UA113538U - MULTILATERAL SIGNAL SPECIAL PROCESSOR OF PARALLEL DATA PROCESSING - Google Patents

Abstract

The multi-core signal special processor contains a control and synchronization device, the first outputs of which are connected to the corresponding inputs of the first core of the VIT special processor. Additionally, the first outputs of the control and synchronization device are connected to the corresponding first inputs of the M-1 VIT special processors. The second output is connected to the second input of the BACC, the second inputs of which are the inputs of the device. The outputs are connected to the corresponding inputs of the BIT processors, the outputs of which are connected to the corresponding inputs of the switching network, the first outputs of which are connected to the corresponding inputs of the control and synchronization device, and the outputs to the outputs of the device.

Description

which have VASET inhibitor activity, their preparation, pharmaceutical compositions containing such compounds, and their use as therapeutically active substances. The active compounds of the present invention are useful in the therapeutic and/or prophylactic treatment of, for example, diseases

Alzheimer's

Prior art

Alzheimer's disease (AD) is a neurodegenerative disease of the central nervous system and is the main cause of progressive dementia in the elderly. Its clinical symptoms are impaired memory, cognitive functions, orientation in time and space, clouding of consciousness and impaired intellectual activity, as well as serious emotional disorders. Currently, there is no effective therapy for the prevention of the onset or progression of this disease or for the stable remission of its clinical symptoms. XA has become a major medical problem in all societies with high life expectancy, as well as a significant economic burden on their health care systems.

XA is characterized by two main pathologies in the central nervous system (CNS): the appearance of amyloid plaques and neurofibrillary tangles (Nagau evi a!., Tne atuoid Nuroineviv oi AI2peitegv aiveavze: rgodgez5 apa rgobietve op She goai yuyu Ipegaretsshiis5, Zsivpse. 2002. Ushi 19:297 (5580):353-6, 5eiKoe, Seii!

AI2Neiteg disease, Appy Nem Seiyi Vio!. 1994:10:373-403). Both pathologies are often found in patients with Down syndrome (trisomy 21), who develop symptoms similar to Alzheimer's disease at a young age. Neurofibrillary tangles are intracellular aggregates of microtubule-associated tau protein (MART). Amyloid plaques are found in the extracellular space; their main components are ABp peptides. The latter are a group of proteolytic fragments that are formed from the precursor of beta-amyloid protein (APP) in several stages of proteolytic cleavage. Several forms of APP have been identified, of which the most common proteins are 695, 751, and 770 amino acids long. They all come from the same gene through differential splicing. AB peptides are formed from the same APP domain, but differ at the M- and C-termini, with the predominant molecules having a length of 40 and 42 amino acids. There are a number of data clearly indicating that aggregated ADP peptides are molecules that play a key role in the pathogenesis of XA: 1) amyloid plaques formed by AB peptides are an integral part of XA pathology; 2) Aβ peptides are toxic to neurons; 3) in hereditary Alzheimer's disease (XHA), mutations in the disease susceptibility genes APP, ROMI, ROM2 lead to an increased level of Ar-peptides and early amyloidosis of the brain; 4) in transgenic mice expressing such CXA genes, it develops

It is a pathology that in many ways resembles a human disease. ArB peptides are formed from APP due to the sequential action of two proteolytic enzymes, designated as β- and β-secretase.

Under the action of B-secretase, cleavage first occurs in the extracellular domain of APP, at a distance of approximately 28 amino acids from the transmembrane domain (TM), with the formation of a C-terminal fragment of APP containing a transmembrane and cytoplasmic domain (STEV).

The STEV domain is a substrate for γ-secretase, which cleaves at several adjacent positions inside the TM with the formation of ABr peptides and a cytoplasmic fragment. in-

Secretase is a complex consisting of at least four different proteins; its catalytic subunit is very similar in structure to the presenilin protein (RZZEMI, RBEM2). B-Secretase (VACET1, Azr2; VACE denotes the p-site of the APP-cleaving enzyme) is an aspartyl protease that is fixed on the membrane due to the transmembrane domain (Mazzag ei ai., Vega-zesteiaze siealkhade oi AI2Neitegv atuioid rhesygzog rgoivip Bu She Shpapotetrgbape azrapis rgoivaze VASE,

All right. 1999 Axis 22:;286(5440):735). It is expressed in many tissues of the human body, but its level is especially high in the central nervous system. By genetic deletion of the VASEI1 gene in mice, it was clearly shown that the activity of this gene plays a key role in the processing of APP, which leads to the formation of Ар-peptides; in the absence of VASE1, Ар-peptides are not produced (I o ei a!., Mise aeisiepi ip Vase1, Pe AI2Neitegz reia-zesteiaze, pame pogtai rpepoiure apa obiiznei reia-atuiia depegaiyop, Mai Mezhgossi. 2001 Mag4(3):231-2, Voregaz eyi ai., VASE KposKotsi tese age

Ppeaiyu aezriie IasKipd She rgitagu Beia-zesgteiaze asiimnu ip Bgaip: itriisayop5 og AI2Peiiteg5 disease Shegareshisv, My thread! Sepoys 2001 dip 1;10(12):1317-24). Mice that have been genetically modified to express the human APP gene, and which develop extensive amyloid plaques and Alzheimer-like pathology with age, do not when VP-secretase activity is reduced by genetically deleting one of the VASET alleles (Mssopiodie ei ai., Ragia! gedisiop oi Vase1 paz agatayis epyesib5 op AI2peiiyteg riadne apa z5upariis raiyoiiiodu ip АРР Tgapzdepis Mise. U Vio! Spet. 2007 Mar 7;282(36):26326). In this regard, it is suggested that VASET activity inhibitors may be effective agents for the therapeutic treatment of Alzheimer's disease (Alzheimer's disease).

In addition, the proposed compounds inhibit the formation or formation and deposition of D-amyloid peptides in, on or in the region of nervous tissue (for example, in the brain), that is, they inhibit the production of Aβ peptides from APP or a fragment of APP. because In addition, VACE1 inhibitors can be used to treat the following diseases:

IVM (myositis with inclusion bodies) (Maineti S. ei a!., I apsei. 2001 Oes 8; 358(9297):1962-4), Down's syndrome (Vaibieego Yis. ei ai, Ehr Meshgoi. 2003 Atso; 182( 2):335-45), Wilson's disease (Biditoio I. eyi ai., U Vioi Spet. 2007 Mom 30; 282(48):34896-903), Whipple's disease (Oezpiez V. eyi aI., Siip Massipe Ittipoi. 2006 Rebr; 13(2):170-8), spinocerebellar ataxia 1 and spinocerebellar ataxia 7 (SaisNei U.V. ei ai., Rhos Mai! Asai Zsi 0 5 A 2008 suppl. 29; 105(4)1291-6) , dermatomyositis (Steepiego 5.A. evy a) I., App Meshgoi. 2005 Sap; 57(5):664-78; Steepbego 5.A. evyi ai., Meshgoi 2005 Sap; 57(5):664-78), Kaposi's sarcoma (I adoz 0. ei ai, ViIosd, 2007 Ber 15; 109(4):1550-8), glioblastoma multiforme (E-"MEHR-2576, por:/Lymly .ebri.as. Mys5sie Megme. 2006 Osi;34(4):444-50; 1 Och. Yei Ai, Adipd Seii. 2006 Arg; 5(2):153-65), Huntington's disease (Cat.

IN). hey aiI., Meshigobio! sat down 2006 Sap; 22(2):346-56. Eryb 2006 supplement 19; Noddez A. Yei a!., Nit Moi

Sepoys 2006 Mag 15;15(6):965-77. Eryb 2006 Re 8), multiple myeloma (Kinaga U. ei ai, Rgos Mai!

Asad 5si 0 5 A. 2009 Oes 22; 106(51): 21807-12), malignant melanoma (Taiapioma 0. ei ai, Siip

Sapseg Vez. 2005 Axis 15; 11(20):7234-42), Sjogren's syndrome (Vazzei b. eyi ai., Zsapa u Ittypo). 2000 Mage; 51(3): 307-11), lupus erythematosus (SteulaI! R.K. yei ai, Moi Seii! Vioi. 2006, d9ii; 26(13):4970-81), macrophage myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis , breast cancer (Neashpa M. ei aI, Sapseg Res. 2008 dap 15; 68(2):388-94; Kopaon K. ei a!., Vgeazi Sapseg Nez Tgeai. 2003 Mag; 78(1):37- 44), diseases of the gastrointestinal tract (Noiitvivieg A. yei ai, CHOR. 2009 Mar 4; 10(5): 501-6), autoimmune/inflammatory diseases (Uuoodaga-diise Am. yei ai., U Vioi Spet. 2008 Mar 26; 283(39): 26364-73. Eryb 2008 Khy! 23), rheumatoid arthritis (Toedei 5. ei aiI, O5ieoagiyyyy5 Sapiade. 2010 Rebr; 18(2): 240-8. Eryb 2009 Mar 22), inflammatory reactions (Hispbepipaeg 5.Yi. ei ai., U Vioi Spet. 2003 Oes 5; 278(49): 48713-9. Eryb 2003 zer 24), arterial thrombosis (Mepep M. ei ai., 2 Kagaioi. 2004 Mom; 93(11): 855-63), cardiovascular diseases, such as myocardial infarction and stroke (Matsdegi M. ei aiI., 5gr Ap Seiok Gek. 2010 dap; 138 Zirri 1:50-2) and Bazedov's disease (Ki |aszkKi in Hey, Tnugoid. 2005 Dy; 15(7): 645-52).

The present invention offers new compounds of formula I, their preparation, medicinal products based on compounds according to the invention and their manufacture, as well as the use of compounds of formula I for the control or prevention of diseases such as Alzheimer's disease. In addition,

It is proposed to use compounds of the formula | in the treatment of amyotrophic lateral sclerosis (ALS 5), arterial thrombosis, autoimmune/inflammatory diseases, cancer such as breast cancer, cardiovascular diseases such as myocardial infarction or stroke, dermatomyositis, Down syndrome, gastrointestinal diseases, glioblastoma multimorpho , Bazed disease, Huntington's disease, inclusion body myositis (IBM), inflammatory reactions, Kaposi's sarcoma, Kostmann's disease, lupus erythematosus, macrophage myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple myeloma, rheumatoid arthritis, Sjogren's syndrome, spinocerebellar ataxia 1, spinocerebellar ataxia 7, Whipple's disease or Wilson's disease. New compounds of formula I have improved pharmacological properties.

Field of technology

This invention offers fluoromethyl-5,6-dihydro-4H-P1,Z|oxazin-2-ylamines, which have the properties of VASET inhibitors, their preparation, pharmaceutical compositions containing such compounds, as well as their use as therapeutically active substances.

The essence of the invention

This invention offers a compound of formula I, co B

And you

VIM kos. t v o

Where the substituents and variables are described below, as well as in the claims, or their pharmaceutically acceptable salts.

The claimed compounds have the activity of inhibitors of Azr2 (VD-secretase, VACE1 or Memplasin-g), and therefore they can be used for the therapeutic and/or prophylactic treatment of diseases and disorders characterized by increased levels of B-amyloid and/or oligomers

B-amyloid and/or p-amyloid plaques and other deposits, in particular, Alzheimer's disease.

Detailed description of the invention

The present invention offers a compound of formula I and its pharmaceutically acceptable salts, the preparation of the above-mentioned compounds, their medicinal products and their manufacture, as well as the use of the above-mentioned compounds for the therapeutic and/or prophylactic treatment of diseases and disorders associated with the inhibition of VASET, such as Alzheimer's disease. In addition, the formation or the formation and deposition of B-amyloid plaques in, on or in the region of nervous tissue (for example, in the brain) are inhibited by the proposed compounds, due to the inhibition of the production of ArD peptides from APP or a fragment of APP.

The following definitions of common terms used in this specification apply regardless of whether the term discussed occurs alone or in combination with other groups.

Unless otherwise noted, the following terms used in this Application, including description and claims, have the meanings set forth below. It should be noted that the singular forms used in this description and the provided claims include references to the plural forms, except when the context does not indicate otherwise.

The term "C 1-6 alkyl", alone or in combination with other groups, denotes a hydrocarbon radical which may be linear or branched, single or multi-branched, said alkyl generally comprising from 1 to 6 carbon atoms, e.g. methyl (Me), ethyl (EU, propyl, isopropyl, n-butyl, isobutyl, 2-butyl (sec-butyl), tert-butyl, isopentyl, 2-ethylpropyl (2-methylpropyl), 1,2-dimethylpropyl, etc. .p. In particular, "C 1-6 alkyl" refers to "C 1-6 alkyl". In particular, such groups are methyl and ethyl. A particular example is methyl.

The term "halo-C:-C alkyl", alone or in combination with other groups, refers to C 1-C alkyl, disclosed herein, which is substituted by one or more halogen atoms, in particular 1-5 halogen atoms, in the individual case 1-3 halogen atoms. In particular, halogen is fluorine. In a separate case, "halo-C:-C alkyl" means fluoro-Ci-C alkyl, and in a special case, "halo-

C1-3-alkyl" means fluoro-C1-3-alkyl. Examples are trifluoromethyl, difluoromethyl, fluoromethyl, etc. In a separate case, such a group is trifluoromethyl.

The term "cyano-C:-C6-alkyl", alone or in combination with other groups, means C1-C6-alkyl, disclosed in this description, which is substituted by one or more cyano groups, in particular one cyano group. Examples are cyanomethyl, cyanoethyl, etc.

The term "C 1 -C 6 -Alkoxy-C 1 -C 6 -Alkyl", alone or in combination with other groups, means C 1 -C 6 -Alkyl, disclosed in this description, which is substituted by one or more C 1 -C 6 -Alkoxy groups, disclosed in this description, in particular, one C-C-Alkoxy group. In a separate case, "Ci1-6-Alkoxy-Ci-6-Alkyl" means methoxy-C1-6-Alkyl. Examples are methoxymethyl, methoxyethyl, etc.

The term "cyano", alone or in combination with other groups, refers to the group MES-(MO-).

The term "halogen", alone or in combination with other groups, means chlorine (CI), iodine (I), fluorine (P) and bromine (VI). In particular, "halogen" denotes SI and E. In a separate case, such a group is the EC atom.

The term "heteroaryl", alone or in combination with other groups, means an aromatic carbocyclic group containing a single ring comprising from 4 to 8 members, in particular from 3 to 5 members, or several fused rings comprising from b to 14 , in particular, from b to 10 ring atoms, and containing 1, 2 or C heteroatoms individually selected from M, O and 5, in particular from one or two M atoms, and in this group at least one heterocyclic ring is aromatic. Examples of "heteroaryl" include benzofuryl, benzoimidazolyl, 1H-benzoimidazolyl, benzoxazinyl, benzoxazolyl, benzothiazinyl, benzothiazolyl, benzothienyl, benzotriazolyl, furyl, imidazolyl, indazolyl, 1H-indazolyl indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, pyrazolyl, pyrazolyl, pyrazinyl. . In particular, "heteroaryl" is pyridinyl and pyrazinyl, as well as oxazolyl and 1H-pyrazolyl. In particular, "heteroaryl" refers to pyridin-2-yl and pyrazin-2-yl, as well as 1H-pyrazol-3-yl and oxazol- 4-il.

The term "C:-C-Alkoxy group", alone or in combination with other groups, means -O-C:-6- alkyl radical, which can be linear or branched, with one or more branches, while the indicated alkyl group in the general case includes from 1 to 6 carbon atoms, for example, methoxy- (OMe, Me), ethoxy- (OEV, propoxy-, isopropoxy-, n-butoxy-, isobutoxy-, 2-butoxy- (second-butoxy-), tert- butoxy-, isopentyloxy group, etc.

In particular, "C1-6-Alkoxy group" means a group containing from 1 to 4 carbon atoms. A special case is the methoxy group.

The term "halogen-C:-C-Alkoxy group", alone or in combination with other groups, means a C-6-Alkoxy group, which is disclosed in this description, contains as a substituent one or more halogen atoms, in particular, fluorine. In a separate case, "halo-C:-C6-Alkoxy group" means fluoro-C3-C6-C6-Alkoxy group. In particular, "halogen-Ci-C-Alkoxy" denotes a trifluoromethoxy group.

The term "Cg-C-alkynyl-Ci-C-Alkoxy", alone or in combination with other groups, means

C-C6-Alkoxy group disclosed in this description, which is substituted by one or more C2-6-alkynyls disclosed in this description, in particular, one C2-6-alkynyl.

The term "C 6 -alkynyl", alone or in combination with other groups, means a monovalent linear or branched saturated hydrocarbon group comprising from 2 to 6 carbon atoms, in particular from 2 to 4 carbon atoms, and comprising one, two or three triple bonds. Examples

C 2 -alkynyl include ethynyl, propynyl and n-butynyl.

The term "aryl" denotes a monovalent aromatic carbocyclic mono- or bicyclic ring system comprising 6 to 10 ring carbon atoms. Examples of aryl groups include phenyl and naphthyl. In particular, "aryl" means phenyl.

The term "pharmaceutically acceptable salts" refers to salts that are suitable for use in contact with human or animal tissues. Examples of suitable salts with inorganic and organic acids are, without limitation, salts of acetic acid, citric acid, formic acid, fumaric acid, hydrochloric acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid acid, succinic acid, sulfuric acid (sulfuric acid), tartaric acid, trifluoroacetic acid, etc. In particular, such acid is formic acid, trifluoroacetic acid, and hydrochloric acid. In particular, such an acid is hydrochloric acid, trifluoroacetic acid and fumaric acid.

The terms "pharmaceutically acceptable carrier" and "pharmaceutically acceptable excipient" refer to carriers and excipients, such as solvents or fillers, compatible with other components of the dosage form.

The term "pharmaceutical composition" includes a product containing the specified ingredients in predetermined amounts or proportions, as well as any product that can be obtained, directly or indirectly, by combining the specified ingredients in specified quantities. In particular, it covers a product comprising one or more active ingredients and possibly a carrier comprising inert ingredients, as well as any product that can be obtained, directly or indirectly, by combining, complexing or aggregating any two or more ingredients or as a result of the dissociation of one or more

From the ingredients or due to other types of reactions or interactions of one or more ingredients.

The term "inhibitor" refers to a compound that competes with the binding of, reduces the binding of, or prevents the binding of a particular ligand to a given receptor, or which reduces or prevents the inhibition of the function of a particular protein.

The term "semi-maximal inhibitory concentration" (MSI) refers to the concentration of a particular compound that is required to achieve 5095 inhibition of the biological process of migo. Magnitudes

ISvo can be logarithmically transformed into riSvo values (-I09 ISvo), for which higher values correspond to greater activity, according to an exponential relationship. The value of IiSvo is not an absolute value, but depends on the experimental conditions, for example, on the concentrations used. The ISso value can be converted into an absolute inhibition constant (Ki) using the Cheng-Prusoff equation (Viospet. РНаптасой. (1973) 22:3099).

The term "inhibition constant" (Ki) denotes the absolute degree of affinity of a particular inhibitor to the receptor. It is quantified using a competitive binding assay and is equal to the concentration at which a particular inhibitor would bind 5095 receptors in the absence of a competing ligand (eg, a radioligand). Ki values can be logarithmically transformed into pKi values (-I09 Ki), for which higher values correspond to greater activity, according to an exponential relationship. "Therapeutically effective amount" means that amount of a compound which, when administered to a subject for the purpose of treating a disease state, is sufficient to provide such treatment for a given disease state. "Therapeutically effective amount" varies depending on the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the method and form of administration, the opinion of the attending physician or veterinarian, and other factors .

The terms ``disclosed herein'' and ``described herein'' when referring to a variable include by reference the broad definition of that variable, as well as the specific, more specific and most specific definition, if any.

The terms "treating," "contacting," and "reacting," when referring to a chemical reaction, mean the addition or mixing of two or more reactants under appropriate conditions to produce a specified and/or desired product. It should be understood that the reaction that leads to the specified and/or desired product is not always the direct result of the combination of the two reactants that were initially added, that is, the formation of one or more intermediate products in the reaction mixture that ultimately leads to the specified and/or desired product.

The term "protecting group" refers to a group that selectively blocks a reactive site in combination with several functional groups so that a chemical reaction can be selectively carried out on another unprotected reactive site, in the generally accepted sense of the field of synthetic chemistry. Protection groups can be removed at any time. Examples of protective groups are amino-protecting groups, carboxy-protecting groups or hydroxy-protecting groups. The term "amino-protecting group" (here also P") denotes groups intended to protect the amino group and includes the following examples: benzyl, benzyloxycarbonyl (carbobenzyloxy, CB), 9-fluorenylmethyloxycarbonyl (EMOS), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC) (and trifluoroacetyl. Additional examples of such groups can be found in the literature (T. MU. Steepe apa R. a. M. M/tsiv, "Rgoiesiime Stoirv5 ip Ogdapis Zupipeviv", 2pa eid., dopp U/ yeu b 5opv5, Ips., Mem mok,

MU, 1991, sparieg 7; E. Naziat, "Rgoiesiime Stoyr5 ip Ogdapis Spetivgu", u). b. MU. Msotiye, Ea., Riepyt Rheb5, Mem/ Moik, MM, 1973, Sparieg 5; T.M. Steepe, "Rgoiesiime Stotsr5 ip Ogdapis zupipevziv", Wopp Umieu apa 5op5, Mem/MogK, MU, 1981). The term "protected amino group" denotes an amino group containing as a substituent amino-protecting groups. In particular, aminoprotecting groups are tert-butoxycarbonyl group and dimethoxytrityl.

The term "substitutable group" refers to a group in the generally accepted sense of the field of synthetic chemistry, that is, an atom or group that can be replaced under the conditions of a substitution reaction. Examples of groups to be substituted are: a halogen atom, in particular bromine, an alkane or arylenesulfonyloxy group, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy and acyloxy.

The term "aromatic" is related to the generally accepted concept of aromaticity, revealed in the literature, in particular, in ISRAS - Sotrepaisht oi Spetis! Teptipoioadu, 2pa, A. O. Mspatsodni 4. A.

MKipzop (Eav5). Viaskmei! Zsiepiyis Rybiysayop5, Ohio (1997).

The term "pharmaceutically acceptable excipient" refers to any ingredient that has no therapeutic activity and no toxicity, such as disintegrants, binders

From substances, fillers, solvents, buffers, substances regulating tonicity, stabilizers, antioxidants, surface-active substances or lubricants, used in the manufacture of dosage forms of pharmaceutical products.

In all cases when a chiral carbon atom is present in the chemical structure, it is meant that this structure covers all stereoisomers bound to this chiral carbon atom, in the form of pure stereoisomers, as well as their mixtures.

This invention also offers pharmaceutical compositions, methods of application and methods of obtaining the above-mentioned compounds.

Individual implementation options can be combined.

In one embodiment of this invention, a compound of formula I is proposed,

NM. Job sho ef Mo is in 0; 2

In where

B' is selected from the group consisting of i) aryl, i) aryl, which includes 1-4 substituents, individually selected from cyano group, cyano-Ci-6-alkyl, halogen, halogen-C:1-6-alkyl group, halogen -C:-alkyl, C1-6-alkyl, C1-6-alkyl, C1-6-alkyl, C1-6-alkynyl, C1-6-alkynyl and C1-6-alkyl, iii) heteroaryl and im) heteroaryl, which includes 1-4 substituents, individually selected from the cyano group, cyano-C1-6-alkyl, halogen, halogen-C:-C-Alkoxy group, halogen-C:-C-Alkyl, C: I-V-Alkyloxy groups, C-V-Alkoxy-

C-C-alkyl, C-C-Alkynyl-C-C-Alkoxy, C-C-C-Alkynyl and C-C-Alkyl;

IN? selected from the group consisting of i) hydrogen, i) C-C-alkyl and iii) halogen;

BZ is selected from the group consisting of i) C-C-alkyl and i) halogen-C-C-alkyl;

B" denotes halogen-C:-C-alkyl; or its pharmaceutically acceptable salts.

In a separate embodiment of this invention, a compound of formula Ia is proposed,

NM. 20. In what 1

Kk M s, 3 is in o ve?

Where is it?

B is selected from the group consisting of i) aryl, i) aryl, containing 1-2 substituents, individually selected from the cyano group, cyano-C:-C-alkyl, halogen, halogen-Ci-C-Alkoxy group, halogenC-C-C -alkyl, C:-C-Alkoxy group, C1-C-Alkoxy-C1-6-alkyl, C1-C-Alkynyl-C1-C-Alkoxy group, C1-C-alkynyl and C1-C-alkyl, iii) heteroaryl and them) heteroaryl containing 1-2 substituents individually selected from cyano group, cyanoCi-C-alkyl, halogen, halogen-C:-C-Alkoxy group, halogen-C:-C-Alkyl, C:C-C-Alkyloxy group , C-C-Alkoxy-

C1-6-alkyl, C1-6-alkynyl-C1-6-alkyl, C6-6-alkynyl and C6-6-alkyl;

IN? selected from the group consisting of i) hydrogen, i) C-C-alkyl and iii) halogen;

BZ is selected from the group consisting of i) C-C-alkyl and i) halogen-C-C-alkyl;

B" denotes halogen-Ci-C-alkyl; or its pharmaceutically acceptable salts.

In a separate embodiment of this invention, a compound of the formula Is, 4 no eV 1 N M is proposed

Kk M t, Z is in o ve?

Is

From where

B' is selected from the group consisting of i) aryl, i) aryl, including 1-4 substituents, individually selected from the cyano group, cyano-C:-c-alkyl, halogen, halogen-C:-c-alkyl, halogen-C:-C-alkyl, C-C-Alkoxy group, C-C-C-Alkoxy-C1-6-alkyl, C-C-Alkynyl-C-C-Alkoxy group, C-C-Alkynyl and C:-C-alkyl , iii) heteroaryl and im) heteroaryl, which includes 1-4 substituents, individually selected from the cyano group, cyano-C1-6-alkyl, halogen, halogen-C:-C-Alkoxy group, halogen-C:-C-Alkyl, C :i-Ve-Alkyloxy groups, C-V-Alkoxy-

C1-6-alkyl, C1-6-alkynyl-C1-6-alkyl, C6-6-alkynyl and C6-6-alkyl;

IN? selected from the group consisting of i) hydrogen, i) C-C-alkyl and iii) halogen;

BZ is selected from the group consisting of i) C-C-alkyl and i) halogen-C1-C-alkyl;

B" denotes halogen-Ci-C-alkyl; or its pharmaceutically acceptable salts.

In a separate embodiment of this invention, a compound of the formula Id is proposed,

NM. 20 What in M M 7 is in 0; 2

Kk Ia where

A" is selected from the group consisting of i) aryl, i) aryl, including 1-4 substituents, individually selected from the cyano group, cyano-C:-C-alkyl, halogen, halogen-C:C-C-Alkoxy group, halogen-C:-C-alkyl, C1-C-Alkoxy group, C1-C-Alkoxy-C1-6-alkyl, C1-C-Alkynyl-C1-C-Alkoxy group, C1-C-alkynyl and C:-C-alkyl; iii) heteroaryl and im) heteroaryl, which includes 1-4 substituents, individually selected from the cyano group, cyano-C1-6-alkyl, halogen, halogen-C:-C-Alkoxy group, halogen-C:-C-Alkyl, C: I-V-Alkyloxy groups, C-V-Alkoxy-

C1-6-alkyl, C1-6-alkynyl-C1-6-alkyl, C6-6-alkynyl and C6-6-alkyl;

IN? selected from the group consisting of i) hydrogen, i) C-C-alkyl and iii) halogen;

BZ is selected from the group consisting of i) C-C-alkyl and i) halogen-C-C-alkyl;

B" denotes halogen-Ci-C-alkyl; or its pharmaceutically acceptable salts.

In a separate embodiment of this invention, a compound of the formula Ia-1, but CE, is proposed

N vi rr is in o

R Ta-1 de

B' is selected from the group consisting of i) aryl, i) aryl, containing 1-2 substituents, individually selected from cyano group, cyano-C:-C-alkyl, halogen, halogen-C:-C-Alkoxy group, halogen -C:-C-alkyl, C--Alkoxy group, C-C-C-Alkoxy-C1-6-alkyl, C-C-Alkynyl-C-C-Alkoxy group, C-C-Alkynyl and C-C-Alkyl , iii) heteroaryl and im) heteroaryl containing 1-2 substituents, individually selected from the cyano group, cyano-Ci1-6-alkyl, halogen, halogen-C:-C-Alkoxy group, halogen-C:-C-Alkyl, C :i-Ve-Alkyloxy groups, C-V-Alkoxy-

C1-C-alkyl, C1-C-alkynyl-C1-C-alkoxy groups, C2-C-alkynyl and C:-C-alkyl; and

BZ is selected from the group consisting of i) C-C-alkyl and i) halo-C-C-alkyl, or its pharmaceutically acceptable salts.

In a separate embodiment of this invention, a compound of the formula Ia-1" is proposed

under "CE,

And you

She A o

R Ia-y1" where

B' denotes a heteroaryl containing 1-2 substituents individually selected from the cyano group and halogen, or its pharmaceutically acceptable salts.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

IN? stands for halogen.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

A: stands for R.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B2 represents hydrogen.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B: denotes C..i.-C alkyl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

IN? denotes methyl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

VZ stands for halogen-Ci-C-alkyl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

BZ stands for fluoro-C: -c-alkyl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

VZ stands for fluoromethyl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

VZ stands for Ci..v.-alkyl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

VZ stands for methyl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

"B" denotes fluoro-C: -c-alkyl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

IN? denotes trifluoromethyl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where B! denotes heteroaryl containing 1-2 substituents individually selected from cyano, cyano-C:-alkyl, halogen, halogen-C:-alkyl, halogen-C:-alkyl, C:i-ve- Alkyloxy groups, C-C-Alkoxy-

C-C-alkyl, C-C-Alkynyl-C1-C-Alkoxy groups, C-C-Alkynyl and C-C-Alkyl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

A" denotes a heteroaryl containing 1-2 substituents individually selected from the cyano group, halogen, halogen-Ci-C-Alkoxy group, halogen-C:-C-alkyl, C-C-Alkoxy group, C-C-Alkynyl-C: -b- alkoxy groups and

C.-C-alkyl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B' denotes heteroaryl containing 1-2 substituents individually selected from cyano group, halogen, halogen-C:-C-Alkoxy group and C-C-Alkoxy group.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B' denotes pyridinyl or pyrazinyl containing 1-2 substituents individually selected from cyano group, halogen, halogen-C:-C-Alkoxy group and C:1-C-Alkoxy group.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B" denotes pyridinyl substituted with a cyano group.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B' denotes pyridinyl substituted with halogen.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B' denotes pyridinyl substituted with a halogen-C:-ve- alkoxy group.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B' denotes pyridinyl substituted by a C:-E-alkyl group.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B' denotes pyridinyl substituted by a cyano group and a C-1-6 alkyl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B' denotes pyridinyl substituted by a cyano group and a halogen.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B denotes pyridinyl substituted with halogen-C:-C-alkyl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

BA" denotes pyridinyl substituted with C: -C-alkyl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B" denotes pyrazinyl substituted with C:-β-alkyl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B' denotes pyrazinyl, substituted by a halogen-C:-V-Alkoxy group.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B' denotes pyrazinyl substituted with halogen-C:-C-alkyl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B' denotes pyrazinyl substituted by a C:-6-alkyl group.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B" denotes pyrazinyl substituted by Cg-b-alkynyl-Ci-e-aluoxy group.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B' denotes oxazolyl substituted with halogen-C:-C-alkyl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B denotes pyrazolyl substituted halogen-C:-C-alkyl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B' denotes 1-(difluoromethyl)-1H-pyrazol-3-yl, 2-(fluoromethyl)oxazol-4-yl, 3,5-dichloro-pyridin-2-yl, 3-chloro-5-cyanopyridin-2 -yl, 3-methylpyrazin-2-yl, 4-chloro-1-(difluoromethyl)-1H-pyrazol-3-yl, 5-(2,2,2-trifluoroethoxy)pyrazin-2-yl, 5-(2 ,2-difluoroethoxy)pyrazin-2-yl, 5-(but-2-ynyloxy)pyrazin-2-yl, 5-(difluoromethoxy)pyrazin-2-yl, 5-(difluoromethyl)pyrazin-2-yl, 5- (fluoromethoxy)pyrazin-2-yl, 5- (fluoromethyl)pyrazin-2-yl, 5-chloropyridin-2-yl, 5-cyano-3-methylpyridin-2-yl, 5-cyanopyridin-2-yl, 5- difluoromethoxypyrazin-2-yl, 5-difluoromethoxypyridin-2-yl, 5-difluoromethylpyridin-2-yl, 5-fluoromethoxypyridin-2-yl, 5-methoxypyrazin-2-yl, 5-methoxypyridin-2-yl, 5-methylpyrazin- 2-yl, 5-trifluoroethoxypyridin-2-yl, 5-trifluoromethoxypyrazin-2-yl or 5-trifluoromethoxypyridin-2-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

A" denotes 5-cyanopyridin-2-yl, 5-chloropyridin-2-yl, 5-(2,2-difluoroethoxy)pyrazin-2-yl, 5-(2,2,2-trifluoroethoxy)pyrazin-2-yl or 5-methoxypyrazin-2-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B denotes 1-(difluoromethyl)-1H-pyrazol-3-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

A" denotes 2-(fluoromethyl)oxazol-a4-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B' denotes 3,5-dichloropyridin-2-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

A stands for 3-chloro-5-cyanopyridin-2-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

AB" denotes 3-methylpyrazin-2-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B" denotes 4-chloro-1-(difluoromethyl)-1H-pyrazol-3-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B' denotes 5-(but-2-ynyloxy)pyrazin-2-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B" denotes 5-(difluoromethoxy)pyrazin-2-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

A" denotes 5-(difluoromethyl)pyrazin-2-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

A" denotes 5-(fluoromethoxy)pyrazin-2-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

A" denotes 5-(fluoromethyl)pyrazin-2-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B stands for 5-cyano-33-methylpyridin-2-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

A" denotes 5-difluoromethoxypyrazin-2-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B" denotes 5-difluoromethoxypyridin-2-yl. Because In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B" denotes 5-difluoromethylpyridin-2-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

A stands for 5-fluoromethoxypyridin-2-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B' denotes 5-methoxypyridin-2-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

AB" denotes 5-methylpyrazin-2-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B" denotes 5-trifluoroethoxypyridin-2-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B" denotes 5-trifluoromethoxypyrazin-2-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B stands for 5-trifluoromethoxypyridin-2-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B" denotes 5-cyanopyridin-2-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

A" denotes 5-chloropyridin-2-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

A" denotes 5-(2,2-difluoroethoxy)pyrazin-2-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B stands for 5-(2,2,2-trifluoroethoxy)pyrazin-2-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, where

B' denotes 5-methoxypyrazin-2-yl.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, selected from the group consisting of the following compounds:

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-cyanopicolinamide,

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-chloropicolinamide,

Zo M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl )-5-cyanopicolinamide,

M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-chloropicolinamide,

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-methoxypyrazine-2-carboxamide,

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-(2,2-difluoroethoxy)pyrazine-2-carboxamide,

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamide,

M-(3-(45,68)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5 -cyanopicolinamide,

M-(3-(45,68)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5 -chlorpicolinamide,

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 3,5-chloropicolinamide,

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-(fluoromethoxy)picolinamide,

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-cyano-Z-methylpicolinamide,

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 3-chloro-5-cyanopicolinamide,

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-Methoxypicolinamide,

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-(difluoromethoxy)picolinamide,

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-(trifluoromethoxy)picolinamide,

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-(difluoromethyl)picolinamide, 60 M-(3-(45,65)-2-amino-4-methyl-6-«(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4- yl)-4-

fluorophenyl)-5-(2,2,2-trifluoroethoxy)picolinamide,

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-(fluoromethyl)pyrazine-2-carboxamide,

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-(difluoromethyl)pyrazine-2-carboxamide,

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-methylpyrazine-2-carboxamide,

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-(but-2-ynyloxy)pyrazine-2-carboxamide,

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-(fluoromethoxy)pyrazine-2-carboxamide,

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-(difluoromethoxy)pyrazine-2-carboxamide,

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 2-(fluoromethyl)oxazole-4-carboxamide,

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxamide,

M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-cyano-Z-methylpicolinamide,

M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -3-chloro-5-cyanopicolinamide,

M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -3,5-dichloropicolinamide,

M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-methoxypicolinamide,

M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-(difluoromethoxy)picolinamide,

M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-(trifluoromethoxy)picolinamide,

Zo M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl )-5-(difluoromethyl)picolinamide,

M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-(2,2,2-trifluoroethoxy)picolinamide,

M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-(fluoromethoxy)picolinamide,

M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-methoxypyrazine-2-carboxamide,

M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-(fluoromethyl)pyrazine-2-carboxamide,

M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-(but-2-ynyloxy)pyrazine-2-carboxamide,

M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-(difluoromethoxy)pyrazine-2-carboxamide,

M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-(2,2-difluoroethoxy)pyrazine-2-carboxamide,

M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamide,

M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-methylpyrazine-2-carboxamide,

M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-(fluoromethoxy)pyrazine-2-carboxamide,

M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -3-methylpyrazine-2-carboxamide,

M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-(difluoromethyl)pyrazine-2-carboxamide,

M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxamide,

M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -2-(fluoromethyl)oxazole-4-carboxamide, because M-(3-(45,68)-2-amino-4-(difluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1, 3-oxazin-4-yl)-4-

fluorophenyl)-5-cyanopicolinamide and

M-(3-(45,65)-2-amino-4-(difluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-cyanopicolinamide or its pharmaceutically acceptable salt.

In a separate embodiment of this invention, a compound disclosed in this description is proposed, selected from the group consisting of the following compounds:

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-cyanopicolinamide,

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-chloropicolinamide,

M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-cyanopicolinamide,

M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-chloropicolinamide,

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-methoxypyrazine-2-carboxamide,

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-(2,2-difluoroethoxy)pyrazine-2-carboxamide and

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamide or a pharmaceutically acceptable salt thereof.

In a separate embodiment of this invention, the compound disclosed in this description is proposed, which denotes M-(3-(45,65)-2-amino-4-methyl-b6-(trifluoromethyl)-5,6-dihydro-4H-1, 3-oxazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide; in a separate embodiment of this invention, the compound disclosed in this description is proposed, which denotes M-(3-(45,65)-2-amino-4-methyl-b6-(trifluoromethyl)-5,6-dihydro-4H-1, 3-oxazin-4-yl)-4-fluorophenyl)-5-chloropicolinamide; in a separate embodiment of this invention, the compound disclosed in this description is proposed, which denotes /- M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro- 4H-1,3-oxazine-4-

Zoyl)-4-fluorophenyl)-5-cyanopicolinamide; in a separate embodiment of this invention, the compound disclosed in this description is proposed, which denotes /- M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro- 4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-chloropicolinamide; in a separate embodiment of this invention, the compound disclosed in this description is proposed, which denotes M-(3-(45,65)-2-amino-4-methyl-b6-(trifluoromethyl)-5,6-dihydro-4H-1, 3-oxazin-4-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide; in a separate embodiment of this invention, the compound disclosed in this description is proposed, which denotes M-(3-(45,65)-2-amino-4-methyl-b6-(trifluoromethyl)-5,6-dihydro-4H-1, 3-oxazin-4-yl)-4-fluorophenyl)-5-(2,2-difluoroethoxy)pyrazine-2-carboxamide; and in a separate embodiment of this invention, the compound disclosed in this description is proposed, which denotes M-(3-(45,65)-2-amino-4-methyl-b6-(trifluoromethyl)-5,6-dihydro-4H-1 ,3-oxazin-4-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamide.

In a separate embodiment of this invention, a method is proposed, which includes the introduction into the reaction of the compound of the formula XH with the compound of the formula XII to obtain the compound of the formula I.

And in V

Mayor of Ion

And there is in? (0;

ХГ ХИГ where В", В, ВЗ and В" are disclosed in this description.

In a separate embodiment of this invention, the compound of formula I, disclosed in this description, is proposed in all cases when it is obtained by the method defined above.

In a separate embodiment of this invention, the compound of formula I, disclosed in this description, is proposed for use as a therapeutically active substance.

In a separate embodiment of this invention, a compound of formula I, disclosed in this description, is proposed for use as an inhibitor of VACE1 activity.

In a separate embodiment of this invention, the compound of formula I, disclosed in this description, is proposed for use as a therapeutically active substance for the therapeutic and/or prophylactic treatment of diseases and disorders characterized by an increased level of VD-amyloid and/or pD-amyloid oligomers and/or B-amyloid plaques and other deposits, or Alzheimer's disease.

In a separate embodiment of this invention, a compound of formula I, disclosed in this description, is proposed for use as a therapeutically active substance for the therapeutic and/or prophylactic treatment of Alzheimer's disease.

In a separate embodiment of this invention, a compound of formula I disclosed in this description is proposed for use as a therapeutically active substance for the therapeutic and/or prophylactic treatment of amyotrophic lateral sclerosis (AG 5), arterial thrombosis, autoimmune/inflammatory diseases, cancer, for example breast cancer, cardiovascular diseases such as myocardial infarction and stroke, dermatomyositis, Down syndrome, diseases of the gastrointestinal tract, glioblastoma multimorpho, Bazed disease, Huntington's disease, inclusion body myositis (IBM), inflammatory reactions, Kaposi's sarcoma, Kostmann's disease, erythematosus lupus, macrophage myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple myeloma, rheumatoid arthritis, Sjögren's syndrome, spinocerebellar ataxia 1, spinocerebellar ataxia 7, Whipple's disease, or Wilson's disease.

In a separate embodiment of this invention, a pharmaceutical composition is proposed, including a compound of formula I, disclosed in this description, and a pharmaceutically acceptable carrier and/or a pharmaceutically acceptable excipient.

In a separate embodiment of this invention, it is proposed to use the compound of the formula |, disclosed in this description, for the manufacture of a medicinal product for use in inhibiting the activity of VACE1.

In a separate embodiment of this invention, it is proposed to use the compound of formula Y, disclosed in this description, for the manufacture of a medicinal product for the therapeutic and/or prophylactic treatment of diseases and disorders characterized by an increased level of VD-

Co) amyloid and/or p-amyloid oligomers and/or B-amyloid plaques and other deposits, or Alzheimer's disease.

In a separate embodiment of this invention, it is proposed to use the compound of formula |, disclosed in this description, for the manufacture of a medicinal product for the therapeutic and/or prophylactic treatment of Alzheimer's disease.

In a separate embodiment of this invention, the use of the compound of the formula | disclosed in this description is proposed for the manufacture of a medicinal product for the therapeutic and/or prophylactic treatment of amyotrophic lateral sclerosis (AG 5), arterial thrombosis, autoimmune/inflammatory diseases, cancer, for example breast cancer, cardiovascular diseases such as myocardial infarction and stroke, dermatomyositis, Down syndrome, diseases of the gastrointestinal tract, glioblastoma multimorpho, Bazed disease, Huntington's disease, inclusion body myositis (IBM), inflammatory reactions, Kaposi's sarcoma, Kostmann's disease, erythematosus lupus, macrophage myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple myeloma, rheumatoid arthritis, Sjögren's syndrome, spinocerebellar ataxia 1, spinocerebellar ataxia 7, Whipple's disease, or Wilson's disease.

In a separate embodiment of this invention, it is proposed to use the compound of formula Y, disclosed in this description, for the manufacture of a medicinal product for the therapeutic and/or prophylactic treatment of Alzheimer's disease.

In a separate embodiment of this invention, a compound of formula I disclosed herein is proposed

BO description, for use in inhibiting the activity of VACE1.

In a separate embodiment of this invention, the compound of formula I disclosed in this description is proposed for use in the therapeutic and/or prophylactic treatment of diseases and disorders characterized by an increased level of β-amyloid and/or β-amyloid oligomers and/or β-amyloid plaques and other deposits, or Alzheimer's disease.

In a separate embodiment of this invention, a compound of formula I disclosed in this description is proposed for use in the therapeutic and/or prophylactic treatment of a disease

Alzheimer's

In a separate embodiment of this invention, a compound of formula I, disclosed in this description, is proposed for use in the therapeutic and/or prophylactic treatment of amyotrophic lateral sclerosis (AG! 5), arterial thrombosis, autoimmune/inflammatory diseases, cancer,

eg breast cancer, cardiovascular diseases such as myocardial infarction and stroke, dermatomyositis, Down syndrome, gastrointestinal diseases, glioblastoma multimorpho, Bazed disease, Huntington's disease, inclusion body myositis (IBM), inflammatory reactions, Kaposi's sarcoma , Kostmann disease, lupus erythematosus, macrophage myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple myeloma, rheumatoid arthritis, Sjogren's syndrome, spinocerebellar ataxia 1, spinocerebellar ataxia 7, Whipple's disease, or Wilson's disease.

In a separate embodiment of this invention, a method is proposed for use in inhibiting VASET activity, in particular for therapeutic and/or prophylactic treatment of diseases and disorders characterized by an increased level of Bb-amyloid and/or B-amyloid oligomers and/or B-amyloid plaques and other deposits , or Alzheimer's disease, comprising administering a compound of formula I disclosed herein to a human or animal.

In a separate embodiment of this invention, a method for use in the therapeutic and/or prophylactic treatment of Alzheimer's disease is proposed, which includes the administration of a compound of formula I, disclosed in this description, to a person or an animal.

In a separate embodiment of this invention, a method is proposed for use in the therapeutic and/or prophylactic treatment of amyotrophic lateral sclerosis (ALS), arterial thrombosis, autoimmune/inflammatory diseases, cancer, such as breast cancer, cardiovascular diseases, such as myocardial infarction and stroke, dermatomyositis, Down's syndrome, diseases of the gastrointestinal tract, glioblastoma multimorpho, Based's disease, Huntington's disease, inclusion body myositis (IBM), inflammatory reactions, Kaposi's sarcoma, Kostmann's disease, lupus erythematosus, macrophage myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple myeloma, rheumatoid arthritis, Sjogren's syndrome, spinocerebellar ataxia 1, spinocerebellar ataxia 7, Whipple's disease or Wilson's disease, comprising administering to a human or animal a compound of formula I disclosed herein.

In addition, the present invention includes all optical isomers, i.e. diastereomers, diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and/or tautomers, as well as corresponding solvates of compounds of formula I.

From Fakhivtsev in this field of technology, it is known that compounds of the formula | can exist in tautomeric forms no V ii NO NM t v o ve?

Iv.

All tautomeric forms are encompassed by the present invention.

Compounds of formula I may contain one or more asymmetric centers and therefore may exist as racemates, racemic mixtures, individual enantiomers, diastereomeric mixtures, and individual diastereomers. Depending on the nature of various substituents in the molecule, the presence of additional asymmetric centers is possible. Each such asymmetric center will independently give two optical isomers, and it is intended that all possible optical isomers and diastereomers in the form of mixtures, as well as in the form of pure or partially purified substances, are covered by the present invention. It is intended that the present invention embrace all such isomeric forms of such spocks. Independent syntheses of these diastereomers or their chromatographic separation can be accomplished by methods known in the art, by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry can be determined by X-ray diffraction analysis of crystalline products or crystalline intermediates, which, if necessary, are derivatized with a reagent containing an asymmetric center with a known absolute configuration. If desired, racemic mixtures of compounds can be separated to isolate individual enantiomers. Separation can be accomplished by methods well known in the art, such as combining a racemic mixture of compounds with an enantiomerically pure compound resulting in a mixture of diastereomers, followed by separation of the individual diastereomers by standard methods such as fractional crystallization or chromatography. Stereoisomers of compounds of formula I are compounds of formula Ia or compounds of formula II, in particular, compounds of formula Ia in which the residues have the meanings disclosed in any of the embodiments.

4 4 pu Kk NOM YO Kk t 1 N M 1 N M dy "-,- 3 Kk M Ky 3 now what; o v? (0) ve?

Ia IB

In those embodiments where optically pure enantiomers are proposed, the term "optically pure enantiomer" means that the given compound contains » 90 wt. 95 of the desired isomer, in particular » 95 wt. , while the specified mass is expressed as a percentage of the total mass of the isomer(s) of the given compound. Chirally pure or chirally enriched compounds can be obtained by chirally selective synthesis or separation of enantiomers. Separation of enantiomers can be carried out at the stage of the final product or, alternatively, at the stage of the corresponding intermediate product.

Compounds of formula I can be prepared according to the following schemes. The starting materials are commercially available or can be obtained by known methods. Any previously defined residuals and variables retain their previously disclosed value unless otherwise noted.

Alkyl-2-chloro-2-(hydroxyimino)acetate is reacted with an olefin in the presence of a base, such as an alkylamine, such as TEA (triethylamine), or an alkali metal carbonate, such as ManHCO3 (sodium hydrogen carbonate), in a solvent such as chlorinated alkanes , in particular SNESSIG (dichloromethane), or an ether, in particular АССОКки (ethyl acetate), with the preparation of ether I.

Ester II is reduced with a hydride, in particular MavVna (sodium borohydride), in a solvent such as an alcohol, in particular EN (ethanol), to obtain the alcohol PP.

The nitro compound is reacted with an olefin in the presence of an activating reagent such as, for example, an isocyanate, in particular phenyl isocyanate, and a catalytic amount of a base, in particular an alkylaluminum, in particular TEA, in a solvent such as benzene or toluene, in particular benzene, or an alkyl ether, in particular, diethyl ether, with the preparation of dihydroisoxazole IM, where

BZ denotes alkyl, in particular methyl.

Dihydroisoxazoles IM, where VZ denotes haloalkyl, in particular fluoromethyl, can be obtained from alcohols I by reaction with a fluorinating agent, such as, for example, morpholinoserum trifluoride, in an inert solvent such as haloalkanes, preferably dichloromethane, at a temperature between -78 and 76 °C.

Arylation of dihydroisoxazole IM with aryl bromide M to obtain isoxazolidine MI is carried out using the reaction of an aryl halide, in particular aryl bromide, with an alkyllithium reagent, in particular p-Vyg, with the formation of aryllithium compounds, which can be introduced into the reaction with

With dihydroisoxazole IM in the presence of a Lewis base, preferably boron trifluoride etherate, in a mixture of solvents consisting of an ether, in particular TNE (tetrahydrofuran), and toluene, at a temperature from -100 "C to -20 "C, in particular at -78 "C .

Separation of racemic isoxazolidine MI to obtain chiral isoxazolidine MI can be carried out using chiral high-performance liquid chromatography (HPLC) using a SpPigairask AYU or Vergosi MA column, in a mixture of n-heptane and ethanol or isopropanol as an eluent.

The hydrogenolysis of chiral isoxazolidine MII to amino alcohol MI is best carried out by hydrogenolysis with hydrogen transfer, with the help of a palladium catalyst, in particular

Ra on charcoal, and a source of hydrogen, such as a formic acid salt, particularly ammonium formate, in a protic solvent such as an alcohol, particularly ethanol.

Oxazine IH can be obtained by the reaction of amino alcohol MI with cyanogen bromide in a solvent such as alcohol, in particular ethanol, at an elevated temperature. Alternatively, this reaction can be carried out in two consecutive steps using cyanogen bromide and a buffer such as, for example, sodium acetate in the presence of a solvent such as, for example, CH3CM, followed by cyclization of the intermediate in the presence of a mineral acid, in particular hydrochloric acid, in a solvent such as an ether, particularly 1,4-dioxane.

Nitration of oxazine Х to obtain nitrooxazine Х is carried out in a standard way using pure sulfuric acid and fuming nitric acid without a solvent.

Reduction of the nitro group in intermediate X to give aniline XI can be accomplished by hydrogenation with a catalyst such as Pa on charcoal in protic solvents such as alcohols, particularly ethanol or methanol.

Selective amide condensation of aniline ХІ and carboxylic acid ХІ to obtain amide I can be carried out using 4-(4,b-dimethoxy|1.3.5|griazin-2-yl)-4-methylmorpholinium chloride (OMTMM) hydrate as a condensing agent in a solvent , such as alcohol, in particular methanol.

Scheme 1: Synthesis of compounds of formula Ia-1

E rn C Z de) SE, Ko, SE, x U. U u-Na - -yav»j oS Os no p sh rai shchi b

CE, NC

SE

Mo, ТЙ who from these s / h in V --". in E

IU (Yu - Me, SN.E) M

BUT THAT'S IT

NM. with (0) KU SE, KU 3 , Go) and SE

In z - -t- t 3 --- - 3

E Kk Kk

E E E

IH USH UP nm o i SE, nm o m SE, v. - Ж ОН ше Км SE,

In about M

M M Ya

5 5 from KP N "vi

OM 54 of the present and M 54 of the century. M

E E E E

16); x XI Ia-1

Compounds of formula Ia-1i can be prepared according to the following Scheme 2, as indicated below.

Sulfinilimines of the general formula KHIM can be obtained by analogy with the method described in the literature (T.r. Tapo 4. uU.a. EPtap, u). Oh Spent 1999, 64, 12), by aryl ketone condensation

of a sulfinamide, for example an alkylsulfinamide, in an individual case (K)-tert-methylsulfinamide or (5)-tert-methylsulfinamide, in the presence of a Lewis acid, such as, for example, titanium(IM) alkoxide, in an individual case titanium(IM) ethoxide , in a solvent such as an ether, for example diethyl ether or, in a separate case, tetrahydrofuran.

The conversion of sulfinilimine KHM to sulfinamide ether KHM proceeds stereoselectively at the expense of a chiral guiding group, as described in the literature (Tapoa ee EIIPPpvap). Sulphinilimine

The CHM can be introduced into the Reformatsky reaction with a zinc enolate generated from a halogen-substituted alkylacetate, for example from ethyl bromoacetate, and activated zinc dust, at room temperature to elevated temperature, in particular from 23 to 60 "C, in a solvent such as ether, e.g. diethyl ether or, in a separate case, tetrahydrofuran, in the presence of a copper(I) salt, preferably copper chloride).

Aldehydes of the formula XMI can be obtained by reducing the ethyl ether of the formula XM with an alkali metal hydride, for example, lithium aluminum hydride, in the presence of diethylamine or sodium dihydrobis(2-methoxyethoxy)daluminate (Ne-AI), preferably with the help of diisomethylaluminum hydride (OIVAN), in an inert solvent such as an ether, for example diethyl ether or, in a separate case, tetrahydrofuran, or in a chlorinated solvent, such as dichloromethane, at a temperature between -78 "C and room temperature.

Alcohols of the formula XM can be obtained by the reaction of aldehydes of the formula XM! with a trifluoromethylating agent, preferably with trifluoromethyltrimethylsilane (Ruppert's reagent

Prakasha), in the presence of tetramethylammonium fluoride in a solvent such as an ether, for example diethyl ether or, in a separate case, tetrahydrofuran, at a temperature between -107C and room temperature.

Hydrolysis of the chiral directing group in the sulfinamido alcohol of the formula XMII to give the amino alcohol of the formula XM can be carried out with a mineral acid, for example sulfuric acid or, in particular, hydrochloric acid, in a solvent such as an ether, for example diethyl ether, tetrahydrofuran or, in a special case, 1, 4-dioxane.

An aminooxazine of the formula XIX can be obtained by the reaction of an amino alcohol of the formula XM! with cyanogen bromide in a solvent such as an alcohol, particularly ethanol.

The nitro derivative of formula XX can be obtained by nitration of oxazine XX in a standard way using pure sulfuric acid and fuming nitric acid, without a solvent.

Reduction of the nitro group in a compound of formula XX to give anilines of formula XXI can be accomplished by hydrogenation using a catalyst such as palladium on carbon in protic solvents such as alcohols, particularly ethanol or methanol.

The selective reaction of anilines of the formula XXI with a carboxylic acid of the formula XIiY to obtain amides of the formula Ia-1 can be carried out with the help of 4-(4,6-dimethoxy|1.3.5)|griazin-2-yl)-4-methylmorpholinium chloride hydrate (OMTMM) as a condensing agent in a solvent such as methanol at a temperature between 0 "C and room temperature. Alternatively, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6- trioxide (TzRU) can be used as a condensing agent in an inert solvent, such as, for example, ethyl acetate, at a temperature between 0 "C and room temperature.

Scheme 2: Synthesis of compounds of the formula Ia"-1 (where ВЗ - СН3, СНеЕ, СНЕ»)

NM NM M fi ZV o-- fi I sh So si So --zh tv"

KE KE E E E

ХхшШ ху ХУ ХМ ХУП

NM OH SE, NA and SE, NA 0 SE NO. SE, t t t

M M M NC. we "woo --- om. "du --- - "du ---nt "du!

E E E E

ХХХ хХХХ ХХХ

She and about HP I SE, 1 this

VE M pz te in 6)

IS

From Ia-1

Appropriate pharmaceutically acceptable salts formed with acids can be prepared by standard methods known to those skilled in the art, for example by dissolving a compound of formula I in a suitable solvent, such as, for example, dioxane or tetrahydrofuran, and adding an appropriate amount of the appropriate acid. Such products can usually be isolated by filtration or chromatography. Conversion of a compound of formula I into a pharmaceutically acceptable salt formed by a base can be accomplished by treating said compound with such a base. One of the possible methods of obtaining such a salt is, for example, the addition of 1/n equivalents of the basic salt, such as, for example, M(OH)", where M is a metal or ammonium cation, and n is the number of hydroxide anions, to a solution of the compound in the corresponding solvent (for example, in ethanol, ethanol-water mixture, tetrahydrofuran-water mixture), and removal of the solvent by evaporation or lyophilization. In particular, such salts can be hydrochloride, formate and trifluoroacetate; in a separate case - with hydrochloride.

If the preparation of compounds is not described in the examples, then such compounds of formula I, as well as all intermediate products, can be obtained by similar methods or methods presented in this description. The starting materials are commercially available, known in the art, or can be obtained by methods known in the art, or analogous to them.

It should be understood that the compounds of the general formula I according to the present invention can be derivatized by functional groups to obtain derivatives that are capable of being converted back into the initial compound i mimo.

Pharmacological tests

The compounds of formula I and their pharmaceutically acceptable salts have valuable pharmacological properties. It was found that the compounds of the present invention are associated with inhibition of activity

VASET. These compounds were tested according to the test described below.

Cellular analysis of B-amyloid concentration reduction

You can use a set of reagents for the analysis of Abeia 40 AIrnai IZA. NEK29Z3 cells

APP were seeded on 96-well MystoishSheg plates in a medium for cultivation (medium

Ivsome, with the addition of 1095 (06./06.) fetal bovine serum, penicillin/streptomycin) to about 8095 confluence and compounds were introduced at a 3-fold concentration in 1/3 volume of the culture medium (the final concentration of OM5O was maintained at 195 ./06.). After 18-20 g of incubation at 37 "С and 595 СО" in a humidified incubator, the culture supernatants were collected to determine AB 40 concentrations using a set of reagents ReiKkip-EIteg Nytap Atuisii reia 1-40 (high specificity) (cat.Mo AI 2756) .

2 2 μl of culture supernatants were combined with 2 μl of a 10-fold mixture of AIrnag granules on Reikip-EIteg M/nye Oririaie-384 (cat. Meo 6007290) plates. IzA Apii-pAVAAsseriog

Antibodies Api-AB 1-40 (anti-pAB acceptor and biotinylated antibodies anti-AB5BO, μg/ml / ZNM). After 1 g of incubation at room temperature, 16 μl of a 1.25-fold preparation of Streptavidin(ZA)-donor granules (25 μg/ml) was added and incubated for 30 min in the dark. After that, the emission was read at 615 nm on the Epmivziop-AIrna reader. Level

AB 40 in culture supernatants was calculated as a percentage of the maximum signal (cells treated with 195 OM5O without inhibitor). The ISvo values were calculated in the Ehsei program environment HI THI. cellular activity

Example Structure of YOUR1

AV4O, ISvo (NMI

GERMAN YO SE

SHI

M

1 H with, 2 and ;

SE E

(0)

GERMAN YO SE, t

M

2 H h 5 Fri "

SE E

(0)

cellular activity

Example Structure of YOUR1

AVAYAO, ISzo (NMI pe ll "SE,

M

Z Mo-I M K young 13

She: E (6) under "SE,

M zay A-E 22 ex E (6) vro "SE, in M

M on -, 50th M

ME

(6)

E under "SE,

M mm o nH -, 24

ME

(6)

E water "SE, w

M

Oh, I

7 M on -,, 15 sh

ME

(6) fo CE,

M

Ms-/y M KM z, 230 - E (6) water SE,

M a-yM mm -, 710 ex E (6)

cellular activity

Example Structure of YOUR1

AVAYAO, ISzo (NMI

Nm OSI CE 2 5-3 t

M a-y mm K -, she E si 9

Nam (6) "SE, y ek M 11 mm nn Kk 4 i

ZE E

(6) about "CE.

M

12 ms M K -, Z me E (6) podo "SE,

M

13 MS and MK -, 13 and E and 9

Nm (6) "SE, shi in M 14 M o nn -, 2 and she: E (6) nyo "SE,

E. I

- M i - 1

X M w E (6)

AT OO SE

EE she sha v-y J 16 and -, ! x M

It is cell activity

Example Structure of YOUR1

AV4O, ISvo (NM vodo "SE,

E M

17 M on -, 2 w; -

IS

(6;

NM OH essay

E 2 k-t Z on M 18 R (F) and M H -, in she E (6;

NM OH SE

2 m From those

E M

19 M n -, raki E (6; water "SE,

E M

M on -, 5

AND

ME

(6;

NM OH essay 2 k-t Z ti

M

21 M H -, 59 - y

Me E (6) water "SE,

She M 22 Mn -, 0.2 o M

ME

(6;

NM OH SE r; C.T. Z

SCHI ek M 23 M o n -, 1 0th M ran E (6;

cellular activity

Example Structure of YOUR1

AVAYAO, ISzo (NMI nyo "SE,

E. I

- M 24 M H -, Z

ME

(6)

Nm OSI essay

E U v Z b - nN -,

M M , o 2- E (6)

Nm OSI essay

E 2 in 3 in mn M 26 x M Ka 1 and E si o about "SE,

M

M H -, 217 MS-x M and 2 me E (0) but "SE,

M

МН -, 28 у --Е 11 ше Е si 9 pf "SE,

M

M n with 29 shock -E 15 sh- E si 9 vro "SE, in M 10) M N -, 11

Ov; -Eh E (6)

cellular activity

Example Structure of YOUR1

AVAYAO, ISzo (NMI

ON OO essay

Hey! - M

Z M H -, 7 and -E

SAME E

(6)

E higher "SE,

E I in-y Y z2 M H -, 7 i -E

ZE E

(6)

Nm ALL AXES

In ace: t

E M

33 M H z, 10 w; what

IS

(6)

Nm OO. "SE

E U Z

E t wl M 34 M H -, 71 i --E

SE E

(6)

ON O.I SE

In Z vol

In M

Mnt, 19 and -E

SAME E

(6)

Nm O.I SE

U Z t u M 36 M H -, Z 0-7 mm -E dl E (6)

Nm O.I SE

In the city of Z y

E M

37 M n z, 53 - M v pra E (6)

cellular activity

Example Structure of YOUR1

AV4O, ISvo (NMI vodo "SE, sp. I

Seam M 28 o - M Kg ran E (6)

Us About Essay

Eh! - M 39 0th KM A-E 0.4 ra E (6)

Nam (0; "SE, t v M 40 0-4 M K AA-E 29

Me E (0;

NAM (6) "SE, scha i m E 0-x n in 17 ran E (6)

Us (0; "SE, vol

M

42 M n of 64

ME

(0;

Us (6) "SE, vol

In M

43 0-5 m KM Ya g; With ra E (6) but "SE,

AND

M

4 ac K -A-E

ME

(6)

cellular activity

Example Structure of YOUR1

AV4O, ISvo (NMI

Nm Ob essay in; 5-3 t

E M

45 M nn Ko 39 -Y M dinya EE

ME

(6; under "CE,

E v- M i 46 M-M N --IE Z shkh u y i E si 9

Nm OO essay in; 5-3

And those

M

Y 5 -E 1

IS

(6;

Nm (6; SE in; Z t

M

48 M n h-E 520 vil SHY Kk shsh- E E (6;

Nm O.I essay in; With t

M

49 M on h--E 82 vil SHY Kk shsh- E E (6;

Table 1: values of ISvho in selected examples

Biological data

Analysis of P-dr (P-glycoprotein)

Cell lines and vesicles used for transport experiments

Cell line 11 C-RKI (ATS ySI-101) is a line of pig kidney epithelial cells. Cell lines transfected with MONI (human multidrug resistance protein 1) were kindly provided by Dr. A. bspipKeI (Te Meyshepapaz Sapseg Ipwzijssche, Amsterdam, The Netherlands). All cell lines were cultured on permeable inserts (Soviag, area 0.33 cm, pore size 3.0 µm, low density) at a density of 4.5:105 cells/cm7. Transport measurements were carried out on the 4th day after sowing. The density of the cell monolayer was controlled by the permeability of the extracellular marker Isiteg uePom (10 μm). Experiments in which the permeability of the Ishsiteg ueiom/ marker was higher than 195/g were excluded.

Experiments on the transport of ip migo

Bidirectional transcellular transport using GI cells C-RKI1 and I-MOV1

And GO-RKI, exogenously expressing human MOV 1

The method used for transport experiments was carried out on the TESAM automatic liquid transport system. Briefly, medium was removed from all compartments and the medium in the receiving compartment was replaced with culture medium. Transcellular transport measurements were initiated by adding the substrate together with the extracellular marker

Insiteg ueOom/ in the feeding compartment. Inhibitors were added to both compartments (1 μm elacridar).

Experiments on transport were carried out in both directions: basolateral-apical and apical-basolateral, along the Z well in each direction. Tablets were incubated at 37 "C and 595

So" in the incubator I hysopis. Samples were taken from the supplying and opposite (receiving) compartments after 2 hours of incubation. Substrate concentrations in both compartments were determined by scintillation counting (digoxin) or with the help of I C-M5/M5. The extracellular marker (Isiiteg ueiIom) was quantified on a spectrophotometer for reading bresigainog Rii tablets at 430/535 nm (excitation/emission wavelength). In each experiment, three different inserts were used for each condition and averaged.

Data analysis

Bidirectional transcellular transport with the use of I and C-RKI and Ii -MOV1 cells in the case of transcepillary transport, the following equation was used to evaluate the data: concentration and the amount transferred over a period of time, respectively. Values of Rar were calculated for a single moment of time (2 g). EV- RarriVA

Transport efflux ratios (EN) were calculated as follows: Раро7В ; where РапрВА denotes the value of permeability in the basolateral-apical direction, and РапрАВ - the value of permeability in the apical-basolateral direction. Rarrs were not corrected for the flow of the extracellular marker Issiteg uvI, which was used to assess the quality of cell monolayers.

Determination of glutathione conjugates (Y4ZH)

The analysis conditions for determining glutathione conjugates correspond to the method described in the literature (S.t.aiesKpaiz eyi a!., Snet.Rev. Tohisoi. 2005, 18, 6300-63).

NENS current measurement

The PENS current was measured in an automated patch-clamp system using the method described in the literature (K.e.tapip eyi a!., Visoga.Mei.Spet. ey 19 (2009), 6106-6113).

From Experiments ip mimo. Inhibition of AB40 in the brain of wild-type mice.

Female mice C57B1I/6) were injected with different doses of compounds, 3-4 animals per injection group.

The tested compound was dissolved in 595 EUN, 1095 solutol, and administered orally in a dose of 10 ml/kg.

After 4 g, the animals were killed and the brain and blood plasma were collected. The brain was divided into two halves and immediately frozen on dry ice. Brain was used to measure AB40, and plasma was used to determine the level of action of the compound. We used the method of determining AVD40 in brain lysates known from the literature (I ap, T.a.; 5spasnieg, UYU. reita yot ula-yture godepi Bgaip. U. Meshgovzsi. Meiyoa5 2006, 157, 71-81). Brain tissue was homogenized in 295 OEA buffer using the device

Vosne Maspaiuzeg (20 sec, 4000 rpm) and then centrifuged for 1 g at 100,000 9.

The concentration of PEA was reduced to 0.295 in 50 mm Mass and a second OEA lysate was passed through a plate for the extraction of Oases of 5000 RNase (U/aegv; cat.Mo 186000679), which was activated with MeOH9nH and equilibrated in ANGO (1 ml each). After washing in 1095 and 3095 MeOH (1 ml each), Ar-peptides were eluted in 0.8 ml of 295 MNAOH in 9095 MeOH. The eluate was dried in a stream of nitrogen, and the dried sample was redissolved in 30 μl of buffer for AIrpag analysis! And for. АВ4О0 was determined by means of the analysis of AlIrpagIzZA (RegKip EITeg). On a white 96-well microplate with half the volume of the wells (RegKip EITeg cat. Mo 6005561), 20 μl of the reconstituted sample was mixed with 5 μl of biotinylated VAR-24 (specific to the C-end of ArB40 (VgoskKpacs, M.; Spipbego, .; Wontgid, 5.; I oeyssneg, N.; MuShepriga, M.; Vashteiivieg, V.; UChasorzep, N.;

Naaztz, b. Savzrave-teaiaiei sieamkhade i5 poi gedtsit og She asimntsu oi rgezepiip5 ip atuioiidodepeziz i MOTSN bzidpaiipud. Meshygogerogi 1998, 9, 1481-6), the concentration of the initial solution is 4.4 mg/ml, i.b. 5.5 μg/ml) and 5 μl of granules with acceptor 25206 (antibodies to 25206,

Ipmygodep AMVO062), previously conjugated with acceptor granules AiYirpagiIzZA (Regkip

EI tag, cat. No. 6772002); final dilution 1:500). This mix was incubated for 1 h and Kt in the dark. Then, 20 μl of streptavidin-coated donor granules (5igeramimip-soyalea) were introduced

Bopog Veadz", RegKkip EITeg cat.Mo 6760002, final dilution 1:125) and this final mix was incubated in the dark for another 30 min at CT, after which fluorescence was measured relative to

unit (KE) on the AIrpazogeep Keadeg reader (Regkip EITeg Epmiziop 2104).

Kinetic analysis of cathepsin 0 and cathepsin E with fluorescent substrate

General principle of analysis

The methods of fluorescence analysis of MA121 described below are based on the following phenomenon:

MA121 forms a non-fluorescent ground state complex with tryptophan. In solution, its formation occurs at millimolar concentrations of tryptophan. This mechanism can be applied to develop a general biochemical assay for proteases. The peptide substrate is labeled at the M-end with tryptophan, and at the C-end with the MA121 fluorophore (for cathepsin 0, the 10-amino acid peptide M/T5MI MAARS-MA1T21 was used; for cathepsin E, MA121-SKI MERAEYUOMU was used). In the absence of protease activity, these substrates remain intact, and MA121 fluorescence decreases under the influence of high local concentrations of Ttr. If the substrates are split under the action of enzymes, then fluorescence

MA121 is being restored.

Analysis procedure

Kinetic analysis of cathepsin O and cathepsin E with a fluorescent substrate was performed at room temperature on 384-well microplates (black with a transparent flat bottom, plates with a non-binding surface produced by Sogpipd) in a final volume of 51 μl. The test compounds were serially diluted in ЮМ5О (15 concentrations, dilution step 1/3), after which 1 μl of the diluted compounds was mixed for 10 min with 40 μl of cathepsin O (from human liver,

Sairiosnet) diluted in analytical buffer (100 mM sodium acetate; 0.0595 BSA; pH 5.5; final concentration: 200 nM) or with 40 μl of recombinant human cathepsin E (HO

Zuzietv), dilution in analytical buffer (100 mm sodium acetate, 0.0595 BSA, pH 4.5; final concentration: 0.01 nM). After adding 10 μl of cathepsin substrate OO MUT5MI MAAROS-

MA121 diluted in analytical buffer for cathepsin O (final concentration: 300 nM) or 10 μl of cathepsin E substrate MA121-SKI MEEAEMMU diluted in analytical buffer for cathepsin E (final concentration: 300 nM), plates were vigorously shaken for 2 min.

The enzymatic reaction was monitored on a spectrophotometer for reading plates in the visible region (ReiKkeep EITeg) (excitation wavelength: 630 nm; emission: 695 nm) for at least 30 min in the kinetic measurement mode, detecting the increase in fluorescence

From MA121 during the reaction. The slope of the linear section of the kinetic curve was calculated and the IS values of the test compounds were determined using a 4-parameter equation to construct the curve.

Analysis of SUR inhibition

Inhibition of cytochromes P450 (SUR5) 209, 206 and ZA4 was evaluated using human liver microsomes and SUR-selective substrate metabolic reactions. Incubations were carried out in a volume of 50 μl containing (ultimately) 0.2 mg/ml of pooled human liver microsomes, 5 μm of substrate (diclofenac for CUR2C9 |4'hydroxylase)|, dextromethorphan for CUR2Ob (O-demethylase| or midazolam for SMURZA4 (PP hydroxylase!), 0.25 µl OM5O containing test inhibitor and NADFIN regeneration system Test inhibitor concentrations of 50, 16.7, 5.6, 1.9, 0.6 and 0 ,2 μm, were evaluated in monoplicates. The incubated material was previously heated to 37 "C for 10 min, after which initiation was carried out by adding the NADPH-regenerating system. The incubation medium was quenched after 5 min (20 min for dextromethorphan) by adding 50 μl of cold acetonitrile, which contains 20 ng/ml of 4-OH-diclofenac-13C6, 20 ng/ml of dextrorphan-JUOZ and 20 ng/ml of 1-OH-midazolam-04. The incubation material after quenching the reaction was kept at -20 "С for at least 1 h, after which was centrifuged (20,000 x 9, 20 min). The supernatants were separated and diluted with water 111, pi therefore, the analysis was carried out using a Rariangihe sample injector and a mass spectrometer

ARI4000. Peak areas for substrate, metabolite, and stable-labeled metabolite standard were determined using M5/M5. The peak plane ratios between the metabolite generated during the enzymatic reaction and the internal standard were used for further calculations.

The percentage share of the activity of the control (0ОМ50О) was calculated for each incubated material and the value of ISvo was estimated by nonlinear regression. Sulfaphenazole, quinidine, or ketoconazole were tested in each experiment to inhibit SUR2OS9, SUR2Ob, or SURZAA4, respectively, to control the sensitivity and reproducibility of the assay. (Mayidayed azzaub5 og pitap suyuspgote P4i50 asiimyiyev5, K.I. Mai5Ku and K.5.orasi, Ogyd Meyaroiivt apa aivrozyop 32: 647-660, 2004; 5. Rowleg apa N.2papa, Tne AARBZ doishtpai, Moi.10, Moi. 2, 410-424, 2008.)

The results

R-dr 7 Iii an Effect ip | Cathepsin E | Cathepsin O

Example | pipe, | people pEVOU my ISvo (μm) | ISvo (μM)| ISvo |μM) 22 | 263 ME | - | 83 | 5200 | 178.69 |550|13.0) 350 46 | t2ez ME | 8 | 61 | 5200 | 5200 | 550|24.0) 550

Table 2: Biological data according to selected examples 1) Efflux ratio 2) ME - ip myo absence of adduct formation, in relation to the control 3) Inhibition (F 10 μm 4) Percentage of control (F 10 mg/kg r.o.

Pharmaceutical compositions

Compounds of the formula and! and pharmaceutically acceptable salts can be used as therapeutically active substances, for example, in the form of pharmaceutical preparations. Such pharmaceutical preparations can be administered orally, for example in the form of pills, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. In addition, the introduction can be carried out rectally, for example in the form of suppositories, or parenterally, for example in the form of solutions for injections.

The compounds of formula I and their pharmaceutically acceptable salts can be processed together with pharmaceutically inert inorganic or organic carriers to obtain pharmaceutical preparations. As such carriers for pills, coated pills, dragees and hard gelatin capsules can be used, for example, lactose, corn starch or its derivatives, talc, stearic acids or their salts, etc. Suitable carriers for soft gelatin capsules are , for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. However, depending on the nature of the active substance, in the case of soft gelatin capsules, carriers are usually not required. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, glycerin, vegetable oil, etc. Suitable carriers for suppositories are, for example, natural or refined oils, waxes, fats, semi-solid or liquid polyols, etc.

In addition, such pharmaceutical preparations may contain pharmaceutically acceptable excipients, such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, dyes, flavors, salts for varying osmotic pressure, buffers, masking agents, or antioxidants. They may also contain other therapeutically useful substances.

The object of this invention is also medicinal products containing a compound of formula I or its

A pharmaceutically acceptable salt and a therapeutically inert carrier, as well as a method of their production, which includes the introduction of one or more compounds of the formula | and/or their pharmaceutically acceptable salts and, optionally, one or more other therapeutically valuable substances, in a galenic dosage form together with one or more therapeutically inert carriers.

The dosage can vary widely, and it should, of course, be selected according to individual requirements in each specific case. When administered orally, the dosage for adults may vary from about 0.01 mg to 1000 mg per day of a compound of general formula I or an appropriate amount of a pharmaceutically acceptable salt thereof. The daily dose can be administered as a single dose or divided doses, and, in addition, the upper limit can be exceeded if indicated.

The following examples are illustrative of the present invention, but are not intended to be limiting, but merely to illustrate it. Pharmaceutical preparations for convenience contain approximately 1-500 mg, in particular, 1-100 mg of a compound of formula I. Examples of compositions according to the invention are presented below.

Example A

Pills of the following composition are made in a standard way:

Va-vkh1500 77777771 11117166 | 16 1 60

Table 3: possible composition of the pill

Manufacturing procedure 1. Mix ingredients 1, 2, C and 4 and granulate with purified water. 2. Dry the granules at 50 "C. 3. Pass the granules through a suitable grinding device. 4. Add ingredient 5 and mix for three minutes; press using a suitable press.

Example B-1

Production of capsules of the following composition:

Hydrated lactose 11591771 123 | 148 | - (Total 77777771 | 171112007 1. 200 | z00 | 60

Table 4: possible ingredient composition of the capsule

Manufacturing procedure 1. Mix ingredients 1, 2 and C in a suitable mixer for 30 minutes. 2. Add ingredients 4 and 5 and mix for 3 min. 3. Place in the appropriate capsule.

The compound of formula I, lactose and corn starch are first mixed in a mixer, and then in a grinder. The resulting mixture is returned to the mixer; talc is added to it and thoroughly mixed. The mixture is automatically packed into appropriate capsules, such as hard gelatin capsules.

Example B-2

Production of soft gelatin capsules of the following composition:

Zhovtiyvosko/////777771111111111111111Ї1111111111111111111111811111111111111

Hydrogenated soybean oils ///Ї777777711111111111111111181111111111ссссСсСсСс20

Table 5: possible ingredient composition of soft gelatin capsules

Table 6: possible composition of soft gelatin capsules

Manufacturing procedure

Compound formula! the rest of the ingredients are dissolved in a warm melt, and this mixture is packed in soft gelatin capsules of the appropriate size. Filled soft gelatin capsules are processed by standard methods.

Example C

Production of suppositories of the following composition:

Table 7: possible composition of suppositories

Manufacturing procedure

The suppository mass is melted in a glass or steel vessel, thoroughly mixed and cooled to 45 "С. Then finely divided compound of formula I is added to it and mixed until it is evenly distributed. This mixture is poured into forms for suppositories of the appropriate size and cooled ; then the suppositories are removed from the form and packed separately in waxed paper or metal foil.

Example O

Production of solutions for injections of the following composition:

Table 8: possible composition of the solution for injections

Manufacturing procedure

The compound of formula I is dissolved in a mixture of polyethylene glycol 400 and water for injections (in part of the volume). Adjust the pH to 5.0 with acetic acid. The volume is brought up to 1.0 ml by adding the remaining amount of water. This solution is filtered, poured into vials with a permissible excess and sterilized.

Example E

Production of a sachet of the following composition:

Zo

Table 9: possible composition of the sachet

Manufacturing procedure

The compound of the formula |! mixed with lactose, microcrystalline cellulose and Ma-carboxymethyl cellulose, and granulated with a mixture of polyvinylpyrrolidone in water. The obtained granulate is mixed with magnesium stearate and aromatic impurities and packed in a sachet.

Experimental part

The following Examples are provided to illustrate the present invention. They should not be considered as limiting the scope of this invention, but only as a visual representation of it.

Abbreviation:

ASOE Her, ethyl acetate; OSM, dichloromethane; OIVAN, diisomethylaluminum hydride; EUN, ethanol; and-

RON, 2-propanol; MeOnH, methanol; CT, room temperature; TVME, tert-methyl methyl ether; TEA, triethylamine; TNE, tetrahydrofuran; TzRe (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide)

General:

M5: Mass spectra (M5) were recorded using either the positive or negative ion sputtering method (I5P or IZM) on the ReyKkip-EITeg ZSIEKH АРИ 300 device, or using the electron impact method (ЕЙ, 70 eV) on the Rippidap MAT 550 7000 spectrophotometer.

Synthesis of intermediate ether ІІІ (6) SE, tas U

OOsS

At -78"C, a solution of (7)-ethyl-2-chloro-2-(hydroxyimino)dacetate (2.81 g; 18.0 mmol) in AcO Her (6 mL), this suspension was heated to 22 C and continued to be stirred for 60 g. This suspension was filtered, the filtrate was evaporated and the residue was purified by chromatography on silica gel using a mixture of heptane/Asoka (10:1) to give ethyl 5-(trifluoromethyl)-4,5-dihydroisoxazole-3-carboxylate (3.2 g) as a colorless oil MO: t/2 - 211 ME.

Synthesis of intermediate alcohol I (6, SE, tas I

And (6)

Zo To a solution of ethyl 5-(trifluoromethyl)-4,5-dihydroisoxazole-3-carboxylate (1.0 g; 4.74 mmol) in

Sodium borohydride (197 mg; 5.21 mmol) was added slowly at 0 "C to EUN (10 ml) and this suspension was stirred at 0 "C for 4 h. This suspension was treated with a semi-saturated aqueous solution of MNACI, continued stirring for 10 min, and the mixture was extracted diethyl ether, the organic layers were dried and evaporated (70 mbar/40 "С) to obtain crude (5-(trifluoromethyl)-4,5-dihydroisoxazol-3-ylmethanol) (803 mg) in the form of a colorless oil, which was used without further purification. Me: t/2 - 169 MI"

Synthesis of intermediate fluorodihydroisoxazole IM

(6) SE,

M tas Shchi

IS

Morpholinosulfur trifluoride (7.98 g; 45.5 mmol) and continued stirring at -78 "C for 15 min, at 0 "C for 1 g and at 22 "C for 30 min. The resulting solution was treated with a cold aqueous solution of ManHsSoO»z, the organic layer was dried, evaporated (70 mbar/40 "C) and the residue was distilled from vessel to vessel at 100"C/08 mbar to obtain /3-(fluoromethyl)-5-(trifluoromethyl) )-4,5- dihydroisoxazole (2.54 g) in the form of a pale yellow liquid. Me: t/2 - 171 (MI.

Synthesis of intermediate dihydroisoxazole IM (6) CE,

M tas U

Nitroethane (5.74 g; 76.5 mmol), TEA (76 mg; 0.75 mmol) and phenyl isocyanate (18.2 g; 153 mmol), this solution was heated to 22°C and continued to stir for 60 g. This suspension was filtered and the filtrate distilled from vessel to vessel at 757C/1.0 mbar with obtaining 3-methyl-5-(trifluoromethyl)-4,5-dihydroisoxazole (4.69 g) in the form of a pale yellow liquid. MO: t/2 - 153 MI".

General method A: Synthesis of intermediate isoxazolidines Mi and MII

To a solution of aryl bromide M (8.26 mmol) in TNE (5 ml) and toluene (15 ml) was added with stirring at -78 "С p-Vy! and (1.6 M in hexane; 4.9 ml) for 10 min and continued to stir at -78 "C for 1 h. To a solution of dihydroisoxazole IM (3.9 mmol) in toluene (35 ml) was added at -78 C HEz-ESO (7.9 mmol), and then the phenyllithium reagent was added, obtained, as described above, with the help of a separate cannula for 10 min, keeping the temperature below -70 "C. The mixture was stirred at -78 "C for 1 g, quenched with a saturated aqueous solution of MNaCl and extracted with AcOEl. The organic layer was washed with saline, dried, evaporated, and the residue was purified by chromatography on silica gel using a mixture of cyclohexane and acetone to obtain pure isoxazolidine MI. about eV, tas NM -,

IS

Intermediate MI-i-: starting from 3-methyl-5-(trifluoromethyl)-4,5-dihydroisoxazole, (35,55)-hteI-3-(2-fluorophenyl)-3-methyl-5-trifluoromethyl- isoxazolidine in the form of pale

From a yellow liquid. MO: t/2 - 250.4 MANI.

Kk; Ai

Chiral EX

IS

The intermediate product MII-1: (35,55)-heI-3-(2-fluoro-phenyl)-3-methyl-5-trifluoromethylisoxazolidine was separated on a chiral HPLC column (SPigairask AOS) using a mixture of n-heptane/BuHNn ( 95:5) to give the desired (35,55)-3-(2-fluorophenyl)-3-methyl-5o-trifluoromethylisoxazolidine as the slower eluting enantiomer with positive optical rotation and (ZA,5НА)-3-(2 - fluorophenyl)-3-methyl-5-trifluoromethylisoxazolidine as a faster eluting enantiomer with negative optical rotation.

IF) S SE, tas NM

KO

IS

Intermediate MI-2: starting from 3-(fluoromethyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole, (35,55)-heI-3-(fluoromethyl)-3-(2-fluorophenyl)-5- (trifluoromethyl)isoxazolidine was obtained as a pale yellow liquid. MO: t/2 - 268.4 M-ANI".

S che SE, and khralpnii hell

Intermediate product MI-2: (35,55)-heI-3-(fluoromethyl)-3-(2-fluorophenyl)-5-(trifluoromethyl)isoxazolidine was separated on a chiral column (NKergoziy MA) using a mixture of n-heptane/- RION (98:2) to give the desired (35,55)-3-fluoromethyl-3-(2-fluorophenyl)-5-trifluoromethylisoxazolidine as the target enantiomer, eluting more slowly, with positive optical rotation and (ZНА,5А8)-3 -fluoromethyl-3-(2-fluorophenyl)-5-trifluoromethylisoxazolidine as the faster eluting enantiomer with negative optical rotation.

General method B: Synthesis of intermediate amino alcohol MI

To the solution of isoxazolidine MI! (6.4 mmol) in EUN (40 ml) was added Ra/C (1095, 288 mg") and ammonium formate (3.2 g) and this mixture was continued to be stirred at 22 "C for 5 h.

The suspension was filtered, the filtrate was evaporated, and the residue was partitioned between NaOH and a saturated aqueous solution of NaHSOO. The organic layer was dried and evaporated to obtain crude amino alcohol MI, which was used without further purification. . 00000 NO, SV, snoring 7

N,,

Ky E

Intermediate MP-1: starting from (35,55)-3-(2-fluorophenyl)-3-methyl-5-trifluoromethylisoxazolidine, target (25,45)-4-amino-1,1,1-trifluoro-4 -(2-fluorophenyl)pentan-2-ol was obtained as a colorless solid. MO: t/2 - 252.2 MANI. . and A hralnyi J nya s y

Intermediate MISH-2: starting from 0/0 (35,55)-3-fluoromethyl-3-(2-fluorophenyl)-5-trifluoromethylisoxazolidine, target (25,45)-4-amino-1,1,1, 5-tetrafluoro-4-(2-fluorophenyl)pentan-2-ol was obtained as a colorless solid. Me: t/2 - 270.4

IM-ANI".

General method C: Synthesis of intermediate oxazine IX

To the solution of amino alcohol MI! (7.3 mmol) in EN (38 ml) was added a solution of cyanide bromide (5 M in

SNZISM, 11 mmol) and this mixture was stirred in a sealed tube at 85 "С for 15 g. The mixture

CO was evaporated and the residue was partitioned between АСОЕІІ and a saturated aqueous solution of МагСО3, the organic layer was dried, evaporated and the residue was purified by means of chromatography (51-МН») using a mixture of heptane/АСОЕІ (from 5:1 to 0:1) to obtain pure oxazine THEM

VL "SE, - I I khralpnii h

T

Intermediate IX-1: starting from (25,45)-4-amino-1,1,1-trifluoro-4-(2-fluorophenyl)pentan-2-ol, the target (45,65)-4-(2 -fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine was obtained as a colorless oil. M: t/2 - 277.1 MANI". - I chiral ch one in E

Intermediate product YH-2: starting from (25,45)-4-amino-1,1,1,5-tetrafluoro-4-(2-fluorophenyl)pentan-2-ol, the target (45,65)-4- (fluoromethyl)-4-(2-fluorophenyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine was obtained as a colorless oil. Me: t/2 - 295.4

IM-ANI..

General method O: Synthesis of intermediate nitrooxazine X

Oxazine IX (3.0 mmol) was added in portions to concentrated sulfuric acid (13 ml) at 22 7C, the resulting solution was cooled to 0 "C and treated with

NMO»z (0.19 mL) for 20 min and continued stirring at 0 C for 1 h. This reaction mixture was slowly added to crushed ice (60 g), the pH was adjusted to 10 with

MaoOnH, the aqueous layer was extracted with AsOE, the organic layer was dried, evaporated and the residue was purified by chromatography on silica gel using a mixture of heptane/AsSOET 3:1 to obtain pure nitrooxazine H. novo "SE. chiral with

IS

Intermediate product X-1: starting from (45,65)-4-(2-fluorophenyl)-4-methyl-b6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine, the target (45,65)-4-(2-fluoro-5-nitrophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine was obtained as pale - yellow oil.

M: t/2 - 322.5 MANI". pe and "E - - khralpnnii xx om shki

Intermediate X-2: starting from /(45,65)-4-(fluoromethyl)-4-(2-fluorophenyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazine-2 -amine, target (45,65)-4-(2-fluoro-5-nitrophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2- amine was obtained as a colorless foam. M: t/2 - 340.4 |M.--NO".

General method E: Synthesis of intermediate aniline XI

A suspension of nitrooxazine X (2.6 mmol) in EN (40 ml) and TEA (02 ml) was treated according to

With the help of Ra/sS (10905, 80 mg) and this mixture was hydrogenated at atmospheric pressure and 22 "C for 2 h.

The mixture was filtered, the filtrate was evaporated and the residue containing crude aniline He was used without further purification. oo SV, chiral »

IS

Intermediate product X-y: starting from (45,65)-4-(2-fluoro-5-nitrophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin- 2-amino, target product (45,65)-4-(5-amino-2-

fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine was obtained as a colorless foam. M: t/2 - 292.5 MANI". меня "SE, - 2 xshZralnyi xX ; nx t

IS

Intermediate Xi-g: starting from (45,65)-4-(2-fluoro-5-nitrophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3- oxazine-2-amine, target (45,65)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazine -2-amine was obtained as a colorless solid. Me: t/72 - 310.4 M.-ANI..

Synthesis of intermediate sulfinilimine KHIM-1 o

M You sot

IS

IS

In an inert atmosphere, a light yellow solution of 2,2-difluoro-1-(2-fluorophenyl)ethanone (8.0 g; 45.9 mmol) in TNE (280 mL) was treated with CT (5)-2-methylpropane-2 -sulfinamide (5.68 g; 45.9 mmol) and then titanium(IM) ethoxide (21.0 g; 19.3 mL, 91.9 mmol). This pale yellow solution was heated to reflux temperature and stirred for 2 h. The reaction mixture was cooled to RT, poured into semi-saturated brine, diluted with NaOH (100 mL) and stirred vigorously for 1 h. and washing with ASOE, the aqueous layer was separated and extracted with ASOE (2 x 150 ml). The organic layers were dried over Md5O5" and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (eluent: heptane/AcSOEi 10:1) to obtain (5,2)-M-(2,2-difluoro-1-(2-fluorophenyl)ethylidene)-2-methylpropane-2 -sulfinamide (8.27 g; yield 64.995) as a yellow oil. Me: m/2 - 278.0 (M.-NI k. 2,2-Difluoro-1-(2-fluorophenyl)-ethanone was obtained as follows.

In a dry flask, a suspension of magnesium (1.26 g; 52.0 mmol) in TNE (100 mL) was treated at CT in an inert atmosphere with chlorotrimethylsilane (11.3 g; 13.3 mL, 104 mmol). This suspension was cooled to 0 °C and 2,2,2-trifluoro-1-(2-fluorophenyl)ethanone (4.99 g; 26 mmol) was added dropwise over 4 min while the internal temperature was raised to 13 °C. After the introduction, the internal temperature reached 20 "C. Then the suspension was cooled to 0 "C and stirred for 1 g. For processing purposes, the obtained yellow solution was heated to RT, decanted, and hydrochloric acid (3790; 20.5 g; 17, 1 ml, 208 mmol) during 3 min while cooling in an ice bath. A cloudy solution is obtained

Zo was stirred at RT for 20 min. The mixture was treated with saline solution (200 ml), the aqueous layer was separated and extracted twice with AsSOEL. The organic layers were washed with a saturated solution of NaHSO3 and brine, then dried and evaporated to give, after standing at RT, 2,2-difluoro-1-(2-fluorophenyl)ethanone (4.292 g; yield 94.895) as a light yellow semi-solid. Me: t/l - 174 (MI.

Synthesis of intermediate sulfinamide esters KhM-1 and KhU-2 1. -O 1. Ko)

You. de SOOBI (Ex. de soOBI

NM

In Art

IS

E E E xU-1 xU-2

Copper(I) chloride (2.74 g; 27.7 mmol) was mixed with activated zinc dust (14.5 g; 221 mmol) in a dry flask in an inert atmosphere and heated to 130 °C. After cooling to

CT was added to dry TNE (80 ml) and the resulting dispersion was heated with stirring to reflux temperature for 30 min. The external heating was removed and a solution of ethyl 2-bromoacetate (11.5 g; 7.65 ml, 69.1 mmol) in dry TNE (40 ml) was added dropwise so as to maintain the temperature at 55 °C. stir at 55"C for 30 min. After that, the mixture was cooled to 5 °C and a solution of (5,2)-M-(2,2-difluoro-1-(2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (7.67 g , 27.1 mmol) in dry TNE (40 ml) for 10 min, while the temperature was kept below 5"C. To complete the reaction, stirring was continued at 0 "C for 1 h. For processing purposes, the reaction mixture was filtered through a layer of Oisoline, which was washed with TVME.

The filtrate was extracted with a saturated solution of MNACI, the organic layer was dried over Mo5oOx and evaporated under reduced pressure. The crude product was purified by performing two successive chromatography on silica gel (eluent: heptane/AcOEII 4:1, then 3:11 for a mixture of isomers) to obtain (K)-ethyl-3-((5)-1,1-dimethylethylsulfinamido)-4 ,4-difluoro-3-(2-fluorophenyl)butanoate (ХУ-1) (yellow oil, 5.17 g; yield 51.295) in the form of the first eluting isomer, and (5)-ethyl-3-((5 )-1,1-dimethylethylsulfinamido)-4,4-difluoro-3-(2-fluorophenyl)butanoate (ХУ-2) (orange solid, 2.59 g; yield 25.790) as the second eluting isomer.

Synthesis of intermediate aldehydes KhMI 1, -O

IVy 5 sleep

NN

IS

E xHmI-1

Intermediate product KhMI-1. In a dry flask in an inert atmosphere, a light yellow solution of (5)-ethyl-3-((5)-1,1-dimethylethylsulfinamido)-4,4-difluoro-3-(2-fluorophenyl)butanoate (HMU-2) ( 2.59 g; 7.09 mmol) in OSM (75 mL) was treated dropwise with OIVAN (1 M in toluene; 10.6 mL, 10.6 mmol), keeping the internal temperature below -72 °C. After completion addition, the reaction mixture was stirred at -78 "C for 30 min. For processing purposes, the mixture was quenched with a saturated solution of MNASI (10 ml), allowed to warm to room temperature and stirred for 30 min. The obtained thick suspension was filtered through a layer of Oisaille?, which was washed twice with the help of USM. The filtrate was treated with a half-saturated solution of MNACI and extracted three times using OCM. The combined organic layers were dried over Ma 5 O 5 and evaporated.

The crude product was purified by silica gel chromatography (eluent: heptane/AcOEI; gradient: 30-5095 AcOEI) to obtain /(5)-M-((5)-1,1-difluoro-2-(2-fluorophenyl)-4- oxobutan-2-yl)-2-methylpropan-2-sulfinamide (HMI-1) (704 mg; yield 3195) in the form of a light yellow oil and the original ether ХУ-2 (1.28 g; yield 4995) in the form of a colorless oils M: t/2 - 322.4 (MAN). 1, -O

You. SNO re A

IS

KhMI-2

Intermediate product KhMI-2: starting from (5)-ethyl-3-((H)-1,1-dimethylethylsulfinamido)-3-(2-

From fluorophenyl)butanoate (IN. Niirepi Yei A. 00520120225858 (20123) and according to the method for the synthesis of the intermediate product KhMI-1, the target product (K)-M-((5)-2-(2-fluorophenyl)-4- oxobutan-2-yl)-2-methylpropan-2-sulfinamide (HMI-2) was obtained as a light yellow oil (yield 46596). M: t/2 - 286.5 (MAN).

Synthesis of intermediate alcohols HMI! and HMIII

In o BUT In it "75 CE, "75 onCE,

NM NM

E E

E E

KhUP-1 KhUP-2

Intermediate products of KhMII-1 and KhMII-2. In a dry flask in an inert atmosphere, a solution of (5)-M-((5)-1,1-difluoro-2-(2-fluorophenyl)-4-oxobutan-2-yl)-2-methylpropane-2-sulfinamide (HMI -1) (1.45 g; 4.51 mmol) in TNE (30 ml) was treated at 0 "C with (trifluoromethyl)trimethylsilane (1.28 g; 1.33 ml,

Coll

9.02 mmol) and dropwise with TVAE (1 M in TNE, dried over molecular sieve 4 A; 0.451 ml, 0.451 mmol). The weakly exothermic addition was completed after 3 min, after which the reaction mixture was stirred at 0 "C for 3 h, then the CT was left to heat and stirred overnight. For processing purposes, the reaction mixture was quenched with a saturated solution

MNASI was extracted three times with the help of AsOE. The organic layers were washed with saline, dried over Md5O»x and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (eluent: heptane/AcSOEC gradient: 0-9095 AsOEU to obtain (5)-2-methyl-M-(25,48)-1,1,5,5,5-pentafluoro-2- (2-Fluorophenyl)-4-hydroxypentane-2-ylpropane-2-sulfinamide (XMII-1) (yellow oil, 377 mg in the form of an approximate 7:3 mixture with its O-trimethylsilyl derivative) as a faster eluting epimer (5)-2-methyl-N-(25,45)-1,1,5,5,5-pentafluoro-2-(2-fluorophenyl)-4-hydroxypentan-2-yl)upropane-2-sulfinamide ( KhMII-2) (yellow solid, 209 mg; yield 1295) in the form of eluted second epimer M5: t/2 - 392.5 (MA-H)U of the initial aldehyde (yellow oil, crystallized on standing, 627 mg; yield

Zb). oh BUT it is

You" 5 not SE, You" 5 SE,

NM NM

E E

KhUP-3 xUP-4

Intermediates KhMII-3 and KhMII-4: starting from (K)-M-((5)-2-(2-fluorophenyl)-4-oxobutan-2-yl)-2-methylpropane-2-sulfinamide (KHMI- 2) and according to the method for the synthesis of an intermediate product

KhMY-1 and KhMII-2, the target products (K)-2-methyl-M-(25,45)-5,5,5-trifluoro-2-(2-fluorophenyl)-4-hydroxypentan-2-yl were obtained )upropane-2-sulfinamide (KHMII-3) and (K)-2-methyl-M-(25,4H8)-5,5,5-trifluoro-2-(2-fluorophenyl)-4-hydroxypentane-2- yl)upropane-2-sulfinamide (KHMII-4).

KhMII-3: the first eluting epimer as a light yellow solid (yield 24396). M: t/2 - 354.6 (M-H).

ChMII-4: second eluting epimer as a light brown solid (yield 8.596). M: t/2 - 356.5 (MAN).

Synthesis of intermediate amino alcohols KhM

IF) essay,

NM zi

IS

IS

Khush-1

Intermediate product KhMIPI-1. A solution of (5)-2-methyl-M-(25,45)-1,1,5,5,5-pentafluoro-2-(2-fluorophenyl)-4-hydroxypentane-2-ylylpropane-2 was stirred in an inert atmosphere -sulfinamide (HMII-2) (261 mg; 0.667 mmol) and hydrochloric acid (4 M in dioxane, 0.667 ml, 2.67 mmol) in

Zo Meon (5 ml) at 25"С. After 4 g, the solvent was removed under reduced pressure. The residue was treated with a half-saturated solution of MazbOz and extracted three times with the help of AcOE Her.

The combined organic layers were dried over M950O:5 and evaporated under reduced pressure.

The crude product was purified by chromatography on silica gel (eluent: heptane/AcSOEi 10:1) to obtain (25,45)-4-amino-1,1,1,5,5-pentafluoro-4-(2-fluorophenyl)pentane-2 -olu (KHMPI-1) (168 mg; 87.795) as a light yellow solid. Me: t/2 - 288.5 (MAN). but

SE,

NM p

IS

IS

Khush-2

Intermediate product KhMPI-2: starting from a mixture of (5)-2-methyl-M-(25,4H8)-1,1,5,5,5-pentafluoro-2-

(2-fluorophenyl)-4-hydroxypentan-2-yl/upropan-2-sulfinamide (HMII-1) and its o-trimethylsilyl derivative and according to the method for the synthesis of the intermediate product KhMPI-1, the target (28,45)-4 -amino-1,1,1,5,5-pentafluoro-4-(2-fluorophenyl)pentan-2-ol (HMIPI-2) was obtained as a light yellow solid (yield 9595). MO: t/2 - 288.5 (MAN).

IF)

SE,

NM

IS

KhUP-3

Intermediate product KMP-3: starting from /(K)-2-methyl-M-(25,4H8)-5,5,5-trifluoro-2-(2-fluorophenyl)-4-hydroxypentan-2-yl)upropane -2-sulfinamide (KHMII-43 and according to the method for the synthesis of the intermediate product KhMIP-1, the target /(2H8,45)-4-amino-1,1,1-trifluoro-4-(2-fluorophenyl)pentane-2 -ol (KHMPI-3) was obtained as a light yellow solid (yield 67.395).MW: t/2 - 252.5 (MAN).

Synthesis of intermediate oxazines XIX

NOM OH OSE r; 2-3 those

M

IS

IS

XIX-1

Intermediate product of the XIXth: based on 0/0 (25,45)-4-amino-1,1,1,5,5-pentafluoro-4-(2-fluorophenyl)pentan-2-ol (HMIPI-1) and according to General Method C, the target (45,65)-4-(difluoromethyl)-4-(2-fluorophenyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2- amine (XIX-1) was obtained as a colorless solid (yield 46.295). M: t/2 - 313, 4 (MANI.

NIM YO SE

7 3 those

M

IS

IS

XIX-2

Intermediate product /XIX-2: starting from // (28,45)-4-amino-1,1,1,5,5-pentafluoro-4-(2-fluorophenyl)pentan-2-ol (HMIPI-2) and according to General Method C, the target (45,6H)-4-(difluoromethyl)-4-(2-fluorophenyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2- amine (XIX-2) was obtained as a colorless oil (yield 80.295; purity ca. 6095). Me: t/72 - 313.4 MANI.

NOM YO SE

3

AI

M

IS

XIX-3

Intermediate product XIX-3: starting from (28,45)-4-amino-1,1,1-trifluoro-4-(2-fluorophenyl)pentan-2-ol (HMIPI-3) and according to General Method C, the target (45,68)-4-(2-fluorophenyl)-4-methyl-b-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XIX-3) was obtained in the form light brown oil (yield 60.695). MO: t/2 - 277.5 MANI".

Synthesis of intermediate nitrooxazines XX

NM YO OSCE r; and 3

M

OM t, 7

IS

E xx-1

Intermediate XX-1: starting from /(45,65)-4-(difluoromethyl)-4-(2-fluorophenyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazine-2 -amine (XIX-1) and according to General method p, the target (45,65)-4-(difluoromethyl)-4-(2-fluoro-5-nitrophenyl)-6-(trifluoromethyl)-5,6-dihydro -4H-1,3-oxazin-2-amine (XX-1) was obtained as a colorless solid (yield 73.295). MO: t/2 - 358.4 MANI.

NIM OH, SE 7 and 3

M

OM t t

IS

E хХхх-2

Intermediate XX-2: starting from (45,68)-4-(difluoromethyl)-4-(2-fluorophenyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2- amine (XIX-2) and according to General method p, the target (45,68)-4-(difluoromethyl)-4-(2-fluoro-5-nitrophenyl)-6-(trifluoromethyl)-5,6-dihydro- 4H-1,3-oxazin-2-amine (XX-2) was obtained as a colorless foam (yield 45.795). MO: t/7 - 358.5

IM-ANI".

NM. YO SE 7 and 3

M

OM t

E xx-3

Intermediate XX-3: starting from (45,68)-4-(2-fluorophenyl)-4-methyl-b6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine ( XIX-3) and according to General Method 0, the target (45,68)-4-(2-fluoro-5-nitrophenyl)-4-methyl-b-(trifluoromethyl)-5,6-dihydro-4H-1, 3-oxazin-2-amine (XX-3) was obtained as a light yellow viscous oil (yield 5495). Me: t/2 - 322.A4IM.-NI".

Synthesis of intermediate anilines XXI

NOM OH ASE in 3

AI

Nm zu y

IS

IS

XXI-1

Intermediate product XXI-1: starting from (45,65)-4-(difluoromethyl)-4-(2-fluoro-5-nitrophenyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3- oxazine-2-amine (XX-1) and according to the General Method E, the target /(45,65)-4-(5-amino-2-fluorophenyl)-4-(difluoromethyl)-6-(trifluoromethyl)-5 ,6-dihydro-4H-1,3-oxazin-2-amine (XXI-1) was obtained as a colorless solid (quant. yield). MO: t/2 - 328.4 MANI.

NM. .O , SE 2 of 3

On M t, t

E E

XXI-2

Intermediate product XXI-2: starting from (45,6H8)-4-(difluoromethyl)-4-(2-fluoro-5-nitrophenyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3- oxazine-2-y (XX-2) and according to General Method E, target /(45,68)-4-(5-amino-2-fluorophenyl)-4-(difluoromethyl)-6-(trifluoromethyl)-5 ,6-dihydro-4H-1,3-oxazin-2-amine (XXI-2) was obtained as a light gray foam (yield 95.495). Me: t/2 - 328.5

IM-ANI..

NM. 0. ,CE 2 7 3

On whether

IS

XXI-3

Intermediate product XXI-3: starting from /(45,6H)-4-(2-fluoro-5-nitrophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazine -2-amine (XX-3) and according to General Method E, the target (45,68)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro -4H-1,3-oxazin-2-amine (XXI-3) was obtained as a white solid (yield 95.195). Me: t/2 - 292.4 MANI.

The general method E for the synthesis of finite examples I

4-(4,6-dimethoxy-1,3,5-triazin-2yl)-4-methyl-morpholinium chloride (0, 19 mmol) and continued stirring at 0 C for 30 min. To this mixture was added a solution of aniline XI (0.15 mmol) in MeOHN (2 ml) and continued stirring at 0 "C for 4 h. The mixture was evaporated and the residue was partitioned between saturated aqueous solution of Mag2bOz and ethyl acetate. The organic layer was dried, evaporated, and the residue was purified by chromatography (51-MH2 using a mixture of heptane/ethyl acetate 1:1) to obtain final examples I.

General method C for the synthesis of finite examples of the formula

In an inert atmosphere, a solution/suspension of carboxylic acid (1.7 mmol) and intermediate aniline

XXI (1.62 mmol) in Asok I (6.7 ml) was treated dropwise with TzRe (5095 in ASOEI) (2.4 mmol, 1.43 ml), while the temperature was maintained at 25 °C. After the end of the addition the reaction mixture was stirred at 25 "С for 20 g. For the purpose of processing, the reaction mixture was quenched with a saturated solution of ManHCO3 (20 ml), the layers were separated and the aqueous phase was extracted with the help of ASOE Her (7 ml). The combined organic layers were washed with brine and dried over NaCl. After removal of the solvent, the crude product remained, which was purified by chromatography on silica gel using a mixture of OSM/MeonH or heptane/AcOEII or by preparative HPLC to obtain pure amides.

The following compounds were prepared according to General Method E or c and, depending on the reaction mixture and the purification conditions, they were isolated either as a free base or as a salt.

Examples 1-7 were obtained according to the General EC method.

Example 1

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-Cyanopicolinamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-methyl-6-trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine and 5-cyanopyridine -2-carboxylic acid gave the title compound as a colorless solid. M: t/:2 - 422.5 MANI.

Example 2

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-chloropicolinamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-methyl-6-trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine and 5-chloropyridine -2-carboxylic acid gave the title compound as a colorless solid. M: t/2 - 431.4 (MANI.

Example C

M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-cyanopicolinamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-"(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-41H-1,3-oxazin-2-amine and of 5-cyanopyridine-2-carboxylic acid gave the title compound as a colorless solid. Me: t/2 - 440.4 (MANI.

Example 4

M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-chloropicolinamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-"(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-43H-1,3-oxazin-2-amine and of 5-chloropyridine-2-carboxylic acid gave the title compound as a colorless solid. Me: t/2 - 449.4 MANI.

Example 5

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-methoxypyrazine-2-carboxamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-methyl-6-trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine and 5-methoxypyrazine -2-carboxylic acid gave the title compound as a colorless solid. Me: t/2 - 428.4 |M.-NO".

Example 6

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-(2,2-difluoroethoxy)pyrazine-2-carboxamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-methyl-6-trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine and 5-( 2,2-difluoro-ethoxy)-pyrazine-2-carboxylic acid (obtained as described in the literature: 5y2ikKi MU. ei aI., UMO 2009/0911 016) gave the title compound in the form of a colorless solid. Me: t/2 - 428.4 M.ANI..

Example 7

M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-methyl-6-trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine and 5-( 2,2,2-trifluoroethoxy)-pyrazine-2-carboxylic acid (obtained as

It is described in the literature: Zygiki U. Yei aI., MO 2009/091 016) gave the compound indicated in the title as a colorless solid. M: t/2 - 496.4 (M.AANI".

Example 8

M-(3-(45,68)-2-Amino-4-methyl-b6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5 -cyanopicolinamide

Condensation of (45.6K)-4-(5-amino-2-fluorophenyl)-4-methyl-6-trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XXI-3 ) and 5-cyanopyridine-2-carboxylic acid according to the General method

E gave the title compound as a light yellow foam. M: t/2 - 422.4 MANI.

Example 9

M-(3-(45,68)-2-Amino-4-methyl-b6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5 -chlorpicolinamide

Condensation of (45.6K)-4-(5-amino-2-fluorophenyl)-4-methyl-6-trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XXI-3 ) and 5-chloropyridine-2-carboxylic acid according to the General method

E gave the title compound as a white foam. MO: t/2 - 431.4 (M. ANEG.

Example 10

M-(3-(45,65)-2-Amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-3 ,5-chloropicolinamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-methyl-6-trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1 ) and 3,5-chloropyridine-2-carboxylic acid according to the General method

E gave the title compound as a colorless solid. Me: t/2 - 465.4

IMAANI", 467.4 (M--2--NO", 469.4 (MA4--NO.

Example 11

M-(3-(45,65)-2-Amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5 -(fluoromethoxy)picolinamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-methyl-6-trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1 ) and 5-(fluoromethoxy)picolinic acid |(СА5 1174321-03-9; U.M. EPaga ei ai.

MO2011009898 (2011)| according to General Method E gave the title compound as a colorless solid. Me: t/2 - 445.4 MANI.

Example 12

M-(3-(45,65)-2-Amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-bo fluorophenyl)- 5-cyano-3-methylpicolinamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-methyl-6-trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1 ) and 5-cyano-3-methylpicolinic acid (5.Vadidezhye a. UUO2011009943 (2011)| according to the General method C gave the compound specified in the title in the form of a colorless amorphous solid. Me: t/2 - 436.5 IM- NOR".

Example 13

M-(3-(45,65)-2-Amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-3 -chloro-5-cyanopicolinamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-methyl-6-trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1 ) and 3-chloro-5-cyanopicolinic acid according to the General method would give the title compound in the form of a colorless amorphous solid. MO: t/2 - 456.4 MANI.

Example 14

M-(3-(45,65)-2-Amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5 -methoxypicolinamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-methyl-6-trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1 ) and 5-methoxypicolinic acid according to the General method gave the title compound as a colorless amorphous solid. MO: t/2 - 427.5 MANI.

Example 15

M-(3-(45,65)-2-Amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5 -(difluoromethoxy)picolinamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-methyl-6-trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1 ) of 5-(difluoromethoxy)picolinic acid (U.O.5Soy eyi ai. UMO2011044181 (2011)| according to the General method C gave the compound indicated in the title in the form of a colorless amorphous solid. Me: t/2 - 463.4 | M--NO."

Example 16

M-(3-(45,65)-2-Amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5 -(trifluoromethoxy)picolinamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-methyl-6-trifluoromethyl)-5,6-dihydro-4H-1,3-

From oxazine-2-amine (XI-1) and 5-(trifluoromethoxy)picolinic acid GU.O.5cSoy and am. UUMO2011044181 (2011)| according to General Method C gave the compound indicated in the title as a colorless amorphous solid. Me: t/2 - 481.4 (MANI.

Example 17

M-(3-(45,65)-2-Amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5 -(difluoromethyl)upicolinamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-methyl-6-trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1 ) and 5-(difluoromethyl)picolinic acid |U.O.5cSoy ei ai. UUO2011044181 (2011)| according to General Method C gave the compound indicated in the title as a colorless amorphous solid. Me: t/2 - 447.5 MANI".

Example 18

M-(3-(45,65)-2-Amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5 -(2,2,2-trifluoroethoxy)picolinamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-methyl-6-trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1 ) and 5-(2,2,2-trifluoroethoxy)picolinic acid (O. Wappeg and others.

MO2010128058 (2010)| according to the General method would give the compound indicated in the title in the form of a colorless amorphous solid. Me: t/2 - 495.4 MANI.

Example 19

M-(3-(45,65)-2-Amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5 -(fluoromethyl)pyrazine-2-carboxamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-methyl-6-trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1 ) of 5-(fluoromethyl)pyrazine-2-carboxylic acid |U.M.EMagi ei ai.

MO2011009898 (2011)) according to General Method E gave the compound indicated in the title in the form of a colorless amorphous solid. Me: t/2 - 430.5 (MANI.

Example 20

M-(3-(45,65)-2-Amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5 -(difluoromethyl)pyrazine-2-carboxamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-methyl-6-trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1 ) of 5-(difluoromethyl)pyrazine-2-carboxylic acid (U.M. EMaga eyi a).

MO2011009898 (2011)| according to General method E gave the compound specified in title 60 as a colorless solid. Me: t/2 - 448.5 MANI.

Example 21

M-(3-(45,65)-2-Amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5 -methylpyrazine-2-carboxamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-methyl-6-"(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-2-amine (XI- 1) and 5-methylpyrazine-2-carboxylic acid according to the General method

E gave the title compound as a colorless amorphous solid. MO: t/2 - 412.5 (MANI.

Example 22

M-(3-(45,65)-2-Amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5 -(but-2-yniloxy)pyrazine-2-carboxamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-methyl-6-trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1 ) and 5-(but-2-ynyloxy)pyrazine-2-carboxylic acid |S. SviegpuiK ei ai.

MO2012087237 (20123) according to General Method E gave the compound indicated in the title as a white solid. MO: t/2 - 466.5 (MANI.

Example 23

M-(3-(45,65)-2-Amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5 -(fluoromethoxy)pyrazine-2-carboxamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-methyl-6-trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1 ) and 5-(fluoromethoxy)pyrazine-2-carboxylic acid ((U.M.Empaga ei ai.

MO2011009898 (2011)| according to the General method would give the compound indicated in the title in the form of a colorless amorphous solid. Me: t/2 - 446.5 MANI".

Example 24

M-(3-(45,65)-2-Amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5 -(difluoromethoxy)pyrazine-2-carboxamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-methyl-6-trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1 ) of 5-(difluoromethoxy)pyrazine-2-carboxylic acid (|.M.EPaga eyi ai.

MO2011009898 (2011)| according to the General method would give the compound indicated in the title in the form of a colorless amorphous solid. Me: t/2 - 446.5 MANI".

Example 25

Zo M-(3-(45,65)-2-Amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 2-(fluoromethyl)oxazole-4-carboxamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-methyl-6-trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1 ) of 2-(fluoromethyl)oxazole-4-carboxylic acid (O. Wappeg and a).

MO2011069934 (2011))| according to General Method E gave the title compound as a colorless solid. Me: t/2 - 419.5 (MANI.

Example 26

M-(3-(45,65)-2-Amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-4 -chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-methyl-6-trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1 ) and 4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxylic acid (O. Vappeg et al. MO2011069934 (2011)) according to General method E gave the compound indicated in the title as an off-white solid . Me: t/2 - 470.4 (M-ANI".

Example 27

M-(3-(45,65)-2-Amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-cyano-3-methylpicolinamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-"(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-2-amine ( ХИ-2) and 5-cyano-3-methylpicolinic acid |5.

MO2011009943 (2011)| according to the General method would give the title compound in the form of a light yellow solid. Me: t/2 - 454.4 MANI".

Example 28

M-(3-(45,65)-2-Amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -3-chloro-5-cyanopicolinamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-"(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-d4n-1,3-oxazin-2-amine ( XI-2) of 3-chloro-5-cyanopicolinic acid according to General Method C gave the title compound as a light yellow solid. MO: t/2 - 474 4 MANI.

Example 29

M-(3-(45,65)-2-Amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -3,5-dichloropicolinamide bo Condensation (45,65)-4-(5-amino-2-fluorophenyl)-4-«(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-

4H-1,3-oxazin-2-amine (XI-2) and 3,5-dichloropicolinic acid according to the General method

C gave the title compound as a colorless solid. Me: t/72 - 483.3

IM-AANI", 485.3 (M--2--NI, 487.2 |(Mi-4--NI.

Example 30

M-(3-(45,65)-2-Amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-methoxypicolinamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-"(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-2-amine ( XI-2) and 5-methoxypicolinic acid according to the General method gave the compound indicated in the title in the form of an amorphous colorless solid. MO: t/2 - 445.5 MANI.

Example 31

M-(3-(45,65)-2-Amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-(difluoromethoxy)picolinamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-"(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-dn-1,3-oxazin-2-amine ( XI-2) and 5-(difluoromethoxy)picolinic acid in accordance with the General method of Cb gave the compound specified in the title in the form of an amorphous colorless solid. MO: t/2 - 481.4 (MANI.

Example 32

M-(3-(45,65)-2-Amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-(trifluoromethoxy)picolinamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-"(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-dn-1,3-oxazin-2-amine ( XI-2) and 5-"'trifluoromethoxy)picolinic acid according to the General method of Sb gave the compound indicated in the title in the form of an amorphous colorless solid. MO: t/2 - 499.4 MANI.

Example 33

M-(3-(45,65)-2-Amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-(difluoromethyl)upicolinamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-"(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-dH-1,3-oxazin-2-amine ( XI-2) and 5-"(difluoromethyl)picolinic acid in accordance with General

The method would yield the title compound in the form of an amorphous, colorless solid. MO: t/2 - 465.4 (MANI.

Example 34

M-(3-(45,65)-2-Amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-(2,2,2-trifluoroethoxy)picolinamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-"(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-2-amine ( KhI-2) and 5-(2,2,2-trifluoroethoxy)picolinic acid according to

The general method would give the compound indicated in the title in the form of an amorphous, colorless solid. Me: t/2 - 513.4 (MANI.

Example 35

M-(3-(45,65)-2-Amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-(fluoromethoxy)picolinamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-"(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-dn-1,3-oxazin-2-amine ( XI-2) and 5-(fluoromethoxy)picolinic acid according to General Method C gave the title compound as a white solid. Me: t/2 - 463.6 (MANE.

Example 36

M-(3-(45,65)-2-Amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-methoxypyrazine-2-carboxamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-"(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-2-amine ( XI-2) and 5-methoxypyrazine-2-carboxylic acid according to General Method E gave the title compound as a colorless solid. MO: t/2 - 446.4 (MANI.

Example 37

M-(3-(45,65)-2-Amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-(fluoromethyl)pyrazine-2-carboxamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-"(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-43H-1,3-oxazin-2-amine ( XI-2) and 5-(fluoromethyl)pyrazine-2-carboxylic acid according to

General method E gave the title compound as a white solid.

M: t/2 - 448.6 (MANI. (510)

Example 38

M-(3-(45,65)-2-Amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-(but-2-ynyloxy)pyrazine-2-carboxamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-"(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-43H-1,3-oxazin-2-amine ( XI-2) and 5-(but-2-ynyloxy)pyrazine-2-carboxylic acid according to

General method E gave the title compound as a white solid.

M: t/2 - 484.4 MANI".

Example 39

M-(3-(45,65)-2-Amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-(difluoromethoxy)pyrazine-2-carboxamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-"(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-41H-1,3-oxazin-2-amine ( XI-2) and 5-"(difluoromethoxy)pyrazine-2-carboxylic acid according to

The general method would give the compound specified in the title in the form of a colorless solid. MO: t/2 - 482.6 (MANI.

Example 40

M-(3-(45,65)-2-Amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-(2,2-difluoroethoxy)pyrazine-2-carboxamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-"(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-2-amine ( XI-2) and 5-(2,2-difluoroethoxy)-pyrazine-2-carboxylic acid (U.5y2ikKi ei ai.

MO2009091016 (2009)| according to the General method would give the compound indicated in the title in the form of a colorless solid. Me: t/7 - 496.6 (MANG.

Example 41

M-(3-(45,65)-2-Amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-"(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-2-amine ( XI-2) of 5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylic acid according to General Method C gave the title compound as a colorless solid. M5: t/2 - 514.6 (MANI.

Example 42

Zo M-(3-(45,65)-2-Amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl )-5-methylpyrazine-2-carboxamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-"(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-2-amine ( XI-2) and 5-methylpyrazine-2-carboxylic acid according to General Method C gave the title compound as a colorless solid. MO: t/2 - 430.6 MANI".

Example 43

M-(3-(45,65)-2-Amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-(fluoromethoxy)pyrazine-2-carboxamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-"(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-41H-1,3-oxazin-2-amine ( XI-2) and 5-(fluoromethoxy)pyrazine-2-carboxylic acid according to

The general method would give the compound indicated in the title in the form of a colorless amorphous solid. Me: t/2 - 464.4 M.-NI..

Example 44

M-(3-(45,65)-2-Amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -3-methylpyrazine-2-carboxamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-"(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-2-amine ( XI-2) and 3-methylpyrazine-2-carboxylic acid according to the General method would give the title compound in the form of a light yellow oil. M: t/7 - 430.4 | MANG.

Example 45

M-(3-(45,65)-2-Amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-(difluoromethyl)pyrazine-2-carboxamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-"(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-43H-1,3-oxazin-2-amine ( XI-2) and 5-(difluoromethyl)pyrazine-2-carboxylic acid according to

General method E gave the title compound as a colorless solid. M5: t/2 - 466.4 (M-ENG..

Example 46

M-(3-(45,65)-2-Amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxamide bo Condensation (45,65)-4-(5-amino-2-fluorophenyl)-4-«(fluoromethyl)-6-(trifluoromethyl) -5,6b-dihydro-

4H-1,3-oxazin-2-amine (XI-2) and 4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxylic acid according to General Method C gave the title compound as a colorless solid . Me: t/2 - 488.5 (M.--NO..

Example 47

M-(3-(45,65)-2-Amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -2-(fluoromethyl)oxazole-4-carboxamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-"(fluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-43H-1,3-oxazin-2-amine ( XI-2) and 2-(fluoromethyl)oxazole-4-carboxylic acid according to

General method C gave the title compound as an off-white solid. M5: t/2 - 437.4 MANI.

Example 48

M-(3-(45,68)-2-Amino-4-(difluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-cyanopicolinamide

Condensation of (45.6K)-4-(5-amino-2-fluorophenyl)-4--(difluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine ( XXI-2) and 5-cyanopicolinic acid according to General Method E gave the title compound as a white solid. Me: t/2 - 458.6 |M-AANG.

Example 49

M-(3-(45,65)-2-Amino-4-(difluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-cyanopicolinamide

Condensation of (45,65)-4-(5-amino-2-fluorophenyl)-4-(difluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XXI -1) of 5-cyanopicolinic acid according to General Method C gave the title compound as a colorless solid. MO: t/2 - 458.4 MANI.

Claims (27)

FORMULA OF THE INVENTION 1. The compound of the formula I Che v' 1 ee Kk M z Vij v (c) 2 zo Kk ShCI where B' is selected from the group consisting of i) aryl, i) aryl, including 1-4 substituents, individually selected from cyano group, cyano-Ci-C-alkyl, halogen, halogen-C:-C-Alkoxy group, halogen-C:-C-Alkyl, C:-C-Alkoxy group, C:-C-Alkoxy-C:1-6- alkyl, C 1 -C 6 -alkynyl-C:C 1 -C 6 -alkyl groups, C 1 -C 6 -alkynyl and C 1 -C 6 -alkyl ii) heteroaryl and ii) heteroaryl, which includes 1-4 substituents individually selected from the cyano group, cyano-C :-C-alkyl, halogen, halogen-C:-C-Alkoxy group, halogen-C:-C-Alkyl, C:-C-Alkoxy group, C:-C-Alkoxy-C:1-6-alkyl, Cg- γ-alkynyl-C: 1-6-alkyl groups, C 1-γ-alkynyl and C:-γ-alkyl; B2 is selected from the group consisting of i) hydrogen, i) C-C-alkyl and i) halogen; BZ is selected from the group consisting of i) C-C-alkyl and i) halogen-C-C-alkyl; B" denotes halogen-Ci-C-alkyl; or its pharmaceutically acceptable salts. 2. The compound according to claim 1, where A" denotes a heteroaryl containing 1-2 substituents individually selected from the cyano group, cyano-C:1-6-alkyl, halogen, halogen-C:-C-alkyl, halogen-C: C1-6 alkyl, C1-6-alkyl, C1-6-alkyl, C1-6-alkynyl-C1-6-alkyl, C1-6-alkynyl and C1-6-alkyl. 3. The compound according to any of claims 1-2, where Bg denotes halogen. 4. The compound according to any of claims 1-3, where ШХВ2 denotes EC. 5. The compound according to any of claims 1-4, where BZ denotes fluoro-Ci-6-alkyl. 6. The compound according to any one of claims 1-5, where VZ denotes fluoromethyl. 7. The compound according to any of claims 1-4, where VZ denotes C -C alkyl. 8. The compound according to any of claims 1-4 and 7, where VZ represents methyl. 9. The compound according to any of claims 1-8, where B" denotes fluoro-Ci-6-alkyl. 10. The compound according to any one of claims 1-9, where B" denotes trifluoromethyl. 11. The compound according to any one of claims 1-10, which denotes a compound of the formula Ia-1 Che CE, 1 N M v M t, z z v i Ma-i where B' is selected from the group consisting of i) aryl , iii) aryl containing 1-2 substituents individually selected from the cyano group, cyano-C:-C alkyl, halogen, halogen-C:-C-Alkoxy group, halogen-C:-C-Alkyl, C:- C:-C-Alkoxy, C:-C-Alkoxy-C:1-6-Alkyl, C:-C-Alkynyl-C:C-C-Alkoxy, C:-C-Alkynyl and C:-C-Alkyl, i) heteroaryl and them) heteroaryl containing 1-2 substituents individually selected from the cyano group, cyano-C:-in-alkyl, halogen, halogen-C:-in-alkyl group, halogen-C:-in-alkyl, C:-in- Alkoxy group, C:-C-Alkoxy-C:1-6-alkyl, C:-C-Alkynyl-C:-E-Alkyloxy group, C:-C-Alkynyl and C:-C-Alkyl; and BZ is selected from the group consisting of ii) C-C-alkyl and iii) halogen-C-C-alkyl, or its pharmaceutically acceptable salts. 12. The compound according to any one of claims 1-11, where B' denotes a heteroaryl containing 1-2 substituents individually selected from the cyano group, halogen, halogen-C:1-C-Alkoxy group, halogen-Ci-C-Alkyl . 13. The compound according to any one of claims 1-12, where B' denotes a heteroaryl containing 1-2 substituents individually selected from the cyano group, halogen, halogen-C:-C-Alkoxy group and C-V-Alkoxy group. 14. The compound according to any of claims 1-13, where B" denotes 1-(difluoromethyl)-1H-pyrazol-3-yl, 2-(fluoromethyl)oxazol-4-yl, 3,5-dichloropyridin-2- yl, 3-chloro-5-cyanopyridin-2-yl, 3-methylpyrazin-2-yl, 4-chloro-1-(difluoromethyl)-1H-pyrazol-3-yl, 5-(2,2,2-trifluoroethoxy )pyrazin-2-yl, 5-(2,2-difluoroethoxy)pyrazin-2-yl, 5-(but-2-ynyloxy)pyrazin-2-yl, 5-(difluoromethoxy)pyrazin-2-yl, 5- (difluoromethyl)pyrazin-2-yl, 5-(fluoromethoxy)pyrazin-2-yl, 5-(fluoromethyl)pyrazin-2-yl, 5-chloropyridin-2-yl, 5-cyano-3-methylpyridin-2-yl , 5-cyanopyridin-2-yl, 5-difluoromethoxypyrazin-2-yl, 5-difluoromethoxypyridin-2-yl, 5-difluoromethylpyridin-2-yl, 5-fluoromethoxypyridin-2-yl, 5- methoxypyrazin-2-yl, 5 -methoxypyridin-2-yl, 5-methylpyrazin-2-yl, 5-trifluoroethoxypyridin-2-yl, B-trifluoromethoxypyrazin-2-yl or 5-trifluoromethoxypyridin-2-yl. 15. The compound according to any of claims 1-14, where B' denotes 5-cyanopyridin-2-yl, 5-chloropyridin-2-yl, 5-(2,2-difluoroethoxy)pyrazin-2-yl, 5- (2,2,2-trifluoroethoxy)pyrazin-2-yl or 5-methoxypyrazin-2-yl. 16. The compound according to any one of claims 1-15, where B' denotes 5-cyanopyridin-2-yl. 17. The compound according to any of claims 1-16, which is selected from the group including: M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6 -dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-B5-cyanopicolinamide, M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl) -5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-B-chloropicolinamide, M-(3-(45,65)-2-amino-4-(fluoromethyl)- 6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide, M-(3-(45,65)-2-amino-4 -(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-chloropicolinamide, M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- B-Methoxypyrazine-2-carboxamide, M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4- yl)-4-fluorophenyl)-5-(2,2-difluoroethoxy)pyrazine-2-carboxamide, M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamide, M-(3-(45,68)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H- 1,3-oxazin-4-yl)-4-fluorophenyl)-B5-cyanopicolinamide, M-(3-(45,68)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro -4H-1,3-oxazin-4-yl)-4-fluorophenyl)- B-chloropicolinamide, M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4 -fluorophenyl)- 3,5-chloropicolinamide, M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazine- 4-yl)-4-fluorophenyl)-5B-(fluoromethoxy)picolinamide, M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- B-cyano-3-methylpicolinamide, M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4- yl)-4-fluorophenyl)-3-chloro-5-cyanopicolinamide, M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6-dihydro-4H- 1,3-oxazin-4-yl)-4-fluorophenyl)- B-Methoxypicolinamide, M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4 -fluorophenyl)- 5-(difluoromethoxy)picolinamide, M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazine -4-yl)-4-fluorophenyl)-5B-(trifluoromethoxy)picolinamide, M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-(Difluoromethyl)picolinamide, M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl )-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)picolinamide, M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6- dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- Zo B-(fluoromethyl)pyrazine-2-carboxamide, M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6-dihydro-4H-1,3- oxazin-4-yl)-4-fluorophenyl)-B-(difluoromethyl)pyrazine-2-carboxamide, M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5 ,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-B-methylpyrazine-2-carboxamide, M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- B-(but-2-ynyloxy)pyrazine-2-carboxamide, M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6-dihydro-4H-1 ,3-oxazin-4-yl)-4-fluorophenyl)-B-(fluoromethoxy)pyrazine-2-carboxamide, M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl )-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- B-(difluoromethoxy)pyrazine-2-carboxamide, M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazine -4-yl)-4-fluorophenyl)-2-(fluoromethyl)oxazole-4-carboxamide, M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5, 6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxamide, M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-cyano-3-methylpicolinamide, M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazine- 4-yl)-4-fluorophenyl)-3-chloro-5-cyanopicolinamide, M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro -4H-1,3-oxazin-4-yl)-4- fluorophenyl)-3,5-dichloropicolinamide, M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazine- 4-yl)-4-fluorophenyl)-5-methoxypicolinamide, M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1 ,3-oxazin-4-yl)-4-fluorophenyl)-5-(difluoromethoxy)picolinamide, M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-(trifluoromethoxy)picolinamide, M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4 -yl)-4-fluorophenyl)-5-(difluoromethyl)picolinamide, M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H -1,3-oxazin-4-yl)-4- bo fluorophenyl)-5-(2,2,2-trifluoroethoxy)picolinamide, M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) -5-(fluoromethoxy)picolinamide, M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4 -yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide, M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro- 4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide, M-(3-(45,65)-2-amino-4-(fluoromethyl)- 6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-(but-2-ynyloxy)pyrazine-2-carboxamide, M-(3- (45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-(difluoromethoxy )pyrazine-2-carboxamide, M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4- yl)-4-fluorophenyl)-5-(2,2-difluoroethoxy)pyrazine-2-carboxamide, M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)- 5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamide, M-(3-(45.65 )-2-amino-4-(fluoromethyl)-6-(tri fluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-methylpyrazine-2-carboxamide, M-(3-(45,65)-2-amino- 4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-(fluoromethoxy)pyrazine-2-carboxamide, M-( 3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-3- methylpyrazine-2-carboxamide, M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl )-4-fluorophenyl)-5-(difluoromethyl)pyrazine-2-carboxamide, M-(3-(45,65)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro -4H-1,3-oxazin-4-yl)-4-fluorophenyl)-4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxamide, M-(3-(45,65)-2- amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-2-(fluoromethyl)oxazole-4-carboxamide, M -(3-(45,68)-2-amino-4-(difluoromethyl)-6-(trifluoromethyl)-5,6b-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-Cyanopicolinamide and M-(3-(45,65)-2-amino-4-(difluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)- 4- Zo fluorophenyl) -5-cyanopicolinamide or its pharmaceutically acceptable salt. 18. The compound according to any of claims 1-17, which is selected from the group including: M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6 -dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-B5-cyanopicolinamide, M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl) -5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-B-chloropicolinamide, M-(3-(45,65)-2-amino-4-(fluoromethyl)- 6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide, M-(3-(45,65)-2-amino-4 -(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-chloropicolinamide, M-(3-(45,65)- 2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-B-methoxypyrazine-2-carboxamide, M-( 3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)- 5-( 2,2-difluoroethoxy)pyrazine-2-carboxamide and M-(3-(45,65)-2-amino-4-methyl-6-"(trifluoromethyl)-5,6-dihydro-4H-1,3- oxazin-4-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamide, or its pharmaceutically acceptable salt. 19. The method of obtaining the compound of the formula | according to any of claims 1-18, according to which 3 the compound of the formula ХХ is introduced into the reaction with the compound of the formula ХХ! with the formation of a compound of the formula не и в' ц ' nm dz V. on (v) v2 ХІХ Хи! where B", V-d, VZ and B" are disclosed in any of claims 1-16. 20. The compound of formula I according to any of claims 1-18, in all cases when it is obtained by the method disclosed in claim 19. 21. The compound of the formula | according to any of claims 1-18 for use as a therapeutically active substance. 22. The compound of formula I according to claims 1-18 for use as a therapeutically active substance for the therapeutic and/or prophylactic treatment of diseases and disorders characterized by an increased level of p-amyloid and/or p-amyloid oligomers, and/or pD-amyloid plaques and other deposits, or Alzheimer's disease. 23. The compound of formula I according to claims 1-18 for use as a therapeutically active substance for the therapeutic and/or prophylactic treatment of amyotrophic lateral sclerosis (AI5), arterial thrombosis, autoimmune/inflammatory diseases, cancer, for example breast cancer, cardiovascular diseases, such as myocardial infarction and stroke, dermatomyositis, Down syndrome, diseases of the gastrointestinal tract, glioblastoma multimorpho, Bazed disease, Huntington's disease, inclusion body myositis (IBM), inflammatory reactions, Kaposi's sarcoma, Kostmann's disease, lupus erythematosus, macrophage myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple myeloma, rheumatoid arthritis, Sjogren's syndrome, spinocerebellar ataxia 1, spinocerebellar ataxia 7, Whipple's disease or Wilson's disease. 24. A pharmaceutical composition that includes a compound of formula I according to any one of claims 1-18 and a pharmaceutically acceptable carrier and/or a pharmaceutically acceptable excipient. 25. Use of the compound of formula I according to any of claims 1-18 for the manufacture of a medicinal product for the therapeutic and/or prophylactic treatment of Alzheimer's disease. 26. Application of the compound of the formula | according to any of claims 1-18 for the manufacture of a medicinal product for the therapeutic and/or prophylactic treatment of amyotrophic lateral sclerosis (AG 5), arterial thrombosis, autoimmune/inflammatory diseases, cancer, for example breast cancer, cardiovascular diseases such as myocardial infarction and stroke, dermatomyositis, Down syndrome, diseases of the gastrointestinal tract, multimorphic Ko) glioblastoma, Bazed disease, Huntington's disease, inclusion body myositis (IBM), inflammatory reactions, Kaposi's sarcoma, Kostmann's disease, lupus erythematosus, macrophage myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple myeloma, rheumatoid arthritis, Sjogren's syndrome, spinocerebellar ataxia 1, spinocerebellar ataxia 7, Whipple's disease or Wilson's disease. 27. Method for use in the therapeutic and/or prophylactic treatment of Alzheimer's disease or amyotrophic lateral sclerosis (A 5), arterial thrombosis, autoimmune/inflammatory diseases, cancer, such as breast cancer, cardiovascular diseases, such as myocardial infarction and stroke, dermatomyositis, Down's syndrome, diseases of the gastrointestinal tract, glioblastoma multimorpho, Based's disease, Huntington's disease, inclusion body myositis (IBM), inflammatory reactions, Kaposi's sarcoma, Kostmann's disease, lupus erythematosus, macrophage myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple myeloma, rheumatoid arthritis, Sjogren's syndrome, spinocerebellar ataxia 1, spinocerebellar ataxia 7, Whipple's disease or Wilson's disease, comprising administering a compound of formula I according to any one of claims 1-18 to a human or animal. 0 Computer keyboardA. Kryzhanivskyi (00000000 State Intellectual Property Service of Ukraine, Vasyl Lypkivskyi St., 45, Kyiv, MSP, 03680, Ukraine SE "Ukrainian Intellectual Property Institute", Glazunova St., 1, Kyiv - 42, 01601