, 1.0 equiv.), Cu(SLA)2(0,902 g, 4,96 mmol, 1.04 million equiv.), bipyridine (0,785 g of 5.03 mmol, 1.05 equiv.), cyclopropylboronic acid (0,846 g, 9,85 mmol, of 2.06 equiv.) and solution of Na2CO3(g 1,110 land only, of 10.47 mmol, 2,20 equiv.) in dichloroethane (30 ml) were mixed at 70°C for 22 h in air. The reaction mixture was stopped by means of a saturated aqueous solution of NH4Cl, diluted with CH2Cl2and dried over Na2SO4. After removal under vacuum of the solvent the residue was purified by chromatography using silica gel and subjected to elution with a mixture of hexanol/EtOAc to obtain 0,585 g (58%) of 5-bromo-1-cyclopropylmethyl-2(1H)-she. Method LC-MS 1 tR=1,05 min, the mass/charge 214, 216 (MH+);1H NMR (400 MHz, CDCl3) 7,41 (d, J=2.7 Hz, 1H), 7,31 (dd, J=9,7, 2,9 Hz, 1H), 6,47 (d, J=9.9 Hz, 1H), 3.33 and-of 3.27 (m, 1H), 1,17-1,12 (m, 2H), 0,89-0,84 (m, 2H);13With NMR (100 MHz, CDCl3) 162,58, 142,29, 137,00, 121,77, 97,92, 32,83, 6,93.

Step 2. (S)-3-((S)-1-(4-(1-cyclopropyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-he

To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it (advanced 0.729 g of 1.52 mmol) in 1,4-dioxane (16 ml) were added 5-bromo-1-ecoproperty-2(1H)-he (0,323 g, is 1.51 mmol), 2 M aqueous solution of Cs2CO3(4 ml) and PdC2(dppf)·CH2Cl2(0,079 g, 0,0964 mmol). Then the mixture was subjected to degassing and heated in nitrogen atmosphere at a temperature of 120°C for 16 h, was diluted with CH2Cl2and dried Na2SO4. After evaporation of the solvent the obtained residue was purified by chromatography using silica gel and subjected to elution with MeOH/CH2Cl2to obtain 0,543 g (74%) of (S)-3-((S)-1-(4-(1-cyclopropyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-it. Method LC-MS 1 tR=1,41 min, the mass/charge 487 (MN+);1H NMR (400 MHz, CD3OD) 7,66-to 7.64 (m, 2H), 7,30-7,19 (m, 7H), 6,94 (d, J=8,2 Hz, 2H), of 6.52 (d, J=10 Hz, 1H), 5,48 (q, J=7,0 Hz, 1H), 3,32-3,26 (m, 1H), 2,97 of 2.92 (m, 1H), 2,46 of-2.32 (m, 2H), 2,16-of 2.09 (m, 1H), 2,08 (s, 2H), of 1.45 (d, J=7,0 Hz, 3H), 1,19 (s, 3H), 1,10-of 1.05 (m, 2H), 0,90 is 0.86 (m, 5H);13With NMR (100 MHz, CD3OD) 165,59, 155,82, 144,08, 141,05, 139,60, 136,60, 136,30, 129,77, 128,86, 128,64, 126,83, 126,15, 121,93, 120,53, 85,33, 71,67, 55,18, 54,78, 37,46, 34,10, 33, 04, 31,79, 30,00, 15,60, 7,49, 7,47.

EXAMPLE 4

(S)-3-((S)-1-(4-(1-(deformity)-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-he

Into the flask for processing microwave, equipped with a magnetic stirrer, were placed (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-he (20 is g, 0,047 mmol), 5-bromo-1-(deformity)pyridine-2(1H)-he (25 mg, 0,113 mmol), Cs2CO3(27 mg, 0,083 mmol), N2About (0.1 ml) and dry dioxane (1 ml). The resulting mixture was treated by spraying N2 for 10 min and was heated at a temperature of 110°C in the microwave for 0.5 h the resulting mixture was diluted with ice SPLA (0.1 ml) and Meon (0.5 ml) and subjected to filtration. The filtrate was purified using preparative HPLC to obtain (S)-3-((S)-1-(4-(1-(deformity)-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-it (11.8 mg, 57%) as oil. Method LC-MS 1 tR=1,55 min, the mass/charge = 497, 248;1H NMR (CDCl3) of 1.13 (s, 3H), 1,19 (s, 3H), and 1.56 (d, 3H), of 2.15 to 2.35 (s, 4H), 2,42(m, 2H), 2,88 (m, 1H), 5,71 (q, 1H), only 6.64 (d, 1H),? 7.04 baby mortality (d, 2H), 7,18 (d, 2H), 7,30-7,40 (5H), 7,52 (1H), 7,60 (m, 1H), of 7.75 (t, 1H).

5-bromo-1-(deformity)pyridine-2(1H)-it was obtained in accordance with the procedure described in Ando, M.; Wada, T.; Sato, N. Org. Lett. 2006, 8, 3805-3808.

EXAMPLE 5 (S)-3-((S)-1-(4-(1-(deformity)-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-he

Stage 1

The stirred mixture of 2-chloro-4-iodopyridine (1,33 g, 5.6 mmol) and powdered NaHCO3(935 mg, and 11.2 mmol) in MeCN (2 ml) was heated to 40°C. in an oil bath, after which the mixture drop by drop within 10 min was added a solution of 2,2-debtor-2-(torso hanil)acetic acid (or 0.57 ml, 5.6 mmol) in MeCN (10 ml). The mixture was mixed at 40°C for 2 hours during LC-MS were observed partial conversion to the target product. Then to the mixture was added powdered NaHCO3(935 mg, and 11.2 mmol), and then drop by drop in for 10 minutes a solution of 2,2-debtor-2-(persulfonic)acetic acid (or 0.57 ml, 5.6 mmol) in MeCN (10 ml). The resulting mixture was stirred at 40°C for 2 h, then was diluted with saturated aqueous NaHCO3(25 ml) and was subjected to evaporation in a vacuum. The aqueous residue was subjected to extraction using EtOAc (90 ml). The organic extract was washed with brine (20 ml), dried over Na2SO4and was subjected to evaporation to obtain an amber oil (1,14 g). After conducting chromatography using a cartridge containing 40 g of silica gel and elution with a gradient - 0-40% mixture of EtOAc and hexanol was obtained 1-(deformity)-4-iodopyridine-2(1H)-he (255 mg, yield: 16%, the estimated purity: 45%) as a yellow oil. Method LC-MS 1 tR=1,23 min, the mass/charge = 272. The material was used without additional purification.

Stage 2

Into the flask for processing microwave, equipped with a magnetic stirrer, were placed (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-he (52 mg, 0.11 mmol), 1-(deformity)4-iodopyridine-2(1H)-one (29 mg, 0.11 mmol), Cs2CO3(71 mg, 0.22 mmol), H2O (0.1 ml) and dry dioxane (1 ml). After that, the mixture was treated with a spray N2within 5 min followed by the addition PdCl2(dppf) (5 mg, to 0.007 mmol). The mixture was processed by sputtering for 5 min and was heated in a microwave for 1 hour at 110°C. the resulting mixture was diluted with 5% aqueous HCl solution (0.2 ml) and Meon (2 ml) and subjected to filtration. The filtrate was purified by preparative HPLC to obtain brown oil (16.2 mg), which was applied to the SPE cartridge containing 2 g of silica gel, and subjected to sequential elution of 25 and 50% mixtures of EtOAc in hexano (15 ml) and EtOAc (3×15 ml) to obtain five fractions. Fractions 3 and 4 were mixed together and evaporated to obtain (S)-3-((S)-1-(4-(1-(deformity)-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-it (13,4 mg, 25%) as a colourless oil. Method LC-MS 1 tR=1,57 min, the mass/charge = 497, 439;1H NMR (CD3OD) of 0.96 (s, 3H), of 1.27 (s, 3H), and 1.56 (d, 3H), of 2.15 (s, 2H), of 2.21 (m, 1H), 2,40-2,60 (2H), is 3.08 (m, 1H), 5,59 (q, 1H), 6,66 (s, 1H), 6,74 (d, 1H), 7,07 (d, 2H), 7,30-7,40 (5H), was 7.45 (d, 2H), to 7.77 (1H), 7,79 (t, 1H).

EXAMPLE 6

2,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propanamide

Stage 1

See the camping 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-6-yl)propanenitrile (392 mg, 0,775 mmol), 5-bromo-1-methylpyridin-2(1H)-she (220 mg, 1.5 equiv.). 2M aqueous solution of Cs2CO3(900 μl), Pd(PPh3)2Cl2(40 mg, 7 mol%) and anhydrous 1,4-dioxane (8.5 ml) was three-fold subjected to degassing and re-saturation of the gaseous N2Then the mixture during the night was heated at a temperature of 85°C With use as a protective gas gaseous N2. After cooling to room temperature the mixture was diluted with EtOAc (20 ml) and washed with water (20 ml), after which the aqueous layer was subjected to extraction using EtOAc (2×10 ml). The combined organic layer was washed with water (10 ml), brine (2×10 ml) and dried over Na2SO4, and then was subjected to filtration and evaporation to obtain a precipitate, which was then purified using chromatograph Gilson company to obtain 34 mg of product (yield: 9%). LC-MS (3 min method) tR=1,44 min, the mass/charge 470 (M+1).1H NMR (CDCl3) δ to 7.68 (dd, 1H), 7,52 (d, 1H), 7,31 (q, 2H), 7,16 (d, 2H), 7,07 (t, 2H), 6,97 (d, 2H), 6,91 (d, 1H), to 5.66 (q, 1H), 3,71 (s, 3H), 2,99 (dt, 1H), 2,47 (dd, 2H), and 2.27 (m, 1H), 2,13 (s, 2H), of 1.55 (d, 3H), the 1.44 (s, 3H), 1,24 (s, 3H).

Stage 2

A solution of 2,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propanenitrile (55 mg, 0.12 mmol), ndimethylacetamide (177 mg, 3 mmol) and PdCl2(21 mg, 0.12 mmol) in tetrahydrofuran: H2O (2 ml, 3:1) were mixed up during the night. After removal of the of astorias was re-dissolving the crude material in CH 3CN, followed by purification of the obtained product by preparative HPLC to obtain 2,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propanamide (28 mg). Method LC-MS 1 tR=1,25 min, the mass/charge = 488 (M+1);1H NMR (CDCl3) of 7.55 (dd, 1H, J=9 Hz, 3 Hz), 7,42 (d, 1H, J=3 Hz), 7,32 (d, 1H, J=4 Hz), 7,29 (m, 4H), 7,14 (d, 2H, 8 Hz), 7,00 (d, 2H, J=8 Hz), 6,79 (d, 1H, J=9 Hz), to 5.66 (q, 1H, J=8 Hz), 3,62 (s, 3H), 2,95-2,89 (m, 1H), 2,5 (d, 1H, J=15 Hz), 2.26 and-2,1 (m, 3H), 2,2 (d, 1H, J=15 Hz), 2,5 (d, 1H, J=15 Hz), 2.26 and is 2.10 (m, 3H), 2,2 (d, 1H, J=15 Hz), 1,53 (d, MN, J=7 Hz), 1,22(s,3H),1,20(s,3H).

EXAMPLE 7

(S)-6-(2-amino-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-he

In covered with foil flask containing a mixture of 2,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propanamide (20 mg, 0.04 mmol) and 1:1 CH3CN/H2O (1 ml) was placed Phl(O2CCF3)2(31 mg, 0.07 mmol). The end of the reaction was observed after 24 hours After removal of the solvent the crude material was subjected to purification by preparative HPLC to obtain (S)-6-(2-amino-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-it (16 mg). LC/MS ionization elektrorazpredelenie+= 460 (M+1). Method LC-MS 1 tR=1,06 min, the mass/charge = 460 (M+1);1H NMR (CDCl3) 7,60 (d, 1H, J=9 Hz, 2 Hz), 7,46 (d, 1H, J=3 Hz), 7,39-7,27 (m, 5H), 7,20 (d, 2H, J=7 Hz), and 7.1 (d, 2H, J=8 Hz), 6,78 (d, 1H, J=9 Hz, 5,61 (q, 1H, J=7 Hz), the 3.65 (s, 3H), 2,87 (m, 1H), 2,80 (d, 1H, J=16 Hz), 2,23 (d, 1H, J=16 Hz), 2,19-of 2.08 (m, 3H), and 1.54 (d, 3H, J=7 Hz), of 1.41 (s, 3H), of 0.96 (s, 3H).

EXAMPLE 8

N-(2-methyl-1-((S)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propan-2-yl)ndimethylacetamide

A solution of (S)-6-(2-amino-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-sreni-1,3-oxazine-2-it (5 mg, 0,009 mmol) in CH2Cl2(1 ml) was treated with DMAP (5 mg, 0.04 mmol), i-Pr2NEt (10 drops) and acetic anhydride (20 drops). The resulting mixture was stirred overnight, after which the reaction mixture was rinsed with water. Obtained after evaporation organicheskoi layer the crude material was purified by preparative HPLC to obtain N-(2-methyl-1-((S)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propan-2-yl)ndimethylacetamide (0,88 mg). Method LC-MS 1 tR=1,3 min, the mass/charge = 502 (M+1).

EXAMPLE 9

Methyl 2-methyl-1-((S)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propan-2-ylcarbamate

A solution of (S)-6-(2-amino-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-it (5 mg, 0,009 mmol) in CH2Cl2(1 ml) was processing the n DMAP (5 mg, 0.04 mmol), i-Pr2NEt (10 drops) and methylchloroform (20 drops). The resulting mixture was stirred overnight, after which the reaction mixture was purified by preparative HPLC to obtain methyl 2-methyl-1-((S)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propan-2-ylcarbamate (2.58 mg). Method LC-MS 1 tR=1,45 min, the mass/charge = 518 (M+1);1H NMR (CDCl3) 7,66 (dd, 1H, J=9 Hz, 2 Hz), of 7.48 (d, 1H, J=3 Hz), 7,35-7,27 (m, 5H), to 7.15 (d, 2H, J=8 Hz), 7,01 (d, 2H, J=8 Hz), 6.87 in (d, 1H, J=9 Hz), 5,67 (q, 1H, J=7 Hz), of 3.69 (s, 3H), 2,2 (s, 3H), and 1.54 (d, 3H, J=7 Hz), 1,46-of 1.36 (m, 2H), 1,30 (s, 3H), of 1.20 (s, 3H).

EXAMPLE 10

N-(2-methyl-1-((S)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-6-yl)propan-2-yl)methanesulfonamide

The title compound was obtained from N-(1-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)-2-methylpropan-2-yl)methanesulfonamide and 2-oxo-1,2-dihydropyridines-5-albarinos acid after the procedure, similar to that described in Example 4. Method LC-MS 1 tR=1,3 min, the mass/charge = 524 (M+1);1H NMR (CDCl3) 7,81 (d, 1H, J=9 Hz), 7,63 (brs, 1H), 7,39-7,31 (m, 5H), 7,18 (d, 2H, J=8 Hz), 7,03 (d, 2H, J=7 Hz), 6,79 (d, 1H, J=9 Hz), 5,67 (q, 1H, J=6 Hz), with 2.93 (s, 3H), 2,90 (m, 1H), 2.49 USD (d, 1H, J=15 Hz), 2,32 (d, 1H, J=15 Hz), 2,28-to 2.18 (m, 3H), and 1.54 (d, 3H, J=7 Hz), of 1.36 (s, 3H), 1,25 (s, 3H).

N-(1-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)-2-methylpropan-2-yl)methanesulfonamide was obtained and the 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)-2,2-dimethylpropanamide by sequential procedures, similar to that described as step 2 of Example 6 and Examples 7 and 11.

EXAMPLE 11

N-(2-methyl-1-((S)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propan-2-yl)methanesulfonamide

A solution of (S)-6-(2-amino-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-it (5 mg, 0,009 mmol) in CH2Cl2(1 ml) was treated with DMAP (5 mg, 0.04 mmol), i-Pr2NEt (10 drops) and MsCl (20 drops). The resulting mixture was stirred overnight, after which the reaction solution was washed with water. Obtained after evaporation of the organic layer, the crude material was purified by preparative HPLC to obtain N-(2-methyl-1-((S)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propan-2-yl)methanesulfonamide (3,30 mg). Method LC-MS 1 tR=1,39 min, the mass/charge = 538 (M+1);1H NMR (CDCl3) to 7.61 (dd, 1H, J=9 Hz, 3 Hz), 7,46 (d, 1H, J=2 Hz), 7,40-7,27 (m, 5H), 7,17 (d, 2H, J=8 Hz),? 7.04 baby mortality (d, 2H, J=8 Hz), 6,79 (d, 1H, J=9 Hz), 5,67 (q, 1H, J=7 Hz), 3,66 (s, 3H), of 2.93 (s, 3H), 2,31-2,22 (m, 2H), of 1.55 (d, 3H, J=7 Hz), 1,48-of 1.36 (m, 2H), 1,33 (s, 3H), 1,24 (s, 3H).

EXAMPLE 12

N-methyl-N-(2-methyl-1-((S)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propan-2-yl)methanesulfonamide

To a solution of N-(2-methyl-1-((S)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridines-3-the l)phenyl)ethyl)-6-phenyl-1,3-oxazine-6-yl)propan-2-yl)methanesulfonamide (7 mg, of 0.013 mmol) in tetrahydrofuran, with a room temperature was added first, NaH (10 mg, 0.20 mmol), and then methyliodide (30 μl, 0,080 mmol). The resulting mixture was heated to 60°C for 5 h, after which the flask with the solution was cooled first to room temperature and then to 0°C followed by stopping the reaction with saturated aqueous solution of NH4Cl. Next, the mixture was subjected to extraction using EtOAc (3×), the combined organic layer was dried over Na2SO4, and then was subjected to filtration, evaporation and purification by preparative HPLC to obtain the N-methyl-N-(2-methyl-1-((S)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propan-2-yl)methanesulfonamide (4,63 mg). Method LC-MS 1 tR=1,45 min, the mass/charge = 552 (M+1);1H NMR (CDCl3) of 7.55 (dd, 1H, J=9 Hz, 3 Hz), 7,41 (d, 1H, J=3 Hz), 7,35 -7,27 (m, 5H), 7,13 (d, 2H, J=8 Hz), 6,98 (d, 2H, J=8 Hz), 6,79 (d, 1H, J=9 Hz), 6,55 (q, 1H, J=7 Hz), 3,62 (s, 3H), 2.91 in-2,86 (m, 1H), of 2.86 (s, 3H), 2,73 (d, 1H, J=15 Hz), is 2.74 (s, 3H), 2,46 (d, 1H, J=15 Hz), 2,39 -2,36 (m, 2H), 2,25-21,6 (m, 1H), 1,53 (d, 3H, J=7 Hz), 1,53 (s, 3H), 1,22 (s, 3H).

EXAMPLE 13

N-(2-methyl-1-((S)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propan-2-yl)methanesulfonamide

Stage 1

To a solution of 3-(R-3-S-1-(4-bromophenyl)-ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)-2,2-dimethylpropanoate (1 g, of 2.27 mmol) in with the art of tetrahydrofuran/H 2O (3:1, 10 ml) were added ndimethylacetamide (3,35 g, 56,75 mmol) and PdCl2(0,402 g of 2.27 mmol). The resulting mixture was stirred over night. Obtained after removal of solvent the residue was purified by TLC to obtain 3-(R-3-S-1-(4-bromophenyl)-ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)-2,2-dimethylpropanamide (0,745 g, 71.6 per cent).

Stage 2

To a solution of 3-(R-3-S-1-(4-bromophenyl)-ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)-2,2-dimethylpropanamide (0.74 g, 1,612 mmol) in a mixture of CH3CN/H2O (20 ml, 1:1) were added Phl(OC2CCF3)2(1,178 g, is 2.74 mmol). The mixture is stirred overnight, then was subjected to extraction using EtOAc (30 ml). The organic layer was washed with saline solution and subjected to evaporation to obtain S-6-(2-amino-2-methylpropyl)-3-S-1-(4-bromophenyl)-ethyl)-6-phenyl-1,3-oxazine-2-she (0.6 g, 87%).

Stage 3

Into a solution of S-6-(2-amino-2-methylpropyl)-3-S-1-(4-bromophenyl)-ethyl)-6-phenyl-1,3-oxazine-2-she (0.6 g, of 1.39 mmol) in CH2Cl2(10 ml) was added Et3N (0.84 g, a 8.34 mmol). The mixture was chilled at 0°C, followed by addition of MsCl (0,48 g of 4.17 mmol). The mixture is then stirred at room temperature for 1 h and was evaporated to obtain the crude product. The obtained residue was purified by column chromatography to obtain N-1-S-3-S-1-(4-bromophenyl)-ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)-2-methylpropan-2-yl)-meth is l-sulfonamida (0.5 g, 70,4%).

Stage 4

To a solution of N-1-S-3-S-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)-2-methylpropan-2-yl)-methyl-sulfonamida (0.5 g, 0.98 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0,399 g, 1.57 mmol) in dry DMSO (15 ml) were added COAs (0.31 g, 3.14 mmol) and Pd(dppf)Cl2(0.025 g, 0.03 mmol) in an atmosphere of N2. After the addition the mixture is stirred at a temperature of 90°C during the night. After receiving the results of TLC showed disappearance of starting material, the solid was filtered. Then were added water (30 ml) and EtOAc (50 ml), after which the mixture was subjected to extraction using EtOAc (3×30 ml). The combined organic layer was washed with brine, dried over Na2SO4, was subjected to filtration and evaporation to obtain a dry substance. The obtained residue was purified by column chromatography to obtain N-(2-methyl-1-S-2-oxo-6-phenyl-3-S-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-6-yl)propan-2-yl)-methyl-sulfonamida (0.2 g, yield: 37%).

Step 5

To a solution of N-(2-methyl-1-S-2-oxo-6-phenyl-3-S-1-4-4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-6-yl)propan-2-yl)-methyl sulfonamida (150 mg, 0.27 mmol) and 4-iodine-1-methylpyridin-2(1H)-she's in dry 1,4-dioxane (5 ml) were added Cs2CO3(0.3 ml, 6 mmol) and Pd(PPh3)Cl2(20 mg). After adding the mixture which was agrawals at 110°C for 2 minutes After receiving the results of TLC showed disappearance of starting material, the solid was filtered. Then were added water (20 ml) and EtOAc (30 ml), after which the mixture was subjected to extraction using EtOAc (3×30 ml). The combined organic layer was washed with brine (50 ml), dried over Na2SO4, was subjected to filtration and evaporation to obtain crude product, which was purified by preparative HPLC to obtain the N-2-methyl-1-S-3-S-1-4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)-phenyl)-ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl) propan-2-yl) methyl sulfonamida (20 mg, 14%). Method LC-MS 2 tR=1,154 min, the mass/charge = 538,1;1H NMR (CDCl3): δ 1,25 (s, 3H), 1,32 (s, 3H), of 1.55 (d, 3H), 2,50 (d, 2H), 2.91 in (s, 3H), 3,63 (s, 3H), 4,54 (b, 1H), 5,67 (m, 1H), 6,53 (d, 1H), 6,92 (s, 1H), 7,06 (d, 2H), 7,30-to 7.50 (m, 8H).

EXAMPLE 14

2,2-dimethyl-3-((R)-2-oxo-3-((S)-1-(4-(2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-6-yl)propanenitrile

The title compound was obtained from 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-6-yl)propanenitrile and 4-yodellin-2(1H)-it is the result of a procedure similar to that described in Example 4. Method LC-MS 1 tR=1,36 min, the mass/charge = 456(M+1);1H NMR (CDCl3) to 7.77 (d, 1H), 7,43-to 7.32 (m, 7H), 7,01 (t, 4H), 5,67 (q, 1H), 2,99 (dd, 1H), 2.57 m) is 2.43 (m, 2H), 2,32 (m, 1H), 2,17 (s, 2H), 1.57 in (d, 3H), 140 (s, 3H), of 1.33 (s, 3H).

EXAMPLE 15

3-((R)-6-(4-forfinal)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-6-yl)-2,2-dimethylpropanoyl

The title compound was obtained from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-2-oxo-1,3-oxazine-6-yl)-2,2-dimethylpropanamide and 2-oxo-1,2-dihydropyridines-5-elborno acid in the procedure similar to that described in Example 4, Method LC-MS 1 tR=1,37 min, the mass/charge = 474(M+1);1H NMR (CDCl3) 7,97, (dd, 1H), 7,73 (s, 1H), 7,33 (m, 2H), 7,20 (d, 2H), 7,17 (t, 2H), 6,98 (m, 3H), 5,67 (q, 1H), 3,00 (dt, 1H), 2.49 USD (m, 2H), 2,30 (m, 1H), 2,13 (s, 2H), of 1.55 (d, 3H), 1,45 (s, 3H), of 1.34 (s, 3H).

EXAMPLE 16

3-((R)-6-(4-forfinal)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-2-oxo-1,3-oxazine-6-yl)-2,2-dimethylpropanoyl

A mixture of 3-((R)-6-(4-forfinal)-2-oxo-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-6-yl)-2,2-dimethylpropanamide (100 mg, 0.21 mmol) and 4-iodine-1-methyl-1H-pyridine-2-it (40 mg, 0,17 mmol), Pd(PPh3)2Cl2(20 mg) and aqueous solution of Cs2CO3(2.0 ml, 2M) in 1,4-dioxane (5 ml) were mixed under conditions of reverse condensation within 2 hours the Organic phase was separated and subjected to evaporation to obtain crude product, which was then purified by preparative TLC to obtain 3-((R)-6-(4-forfinal)-3-((S)-1-(4-(1-�ethyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-2-oxo-1,3-oxazine-6-yl)-2,2-dimethylpropanamide (55 mg, 66%). Method LC-MS 2 tR=1,096 min, the mass/charge = 488,3;1H NMR (CDCl3): δ of 1.27 (s, 3H), of 1.40 (s, 3H), of 1.48 (d, 3H), 2.06 to (s, 2H), 2,23 (m, 1H), 2,41 (m, 2H), 2,90 (m, 1H), 3,51 (s, 3H), ceiling of 5.60 (m, 1H), 6,27 (m, 1H), 6,65 (d, 1H), 6.89 in (d, 2H), 6,99 (t, 2H), 7,26 (m, 5H).

EXAMPLE 17

6-(2-hydroxy-2-methylpropyl)-6-isopropyl-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-1,3-oxazine-2-he

Stage 1

To a solution of methyl 4-methyl-3-oxopentanoate (72 g, 0.5 mol) and ethylene glycol (56 g, 1 mol) in toluene (500 ml) was added 4-methylbenzenesulfonic acid (1.9 g, 0.01 mol). The mixture was mixed under conditions of reverse condensation using water separator Dean-stark removal of water. The reaction mixture was then washed with a small amount of water and saline, dried over anhydrous Na2SO4and evaporated in vacuum to obtain crude methyl 2-(2-isopropyl-1,3-dioxolane-2-yl)-acetate (67 g, yield: 71%) that was used in the next step without additional purification.

Stage 2

In the dried using flame flask with three necks, equipped with an addition funnel, magnetic stir bar, a rubber gasket injector and valve for injection of nitrogen, were placed LiAlH4(3.12 g, to 82.1 mmol) and tetrahydrofuran (700 ml). After cooling at a temperature of 0°C. one drop was added to a solution of methyl 2-(2-isopropyl-1,3-dioxolane-2-yl) acetate (12 g, 63 mmol) in tetrahydrofuran (160 ml) while stirring. The mixture was heated to room temperature and stirred for 24 hours. Then it was stopped the reaction by slowly adding water (5 ml), 15% aqueous NaOH (10 ml) and again water (5 ml). Was made separation of the organic layer, after which the residue was extracted with EtOAc (3×100 ml). The combined organic phase was dried over Na2SO4and evaporated to obtain the crude product, which was then purified by column chromatography to obtain 2-(2-isopropyl-1,3-dioxolane-2-yl)-ethanol (6.8 g, 67%).1H NMR (CDCl3): δ of 0.90 (d, J=6,8 Hz, 6N), 1,87 is 1.96 (m, 3H), of 2.81 (br, 1H), 3,69-and 3.72 (m, 2H), 3,92-4,01 (m, 4H).

Stage 3

To a solution of 2-(2-isopropyl-1,3-dioxolane-2-yl)-ethanol (8.0 g, 50 mmol) and triethylamine (23,5 ml, 170 mmol) in anhydrous CH2Cl2(120 ml) at 0°C was added methanesulfonyl chloride (to 11.6 ml, 150 mmol), after which the reaction mixture is stirred at room temperature until completion of the reaction. Then the reaction mixture was washed with water and brine, dried over Na2SO4, was subjected to filtration and evaporation to obtain crude 2-(2-isopropyl-1,3-dioxolane-2-yl)ethyl of methansulfonate (12 g, crude), which was used in the next step without additional purification.

Stage 4

To a solution of 2-(2-isopropyl-1,3-dioxolane-2-yl)ethyl m is consultant (12 g, 50 mmol) and (S)-1-(4-methoxyphenyl)-ethyl amine (to 19.9 g, 100 mmol) in CH3CN (250 ml) was added K2CO3(8 g, 58 mmol), after which the mixture was subjected to reverse or within 10 hours Then the solution was subjected to filtration, followed by evaporation of the resulting filtrate to obtain the crude product is subsequently purified by column chromatography to obtain (S)-1-(4-bromophenyl)-N-(2-(2-isopropyl-1,3-dioxolane-2-yl)ethyl)ethanamine (6.5 g, yield: 38%).

Step 5

To a solution of (S)-1-(4-bromophenyl)-N-(2-(2-isopropyl-1,3-dioxolane-2-yl)ethyl)ethanamine (6.5 g, 19 mmol) in Meon (60 ml) was added concentrated HCl (60 ml). The mixture was mixed at a temperature of 65°C until the end of the reaction, and then was cooled to 0°C. the pH of the mixture was adjusted to 7 by adding saturated aqueous solution of NaHCO3. Next, the mixture was subjected to evaporation and subsequent sediment extraction using EtOAc (3×100 ml). The organic layer was washed with brine, dried over Na2SO4and evaporated to obtain (S)-1-(1-(4-bromophenyl)ethylamino)-4-methylpentan-3-one (5.5 g, yield: 97%) that was used in the next step without additional purification.1H NMR (CDCl3): δ of 1.07 (d, J=6,8 Hz, 6N), of 1.29 (d, J=6.4 Hz, 3H), 1,89 (br, 1H), 2,54-2,62 (m, 4H), 2,66-2,69 (m, 1H), 3,68-and 3.72 (m, 1H), 7.18 in-7,20 (m, 2H), 7,41-7,44 (m, 2H).

Stage 6

To a suspension of Mg (11 g, 458 mmol) and 12(0.5 g) bezvodnom tetrahydrofuran (50 ml) was added 3-chloro-2-methylprop-1-ene (1 ml), to cause a reaction. Then was added tetrahydrofuran (300 ml), and the additional amount of the solution of 3-chloro-2-methylprop-1-ene (15 ml) in tetrahydrofuran (20 ml) drop by drop at 0°C in an atmosphere of N2within 30 minutes Then drop was added a solution of (S)-1-(1-(4-bromophenyl)-ethyl amino)-4-methylpentan-3-one (5 g) in tetrahydrofuran (50 ml) at -78°C for 45 minutes, the Reaction mixture was stirred for 2 h, after which the reaction was gently stopped using saturated aqueous solution of NH4Cl and was subjected to filtration. The obtained filtrate was subjected to extraction using EtOAc (3×100 ml), washing with salt solution, drying over anhydrous Na2SO4and evaporation in vacuo to obtain 1-(S-1-(4-brompheniramine)-3-isopropyl-5-metrex-5-EN-3-ol (6.4 g, yield: 90%), which was used in the next step without additional purification.

Step 7

In a solution of 1-(S-1-(4-brompheniramine)-3-isopropyl-5-metrex-5-EN-3-ol (6.4 g, a 16.8 mmol) and triethylamine (5.34 g, 52 mmol) in CH2Cl2(260 ml) was added triphosgene (2,52 g, 8.5 mmol) at 0°C in an atmosphere of nitrogen (N2, after which the mixture is stirred at room temperature overnight. The reaction mixture was stopped with water, after which the mixture was subjected to extraction using CH2Cl2(3×50 ml). About yedinenii the organic layer was washed with brine, dried over Na2SO4, was subjected to filtration and evaporation to obtain crude product, which was then purified by column chromatography to obtain two isomers of 3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-6-(2-methylallyl)-1,3-oxazine-2-it.

Isomer 1: (1.85 g, yield: 27%)1H NMR (CDCl3): δ 0,83(d, J=7.2 Hz, 3H), 0,89 (d, J=7.2 Hz, 3H), of 1.45 (d, J=6.8 Hz, 3H), 1,64 is 1.70 (m, 2H), 1,79 (s, 3H), 1,88-of 1.95 (m, 1H), 2,20-of 2.34 (m, 2H), 2,59-to 2.65 (m, 1H), 3,01-is 3.08 (m, 1H), 4,70 (s, 1H), to 4.87 (s, 1H), 5,68 is 5.77 (m, 1H), 7,14 (d, J=8,4 Hz, 2H), 7,41 (d, J=8,4 Hz, 2H).

Isomer 2: (1.25 g, yield: 18%)1H NMR (CDCl3): δ of 0.87 (d, J=6.8 Hz, 3H), of 0.92(d, J=6.8 Hz, 3H), 1,50 (d, J=7.2 Hz, 3H), 1.60-to of 1.66 (m, 1H), 1,78 (s, 3H), 1,73-to 1.79 (m, 1H), 1,78-2,05 (m, 1H), 2,08 (d, J=14,0 Hz, 1H), 2,30 (d, J=14,0 Hz, 1H), 2,62 of 2.68 (m, 1H), 2,98 was 3.05 (m, 1H), with 4.64 (s, 1H), 4,84 (s, 1H), 5,70-of 5.75 (m, 1H), 7,13 (d, J=8,4 Hz, 2H), 7,40 (d, J=8,4 HZ, 2H).

Step 8

To a solution of isomer 1 of 3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-6-(2-methylallyl)-1,3-oxazine-2-she (500 mg, of 1.32 mmol) in dry CH2Cl2(64 ml) was added at room temperature m-SRV (455 g of 2.64 mmol). The reaction mixture is stirred until the disappearance of starting material (determined by TLC). The mixture was diluted (CH3)3PINES3(70 ml), washed with 30% Na2S3and aqueous NaHCO3(3×), dried over Na2SO4, was subjected to filtration and evaporation to obtain isomer 1 of 3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-6-((2-methyloxiran-2-yl)methyl)-1,3-oxazine-2-it (20 mg, 99%), which was used in the next step without additional purification.

Step 9

To a solution of isomer 1 of 3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-6-((2-methyloxiran-2-yl)methyl)-1,3-oxazine-2-she (520 mg, of 1.32 mmol) in tetrahydrofuran (32 ml) at 0°C in an atmosphere of N2within 30 min was added drop by drop LiEt3BH (Superseded, with 13.6 ml of 13.6 mmol). The resulting solution was stirred at a temperature of 10-13°C for a 21.5 hours To the mixture was added H2O2(40 ml). The resulting solution was diluted (CH3)3PINES3(380 ml) and washed with water, 30% aqueous solution of Na2S2O3and saline. The organic phase was dried over Na2SO4, and then was subjected to filtration. The obtained filtrate was evaporated to obtain the crude product, later purified by column chromatography to obtain isomer 1 of 3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-isopropyl-1,3-oxazine-2-it (320 mg, 61%).1H NMR (CDCl3): δ of 0.82 (d, J=6.8 Hz, 3H), of 0.95 (d, J=6.8 Hz, 3H), of 1.31 (s, 3H), of 1.34 (s, 3H) and 1.51 (d, J=10.0 Hz, 3H), of 1.61 (d, J=15.2 Hz, 1H), 1,78-of 1.84 (m, 1H), 1,91 (d, J=15.2 Hz, 1H), 2,02-of 2.15 (m, 2H), 2,36 (br, 1H), 2,62 of 2.68 (m, 1H), 3,03-to 3.09 (m, 1H), 5,73 (t, J=7.2 Hz, 1H), 7,17-7,19 (m, 2H), 7,44-of 7.48 (m, 2H).

Step 10

To a solution of isomer 1 of 3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-isopropyl-1,3-oxazine-2-she (315 mg, 0,793 mmol) in DMSO (10 ml) in the atmosphere N 2were added 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (602 mg, of 2.38 mmol), CH3CO2K (770 mg, 79.3 mmol), Pd(dppf)2Cl2(50 mg, 0.06 mmol), after which the mixture was mixed at a temperature of 90°C for 4 h the Reaction was stopped with the help of NH4Cl and was subjected to extraction using EtOAc and washing with water and brine. The organic phase was dried over Na2SO4and was subjected to filtration. The obtained filtrate was evaporated to obtain the crude product, which was then purified by preparative TLC to obtain isomer 1 6-(2-hydroxy-2-methylpropyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-she (250 mg, 71%).

Step 11

To a solution of isomer 1 6-(2-hydroxy-2-methylpropyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-she (250 mg, 0,39 mmol), 4-bromo-1-methylpyridin-2(1H)-she (127 mg, of 0.68 mmol) and Cs2CO3(2N, 4 ml) in 1,4-dioxane (20 ml) in an atmosphere of N2was added Pd(PPh3)2Cl2(54 mg, 0,056 mmol). The reaction mixture was subjected to reverse or within 2 h, after which the reaction was stopped with water, and the mixture was subjected to extraction using EtOAc. The organic phase was washed with H2O and brine, dried over Na2SO4and powerglaz the filter. The filtrate was evaporated to obtain the crude product, which was then purified by preparative TLC and preparative HPLC to obtain isomer 1 6-(2-hydroxy-2-methylpropyl)-6-isopropyl-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-1,3-oxazine-2-she (79 mg, yield; 47%). Method LC-MS 2 tR=1,023 min, the mass/charge = 427,6;1H NMR (CDCl3) of 0.85 (d, 3H), of 0.96 (d, 3H), 1.26 in (s, 3H), of 1.28 (s, 3H), and 1.54 (m, 4H), 1,84-of 1.88 (m, 2H), 2,04 (br, 1H), 2,01-to 2.18 (m, 2H), 2,75 (m, 1H), 3,10 (m, 1H), 3,52 (s, 3H), 5,80 (t, 1H), 6,37 (m, 1H), 6,74 (m, 1H), 7,28 (m, 1H), 7,25-7,37 (m, 2H), 7,50 (m, 2H).

Isomer 2 6-(2-hydroxy-2-methylpropyl)-6-isopropyl-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-1,3-oxazine-2-it was obtained from isomer 2 of 3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-6-(2-methylallyl)-1,3-oxazine-2-by procedures similar to those described for steps 8-11. Method LC-MS 2 tR=1,023 min, the mass/charge = 427,6;1H NMR (CDCl3) of 0.79 (d, 3H), of 0.92 (d, 3H), of 1.27 (s, 3H), of 1.30 (s, 3H) and 1.51 (d, 3H), 1,58 (d, 1H), 1,73-of 1.81 (m, 1H), 1,88 (d, 1H), 2,0 (br, 1H), 2,04-of 2.08 (m, 2H), 2,65 of 2.68 (m, 1H),3,04-3,07 (m, 1H), 3,52 (s, 3H), of 5.75 (t, 1H), 6,37 (m, 1H), 6,74 (m, 1H), 7,21-7,35 (m, 3H), 7,51 (m, 2H).

EXAMPLE 18

6-cyclopropyl-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-1,3-oxazine-2-he

Two diastereoisomer of 3-((S)-1-(4-bromophenyl)ethyl)-6-cyclopropyl-6-(2-hydroxy-2-methylpropyl)-1,3-oxazine-2-it was obtained from methyl 3-cyclopropyl-3-oxopropanoic after por the application procedures, similar to those described for steps 1-7 of Example 17. The title compound was obtained in the following way.

Stage 1

To a solution of isomer 1 of 3-((S)-1-(4-bromophenyl)ethyl)-6-temporaril-6-(2-hydroxy-2-methylpropyl)-1,3-oxazine-2-she (230 mg, of 0.58 mmol) in DMSO (15 ml) in an atmosphere of N2were added 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (450 mg, 1.77 mmol), CH3CO2To (800 mg, 8.16 mmol), Pd(pddf)2Cl2(50 mg, 0.06 mmol). The mixture is stirred at 90°C. for 34 h, after which the reaction was stopped with NH4Cl and was subjected to extraction using EtOAc. The organic phase was washed with water and brine, dried over Na2SO4and was subjected to filtration. The obtained filtrate was subjected to evaporation to obtain crude product, which was then purified by preparative TLC to obtain isomer 1 6-cyclopropyl-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-she (140 mg, 54,3%).

Stage 2

To a solution of isomer 1 6-cyclopropyl-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-she (140 mg, 0,316 mmol), 4-bromo-1-methylpyridin-2(1H)-she (74,3 mg, 0,316 mmol) and 2 M aqueous solution of Cs2CO3(3 ml) in 1,4-dioxane (20 ml) in an atmosphere of N2was added Pd(dppf)2Cl2(30 mg, 0,043 mmol who). The reaction mixture was subjected to reverse or within 2 h, after which the reaction was stopped with water, and the mixture was subjected to extraction using EtOAc. The organic phase was washed with N2O and brine, dried over Na2SO4and then subjected to filtration. The obtained filtrate was subjected to evaporation to obtain crude product, which was then purified by preparative TLC and preparative HPLC to obtain isomer 1 6-cyclopropyl-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-1,3-oxazine-2-it (49.5 mg, 37.7 per cent). Method LC-MS 2 tR=1,016 min, the mass/charge = 367,2;1H NMR (CDCl3) of 0.50 (m, 2H), and 0.62 (m, 2H), 0,97 (m, 1H), 1,32 (m, 6H), was 1.58 (d, 3H), of 1.97(m, 3H), 2,28 (m,1H), 2,78 (m, 1H), 3,40 (m, 1H), to 3.58 (s,3H), of 5.85 (m, 1H), 6,41 (d, 1H), 6,79 (s, 1H), 7,33 (d, 1H), 7,41 (d, 1H), 7,56 (d, 1H)

Isomer 2 6-cyclopropyl-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-1,3-oxazine-2-it was obtained from isomer 2 of 3-((S)-1-(4-bromophenyl)ethyl)-6-cyclopropyl-6-(2-hydroxy-2-methylpropyl)-1,3-oxazine-2-through procedures similar to those described above for the 1 and 2 stages. Method LC-MS 2 tR=0,99 min, the mass/charge = 367,1;1H NMR (CDCl3) 0,02 (m, 3H), 0,23 (m, 1H), 0,51 (m,1H), of 0.96 (s, 6H), of 1.17 (d, 3H), 1,40-1,60 (m, 4H), of 1.94 (m, 1H), to 2.55 (m, 1H), 2,73 (m, 1H), 3,20 (s, 3H), 5,41 (m, 1H), 6,03 (d, 1H), 6,40 (s, 1H), 6,98 (m, 1H), 7,03 (m, 2H), 7,18 (m, 2H).

EXAMPLE 19

(R)-6-(2-(5-methyl-1,3,4-oxides the l-2-yl)ethyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-he

Stage 4

To a solution of N'-acetyl-3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)proprietatea (0.1 g, 0.21 mmol) in tetrahydrofuran (2 ml) was added Burgess reagent (75 mg, 0,315 mmol). The sealed vial was subjected to processing in a microwave oven at 100°C for 15 minutes the mixture was subjected to extraction using EtOAc (3×30 ml). The combined organic layer was washed with brine (50 ml), dried over Na2SO4, and then was subjected to filtration and evaporation. The obtained residue was purified by preparative TLC to obtain (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl-1,3-oxazine-2-she (58 mg, yield: 59%).1H NMR (CDCl3): 01,49-is 1.51 (m, 3H), 2,23-of 2.26 (m, 2H), 2,30 is 2.33 (m, 2H), 2,42 (s, 3H), 2,43 at 2.45 (m, 1H), 2,49-of 2.54 (m, 1H), 2,87-only 2.91 (m, 1H), 3,06-to 3.09 (m, 1H), 5,61-5,63 (m, 1H), 6,76-of 6.78 (d, 2H), 7,20-7,22 (m, 2H), 7,26-7,33 (m, 2H), 7,35-7,37 (m, 3H).

Step 5

To a solution of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl-1,3-oxazine-2-it (490 mg, 1.04 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (424 mg, 1,67 mmol) in dry DMSO (20 ml) in an atmosphere of N2were added COAs (326 mg, of 3.33 mmol) and Pd(dppf)Cl2(to 25.3 mg, 0,031 mmol). The mixture was heated at 100°C for 3 hours After receiving the results of TLC, indicating the disappearance of starting material was tfilter the Vano solid, then added water (50 ml) and EtOAc (50 ml), after which the mixture was subjected to extraction using EtOAc (3×50 ml). The combined organic layer was washed with brine (50 ml), dried over Na2SO4, and then was subjected to filtration and evaporation. The obtained residue was purified by preparative TLC to obtain (R)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it (0,395 g, yield: 73.6 per cent).

Stage 6

To a solution of (R)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-she (60 mg, 0.12 mmol) and 4-iodine-1-methylpyridin-2(1H)-it (33 mg, 0.14 mmol) in dry 1,4-dioxane (15 ml) was added Cs2CO3(2M, 1 ml) and Pd(PPh3)Cl2(7.7 mg, 0.01 mmol). The mixture was heated under conditions of reverse condensation within 2 h in an atmosphere of N2, after which the resulting solid substance was filtered off, and the mixture was diluted with water (30 ml) and EtOAc (30 ml). The combined organic layer was washed with brine (50 ml), dried over Na2SO4, and then was subjected to filtration and evaporation. The obtained residue was purified by preparative TLC to obtain (R)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-it (25 mg, yield: 41.8 per cent). Method LC-MS 2 t =0,984 min, the mass/charge = 499,1;1H NMR (CDCl3): δ 1,48 of 1.50 (m, 3H), 2,16-of 2.20 (m, 1H), 2,23-of 2.26 (m, 1H), 2,27 of-2.32 (m, 2H), 2,39 (s, 3H), 2.40 a-2,47 (m, 1H), 2,49-of 2.54 (m, 1H), 2,87-2,90 (m, 1H), 2,98-a 3.01 (m, 1H), to 3.58 (s, 3H), 5,62-5,64 (m, 1H), of 6.45-6.48 in (m, 1H), 6.87 in (s, 1H), 6,92-6,94 (d, 2H), 7,20-7,24 (m, 4H), 7,25-7,35 (m, 4H).

EXAMPLE 20

(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-he

Stage 1

In a mixture of 4-yodellin-2(1H)-it (50 mg, 0.213 mmol) and DMF (3 ml) were added 2-oztuna (73 mg, 0,426 mmol), K2CO3(88 mg, 0,638 mmol) at room temperature. The mixture was mixed for 2 h at room temperature. After the reaction mixture was washed with water and subjected to extraction using EtOAc. The organic phase was washed with brine, dried over Na2SO4, and then was subjected to filtration and evaporation to obtain crude product, which was purified by TLC to obtain 1-(2-hydroxyethyl)-4-yodellin-2(1H)-she (60 mg, 100%).

Stage 2

The mixture of compounds (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-she (72 mg, 0,150 mmol), 1-(2-hydroxyethyl)-4-yodellin-2(1H)-it (48 mg, 0,181 mmol), Pd(PPh3)2Cl2(14 mg, at 0.020 mmol), and Cs2CO3(2 ml) in 1,4-dioxane (8 ml) were mixed under conditions of reverse condensers the Deposit within 2 hours After the reaction mixture was washed with water and subjected to extraction with EtOAc. The organic phase was washed with brine, dried over Na2SO4, and then was subjected to filtration and evaporation to obtain crude product, which was purified by TLC to obtain the compound (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-it (19.7 mg, 28%). Method LC-MS 2 tR=1,065 min, the mass/charge = 491,2;1H NMR (CDCl3): δ of 1.10 (d, 6H), 1.50 in (d, 3H), of 2.20 (m, 5H), to 2.35 (m, 1H), 3,50 (m, 1H), 3,90 (m, 2H), 4,10 (m, 2H), ceiling of 5.60 (m, 1H), 6,40 (m, 1H), 6,70 (s, 1H), 6,95 (d, 2H), 7,35 (m, 8H).

EXAMPLE 21

(6S)-6-(2,3-dihydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-he

Stage 1

A solution of 3-chloro-1-phenylpropane-1-she (to 16.8 g, 0.1 mol) in tetrahydrofuran (50 ml) was added to a thoroughly stirred suspension of zinc powder (13 g, 0.2 mol) in a mixture of a saturated aqueous solution of NH4Cl (260 ml) and tetrahydrofuran (65 ml). Then, the resulting mixture was added drop by drop a solution of 3-iodine-2-methylprop-1-ene (36,4 g, 0.2 mol) in tetrahydrofuran (50 ml). During the reaction there was a slight evolution of heat, as well as unexpected reverse condensation. After the termination of the reverse condensing the mixture was mixed for 1 h Raza is Italy TLC showed the reaction of 3-chloro-1-phenylpropane-1-it was not completely finished. To the mixture was added a solution of 3-iodine-2-methylprop-1-ene (18.2 g, 0.1 mol) in tetrahydrofuran (30 ml), after which the mixture is stirred over night at room temperature. Then the mixture was subjected to extraction using EtOAc (2×500 ml). The combined organic layer was dried and evaporated, the Obtained residue was purified by column chromatography using silica gel, lirovannomu using petroleum ether / EtOAc 50:1→30:1→5:1, to obtain 1-chloro-5-methyl-3-phenylhexa-5-EN-3-ol (17 g, yield 76%) as oil.1H NMR (CDCl3): δ 1.28 (in s, 3H), 2,31 (m, 2H), 2,54 (m, 2H), 2,68 (d, 1H), 3.15 in (m, 1H), to 3.58 (m, 1H), 4,78 (m, 1H), is 4.93 (m, 1H), 7,27 (t, 1H), 7,38 (m, 4H).

Stage 2

A mixture of 1-chloro-5-methyl-3-phenylhexa-5-EN-3-ol (2.9 g, 13 mmol), (S)-1-bromo-4-(1-isocyanatomethyl)benzene (3.5 g, 16 mmol), and DBU (8 g, 33 mmol) in tetrahydrofuran (80 ml) was heated under conditions of reverse condensation during the night. The mixture was diluted with EtOAc, washed with 1N aqueous solution of HCl. The aqueous phase was subjected to extraction using EtOAc (3×), then Obyedinennaya organic phase was dried over Na2SO4. After evaporation of the solvents the crude product was purified by column chromatography to obtain (R)-3-((S)-1-(4-bromophenyl)-ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazine-2-it (of 1.62 g, yield: 30%).

Stage 3

In RA the solution of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazine-2-she (300 mg, 0,726 mmol), 4-methylmorpholine 4-oxide (195 mg, 1.44 mmol) in a mixture of H2O (6 ml), tetrahydrofuran (30 ml) and f-BuOH (12 ml) was added oxide of osmium (VIII) (4%, 0,231 ml) at 0°C. the Mixture is stirred at room temperature overnight, after which the reaction was stopped with 3% NaHSO3(15 ml × 3), and the mixture was subjected to extraction using EtOAc. The organic layer was dried over Na2SO4and evaporated to obtain the crude product (S)-3-((S)-1-(4-bromophenyl)-ethyl)-6-(2,3-dihydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-she (242 mg, 74,5%).

Stage 4

To a solution of (S)-3-((S)-1-(4-bromophenyl)-ethyl)-6-(2,3-dihydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-she (235 mg, 0,524 mmol) in DMSO (5 ml) in an atmosphere of N2were added COAs (771,6 mg, 7,86 mmol) and Pd(dppf)Cl2(40 mg). The mixture was mixed at a temperature of 90°C for 3 hours the Reaction was stopped with water and subjected to extraction using EtOAc. The organic layer was dried over Na2SO4and was subjected to evaporation to obtain crude product, which was then purified by preparative TLC to obtain (S)-6-(2,3-dihydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-she (121 mg, 46.6 per cent).

Step 5

A mixture of (S)-6-(2,3-dihydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxaz the NAS-2-she (105 mg, 211,9 mmol), 4-iodine-1-methylpyridin-2(1H)-she (65 mg, 275,5 mmol), and Pd(PPh3)2Cl2(20 mg) in water solution Cs2CO3(3 ml) were mixed under conditions of reverse condensation within 2 hours After the reaction mixture was washed with water and subjected to extraction using EtOAc. The organic layer was dried over Na2SO4and was subjected to evaporation to obtain crude product, which was then purified by preparative HPLC to obtain two isomers of (6S)-6-(2,3-dihydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-it.

Isomer 1 (6,11 mg, 6%): LC-MS 2 tR=0,84 min, the mass/charge =477,4;1H NMR (CDCl3): δ 0,97 (s, 3H), of 1.55 (d, 3H), and 2.27 (m, 3H), of 2.38 (m, 3H), 2.91 in (m, 1H), 3,34 (d, 1H), to 3.58 (s, 3H), of 5.68 (m, 1H), 6.35mm (d, 1H), of 6.71 (s, 1H), 7,02 (d, 2H), was 7.36 (m, 8H).

Isomer 2 (6.78 mg, 6,7%): LC-MS 2 tR=0,832 min, the mass/charge =477;1H NMR (CDCl3): δ 1.14 in (s, 3H), of 1.48 (d, 3H), of 2.09 (m, 1H), and 2.14 (m, 2H), 2,31 (m, 2H), 2,81 (m, 1H), 3,24 (d, 1H), 3.27 to (d, 1H), 3,50 (s, 3H), 5,62 (m, 1H), 6,28 (d, 1H), 6,63 (s, 1H), 6,98 (d, 2H), 7,27 (m, 8H).

EXAMPLE 22

(6S)-6-(2-hydroxy-3-methoxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-he

Stage 1

In the Meon (5 ml) was added sodium (90 mg). After the disappearance of the sodium in the mixture was added a solution of 6(S)-3-(5-1-(4-bromophenyl)ethyl)-6-((2-methyloxiran-2-yl-methyl)-6-phenyl-1,3-oxazine-2-she (500 mg, to 1.16 mmol). The mixture was mixed at 65°C for 5 h, then it was added N2Oh, after which the mixture was subjected to evaporation. The obtained residue was subjected to extraction using EtOAc, the organic layer was dried over Na2SO4and evaporated to obtain the crude product, which was then purified by TLC (2:1 PE/EtOAc) to obtain (S)-3-(5-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-3-methoxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-she (227 mg, 42,3%).

Stage 2

To a solution of (S)-3-(S-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-3-methoxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-she (205 mg, 0,443 mmol) in DMSO (5 ml) in an atmosphere of N2were added COAs (435,13 mg, 4,43 mmol), Pd(dppf)Cl2(45 mg). The mixture was mixed at a temperature of 90°C for 3 hours. The reaction was stopped with water, after which the mixture was subjected to extraction using EtOAc. The organic layer was dried over Na2SO4and evaporated to obtain the crude product, which was purified by TLC (PE:EA=1:2) to obtain (S)-6-(2-hydroxy-3-methoxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-she (113 mg, 50%).

Stage 3

A mixture of (S)-6-(2-hydroxy-3-methoxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it (100 mg, 196,29 mmol), 4-iodine-1-methylpyridin-2(1H)-she (60,49 mg, 255 mmol), Pd(PPh3)2Cl2(20 mg) and aqueous solution of Cs2CO3(2 mol/l, 3 ml) in 1,4-dioxane (4 ml) were mixed under conditions of reverse kundenservice within 2 hours. After the reaction mixture was washed with water and subjected to extraction using EtOAc. The organic layer was dried over Na2SO4and was subjected to evaporation to obtain crude product, which was then purified by preparative HPLC to obtain two isomers of (6S)-6-(2-hydroxy-3-methoxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-it.

Isomer 1 (the 5.25 mg, 5.6 per cent); the Method LC-MS 2 tR=0,921 min, the mass/charge=403,2;1H NMR (CDCl3): δ were 0.94 (s, 3H), of 1.47 (d, 3H), 2,28 (m, 4H), to 2.35 (m, 1H), 2,82 (m,1H), 3,11 (d, 1H), and 3.16 (s, 3H), of 3.25 (d, 1H), 3,50 (s, 3H), 5,62 (m, 1H), 6,27 (d, 1H), 6,63 (s, 1H), 6,92 (d, 2H), 7,25 (m, 8H).

Isomer 2 (of 5.40 mg, 5.8 per cent); the Method LC-MS 2 tR=0,923 min, the mass/charge=513,1;1H NMR (CDCl3): δ of 1.18 (s, 3H), of 1.47 (d, 3H), 2,11 (m, 2H), 2,23 (m, 2H), 2,45 (m, 1H), 2,81 (d, 2H), 2,96 (d, 1H), 3.15 in (s, 3H), 3,50 (s, 3H), 5,62 (m, 1H), 6,27 (d, 1H), 6,65 (s, 1H), 6.90 to (d, 2H), 7,26 (m, 8H).

EXAMPLE 23

(S)-6-(2-forfinal)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-he

Stage 1

To a solution of 2-tormentilla (50 g, 0.31 mol) in CH2Cl2(200 ml) at 0°C was added N,O-dimethylhydroxylamine (46 g, 0.47 mol), as well as the solution of triethylamine (127 g, of 1.26 mol) in CH2Cl2(100 ml). The reaction mixture was slowly warmed to room temperature, then stirred for 3 h Then the reaction was stopped with ice water, and the mixture was subjected to extraction with CH2Cl2(200 ml). The organic layer was dried over Na2SO4and was subjected to filtration and evaporation to obtain 2-fluoro-N-methoxy-N-methylbenzamide (48 g, output: 84,6%).

Stage 2

A solution of 2-fluoro-N-methoxy-N-methylbenzamide (16 g, which is 87.4 mmol) in tetrahydrofuran (150 ml) was cooled to -78°C. Then was added slowly vinylmania bromide (120 ml, 120 mmol), after which the mixture is stirred at -78°C for 10 min, slowly warmed to room temperature and additionally stirred for 3 hours the Reaction was stopped with 1 N aqueous HCl (100 ml) at 0°C. the Aqueous layer was subjected to extraction using EtOAc (100 ml). The combined organic phase was washed with brine (50 ml), dried over Na2SO4and evaporated. The obtained residue was purified by column chromatography to obtain 1-(2-forfinal)-prop-2-EN-1-she (7.6 g, yield: 58,4%) as a colourless oil.

Stage 3

In a solution of 1-(2-forfinal)-prop-2-EN-1-she (5.6 g, of 37.3 mmol) in CH3CN (50 ml) was added (S)-1-(4-bromophenyl)-ethylamine (7,4 g, 37 mmol), after which the mixture was mixed in ECENA 12 h at 40°C. The resulting solution was evaporated to obtain the crude product, which was then purified by column chromatography to obtain (S)-3-(1-(4-bromophenyl)-ethylamino)-1-(2-forfinal)-propane-1-she (4 g, yield: 30,7%) as a yellow liquid.

Stage 4

To a suspension of Mg (2.5 g, 104 mmol) and (I2(0.1 g) in anhydrous tetrahydrofuran (15 ml) was added 3-chloro-2-methylprop-1-ene (0.6 ml, 6 mmol). After adding 3-chloro-2-methylprop-1-ene (9 ml, 90 mmol) in tetrahydrofuran (120 ml) drop by drop at 0°C in an atmosphere of N2within 30 min, as well as drop by drop at -78°C for 45 minutes was added (S)-3-(1-(4-bromophenyl)-ethylamino)-1-(2-forfinal)-propane-1-he (3 g, 8.6 mmol) in tetrahydrofuran (50 ml). The reaction mixture was stirred at room temperature for 2 h, after which the reaction was gently stopped by adding a saturated aqueous solution of NH4Cl. The mixture was subjected to extraction using EtOAc, then the organic layer was washed with brine, dried over anhydrous Na2SO4and evaporated in vacuo to obtain 1-(5-1-(4-bromophenyl)-ethylamino)-3-(2-forfinal)-5-metrex-5-EN-3-ol (3.3 g, yield: 94,5%), which was then used in the next step without additional purification.

Step 5

In a mixture of 1-(S-1-(4-bromophenyl)ethylamino)-3-(2-forfinal)-5-metrex-5-EN-3-ol (2 g, 5 mmol) and the solution is of ritilin (1.5 g, 15 mmol) in 1,2-dichloroethane (100 ml) at 0°C in an atmosphere of N2was added triphosgene (of 1.46 g, 5 mmol), after which the mixture was heated to a temperature of 100°C for 4 h the Reaction was stopped with water, after which the mixture was subjected to extraction with CH2Cl2(100 ml). The combined organic layer was washed with brine and dried over Na2SO4, and then was subjected to filtration and evaporation to obtain crude product (2.1 g, yield: 99%), which was used in the next step without additional purification.

Stage 6

In the solution (S)-3-(1-(4-bromophenyl)ethyl)-6-(2-forfinal)-6-(2-methylallyl)-1,3-oxazine-2-she (3.2 g, 7.4 mmol) in dry CH2Cl2(100 ml) at room temperature was added m-SRV (2.6 g, of 14.8 mmol), after which the mixture stirred over night. Then the mixture was diluted with (CH3)3PINES3(100 ml), washed with 30% aqueous solution of Na2S2O3and in an aqueous solution of NaHCO3, and dried over Na2SO4, and then was subjected to filtration and evaporation to obtain 3-(S-1-(4-bromophenyl)-ethyl)-6-(2-forfinal)-6-(2-methyloxiran-2-yl-methyl)-1,3-oxazine-2-she (2.8 g, yield: 84.3 percent), which was used in the next step without additional purification.

Step 7

To a solution of 3-(S-1-(4-bromophenyl)-ethyl)-6-(2-forfinal)-6-(2-methyloxiran-2-yl)methyl)-1,3-oxazine-2-she (2.2 g, to 4.92 mmol) in tetrahydrofuran (100 ml) drop by drop at 0°C in an atmosphere of N2within 30 min was added LiEt3BH (superseded, 50 ml, 50 mmol). The resulting mixture was stirred at 2-3°C for 1.5 h, and then at a temperature of 10-13°C for 2.5 h In a mixture of one drop was added to H2O2(20 ml), after which the reaction mixture was diluted (CH3)3PINES3(280 ml) and washed with water, 30% aqueous solution of Na2S2O3and salt solution and the Organic phase was dried over Na2SO4and was subjected to filtration. The obtained filtrate was evaporated to obtain the crude product, which was then purified by column chromatography to obtain (S)-3-(S-1-(4-bromophenyl)-ethyl)-6-(2-forfinal)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazine-2-she (550 mg, 23.9 percent) in the form of a solid white color.1H NMR (CDCl3): δ of 1.03 (s, 3H), 1.14 in (s, 3H), USD 1.43 (d, J=6.8 Hz, 3H), of 2.08 and 2.13 (m, 1H), 2,17 (d, J=2,8 Hz, 1H), 2.21 are 2,22 (m, 1H), 2,31 (dd, J=0,8, 15.2 Hz, 1H), 2.77-to of 2.81 (m, 1H), 5.56mm (q, J=2,8 Hz, 2 H), 6,82-6,83 (m, 2H), 6,85-6,94 (m, 1H), 7,08-7,13 (m, 1H), 7.18 in-7,25 (m, 1H), 7,26-7,40 (m, 2H), 7,42-7,44 (m, 1H).

Step 8

To a solution of (S)-3-(S-1-(4-bromophenyl)-ethyl)-6-(2-forfinal)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazine-2-she (540 mg, 1.2 mmol) in DMSO (15 ml) in an atmosphere of N2were added 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (900 mg, 3.3 mmol), CH3CO2K (1.5 g, 16 mmol who), Pd(dppf)Cl2(108 mg, 0.13 mmol), after which the reaction mixture is stirred at a temperature of 90°C for 2.5 hours the Reaction was stopped with water, then the mixture was subjected to extraction using EtOAc (90 ml). The organic layer was washed with water and brine, dried over Na2SO4and was subjected to filtration. The obtained filtrate was evaporated to obtain the crude product, which was then purified by preparative TLC to obtain (S)-6-(2-forfinal)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-she (360 mg, 62%) as a yellow liquid.

Step 9

To a solution of (S)-6-(2-forfinal)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-she (120 mg, 0.24 mmol), 5-bromo-1-methylpyridin-2-(1H)-she (54 mg, 0.28 mmol) and 2N aqueous solution of Cs2CO3(2 ml) in dioxane (8 ml) in an atmosphere of N2was added Pd(PPh3)2Cl2(17 mg, 0,024 mmol). The reaction mixture was subjected to reverse or within 2 h, after which it was added water to stop reaction. Then the mixture was subjected to extraction using EtOAc (30 ml), after which the organic layer was washed with H2O and brine, dried over Na2SO4and was subjected to filtration. The obtained filtrate was evaporated to obtained the I of the crude product, which was then purified by preparative TLC and preparative HPLC to obtain (S)-6-(2-forfinal)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-it (14 mg, yield:10%). Method LC-MS 2 tR=1,2 min, the mass/charge=473,9;1H NMR (CDCl3): δ 1.21 (s, 3H), 1.30 (s, 3H), of 1.48 (d, J=7.2 Hz, 3H), 2,15-of 2.26 (m, 3H), 2,33 (dd, J=11,2, 26,4 Hz, 1H), 2,43 is 2.46 (m, 1H), 2,79-to 2.85 (m, 1H), 3,63 (s, 3H), 5,62 (q, J=6,8 Hz, 1H), 6,58-6,60 (m, 1H), 6,89-6,94 (m, 1H), 7,00-7,02 (m, 2H), 7,10-7,24 (m, 3H), 7,34-7,39 (m, 1H), 7,40 was 7.45 (m, 1H), of 7.48-of 7.70 (m, 2H).

EXAMPLE 24

(S)-6-(3-forfinal)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-he

The title compound was obtained from (S)-3-(1-(4-bromophenyl)ethylamino)-1-(3-forfinal)propane-1-following the procedures similar to those described for steps 4-9 Example 23. Method LC-MS 2 tR=1,416 min, the mass/charge=500,9;1H NMR (CDCl3) of 1.18 (s, 3H), of 1.29 (s, 3H), of 1.47 (d, 3H), 2.05 is-of 2.28 (m, 4H), 2,31-2,39 (m, 1H), 2,82-2,87 (m, 1H), to 3.58 (s, 3H), 5,64 (q, 1H), 6,57-6,59 (m, 1H), 6,88-7,19 (m, 5H), 7,21-7,25 (m, 2H), 7,28 (m, 1H), of 7.36 (m, 1H), 7,40 was 7.45 (m, 1H), 7,45-of 7.48 (m, 1H)

(S)-3-(1-(4-bromophenyl)ethylamino)-1-(3-forfinal)propane-1-he was prepared according to the following procedures.

Stage 1

A solution of 3-fluoro-N-methoxy-N-methylbenzamide (16 g, which is 87.4 mmol) in tetrahydrofuran (150 ml) was cooled to -78°C. Then the solution was slowly add the Yong vinylmania bromide (120 ml, 120 mmol), after which the mixture is stirred at -78°C for 10 min, and at room temperature for 3 hours the Reaction was stopped with 1 N aqueous HCl (100 ml) at 0°C. the Aqueous layer was subjected to extraction using EtOAc (100 ml). The combined organic layer was washed with brine (50 ml), dried over Na2SO4and evaporated. The obtained residue was purified by column chromatography to obtain 1-(3-forfinal)ethanone (9.7 g, yield: 75%) as a colourless oil.

Stage 2

1-(3-Forfinal)alanon (17 g, 0,123 mol), dimethylamine (13,7 g, 0,172 mol) and paraformaldehyde (5.5 g, 0.185 mol) were suspended in ethanol (50 ml), after which the suspension was added concentrated HCl solution (0.3 ml). The mixture was heated under conditions of reverse condensation during the night. After removal under vacuum of the solvent, the obtained residue was washed with EtOAc (3×) to obtain 3-(dimethylamino)-1-(3-forfinal)propane-1-it (20.7 g, 88%) which was used in the next step without additional purification.

Stage 3

A solution of 3-dimethylamino-1-(3-fluoro-phenyl)-propane-1-it (17 g, 0,087 mol) and (S)-1-(4-bromophenyl)-ethanamine (17 g, 0,087 mol) in a mixture of EtOH (50 ml) and H2O (50 ml) was subjected to reverse or over night at a temperature of 80°C. After removal of the solvent in vacuum, the obtained residue was purified what exploits column chromatography to obtain (S)-3-(1-(4-bromophenyl)-ethylamino)-1-(3-forfinal)-propane-1-she (6.2 g, 20%).

EXAMPLE 25

(S)-3-((S)-1-(4-(1-(2-foradil)-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-he

1-(2-foradil)-4-yodellin-2(1H)-it was obtained from 4-yodellin-2(1H)-it 2-foradil triftoratsetata in the procedure similar to that described for stage 1 of Example 20.

The title compound was obtained from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it 1-(2-foradil)-4-yodellin-2(1H)-it is the result of a procedure similar to that described for stage 1 of Example 6. Method LC-MS 2 tR=1,09 min, the mass/charge=515, 493, 475, 435.

EXAMPLE 26

(S)-6-(2-forfinal)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-1,3-oxazine-2-he

The title compound was obtained from (S)-6-(2-forfinal)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it 4-iodine-1-methylpyridin-2(1H)-it is the result of a procedure similar to that described for the 9th stage of Example 23. Method LC-MS 2 tR=1,58 min, the mass/charge=501, 479, 421.

EXAMPLE 27

(S)-6-(3-forfinal)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-1,3-oxazine-2-he

The title compound was recip is but from (S)-6-(3-forfinal)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it 4-iodine-1-methylpyridin-2(1H)-it is the result of the procedure, similar to that described for the 9th stage of Example 23. Method LC-MS 2 tR=1,57 min, the mass/charge=501, 479, 421.

EXAMPLE 28

6-(3-hydroxypropyl)-6-Hapoel-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-1,3-oxazine-2-he

Stage 1

In a mixture of 3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-isopropyl-1,3-oxazine-2-it (100 mg, 0.26 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (198 mg, 0,783 mmol) and potassium acetate (256 mg, 2,61 mmol) in DMSO (5 ml) in an atmosphere of N2was added Pd(dppf)Cl2(21 mg, 0,0261 mmol). The resulting mixture was stirred at 85°C for 3 h, was treated with EtOAc (50 ml) and water (50 ml). The organic layer was washed with water (2×50 ml) and brine (50 ml), dried and evaporated to obtain the crude product, which was then purified by preparative TLC to obtain 6-(3-hydroxypropyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it (40 mg, 35%).

Stage 2

A mixture of 6-(3-hydroxypropyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it (40 mg, 0,092 mmol), 4-iodine-1-methylpyridin-2(1H)-it (20 mg, of 0.085 mmol), Pd(PPh3)2Cl2(6 mg, 0,0085 mmol), and Cs2CO3(2 N, 0,425 ml, 0.85 mmol) in 1,4-dioxane (2 ml) was subjected to reverse or in an atmosphere of N2within 3 hours of Reaction the I mixture was treated with EtOAc (20 ml) and water (20 ml), then the organic layer was dried and evaporated in vacuum. The obtained residue was purified by preparative HPLC to obtain two isomers.

Isomer 1: (2.20 mg, 6%). Method LC-MS 2 tR=1,06 min, the mass/charge=413;

the mass/charge=1H NMR (CD3OD): δ 1.00 each (m, 6N), of 1.62 (m, 7H), is 1.82 (m, 1H), 2,10 (m, 2H), 2,85 (m, 1H), 3,29 (m, 1H), 3,54 (t, 2H), 3,63 (s, 3H), 5,71 (q, 1H), 6,78 (dd, 1H), 6,83 (d, 1H), 7,51 (d, 2H), to 7.75 (m, 3H),

Isomer 2: (2.10 mg, 6%) Method LC-MS 2 tR=1,03 min, the mass/charge=413;1H NMR (CD3OD): δ 0,86 (m, 6N), of 1.53 (m, 5H), 1,71 (m, 4H), of 1.92 (m, 1H), 2,82 (m, 1H), 3,25 (m, 1H), 3,49 (t, 2H), 3,52 (s, 3H), 5,59 (q, 1H), to 6.67 (dd, 1H), 6,72 (d, 1H), 7,39 (d, 2H), 7,63 (m, 3H),

EXAMPLE 29

(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-he

Stage 1

A mixture of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazine-2-she (150 mg, the 0.375 mmol) and 6-aminopyridine-3-elborno acid (56 mg, 0.45 mmol), Pd(Ph3P)2Cl2(15 mg) and water solution Cs2CO3(0.5 ml, 2 M) in 1,4-dioxane (10 ml) were mixed and heated to reverse kundenservice within 2 hours After separation of the organic phase was evaporated to obtain the crude product, which was then purified by preparative HPLC to obtain (R)-6-allyl-3-((S)-1-(4-(6- aminopyridine-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-she (90 mg, 60%).

Stage 2

To a solution of (R)-6-allyl-3-((S)-1-(4-(6-aminopurin the n-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-she (90 mg, 0.23 mmol) in tetrahydrofuran (10 ml) at 0°C in an atmosphere of nitrogen was added BH3tetrahydrofuran (3.0 ml, 1 mol/l, 4 mmol). The resulting mixture was stirred for 2 h, after which the reaction was stopped with water. Then the above mixture was added NaOH (2 ml, 3 mol/l) and H2O2(1 ml). After the reaction mixture was subjected to extraction using EtOAc. The combined organic phase was evaporated to obtain the crude product, which was then purified by preparative HPLC to obtain (R)-3-((S)-1-(4-(6-aminopyridine-3-yl)phenyl)ethyl)-6-3-hydroxypropyl)-6-phenyl-1,3-oxazine-2-it (40 mg, 41%).

Stage 3

(R)-3-((S)-1-(4-(6-aminopyridine-3-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazine-2-he (40 mg, 0.09 mmol) was dissolved in 3.5 M H2SO4(10 ml), and then at a temperature of 0°C. the resulting solution was added 2 M NaNO2(10 ml). The reaction mixture was stirred at room temperature for 2 h and was treated with NaOH solution, after which the mixture was subjected to extraction using EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4and evaporated to obtain the residue which was then purified by preparative HPLC to obtain (R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-ACS who Sinan-2-it (10 mg, 20%). Method LC-MS 2 tR=1,66, min, the mass/charge=433, 455;1H NMR (CDCl3): of 1.36 (m, 2H), 1,50 (m, 3H), by 1.68 (m, 2H), 1,92 (m, 2H), 2,10-of 2.30 (m, 3H), 2,84 (m, 1H), 3,50 (m, 2H), 5,12 (m, 1H), 6,62 (m, 1H), 6,86 (m, 2H), was 7.08 (m, 2H), 7.18 in-7,32 (m, 5H), 7,46 (m, 1H), a 7.62 (m, 1H).

EXAMPLE 30

(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-he

Stage 1

To a suspension of NaH (4.8 g, 0.2 mol) in tetrahydrofuran (10 ml) at 0°C was added a solution of 5-bromopyridin-2(1H)-she (8.6 g, 0.05 mol) in tetrahydrofuran (120 ml). The resulting mixture was stirred for 1 h followed by addition of CH3I (35.5 g, 0.25 mol). The mixture is then stirred for another 3 h, after which the reaction was stopped by using aqueous solution of NH4Cl. The organic phase was evaporated to obtain the crude product, which was then purified by column chromatography to obtain 5-bromo-1-methylpyridin-2(1H)-she (8,9 g, 96,78%).1H NMR (CDCl3): δ=3,5 (S, 3H), of 6.52 (m, 1H), 7,32 (m, 1H), 7,45 (m, 1H).

Stage 2

A mixture of (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-she (1.7 g, 3.7 mmol) and 5-bromo-1-methylpyridin-2(1H)-she (816 mg, 4.4 mmol), Pd(Ph3P)2Cl2(200 mg) and aqueous solution of Cs2CO3(4 ml, 2M) in 1,4-dioxane (30 ml) were mixed and heated to reverse kondensierten is within 2 hours After the reaction mixture was washed with water and subjected to extraction using EtOAc. Then the organic phase was washed with brine, dried over Na2SO4and was subjected to filtration and evaporation to obtain crude product, which was then purified by preparative TLC to obtain (R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-it (614 mg, 37%). Method LC-MS 2 tR=1,075 min, the mass/charge=447,1;1H NMR (CDCl3): δ=1,38 (m, 1H),1,47 (d, 3H), at 1.73 (m, 2H), up to 1.98 (m, 2H), measuring 2.20 (m, 1H), 2,31 (m, 2H), equal to 2.94 (m, 1H), 3,51 (m, 2H), of 3.56 (s, 3H), 5,63 (m, 1H), 6,67 (m, 1H), 6.87 in (m, 2H), 7,05 (m, 2H), 7,31-7,41(m, 6H), of 7.48 (m, 1H).

EXAMPLE 31

(S)-6-(4-forfinal)-6-(2-hydroxyethyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-he

To a solution of (R)-6-allyl-6-(4-forfinal)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-it (0,064 g, 0.144 mmol, 1.0 equiv.) in tetrahydrofuran-H2O (1:1, 6 ml) were added NaIO4(0,145 g, 0,678 mmol, 4.7 equiv.) and OsO4(mass concentration in percent solution of t-BuOH - 2,5%, 0,048 g, 0,0047 mmol, 0,033 equiv.), after which the mixture is stirred at room temperature for 1 h Then the mixture was diluted with EtOAc, dried over Na2SO4and evaporated in vacuum. The residue was dissolved in Meon (3 ml) and then added the m NaBH 4(0,100 g). After stirring the mixture for 0.5 h at room temperature the mixture was added acetone. The solvents were removed in vacuo, then the residue was treated with saturated salt solution was subjected to extraction with CH2Cl2and drying over Na2SO4. After evaporation of the solvent the residue was purified by inverse-phase HPLC (column SunFire™ Prep C18OBD™ 5 μm 19×50 mm, 10%→90% CH3CN/H2O, 0.1% of CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% of CF3COOH over 2 min, flow rate 20 ml/min) to obtain (S)-6-(4-forfinal)-6-(2-hydroxyethyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-it. Method LC-MS 1 tR=1,21 min, the mass/charge=451 (M+1);1H NMR (400 MHz, CD3OD) 7,80 (m, 1H), 7,69 (d, J=9.4 Hz, 1H), 7,22-7,19 (m, 4H), 7,00-6,92 (m, 4H), of 6.52 (d, J=9.4 Hz, 1H), the 5.45 (q, J=7,0 Hz, 1H), 3,60-to 3.52 (m, 1H), 3,52 (s, 3H), 3,24-3,18 (m, 1H), 3,02 are 2.98 (m, 1H), 2,39 to 2.35 (m, 1H), 2,23-2,12 (m, 2H), 2,01 (t, J=7,3 Hz, 2H), USD 1.43 (d, J=7,0 Hz, 3H);19F NMR (376 MHz, CD3OD) -117,19 (m).

EXAMPLE 32

(S)-6-(4-forfinal)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-he

Method 1

Stage 1

A mixture of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-1,3-oxazine-2-she (1.6 g, of 3.84 mmol) and 6-aminopyridine-3-elborno acid (1.0 g, 4.61 mmol), Pd(Ph3P)2Cl2(150 mg), and water RA is down Cs 2CO3(3,84 ml, 2 M) in 1,4-dioxane (150 ml) were mixed and heated for reverse condensation within 2 hours Then the mixture was subjected to filtration, and the obtained filtrate extraction using EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4and evaporated to obtain (R)-6-allyl-3-((S)-1-(4-(6-aminopyridine-3-yl)phenyl)ethyl)-6-(4-forfinal)-1,3-oxazine-2-she (1.5 g, 90%) which was used in the next step without additional purification.1H NMR (CDCl3): δ=rate of 1.51 (d, 3H), 2,17-2,31 (m, 3H), 2,54-2,60 (m, 2H), 2,90 (m, 1H), 4,46 (s, 2H), 4,99-5,09 (m, 2H), 5,65-5,71 (m, 2H), 6,54 (m, 2H), to 6.88 (d, 2H), 7,03 (t, 2H), 7,21-7,27 (m, 3H), 7,58 (d, 1H), by 8.22 (d, 1H).

Stage 2

To a solution of (R)-6-allyl-3-((S)-1-(4-(6-aminopyridine-3-yl)phenyl)ethyl)-6-(4-forfinal)-1,3-oxazine-2-she (1.5 g, 3,47 mmol) in 3.5 M H2SO4(25 ml) at 0°C was added 2 M NaNO2(15 ml). The reaction mixture was stirred at room temperature overnight, then was treated with an aqueous solution of NaOH (8%) and was subjected to extraction with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous Na2SO4and evaporated to obtain the crude product, which was then purified by preparative TLC to obtain (R)-6-allyl-6-(4-forfinal)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxaz the NAS-2-it (891 mg, 59%).1H NMR (CDCl3): δ=of 1.52 (d, 3H), 2,15-of 2.38 (m, 3H), of 2.51-2,60 (m, 2H), equal to 2.94 (m, 1H), 4,99-5,11 (m, 2H), 5,65-5,74 (m, 2H), 6,67 (m, 1H), 6.89 in (d, 2H), 7,00 (t, 2H), 7,13-7,20 (m, 2H), 7,20-7,27 (d, 2H), 7,33 (m, 1 H), 7,46 (m,1H), to 7.77 (m, 1H).

Stage 3

To a suspension of NaH (330 mg, 8,24 mmol) in tetrahydrofuran (20 ml) at 0°C was added a solution of (R)-6-allyl-6-(4-forfinal)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-it (891 mg, 0,174 mmol) in tetrahydrofuran (30 ml). The resulting mixture was stirred for 1 h, after which the mixture was added CH3I (2 ml) and the mixture stirred over night. Then the reaction was stopped by using aqueous solution of NH4Cl, the organic phase was separated and evaporated to obtain the crude product, which was then purified by preparative TLC to obtain (R)-6-allyl-6-(4-forfinal)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-it (634 mg, 69%).1H NMR (CDCl3): δ=of 1.52 (d, 3H), 2,16 to 2.35 (m, 3H), 2,52-of 2.64 (m, 2H), equal to 2.94 (m, 1H), 3,61 (s, 3H), 5,00-5,11 (m, 2H), 5,66-5,74 (m, 2H), only 6.64 (d, 1H), 6.90 to (d, 2H), 7,02 (t, 2H), 7,11-7,14 (d, 2H), 7,25-7,28 (m, 2H), 7,41 (m, 1H), 7,53 (m, 1H).

Stage 4

To a solution of (R)-6-allyl-6-(4-forfinal)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-it (320 mg, 0,717 mmol) in acetone (20 ml) was added an aqueous solution of KMnO4and NaIO4(15 ml), after which the resulting mixture was stirred at 0°C for 30 minutes and Then a mixture of powerglaz the filtration with subsequent adjustment of pH of the filtrate to 5-6 with 1 N aqueous HCl. The resulting mixture was subjected to extraction using EtOAc, after which the combined organic phase was washed with brine, dried over anhydrous Na2SO4and evaporated to obtain 2-((S)-6-(4-forfinal)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-2-oxo-1,3-oxazine-6-yl)acetic acid.

Step 5

To a solution of 2-((S)-6-(4-forfinal)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-2-oxo-1,3-oxazine-6-yl)acetic acid (290 mg, of 0.625 mol) in Meon (20 ml) at 0°C was added SOCl2(2 ml), after which the reaction mixture is stirred at room temperature for 2 hours the Reaction mixture was evaporated to obtain the residue which was then purified by preparative TLC to obtain methyl 2-((S)-6-(4-forfinal)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-2-oxo-1,3-oxazine-6-yl)acetate (130 mg, 43,5%).1H NMR (CDCl3): δ=of 1.52 (d, 3H), 2,36 is 2.55 (m, 3H), 2,67-a 2.71 (m, 2H), 2,90 totaling 3.04 (m, 3H), 3,68 (s, 3H), 3,71 (s, 3H), to 5.66 (m, 2H), 6,66 (d, 1H), 6.90 to (d, 2H), 7,03 (t, 2H), 7,13-to 7.15 (d, 2H), 7.23 percent-7,29 (m, 2H), 7,42 (m, 1H), 7,56 (m, 1H).

Stage 6

To a solution of methyl 2-((S)-6-(4-forfinal)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-2-oxo-1,3-oxazine-6-yl)acetate (130 mg, 0.22 mmol) in dry tetrahydrofuran (20 ml) at -78°C was added MeMgBr (2 ml), after which the mixture was mixed at room temp. in an atmosphere of N2within but is I. The reaction was stopped with water, and the resulting mixture was subjected to extraction using EtOAc. The combined organic phase was dried over Na2SO4and evaporated to obtain a residue, which was purified by preparative HPLC to obtain (S)-6-(4-forfinal)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-it (24 mg, 30%). Method LC-MS 2 tR=1,116 min, the mass/charge=479,1;1H NMR (CDCl3): 1,1 (m, 6H), of 1.18 (m, 1H), 1,48 (d, MN), was 1.58 (m, 1H), 1,80-2,00 (m, 2H), of 2.21 (m, 3H), of 2.86 (m, 1H), of 5.55 (m, 1H), 7,72 (m, 2H), 7,00 (m, 2H), 7,18 (m, 4H).

Method 2

Stage 1

To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-1,3-oxazine-2-it (5 g, 12 mmol) and CuCl (2,75 g, 27.8 mmol) in dry DMF (50 ml) at room temperature were added H2O (20 ml) and PdCl2(950 mg, 3.2 mmol). The resulting mixture was thoroughly mixed under the flask with oxygen within 24 hours After receiving the results of TLC, indicating the disappearance of the starting material, the solid was filtered. Then were added water (200 ml) and EtOAc (50 ml), produced by separation of the layers and extraction of the aqueous layer using EtOAc (3×40 ml). The combined organic layer was washed with brine, dried over Na2SO4and was subjected to filtration and evaporation to obtain (S)-3-((S)-1-(4-bromophenyl)this is)-6-(4-forfinal)-6-(2-oxopropyl)-1,3-oxazine-2-she (the 5.25 g, 92%), which was then purified by column chromatography.1H NMR (CDCl3): of 1.47 (s, 3H), of 2.06 (s, 3H), 2,10-of 2.36 (m, 3H), 2,58 (m, 1H), 2,90 (m, 2H), 5,58 (m, 1H), 6,69 (m, 1H), 6,79 (m, 1H), 7,02 (m, 2H), 7,19-7,33 (m, 4H).

Stage 2

To a solution of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-6-(2-oxopropyl)-1,3-oxazine-2-she (the 5.25 g, 12.1 mmol) in anhydrous tetrahydrofuran (100 ml) drop by drop at -78°C in an atmosphere of nitrogen was added Metalmania bromide (20 ml, 60 mmol). The mixture is then stirred at room temperature for 2 h and was cooled in an ice bath. The reaction was stopped by using aqueous solution of NH4Cl, followed by separation of the layers. The aqueous layer was subjected to extraction using EtOAc (15 ml), then was washed with brine (30 ml), dried over Na2SO4and evaporated in vacuo to obtain the crude product, which was then purified by preparative HPLC and chiral HPLC to obtain (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazine-2-she (2.5 mg, 46%).1H NMR (CDCl3): 1,08 (s, 3H), of 1.12 (s, 3H), of 1.48 (m, 3H), 1,99 (m, 1H), 2,10-of 2.24 (m, 4H), to 2.35 (m, 1H), 2,85 (m, 1H), 5,61 (m, 1H), 6,80 (m, 2H), 6,99 (m, 2H), 7,15-7,28 (m, 5H).

Stage 3

A mixture of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazine-2-she (640 mg, of 1.42 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (470 mg, of 1.85 mmol), PdCl2dppf (40 mg, 0,047 mmol) and Kaas (490 mg equal to 4.97 mmol) in DMSO (8 ml) was heated at 90°C for 20 hours The mixture was diluted with EtOAc and washed with water. The organic phase was separated and evaporated to obtain the crude product, which was then purified by preparative TLC to obtain (S)-6-(4-forfinal)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-she (700 mg, 99%).1H NMR (CDCl3): δ=1,08 (s, 3H), of 1.13 (s, 3H), of 1.32 (s, 12H) and 1.51 (t, 3H), of 1.94 (m, 2H), 2,16 (m, 5H), 2,33 (m, 1H), and 2.83 (m, 1H), 5,69 (m, 1H), 6,99 (m, 4H), 7,25 (m,2H), to 7.61 (m, 2H).

Stage 4

A mixture of (S)-6-(4-forfinal)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-she (700 mg, of 1.41 mmol), 5-bromo-1-methylpyridin-2(1H)-she (398 mg, 2,12 mmol), PdCl2(Ph3P)2(70 mg), and Cs2CO3(1.5 ml, 3.0 mmol) in 1,4-dioxane (15 ml) was heated under conditions of reverse condensation within 2 hours the mixture was diluted with EtOAc and washed with water followed by separation and evaporation of the organic phase to obtain the crude product, which was then purified by preparative TLC to obtain (S)-6-(4-forfinal)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-she (150 mg, 22%).1H NMR (CDCl3): δ=1,12 (s, 3H), of 1.13 (s, 3H) and 1.51 (t, 3H), of 2.16 (m, 2H), of 2.21 (m, 2H), 2,41 (m, 1H), 2,92 (m, 1H), 3,63 (s, 3H), 5,69 (q, 1H), 6,69 (m, 1H), 6,99 (m, 4H), 7,18 (m, 2H), 7,27 (m, 2H), 7,42 (m, 1H), 7,52 (m, 1H).

EXAMPLE 33

(R)-6-(4-forfinal)--(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-he

Stage 1

To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-1,3-oxazine-2-it (1.19 g, 2.8 mmol) in tetrahydrofuran (30 ml) at 0°C in an atmosphere of nitrogen was added BH3tetrahydrofuran (8.5 ml, 1 mol/l, 8.5 mmol). The resulting mixture was stirred for 2 h, after which the reaction was stopped with water. Then the above mixture was added NaOH (1 mol/l, 6 ml) and N2About2(5 ml). After the reaction mixture was subjected to extraction using EtOAc. The combined organic phase was evaporated to obtain the crude product, which was then purified by preparative TLC to obtain (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-6-(3-hydroxypropyl)-1,3-oxazine-2-she (1.13 g, 92%).

Stage 2

A mixture of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-forfinal)-6-(3-hydroxypropyl)-1,3-oxazine-2-she (520 mg, 1.2 mmol) and 6-aminopyridine-3-elborno acid (280 mg, 1.44 mmol), Pd(Ph3P)2Cl2(100 mg) and aqueous solution of Cs2CO3(3 ml, 2M) in 1,4-dioxane (20 ml) was stirred and heated under conditions of reverse condensation within 2 h Then the organic phase was separated and evaporated to obtain the crude product, which was then purified by preparative TLC to obtain (R)-3-((S)-1-(4-(6-aminopyridine-3-yl)phenyl)ethyl)-6-(4-forfinal)6-(3-hydroxypropyl)-1,3-oxazine-2-she (400 mg, 74%).

Stage 3

(R)-3-((S)-1-(4-(6-aminopyridine-3-yl)phenyl)ethyl)-6-(4-forfinal)-6-(3-hydroxypropyl)-1,3-oxazine-2-he (400 mg, 0.88 mmol) was dissolved in 3.5 M H2SO4(10 ml), and then at a temperature of 0°C was added 2 M NaNO2(6 ml). The reaction mixture was stirred at room temperature for 20 min, then was treated with an aqueous solution of NaOH (8%) and was subjected to extraction with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous Na2SO4and evaporated to obtain the crude product, which was then purified by preparative TLC to obtain (R)-6-(4-forfinal)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-she (350 mg, 0.78 mmol).1H NMR (CDCl3): δ=1,10-1,25 (m, 8H), to 1.37 (m, 1H), 1,42-of 1.55 (m, 2H), 1,78-of 1.93 (m, 2H), 2,10-of 2.38 (m, 2H), 2,87 (m, 2H), 3,52-to 3.58 (m, 1H), 3,31-of 3.97 (m, 1H), 4,12-4,19 (m, 1H), of 5.53-5,63 (m, 1H), 6,85-to 7.15 (m, 3H), 7,35-of 7.55 (m, 1H), 7,75-7,89 (m, 1H), 8,10-to 8.12 (m, 1H).

Stage 4

A mixture of (R)-6-(4-forfinal)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-it (100 mg, 0.78 mmol), imidazole (of 142.8 mg, 2.1 mmol), and tert-butylcholinesterase (350 mg, 2.34 mmol) in CH2Cl2(20 ml) stirred over night. Then the mixture was washed with water and subjected to extraction using EtOAc. The combined organic phase was washed with brine and washstand Na 2SO4, and then was subjected to filtration and evaporation to obtain crude (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-6-(4-forfinal)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-she (120 mg), which was used in the next step without additional purification.

Step 5

To a suspension of NaH (18 mg, to 0.72 mmol) in tetrahydrofuran (0.5 ml) at 0°C was added a solution of (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-6-(4-forfinal)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-it (100 mg, 0.18 mmol) in tetrahydrofuran (10 ml). The resulting mixture was stirred for 1 h, then it was added CH3I (613 mg, 43.2 mmol), after which the mixture was mixed for 3 hours the Reaction was stopped by using aqueous solution of NH4Cl. The organic phase was separated and evaporated to obtain (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-6-(4-forfinal)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-she (104 mg, 100%) which was used in the next step without additional purification.

Stage 6

A mixture of (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-6-(4-forfinal)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-she (200 mg, 0.35 mmol) and TBAF (182 mg, 0.7 mmol) in CH3CN stirred and heated under conditions of reverse condensation within 15 min After the reaction mixture was washed with water and subjected to extraction using EtOAc. The combined organic phase was washed with brine and dried over Na2SO4, and then was subjected to filtration and evaporation to obtain crude product, which was then purified by preparative HPLC to obtain (R)-6-(4-forfinal)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-it (5,01 mg, 4%). Method LC-MS 2 tR=1,065 min, the mass/charge=464,21;1H NMR (CDCl3): δ=1,38 (m, 1H), 1,47 (d, 3H), and 1.63 (m, 2H), 1.91 a (m, 2H), 2,10-of 2.30 (m, 3H), 2,87 (m, 1H), 2,84 (m, 1H), 3,51 (m, 2H), of 3.56 (s, 3H), 5,63 (m, 1H), 6,67 (m, 1H), 6.87 in-6,98 (m, 4H), to 7.15 (m, 2H), 7,27 (m, 1H), 7,29 (m, 1H), 7,32 (m, 1H), 7,55 (m, 1H).

EXAMPLE 34

N-(3-((R)-6-(4-forfinal)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-2-oxo-1,3-oxazine-6-yl)propyl)methanesulfonamide

The title compound was obtained from (R)-6-(4-forfinal)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-it by treating (i) MeSO2Cl and (ii) MeSO2NH2. Method LC-MS 2 tR=1,02 min, the mass/charge=USD 542.3;1H NMR (CDCl3) to 1.35 (m, 1H), 1,53 (d, 3H), 1.69 in (m, 1H), 1,89 (m, 1H), 2,00 (m, 1H), 2,17 is 2.33 (m, 3H), 2,89 (s, 3H), of 2.97 (m, 1H), 3,06 (m, 2H), 3,66 (s, 3H), of 4.38 (s, 1H), 5,67 (m, 1H), PC 6.82 (d, 1H), 6,99 (m, 4H), to 7.15 (m, 2H), 7,22 (m, 2H), 7,47 (s, 1H), 7,63 (d, 1H).

EXAMPLE 35

3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-6-yl)propanamide

Titeln the e compound was obtained from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propanamide in the procedures similar to that described for 2 and 3 stages of Example 33. Method LC-MS 2 tR=0,999 min, the mass/charge=446,1;1H NMR (CD3OD) of 1.53 (d, 3H), 1,91 is 2.01 (m, 1H), 2,18-of 2.34 (m, 4H), 2,35 is 2.51 (m, 2H), 3,03-of 3.12 (m, 1H), 5.56mm (m, 1H), 6,62 (d, 2H), 7,03 (d, 2H), 7.24 to 7,44 (m, 7H), to 7.59 (m, 1H), 7,87 (m, 1H).

EXAMPLE 36

(S)-6-(2-hydroxyethyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-he

The title compound was obtained from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazine-2-by procedures similar to those described for 2-6 stages of Example 33. Method LC-MS 2 tR=1,038 min, the mass/charge=433,1;1H NMR (CDCl3) to 1.48 (d, 3H), 2.06 to 2,19 (m, 2H), 2,11-2,31 (m, 3H), 2,84 (m, 1H), 3,50 (m, 1H), 3,54 (s, 3H), and 3.72 (m, 1H), 5,62 (m, 1H), 6,60 (d, 1H), 6,86 (d, 2H), 7,06 (d, 2H), 7,26 (m, 3H), 7,32 (m, 3H), 7,47 (d, 1H).

EXAMPLE 37

(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-he

Method 1

The title compound was obtained from (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazine-2-by procedures similar to those described for 2, 3 and 5 stages of Example 33 after the procedure similar to that described for 4 and 6 steps method 1 method of obtaining 1. Method LC-MS 2 tR=1,116 min, the mass/charge=461,1;1H NMR (CDCl3) of 1.09 (s, 3H), of 1.16 (s, 3H) and 1.51 (m, 3H), 2.05 IS-OF 2.20 (4H), 2.40 a (m, 1H), 2,84 (m, 1H) and 3.59 (s, 3H), 5,64 (m, 1H), ,62 (m, 1H), of 6.96 (m, 2H), 7,14 (m, 2H), 7,28-7,39 (m, 5H), of 7.48 (m, 1H), 7,50 (m, 1H).

Method 2

Stage 1

To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3 - oxazine-2-it (20 g, 50 mmol) and CuCl (12.4 g, 125 mmol) in dry DMF (50 ml) at a temperature of 0~-5°C was added H2O (12 ml) and PdCl2(2.66 g, 15 mmol). After the addition the mixture was left at room temperature for 48 h in an atmosphere of O2for heating. After receiving the results of TLC, indicating the disappearance of starting material was filtered solid to which were then added water (200 ml) and EtOAc (50 ml). After separation of the layers the aqueous layer was subjected to extraction using EtOAc (3×40 ml). The combined organic layer was washed with brine and dried over Na2SO4, and then was subjected to filtration and evaporation to obtain a residue, which was purified by column chromatography to obtain (S)-3-((S)-1-(4-bromo-phenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazine-2-it (12 g, 58%).

Stage 2

To a solution of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazine-2-it (12 g, 28.8 mmol) in anhydrous tetrahydrofuran (100 ml) drop by drop at -78°C in an atmosphere of nitrogen was added Metalmania bromide (48 ml, 144 mmol). The resulting mixture was stirred at room temperature for 1 h, after which the reaction was stopped by the introduction of an aqueous solution of NH 4Cl (50 ml) in a water bath with ice. After separation of the layers the aqueous layer was subjected to extraction using EtOAc (150 ml), the combined organic phases were washed with brine (30 ml), dried over Na2SO4and evaporated in vacuo to obtain the crude product, which was then purified by preparative HPLC and chiral HPLC to obtain (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-she (6.6 g, 53%).

Stage 3

To a solution of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2 - methylpropyl)-6-sreni-1,3-oxazine-2-she (6.6 g, 15.2 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (6,1 g, a 24.3 mmol) in dry DMSO (20 ml) were added COAs (4.8 g, to 48.6 mmol) and Pd(dppf)Cl2(372 mg, 0.46 mmol). After the addition the mixture was left for 20 hours at a temperature of 100°C for heating. After receiving the results of TLC, indicating the disappearance of the starting material, the solid was filtered. Then were added water (60 ml) and EtOAc (50 ml), produced by separation of the layers and extraction of the aqueous layer using EtOAc (3×15 ml). The combined organic layer was washed with brine, dried over Na2SO4and was subjected to filtration and evaporation to obtain a precipitate, which was then purified by column chromatography to obtain (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-EN-2-yl)phenyl)ethyl)-1,3-oxazine-2-she (4.4 g, 60%).

Stage 4

To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-she (2.2 g, 4,58 mmol) and 5-bromo-1-methylpyridin-2(1H)-she (1,37 g, 7,33 mmol) in dry 1,4-dioxane (4 ml) were added an aqueous solution CsCO3(10 ml, 10 mmol) and Pd(PPh3)2Cl2(967 mg, 1.38 mmol). After adding the mixture using a microwave oven was heated at 110°C for 30 minutes After receiving the results of TLC, indicating the disappearance of the starting material, the solid was filtered. Then were added water (20 ml) and EtOAc (10 ml), produced by separation of the layers and extraction of the aqueous layer using EtOAc (3×10 ml). The combined organic layer was washed with brine, dried over Na2SO4and was subjected to filtration and evaporation to obtain a precipitate, which was then purified by preparative HPLC to obtain (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-it (730 mg, 35%).1H NMR (CDCl3): 1,09 (s, 3H), of 1.16 (s, 3H) and 1.51 (m, 3H), 2.05 IS-OF 2.20 (4H), 2.40 a (m, 1H), 2,84 (m, 1H) and 3.59 (s, 3H), 5,64 (m, 1H), 6,62 (m, 1H), of 6.96 (m, 2H), 7,14 (m, 2H), 7,28-7,39 (m, 5H), of 7.48 (m, 1H), 7,50 (m, 1H), the compound Obtained was subjected to recrystallization in accordance with the two methods.

Method recrystallization And

A mixture of (S)-6-(2-hydroxy-2-methylprop who yl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-it (approx. 2,94 g) and isopropylacetate (160 ml) were thoroughly mixed at room temperature or heated at a temperature of 50°C to dissolve more solid. The resulting mixture was subjected to filtration through HPLC filter, and then the obtained filtrate was slowly mixed at room temperature over night. A solid substance was subjected to filtration and washing with isopropylacetate, and then were dried at room temperature in high vacuum to obtain 1,43 g (49%) of crystalline solid with a melting point 95-101°C. This form was defined as the hydrate, when heated, emit 3,6% water by weight.

Method recrystallization In

A mixture of (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-it (approx. there is a 10.03 g) and isopropylacetate (600 ml) was heated under conditions of reverse condensation in the oil bath at a temperature of 130°C. to dissolve the solids and form a homogeneous solution. Then heating was discontinued and the mixture slowly stirred in an oil bath for slow cooling to room temperature. Obtained after cooling, the solids were filtered, and then were washed isopropylacetate and dried at room temperature in high HAC the mind to obtain 7.30 g (73%) of crystalline solid with a melting point 180-181°C. This form was defined as waterless.

EXAMPLE 38

3-((R)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propanamide

The title compound was obtained from (R)-6-allyl-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-by the procedure similar to that described for step 2 of Example 29, after the processing of (i) the Jones reagent and (ii) NH3EDC, HOBt. Method LC-MS 2 tR=1,028 min, the mass/charge=460,2;1H NMR (CDCl3) of 1.53 (d, 3H), 1,91 is 2.01 (m, 1H), 2,11-to 2.42 (m, 5H), 2,46-of 2.54 (m, 1H), 2,88-2,96 (m, 1H), 3,60 (s, 3H), of 5.26 (s, 1H), 5,42 (s, 1H), to 5.66 (m, 1H), 6,69 (d, 1H), 6,95-7,03 (d, 2H), 7,12-7,20 (m, 2H), 7,24-7,41 (m, 5H), 7,52 (m, 1H).

EXAMPLE 39

N-(3-((R)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propyl)methanesulfonamide

The title compound was obtained from (R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-it by treating (i) MeSO2Cl and (ii) MeSO2NH2, K2CO3. Method LC-MS 2 tR=1,095 min, the mass/charge=524,1;1H NMR (CDCl3) 1,30-of 1.41 (m, 1H), of 1.52 (d, 3H), 1,71 (m, 1H), 1,87-2,07 (m, 3H), 2,09-of 2.20 (m, 3H), 2,22 of-2.32 (m, 2H), 2,88 (s, 3H), 3,06 (m, 2H), 3,60 (s, 3H), 4,32 (s, 1H), 5,65 (m, 1H), to 6.67 (d, 1H), 6,94 (m, 2H), 7,11 (d, 2H), 7,25 (m, 1H), 7,27-7,40 (m, 4H), 7,53 (dd, 1H).

EXAMPLE 41

(R)-6-(4-forfinal)-6-(3-hydroxypropyl)-3-((S)-1-(4-(2-about the co-1,2-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-he

The title compound was obtained from (R)-6-allyl-6-(4-forfinal)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it 3-bromo-2-hydroxypyridine the application of procedures analogous to those described for step 2 of Example 3, after applying procedures similar to those described for step 2 of Example 29. Method LC-MS 1 tR=1,24, the mass/charge=452 (M+1);1H NMR (CDCl3) 7,76 (d, 1H), 7,52 (d, 1H), 7,42 (dd, 2H), 7,24 (m, 2H), 7,08-7,00 (m, 4H), 6.75 in (t, 1H), 5,70 (m, 1H), to 3.58 (t, 1H), equal to 2.94 (m, 1H), and 1.54 (d, 3H).

EXAMPLE 42

(R)-6-(4-forfinal)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-he

Stage 1

(R)-6-allyl-6-(4-forfinal)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-he (18 mg, 0,039 mmol), 3-bromo-2-hydroxypyridine (14 mg, 2 equiv.), Pd(dppf)Cl2(3 mg, 10% mol), 2M aqueous solution of Na2CO3(800 ml) and 1,4-dioxane (1.5 ml) were mixed, then the mixture was pumped gaseous N2, followed by re-feeding of the gaseous N2(3×) prior to heating at a temperature of 85°C during the night. After cooling to room temperature the mixture was subjected to filtration and oxidation with 5% aqueous HCl solution, followed by purification by preparative HPLC to obtain (R)-6-allyl-6-(4-forfinal)-3-((S)-1-(4-(2-oxo-1,2-d is hydropyridine-3-yl)phenyl)ethyl)-1,3-oxazine-2-she (7.2 mg, yield: 43%). Method LC-MS 1 tR=1,57 min, the mass/charge 433 (M+1).

Stage 2

A solution of (R)-6-allyl-6-(4-forfinal)-3-((S)-1-(4-(2-oxo-1,2-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-it (15,5 mg, being 0.036 mmol) in dry DMF (1 ml) was cooled to 0°C. Then the solution was added sodium hydride (60% in mineral oil, 3 mg, 2 equiv.). After 20 min the mixture was added logmean (4,5 μl, 2 equiv.). The mixture is again stirred for 20 min, then slowly warmed to room temperature and stirred for 2 hours Obtained after carrying out the LC-MS results indicated the completion of reaction, which was stopped with the help of a saturated aqueous solution of NH4Cl (1 ml). The reaction mixture was purified by preparative HPLC to obtain (R)-6-allyl-6-(4-forfinal)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-it (13.3 mg, yield: 83%). Method LC-MS 1 tR=1,63 min, the mass/charge 447 (M+1).

Stage 3

A solution of (R)-6-allyl-6-(4-forfinal)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-it (13.3 mg, 0,030 mmol) in dry tetrahydrofuran (1.5 ml) was cooled to 0°C. Then the solution was added disimilar (0.5 M in tetrahydrofuran, 500 μl, excess). After 10 min the mixture agrawals to room temp. and stirred for 1 h Then the mixture was again cooled down to 0°C, after which the reaction was OST is determined with water (1 ml) and NaBO 3(10 mg). The mixture was evaporated and purified by preparative HPLC to obtain (R)-6-(4-forfinal)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-3-yl)phenyl)ethyl)-1,3-oxazine-2-she (4.2 mg, yield: 30%). Method LC-MS 1 tR=1,33 min, the mass/charge=487(M+1);1H NMR (CD3Cl) δ 7,47 (dd, 1H), 7,38 (m, 3H), 7,24 (m, 2H), 7,07 (t, 2H), of 6.96 (d, 2H), to 6.39 (t, 1H), 5,65 (m, 1H), 4.26 deaths (t, 1H), 3,66 (s, 3H), 2.91 in (m, 1H), 2.40 a with 2.14 (m, 3H), and 1.54 (d, 3H).

EXAMPLE 43

(R)-3-((S)-1-(4-(1-ethyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazine-2-he

The title compound was obtained by procedures similar to those described in Example 30, using ethyliodide in phase 1 to obtain 5-bromo-1-ethylpyridine-2(1H)-it is used during phase 2. Method LC-MS 2 tR=1,297 min, the mass/charge=461,1;1H NMR (CDCl3) to 1.31 (m, 1H), 1,36 (t, 3H) and 1.51 (d, 3H), by 1.68 (m, 1H), 1,86 is 2.01 (m, 2H), 2,18 (m, 1H), and 2.27 (m, 2H), 2.91 in (m, 1H), 3,52 (m, 2H), 4,18 (m, 2H), 5,13 (m, 1H), 5,62 (m, 1H), 6,91 (m, 3H), was 7.08 (m, 2H), 7,18-7,33 (m, 5H), 7,41 (s, 1H), to 7.61 (d, 1H).

EXAMPLE 44

(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)propyl)-6-phenyl-1,3-oxazine-2-he

The title compound was obtained from (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazine-2-it is the result of applying the procedure analogion the th described for step 2 of Example 30. Method LC-MS 2 tR=1,113 min, the mass/charge=461,1;1H NMR (CDCl3) of 0.95 (t, 3H), of 1.30 (m, 1H), 1,68 (m, 1H), 1,81 of 1.99 (m, 2H), 2,11 of-2.32 (m, 3H), 2,88 (m, 1H), 3,50 (m, 2H), to 3.58 (m, 2H), 5,43 (m, 1H), of 6.49 (d, 1H), 6,98 (d, 2H), was 7.08 (d, 2H), 7,19 (m, 1H), 7,25 (m, 4H), 7,32 (s, 1H), 7,47 (m, 1H).

EXAMPLE 45

(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(2-hydroxypyridine-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-he

The title compound was obtained from (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-she and 4-bromo-2-hydroxypyridine the application of procedures analogous to those described for step 2 of Example 30. Method LC-MS 2 tR=1,019 min, the mass/charge=865,4;1H NMR (CDCl3) 1,29-of 1.40 (m, 1H), 1,49 (d, 3H), 1.60-to 1,72 (m, 1H), 1,83 is 2.01 (m, 3H), 2,18 (m, 1H), 2.21 are is 2.37 (m, 2H), 2,88 (m, 1H), 3,51 (m, 2H), 5,63 (m, 1H), 6,41 (d, 1H), of 6.68 (s, 1H), 6.90 to (d, 2H), 7,21-7,33 (m, 7H), 7,39 (d, 1H).

EXAMPLE 46

(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-2-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-he

The title compound was obtained from (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it 6-bromo-1-methylpyridin-2(1H)-it is the result of applying procedures similar to those described for step 2 of Example 30. Method LC-MS 2 tR=1,088 min, the mass/charge=447;1H NMR (CDCl3) to 1.38 (m, 1H), and 1.56 (d, 3H), of 1.70 (m, 1H), 1,95-of 2.08 (m, 2H), 2,23 (m, 1H), 2,37 (s, 2H), 3,05 (m, 1H), 3.33 and (s, 3H), to 3.58 m, 2H), 5,73 (m, 1H), 6,29 (d, 1H), 6.89 in (d, 1H), 7,01-to 7.09 (m, 4H), 7,21-7,39 (m, 5H), 7,53 (t, 1H).

6-Bromo-1-methylpyridin-2(1H)-it was obtained from 6-bromopyridin-2(1H)-it is the result of applying the procedure similar to that described for stage 1 of Example 59.

EXAMPLE 47

(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-he

Stage 1

To a suspension of NaH (80 mg, 2 mmol) in tetrahydrofuran (10 ml) at 0°C was added 4-bromopyridin-2-ol (80 mg, 0.46 mmol). The resulting mixture was stirred for 1 h, after which it was added CH3I (355 mg, 2.5 mmol) and the mixture stirred over night. The reaction was stopped by using aqueous solution of NH4Cl. The organic phase was subjected to evaporation to obtain crude product, which was then purified by column chromatography to obtain 4-bromo-1-methylpyridin-2(1H)-she (of 42.3 mg, 50%).

Stage 2

A mixture of (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it (50 mg, 0.11 mmol) and 4-bromo-1-methylpyridin-2(1H)-it (30 mg, 0.16 mmol), Pd(Ph3P)2Cl2(10 mg) and aqueous solution. Cs2CO3(4 ml, 2 M) in 1,4-dioxane (10 ml) were mixed and heated for reverse condensation within 2 hours After the reaction mixture was washed with water and was subjected to what straccia using EtOAc. The organic phase was washed with brine, dried over Na2SO4, and was subjected to filtration to obtain a crude product, which was then purified by preparative TLC to obtain (R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-it (25 mg, 51%).1H NMR (CDCl3): δ of 1.35 (m, 1H), 1,47 (d, 3H), and 1.63 (m, 2H), was 1.94 (m, 2H), 2,18 (m, 1H), 2,39 (m, 2H), 2,86 (m, 1H), 3,51 (m, 5H), 5,63 (m, 1H), of 6.31 (m, 1H), 6,70 (m, 1H), 6,91 (m, 2H), 7,20-to 7.32 (m, 8H).

EXAMPLE 48

(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-he

Method 1

Stage 1

A solution of 4-bromopyridin-2-amine (600 mg, 3.5 mmol) in a mixture of 2 M H2SO4(20 ml) and 2 M Na2NO2(10 ml) were mixed at a temperature of 0-5°C for 2 h, the Reaction mixture was subjected to extraction with CH2Cl2, after which the organic layer was washed with saturated NaCl solution, dried over anhydrous Na2SO4and was evaporated. The obtained residue was purified by preparative TLC to obtain 4-bromopyridin-2-ol (303 mg, 50%).

Stage 2

To a suspension of NaH (300 mg, 7.5 mmol) in tetrahydrofuran (10 ml) at 0°C was added 4-bromopyridin-2-ol (303 mg, at 1.73 mmol). After stirring the mixture for 1 h, it was added CH3I (491 mg, 3.46 mmol), the Le and the mixture stirred over night. The reaction was stopped by using aqueous solution of NH4Cl. The organic layer was evaporated to obtain the crude product, which was then purified by column chromatography to obtain 4-bromo-1-methylpyridin-2(1H)-she (161 mg, 50%).

Stage 3

A mixture of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-she (200 mg, 0.42 mmol), 4-bromo-1-methylpyridin-2(1H)-she (118 mg, to 0.63 mmol), Pd(Ph3P)2Cl2(20 mg) and 2 M aqueous solution of Cs2CO3(5 ml, 10 mmol) in 1,4-dioxane (20 ml) were mixed and heated for reverse condensation within 2 hours After the reaction mixture was washed with water and subjected to extraction using EtOAc. The organic phase was washed with brine, dried over Na2SO4and was subjected to filtration and evaporation to obtain crude product, which was then purified by preparative TLC to obtain (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-she (83 mg, 43%). Method LC-MS 2 tR=1,16 min, the mass/charge=921,5;1H NMR (CDCl3) a 1.11 (s, 3H), of 1.18 (s, 3H), 1,22 (t, 1H), of 1.52 (m, 3H), of 2.21 (s, 2H), 2,22-of 2.34 (m, 2H), 2,34 is 2.46 (m, 1H), 2,85 (m, 1H), only 3.57 (s, 3H), 5,59 (m, 1H), 6,33 (d, 1H), of 6.68 (s, 1H), 7,01 (d, 2H), 7,29-7,41 (m, 8H);1H NMR (CD3OD) of 0.98 (s, 3H), of 1.29 (s, 3H), 1,58 (d, 3H), 2,17 (s, 2H), 2,22 (, 1H), 2,50 (m, 2H), is 3.08 (m, 1H) and 3.59 (s, 3H), 5,59 (m, 1H), is 6.61 (d, 1H), 6,66 (s, 1H), was 7.08 (m, 2H), 7,30-7,40 (5H), 7,42 (d, 2H), of 7.70 (d, 1H).

Method 2

Stage 1

To a solution of 4-yodellin-2(1H)-she (3 g, of 0.013 mol) and K2CO3(3.55 g, was 0.026 mol) in DMF (30 ml) was added logmean (4.7 g, 0,033 mmol). The mixture is stirred at room temperature overnight, after which it was added water and EtOAc. The organic phase was dried over Na2SO4and evaporated to obtain 4-iodine-1-methylpyridin-2(1H)-she (1.6 g, 53%).

Stage 2

A mixture of 4-iodine-1-methylpyridin-2(1H)-she (0,909 g, 3,76 mmol), (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-she (1.5 g, of 3.13 mmol), 2 M aqueous solution of Cs2CO3(3 ml, 6 mmol), and PdCl2(PPh3)2(0,201 g, 0,282 mmol) in 1,4-dioxane (15 ml) was subjected to reverse or in an atmosphere of N2within 2 hours. Obtained after filtering the reaction mixture, the filtrate was subjected to extraction using EtOAc. United organicheskoi layer was washed with brine, dried over Na2SO4and was subjected to evaporation to obtain crude product, which was then purified by preparative HPLC and chiral HPLC to obtain (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine--she (399 mg, 28%). The results of LC-MS and1H NMR (CD3OD) were similar to those obtained for the product produced by Method 1. Then the connection was subjected to recrystallization in accordance with the methods described below.

The compound was obtained in the form of a crystalline monohydrate by adding a drop of 60 ml of water in a solution of 7.6 g of compound in 15 ml of methanol. After stirring for 1 h, the solid was subjected to filtration by suction, washing with water and titilation, and drying in a drying Cabinet over concentrated sulfuric acid/potassium hydroxide. Then the connection was subjected to recrystallization from water/ethanol (80:20) to obtain the monohydrate. Melting point: 118-122°C.

The compound was subjected to recrystallization from isopropylacetate. using procedures similar to those described for the Method of recrystallization In Example 37 to obtain crystalline solid with a melting point 106-116°C. the Compound is also was subjected to recrystallization in accordance with the above-described method of EtOAc (melting point 90-93°C, melting point 102-122°C), from isobutylacetate (melting point 108-126°C), EtOH/TWO (melting point 108-126°C), and 2-butanone.

Method 3

Stage 1

A mixture of (S)-3-((S)-1-(4-bromphen the l)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-it (100 mg, 0.23 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (68 mg, 1.25 equiv.), Pd(dppf)Cl2.CH2Cl2(19 mg, 10% mol), 2M aqueous solution of Na2CO3(1 ml) and 1,4-dioxane (3 ml) was subjected to three degassing and re-saturation of the gaseous N2before processing in a microwave oven for 2 hours at a temperature of 130°C. the Obtained results LC-MS indicated the completion of reaction. The mixture was diluted with EtOAc (50 ml), washed with water (10 ml) and brine (8 ml), and dried over Na2SO4. After filtration and evaporation the residue was purified by chromatography using a column containing 12 g of silica gel and elyuirovaniya using a gradient of 0-10% Meon in CH2Cl2to obtain (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-methoxypyridine-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-she (112 mg, Quant. output). Method LC-MS 1 tR=1,66 min, the mass/charge=461 (M+1).

Stage 2

(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-methoxypyridine-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-he (28 mg, 0.061 mmol), potassium carbonate (17 mg, 2 equiv.) and jodean (40 μl, 10 equiv.) was mixed with acetonitrile (2.5 ml), after which the mixture was heated under conditions of reverse condensation within 4 hours After cooling to room temperature the mixture was oxidized using 5% aqueous HCl and purified through the om preparative HPLC to obtain (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-it (14.4 mg, 52%). The results of LC-MS and1H NMR (CD3OD) were similar to those obtained for the product produced in accordance with Method 1.

EXAMPLE 49

2,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propanenitrile

Method 1

The title compound was obtained from 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-6-yl)propanenitrile and 5-bromo-1-methylpyridin-2(1H)-it is the result of applying the procedure similar to that described for stage 1 of Example 6. Method LC-MS 2 tR=1,231 min, the mass/charge=470,1;1H NMR (CDCl3) of 1.28 (s, 3H), of 1.40 (s, 3H), of 1.47 (d, 3H), of 2.09 (s, 2H), of 2.21 (m, 1H), 2,41 (m, 2H), and 2.83 (m, 1H), 3,52 (s, 3H), 5.56mm (m, 1H), return of 6.58 (d, 1H), PC 6.82 (d, 2H), 7,02 (d, 2H), 7,30 (m, 6H), 7,43 (m, 1H).

Method 2

A solution of 2,2-dimethyl-3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-6-yl)propanenitrile (202 mg, 0,444 mmol) and MeI (110 μl, equiv.) in dry tetrahydrofuran (5 ml) was cooled to 0°C. Then the solution was added NaH (60% in mineral oil, 36 mg, 2 equiv.). After 10 min the mixture was slowly heated to room temperature and stirred for 3 h the Results of LC-MS testified about 50% conversion. The mixture was heated for 1 h at 60°C, after which LC-MS showed the head of the gasification reactions. After cooling to room temperature the mixture was cooled to 0°C. the Reaction was stopped with saturated aqueous solution of NH4Cl (3 ml), after which the mixture was diluted with CH2Cl2(20 ml), washed with 1% aqueous HCl solution (5 ml) and brine (4 ml), and dried over Na2SO4. After filtration and evaporation, the obtained residue was purified by preparative HPLC to obtain 2,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propanenitrile (177,4 mg, yield: 85%) as oil is light yellow in color.

Method 3

2,2-dimethyl-3-(3-{(S)-1-[4-(1-methyl-6-oxo-1,6-dihydro-pyridine-3-yl)-phenyl]-ethyl}-2-oxo-(S)-6-phenyl-[1,3]oxazine-6-yl)-propionitrile was obtained from (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-it is the result of applying procedures similar to those described in Method 2 of Example 71, to obtain 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)-2,2-dimethylpropanamide. (S)-6-(2-hydroxy-2-methyl-propyl)-3-{(S)-1-[4-(1-methyl-6-oxo-1,6-dihydro-pyridine-3-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazine-2-it was obtained by binding (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazine-2-one with 5-iodine-1-methyl-1H-pyridine-2-it is m through the impact of the Pd(PPh 3)4and 2 M aqueous solution of Na2CO3in a mixture of methanol and dioxane (1:3) at a temperature of 80°C. the Compound obtained in the form of a foam which was dissolved in a small amount of ethyl acetate, and then stirred over night at room temperature. The obtained solid was subjected to filtration by suction, washed with a small amount of diethylether and dried. Melting point: 143-145°C.

EXAMPLE 50

2,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propanenitrile

Method 1

The title compound was obtained from 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-6-yl)propanenitrile and 4-bromo-1-methylpyridin-2(1H)-it is the result of applying the procedure similar to that described for stage 1 of Example 6. Method LC-MS 2 tR=1,103, the mass/charge=470,4;1H NMR (CDCl3) of 1.26 (s, 3H), of 1.41 (s, 3H), 1,49 (d, 3H), of 2.09 (s, 2H), 2,24 (m, 1H), 2,53 (m, 2H), 2,88 (m, 1H), of 3.56 (s, 3H), 5,59 (m, 1H), 6,38 (d, 1H), 6,78 (s, 1H), at 6.84 (d, 2H), 7,19 (m, 2H), 7,31 (m, 6H).

Method 2

(S)-2,2-dimethyl-3-(3-{1-[(S)-4-(1-methyl-2-oxo-1,2-dihydro-pyridine-4-yl)-phenyl]-ethyl}-2-oxo-6-phenyl-[1,3]oxazine-6-yl)-propionitrile was obtained from (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxa is Inan-2-it is the result of applying the procedures, similar to those described Method 2 of Example 71 for subsequent preparation of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)-2,2-dimethylpropanamide. The original connection, (5)-6-(2-hydroxy-2-methylpropyl)-3-{(S)-1-[4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazine-2-it was obtained by binding (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(5)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazine-2-it, trifter-methanesulfonic acid 1-methyl-2-oxo-1,2-dihydropyridines-4-yl ester under standard conditions; Pd(dppf)Cl2*CH2Cl2a 2 M aqueous solution of Na2CO3, DMF, 90°C, 2 h Compound obtained resin was dissolved in a small amount of EtOAc and stirred at room temperature overnight. The solid was subjected to filtration by suction, washed with a small amount of diethylether and dried. Melting point 195-198°C.

EXAMPLE 51

2,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)propanamide

The title compound was obtained from 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-6-yl)propanenitrile and 4-bromo-1-methylpyridin-2(1H)-it is the result of applying the procedure similar to that described for stage 1 When the EPA 6, with subsequent treatment of the H2O2, K2CO3. Method LC-MS 2 tR=1,133 min, the mass/charge=488,1;1H NMR (CDCl3) of 1.12 (s, 3H), 1,19 (s, 3H), 1,49 (d, 3H), 2,09-of 2.28 (m, 3H), 2,32-of 2.58 (m, 2H), 2,89 (m, 1H) and 3.59 (s, 3H), 5,61 (m, 1H), 6,54 (m, 1H), to 6.88 (m, 1H), 6,97-7,10 (m, 2H), 7,28 (m, 6H), 7,42 (m, 1H), 7,53 (m, 1H).

EXAMPLE 52

(S)-3-((S)-1-(4-(1-ethyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)propyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-he

The title compound was obtained from (R)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-phenyl-1,3-oxazine-2-it is the result of applying procedures similar to those described in Method 2 of Example 32, using 5-bromo-1-ethylpyridine-2(1H)-she is in the 4th stage. Method LC-MS 2 tR=1,732 min, the mass/charge=475,1;1H NMR (CDCl3) of 0.95 (s, 3H), of 1.01 (t, 3H), 1.26 in (s, 3H), of 1.38 (t, 3H), of 2.06 (m, 2H), 2,18-2,31 (m, 3H), of 2.36 (m, 1H), to 2.55 (m, 1H), 3.04 from (m, 1H), 4,11 (m, 2H), lower than the 5.37 (m, 1H), 6,66 (d, 1H), 7,11 (m, 2H), 7,20-7,33 (m, 7H), 7,76 (d, 1H), 7,88 (s, 1H).

EXAMPLE 53

(S)-3-((S)-1-(4-(1-ethyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-he

The title compound was obtained from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it and 5-bromo-1-ethylpyridine-2(1H)-it is the result of applying the procedure similar to that described for stage 1 of Example 6. Method LC-MS 2 tR=1,224 min, the mass/charge=475,1;1N I Is R (CDCl 3) a 1.11 (s, 3H), 1,19 (s, 3H), of 1.39 (t, 3H), and 1.56 (d, 3H), 2,20 (s, 2H), and 2.26 (m, 1H), 2,36-to 2.57 (m, 2H), 2,87 (m, 1H), a 4.03 (m, 2H), 5,69 (m, 1H), 6,62 (d, 1H), 7,00 (d, 2H), 7,17 (d, 2H), 7,28-7,51 (m, 6H), to 7.50 (d, 1H). As a result of recrystallization of isopropylacetate using procedures similar to that described in Example 37, recrystallization Method, was obtained crystalline solid with a melting point 167-168°C.

EXAMPLE 54

(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)propyl)-6-phenyl-1,3-oxazine-2-he

The title compound was obtained from (R)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-phenyl-1,3-oxazine-2-it is the result of applying procedures similar to those described in Method 2 of Example 32, using 5-bromo-1-methylpyridin-2(1H)-she is in the 4th stage. Method LC-MS 2 tR=1,746 min, the mass/charge=475,2;1H NMR (CD3OD) was 1.04 (t, 3H), 1,11 (s, 3H), 1,24 (s, 3H), 1,95-2,04 (m, 2H), 2,13-of 2.26 (m, 4H), 2,44 (m, 1H), 2.91 in (m, 1H), 3,61 (s, 3H), are 5.36 (m, 1H), to 6.67 (d, 1H), 7,10-7,33 (m, 8H), 7,42 (s, 1H), 7,55 (d, 1H).

EXAMPLE 55

(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)propyl)-6-phenyl-1,3-oxazine-2-he

The title compound was obtained from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazine-2-she and 4-bromo-1-methylpyridin-2(1H)-it is the result of applying the procedure analogion the th described for step 2 of Example 59. Method LC-MS 2 tR=1,203 min, the mass/charge=971,4;1H NMR (CDCl3) to 0.97 (t, 3H), of 1.12 (s, 3H), 1,19 (s, 3H), 1,79-2,02 (m, 2H), 2,11-of 2.24 (m, 4H), 2,29-to 2.42 (m, 1H), 2,81 (m, 1H), 3,50 (s, 3H), of 5.40 (m, 1H), 6,28 (d, 1H), only 6.64 (s, 1H), 7,02 (d, 2H), 7,18 (m, 3H), 7,20 (m, 2H), 7,28 (m, 3H).

EXAMPLE 56

(R)-6-ethyl-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)propyl)-6-phenyl-1,3-oxazine-2-he

The title compound was obtained from (R)-3-((S)-1-(4-bromophenyl)propyl)-6-ethyl-6-phenyl-1,3-oxazine-2-it is the result of applying procedures similar to those described for 3 and 4 stages of the Method 2 of Example 32. Method LC-MS 1 tR=1.6 minutes, the mass/charge=431 (M+1).

(R)-3-((S)-1-(4-bromophenyl)propyl)-6-ethyl-6-phenyl-1,3-oxazine-2-it was obtained from 1-chloro-3-phenylpentane-3-ol and (S)-1-(4-bromophenyl)propan-1-amine in the application of procedures analogous to those described for step 2 of Example 71.

1-chloro-3-phenylpentane-3-ol was obtained from 3-chloro-1-phenylpropane-1-she and etermine bromide in the application of procedures analogous to those described for phase 2 Method 1 method of obtaining 1.

EXAMPLE 57

(R)-6-ethyl-3-((S)-1-(4-(1-ethyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)propyl)-6-phenyl-1,3-oxazine-2-he

The title compound was obtained from (R)-3-((S)-1-(4-bromophenyl)propyl)-6-ethyl-6-phenyl-1,3-oxazine-2-it is the result of applying procedures similar to those described for 3 and 4 stages of the Method 2 of Example 32, using a-bromo-1-ethylpyridine-2(1H)-she is in the 4th stage. Method LC-MS 1 tR=1,68 min, the mass/charge=445 (M+1).

EXAMPLE 58

(R)-6-ethyl-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)propyl)-6-phenyl-1,3-oxazine-2-he

The title compound was obtained from (R)-3-((S)-1-(4-bromophenyl)propyl)-6-ethyl-6-phenyl-1,3-oxazine-2-it is the result of applying procedures similar to those described for 3 and 4 stages of the Method 2 of Example 32 using 4-iodine-1-methylpyridin-2(1H)-she is in the 4th stage. Method LC-MS 1 tR=1,58 min, the mass/charge=431 (M+1);1H NMR (CDCl3) 7,33 (1H, d, J=7.03 is Hz), 7,29-7,21 (7H, m), 7,01 (2H, d, J=8,20 Hz), to 6.75 (1H, d, J=2,05), TO 6.39 (1H, dd, J=2,05, 7,03), OF 5.48 (1H, ar, dd, J=6,44, 9,66), to 3.58 (3H, s), 2.95 and-2,87 (1H, m), 2,37 with 2.14 (3H, m), 2.06 to is 1.81 (m, 4H), and 1.00 (3H, t, J=7,32), 082 (3H, t, J=to 7.61).

EXAMPLE 59

(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-isopropyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-he

Stage 1

To a solution of 5-bromopyridin-2-ol (1 g, of 5.75 mmol) in DMF (10 ml) were added 2-jumprope (4.9 g, 28,75 mmol) and K2CO3(4 g, 28,75 mmol). The mixture is stirred at room temperature overnight, then was diluted (20 ml) and subjected to extraction using EtOAc (3×25 ml). The combined organic phase was washed with brine, dried over Na2SO4evaporated and purified by preparative TLC to obtain 5-bromo-1-isopropylpyridine-2(1H)-she (380 mg, 31%).1H the Mr (CDCl 3): of 1.35 (d, 6N), 5,65-of 5.75 (m, 1H), 6.48 in (d, 1H), 7,30 (m, 1H), 7,41 (d, 1H).

Stage 2

To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it (100 mg, 0.21 mmol) in 1,4-dioxane (2 ml) was added 5-bromo-1-isopropylpyridine-2(1H)-he (54,2 mg, 0.25 mmol). Then to the mixture were added the catalyst, Pd(PPh3)2Cl2(14 mg, 0.02 mmol) and Cs2CO3(1 ml, 2 M). The vessel was sealed with pressure cap and placed in a microwave resonator. Was applied microwave irradiation power of 100 W with increasing temperature from room temperature to 120°C. After reaching this temperature, the reaction mixture was maintained at this temperature for 30 minutes After cooling the mixture to room temperature was carried out its filtering. The obtained filtrate was subjected to extraction using EtOAc (20 ml × 4), the organic layer was washed with brine, dried over Na2SO4and evaporated to obtain the crude product, which was then purified by preparative HPLC to obtain (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-isopropyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-it (22 mg, 21%).1H NMR (CDCl3): of 1.13 (s, 3H), 1,19 (s, 3H), 1,40 (6N), of 1.53 (d, 3H), 2,18-of 2.30 (m, 4H), 2.40 a (m, 1H), 2,88 (m, 1H), 5,31 (m, 1H), 5,70 (m, 1H), 6.73 x (d, 1H), 7,02 (d, 2H), 7,15 (d, 2H), 7,27-7,38 (m, 5H), the 7.43 (d, 1H), 7,50 (d, 1H).

EXAMPLE 60

(R)-6-e of the Il-3-((S)-1-(4-(1-isopropyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)propyl)-6-phenyl-1,3-oxazine-2-he

The title compound was obtained from (R)-3-((S)-1-(4-bromcresol)propyl)-6-ethyl-6-phenyl-1,3-oxazine-2-it is the result of applying procedures similar to those described for 3 and 4 stages of the Method 2 of Example 32, using 5-bromo-1-isopropylpyridine-2(1H)-she is in the 4th stage. Method LC-MS 1 tR=1,75 min, the mass/charge=459 (M+1);1H NMR (CDCl3) 7,49, (1H, dd, J=2,34, 9,37 Hz), 7,42 (1H, d, J=2,34 Hz), 7,32-of 7.24 (5H, m), 7,13 (1H, d, J=8,20),? 7.04 baby mortality (1H, d, J=8,49), of 6.66 (1H, d, J=9,37), 5,49 (1H, aq, q, J=6,44, 9,37), 5,33 (1H, m), 2,96-only 2.91 (1H, m), 2,39 of-2.32 (1H, m), 2,29-2,17 (2H, m), 2.05 is-of 1.85 (m, 4H), of 1.41 (6H, dd, J=1,17, 6.73 x), of 1.01 (3H, t, J=to 7.32 Hz), 0,832 (3H, t, J=7,32 Hz).

5-bromo-1-isopropylpyridine-2(1H)-it was obtained from 5-bromopyridin-2(1H)-she and isopropylated the application procedure analogous to that described for stage 1 of Example 59.

EXAMPLE 61

(S)-3-((S)-1-(4-(1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-he

The title compound was obtained by procedures similar to those described in Example 59 using 1-5-bromo-3-methylpyridin-2(1H)-she and methyliodide during the 1st phase. Method LC-MS 2 tR=1,197 min, the mass/charge=475,1;1H NMR (CDCl3) was 1.04 (s, 3H), 1,11 (s, 3H), of 1.46 (d, 3H), 2,18 (m, 5H), of 2.21 (m, 1H), 2,29-to 2.40 (m, 1H), 2,80 (m, 1H), 3,41 (s, 3H), of 3.56 (s, 3H), ceiling of 5.60 (m, 1H), 6,91 (d, 2H), 7,07 (d, 2H), 7,21-7,40 (m, 7H).

EXAMPLE 62

(S)-3-((S)-1-(4-(1-ethyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)this is)-6-(4-forfinal)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazine-2-he

The title compound was obtained by procedures similar to those described in Example 59 using 5-bromopyridin-2(1H)-she and ethyliodide during stage 1, and (S)-6-(4-forfinal)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it is during phase 2. Method LC-MS 2 tR=1,205 min, the mass/charge=493,2;1H NMR (CDCl3) to 1.16 (d, 6N), of 1.39 (t, 3H), of 1.52 (d, 3H), 2,19 (s, 4H), 2,20-2,31 (m, 2H), 2,38-of 2.50 (m, 1H), 2,90 (m, 1H), Android 4.04 (m, 2H), 5,69 (m, 1H), 6,66 (d, 1H), 7,00 (m, 4H), 7,18 (d, 2H), 7,30 (m, 2H), 7,41 (s, 1H), 7,51 (d, 1H). As a result of recrystallization of isopropylacetate using procedures similar to that described in Example 37, recrystallization Method, was obtained crystalline solid with temperature 172-173,6°C.

EXAMPLE 63

(R)-6-methyl-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)propyl)-6-phenyl-1,3-oxazine-2-he

The title compound was obtained from (R)-3-((S)-1-(4-bromophenyl)propyl)-6-methyl-6-phenyl-1,3-oxazine-2-it is the result of applying procedures similar to those described for 3 and 4 stages of the Method 2 of Example 32 using 4-iodine-1-methylpyridin-2(1H)-she is in the 4th stage. Method LC-MS 1 tR=1,55 min, the mass/charge=417 (M+1);1H NMR (CDCl3) 7,41 (1H, d, J=7.03 is Hz), 7,33 (2H, d, J=8,20 Hz), 7,29-7,19 (5H, m), 7,10 (1H, d, J=8,20), to 6.95 (1H, d=1,76), 6,55 (1H, dd, J=2, 7,03 Hz), the 5.51 (1H, q, J=of 6.49, to 9.66 Hz), the 3.65 (3H, ), 3,00-2,95 (1H, m), 2,44-of 2.36 (1H, m), 2,33-of 2.15 (2H, m), 2.06 to to 1.86 (2H, m), of 1.64 (3H, s), of 1.02 (3H, t, J=7,32 Hz).

(R)-3-((S)-1-(4-bromophenyl)propyl)-6-methyl-6-phenyl-1,3-oxazine-2-it was obtained from 4-chloro-2-phenylbutane-2-ol and (S)-1-(4-bromophenyl)propan-1-amine in the application of procedures analogous to those described for step 2 of Example 71.

4-chloro-2-phenylbutane-2-ol was obtained from 3-chloro-1-phenylpropane-1-she Metalmania bromide in the application of procedures analogous to those described for phase 2 Method 1 method of obtaining 1.

EXAMPLE 64

(S)-3-((S)-1-(4-(1,6-dimethyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-he

The title compound was obtained from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazine-2-she and 4-bromo-1,6-dimethylpyridin-2(1H)-it is the result of applying the procedure similar to that described for stage 1 of Example 6. Method LC-MS 2 tR=1,173 min, the mass/charge=475,2;1H NMR (CDCl3) of 1.10 (s, 3H),1,16 (s, 3H) and 1.51 (d, 3H), 2,18 (m, 3H), of 2.21 (m, 1H), 2,42 (m, 4H), of 2.86 (m, 1H), 3,54 (s, 3H), to 5.66 (m, 1H), 6,21 (s, 1H), 6,60 (s, 1H), 6,97 (m, 2H), 7.23 percent-7,34 (m, 7H).

4-bromo-1,6-dimethylpyridin-2(1H)-it was obtained by methylation of 4-bromo-6-methylpyridin-2(1H)-she methyliodide using the K2CO3the application procedure analogous to that described for stage 1 of Example 59.

EXAMPLE 65

(S)-3-((S)-1-(4-1-ethyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-he

The title compound was obtained from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazine-2-it 1-ethyl-4-yodellin-2(1H)-it is the result of applying the procedure similar to that described for stage 1 of Example 6. Method LC-MS 2 tR=1,228 min, the mass/charge=971,4;1H NMR (CDCl3) of 1.10 (s, 3H), 1.14 in (s, 3H), of 1.36 (m, 3H), of 1.53 (d, 3H), 2,17 (s, 2H), 2,21 of-2.32 (m, 2H), 2,32-2,48 (m, 1H), 2,88 (m, 1H), 4.00 points (m, 2H), of 5.68 (m, 1H), to 6.39 (d, 1H), 6,78 (s, 1H), 6,99 (d, 2H), 7,27-7,38 (m, 8H).

1-ethyl-4-yodellin-2(1H)-it was obtained from 4-yodellin-2(1H)-she and ethyliodide the application procedure analogous to that described for stage 1 of Example 59.

EXAMPLE 66

(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-oxo-1-(2,2,2-triptorelin)-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-he

The title compound was obtained from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazine-2-it 4-iodine-1-(2,2,2-triptorelin)pyridine-2(1H)-it is the result of applying the procedure similar to that described for stage 1 of Example 6. Method LC-MS 2 tR=1,871 min, the mass/charge=471,1;1H NMR (CDCl3) a 1.11 (s, 3H), of 1.17 (s, 3H), of 1.53 (d, 3H), 2,16 is 2.33 (m, 4H), 2,35-2,47 (m, 1H), 2,89 (m, 1H), 4,58-4,70 (m, 2H), 5,69 (m, 1H), of 6.71 (s, 1H), 7,00 (d, 2H), 7,19-7,38 (m, 8H). As a result of recrystallization of isopropylacetate using the% is ur similar to that described in Example 37, recrystallization Method, was obtained crystalline solid with a melting point of 144-145,5°C.

4-iodine-1-(2,2,2-triptorelin)pyridine-2(1H)-it was obtained from 4-yodellin-2(1H)-she and 2,2,2-triptorelin triftoratsetata the application procedure analogous to that described for stage 1 of Example 59.

EXAMPLE 67

(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(6-oxo-1-(2,2,2-triptorelin)-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-he

The title compound was obtained from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazine-2-it and 5-bromo-1-(2,2,2-triptorelin)pyridine-2(1H)-it is the result of applying the procedure similar to that described for stage 1 of Example 6. Method LC-MS 2 tR=1,323 min, the mass/charge=471,1;1H NMR (CDCl3) of 1.13 (s, 3H), 1,19 (s, 3H), of 1.53 (d, 3H), 2,19-of 2.30 (m, 4H), 2.40 a (m, 1H), 2,89 (m, 1H), 4,67 (m, 2H), 5,69 (m, 1H), 6,70 (d, 1H), 7,03 (d, 2H), 7,13 (d, 2H), 7,29-7,38 (m, 6H), at 7.55 (d, 1H).

5-bromo-1-(2,2,2-triptorelin)pyridine-2(1H)-it was obtained from 5-bromopyridin-2(1H)-she and 2,2,2-triptorelin triftoratsetata the application procedure analogous to that described for stage 1 of Example 59.

EXAMPLE 68

(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-isopropyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-he

The title compound was obtained from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazine-2-it 4-iodine-1-isopropylpyridine-2(1H)-it is the result of applying the procedure similar to that described for stage 1 of Example 6. Method LC-MS 2 tR=1,846 min, the mass/charge=489,2;1H NMR (CDCl3) of 1.10 (s, 3H), 1,24 (s, 3H), of 1.39 (d, 6H), of 1.52 (d, 3H), 2,17-2,31 (m, 4H), 2,35 is 2.46 (m, 1H), 2,88 (m, 1H), 5,27 (m, 1H), 5,69 (m, 1H), of 6.49 (d, 1H), to 6.88 (s, 1H), 7,00 (d, 2H), 7,29-7,38 (m, 7H), 7,40 (d,1H). As a result of recrystallization of isopropylacetate using procedures similar to that described in Example 37, recrystallization Method, was obtained crystalline solid with a melting point 134-139°C.

4-iodine-1-isopropylpyridine-2(1H)-it was obtained from 4-yodellin-2(1H)-she and isopropylated the application procedure analogous to that described for stage 1 of Example 59.

EXAMPLE 69

3-((R)-6-(4-forfinal)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-2-oxo-1,3-oxazine-6-yl)-2,2-dimethylpropanoyl

The title compound was obtained from 3-((R)-6-(4-forfinal)-2-oxo-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-6-yl)-2,2-dimethylpropanamide and 5-bromo-1-methylpyridin-2(1H)-it is the result of applying procedures similar to those described for step 2 of Example 3. Method LC-MS 1 tR=1,45 min,the mass/charge=488; 1H NMR (CDCl3) to 7.68 (dd, 1H), 7,52 (d, 1H), 7,32 (q, 2H), 7,17 (d, 2H), 7,06 (t, 2H), 6,97 (d, 2H), 6,91 (d, 1H), to 5.66 (q, 1H), and 3.72 (s, 3H), 2,99 (dt, 1H), 2,48 (dd, 2H), and 2.27 (m, 1H), 2,11 (s, 2H), of 1.55 (d, 3H), the 1.44 (s, 3H), of 1.34 (s, 3H).

EXAMPLE 70

(S)-3-((S)-1-(4-(1-ethyl-5-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-he

The title compound was obtained from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it and 5-bromo-1-ethyl-3-methylpyridin-2(1H)-it is the result of applying the procedure similar to that described for stage 1 of Example 6. Method LC-MS 2 tR=1.314 GC min, the mass/charge=489;1H NMR (CDCl3) of 1.09 (s, 3H) and 1.15 (s, 3H), of 1.35 (t, 3H), of 1.50 (d, 3H), 2,15 was 2.25 (m, 7H), to 2.35 (m, 1H), 2,86 (m, 1H), a 4.03 (m, 2H), to 5.66 (q, 1H), of 6.96 (d, 2H), 7,13 (d, 2H), 7,25 was 7.36 (m, 7H).

5-bromo-1-ethyl-3-methylpyridin-2(1H)-it was obtained by alkylation of 5-bromo-3-methylpyridin-2(1H)-she ethyliodide using procedures similar to those described for stage 1 of Example 59,

EXAMPLE 71

2,2-dimethyl-3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-6-yl)propanenitrile

Method 1

Stage 1

In a flask with a capacity of 250 ml were placed anhydrous CeCl3(7,1890 g, 29.2 mmol) and tetrahydrofuran (55 ml). The mixture was thoroughly stirred for 2 h at room temperature, then the resulting suspension was cooled what about -78°C, then it was added a solution of 2-methylaniline chloride (0.5 M in tetrahydrofuran, 56 ml of 28.0 mmol). After stirring for 2 h at -78°C in a mixture via cannula was added a solution of 3-chloropropiophenone (3,350 grams of 19.8 mmol) in tetrahydrofuran (30 ml). The reaction mixture was defended during the night for slow heating up to 8°C and simultaneously mixed (18 h). The reaction was stopped with the help of a saturated aqueous solution of NaHCO3, after which the mixture was subjected to extraction using EtOAc and dried over Na2SO4. After evaporation of the solvents the crude 1-chloro-5-methyl-3-phenylhexa-5-EN-3-ol was used in the next step without additional purification. Method LC-MS 1 tR=1,91 min, the mass/charge 248, 207 (M-HE)+;1H NMR (400 MHz, CDCl3) 7,39-7,22 (m, 5H), to 4.92 (m, 1H), 4,77 (m, 1H), 3,60-of 3.53 (m, 1H), 3,17-3,10 (m, 1H), to 2.67 (d, J=13,2 Hz, 1H), 2,55 (d, J=13,2 Hz, 1H), 2,41 was 2.25 (m, 2H), 1,29 (s, 3H);13With NMR (100 MHz, CDCl3) 144,55, 141,72, 128,32, 126,88, 125,07, 116,50, 74,44, 51,46, 46,34, 40,19, 24,22.

Stage 2

1-chloro-5-methyl-3-phenylhexa-5-EN-3-ol (1.28 g, 5.7 mmol), (S)-1-(4-bromophenyl)ethanamine (1,37 g, 1.2 equiv.), KI (995 mg, 1.05 equiv.) and K2CO3(1,57 g, 2 equiv.) was mixed with acetonitrile (15 ml) and was heated to reverse the condensation of (oil bath at 96°C) during the night. After cooling to room temperature the mixture was subjected to filtration, evaporation and PTS is the site by chromatography using a column, containing 40 g of silica gel and elyuirovaniya using 0~8% Meon in CH2Cl2to obtain 1-((S)-1-(4-bromophenyl)ethylamino)-5-methyl-3-phenylhexa-5-EN-3-ol (1,33 g, 60%).

Stage 3

In a solution of 1-((S)-1-(4-bromophenyl)ethylamino)-5-methyl-3-phenylhexa-5-EN-3-ol (1,33 g of 3.43 mmol) in CH2Cl2(100 ml) were added pyridine (277 μl, 1 equiv.) and triethylamine (717 μl, 1.5 equiv.). The mixture was cooled to a temperature of 0°C, after which it was slowly added methylchloroform (397 μl, 1.5 equiv.). After 15 min the mixture was slowly warmed to room temperature and stirred for 3 h Then the mixture was diluted with ether (200 ml), washed with 5% aqueous HCl solution (2×25 ml), saturated aqueous NaHCO3(25 ml) and brine (20 ml) and dried over Na2SO4. After filtration and evaporation the crude methyl (S)-1-(4-bromophenyl)ethyl(3-hydroxy-5-methyl-3-phenylhexa-5-enyl)carbamate was used in the following steps without further purification.

Stage 4

The crude methyl (S)-1-(4-bromophenyl)ethyl(3-hydroxy-5-methyl-3-phenylhexa-5-enyl)carbamate obtained by the procedure described above, was dissolved in dry tetrahydrofuran (75 ml), after which the mixture slowly at room temperature was added NaH (60% in mineral oil, 274 mg, 2 equiv.). After 10 min the mixture was heated for reverse condensation within 2 h of Th is conducting LC-MS, the results of which testified to the completion of the reaction, the mixture was cooled to 0°C. the Reaction was stopped with the help of a saturated aqueous solution of NH4Cl (10 ml), after which the mixture was diluted with ether (100 ml), washed with 1% aqueous HCl solution (25 ml) and brine (15 ml), and dried over Na2SO4. After filtration and evaporation the crude product was purified by chromatography using a column containing 40 g of silica gel and elyuirovaniya using 10~35% solution of EtOAc in hexano. A substance which was received by the second active peak UV, were collected to obtain (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazine-2-it (490 mg, total yield for 3 and 4 stages: 34,5%).

Step 5

A mixture of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazine-2-it (490 mg, 1.18 mmol), TsCN (257 mg, 1.2 equiv.), PhSiH3(157 μl, of 1.07 equiv.), catalyst cobalt N,N'-bis(3,5-di-tert-butylchloride)-1,1,2,2-tetramethylethylenediamine received in accordance with the procedures described in the Method of obtaining 3 (7.5 mg, 0.01 equiv.), and ethanol (20 ml) was stirred for 4 h at room temperature. After conducting LC-MS, the results of which indicated the completion of reaction, the mixture was evaporated and purified using the system for flash chromatography ISCO (column capacity 40 g, 25~80% solution of EtOAc in hexano) d is I obtain 267 mg of product (yield: 51%). Method LC-MS 1 tR=1,89 min, the mass/charge 441/443 (M+1).

Stage 6

To a solution of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)-2,2-dimethylpropanamide (208 mg, 0.47 mmol) in 1,4-dioxane (5 ml) were added 6-oxo-1,6-dihydropyridines-3-iverna acid (98 mg, 1.5 equiv.), 2.0 M aqueous solution Cs2CO3(500 μl) and Pd(dppf)Cl2(20 mg, 0.06 to equiv.). The resulting mixture was subjected to three degassing and re-saturation of the gaseous N2, then was heated to 90°C (oil bath) for 3 hours After carrying out LC-MS, the results of which indicated the completion of reaction, the mixture was cooled to room temperature, diluted with EtOAc (25 ml) and washed with water (10 ml). The aqueous layer was subjected to extraction using EtOAc (2×10 ml). The combined organic layer was washed with water (10 ml) and brine (8 ml), and dried over Na2SO4. Obtained after filtration and evaporation the residue was purified by chromatography (cartridge containing 12 g silica gel, 0~10% solution Meon in CH2Cl2the main UV peak) to obtain 2,2-dimethyl-3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-6-yl)propanenitrile (202 mg, 94%) as a brown oil. Method LC-MS 1 tR=1,34 min, the mass/charge=456 (M+1);1H NMR (CDCl3) 8,01 (d, 1H), 7,80 (S, 1H), was 7.36 (dt, 6H), 7,19 (d, 2H), 6,98 (m, 3H), 5,65 (d, 1H), 2,98 (d, 1H), 2,50 (, 2H), 2,32 (m, 1H), 2,17 (s, 2H), 1.57 in (d, 3H), of 1.40 (s, 3H), 1,32 (s, 3H).

Method 2

Step 1. 3-[(S)-1-(4-Bromo-phenyl)-ethyl]-(S)-6-(2-methyl-allyl)-6-phenyl-[1,3]oxazine-2-he

(Methoxycarbonylamino)triethylamine hydroxide (1,38 g) was added to a solution of 3-[(S)-1-(4-bromo-phenyl)-ethyl]-(5)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazine-2-she (2.0 g) in tetrahydrofuran (30 ml) and toluene (15 ml). The resulting solution was stirred at room temperature for 0.5 h and at a temperature of 75°C for 1 h, After cooling at room temperature the solution was evaporated, after to the precipitate was added ethyl acetate. The resulting mixture was washed with aqueous solution of NaHCO3and brine and then dried (MgSO4). The title compound was obtained after removal of the solvent. Yield: 1.9 g (quantitative). Mass spectrum (electrospray ionization+): the mass/charge=414/416 (Br) [M+H]+

Step 2. 3-{3-[(S)-1-(4-bromo-phenyl)-ethyl]-2-oxo-(S)-6-phenyl-[1,3]oxazine-6-yl}-2,2-dimethyl-propionitrile

3-[(S)-1-(4-bromo-phenyl)-ethyl]-(S)-6-(2-methyl-allyl)-6-phenyl-[1,3]oxazine-2-he (0.21 g), p-toluensulfonyl cyanide (143 mg), tert-BuOOH (5.5 M solution in decane, 27 μl) and phenylsilane (64 μl) were added in this order into a flask equipped with a magnetic stir bar and containing (1R,2R)-(-)-1,2-cyclohexanediamine-N,N'-bis(3,5-di-tert-butylchloride)cobalt(II) (3 mg) and e is any (15 ml) in an argon atmosphere. The resulting solution was stirred at room temperature for 3 h and evaporated in vacuum. The obtained residue was purified by chromatography using silica gel (a mixture of cyclohexane/ethyl acetate 60:40->0:100) to obtain the title compound in the form of retinoid solids. Yield: 0.16 g (70% of theoretical value). Mass spectrum (electrospray ionization+): the mass/charge=441/443 (Br) [M+H]+

EXAMPLE 72

(S)-3-((S)-1-(4-(1-ethyl-6-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-he

The title compound was obtained from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-she and 4-bromo-1-ethyl-6-methylpyridin-2(1H)-it is the result of applying procedures similar to those described for stage 1 of Example 6. Method LC-MS 2 tR=1,211 min, the mass/charge=489,2;1H NMR (CDCl3) of 1.10 (s, 3H), of 1.17 (s, 3H), 1,49 (s, 9H), 1.57 in (d, 3H), 2,22 (m, 4H), is 2.37 (m, 1H), 2,84 (m, 1H), ceiling of 5.60 (m, 1H), 5,91 (s, 1H), 7,06 (d, 2H), 7,27-7,40 (m, 5H), to 7.68 (d, 1H), 7,24 (d, 2H), of 8.09 (d, 1H), of 8.90 (s, 1H).

4-bromo-1-ethyl-6-methylpyridin-2(1H)-it was obtained by alkylation of 4-bromo-6-methylpyridin-2(1H)-it is with ethyliodide using the2CO3in accordance with the procedure similar to that described for stage 1 of Example 59.

EXAMPLE 73

(S)-6-(2-hydroxy-2-methylprop the l)-6-phenyl-3-((S)-1-(4-(1,5,6-trimethyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-1,3-oxazine-2-he

The title compound was obtained from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-she and 4-bromo-1,5,6-trimethylpyridine-2(1H)-it is the result of applying procedures similar to those described for stage 1 of Example 6. Method LC-MS 2 tR=to 1.187 min, the mass/charge=489,2;1H NMR (CDCl3) of 1.10 (s, 3H) and 1.15 (s, 3H), 1,32 (m, 3H),1,52 (m, 3H), 1,72 (s, 1H), 2,18 (m, 3H), 2,19 (m, 1H), 2,42 (m, 4H), of 2.86 (m, 1H), 4,12 (m, 2H), to 5.66 (m, 1H), 6,16 (s, 1H), 6,53 (s, 1H), 6,98 (m, 2H), of 7.23-7,34 (m, 7H).

4-bromo-1,5,6-trimethylpyridine-2(1H)-it was obtained by alkylation of 4-bromo-5,6-dimethylpyridin-2(1H)-it is with methyliodide with the use of K2CO3in accordance with the procedure similar to that described for stage 1 of Example 59. 4-bromo-5,6-dimethylpyridin-2(1H)-it was obtained by applying the procedure described in the publication McElroy, W. T. and DeShong, P. Org. Lett. 2003, 5, 4779.

EXAMPLE 74

3-((R)-3-((S)-1-(4-(1-isopropyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)-2,2-dimethylpropanoyl

2,2-dimethyl-3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-6-yl)propanenitrile (6 mg, of 0.013 mmol) was dissolved in DMF (2.5 ml). In the resulting solution were added Cs2CO3(approx. 15 mg, excess) and i-PrI (100 μl, excess). The mixture was mixed for 3 h at room Tempe is the atur. After conducting LC-MS, the results of which indicated the completion of reaction, the mixture was purified by preparative HPLC to obtain 3-((R)-3-((S)-1-(4-(1-isopropyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazine-6-yl)-2,2-dimethylpropanamide (1,99 mg, 30%). Method LC-MS 1 tR=2,03 min, the mass/charge=498;1H NMR (CDCl3) 8,35 (d, 1H), 7,80 (dd, 1H), 7,37 (m, 5H), 7,22 (d, 2H), 6,92 (d, 2H), 6,83 (d, 1H), to 5.66 (q, 1H), 5,22 (m, 1H), 2,93 (m, 1H), 2,16 (s, 2H), of 1.55 (d, 3H), of 1.46 (s, 3H), of 1.40 (d, 6H), of 1.33 (s, 3H),

EXAMPLE 75

3-{(S)-1-[4-(1-Cyclopropyl-2-oxo-1,2-dihydro-pyridine-4-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazine-2-he

Method 1

2 M aqueous solution of Na2CO3(0,23 ml) was added to a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazine-2-she (0.11 g) and triftormetilfullerenov acid 1-cyclopropyl-2-oxo-1,2-dihydro-pyridine-4-yl ester (74 mg; an alternative option is to use 4-bromo-1-cyclopropyl-1H-pyridine-2-it) in dimethylformamide (3 ml). In the mixture for 15 min was sprayed argon, after which was added to the complex [1,1'-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) dichloromethane (10 mg). The mixture was heated to 100°C and stirred at the same temperature throughout the night. After cooling to ambient temperature the mixture was add the Jena water, after which the mixture was subjected to extraction with ethyl acetate. The combined organic extract was washed with brine, dried (MgSO4) and evaporated. The obtained residue was purified by chromatography using silica gel (CH2Cl2/MeOH 99:1 to>90:10) to obtain the title compound, such foamy solid, which was subjected to crystallization using a small amount of ethyl acetate. Yield: 30 mg (27% of theoretical value); Mass spectrum (electrospray ionization+): the mass/charge=487 [M+H]+. The compound (1.3 g) was subjected to crystallization from 30 ml of isopropylacetate. The hot solution were simultaneously mixed and slowly cooled to room temperature overnight in an oil bath to obtain a crystalline monohydrate. Melting point 108-110°C.

Crystalline monohydrate also was obtained by recrystallization 10.6 g of the compound from Example 75 of 170 ml of isopropylacetate, which was sturiale with water. The hot solution were simultaneously mixed and slowly cooled to room temperature, stirred for 2 hours at room temperature and for 1 hour in an ice bath. The solid was filtered by suction and dried over night at 50°C. Yield 10.2 g, tempertaure melting point of 112-114°C.

Connect the s, obtained in Example 75 (2.0 g) was also subjected to recrystallization from a mixture of 30 ml of tributylamine and 15 ml of isopropanol. The obtained solid was subjected to filtration by suction, was washed tributylammonium and dried at a temperature of 45°C and then at a temperature of 65°C over night. 100 mg of the obtained solid substance was mixed in 3 mg water for the formation of resinous substances, which then turned into a solid white color. This substance is then stirred for another hour, and was subjected to filtration by suction and drying at room temperature overnight, and then at 65°C for 3 hours in the dryer with circulating air, to obtain a crystalline monohydrate. Melting point 102-108°C.

Intermediate compound XX

1-Cyclopropyl-4-(4-methoxy-benzyloxy)-1H-pyridine-2-he

In a container suitable for microwave ovens and equipped with a magnetic stirrer and containing 4-(4-methoxy-benzyloxy)-1H-pyridine-2-it (0,60 g), cyclopropylboronic acid (0.45 g), pyridine (1.50 ml), triethylamine (1.50 ml) and toluene (4 ml) was sprayed argon for 5 minutes and Then was added Cu(OAc)2(0,94 g), after which the mixture was mixed in a microwave oven at a temperature of 140°C for 45 minutes Then it was produced is prohibited evaporation of the solvent followed by the addition of water. The resulting mixture was subjected to extraction with ethyl acetate, then the combined organic extract was washed with water and aqueous solution of NaHCO3. After drying (MgSO4) and removal of solvent the residue was purified by chromatography using silica gel (CH2Cl2/MeOH 99:1 to>95:5) to obtain the title compounds as solids. Yield: 0.17 g (25% of theoretical value); Mass spectrum (electrospray ionization+): the mass/charge=272 [M+H]+.

Intermediate compound XXI

1-Cyclopropyl-4-hydroxy-1H-pyridine-2-he

Triperoxonane acid (1 ml) was added to a flask equipped with a magnetic stir bar and containing 1-cyclopropyl-4-(4-methoxy-benzyloxy)-1H-pyridine-2-he (0.17 g), after which the flask was cooled in a bath of ice/EtOH. The resulting mixture was mixed simultaneously with cooling for 1.5 h and then at ambient temperature for 4.5 h Then the solution was subjected to evaporation in a vacuum, then the residue was powdered with tert-butylmethylether and dried to obtain the title compound in the form of a solid substance. Yield: 0.10 g (quantitative indicator). Mass spectrum (electrospray ionization+): the mass/charge=152 [M+H]+.

Intermediate compound XXII

Trifter-means honowai acid 1-cyclopropyl-2-oxo-1,2-dihydro-pyridine-4-yl ester

Triftormetilfullerenov anhydride (0,12 ml) was added to a flask equipped with a magnetic stir bar and containing 1-cyclopropyl-4-hydroxy-1H-pyridine-2-he (0.10 g), NEt3(of 0.24 ml) and dichloromethane (8 ml), after which the flask was cooled in a bath of ice/EtOH. The resulting mixture was mixed simultaneously with cooling for 2 h and then at ambient temperature for another 2 hours Then the solution was diluted with dichloromethane and washed first with water, then aqueous solution of NaHCO3and again with water. The organic solution was dried (MgSO4), the solvent was removed, and the residue was purified by chromatography using silica gel (dichloromethane/methanol 99:1 to>90:10) to obtain the title compound in the form of retinoid solids. Yield: 0.07 g (36% of theoretical value). Mass spectrum (electrospray ionization+): the mass/charge=284 [M+H]+.

Intermediate compound XXIII

4-Bromo-1-cyclopropyl-1H-pyridine-2-he

A flask equipped with a magnetic stir bar and containing 4-bromo-1 H-pyridin-2-he (1,80 g), cyclopropylboronic acid (2.00 g), Cu(SLA)2(2.00 g), 2,2'-bipyridine (1.70 g), Na2CO3(2,47 g), and 1,2-dichloroethane (75 ml) was heated to 70°C., then the mixture is mixed with the air at the same temperature during the night is. After adding another part cyclopropylboronic acid (0.50 g) and Na2CO3(0.55 g) and the mixture was mixed for 4 hours at a temperature reverse of condensation. After cooling to ambient temperature was added an aqueous solution of NH4Cl, after which the resulting mixture was subjected to extraction with dichloromethane. The combined organic extract was dried (MgSO4), was then produced by evaporation of the solvent. The obtained residue was purified by chromatography using silica gel (a mixture of cyclohexane/ethyl acetate 50:50->35:65) to obtain the title compound in the form of oil, crystallising when defending. Output: 0,82 g (37% teoreticheskoi index); Mass spectrum (electrospray ionization+): the mass/charge=214/216 (Br) [M+H]+.

Method 2

Step 1. 4-yodellin-2(1H)-he

A mixture of 2-chloro-4-iopidine (4,943 g of 20.6 mmol) and formic acid (88%, 10 ml) was stirred at 105°C for 21 hours, the Excess formic acid was removed in vacuo, the reaction mixture was stopped using 2M aqueous solution of Na2CO3after that the mixture was subjected to extraction using CH2Cl2and drying over Na2SO4. After removal of the solvent in vacuum, the obtained residue was purified by chromatogra the AI using silica gel, lirovannomu using CH2Cl2/Meon, to obtain 1,716 g (38%) 4-yodellin-2(1H)-it is in the form of a solid substance. Method LC-MS 1 tR=0,82 min, the mass/charge=222 (MH+);1H NMR (400 MHz, (CD3)2SO) 7,14 (d, J=6,5 Hz, 1H), 6.87 in (s, 1H), of 6.49 (d, J=7,0 Hz, 1H).

Step 2. (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-he

To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it (2,646 g, 5,52 mmol) in 1,4-dioxane (60 ml) were added 4-yodellin-2(1H)-he (1,200 g, 5.43 mmol), 2 M Cs2CO3(14,5 ml) and PdCl2(dppf)·CH2Cl2(0,230 g, 0.28 mmol). The mixture was subjected to degassing and heated in nitrogen atmosphere at a temperature of 120°C for 15 h the Mixture was diluted with CH2Cl2and dried over Na2SO4. After evaporation of the solvents the residue was purified by chromatography using silica gel, lirovannomu using MeOH/CH2Cl2to obtain 1,717 g (71%) of (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-it. Method LC-MS 1 tR=1,23 min, the mass/charge 389, 447 (MH+);1H NMR (400 MHz, CD3OD) 7,40 (d, J=6,7 Hz, 1H), 7,31 (d, J=8,2 Hz, 2H), 7,29-7,20 (m, 5H), of 6.96 (d, J=8,2 Hz, 2H), 6,57-of 6.52 (m, 2H), 5,49 (q, J=7,0 Hz, 1H), 2,98-of 2.93 (m, 1H), 2,47-of 2.34 (m, 2H), 2,16-of 2.09 (m, 1H), 2,07 (s, 2H), 1,45 (d, J=7,0 Hz, 3H), 1,19 (s, 3H) 0,87 (s, 3H).

Step 3. (S)-3-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-it. A mixture of (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-it (1,683 g of 3.77 mmol, 1.0 equiv.), Cu(SLA)2(0,692 g, 3,81 mmol, 1,01 equiv.), bipyridine (0,599 g, a 3.83 mmol, of 1.02 equiv.), cyclopropylboronic acid (0,681 g of 7.93 mmol, 2,10 equiv.) and Na2CO3(0,890 g of 8.40 mmol, 2,23 equiv.) in dichloroethane (40 ml) stirred in air at a temperature of 70°C for 22 h, the Reaction was stopped with the help of a saturated aqueous solution of NH4Cl, after which the mixture was diluted with CH2Cl2and dried over Na2SO4. After removal of the solvent in vacuo the residue was purified by chromatography using silica gel, lirovannomu using MeOH/CH2Cl2to obtain 1,560 g (85%) of (S)-3-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-it. LC-MS tR=1,41 min, 3 min chromatography, mass/charge 429, 487 (MN+);1H NMR (400 MHz, CD3OD) 7,52 (d, J=7,0 Hz, 1H), 7,29-to 7.18 (m, 7H), 6,92 (d, J=8,2 Hz, 2H), is 6.54 (d, J=1.8 Hz, 1H), 6,47 (dd, J=7,3, 1.8 Hz, 1H), vs. 5.47 (q, J=7,0 Hz, 1H), 3.27 to is 3.21 (m, 1H), 2.95 and-only 2.91 (m, 1H), 2,48 is 2.33 (m, 2H), 2,15-of 2.08 (m, 1H), 2,07 (s, 2H), 1,42 (d, J=7,0 Hz, 3H), of 1.20 (s, 3H), of 1.05 to 1.00 (m, 2H), 0,87 (s, 3H), 0,83-of 0.79 (m, 2H);13With NMR (100 MHz, CD3OD) 166,17, 155,63, 152,88, 44,03, 142,27, 138,90, 136,91, 129,71, 128,70, 128,58, 127,67, 126,09, 116,08, 107,10, 85,19, 71,49, 55,13, 54,62, 37,44, 33,24, 32,71, 31,86, 30,03, 15,60, 7,27. (S)-3-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-he (approx. 1.5 g) and isopropylacetate (30 ml) was heated in an oil bath at a temperature of 120°C. until a homogeneous solution. Heating was discontinued, after which the resulting solution during the night was slowly mixed for slow cooling to room temperature in an oil bath. The obtained solid was subjected to filtration and washing with isopropylacetate, and then were dried at room temperature in high vacuum to obtain a crystalline solid with a melting point 91-94°C.

EXAMPLE 76

3-{(S)-1-[4-(1-cyclopropylmethyl-6-oxo-1,6-dihydro-pyridine-3-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazine-2-he

2 M aqueous solution of Na2CO3(0,84 ml) was added to a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3 - oxazine-2-it (0.40 g) and 5-bromo-1-temporoparietal-1H-pyridine-2-it (0.24 g) in dimethylformamide (4 ml). In the resulting mixture for 10 min was sprayed argon before adding complex [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane (34 mg). A mixture of n which was grewals to 100°C and stirred at the same temperature for 4 hours After cooling to ambient temperature the mixture was added water, that was followed by extraction of the mixture with ethyl acetate. The combined organic extract was washed with brine, dried (MgSO4) and evaporated. The obtained residue was purified by chromatography using silica gel (a mixture of dichloromethane/methanol 99:1 to>95:5) to obtain the title compound which was subjected to crystallization using a small amount of ethyl acetate. Output: 0,19 g (46% of theoretical value); Mass spectrum (electrospray ionization+): the mass/charge=501 [M+H]+.

Intermediate compound XXIV

5-Bromo-1-cyclopropylmethyl-1H-pyridine-2-he

KOtBu (0.68 g) was added to a solution of 5-bromo-1H-pyridine-2-it (1,00 g) in tetrahydrofuran (20 ml) at room temperature. After stirring for 30 min the suspension were added cyclopropylamine (0,77 ml) and dimethylformamide (3 ml), the mixture was heated to 70°C. After stirring the mixture at 70°C for 2 h the reaction was complete. The mixture was cooled to room temperature, diluted with ethyl acetate (50 ml) and washed with water (2×20 ml) and brine (20 ml). Then the solution was dried (MgSO4with the subsequent removal of solvent to obtain Titus is a high connection in the form of a colorless oil. Yield: 1.18 g (90% of theoretical value). Mass spectrum (electrospray ionization+): the mass/charge=228/230 (Br) [M+H]+

EXAMPLE 77

(R)-6-Methoxymethyl-3-{(S)-1-[4-(1-methyl-6-oxo-1,6-dihydro-pyridine-3-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazine-2-he

The title compound was obtained from (R)-6-(methoxymethyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it and 5-bromo-1-methylpyridin-2(1H)-it is the result of applying the procedures similar to that described in Example 76. Mass spectrum (electrospray ionization+): the mass/charge=433 [M+H]+

EXAMPLE 78

(R)-6-methoxymethyl-3-{(S)-1-[4-(1-methyl-2-oxo-1,2-dihydro-pyridine-4-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazine-2-he

The title compound was obtained from (R)-6-(methoxymethyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it, trifter-methanesulfonic acid 1-methyl-2-oxo-1,2-dihydro-pyridine-4-yl ester resulting from the application of procedures analogous to those described in Example 76. Mass spectrum (electrospray ionization+): the mass/charge=433 [M+H]+.

EXAMPLE 79

3-{(S)-1-[4-(5-fluoro-1-methyl-2-oxo-1,2-dihydro-pyridine-4-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazine-2-he

The title compound was obtained from (S-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 - yl)phenyl)ethyl]-1,3-oxazine-2-she and 4-bromo-5-fluoro-1-methyl-1H-pyridine-2-it is the result of applying the procedures, similar to that described in Example 76. Mass spectrum (electrospray ionization+): the mass/charge=479 [M+H]+. The compound obtained was in the form of oil and crystallinewas when defending. The solid was dried in vacuum at a temperature of 80°C. melting point: 120-125°C With evolution of gas and subsequent crystallization with a melting point 183-184°C.

Intermediate compound XXV

4-Bromo-5-fluoro-1-methyl-1H-pyridine-2-he

Methyliodide (0.9 ml) at room temperature was added to a mixture of potassium carbonate (2,34 g) and 4-bromo-5-fluoro-1H-pyridine-2-it (2.50 g) in dimethylformamide (25 ml). The resulting mixture was stirred at room temperature overnight, after which it was added water. The resulting mixture was subjected to extraction with ethyl acetate, the combined extracts were washed with brine and dried (MgSO4). Then there was the evaporation of solvent to obtain the crude title compound which was subjected to recrystallization from Et2O Yield: 1.22 g (45% of theoretical value); Mass spectrum (electrospray ionization+): the mass/charge=206/208 (Br) [M+H]+.

EXAMPLE 80

(S)-6-(2-Hydroxy-2-methyl-propyl)-3-((S)-1-{4-[1-(2-hydroxy-2-methyl-propyl)-2-oxo-1,2-dihydro-pyridine-4-yl]-phenyl}-ethyl)-6-phenyl-[1,3]oxazine-2-he

The title compound was obtained from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 - yl)phenyl)ethyl]-1,3-oxazine-2-she and 4-bromo-1-(2-hydroxy-2-methyl-propyl)-1H-pyridine-2-it is the result of applying procedures similar to those described in Example 75. Mass spectrum (electrospray ionization+): the mass/charge=519 [M+H]+.

Intermediate compound XXVI

4-Bromo-1-(2-hydroxy-2-methyl-propyl)-1H-pyridine-2-he

A mixture of 4-bromo-1H-pyridine-2-she (0.25 g), 2,2-dimethyl-oxirane (0,26 ml) and potassium carbonate (0.40 g) in dimethylformamide (2.5 ml) were mixed under the influence of microwaves at a temperature of 120°C for 30 minutes After cooling to ambient temperature the mixture was evaporated and purified by HPLC with reversed phase (mixture of acetonitrile/water) to obtain the title compound. Yield: 0.34 g (96% of theoretical value); Mass spectrum (electrospray ionization+): the mass/charge=246/248 (Br) [M+H]+.

EXAMPLE 81

(S)-6-(2-Hydroxy-2-methyl-propyl)-3-((S)-1-{4-[1-(3-methoxy-2-methyl-propyl)-2-oxo-1,2-dihydro-pyridine-4-yl]-phenyl}-ethyl)-6-phenyl-[1,3]oxazine-2-he

The title compound was obtained from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazine-2-she and 4-bromo-1-(3-meth is XI-2-methyl-propyl)-1H-pyridine-2-it is the result of applying the procedures, similar to that described in method 1 of Example 75. Mass spectrum (electrospray ionization+): the mass/charge=533 [M+H]+.

Intermediate compound XXVII

3-(4-bromo-2-oxo-2H-pyridin-1-yl)-2-methyl-propionic acid methylether

A mixture of 4-bromo-1H-pyridine-2-she (0.50 g), methyl 2-bromoisobutyrate (0.45 ml) and potassium carbonate (0.68 g) in dimethylformamide (5 ml) was stirred at 60°C for 3 hours After cooling to ambient temperature the mixture was added water, then the mixture was subjected to extraction with ethyl acetate. The combined extract was washed with brine, dried (MgSO4) and evaporated. The obtained residue was purified by chromatography using silica gel (a mixture of cyclohexane/ethyl acetate 70:30 to>50:50) to obtain the title compound. Output: 0,53 g (67% of theoretical value); Mass spectrum (electrospray ionization+): the mass/charge=274/276 (Br) [M+H]+. Additionally, there was obtained 2-(4-bromo-pyridine-2-yloxy)-2-methyl-propionic acid methylether {Yield: 0.15 g; mass spectrum (electrospray ionization+): the mass/charge=274/276 (Br) [M+H]+}

Intermediate compound XXVIII

4-Bromo-1-(3-hydroxy-2-methyl-propyl)-1H-pyridine-2-he

LiAlH4(1 M solution in tetrahydrofuran, of 1.16 ml) was added to rest the p 3-(4-bromo-2-oxo-2H-pyridin-1-yl)-2-methyl-propionic acid methylether (0,53 g) in tetrahydrofuran (6 ml), cooled in an ice bath. After stirring and simultaneous cooling solution for 2 h was added one part of LiAlH4(1 M in tetrahydrofuran, to 0.29 ml). Then, after stirring and simultaneous cooling for a further 1 hour the reaction was terminated by adding water. The resulting mixture was subjected to extraction with ethyl acetate, then the combined organic extract was washed with brine and dried (MgSO4). The solvent was removed to obtain the title compound. Output: 0,37 g (78% of theoretical value); Mass spectrum (electrospray ionization+): the mass/charge=246/248 (Br) [M+H]+.

Intermediate compound XXIX

4-bromo-1-(3-methoxy-2-methyl-propyl)-1H-pyridine-2-he

NaH (60% in mineral oil, 57 mg) was added to a solution of 4-bromo-1-(3-hydroxy-2-methyl-propyl)-1H-pyridine-2-it (0,53 g) in dimethylformamide (6 ml), cooled in an ice bath. After stirring and simultaneous cooling of the solution for 0.5 h, it was added methyliodide (110 μl). After removing the cooling bath, the solution was mixed at room temperature over night. Then the solution was evaporated in vacuum, and then the obtained residue was diluted with water. The resulting mixture was subjected to extraction with ethyl acetate, then the combined organic EXT the act was washed with brine and dried (MgSO 4). The solvent was evaporated, and the obtained residue was purified by HPLC with reversed phase (mixture of acetonitrile/water) to obtain the title compound in the form of oil. Yield: 70 mg (30% of theoretical value); Mass spectrum (electrospray ionization+): the mass/charge=260/262 (Br) [M+H]+.

EXAMPLE 82

(S)-6-(2-hydroxy-2-methyl-propyl)-3-((S)-1-{4-[1-(3-hydroxy-2-methyl-propyl)-2-oxo-1,2-dihydro-pyridine-4-yl]-phenyl}-ethyl)-6-phenyl-[1,3]oxazine-2-he

The title compound was obtained from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 - yl)phenyl)ethyl]-1,3-oxazine-2-she and 4-bromo-1-(3-hydroxy-2-methyl-propyl)-1H-pyridine-2-it is the result of applying the procedure similar to that described in Example 75. Mass spectrum (electrospray ionization+): the mass/charge=519 [M+H]+.

EXAMPLE 83

(S)-6-(2-hydroxy-2-methyl-propyl)-3-(1-{4-[1-(2-methoxy-2-methyl-propyl)-2-oxo-1,2-dihydro-pyridine-4-yl]-phenyl}-ethyl)-6-phenyl-[1,3]oxazine-2-he

The title compound was obtained from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazine-2-she and 4-bromo-1-(2-methoxy-2-methyl-propyl)-1H-pyridine-2-it is in effect, similar to that described in method 1 of Example 75. Mass spectrum (ei e is chronosystem +): the mass/charge=533 [M+H]+.

The intermediate connection XXX

4-Bromo-1-(2-methoxy-2-methyl-propyl)-1H-pyridine-2-he

The title compound was obtained from 4-bromo-1-(2-hydroxy-2-methyl-propyl)-1H-pyridine-2-she and methyliodide the application procedure analogous to that described for Intermediate XXIX. Mass spectrum (electrospray ionization+): the mass/charge=260/262 (Br) [M+H]+.

EXAMPLE 84

6-(3-hydroxy-3-methylbutyl)-6-isopropyl-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-1,3-oxazine-2-he

Stage 1

In the solution (S)-1-(1-(4-bromophenyl)ethylamino)-4-methylpentan-3-one (740 mg, 2.5 mmol) in tetrahydrofuran (25 ml) was added drop by drop Allemagne bromide (25 ml, 25 mmol) in an atmosphere of N2at -78°C. the Reaction mixture was stirred at -78°C for 2 h, after which the reaction was stopped by adding a saturated aqueous solution of NH4Cl, and the mixture was subjected to extraction using EtOAc. The organic layer was washed with brine, dried over Na2SO4and was subjected to filtration. After removal of the solvent in vacuo there was obtained 1-((S)-1-(4-bromophenyl)ethylamino)-3-isopropylene-5-EN-3-ol (802 mg, yield: 95%) that was used in the next step without additional processing.

This is 2

In a solution of 1-((S)-1-(4-bromophenyl)ethylamino)-3-isopropylene-5-EN-3-ol (802 mg, 2,366 mmol) and triethylamine (139 mg, 2,366 mmol) in CH2Cl2(20 ml) at 0°C in an atmosphere of N2was added triphosgene (348 mg, 1.18 mmol), after which the resulting mixture was stirred over night. After stopping the reaction with water, the mixture was subjected to extraction with CH2Cl2The organic layer was subjected to washing, drying over Na2SO4, filtration, evaporation and purification by column chromatography to obtain 6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-1,3-oxazine-2-she (480 mg, yield: 56%).

Stage 3

To a solution of 6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-1,3-oxazine-2-she (480 mg, 1,315 mmol) in tetrahydrofuran (5 ml) at 0°C in an atmosphere of N2was added BH3tetrahydrofuran (5.3 ml, 5.3 mmol). The reaction mixture was stirred for 2 h, after which the reaction was stopped with water, 3 M aqueous NaOH solution (1 ml) and H2O2(5 ml). The resulting mixture was stirred for 2 h, and then was subjected to extraction using EtOAc, washing with salt solution, drying over Na2SO4, filtration and evaporation to obtain crude product, which was then purified by preparative TLC to obtain 3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxyp who drank)-6-isopropyl-1,3-oxazine-2-it. (110 mg, yield: 22%).1H NMR (CDCl3): δ 0.88 to (m, 6N), a 1.45 (m, MN), to 1.60 (m, 4H), 1,71 (m, 1H), equal to 1.82 (m, 1H), 1,99 (m, 1H), 2.63 in (m, 1H), 3,03 (m, 1H) and 3.59 (m, 2H), of 5.68 (m, 1H), 7,13 (d, 2H), 7,40 (d, 2H),

Stage 4

In a mixture of 3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-isopropyl-1,3-oxazine-2-she (41 mg, 0.1 mmol) and acetone (10 ml) at 0°C was added Jones reagent (2.5 M, 1 ml). The resulting mixture was stirred at room temperature for 1 h, evaporated and subjected to extraction using EtOAc. The organic layer was evaporated to obtain the crude product 3-(3-((S)-1-(4-bromcresol)ethyl)-6-isopropyl-2-oxo-1,3-oxazine-6-yl)propanoic acid (51 mg, yield: 95%) that was used in the next step without additional purification.

Step 5

To a solution of 3-(3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-2-oxo-1,3-oxazine-6-yl)propanoic acid (41 mg, 0.1 mmol) in Meon (10 ml) at 0°C was added SOCl (5 ml). The reaction mixture was stirred at room temperature for 2 h, evaporated and purified by preparative TLC to obtain methyl 3-(3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-2-oxo-1,3-oxazine-6-yl)propanoate (42 mg, yield: 96%).

Stage 6

To a solution of methyl 3-(3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-2-oxo-1,3-oxazine-6-yl)propanoate (42 mg, 0.1 mmol) in dry tetrahydrofuran (5 ml) at -78°C was added MeMrBr (2.5 ml, 2.5 mmol, 1 M solution in tetrahedr is the furan). The mixture is stirred at room temperature for 0.5 hours After stopping the reaction by means of a saturated aqueous solution of NH4Cl and the mixture was subjected to extraction of EtOAc. The organic layer was evaporated to obtain crude 3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxy-3-methylbutyl)-6-isopropyl-1,3-oxazine-2-it.

By preparative HPLC can be allocated two isomers:

Isomer 1: (1.1 mg, yield: 12%),1H NMR (CDCl3): δ of 0.91 (m, 6H), 1,25 (m, 6H), of 1.44 (d, MN), to 1.70 (m, 4H), of 1.85 (m, 2H), 2,01 (m, 1H), 2,74 (m, 1H), 3,18 (m, 1H), 5,79 (m, 1H), 7,24 (d, 2H), 7,50 (d, 2H),

Isomer 2: (0.9 mg, yield: 10%),1H NMR (CDCl3): δ 0,89 (m, 6H) and 1.15 (s, 6H), of 1.45 (m, 5H), of 1.55 (m, 3H), of 1.85 (m, 1H), 1,99 (m, 1H), 2,64 (m, 1H), 2,99 (m, 1H), 5,72 (m, 1H), 7,17 (d, 2H), 7,40 (d, 2H),

Step 7

To a solution of compound 3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxy-3-methylbutyl)-6-isopropyl-1,3-oxazine-2-she (105 mg, 0,255 mmol) in DMSO (8 ml) were added compound 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (198,5 mg, 0,781 mmol), COAs (351,6 mg, 3,587 mmol) and Pd(dppf)Cl2(to 21.9 mg, or 0.027 mmol) in an atmosphere of N2. The reaction mixture was stirred at 90°C for 3.5 h, followed by addition of N2Oh and extraction with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4evaporated and purified by preparative TLC to obtain two isomers of 6-(3-hydroxy-3-methylbutyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-Tetra is ethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it

Isomer 1 (17 mg, 15%).

Isomer 2 (10,3 mg, 9%).

Step 8

To a solution of compound 4-iodine-1-methylpyridin-2(1H)-it (17 mg, 0,074 mmol) in DME (4.6 ml) under nitrogen atmosphere was added Pd(PPh3)4(6,7 mg to 0.007 mmol). The mixture is stirred at room temperature for 1 h, after which it was added a solution of compound isomer 1 6-(3-hydroxy-3-methylbutyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it (17 mg, 0,037 mmol) in EtOH (2 ml) and a saturated aqueous solution of NaHCO3(1.5 ml). The mixture was mixed at a temperature of 100°C for 2 h followed by stopping the reaction with water and extracted using EtOAc. The combined organic layer was dried over anhydrous Na2SO4and evaporated to obtain compound isomer 1 6-(3-hydroxy-3-methylbutyl)-6-isopropyl-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-1,3-oxazine-2-it (of 10.73 mg, 65.8 per cent). Method LC-MS method 2 2 tR=1,03 min, the mass/charge=463, 441;1H NMR (CD3OD): δ 0,89 (m, 6H), is 1.11 (s, 6H), of 1.42 (m, 2H) and 1.51(m, 3H), 1,60 (m, 2H), 1,82-2,02 (m, 2H), 2,69 (m, 1H), 3,03 (m, 1H), 3,51 (s, 3H), 5,79 (m, 3H), 6.35mm (d, 1H), 6,72 (s, 1H), 7,28 (d, 1H), 7,39 (d, 2H), 7,49 (m, 2H).

Isomer 2 6-(3-hydroxy-3-methylbutyl)-6-isopropyl-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-1,3-oxazine-2-it was obtained from isomer of 6-(3-hydroxy-3-methylbutyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-ACS who Sinan-2-it is in effect, similar to that described above for the 8th stage. Method LC-MS Method 2 2 tR=1,00 min, the mass/charge=463, 441;1H NMR (CD3OD): δ 0,89 (m, 6H), of 1.18 (m, 6H), USD 1.43 (m, 1H) and 1.51 (m, 3H), and 1.63 (m, 2H), 1,76 (m, 2H), 1,92 (m, 1H), 2,61 (m, 1H), 3,12 (m, 1H), 3,51 (s, 3H), 5,79 (m, 1H), 6,37 (d, 1H), 6,72 (s, 1H), 7,28 (d, 1H), 7,35 (d, 2H), 7,51 (m, 2H).

EXAMPLE 85

(S)-3-((S)-1-(4-(1 -cyclopropyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-isopropyl-1,3-oxazine-2-he

Stage 1

A mixture of 4-yodellin-2(1H)-she (0,2425 g, 1.10 mmol, 1.0 equiv.), Cu(OAc)2(0,2146 g, 1.18 mmol, of 1.07 equiv.), bipyridine (0,1832 g at 1.17 mmol, of 1.07 equiv.), cyclopropylboronic acid (0,2122 g, 2,47 mmol, 2.25 equiv.) and Na2CO3(0,2638 g, 2.49 mmol, 2,27 equiv.) in dichloroethane (10 ml) were mixed at 70°C for 18 hours the Reaction was stopped with the help of a saturated aqueous solution of NH4Cl, after which the mixture was diluted with CH2Cl2and dried over Na2SO4. After removal of the solvent in vacuum, the obtained residue was purified by chromatography using silica gel, lirovannomu using a mixture of hexanol/ethyl acetate, to obtain 0,2309 g (81%) 1-cyclopropyl-4-yodellin-2(1H)-it.

Stage 2

To a solution of compound 1-cyclopropyl-4-yodellin-2(1H)-she (17,60 mg, 0,067 mmol) in DME (2.5 ml) under nitrogen atmosphere was added Pd(PPh3)4(6,12 mg, 0,006 mmol). The mixture was mixed at on the th temperature for 1 h, then it was added a solution of the compound (S)-6-(2-hydroxy-2-methylpropyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it (15 mg, 0,034 mmol) in EtOH (1 ml) and a saturated aqueous solution of NaHCO3(1 ml). The resulting mixture was stirred at 100°C for 2 h, after which the reaction was stopped with EtOAc. The combined organic layer was dried over anhydrous Na2SO4and evaporated to obtain the crude finished product, which was then purified by preparative HPLC to obtain compound (S)-3-((S)-1-(4-(1 -cyclopropyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-isopropyl-1,3-oxazine-2-it (6,50 mg, 43%). Method LC-MS 2 tR=1,00 min, the mass/charge=453;1H NMR (CD3OD): δ of 0.82 (d, 3H), 0,89 (m, 2H), 0,99 (d, 3H), 1,17 (m, 2H), of 1.35 (m, 6H), was 1.58 (d, 3H), of 1.62 (m, 2H), of 1.85 (m, 1H), 1,96 (d, 1H), 2,09-to 2.18 (m, 2H), 2,68-2,78 (m, 1H), 3,11 (m, 1H), 3,37 (m, 1H), of 5.81 (m, 1H), 6,40 (d, 2H), 6,78 (s, 1H), 7,31-7,42 (m, 3H), 7,58 (d, 2H).

EXAMPLE 86

(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-he

The title compound was obtained from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it and 5-bromo-1-(2-hydroxyethyl)pyridine-2(1H)-it is in effect, an is a logical described for step 2 of Example 20. Method LC-MS 2 tR=1,08 min, the mass/charge=513, 491;1H NMR (CD3OD) δ of 0.95 (s, 3H), 1,24 (s, 3H), 1.26 in (s, 1H), of 1.52 (d, 3H), 2,12 (s, 2H), 2,18 (m, 1H), 2,40 of $ 2.53 (m, 2H), to 3.02 (m, 1H), 3,52 (m, 0.5 H), to 3.64 (m, 0.5 H), 3,83 (t, 1H), 4,15 (t, 1H), of 5.53 (m, 1H), of 6.61 (m, 1H), 7,01 (d, 2H), 7,25-7,40 (m, 7H), 7,79 (m, 2H).

5-bromo-1-(2-hydroxyethyl)pyridine-2(1H)-it was obtained from 5-bromopyridin-2(1H)-it 2-gadatanili the application procedure analogous to that described for stage 1 of Example 20.

EXAMPLE 87

(S)-3-((S)-1-(4-(1-(2-foradil)-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-he

Stage 1

To a solution of 2-ftramadol (3.2 g, 50 mmol) and triethylamine (5.5 g, 55 mmol) in dichloromethane (60 ml) drop by drop at -78°C in an atmosphere of N2was added (CF3SO2)2On (15.5 g, 55 mmol). The mixture was mixed at a temperature of 10~20°C for 1 h and was treated with water (100 ml). Then the organic layer was washed with saturated aqueous NaHCO3(100 ml) and brine (100 ml), dried and evaporated to obtain triftoratsetata (8 g, yield 82%).

Stage 2

A solution of 5-bromopyridin-2(1H)-it (100 mg, of 0.58 mmol), 2-foradil triftoratsetata (1.1 g, 5.8 mmol) and K2CO3(800 mg, 5.8 mmol) in DMF (3 ml) stirred at room temperature overnight. After adding 2-Foradil triftoratsetata (1.1 g, 5.8 mmol) and K2CO3(00 mg, 5.8 mmol), the mixture was treated with ethyl acetate (20 ml) and water (20 ml). The organic layer was washed with water (2×20 ml) and brine (20 ml), dried over Na2SO4evaporated and purified by preparative TLC (1:1 mixture of petroleum ether/EtOAc) to obtain two isomers.

5-bromo-1-(2-foradil)pyridine-2(1H)-he (30 mg, yield: 24%).1H NMR (CD3OD): δ 4.25 in (t, 1H), 4,32 (t, 1H), to 4.62 (t, 1H), 4,74 (t, 1H), of 6.52 (d, 1H), to 7.61 (dd, 1H), a 7.85 (s, 1H).

5-bromo-2-(2-floratone) pyridine (30 mg, yield: 24%).1H NMR (CD3OD): δ of 4.46 (t, 1H), 4.53-in (t, 1H), with 4.64 (t, 1H), amounts to 4.76 (t, 1H), 6,79 (d, 1H), 7,79 (dd, 1H), 8,18 (s, 1H),

Stage 3

To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it (20 mg, 0,041 mmol), 5-bromo-1-(2-foradil)pyridine-2(1H)-she (9,2 mg, 0,041 mmol) and Cs2CO3(2 N, 0.2 ml, 0.41 mmol) in 1,4-dioxane (2 ml) in an atmosphere of N2was added Pd(PPh3)2Cl2(3 mg, 0,0041 mmol). The mixture was subjected to reverse or for 2 h, then was treated with EtOAc (10 ml) and water (10 ml). The organic layer was dried over Na2SO4evaporated and purified by preparative Weghts obtain (S)-3-((S)-1-(4-(1-(2-foradil)-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazine-2-it (4,20 mg, 20%). Method LC-MS 2 tR=1,01 min, the mass/charge=515, 493;1H NMR (CD3OD): δ 0,97 (s, 3H), of 1.28 (s, 3H), and 1.56 (d, 3H), and 2.8 (s, 2H), 2,22 (m, 1H), 2.49 USD (m, 2H), 3,05 (m, 1H), 4,37 (t, 1H), 4,43 (t, 1H), 4,69 (t, 1H), to 4.81 (t, 1H), 5,59 (q, 1H), 6,66 (d, 1H), 7,05 (d, 2H), 7,33 (m, 7H), 7,82 (m, 2H).

EXAMPLE 88

(S)-3-((S)-1-(4-(1-temporaril-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-(2-forfinal)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazine-2-he

The title compound was obtained from (S)-6-(2-forfinal)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it 1-cyclopropyl-4-yodellin-2(1H)-it is the result of applying the procedure similar to that described for the 9th stage of Example 23. Method LC-MS 2 tR=1,05 min, the mass/charge=505;1H NMR (CDCl3) δ 0,88 (m, 2H), 1,12 (s, 3H) and 1.15 (s, 1H), 1,17 (s, 1H), 1,21 (s, 3H), 2,18-to 2.29 (m, 2H), 2,30-of 2.34 (m, 1H), 2,42 (d, 1H), 2,54 (d, 1H), 2,90 (m,1H), 3,35 (m, 1H), 5,70 (m, 1H), 6,32 (m, 1H), of 6.68 (m, 1H), 6,98 (m, 1H), to 7.09 (d, 2H), 7,18 (t, 1H), 7,25 was 7.36 (m, 4H), to 7.50 (t, 1H).

EXAMPLE 89

(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-(2-hydroxy-2-methylpropyl)-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-he

Stage 1

To a solution of compound 5-bromopyridin-2(1H)-she (348 mg, 2.0 mmol) and K2CO3(830 mg, 6.0 mmol) in DMF (15 ml) was added drop by drop ethylbromoacetate. The mixture is stirred at room temperature for 2 h, and then subjected to filtration. The obtained filtrate was evaporated in vacuum, and then the obtained residue was purified by preparative TLC (1:1 PE/EtOAc) to which Holocene ethyl 2-(5-bromo-2-oxopyridine-1(2H)-yl)acetate (300 mg, 57,7%).1H NMR CDCl3: δ 7,41-7,26 (m, 2H), 6,53 to 6.5 (d, 1H), 4,59 (s, 2H), 4,28-is 4.21 (q, 2H), 1.32 to 1,23 (q, 3H).

Stage 2

To a solution of ethyl 2-(5-bromo-2-oxopyridine-1(2H)-yl)acetate (130 mg, 0.5 mmol) in anhydrous tetrahydrofuran (5 ml) at -78°C was added drop by drop 1 M solution of MeMgBr (5 ml, 5 mmol). Simultaneously with the addition of the solution was mixed. The reaction mixture was stirred for 1 h at -78°C. Then the reaction was stopped by using aqueous solution of NH4Cl (5 ml) and the resulting mixture was subjected to extraction using EtOAc (3×10 ml). The combined organic layer was dried and evaporated to obtain the crude finished product, which was then purified by preparative TLC (1:1 PE/EtOAc) to obtain 5-bromo-1-(2-hydroxy-2-methylpropyl " pyridine-2(1H)-she (65 mg, 52,9%).

Stage 3

To a solution of 5-bromo-1-(2-hydroxy-2-methylpropyl " pyridine-2(1H)-it (20 mg, 81,3 mmol) in DME (6 ml) under nitrogen atmosphere was added Pd(PPh3)4(10 mg). The mixture was mixed for 1 h at room temperature, then it was added a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazine-2-it (38,95 mg, 81,3 mmol) in EtOH (2 ml) and a saturated aqueous solution of NaHCO3(2 ml). The resulting mixture was stirred at 100°C for 2 h and, after stopping the reaction was subjected to extraction at the same time EtOAc. The combined organic layer was dried over anhydrous Na2SO4and evaporated to obtain the crude product, which was then purified by preparative TLC and preparative HPLC to obtain (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-(2-hydroxy-2-methylpropyl)-6-oxo-1,6-dihydropyridines-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazine-2-she (6.5 mg, 15.5 per cent). Method LC-MS 2 tR=0,99 min, the mass/charge=519;1H NMR (CDCl3): δ 7,60-EUR 7.57 (d, 1H), 7,43 (s, 1H), was 7.36-7,26 (m, 5H), to 7.15 (d, 2H), 7,01 (d, 2H), 6,70 (d, 1H), 2,85 (m, 1H), 5,69-to 5.66 (m, 1H), 4,13-4.09 to (s, 2H), 4,05-3,98 (s, 1H), 2,89-of 2.86 (m, 1H), 2,44-of 2.36 (m, 1H), 2,28-of 2.16 (m, 5H), 1,58-of 1.53 (d, 3H), 1,33-of 1.30 (s, 6H), 1,19 (s, 3H), of 1.12 (s, 3H).

EXAMPLE 90

3-((S)-1-{4-[1-(3-hydroxy-2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-pyridine-4-yl]-phenyl}-ethyl)-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazine-2-he

2 M aqueous solution of Na2CO3(0,32 ml) was added to a mixture of 4-bromo-1-(3-hydroxy-2,2-dimethyl-propyl)-1H-pyridine-2-it (0,13 g) and (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazine-2-she (0.15 g) in N,N-dimethylformamide (3 ml). To the resulting mixture for 5 min produced a sputtering argon before adding complex [1,1'-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) dichloromethane (26 mg). The mixture was heated to 100°C and stirred at the same temperature for 4 hours After cooling to ambient temperature the ment environment to the mixture was added water, after which the mixture was subjected to extraction with ethyl acetate. The combined organic extract was washed with brine and dried (MgSO4). Obtained after evaporation of the solvent the residue was purified by HPLC with reversed phase (methanol/water/NH4OH to obtain a compound in a solid beige color. Yield: 0.10 g (60% of theoretical value); Mass spectrum (electrospray ionization+: the mass/charge=533 [M+H]+.

3-(4-bromo-2-oxo-2H-pyridin-1-yl)-2,2-dimethyl-propionic acid methylether

3-bromo-2,2-dimethyl-propionic acid methylether (0.75 g) was added to a mixture of 4-bromo-1H-pyridine-2-it (0.55 g) and potassium carbonate (0.75 g) in N,N-dimethylformamide (10 ml) at room temperature. The mixture was heated to 60°C., then stirred at the same temperature throughout the night. After additional stirring at a temperature of 80°C for 8 h the mixture was cooled to room temperature, then it was added to the water. The resulting mixture was subjected to extraction with ethyl acetate, then the combined organic extract was washed with brine and dried (MgSO4). Obtained after evaporation of the solvent the residue was purified by chromatography using silica gel (a mixture of cyclohexane/ethyl acetate 4:1) to obtain titul the CSOs connection; as a result of this reaction was obtained 3-(4-bromo-pyridine-2-yloxy)-2,2-dimethyl-propionic acid methylether (0.35 g). Output: 0.29 grams (32% of theoretical value); Mass spectrum (electrospray ionization+): the mass/charge=288/300 (Br) [M+H]+.

4-bromo-1-(3-hydroxy-2,2-dimethyl-propyl)-1H-pyridine-2-he

Borohydride lithium (25 mg) was added to a solution of 3-(4-bromo-2-oxo-2H-pyridin-1-yl)-2,2-dimethyl-propionic acid methylether (0,29 g) in tetrahydrofuran (3 ml), cooled in an ice bath. After adding methanol (45 ml) and the mixture was mixed in the cooling bath for 1 h and then at room temperature overnight. Then the mixture was diluted with tetrahydrofuran, followed by addition of MgSO4. The filtrate obtained after filtration was evaporated, and the obtained residue was purified by chromatography using silica gel (a mixture of cyclohexane/ethyl acetate 1:1) to obtain the title compound as a colourless oil. Output: 0,13 g (49% of theoretical value); Mass spectrum (electrospray ionization+: the mass/charge=260/262 (Br) [M+H]+.

EXAMPLE 91

3-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-(tetrahydro-2H-Piran-4-yl)-1,3-oxazine-2-he

The title compound would be what about the resulting procedures, similar to that described in Example 23 with the following changes. During phase 1 of tetrahydro-2H-Piran-4-carboxylic acid and carbonyldiimidazole was used instead of 2-perbenzoic chloride, and during the 9 stage 1-cyclopropyl-4-yodellin-2(1H)-was used instead of 5-bromo-1-methylpyridin-2(1H)-she. During the reaction were allocated two isomers.

Isomer 1. Method LC-MS 2 tR=0,95 min, the mass/charge=495.

Isomer 2. Method LC-MS 2 tR=0,93 min, the mass/charge=495.

EXAMPLE 92

(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-trideuteromethyl-2-oxo-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-sreni-1,3-oxazine-2-he

The title compound was obtained by procedures similar to those described in Method 2 of Example 48 with the following changes. During phase 1 of trideuteromethyl iodide was used instead of methyliodide, and during phase 2 PdCl2(dppf) was used instead of PdCl2(PPh3)2. Method LC-MS 1 tR=1,30 min, the mass/charge=464.

EXAMPLE 93

3-((S)-1-(4-(2-oxo-1-cyclopropyl-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-(cyclopropylmethyl)-1,3-oxazine-2-he

The target compound was obtained according to the method similar to that described in Example 23, steps 2-9. Phase 2 used N-methoxy-N-methyl-2-cyclopropylacetic obtained by condensation of 2-cyclopropylamino the acid with N,O-dimethylhydroxylamine in the presence of carbodiimide. Two isomeric 3-((1S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-(cyclopropylmethyl)-1,3-oxazine-2-it is formed in step 5, divided by the method of column chromatography. The obtained isomers were separately introduced in stages 6 to 9, in step 9, the applied 4-iodine-1-cyclopropylmethyl-2(1H)-he received two isomer of the target compound.

Isomer 1: Method 2, GC-MS, tR=1.04 min, m/z=465, 447.

Isomer 2: Method 2, GC-MS, tR=1.06 min, m/z=465, 447.

EXAMPLE 94

3-((S)-1-(4-(2-oxo-1-cyclopropyl-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-neopentyl-1,3-oxazine-2-he

The target compound was obtained according to the method similar to that described in Example 23, steps 2-9. Phase 2 used N-methoxy-N-methylamide 3,3-dimethylbutanol acid obtained by condensation of 3,3-dimethylbutanol acid with N,O-dimethylhydroxylamine in the presence of HATU [O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethyluronium of hexaflurophosphate]. Two isomeric 3-((1S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-neopentyl-1,3-oxazine-2-it is formed in step 5, divided by the method of column chromatography. The obtained isomers were separately introduced in stage 6 to 9, in step 9, the applied 4-iodine-1-cyclopropyl pyridine-2(1H)-he received two isomer of the target compound.

Isomer 1: Method 2, GC-MS 2 tR=1,09 min, m/z=503, 481, 423.

Isomer 2: Method 2, GC-MS 2 tR=1.16 min, m/z=481.

PRIMER

3-((S)-1-(4-(2-oxo-1-cyclopropyl-1,2-dihydropyridines-4-yl)phenyl)ethyl)-6-(3,3-diversilobum)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazine-2-he

The target compound was obtained according to the method similar to that described in Example 23, steps 2-9. Phase 2 used a 3.3-debtor-N-methoxy-N-methylcyclohexanecarboxylic obtained by the condensation of 3,3-divertikulyarnoy acid with N,O-dimethylhydroxylamine in the presence of carbodiimide. Two isomeric 3-((S)-1-(4-bromophenyl)ethyl)-6-(3,3-diversilobum)-6-(2-methylallyl)-1,3-oxazine-2-it is formed in step 5, divided by the method of column chromatography. The obtained isomers were separately introduced in steps 6-9, in step 9, the applied 4-iodine-1-cyclopropylmethyl-2(1H)-he received two isomer of the target compound.

Isomer 1: Method 2, GC-MS 1 tR=1.08 min, m/z=501.

Isomer 2: Method 2, GC-MS 1 tR=1.07 min, m/z=501.

Examples 96-98

Intermediate 1

(S)-4-Bromo-1-(1-isocyanatomethyl)-2-methylbenzo

Step 1: [1-(4-bromo-2-were)ethylidene]amide (R)-2-methylpropan-2-sulinowo acid

To a solution of 1-(4-bromo-2-were)ethanone (4.41 g) and (R)-2-methyl-2-propanesulfinamide (2.76 g) in tetrahydrofuran (45 ml) was added to tetraethoxysilane(IV) (10.7 ml). The resulting solution was heated to 65°C. and stirred at this temperature for 20 hours Then the solution was cooled to a normal pace atory and added more tetraethoxysilane(IV) (5.4 ml) and (R)-2-methyl-2-propanesulfinamide (1.25 g). The solution was stirred for another 12 h at 65°C, cooled to room temperature and poured into an aqueous solution of NaCl. The resulting mixture was filtered through celite, and the separated organic layer of the filtrate. The aqueous layer of the filtrate was extracted with ethyl acetate, and the combined extracts and organic layer. The combined organic phase was washed with NaCl solution and dried (MgSO4), then the solvent was evaporated. The residue was chromatographically on silica gel (eluent - cyclohexane/ethyl acetate 9:1→1:1), obtaining the target compound. Output: 6.24 g (95% of theory); Mass spectrum (ER+): m/z=316/318 (Br) [M+H+].

Step 2: [(S)-1-(4-Bromo-2-were)ethyl]amide (R)-2-methylpropan-2-sulinowo acid

To a solution of [1-(4-bromo-2-were)ethylidene]amide (R)-2-methylpropan-2-sulinowo acid (6.24 g) in tetrahydrofuran (50 ml) while cooling in an ice bath was added three second-butylbromide lithium (1 mol/l in tetrahydrofuran, 59.2 ml). The solution was stirred 2 h, allowing to warm to room temperature at a cooling bath. Then the solution was again cooled in an ice bath and carefully added water. The resulting mixture was extracted with ethyl acetate, and the combined extracts were washed with water, saturated aqueous NaHCO3and an aqueous solution of NaCl. After drying (MgSO4) and evaporation of the solvent was obtained target compound that BBO is or without purification in the next stage of the synthesis. Output: 8.85 g (purity 75%); Mass spectrum (ER+): m/z=318/320 (Br) [M+H]+.

Step 3: (S)-1-(4-Bromo-2-were)ethylamine

To a solution of [(S)-1-(4-bromo-2-were)ethyl]amide (R)-2-methylpropan-2-sulinowo acid (the product of step 2 without purification, 8.85 g, purity 75%) in ethyl acetate (80 ml) at room temperature was added hydrochloric acid (4 mol/l 1,4-dioxane, 46 ml). The solution was stirred 1 hour at room temperature and was evaporated. To the residue was added water, and the resulting mixture was washed with diethyl ether. The aqueous phase was podslushivaet the addition of 1 M aqueous NaOH and was extracted with methylene chloride. The combined extracts were washed with NaCl solution, dried (MgSO4) and was evaporated, obtaining the target compound. Output: 4.04 g (90% of theory); Mass spectrum (ER-): m/z=214/216 (Br) [M+H]+.

Step 4: (S)-4-Bromo-1-(1-isocyanatomethyl)-2-methylbenzo

To a mixture of NaHCO3(3.65 g) in water (80 ml) and (S)-1-(4-bromo-2-were)ethylamine (4.04 g) in methylene chloride (80 ml) under vigorous stirring and cooling in an ice bath was added one portion of triphosgene (2.24 g). The cooling bath was removed and the reaction mass was stirred at room temperature for another 30 minutes Then the organic layer was separated and dried (MgSO4) and the solvent was evaporated, obtaining the isocyanate in the form of oil, which was used without purification in the next step. Yield: 4.50 g (9% of theoretical); Mass spectrum (ER-): m/z=240/242 (Br) [M-N]-.

Intermediate 2

(S)-1-Bromo-4-(1-isocyanatomethyl)-2-methylbenzo

Step 1: [1-(4-Bromo-3-were)ethylidene]amide (R)-2-methylpropan-2-sulinowo acid

The target compound was obtained from 1-(4-bromo-3-were)ethanone and {R)-2-methyl-2-propanesulfinamide by the method similar to step 1 upon receipt of intermediate 1. Mass spectrum (ER+): m/z=316/318 (Br) [M+H]+.

Step 2: [(S)-1-(4-bromo-3-were)ethyl]amide (R)-2-methyl-propane-2-sulinowo acid

The target compound was obtained from [1-(4-bromo-3-were)ethylidene]amide (R)-2-methylpropan-2-sulinowo acid by the method similar to step 2 upon receipt of intermediate 1. GC-MS (method 5): tR=4.04 min; Mass spectrum (ER+): m/z=318/320 (Br) [M+H]+.

Step 3: (S)-1-(4-Bromo-3-were)ethylamine

The target compound was obtained from [(S)-1-(4-bromo-3-were)ethyl]amide (R)-2-methylpropan-2-sulinowo acid by the method similar to step 3 upon receipt of intermediate 1. GC-MS (method 4): tR=3.56 min; Mass spectrum (ER+): m/z=214/216 (Br) [M+H]+.

Step 4: (S)-1-Bromo-4-(1-isocyanatomethyl)-2-methylbenzo

The target compound was obtained from (S)-1-(4-bromo-3-were)ethylamine and triphosgene by the method similar to step 4 upon receipt of intermediate 1, Mass spectrum (ER+): m/z=272/274 (Br) [M+H+Meon]+.

Intermediate 3

5-Bromo-2-isocyanatomethyl-1,3-xylene

The target compound was obtained from 4-bromo-2,6-dimethylbenzylamine and triphosgene by the method similar to step 4 upon receipt of intermediate 1. Mass spectrum (EI): m/z=239/241 (Br) [M]+.

Intermediate 4

4-Bromo-1-cyclopropyl-1H-pyridine-2-he

In a flask with a magnetic stirrer was loaded with 4-bromo-1 H-pyridin-2-he (1.80 g), cyclopropylboronic acid (2.00 g), Cu(O2CCH3)2(2.00 g), 2,2'-bipyridyl (1.70 g), Na2CO3(2.47 g) and 1,2-dichloroethane (75 ml) and was heated to 70°C. the Mixture was stirred in air at this temperature until the morning. Next there was added an additional amount cyclopropylboronic acid (0.50 g) and MA2CO3(0.55 g) and boiled under reflux for another 4 hours. After cooling to normal temperature was added an aqueous solution of NH4Cl, and the resulting mixture was extracted with methylene chloride. The combined organic extracts were dried (MgSO4) and the solvent was evaporated. The residue was purified by chromatography on silica gel (eluent - cyclohexane/ethyl acetate 50:50→35:65) to give the target compound in the form of oil, which crystallized upon standing. Yield: 0.82 g (37% of theory); Mass spectrum (ER+): m/z=214/216 (Br) [M+H]+.

Example 96

3-{(S)-1-[4-(1-Cyclopropyl-2-oxo-1,2-dihydropyridines-4-yl)-2-m is terphenyl]-ethyl}-(5)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-[1,3]oxazine-2-he

Step 1: 3-[(S)-1-(4-Bromo-2-were)ethyl-(R)-6-(2-methylallyl)-6-phenyl-[1,3]oxazine-2-he

To a solution of 5-methyl-3-phenyl-1-chlorhex-5-EN-3-ol (3.82 g) and (5)-4-bromo-1-(1-isocyanatomethyl)-2-methylbenzene (4.49 g) in tetrahydrofuran (140 ml) under cooling in an ice bath was added dropwise hexamethyldisilazide lithium (1 mol/l in tetrahydrofuran, 18.7 ml) with such speed, so that the solution temperature remained below 25°C. the Solution was stirred 30 min in the cooling bath and another 60 min at room temperature. Next, to the reaction mixture was slowly added a solution of acetic acid (1.9 ml) in water (40 ml). The resulting mixture was evaporated under reduced pressure and to the residue was added tert-butyl methyl ether. The resulting solution was washed with water, dried (MgSO4) and was evaporated. The residue was chromatographically on silica gel (eluent - cyclohexane/ethyl acetate 90:10→40:60) to give the target compound as a colorless solid. In addition to the target compound was isolated its diastereoisomer - 3-[(S)-1-(4-bromo-2-were)-ethyl]-6-(S)-(2-methylallyl)-6-phenyl-[1,3]oxazine-2-he - in the form of oil {1.55 g, mass spectrum (ER+): m/z=428/430 (Br) [M+H]+. Yield: 1.34 g (18% of theory); Mass spectrum (ER+): m/z=428/430 (Br) [M+H]+; PMR spectrum (400 MHz, DMSO-d6): 1.40 (d, J=6.8 Hz, 3H), 1.53 (s, 3H), 1.71 (s, MN), 1.81-190 (m, 1H), 1.98-2.08 (m, 1H), OK. 2.43. 2.51 (m, 3H), 2.86-2.94 (m, 1H, 4.58 (poorly resolved m, 1H), 4.77 (poorly resolved m, 1H), 5.30 (K, J=6.8 Hz, 1H), 7.15-7.19 (m, 2H), 7.24-7.35 (m, 6N). The assignment of the stereogenic centers of the target compounds was based on comparison of the data of its PMR spectrum data for a known analog - 3-[(S)-1-(4-bromophenyl)ethyl]-(R)-6-(2-methylallyl)-6-phenyl-[1,3]oxazine-2-it.

Step 2: 3-[(S)-1-(4-Bromo-2-methyl-phenyl)-ethyl]-(S)-6-(2-methyl-iranyl)-6-phenyl-[1,3]oxazine-2-he

To a solution of 3-Chlordecone acid (77%, 0.81 g) in methylene chloride (15 ml) and cooled to 5°C was added 3-[(S)-1-(4-bromo-2-were)ethyl]-(R)-6-(2-methylallyl)-6-phenyl-[1,3]oxazine-2-he (1.34 g) in solution in methylene chloride (15 ml). The cooling bath was removed and the solution was stirred at room temperature until the morning. Was added a 10% aqueous solution of Na2S2O3(10 ml) and saturated aqueous solution of NaHCO3(25 ml) and the resulting mixture was stirred for another 30 minutes the Organic layer was separated and washed with an aqueous solution of Na2S2O3in a mixture with saturated aqueous NaHCO3, water and NaCl solution. The organic phase was dried (MgSO4) and was evaporated, obtaining the target compound. Yield: 1.55 g (purity about 85-90%); GC-MS (method 4): tR=4.28 min; mass spectrum (ER+): m/z=444/446 (Br) [M+H]+.

Step 3: 3-[(S)-1-(4-Bromo-2-were)ethyl]-(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-[1,3]oxazine-2-he

To a cooled with ice to a solution of 3-[(S)-1-(4-the rum-2-were)ethyl]-(S)-6-(2-methoxyaniline)-6-phenyl-[1,3]oxazine-2-it (1.55 g, purity of about 85-90%) in tetrahydrofuran (15 ml) were added triethylborohydride (1 mol/l in tetrahydrofuran, 4,2 ml) at such a rate that the solution temperature remained below 10°C. the resulting solution was stirred for another 1 hour in the cooling bath and 2 hours at room temperature. Then the solution was cooled in an ice bath and stopped the reaction by careful addition of water (7 ml). After addition of aqueous hydrochloric acid and ethyl acetate (80 ml) the organic layer was separated, washed with NaCl solution and dried (MgSO4). The solvent was evaporated, obtaining the target compound. Yield: 1.48 g (95% of theoretical); GC-MS (method 4): tR=4.00 min; Mass spectrum (ER+): m/z=446/448 (Br) [M+H]+.

Step 4: (S)-6-(2-Hydroxy-2-methylpropyl)-3-{(S)-1-[2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]ethyl}-6-phenyl-[1,3]oxazine-2-he

In a flask with a magnetic stir bar was loaded potassium acetate (1.14 g), bis(pinacolato)LIBOR (1.10 g), 3-[(S)-1-(4-bromo-2-were)ethyl]-(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl[1,3]oxazine-2-he (1.48 g) and dimethyl sulfoxide (20 ml) and was barbotirovany argon for 10 minutes Then added the complex [1,L-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) with methylene chloride (0.27 g), the mixture was heated to 90°C and stirred 2.5 h at this temperature. After cooling the mixture to normal temperature was added water and ethyl acetate, and the resulting mixture filtrowanie celite. The aqueous phase of the filtrate was separated and was extracted twice with ethyl acetate. Organic extracts and the organic phase of the filtrate were combined and washed with water and NaCl solution and dried (MgSO4). The solvent was evaporated and the residue was chromatographically on silica gel (eluent - cyclohexane/ethyl acetate 1:1→1:4) to give the target compound. Yield: 1.23 g (75% of theory); Mass spectrum (ER+): m/z=494 [M+H]+.

Step 5: 3-{(S)-1-[4-(1-Cyclopropyl-2-oxo-1,2-dihydropyridines-4-yl)-2-were]ethyl}-(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-[1,3]oxazine-2-he

To a mixture of 4-bromo-1-cyclopropyl-1H-pyridine-2-she (0.11 g) and (S)-6-(2-hydroxy-2-methylpropyl)-3-{(S)-1-[2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]ethyl}-6-phenyl-[1,3]oxazine-2-she (0.20 g) in N,N-dimethylformamide (2 ml) was added 2 M aqueous solution of Na2CO3(0.41 ml). After the resulting mixture was barbotirovany argon for 10 minutes, and then added the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) with methylene chloride (33 mg). The mixture was heated to 100°C and stirred at this temperature until the morning. After cooling the mixture to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and NaCl solution and dried (MgSO4). The solvent was evaporated and the residue was purified by the method of reversed-phase HPLC (elwen is - methanol/water/NH4OH), obtaining the target compound. Yield: 0.13 g (64% of theoretical); GC-MS (method 5): tR=3.43 min; Mass spectrum (ER+): m/z=501 [M+H]+.

Example 97

3-{(S)-1-[4-(1-Cyclopropyl-2-oxo-1,2-dihydropyridines-4-yl)-3-were]-ethyl}-(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-[1,3]oxazine-2-he

Step 1: 3-[(S)-1-(4-Bromo-3-were)ethyl]-(R)-6-(2-methylallyl)-6-phenyl-[1,3]oxazine-2-he

The target compound was obtained from 5-methyl-3-phenyl-1-chlorhex-5-EN-3-ol and (S)-1-bromo-4-(1-isocyanatomethyl)-2-methylbenzoyl by the method similar to step 1 in example 96. Mass spectrum (ER+): m/z=428/430 (Br) [M+H]+; PMR spectrum (400 MHz, DMSO-d6) 1.40 (d, J=6.9 Hz, 3H), 1.55 (s, 3H), 2.13 (s, 3H) blocked 2.07-2.18 (m, 2H), 2.42-2.47 (m, 1H), 2.53 (ush.S., 2H), 2.92-3.03 (m, 1H), 4.60 (poorly resolved m, 1H), 4.77 (poorly resolved m, 1H), 5.33 (K, J=6.9 Hz, 1H), 6.62 (DD, J=8.2 Hz, 2.0 Hz, 1H), 6.76 (poorly resolved d, 1H), 7.26-7.33 (m, 4H), 7.34-7.40 (m, 2H). The assignment of the stereogenic centers of the target compounds was based on comparison of the data of its PMR spectrum data for a known analog - 3-[(S)-1-(4-bromophenyl)ethyl]-(R)-6-(2-methylallyl)-6-phenyl-[1,3]oxazine-2-it.

Step 2: 3-[(S)-1-(4-Bromo-3-were)ethyl]-(S)-6-(2-methyl-oxiranylmethyl)-6-phenyl-[1,3]oxazine-2-he

The target compound was obtained from 3-[(S)-1-(4-bromo-3-were)ethyl]-(R)-6-(2-methylallyl)-6-phenyl-[1,3]oxazine-2-it is by the method similar to step 2 in the application is e 96. GC-MS (method 4): tR=4.03 min; Mass spectrum (ER+): m/z=444/446 (Br) [M+H]+.

Step 3: 3-[(S)-1-(4-Bromo-3-were)ethyl]-(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-[1,3]oxazine-2-he

The target compound was obtained from 3-[(S)-1-(4-bromo-3-were)ethyl]-(S)-6-(2-methoxyaniline)-6-phenyl-[1,3]oxazine-2-it is by the method similar to step 3 of example 96. GC-MS (method 4): tR=4.03 min; Mass spectrum (ER+): m/z=446/448 (Br) [M+H]+.

Step 4: (S)-6-(2-Hydroxy-2-methylpropyl)-3-{(S)-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]ethyl}-6-phenyl-[1,3]oxazine-2-he

The target compound was obtained from 3-[(S)-1-(4-bromo-3-were)ethyl]-(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-[1,3]oxazine-2-it is by the method similar to step 4 in example 96. Mass spectrum (ER+): m/z=494 [M+H]+.

Step 5: 3-{(S)-1-[4-(2-Oxo-1-cyclopropyl-1,2-dihydropyridines-4-yl)-3-were]ethyl}-(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-[1,3]oxazine-2-he

The target compound was obtained from (S)-6-(2-hydroxy-2-methylpropyl)-3-{(S)-1-[3-methyl-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]ethyl}-6-phenyl[1,3]oxazine-2-she and 4-bromo-1-cyclopropyl-1H-pyridine-2-it is by the method similar to that of step 5 in example 96. GC-MS (method 5): tR=3.42 min; Mass spectrum (ER+): m/z=501 [M+H]+.

Example 98

3-[4-(2-Oxo-1-cyclopropyl-1,2-dihydropyridines-4-yl)benzyl]-6-(2-hydroxy-2-methylpropyl)-6-phenyl[1,3]oxazine-2-he

Step 1: 3-(4-Bromo-2,6-dimethylbenzyl)-6-(2-methylallyl)-6-phenyl-[1,3]oxazine-2-he

The target compound was obtained from 5-methyl-3-phenyl-1-chlorhex-5-EN-3-ol and 5-bromo-2-isocyanatomethyl-1,3-xylene by the method similar to step 1 in example 96. GC-MS (method 5): tR=4.95 min; Mass spectrum (ER+): m/z=428/430 (Br) [M+H]+.

Step 2: 3-(4-Bromo-2,6-dimethylbenzyl)-6-(2-methoxyaniline)-6-phenyl[1,3]oxazine-2-he

The target compound was obtained from 3-(4-bromo-2,6-dimethylbenzyl)-6-(2-methylallyl)-6-phenyl-[1,3]oxazine-2-it is by the method similar to step 2 of example 96. GC-MS (method 4): tR=4.05 min; Mass spectrum (ER+): m/z=444/446 (Br) [M+H]+.

Step 3: 3-(4-Bromo-2,6-dimethylbenzyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-[1,3]oxazine-2-he

The target compound was obtained from 3-(4-bromo-2,6-dimethylbenzyl)-6-(2-methoxyaniline)-6-phenyl[1,3]oxazine-2-it is by the method similar to step 3 of example 96. GC-MS (method 4): tR=4.05 min; Mass spectrum (ER+): m/z=446/448 (Br) [M+H]+.

Step 4: 3-[2,6-Dimethyl-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]-6-(2-hydroxy-2-methylpropyl)-6-phenyl[1,3]oxazine-2-he

The target compound was obtained from 3-(4-bromo-2,6-dimethylbenzyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl[1,3]oxazine-2-it is by the method similar to step 4 in example 96. Mass spectrum (ER+): m/z=494 [M+H]+.

Stage 5: 3-[4-(2-Oxo-1-cyclopropyl-1,2-dihydropyridines-4-yl)benzyl]-6(2-hydroxy-2-methylpropyl)-6-phenyl-[1,3]oxazine-2-he

The target compound was obtained from 3-[2,6-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl]-6-(2-hydroxy-2-methylpropyl)-6-phenyl-[1,3]oxazine-2-she and 4-bromo-1-cyclopropyl-1H-pyridine-2-it is by the method similar to that of step 5 in example 96, GC-MS (method 5): tR=3.53 min; Mass spectrum (ER+): m/z=501 [M+H]+.

BIOLOGICAL TEST EXAMPLE 1

The degree of inhibition of microsome preparation 11β-HSD compounds described in the invention was largely measured by the methods described above (K. Solly, S. S. Mundt, H. J. Zokian, G. J. Ding, A. Hermanowski-Vosatka, B. Strulovici, and W. Zheng, High-Throughput Screening of 11-Beta-Hydroxyseroid Dehydrogenase Type 1 in Scintillation Proximity Assay Format. Assay Drug Dev Technol 3 (2005) 377-384). All reactions were carried out at room temperature in 96-well transparent flexible PET-tablets Microbeta (PerkinElmer). The analysis begins with dispensive 49 μl of substrate solution (50 mm N-2-hydroxyethylpiperazine-N-2-econsultancy acid (HEPES), pH=7,4, 100 mm KCI, 5 mm NaCl, 2 mm MgCl2, 2 mm adenine dinucleotide phosphate(NADPH) and 160 nm of [3N] cortisone (1 Ci/mmol)) and mixing 1 μl of the test compounds in DMSO, pre razvalivshegosya half increment (8 points) starting with 0.1 mm. After pre-incubation for 10 minutes was added 50 μl of an enzyme solution containing microsome assay, isolated from the cell lines Cho, sverkhekspressiya 11-HSD person (shared with the holding of the protein 10-20 µg/ml) and plates were incubated at room temperature for 90 minutes. The reaction was stopped by adding 50 μl of the suspension of beads for SPA-analysis containing 10 μm 18 - glycyrrhetic acid, 5 mg/ml of beads for YSi SPA, covered with protein A (GE Healthcare) and 3.3 μg/ml of anti-cortisol antibody (East Coast Biologies) in Superblock buffer (Bio-Rad). The plate was shaken at room temperature for 120 minutes, and measured the signal SPA, the corresponding [3H] cortisol, using reader Microbeta plate.

BIOLOGICAL TEST EXAMPLE 2

Inhibition of 11-HSD compounds described in this invention was measured in all cells, as specified below. Cells for analysis came from two sources: a fully differentiated omental fat cells (adipocytes) from Zen-Bio Inc.; undifferentiated cells (preadipocyte) - from Lonza Group Ltd. Pre-differentiated omental adipocytes Zen-Bio was delivered in 96-well tablets and used in the analysis, at least 2 weeks after it happened differentiation preadipocytes. Zen-Bio induced differentiation of pre-adipocytes, filling the medium containing adipogenic and lipogensis hormones (human insulin, dexamethasone, isobutylmethylxanthine, agonist of PPAR-gamma). The cells were kept at the fully adipocyte medium (DMEM/Ham's F-12 (1:1, about./vol.), HEPES with pH=7,4, fetal bovine serum, penicillin, streptomycin, amphotericin b, supplied by Zen-Bio, Inc.) at a temperature of 37°C, the content of CO25%.

Pre-adipocytes, supplied by Lonza Group Ltd. and placed in a growing medium of adipocytes (Preadipocyte Growth Medium-2), supplemented with fetal bovine serum, penicillin and streptomycin (from Lonza), was cultivated at 37°C, the carbon dioxide content of 5%. Pre-adipocytes were differentiability by adding insulin, dexamethasone, indomethacin, and isobutyl-methylxanthines (from Lonza) on Wednesday Preadipocyte Growth Medium-2. Cells were exposed to differenzierung factors within 7 days; by that time, the differentiation was completed, and the cells were ready for analysis. 1 day before his execution, differentiated omental adipocytes were transferred to a medium devoid of serum and phenol red, for incubation overnight. The total amount of samples in the analysis of 200 μl. Cells pre-incubated in the medium, purified from serum and phenol red, containing 0.1% (vol./about.) DMSO and test compounds in different concentrations, at least 1 hour before the addition of [3H]-cortisol in ethanol (50 Ci/mmol, ARC, Inc.), to achieve a final concentration of cortisone, 100 nm. Incubation of cells proishodila for 3-4 hours at 37°C, the content of CO25%. Negative controls were incubated without radioactive substrate and the end of the incubation took a similar amount of [3H]-cortisol. The formation of [3H] cortisol were monitored by analysis of 25 µl of each supernatant by the method of analysis of rapprochement with the scintillator (SPA). (Solly, K.; Mundt, S. S.; Zokian, H. J.; Ding, G. J.; Hermanowski-Vosatka, A.; Strulovici, B.; Zheng, W. Assay Drug Dev. Technol. 2005, 3, 377-384). Many of the compounds described in this invention, showed significant activity in this study.

BIOLOGICAL TEST EXAMPLE 3

The degree of inhibition of 11β-HSD the tested compounds was determined by the method of HTRF (homogeneous fluorescence with a time resolution) (cisbio international, France); method allows the detection of cortisol produced from nortesterone by human liver microsomes. Compounds were incubated for 1 hour at 37°C in Tris-buffer (20 mm Tris (hydroxyethylaminomethyl), 5 mm add with pH 6.0) containing NADPH (200 μm) and cortisone (80 nm). Cortisol is produced during the reaction is detected by a method competitive enzyme immunoassay using two conjugates HTRF: cortisol associated with XL665, and anti-cortisol antibodies labeled with Cryptocom europium. The incubation period for reaction discovery about what the rule was 2 hours. The amount of cortisol was determined by the degree of fluorescence with a time resolution of holes. (Ex 320/75 nm; Em 615/8,5 nm and 665/7,5 nm). Then, we calculated the ratio of the two emission signals (Em665*10000/Em615). Each analysis consisted of incubation with control solvent instead of the compounds being considered as control solutions neighborouing cortisol (100% CTL; 'high value') and incubation with carbenoxolone as control fully inhibited enzyme and cortisolemia background (0% CTL; 'low value'). Each study also included the preparation of a calibration curve to match the performance of fluorescence with concentrations of cortisol. Suppression of each connection in terms of a percentage, was determined relative to the signal carbenoxolone.

The table below shows the inhibitory effect on 11β-HSD-1 defined above; 100% means no inhibition, zero or negative value - full inhibition.

TABLE of INDICATORS of BIOLOGICAL ANALYSES BATISTA 3
ExampleThe average value of the control inhibition (%), 100 nm
75-14
7617
7759
7858
7915
8037
8111
82-12
8354
904
9621
9747
9867

BIOLOGICAL TEST EXAMPLE 4

The degree of inhibition of the chip drug 11β-HSD compounds of the present invention, in prisutstvie 50% human blood plasma, were measured in more methods described below. Microsome assay cell line of Cho, sverkhekspressiya 11β-HSD man, was introduced into a reaction buffer consisting of 25 mm N-2-hydroxyethylpiperazine-N-2-econsultancy acid (HEPES) pH 7.4, 50 mm KCl, 2.5 mm NaCl, 1 mm MgCl2and 50% (vol./about.) the human blood plasma (BioChemed). The analysis begins with dispensive 49 μl of rastvoronasosom in 96-well polypropylene plates, and add 1 μl of the test compounds in DMSO, pre razbivshihsya half increment (8 points) starting with 1.0 mm. The reaction was initiated by adding 50 μm solution of substrate consisting of reaction buffer with 2 mm of NADPH and 160 nm of [3H]cortisone (1 Ci/mmol). Plates were incubated for 120 minutes at room temperature. To stop makes reactions were added 100 μl of acetonitrile with 20 mm of cortisone and 20 mm of cortisol. After 10-minute incubation at room temperature, 100 ál of the contents of each well was filtered through a plate HV-filter Multiscreen HTS (Millipore) and diluted to 100 μl of reaction buffer, purified from human blood plasma, [3H]cortisone and [3-H]-cortisol were separated by HPLC, chromatographic column Bond SB-C8 (of 4.6×250 mm, manufacturer Agilent) by isocratic elution with 25% acetonitrile in water containing 0.01% of triperoxonane acid; the degree of radioactivity was determined using the built-in detector β-RAM (IN/US Systems, Inc.).

BIOLOGICAL TEST EXAMPLE 5

(Unbound fraction in plasma of human blood)

The degree of binding of compounds to plasma proteins was determined by the method of equilibrium dialysis plasma with the entered connection compared to free from connection dextrane buffer, through a dialysis membrane with a permeability of 5000 Da. Concentration of the compound in plasma and buffer after incubi the tion was measured by HPLC/Mass spectrometry.

BIOLOGICAL TEST EXAMPLE 6

(CYP3A4 inhibition)

The analysis was based on the method published by Moody and others (Xenobiotica 1999). Inhibition makes reactions of N-demethylation [N-methyl-14C]-erythromycin a test connection, catalyzed by the 3A4 isoenzyme of cytochrome P450, were studied at 37°C with recombinant cytochrome P450 3A4. All analyses were performed using a robotic system with 96-well plates. The final volume of sample for incubation was 200 μl; it included, Tris-buffer (0.1 M), MgCl2(5 mm), recombinant protein (40 pmol/ml), erythromycin (50 μm) and the test compound, or in four different concentrations in duplicate (e.g. the highest concentration of 10-50 μm with subsequent serial dilutions 1:5), or at a concentration of 10 μm in triplicate. After a short coincubation period, the reaction was initiated by addition of the cofactor (NADPH, 1 mm) and stopped by adding 50 μl of an aqueous solution of trichloroacetic acid (10% m/Rev). An aliquot of incubate were transferred to 96-well plates to solid phase extraction (SPE) and was extracted in the cartridge. The resulting [14C]-formaldehyde/formic acid retained in the cartridge, and it was isolated from nematerializiranih substrate by washing the wells SPE water. An aliquot of the eluates endured the camping hole in tablets, suitable for liquid scintillation measurement activity. The rate of formation of [14C]-formaldehyde/formic acid at these inkubirovanija were compared with the control activity that does not contain the test compound. If the connection was tested with four concentrations were calculated experimental values IC50.

BIOLOGICAL TEST EXAMPLE 7

(CYP2C9 inhibition)

The degree of inhibition of cytochrome P450 isoenzyme 2S9 that catalyzes the O-demethylation of [O-methyl14S]-naproxen test compound was analyzed at 37°C with recombinant cytochrome P450 2S9 person; a procedure similar to that described in example 6. The experimental value IC50was calculated based on the percentage of control at four different concentrations.

BIOLOGICAL TEST EXAMPLE 8

(Inhibition of CYP2C19)

The degree of inhibition of cytochrome P450 2C19 isoenzyme, which catalyzes N-demethylation [N-methyl-N14S]-diazepam test compound was analyzed at 37°C with recombinant cytochrome P450 2C19 person; a procedure similar to that described in example 6. The experimental value IC50was calculated based on the percentage of control at four different concentrations.

BIOLOGICAL TEST EXAMPLE 9

(Inga is the key CYP2C9)

The degree of inhibition of recombinant cytochrome CYP2C9 compounds of the present invention, was measured using industrial recruitment company Invitrogen (cat. No. 2859) Supplied microsome assay, isolated from insect cells infected with baculoviruses, rebuild the expression of CYP2C9 man, were brought to a volume of 10 mm reaction buffer (100 mm sodium phosphate buffer, pH=8,0) using systems for generation of NADPH (3,33 mm glucose-6-phosphate and 0.4 u/ml glucose-6-phosphate dehydrogenase). 89 μl of this solution was dispensibility in each well of 96-well plate of polystyrene black and mixed with 1 μl of test compound, pre-diluted DMSO half increment, starting from 3 mm. The analysis was initiated by adding 10 µl foraging substrate n-octyloxybenzoate (OOMR, 20 μm) with NADP (100 μm), diluted in the reaction buffer. The tablet is immediately placed in the reader Perkin Elmer Fusion. The reaction was monitored by measuring fluorescence every 2 minutes for 20 minutes (excitation filter 530 nm/filter emission 605 nm).

TABLE of RESULTS of the ANALYSIS of BIOLOGICAL ACTIVITY of COMPOUNDS of the COMPARISON IN the COURSE of BIOLOGICAL TESTS 6-9
Connection comparisonBiological test. Example 6 CYP3A4, IR50[µm]Biological test. Example 7 CYP2C9, IR50[µm]Biological test. Example 8 CYP2C19, IR50[µm]Biological test. Example 9 CYP2C9 IR50[µm]
127,0
21,4
37,44,1the 5.7a 4.9
45,1
59,95,18,33,7
64,42,35,0
74,0
85,32,45,63,0
97,03,19,32,5
103,6
1114,16,312,55,5
12a 4.94,69,52,5
13a 4.9a 3.9the 10.1
144,45,6<0,47,3
1519,7 25,96,424,6
163,17,7<0,49,5

The connection of comparison 1The connection of comparison 2
Connection comparison 3Connection comparison 4
Connection compare 5Connection comparison 6
Connection comparison 7Connection comparison 8
Connection CPA is the link 9 Connection comparison 10

Connection comparison 11Connection comparison 12
Connection comparison 13Connection comparison 14
Connection comparison 15

The compounds presented in this invention, are useful in reducing the intensity of symptoms or treatment of diseases or disorders in which reduced levels of cortisol has a beneficial effect on the course of diseases. Thus, the compounds presented in this invention can be used in the treatment of diabetes (e.g. type II diabetes), obesity, symptoms of metabolic syndrome, glucose intolerance, hyperglycemia, hypertension, hyperlipidemia, insulin resistance, cardiovascular systems is, dyslipidemia, atherosclerosis, lipodystrophy, osteoporosis, glaucoma, Cushing's syndrome, Addison disease, visceral fat, is associated with glucocorticoid therapy, depression, anxiety, Alzheimer's disease, dementia, cognitive disorders (including age), syndrome of polycystic ovaries, infertility, hypergonadism. Compounds of the present invention can be used as therapeutic agents for the treatment of pseudointima Cushing syndrome caused by liver disease in alcoholism. In addition to this compound reduces cell function and T the immune system and, thus, can be used in the treatment of tuberculosis, leprosy and psoriasis. The drug can also be used to accelerate the healing of wounds, especially in diabetes.

Other diseases or disorders related to the effects of 11β-HSD include diseases of the group, including lipid disorders, hypertriglyceridemia, hypercholesterolemia, low levels of HDL cholesterol and high levels of LDL-cholesterol, vascular restenosis, pancreatitis, Central obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, diabetes, coronary heart disease, stroke, peripheral vascular disease, Cushing's syndrome, hyperinsulinemia, viral diseases, and syndrome X. in Addition to this the th, the activity of 11β-HSD can cause pseudo-Cushing's syndrome associated with liver disease in alcoholism.

The drug of the present invention an alternative or in addition to the inhibitor of 11β-HSD may include a pharmaceutically acceptable salt of the indicated inhibitor and one or more pharmaceutically acceptable carriers. Alternatively, the drug may include direct inhibitor of 11β-HSD or its salt as the sole pharmaceutically active substances in medicinal drug. Considered inhibitors of 11β-HSD can be used as individual therapeutic agents or in combination with one or more additional drugs for the treatment of diabetes, dyslipidemia, cardiovascular disease, hypertension, obesity, cancer or glaucoma.

In the compositions of the present invention are inhibitors of 11β-HSD. These compositions contain compounds with a mean inhibition constant (IC50) less than 1,000 nm in comparison with 11β-HSD; preferably less than 100 nm; more preferably less than 50 nm; even more practicelink is less than 5 nm; the most preferred option is less than 1 nm.

The present invention includes a therapeutic method for the treatment or improvement of diseases mediated by the presence of 11β-HSD the patients need admission in effective amounts of an inhibitor 1β-HSD, or its enantiomer, diastereoisomer, or a pharmaceutically acceptable salt, or a compound thereof. The term "Treatment" will denote both prophylactic and therapeutic treatment. Therapeutic treatment includes a reduction of symptoms associated with the disease or condition and(or) increasing life expectancy of a patient with this disease or this state. Prophylactic treatment refers to the delay in the occurrence of disease or condition, if there is a risk of such occurrence; or reducing the likelihood that the patient will develop a disease or condition, if there is a risk of such occurrence.

One of the embodiments of the present invention involves a technique of connecting, inhibition 1β-GSD or composition, which includes such inhibitor - in combination therapy with one or more other drugs for treatment of diabetes, dyslipidemia, cardiovascular disease, hypertension, obesity, cancer or glaucoma. The number of drugs to treat diabetes include insulin such as Humulin® (Eli Lilly), Lantus® (Sanofi Aventis), Novolin (Novo Nordisk), and Exubera® (Pfizer); PPAR-gamma agonists, such as Avandia® (rosiglitazone maleate, GSK) and Actos® (pioglitazone hydrochloride, Takeda/Eli illy); the sulfonylurea, e.g. Aaryl® (glimepiride, Sanofi Aventis), Diabeta® (gliburid, Sanofi Aventis), Micronase®/Glynase® (gliburid, Pfizer), and Glucotrol®/Glucotrol XL® (glipizide, Pfizer); meglitinides, such as Prandin®/NovoNorm® (Repaglinide, Novo Nordisk), Starlix® (nateglinide, Novartis), and Glufast® (mitiglinide, Takeda); biguanides, such as Glucophase®/Glucophase XR® (Metformin HCL, Bristol Myers Squibb) and Glumetza (Metformin HCl, Depomed); thiazolidinedione; Amylin analogs, analogs of GLP-1; inhibitors of DPP-IV, inhibitors PTB-1B; inhibitors of protein kinases (including AMR-activated inhibitors of protein kinases); glucagon antagonists, beta inhibitors kinase glycogen synthase-3; inhibitors of glucose-6-phosphatase; inhibitors of glycogen phosphorylase; inhibitors of cotransporter sodium glucose; alpha-glucosidase inhibitors, such as Precose®/Glucobay®/Prandase®/Glucor® (acarbose, Bayer) and Glyset® (miglitol, Pfizer). Drugs for the treatment of dyslipidemia and cardiovascular diseases include statins, fibrates and ezetimibe. Drugs to treat hypertension include alpha-blockers, beta-blockers, calcium channel blockers, diuretics, inhibitors of angiotensin-converting enzyme (ACE) inhibitors, dual action inhibitors that inhibit the enzyme and neutral endopeptidase, inhibitors of receptors of Anglomania, synthase inhibitors aldosterone antagonists aldosterone receptor or receptor antagonists endothelin. Drugs for the treatment of obesity vlachochristos, phentermine, sibutramine and rimonabant.

One of the embodiments of the present invention includes receiving compound that inhibits 11β-HSD or composition containing such a compound, or the use of combination therapy with one or more inhibitors of 11β-HSD or in combination with other products, such as Avandamet® (Metformin HCl and rosiglitazone maleate, GSK); Avandaryl® (glimepiride and rosiglitazone maleate, GSK); Metaglip® (glipizide and Metformin Bristol Myers Squibb); and Glucovance® (gliburid and Metformin HCl, Bristol Myers Squibb).

Compounds of the present invention, can be prepared and applied in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention, can be introduced by injection intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, intraperitoneally. In addition, the compounds of the present invention, can be introduced through the nasal cavity or through the skin. Specialists in the art should be obvious that the following dosage forms may include an active component, other components, or a corresponding pharmaceutically acceptable salt of the compounds being considered.

For the preparation of medicinal products of the components discussed in this innovation is the invention, must be used pharmaceutically acceptable carriers, liquid or solid. Drugs in solid form include powders, tablets, pills, capsules, starch capsules, suppositories, and dispersible granules. Solid media can be a substance or substances which may also act as diluents, flavoring agents, soljubilizatory, lubricants, suspendresume agents, binders, preservatives, disintegrators tablets or as an encapsulating material. In powders, the carrier is a finely divided solid substance is mixed with the finely divided active component.

In tablets, the active ingredient is mixed with a carrier that requires the addition of a binder in certain quantities, and korrektiruete order to obtain the desired shape and size.

The composition of the powders and tablets often includes from 1% to 70% of the active component. Suitable carriers - magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragakant, methylcellulose, sodium carboxymethyl, wax with a low melting temperature, cocoa butter, etc., Tablets, powders, starch capsules, lozenges, instant strips, capsules and pills can be used as solid dosage forms containing the active ingredient, suitable for the reception of Perera is Ino.

For preparing suppositories, first of all melted wax with a low melting point, which is a mixture of glycerides of fatty acids or cocoa butter, and it is the active ingredient; the uniformity in the introduction is provided, for example, by continuous stirring. The molten homogeneous mixture is poured into molds of the desired size, then she is allowed to cool and harden.

The liquid forms include solutions, suspensions, retention enemas and emulsion - for example, water or water-propylene glycol solutions. For parenteral injection, liquid preparations can be represented in the form of solutions in the composition of the aqueous solution of polyethylene glycol.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers and thickeners, as desired. Aqueous suspensions for oral use can be prepared by dispersing the active ingredient in water containing a viscous material is a natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspendresume agents.

Drug in most cases presented in the form of dozirovanno is x units. In such form the preparation is subdivided into unit doses containing the active ingredient in the proper amounts. The form of dosage units may be different - the drug in the package; the package containing, for example, tablets, powders and capsules in vials or ampoules in discrete quantities. Form of unit dosages may also be different - tablet, a starch capsule, a conventional capsule, toffee; or any of the specified in the required quantities, in Packed form.

The content of active ingredient in the drug per unit dosage can vary or be adjusted from 0.1 mg to about 1000,0 mg, preferably, from 0.1 mg to 100 mg However the dosage may vary depending on the requirements of the patient, the severity of the condition under treatment and the used composition. Determining the right dosage for a particular situation is determined by the level of competence of specialists in a particular field of technology. Drug, if necessary, may also include other compatible therapeutic agents.

When therapeutic treatment, or as a method of use as an inhibitor of 11β-HSD or inhibitor in the production of cortisol in a cell, it is preferable to use oral intake of the drug in solid dosage form described above, the amount of about 0.1 - 100 mg daily; admission is 1 or more times per day.

All publications, patents and patent applications referred to herein included by reference, to the same extent as if each individual publication or patent application was specifically and individually indicated as included by reference. The described examples and embodiments of the present invention are included herein for illustrative purposes only, and it should be understood that modifications and changes to the above invention, while maintaining the scope and meaning of the accompanying claims.

Although the advantages of the present invention have been partially disclosed and described herein in the example of preferred embodiments, it should be understood that various changes in form and detail while maintaining the scope of the invention, which are shown in the attached claims.

1. The compound of formula (Ip1) or (Ip3):


or its pharmaceutically acceptable salt;
where
G1is a (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)halogenated, (C1-C4)halogenoalkane, halogen, cyano or nitro;
n 0;
G2ais a (C3 4)cycloalkyl or (C3-C4)cycloalkyl(C1-C2)alkyl;
G2brepresents hydrogen;
R1represents methyl or ethyl;
R2represents phenyl or forfinal; and
R3represents a 2-hydroxy-2-methylpropyl or 2-methyl-2-cyanopropyl.

2. Connection on p. 1, which has the following formula:

or

or its pharmaceutically acceptable salt.

3. Connection on p. 1, having the formula:

or its pharmaceutically acceptable salt.

4. Pharmaceutical composition for the treatment of human disease or condition selected from diabetes type II, obesity, glucose intolerance, hyperglycemia, hyperlipidemia, insulin resistance, reduced cognitive function, and dyslipidemia, including: i) a pharmaceutically acceptable carrier or diluent; and ii) the compound according to any one of paragraphs.1-3 or its pharmaceutically acceptable salt.

5. The use of compounds according to any one of paragraphs.1-3 or its pharmaceutically acceptable salt for the manufacture of a medicinal product for the treatment of human disease or condition selected from diabetes type II, obesity, glucose intolerance, hyperglycemia, hyperlipidemia, resi is mentasti to insulin, reduction of cognitive functions and dyslipidemia.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to isoxazoline FAAH inhibitors of formula (I) or their pharmaceutically acceptable forms, wherein each of G, Ra, Rb, Rc and Rd has a value described in the present application, to pharmaceutical compositions, and methods of treating a FAAH-mediated condition.

EFFECT: developing the method of treating the FAAH-mediated condition.

32 cl, 22 tbl, 351 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compound - 6-methyl-5-morpholynomethyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-dione of formula 6-methyl-5-morpholynomethyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-dione of formula: .

EFFECT: novel compound, possessing antioxidant activity, is obtained.

2 cl, 6 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrimidine compounds of general formula (I) or their pharmaceutically acceptable salts, which can be used in treating the diseases related to mTOR kinase or PI3K kinase, such as cancer, immune diseases, viral infections, inflammations, neurological and other disorders. In general formula (I) , R1 means a group (A), wherein P represents C6aryl optionally substituted by a halogen, -OH, -NH2, -OC1-C6alkyl, unsubstituted 6-merous heteroaryl containing 1-2 heteroatoms N, unsubstituted indolyl, unsubstituted indazolyl, Q is specified in -H, -OR, -SR, -halo, -NR3R4, -OS(O)mR, -OC(O)NHR, -S(O)mNR3R4, -NRC(O)R, -NRS(O)mR, -NRC(O)NR3R4 and -NRC(S)NR3R4, wherein each R, R3 and R4 are independently specified in H, C1-C6 alkyl optionally substituted by a halogen, -N(C1-C3alkyl)2, 5-, 6-merous heterocyclic group containing 1-2 heteroatoms specified in N and O, 6-merous heterocyclic group containing 1-2 heteroatoms specified in N and O, optionally substituted by C1-C6alkyl, C6aryl group optionally substituted by one or two substitutes specified in a halogen, -OC1-C3alkyl, -CF3, -NH2, -C(O)NH2, -NHC(O)C1-C3alkyl, -N(C1-C3alkyl)2, -COOH, -SO2NH2, -SO2C1-C3alkyl, -NHSO2C1-C3alkyl, -CO2C1-C6alkyl, dioximethylene group, -NHC(O)CF3, -C(O)NH(CH2)2÷3N(C1-C3alkyl)2, -O(CH2)2N(C1-C3alkyl)2, 6-merous heterocyclyl containing 1-2 heteroatoms specified in N, O and S optionally substituted by oxo, C1-C3alkyl, -SO2C1-C3alkyl, -C(O)-6-merous heterocyclyl optionally substituted by C1-C3alkyl, 6-merous heteroaryl containing 1-2 heteroatoms N optionally substituted by one or two substitutes presenting a 6-merous heterocyclyl or -SC1-C3alkyl, or a 5-, 6-merous heteroaryl group containing 1-2 heteroatoms specified in N, O and S, optionally condensed with a benzene ring and optionally substituted by a halogen, -CO2C1-C3alkyl, oxo, -NHC(O)C1-C3alkyl, C1-C3alkyl, 6-merous heterocyclyl containing 2 heteroatoms specified in N and O optionally substituted by C1-C3alkyl, m means 1 or 2, or R3 and R4 together with a nitrogen atom to which they are attached, form a saturated 5-, 6-merous N-containing heterocyclic group, which is unsubstituted or substituted by C1-C3alkyl, -SO2C1-C3alkyl, oxo, Y is specified in -O-(CH2)n-, -S-(CH2)n- and -S(O)m(CH2)n-, wherein m means 1, n means 0 or an integer from 1 to 2, R2 is specified in H or a group -NR3R4, wherein R3 and R4 are those as specified above, Z is specified in halo, -(CH2)s-COOR, -(CH2)sCONR3R4, -(CH2)sCH2NR3R4, wherein s means 0 or an integer from 1 to 2 and wherein R, R3 and R4 are those as specified above, unsubstituted 6-merous heteroaryl containing one heteroatom N, substituted or unsubstituted heterocyclyl containing two heteroatoms specified in N and O; the substitute is specified in C1-C3alkyl and C1-C3alkylsulphonyl, and W is specified in a morpholine cycle and pyridine cycle. The invention also refers to a method for preparing the compounds of formula (I).

EFFECT: preparing the new pyrimidine compounds.

12 cl, 5 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

,

where R2 is a heteroaryl group and where said monocyclic heteroaryl group is unsubstituted or substituted with one or more groups selected from F, Cl, Br, I, -NR10R11 and C1-C12 alkyl; and groups selected from F, -NH2, -NHCH3, -N(CH3)2, -OH, -OCH3, -C(O)CH3, -NHC(O)CH3, -N(C(O)CH3)2, -NHC(O)NH2, -CO2H, -CHO, -CH2OH, -C(=O)NHCH3, -C(=O)NH2, and -CH3; R3x, R3y, R3z and R3p is hydrogen; R4x, R4y, R4z and R4p are independently selected from a group consisting of: hydrogen, F, Cl, Br, I, and -C(C1-C6 alkyl)2NR10R11; and R10 and R11 are hydrogen, which are phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitors.

EFFECT: high effectiveness of compounds.

7 cl, 7 tbl, 50 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

Amide derivative // 2536409

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where R1 is a hydrogen atom or a C1-C6-alkyl group, substituted with one or two substitutes selected from C1-C6-alkoxy group, hydroxyl group, which can be substituted with a C1-C6-alkylcarbonyl group (substituted with one or two substitutes γ), and a 4-6-member saturated monocyclic heterocyclic carbonyl group containing a N atom; γ is a hydroxyl group, amino group, di(C1-C6-alkyl)amino group and carbamoyl group; R2 is a H atom or a C1-C6alkyl group, which can be substituted with a hydroxyl group; or R1 and R2, together with the nitrogen atom with which they are bonded, can be combined to form an azetidine group, a pyrrolidine group or morpholine group, which can be substituted with one hydroxyl group or a hydroxy-C1-C6-alkyl group; R3 and R4 is a C1-C6-alkyl group; R5 is a halogen atom or a C1-C6-alkyl group; R6 is a halogen atom; m and n denote an integer from 0 to 1; V and W are CH; X, Y and Z each independently can be CH or N. The invention also relates to a pharmaceutical composition containing a compound of formula (I), use of the compound of formula (I) and a method of treating sugar diabetes a disease associated with diabetes.

EFFECT: compounds of formula (I), having hypoglycemic activity.

21 cl, 6 tbl, 72 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of general formula [1] or their pharmaceutically acceptable salts, which possess properties of an inhibitor of the JAK2 thyrokinase activity. In general formula radicals are selected from group (I) or (II). In group (I) X represents CH or N; R1 represents a halogen atom and R2 represents H, a halogen atom, CN, or is selected from the groups of formulas

,

or a group -ORP or 5-6-membered heteroaryl, containing 1-4 nitrogen atoms and optionally additionally containing an oxygen or sulphur atom or containing an oxygen atom as a heteroatom, optionally substituted; or (II) X represents -CRA; and RA represents a group of formula , RB represents (a) amino, optionally substituted with one or two groups, selected from the group, consisting of C1-6alkyl, C3-6cycloalkyl, (C3-6cycloalkyl)C1-6alkyl and C1-3alcoxyC1-3alkyl, (b) C1-3alcoxy, (c) hydroxy or (d) a 5-6-membered saturated cyclic amino group, which additionally can contain a heteroatom, selected from an oxygen atom; R1 represents a halogen atom and R2 represents H; R3 -R5 have values given above. Other values of the radicals are given in the invention formula.

EFFECT: compounds can be applied for the prevention or treatment of cancer, for instance hematologic cancer disease or a solid form of cancer, inflammatory disorder, for instance, rheumatoid arthritis, inflammatory intestinal disease, osteoporosis or multiple sclerosis and angiopathy, for instance, pulmonary hypertension, arteriosclerosis, aneurism or varicose veins.

14 cl, 19 tbl, 234 ex

FIELD: medicine, pharmaceitics.

SUBSTANCE: invention relates to particular derivatives of N-(phenylsulphonyl)benzamide, given in i.1 of the invention formula. The invention also relates to a pharmaceutical composition, possessing an inhibiting activity with respect to anti-apoptotic proteins Bcl-2, containing an effective quantity of one of the said compounds or a therapeutically acceptable salt of such a compound.

EFFECT: N-(phenylsulphonyl)benzamide derivatives as inhibitors of the anti-apoptotic proteins Bcl-2.

2 cl, 2 tbl, 458 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to a heterocyclic compound of formula I and its pharmaceutically acceptable salt, wherein if a chemical valency permits, i represents 1 or 2, R1 represents H; a linear (C1-C4) alkyl group, R2 represents H, Cl or F, X represents either N, or CR3, R3 represents H; halogen; a linear (C1-C4) alkyl or (C1-C4) alkoxyl group, Y represents Z represents O or NRx, Rx represents H or a linear or branched (C1-C4) alkyl, k is equal to 2, 3 or 4, n and p independently represents 2, and a sum of n+p cannot exceed 4, T represents H or a linear (C1-C4) alkyl group; T′ represents a linear C1-C3 alkyl chain substituted by either (C1-C6)-dialkylaminogroup, or a 5-6-merous saturated heterocycle containing one nitrogen atom and optionally containing the second heteroatom specified in O, such a heterocyclic ring is optionally substituted by a (C1-C4) alkyl chain at nitrogen atoms; or a 5-merous saturated heterocycle containing one nitrogen atom, such a heterocyclic ring is optionally substituted by a (C1-C4) alkyl chain at nitrogen atoms; r represents zero, 1; R′ represents di(C1-C4)alkylamino, (C1-C4)alkoxy; except for the compounds specified in the clause. The invention also refers to a pharmaceutical composition based on the compound of formula (I), using the compound of formula (I) and to a method of treating diseases, in which the hedgehog signalling pathway modulation is effective.

EFFECT: there are prepared new heterocyclic compounds possessing t effective biological properties.

20 cl, 193 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to a new compound of formula or its pharmaceutically acceptable salt, wherein R1 represents (C1-C6)alkyl; an oxodihydropyridyl ring in the formula is optionally substituted by 1-3 groups optionally specified in fluorine, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, halo(C1-C6)alkyl and (C1-C6)alkoxy(C1-C6)alkoxy; R2 represents (C1-C6)alkyl, phenyl, or tetrahydropyranyl optionally substituted by a group in the number of up to 1 independently specified in fluorine, hydroxy(C1-C6)alkyl and (C3-C6)cycloalkyl; R3 is specified in (C1-C6)alkyl optionally substituted by groups in the number of up to 3 independently specified in fluorine, cyano, R4, R4O-, (R4)2N-, R4C(=O)NR4-, (R4)2NC(=O)-, R4OC(=O)NR4-, R4S(=O)2NR4- and oxadiazolyl optionally substituted by (C1-C6)alkyl; R4 independently represents H or (C1-C6)alkyl. Also, the invention refers to a method of treating an individual by using the above compound, a method of inhibiting 11β-HSD1, and a compound-based pharmaceutical composition.

EFFECT: there are prepared new compounds effective in treating the diseases related to 11β-HSD1 activity or expression.

15 cl, 6 tbl, 101 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyrimidine derivatives of structural formula (I-L0) and their crystalline forms possessing the inhibitory activity on the hepatitis C virus (HCV) polymerase. In formula is specified in a single or double carbon-carbon bond; R1, R2 and R3 represent hydrogen; R4 is specified in halo, C1-C6alkyl, C2-C6alkinyl, amino, C1-C6alkylsulphonyl, C3-C10carbocyclyl and 5-6-merous heterocyclyl having a heteroatom specified in a group consisting of O and S, wherein amino is optionally substituted by one or two C1-C6alkylsulphonyls, and C1-C6alkyl and C2-C6alkynyl are optionally substituted by one or more substitutes optionally specified in a group consisting of halo, oxo, hydroxy, C1-C6alkyloxy and trimethylsilyl, and C3-C10carbocyclyl and 5-6-merous heterocyclyl are optionally substituted by substitutes specified in C1-C6alkyl, halo and amino, wherein amino is optionally substituted by one or two C1-C6alkylsulphonyls; R5 is specified in a group consisting of hydrogen, hydroxy, C1-C6alkyloxy and halo; R6 represents a condensed 2-ring C3-C10carbocyclyl optionally substituted by substitutes specified in RE, RF, RG, RH, RI, RJ and RK, the values of which are specified in the patent claim.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, to using the compounds for producing a therapeutic agent for hepatitis C, to an intermediate compound for producing the compound of structural formula (I-L0) and to a method for preparing the above compounds and their crystalline forms.

70 cl, 23 dwg, 9 tbl, 83 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to a new compound of formula or its pharmaceutically acceptable salt, wherein R1 represents (C1-C6)alkyl; an oxodihydropyridyl ring in the formula is optionally substituted by 1-3 groups optionally specified in fluorine, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, halo(C1-C6)alkyl and (C1-C6)alkoxy(C1-C6)alkoxy; R2 represents (C1-C6)alkyl, phenyl, or tetrahydropyranyl optionally substituted by a group in the number of up to 1 independently specified in fluorine, hydroxy(C1-C6)alkyl and (C3-C6)cycloalkyl; R3 is specified in (C1-C6)alkyl optionally substituted by groups in the number of up to 3 independently specified in fluorine, cyano, R4, R4O-, (R4)2N-, R4C(=O)NR4-, (R4)2NC(=O)-, R4OC(=O)NR4-, R4S(=O)2NR4- and oxadiazolyl optionally substituted by (C1-C6)alkyl; R4 independently represents H or (C1-C6)alkyl. Also, the invention refers to a method of treating an individual by using the above compound, a method of inhibiting 11β-HSD1, and a compound-based pharmaceutical composition.

EFFECT: there are prepared new compounds effective in treating the diseases related to 11β-HSD1 activity or expression.

15 cl, 6 tbl, 101 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new phenylpyrimidone derivatives of formula I possessing the properties of a phosphodiesterase type 5 (PDE5) inhibitor. The compounds of formula I can be used for treating various vascular disorders, such as erectile dysfunction, pulmonary arterial hypertension, etc. In formula each R1 and R2 independently means H; C1-C10alkyl; halogen; CF3; CN; OR5; NR6R7; NHCOR8; aryl; or C1-C4alkyl optionally substituted by OR5; Z means OR3; R3 means C1-C6alkyl or C1-C3alkyl, substituted by C1-C3alkoxy group; R4 means SO2NR6R7; NR9R10, providing NR9R10 is other than NH2; COR11; OR12; or R4 means 5-6-merous heterocyclyl optionally substituted by one or more substitutes specified in a group consisting of OH and C1-C6 alkyl; or R4 means 5- or 6-merous cyclic monosaccharide group; R5 means C1-C6alkyl; C1-C4alkyl optionally substituted by C1-C4alkoxy group; each R6 and R7 independently means H, OH, C1-C6alkyl, C1-C6alkoxy group, C3-C6alkenyl, C3-C6cycloalkyl, adamantyl, C3-C8lactamyl, aryl, Het or (CH2CH2O)jH, wherein j is 1-3; or each R6 and R7 independently means C1-C6alkyl, optionally substituted by OH, C1-C4alkoxy group, SO3H, SO2NR13R14, SO2R16, NR13R14, aryl, Het or 5-6-merous heterocyclyl; or each R6 and R7 independently means 5-6-merous heterocyclyl optionally substituted by one or more substitutes specified in a group consisting of C1-C6 alkyl and C1-C6alkyl substituted by hydroxyl; or R6 and R7 together with a nitrogen atom attached whereto form 5-7-merous heterocyclyl optionally substituted by one or more substitutes specified in a group consisting of OH, COOR8, (CH2CH2O)jH, wherein j is 1-3, C1-C4alkoxy group, Het and C1-C6alkyl substituted by aryl; or R6 and R7 together with a nitrogen atom attached whereto form a glucosyl amino group, an amino acid residue, a residue of an amino acid ester or an amino amide residue. The other radical values are specified in the patent claim.

EFFECT: invention refers to pharmaceutical compositions based on the above compounds, using them, methods for preparing the compounds, and intermediate products.

18 cl, 2 tbl, 224 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 4-substituted-N-phenyl-1,8-naphthalimides which contain in the N-aryl nucleus a crown ether residue (with a different combination of oxygen, nitrogen and sulphur atoms) of general formula (I) , where R1=NO2, Br, NH2, OCH3, NHCOCH3, Ia: Rl=NO2, X=S, n=1; Ib: R1=NO2, x=NCH3, n=1; Ic: R1=NO2, X=NCH3, n=2; Id: R1=Br, X=NCH3, n=2; Ie: R1=NH2, X=S, n=1; If: R1=NHCOCH3, X=S, n=1; Ig: R1=OMe, X=S, n=1; Ih: R1=OMe, X=NCH3, n=1; Ii: R1=OMe, X=NCH3, n=2, where compounds If-Ii exhibit properties of fluorescent sensors on cations of alkali-earth, transition and heavy metals, and compounds Ia-Ie are intermediate compounds in the process of synthesis of compounds If-Ii. The invention also relates to a method of producing a compound of formula (I) and intermediate compounds of formula (II)

EFFECT: obtaining novel sensors on cations of alkali-earth, transition and heavy metals, novel methods of producing compounds of the given formula.

7 cl, 3 tbl, 7 ex

Cetp inhibitors // 2513107

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula I, or its pharmaceutically acceptable salt where: X stands for -O-; Z stands for -C(=O)-; Y stands for -(CRR1)-, where R1 is selected from -C1-C2alkyl; R stands for H or -C1-C5alkyl; R5 stands for H; R2 and B each is selected from A1 and A2, where one of R2 and B stands for A1, and the other from R2 and B stands for A2; where A1 has structure (a); A2 is selected from the group, which includes phenyl, pyridyl, pyrazolyl, thienyl, 1,2,4-triazolyl and imodazolyl; A3 is selected from the group including phenyl, thiazolyl and pyrazolyl; A4 is selected from the group, including phenyl, pyridyl, thiazolyl, pyrazolyl, 1,2,4-triazolyl, pyrimidinyl, piperidinyl, pyrrolidinyl and asetidinyl; A2 is optionally substituted with 1-3 substituents, independently selected from halogen atom, -OCH3 and -OCF3 and -C1-C3alkyl, optionally substituted with 1-3 halogen atoms; A3 is substituted with one A4 group and is optionally substituted with 1-2 substituents, independently selected from halogen atom, -OH, -OCH3, -OCF3 and -C1-C3alkyl, optionally substituted with 1-3 halogen atoms; A4 is optionally substituted with 1-3 substituents, independently selected from the group, which includes: (a) -C1-C5alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with group -OH, (b) -C2-C4alkenyl, optionally substituted with 1-3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group selected from -OH, -CO2CH3, -C(=O)CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (d) -C(=O)H, (e) -CO2H, (f) -CO2C1-C4alkyl, optionally substituted with one group, selected from -C(=O)C1-C2alkyl, -OH, -CO2CH3, -CO2H, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (g) -OH, (h) -S(O)xC1-C2alkyl, (i) halogen atom, (j) -CN, (k) -NO2, (l) -C(=O)NR3R4, (m) -OC1-C2alkyleneOC1-C2alkyl, (n) -OC1-C3alkyl, optionally substituted with 1-3 halogen atoms, (o) -C(=O)OC1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group, selected from -OH, -CO2CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (q) -NR3R4 and (r) -S(O)xNR3R4, on condition that A4 stands for heterocyclic group, attached to A3 by means of ring carbon atom in A4, at least, one substituent in A4 must be selected from Re, where Re is selected from the group including: (a) -C1-C5alkyl, substituted with -OH group and optionally substituted with 1-3 halogen atoms, (b) -C2-C4alkenyl, optionally substituted with 1-3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group selected from -OH, -CO2CH3, -C(=O)CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (d) -C(=O)H, (e) -CO2H, (f) -CO2C1-C4alkyl, optionally substituted with one group, selected from -C(=O)C1-C2alkyl, -OH, -CO2CH3, -CO2H, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (g) -OH, (h) -S(O)xC1-C2alkyl, (i) -CN, (j) -NO2, (k) -C(=O)NR3R4, (l) -OC1-C2alkyleneOC1-C2alkyl, (m) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group, selected from -OH, -CO2CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (n) -NR3R4(=O)OC1-C2alkyl, (o) -NR3R4 and (p) -S(O)xNR3R4; p equals 0, 1 or 2; and Ra is selected from halogen atom, -CH3, -CF3, -OCH3 and -OCF3; R3 and R4 each is independently selected from H and CH3; and x equals 0, 1 or 2.

EFFECT: formula (I) compound is applied for medication, which possesses properties of CETP inhibitor, for increase of HDL-C and for reduction of LDL-C Technical result is compounds, inhibiting cholesterol ether transferring protein (CETP).

10 cl, 140 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an amide derivative of formula (I), where A is benzene or pyridine, where the benzene or pyridine optionally contain 1 or 2 or 3 identical or different substitutes selected from an alkyl containing 1-6 carbon atoms, a cycloalkyl containing 3-6 carbon atoms, an alkoxy containing 1-6 carbon atoms, a halogen atom, nitro, cyano, alkylsulphonyl containing1-6 carbon atoms, amino, cyclic amine selected from 1,1-di-oxoisothiazolidinyl, 2-oxooxazolidinyl, oxopyrrolidinyl, 1,1-dioxothiazinyl and 2-oxoimidazolidinyl optionally having a substitute selected from an alkyl containing 1-6 carbon atoms and an alkylcarbonyl containing a total of 2-7 carbon atoms, acylamino containing a total of 2-7 carbon atoms, and an alkylsulphonyl amino containing 1-6 carbon atoms, wherein the right-side bond is linked to the carbonyl and the left-side bond is linked to the nitrogen atom, R1 and R2 are identical or different and each is a hydrogen, an alkyl containing 1-6 carbon atoms and optionally containing 3 halogen atoms as substitutes, a cycloalkyl containing 3-6 carbon atoms, a phenyl, a halogen atom or a cyano group and R1 and R2 are not a hydrogen atom at the same time, R3 is a hydrogen atom, an alkyl containing 1-6 carbon atoms, an alkenyl containing 2-6 carbon atoms, a cycloalkyl containing 3-6 carbon atoms, or a halogen, R4a, R4b and R4c are each independently a hydrogen atom, an alkyl containing 1-6 carbon atoms, or an oxo, R5a, R5b and R5c are identical or different and each is a hydrogen atom, an alkyl containing 1-6 carbon atoms and optionally containing substitute(s) selected from phenyl, an alkoxy group containing 1-6 carbon atoms, optionally substituted with an alkoxy group containing 1-6 carbon atoms, a phyenylcarbonyloxy group and a hydroxy group, or a phenyl, X is a carbon atom (any of R4a, R4b and R4c can be bonded to a carbon atom, but the carbon atom is not substituted with oxo) or a nitrogen atom (if Y is a single bond, the nitrogen atom can be oxidised to form an N oxide), Y is a single bond, a carbonyl or an oxygen atom, Z1 and Z2 are each independently a carbon atom (substitute R3 is optionally bonded to a carbon atom) or a nitrogen atom, and m equals 1 or 2, a pharmacologically acceptable salt thereof. The amide derivative is used as a preventive/therapeutic drug for treating autoimmune diseases, inflammatory bowel diseases or osteoarthritis.

EFFECT: amide derivative which suppresses production of inductive type MMP-9.

14 cl, 4 tbl, 581 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel azabiphenylaminobenzoic acid derivatives, having the chemical formula: , where R1 is selected from a group consisting of hydrogen atoms, halogen atoms, C1-4-alkyl, C3-4-cycloalkyl and -CF3, R2 is selected from a group consisting of hydrogen atoms, halogen atoms and C1-4-alkyl group, R3 is -COOR5, where R5 is selected from a group consisting of a hydrogen atom and linear or branched C1-4-alkyl groups, R4 is selected from a group consisting of a hydrogen atom and C1-4-alkyl group; R9 is selected from a group consisting of a hydrogen atom and a phenyl group, G1 is a group selected from N and CR6, where R6 is selected from a group consisting of hydrogen atoms, halogen atoms, C1-4-alkyl, C3-4-cycloalkyl, -CP3 and C6-10-aryl group, G2 is a group selected from: - a hydrogen atom, hydroxy group, halogen atom, C3-4-cycloalkyl group, C1-4-alkoxy group and -NRaRb, where Ra is C1-4-alkyl group and Rb is selected from a group consisting of C1-4-alkyl group and C1-4-alkoxy-C1-4-alkyl group, or Ra and Rb together with the nitrogen atom with which they are bonded, form a saturated 6-8-member heterocyclic ring optionally containing one oxygen atom as an additional heteroatom, -monocyclic or bicyclic 5-10-member heteroatomatic ring containing one or more nitrogen atoms which are optionally substituted with one or more halogen atoms, and a phenyl group which is optionally substituted with one or more substitutes selected from halogen atoms, C1-4-alkyl, hydroxy group, C1-4-alkoxy group, C3-4-cycloalkyl, C3-4-cycloalkoxy group, cyano group, -CF3, -OCF3, -CONR7R8, oxadiazolyl, and where R7 and R8 are independently selected from a hydrogen atom, a linear or branched C1-4-alkyl group, C3-7-cycloalkyl group, or R7 and R8 together with a nitrogen atom with which they are bonded form a group of formula: , where n equals 0-3; or G2 together with R6 form a non-aromatic C5-10-carbocyclic group or a C6-10-aryl group, and pharmaceutically acceptable and N oxides thereof. Also described are pharmaceutical compositions containing said compounds and use thereof in treatment as dehydroorotate dehydrogenase (DHODH) inhibitors.

EFFECT: novel compounds which can be used as dehydroorotate dehydrogenase inhibitors are obtained and described.

30 cl, 118 ex

FIELD: chemistry.

SUBSTANCE: invention relates to bicyclosulphonyl acid (BCSA) compounds of formula: where: where each of -Rpw, -Rpx, -RPY, and -RPZ independently denotes H or -RRS1; each -RRS1 independently denotes -F, -Cl, -Br, -I, -RA1, -CF3, -OH, -OCF3 or -ORA1; where each RA1 independently denotes C1-4alkyl, phenyl or benzyl; and additionally, two neighbouring -RRS1 groups can together form -OCH2O-, -OCH2CH2O- or -OCH2CH2CH2O-; -RAK independently denotes a covalent bond, -(CH2)- or -(CH2)2-; -RN independently denotes -RNNN, or -LN-RNNN; the rest of the values of the radicals are given in claim 1, which act as inhibitors of inhibitors of tumor necrosis factor-α converting enzyme (TACE).

EFFECT: compounds are useful in treating TNF-α mediated conditions.

36 cl, 303 ex

FIELD: medicine.

SUBSTANCE: in claimed invention described is compound of general formula 1, or its pharmaceutically acceptable salt, where in each case independently on each other m equals 0, 1; p equals 1 or 2; R1 is selected from group, including -OH, -OC(O)NHMe, -OC(O)NMe2, -OC(O)NH(CH2)2Ph and OC(O)NH(CH2)2NMe2; R2 stands for -OH, -OC(O)Me, -OCH2CO2H, -OCH2CO2Et, -N3, -N=C(NMe2)2, -NH2, -NMe2, -NHC(O)Me, -NHC(O)CF3, - NHC(O)Ph, -NHC(O)NHPh, -NHC(O)CH2CH2CO2H, -NHC(O)CH2CH2CO2Me, - NHCH2Ph, -NHCH2(4-pyridyl), -NHCH2(2-pyridyl), -NHCH2(4-(CO2H)Ph), - NHCH2(3-(CO2H)Ph), -NHEt, -NHCHMe2, -NHCH2CHMe2, -N(CH2CHMe2)2, - NHCH2(cyclopropyl) or -NHC(O)CH2CH2NMe2; R3 stands for -OMe, -OEt, - OCH2(cyclopropyl), F, -O(CH2)2NMe2 or -O(CH2)2(4-morpholino); R4 stands for -NMe2, -NEt2, -NHEt, -NHCH2CHMe2, -N(Me)CH2CHMe2, - N(Me)CH2CH2NHS(O)2Me, -N(Me)CH2CH2NHS(O)2CF3, -NHCH2CH2OH, - N(Me)CH2CH2OH, -N(Me)CH2CO2H, -N(Me)CH2C(O)NH2, N(Me)CH2C(O)NHMe, -N(Me)CH2C(O)NMe2, -NHC(O)Me, 1-piperidinyl, 4-morpholino, (R)-2-(hydroxymethyl)-1-pyrrolidinyl, -NH2, -NO2, Br, CI, F, -C(O)Me or -CH2NH2; R5 stands for -OH or -N(R17)(R18); R17 and R18 independently in each case stand for H, (C1-C6)-alkyl, (C5-C7)-aryl-(C1-C6)-alkyl, where said aryl contains from zero to two heteroatoms, (C1-C6)-alkoxy or -[C(R19)(R20)]P-R21 R19 and R20 independently in each case represent H, (C1-C6)-alkyl, (C1-C6)-alkoxy, amino-(C1-C6)-alkyl, acylamino, sulfonylamino, (C5-C7)-aryl, (C5-C7)-aryl-(C1-C6)-alkyl or 3-10-membered heterocyclyl-(C1-C6)-alkyl, containing in ring from one to two heteroatoms; R21 independently in each case represents H, 3-10-membered heterocyclyl, containing in ring one heteroatom, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylsulfonamido or amido; R22 stands for halogen; R23 stands for methyl; R24 stands for methyl and R25 stands for methyl, where said aryl stands for 5-7-membered ring, containing from zero to two heteroatoms, and said aryl or said heterocyclyl can be non-substituted or substituted halogen, (C1-C6)-alkyl or amino. Also described is pharmaceutical composition, possessing inhibiting activity with respect to Bcl-2 and/or Bcl-XL proteins, which includes said compound, also described is method of treating disorder, mediated by Bcl-2 and/or Bcl-XL proteins, which lies in introduction of said compound to patient, who needs such treatment, in therapeutically efficient amount.

EFFECT: increased efficiency of compound application.

41 cl, 6 dwg, 125 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrimidine compounds of general formula (I) or their pharmaceutically acceptable salts, which can be used in treating the diseases related to mTOR kinase or PI3K kinase, such as cancer, immune diseases, viral infections, inflammations, neurological and other disorders. In general formula (I) , R1 means a group (A), wherein P represents C6aryl optionally substituted by a halogen, -OH, -NH2, -OC1-C6alkyl, unsubstituted 6-merous heteroaryl containing 1-2 heteroatoms N, unsubstituted indolyl, unsubstituted indazolyl, Q is specified in -H, -OR, -SR, -halo, -NR3R4, -OS(O)mR, -OC(O)NHR, -S(O)mNR3R4, -NRC(O)R, -NRS(O)mR, -NRC(O)NR3R4 and -NRC(S)NR3R4, wherein each R, R3 and R4 are independently specified in H, C1-C6 alkyl optionally substituted by a halogen, -N(C1-C3alkyl)2, 5-, 6-merous heterocyclic group containing 1-2 heteroatoms specified in N and O, 6-merous heterocyclic group containing 1-2 heteroatoms specified in N and O, optionally substituted by C1-C6alkyl, C6aryl group optionally substituted by one or two substitutes specified in a halogen, -OC1-C3alkyl, -CF3, -NH2, -C(O)NH2, -NHC(O)C1-C3alkyl, -N(C1-C3alkyl)2, -COOH, -SO2NH2, -SO2C1-C3alkyl, -NHSO2C1-C3alkyl, -CO2C1-C6alkyl, dioximethylene group, -NHC(O)CF3, -C(O)NH(CH2)2÷3N(C1-C3alkyl)2, -O(CH2)2N(C1-C3alkyl)2, 6-merous heterocyclyl containing 1-2 heteroatoms specified in N, O and S optionally substituted by oxo, C1-C3alkyl, -SO2C1-C3alkyl, -C(O)-6-merous heterocyclyl optionally substituted by C1-C3alkyl, 6-merous heteroaryl containing 1-2 heteroatoms N optionally substituted by one or two substitutes presenting a 6-merous heterocyclyl or -SC1-C3alkyl, or a 5-, 6-merous heteroaryl group containing 1-2 heteroatoms specified in N, O and S, optionally condensed with a benzene ring and optionally substituted by a halogen, -CO2C1-C3alkyl, oxo, -NHC(O)C1-C3alkyl, C1-C3alkyl, 6-merous heterocyclyl containing 2 heteroatoms specified in N and O optionally substituted by C1-C3alkyl, m means 1 or 2, or R3 and R4 together with a nitrogen atom to which they are attached, form a saturated 5-, 6-merous N-containing heterocyclic group, which is unsubstituted or substituted by C1-C3alkyl, -SO2C1-C3alkyl, oxo, Y is specified in -O-(CH2)n-, -S-(CH2)n- and -S(O)m(CH2)n-, wherein m means 1, n means 0 or an integer from 1 to 2, R2 is specified in H or a group -NR3R4, wherein R3 and R4 are those as specified above, Z is specified in halo, -(CH2)s-COOR, -(CH2)sCONR3R4, -(CH2)sCH2NR3R4, wherein s means 0 or an integer from 1 to 2 and wherein R, R3 and R4 are those as specified above, unsubstituted 6-merous heteroaryl containing one heteroatom N, substituted or unsubstituted heterocyclyl containing two heteroatoms specified in N and O; the substitute is specified in C1-C3alkyl and C1-C3alkylsulphonyl, and W is specified in a morpholine cycle and pyridine cycle. The invention also refers to a method for preparing the compounds of formula (I).

EFFECT: preparing the new pyrimidine compounds.

12 cl, 5 tbl, 9 ex

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