New compounds and compositions for cathepsin inhibition

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I), their isomers and pharmaceutically acceptable salts. In the general formula (I) A is (II) ; X1 is methylene; X2 is CN, CHO, C(O)R6; X6 is a link; R1 is R13C(O)-; R2 is hydrogen; R3 is selected out of group including H, phenyl-(C0-6)alkyl, (C1-6)alkyl, optionally substituted by -X6OR9 group; R4 is H or (C1-6)alkyl; or R3 and R4 form (C3-8)cycloalkylene together with carbon atom to which R3, R4 are linked; R5 is (C1-9)alkyl, benzyl. Invention also concerns compounds of formulae (la), (lb), (Ic), and pharmaceutical composition based on the claimed compounds.

EFFECT: new compounds inhibiting cathepsin.

22 cl, 2 dwg, 89 ex

 

The scope of the invention

The present invention relates to the use of new diploblastic for the treatment of diseases associated with systemprocesses, particularly diseases associated with the activity of cathepsin S, K and B. the Present invention also relates to methods for obtaining such compounds.

Background of invention

Cysteinate are a class of peptidases, characterized by the presence of a cysteine residue in the catalytic center of the enzyme. Cysteinate associated with normal decomposition and protein processing. However, the violation activity cysteinate, for example, as a result of increased expression or enhanced activation may have pathological consequences. In this regard, some cysteinate associated with several pathological conditions, including arthritis, atherosclerosis, emphysema, osteoporosis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, periodontis, metachromatic leukodystrophy, etc.

The increased activity of cathepsin, such as cathepsin S, contributes to the pathology and/or symptomatology of diseases, such as autoimmune disorders, including, but not limited to, juvenile diabetes, multiple sclerosis, common bladderwort, graves ' disease malignant male, systemic lupus erythematosus, irritable bowel syndrome, rheumatoid arthritis and Hashimoto's thyroiditis, allergic diseases, including, but not limited to, asthma and allogeneic immune responses, including, but not limited to, reactions by transplantation of organs or tissues. Cathepsin S also associated with violations, including excessive elastolin, such as chronic obstructive lung disease (e.g. emphysema), bronchiolitis, excessive elastosis of the Airways in asthma and bronchitis, pneumonitis and cardiovascular disease, such as the destruction of plaques and atheroma. Cathepsin S involved in the formation of fibrils, therefore, inhibitors of cathepsin S may be used in the treatment of systemic amyloidosis.

Activity, for example, cathepsin B in synovial fluid were significantly increased in models of osteoarthritis (F. Mehraban Ann. Rheum. Dis. 1997; 56, 108-115). Similarly, cathepsin K is a protease, which plays an important role in the breakdown of collagen mediated synovial fibroblasts (W.-S. Hou (et al.) Am. J. Pathol. 2001, 159, 2167-2177). Thus, inhibition of cathepsin B and K is, for example, effective treatment of degenerative lesions of the joints, such as osteoarthritis. Inhibition of cathepsin K, for example, leads to inhibition of bone resorption (G. B. Stroup (et al.) J Bone Mineral Res. 2001, 16, 739-1746). Therefore, inhibitors of cathepsin K can be used for the treatment of osteoporosis.

It is known that cathepsins play an important role in the destruction of connective tissue, the production of biologically active proteins and the processing of antigens. They are involved in the pathogenesis of osteoporosis, muscular dystrophy, bronchitis, emphysema, viral infection, cancer metastasis, and neurodegenerative diseases such as Alzheimer's disease and Huntington's disease. Recently an increasing interest in inhibitors of cathepsins has been associated with the emergence of potential therapeutic targets, such as cathepsin K or cathepsin L, in the case of osteoporosis, and cathepsin S, in the case of modulation of the immune response (W. Kim., K. Kang. Expert Opin. Ther. Pat. 2002, 12, 419-432). The increased activity of cathepsin K or B leads to the pathology and/or symptomatology of diseases. In accordance with this molecule, inhibiting the activity of catalinbread, can be used as therapeutic agents in the treatment of such diseases.

Brief description of the invention

In one aspect of the present invention describes compounds that inhibit the enzymatic activity of cathepsin S, B and K, and having a structure of formula (I):

where

A represents

orX1represents a methylene, ethylene or communications;

X2represents CN, CHO, C(O)R6C(O)C(O)NR7R7C(O)C(O)NR7R8C(O)C(O)R13C(O)C(O)OR13C(O)CH2X3R13;

X3selected from the group consisting of O, S(O)n, CO, CONH, NHCO, NHSO2and SO2NH;

X4represents CH(R12) or CH(R12)-CH2;

X5represents a methylene, ethylene, propylene, or a bond;

X6represents a bond or (C1-2)alkylen;

R1represents H, R13C(O)-, R13S(O)2-, R13OC(O)-, R8R7NC(O)-, R8R7NS(O)2-; R13S(O)2NC(O)- or R13C(O)NS(O)2-; or R1selected from the group consisting of (C1-9)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C5-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl and hetero(C5-13)aryl(C0-6)alkyl, each of which may be substituted by 1 to 5 radicals independently selected from the group consisting of (C1-4)alkyl, ceanography, halogen, halogen-substituted C1-4)alkyl, -X6NR9R9, -X6OR9, -X6SR9, -X6C(O)NR9R9, -X6OC(O)NR9R9, -X6C(O)OR9, -X6NC(O)OR9, -X6S(O)R10, -X6S(O)2R10and-X6C(O)R1 ;

R2selected from the group consisting of hydrogen, (C1-6)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C5-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl or hetero(C5-12)aryl(C0-6)alkyl;

R3selected from the group consisting of H, (C1-6)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C5-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl or hetero(C5-13)aryl(C0-6)alkyl, optionally substituted by 1 to 5 radicals independently selected from the group consisting of (C1-4)alkyl, ceanography, halogen, halogen-substituted C1-4)alkyl, -X6NR9R9, -X6OR9, -X6SR9, -X6C(O)NR9R9, -X6OC(O)NR9R9, -X6C(O)OR9, -X6NC(O)OR9, -X6S(O)R10, -X6S(O)2R10and-X6C(O)R10;

R4represents H or (C1-6)alkyl; or R3and R4together with the carbon atom that is attached to R3and R4form (C3-8)cycloalkyl or (C3-8)heterocyclochain;

R5represents H, F, or R5is a (C1-9)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-13)aryl(C0-61-4)alkyl, ceanography, halogen, halogen-substituted C1-4)alkyl, -X6NR9R9, -X6OR9, -X6SR9, -X6C(O)NR9R9, -X6OC(O)NR9R9, -X6C(O)OR9, -X6NC(O)OR9, -X6S(O)R10, -X6S(O)2R10and-X6C(O)R10;

R6is a (C6-12)aryl, hetero(C5-13)aryl and halogen-substituted C1-6)alkyl; where R6may be substituted by 1 to 5 radicals independently selected from the group consisting of (C1-9)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C5-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-13)aryl(C0-6)alkyl, ceanography, halogen, halogen-substituted C1-6)alkyl, -X6NR9R9, -X6OR9, -X6SR9, -X6C(O)NR9R9, -X6OC(O)NR9R9, -X6C(O)OR9, -X6NC(O)OR9, -X6S(O)R10, -X6S(O)2R10and-X6C(O)R10;

R7represents H, (C1-6)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-13)aryl(C0-6)alkyl and halogenase the output (C 1-6)alkyl; where R7may be substituted by 1 to 5 radicals independently selected from the group consisting of (C1-4)alkyl, ceanography, halogen, halogen-substituted C1-4)alkyl, -X6NR9R9, -X6OR9, -X6SR9, -X6C(O)NR9R9, -X6OC(O)NR9R9, -X6C(O)OR9, -X6NC(O)OR9, -X6S(O)R10, -X6S(O)2R10and-X6C(O)R10;

R8selected from the group consisting of H, (C1-6)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl and hetero(C5-13)aryl(C0-6)alkyl; or R7and R8together with the attached atom, form a (C3-8)cycloalkyl or (C3-8)heterocyclochain;

R9independently in each case represents hydrogen, (C1-6)alkyl or halogen-substituted C1-6)alkyl;

R10is a (C1-6)alkyl or halogen-substituted C1-6)alkyl;

R11selected from the group consisting of hydrogen, (C1-9)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C5-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-13)aryl(C0-6)alkyl, (C9-12)bicycloalkyl(C0-3)alkyl, hetero(C8-12)bicycloalkyl(C0-3)alkyl, -C(O)R13 , -C(S)R13, -S(O)2R13, -C(O)OR13, -C(O)N(R7R8, -C(S)N(R7R8and-S(O)2N(R7R8;

R12represents H or (C1-6)alkyl, optionally substituted by amidon, (C6-12)aryl, hetero(C5-12)aryl, hetero(C5-12)cycloalkyl or hydroxy;

R13is a (C1-6)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-13)aryl(C0-6)alkyl and halogen-substituted C1-6)alkyl; where R13optionally may be substituted by 1 to 5 radicals independently selected from the group consisting of (C1-4)alkyl, ceanography, halogen, halogen-substituted C1-4)alkyl, -X6NR9R9, -X6OR9, -X6SR9, -X6C(O)NR9R9, -X6OC(O)NR9R9, -X6C(O)OR9, -X6NC(O)OR9, -X6S(O)R10X6S(O)2R10or-X6C(O)R10; and

n is zero or an integer 1 or 2;

and their corresponding N-oxides, prodrugs, protected derivatives, individual isomers and mixtures of these isomers and their pharmaceutically acceptable salt and solvate (e.g., hydrates) of such compounds of formulas (Ia) and N-oxides and prodrugs, protected derivatives, individual isomers and mixtures of these isomers the century

In another aspect the present invention relates to frame structures of formulas II, III, IV or V, where sub1-sub8denote the total substituents. Preferred substituents sub1-sub8are not part of this aspect of the invention and can be any chemical group or radical which can be substituted in these positions (hereinafter referred to as "General deputies"), including substitutions that can be made by any conventional methods or with the use of any new technologies that will be developed in the future. Thus, for the purposes of this application, "General substituents are not included in the claims or not limit the claims of this application; and they themselves may be new and non-obvious, or unknown at the inception of the present invention.

In another aspect the present invention relates to the basic structure of formulas II, III, IV or V with conventional substituents in the provisions of sub1-sub8. In the description of this application under "normal office" shall mean any chemical group or radical, which, at the time of invention, according to experts in this field can be entered in the provisions of sub1-sub8methods of introduction, the preferred mixture is Italy, listed below as a guide, without unnecessary experiments on the implementation of the present invention.

In still another aspect of the present invention includes the basic structures of formulas II, III, IV or V and referred to below as preferred substituents in positions sub1-sub8. Preferred substituents described in this application, hereinafter will be referred to as "special deputies". For the purposes of this application a special Deputy, if he is mentioned in the claims, is limited claims and may report the patentability by itself or in conjunction with the principal structure and present it to the Deputy.

Definitions

Unless specifically indicated, the following terms used in the description and in the claims, in the context of the present application have the following meanings.

"Chemical structural unit relating to the connection is called N-oxide derivative, derivative prodrugs, protected derivative, individual isomer, mixture of isomers, or pharmaceutically acceptable salt or MES-mentioned compounds, which can be obtained by specialists in the field without undue experimentation.

"Acyl" means an H-CO - or alkyl-CO-group, where the alkyl group defined in the present description.

"Acylamino" represents an acyl-NH-group, where the acyl is defined in the present description.

"Alkoxy" means alkyl-O-group, where the alkyl group defined in the present description. Examples of alkoxygroup are allyloxy, deformedarse, methoxy, triptoreline, ethoxy, n-propoxy, isopropoxy, n-butoxy, heptox.

"Alkoxycarbonyl" means alkyl-O-CO-group, where the alkyl group defined in the present description. Examples alkoxycarbonyl groups are methoxy and etoxycarbonyl.

"Alkyl" by itself means a linear or branched, saturated or unsaturated aliphatic radical with the specified number of carbon atoms (for example, (C1-6)alcelam include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, Isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethinyl, 1-PROPYNYL, 2-PROPYNYL and the like). Alkyl, along with another radical (e.g., such as arylalkyl) means a linear or branched, saturated or unsaturated aliphatic divalent radical having the specified number of carbon atoms, or if the number of atoms is not specified, it means a direct connection (e.g., (C6-12)aryl(C0-6)alcelam include phenyl, benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl etc). Specialists in this field it is known that if lcil is an unsaturated aliphatic radical, such radicals can not join directly to the oxygen atom, nitrogen or sulfur through a multiple carbon-carbon bond of the specified unsaturated aliphatic radical.

"Alkylen"if it is not specifically mentioned, means a linear or branched, saturated or unsaturated aliphatic divalent radical having the specified number of carbon atoms; and the number (C1-2)alkylene include methylene (-CH2-) and ethylene (-CH2CH2-). Professionals in this field know that if alkylen represents an unsaturated aliphatic divalent radical, this radical can not be attached directly to the oxygen atom, nitrogen or sulfur through a multiple carbon-carbon bond of the specified unsaturated aliphatic divalent radical.

"Alkylenedioxy" means-O-alkylene-O-group in which alkylen defined above. Examples of alkylenedioxy are methylendioxy, Ethylenedioxy.

"Alkylsulfonyl" means alkyl-SO-group in which the alkyl group defined above. Preferred alkylsulfonyl groups are groups in which the alkyl group is a (C1-4)alkyl.

"Alkylsulfonyl" means an alkyl-SO2-the group in which the alkyl group defined above. Preferred alkylsulfonyl and groups are groups in which the alkyl group is a (C1-4)alkyl.

"Alkylthio" means alkyl-S-group in which the alkyl group defined above. Examples of alkylthio are methylthio, ethylthio, isopropylthio, reptillia.

"Aromatic" refers to any compound, the atoms which form an unsaturated ring system, all atoms which sp2-hybridized, and in which the total number of PI-electrons is 4n+2.

"Aroyl" means an aryl-CO-group in which the aryl group defined above. Examples rolnych groups are benzoyl and 1 - and 2-naphtol.

"Aroylamino" is aroyl-NH-group in which aroyl defined above.

"Aryl" as a group or part of a group denotes: (i) optionally substituted monocyclic or polycyclic aromatic carbocyclic group having from 6 to 12 carbon atoms, such as phenyl or naphthyl; or (ii) an optionally substituted partially saturated polycyclic aromatic carbocyclic group in which the aryl and cycloalkyl or cycloalkenyl groups are condensed to form a cyclic structure, such as tetrahydronaphthalene, ingenernoe or indanamine ring. If it is not specifically mentioned, the aryl group may have substituents in the form of one or more identical or different arilin the x groups, where the substituent in the form of the aryl group is, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfonyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyl, arylalkylamines, arylalkyl, aryloxy, aryloxyalkyl, arylsulfonyl, arylsulfonyl, aaltio, carboxy (or an acid bioisostere), cyano, cycloalkyl, halogen, heteroaryl, heteroaryl, heteroaromatic, heteroaromatic, heteroaromatic, heteroseksualci, hydroxy, nitro, trifluoromethyl, -NY3Y4, -CONY3Y4, -SO2NY3Y4, -NY3-C(=O)alkyl, -NY3SO2alkyl or alkyl, optionally substituted aryl, heteroaryl, hydroxy or-NY3Y4(where Y3and Y4independently represent hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroaromatic; or the group-NY3Y4may form a cyclic amine). Examples of optionally substituted C6-12)arilou are, but not limited to, biphenyl, bromophenyl, chlorophenyl, dichlorophenyl, deformational, dimetilfenil, ethoxycarbonylphenyl, forfinal, isopropylphenyl, methoxyphenyl, were, methylsulfinylphenyl, naphthyl, pentafluorophenyl, phenyl, trifloromethyl, triptoreline etc. Optionally substituted C6-12)aryl, as used in this described and to indicate a radical Deputy, attached to the group R6is trifloromethyl, deformational, 4-forfinal etc.

"Arylalkyl" means arylalkyl-O-group in which arylalkyl group defined above. Examples of arylalkylamine are benzyloxy and 1 - or 2-naphthalenyloxy.

"Arylalkylamines" means arylalkyl-O-CO-group in which arylalkyl group defined above. Example arylalkylamines group is benzyloxycarbonyl.

"Arylalkyl" means arylalkyl-S-group in which arylalkyl group defined above. An example of arylalkylamine is benzylthio.

"Aryloxy" means aryl-O-group in which the aryl group defined above. Examples of aryloxy are phenoxy, naphthoxy, each of which may have substituents.

"Aryloxyalkyl" means aryl-O-C(=O)-group in which the aryl group defined above. Examples aryloxyalkyl groups are phenoxycarbonyl and mattoxicator.

"Arylsulfonyl" means aryl-SO-group, in which aryl group defined above.

"Arylsulfonyl" means aryl-SO2-the group in which the aryl group defined above.

"Aristeo" means an aryl-S-group in which the aryl group defined above. Examples of aricioglu are phenylthio, naphthylthio.

"Cyclol the sludge" means a saturated or partially unsaturated monocyclic, condensed bicyclic or associated bridge connection polycyclic system with the specified number of carbon atoms in the ring and any carbocyclic keto, taketo or imidaclopride (for example, (C3-12)cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantane-1-yl, decahydronaphthalene, oxocyclohexyl, chlorides, thiacyclohexane, 2-oxobicyclo[2.2.1]hept-1-yl and the like). Professionals in this field know that if cycloalkyl is an unsaturated system of rings, such a system cannot be directly connected through a multiple carbon-carbon bond to the oxygen atom, nitrogen or sulfur.

"Cycloalkyl" means a divalent saturated or partially unsaturated monocyclic or associated bridge connection polycyclic system containing the specified number of carbon atoms in the ring and any carbocyclic keto, taketo or imidaclopride.

"Heteroaryl" means heteroaryl-C(=O)-group in which the heteroaryl group defined above. An example of a heteroaryl group is pyridylcarbonyl.

"Heteroarenes" means heteroaryl-NH-group in which the heteroaryl group defined above.

"Heteroaryl" as a group or part of a group denotes: (i) aromatic optionally substituted monocyclic or polycyclic organic functional group containing from approximately 5 to approximately the part 13 ring members, in which one or more atoms are carbon, for example nitrogen, oxygen or sulfur (examples of such groups are benzimidazolinone, benzoxazolinone, benzothiazoline, furilla, imidazolidine, indayla, indolizinyl, isoxazolyl, sochineniia, isothiazolinone, oxadiazolidine, oxazolidine, piratininga, pyridinoline, pyrazolidine, perederina, pyrimidinyl, pyrrolidine, chinadaily, hyalinella, 1,3,4-thiadiazolidine, thiazolidine, thienyl and triazolinone, optionally substituted by one or more aryl groups defined above, unless otherwise noted); (ii) optionally substituted partially saturated polycyclic group heteroeroticism in which heteroaryl and cycloalkyl or cycloalkenyl group condensed to form a cyclic structure (examples of such groups are pyridinoline group, optionally substituted by one or more "substituents in the form of aryl groups defined above, unless otherwise stated). Possible substituents are one or more "substituents in aryl group"defined above, if it is not specifically mentioned. Optionally substituted hetero - (C5-13)aryl, which in this application is denoted by R6includes benzox the evils-2-yl, 5-tert-butyl[1,2,4]oxadiazol-3-yl, 3-cyclopropyl-1,2,4-oxadiazol-5-yl, 5-cyclopropyl-1,2,4-oxadiazol-5-yl, 5-cyclopropyl-1,3,4-oxadiazol-2-yl, 5-ethyl[1,3,4]oxadiazol-2-yl, 5-(4-forfinal)-1,2,4-oxadiazol-3-yl, 5-isopropylthiazole-3-yl, 5-(5-methylisoxazol-3-yl)oxazol-2-silt, oxazol-2-yl, 3-phenyl-1,2,4-oxadiazol-5-yl, 5-phenyl-1,2,4-oxadiazol-3-yl, 3-(tetrahydropyran-4-yl)-1,2,4-oxadiazol-5-yl, 5-thiophene-2-isoxazol-2-yl, 5-(4-trifloromethyl)-1,3,4-oxadiazol-2-yl, etc.

"Heteroaromatics" means heteroallyl-O-group in which heteroallyl group defined above. An example of heterokaryosis is optionally substituted, pyridyloxy.

"Heteroaromatic" means heteroaryl-O-group in which the heteroaryl group defined above. An example of heterokaryosis is optionally substituted, pyridyloxy.

"Heteroseksualci" means cycloalkyl defined in this application, provided that one or more of these carbon atoms in the ring is replaced by a heteroatom group selected from-N=, -NR-, -O - or-S-, where R represents hydrogen, (C1-6)alkyl, a protective group or a free valency, which serves as a place of attachment to the nitrogen atom in the ring, and any carbocyclic keto, taketo or imidaclopride (for example, the term "hetero(C5-12)cycloalkyl" includes imidazole is dinil, morpholinyl, piperazinil, piperidyl, pyrrolidinyl, pyrrolyl, hinokitiol etc). Suitable protective groups are tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl etc. In the scope of the present invention includes both unprotected and protected derivatives.

"Heterocyclochain" means cycloalkyl defined herein, provided that one or more of these carbon atoms in the ring is replaced by a heteroatom group selected from-N=, -NR-, -O-, -S - and-S(O)2-where R represents hydrogen, (C1-6)alkyl or a protective group.

Used in the present description, the term "isomer" refers to compounds according to the invention, having the same molecular formula but differ in the nature or sequence of links between atoms or the arrangement of atoms in space. Isomers having different arrangement of atoms in space are called stereoisomers". Stereoisomers that are not mirror images of each other are termed "diastereomers"and stereoisomers that are not shared mirror images of each other, are called "enantiomers" or, sometimes, "optical isomers". A carbon atom with four different substituents is called a "chiral center". The connection that they is no one chiral center, there are two enantiomers of opposite chirality. "Racemic mixture" contains both enantiomers in a ratio of 1:1. However, in this description, the term "racemic mixture" is used if both enantiomers are present regardless of their correlation. A compound that contains more than one chiral center, is 2n-1enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist in the form of individual diastereoisomer, or a mixture of diastereomers, called "diastereomeric mixture". If there is one chiral center, the stereoisomer may be characterized by the absolute configuration of the chiral center. Under the absolute configuration understand the spatial arrangement of the substituents attached to this chiral center. Enantiomers are characterized by the absolute configuration of chiral centers and are described by rules R and S nomenclature of Cahn, Ingold and Prelog. Rules stereochemical nomenclature, methods for the determination of stereochemical structures and methods of separation of isomers is well known to specialists in this field (for example, see "Advanced Organic Chemistry", 4th edition, March, Jerry, John Wiley & Sons, New York, 1992). It should be noted that the names and examples used in this application to describe the Oia compounds of the present invention, should encompass all possible stereoisomers. So, for example, name {1-[1-(3-cyclopropyl[1,2,4]oxadiazol-5-carbonyl)propellerblades]-3,3-divergence}amide morpholine-4-carboxylic acid must include {(S)-1-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-carbonyl)propellerblades]-3,3-divergence}amide morpholine-4-carboxylic acid {(R)-1-[(R)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-carbonyl)propellerblades]-3,3-divergence}amide morpholine-4-carboxylic acid, and any mixture, including racemic or similar

"N-oxide derivatives" means derivatives of compounds according to the invention, in which the nitrogen atoms are oxidized state (i.e., N-O), and which possess the desired pharmacological activity.

The term "pharmaceutically acceptable" refers to a connection that can be used to obtain a pharmaceutical composition, which is essentially safe, non-toxic and do not have undesirable biological or other properties, and which can be used in veterinary medicine, as well as in medicine.

"Pharmaceutically acceptable salts" refers to salts of the compounds according to the invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts are acid additive salts, formed the haunted inorganic acids, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as acetic acid, propionic acid, hexanoic acid, heptane acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methylsulfonate acid, econsultancy acid, 1,2-ethicality acid, 2-hydroxyethanesulfonic acid, benzolsulfonat acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonate acid, p-toluensulfonate acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]Oct-2-ene-1-carboxylic acid, glucoheptonate acid, 4,4'-Methylenebis(3-hydroxy-2-EN-1-carboxylic acid), 3-phenylpropionate acid, trimethylhexane acid, tert-Butylochka acid, louisanna acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, Mukanova acid, etc.

Pharmaceutically acceptable salts also are basically additive salts, which can form the I in the event that if your acidic protons can react with inorganic or organic bases. Acceptable inorganic bases are sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like

"Prodrug" means a compound which is in the process of metabolismin vivocan turn into a connection according to the invention. For example, ester compounds according to the invention containing a hydroxy-group, by hydrolysis to turnin vivoin the original molecule. Alternatively, the ester compound according to the invention containing carboxypropyl may, by hydrolysis to turnin vivoin the original molecule. Suitable esters of compounds according to the invention containing a hydroxy-group, are for example acetates, citrates, lactates, tartratami, malonate, oxalates, salicylates, propionate, succinate, fumarate, maleate, methylene-bis-b-hydroxynaphthoate, gentisate, isethionate, di-p-toluoyltartaric, methylsulfonate, econsultancy, bansilalpet, p-toluensulfonate, cyclohexylsulfamate and hinata. Suitable esters of compounds according to the invention, containing the carboxyl group, are, for example, described in the work of F.J. Leinweber, Drug Metab. Res., 1987, 18, str. A particularly suitable class of esters of the compounds according to the invention containing a hydroxyl group may be formed from acid groups selected from described by Bundgaard et al., J. Med. Chem., 1989, 32, str-2507, and may include substituted (aminomethyl)benzoate, such as dialkylaminomethyl, in which the two alkyl groups can be either connected together or separated by an oxygen atom or optionally substituted nitrogen atom, for example alkilirovanny a nitrogen atom, namely (morpholinomethyl)benzoate, for example 3 - or 4-(morpholinomethyl)benzoate and (4-alkylpiperazine-1-yl)benzoate, for example 3 - or 4-(4-alkylpiperazine-1-yl)benzoate.

"Protected derivative" refers to derivatives of the compounds according to the invention, in which the reaction center or centers are blocked by protective groups. Protected derivatives of compounds according to the invention can be used to obtain compounds according to the invention, or they can be active inhibitors of cathepsin S. the Complete list of suitable protective groups can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc., 1999.

"Therapeutically effective amount" refers to the number that, when introduced him to an animal for treatment of illness is evania is sufficient for the treatment of this disease.

"Treating" or "treatment process" means the administration of the compounds according to the invention and includes:

(1) the prevention of the disease in an animal that may have a predisposition to the disease, but which is not yet available or is not presented in the pathology or symptomatology of the disease;

(2) the suppression of the disease in an animal that has or is manifested pathology or symptomatology of the disease (i.e., the prevention of further development of the pathology and/or symptomatology), or

(3) achieving a more favorable course of the disease in an animal that has or is manifested pathology or symptomatology of the disease (i.e. the weakening of the pathology and/or symptoms).

Nomenclature

Compounds according to the invention or the intermediate and source materials used for their production, are named in accordance with the rules of IUPAC nomenclature, where the characteristic of the groups listed below have the following priority, in descending order of importance: acids, esters, amides, etc. Alternative, the names of these compounds assigned using AutoNom 4.0 (Beilstein Information Systems, Inc.). For example, the compound of formula (I)in which R1represents morpholine-4-carbonyl, X1represents a methylene, R5presented yet a methyl, R2represents H, A representswhere R3represents ethyl, R4represents H, and X2represents C(O)R6where R6is a 3-cyclopropyl-1,2,4-oxadiazol-5-yl; i.e., the compound of the following structure:

called {(S)-1-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-carbonyl)propellerblades]-3,3-deformaty}amidon morpholine-4-carboxylic acid.

However, it should be noted that if for any preferred compounds represented by structural formula and nomenclature the name, there is a mismatch between the structural formula and nomenclature title, preference should be given to structural formula.

Various features of the present inventions that are new, are described in detail in the attached claims and are part of the description of the present invention. For a better understanding of the invention, the advantages of its use and the preferred implementation is described below, in which are illustrated and described preferred embodiments of the present invention.

Detailed description of preferred embodiments of the invention

In the above formula (I) used is described by the following preferred groups:

X1can represent, in particular methylene.

A can represent, in particular,where: R3represents H, (C6-12)aryl(C2-6)alkyl or (C1-6)alkyl, which is optionally substituted by-X6OR9[in which X6represents a bond, and R9is a (C1-6)alkyl]; R4represents H or (C1-6)alkyl; and X2represents CHO, CN or C(O)R6[in which R6represents a hetero(C5-13)aryl, optionally substituted (C1-9)alkyl, (C3-12)cycloalkyl, (C6-12)aryl or hetero(C5-13)aryl].

A can also be awhere X5represents propylene, and R11represents-C(O)OR13or-S(O)2R13where R13represents alkyl or (C6-12)aryl.

R1may, in particular, be an R13C(O)-, where R13represents a hetero(C5-12)cycloalkyl.

R1also, in particular, be an R13OC(O)-, where R13is a (C6-12)aryl(C1-6)alkyl.

R1also, in particular, represent a (C1-9)alkyl.

R1also, in particular, can be a hetero(C5-12)cycloalkyl.

R2may, in particular, represent H.

R5may, in particular, represent a (C1-9)alkyl.

R5also, in particular, represent a (C6-12)aryl(C1-6)alkyl.

Preferred types of connections

One of the preferred groups of compounds according to the invention are the compounds of formula (Ia):

where R1, R3, R4and R5described above, and their corresponding N-oxides, prodrugs, protected derivatives, individual isomers and mixtures of these isomers, and pharmaceutically acceptable salt and solvate (e.g., hydrates) of such compounds of formulas (Ia) and their N-oxides and prodrugs, protected derivatives, individual isomers and mixtures of these isomers.

Examples are the compounds of formula (Ia)in which R1is an R13C(O)-, and R13represents a hetero(C5-12)cycloalkyl. In particular, examples of the compounds of formula (Ia)in which R1represents.

Examples are the compounds of formula (Ia)in which R3represents H, (C6-12)aryl(C1-6)alkyl or (C1-6)alkyl. In particular, examples of the compounds of formula (Ia)in which R3represents H, or CH3-CH2-CH2-.

Examples are the compounds of formula (Ia)in which R4represents H or methyl.

Examples are the compounds of formula (Ia)in which R5is a (C6-12)aryl(C1-6)alkyl.

In particular, examples of the compounds of formula (Ia)in which R5represents.

One preferred group of compounds according to the invention are the compounds of formula (Ia)in which: R1is an R13C(O)- (in particular,); R3represents H, (C6-12)aryl(C1-6)alkyl (in particular,) or (C1-6)alkyl (in particular, CH3-CH2-CH2-);

R4represents H or methyl, and R5is a (C6-12)aryl(C1-6)alkyl (in particular,).

Another preferred group of compounds according to the invention are the compounds of formula (Ib):

where R1, R3, R4and R5defined above, and their corresponding N-oxides, prodrugs, protected derivatives, individual isomers and mixtures of these isomers, and pharmaceutically acceptable salt and solvate (e.g., hydrates) of such soy is ineni formula (Ib) and their N-oxides and prodrugs, protected derivatives, individual isomers and mixtures of these isomers.

Examples are the compounds of formula (Ib)in which R1is an R13C(O)-, and R13represents a hetero(C5-12)cycloalkyl. In particular, examples of the compounds of formula (Ib)in which R1represents.

Examples are the compounds of formula (Ib)in which R3represents H, (C6-12)aryl(C1-6)alkyl or (C1-6)alkyl. In particular, examples of the compounds of formula (Ib)in which R3represents H,or CH3-CH2-CH2-.

Examples are the compounds of formula (Ib)in which R4represents H or methyl.

Examples are the compounds of formula (Ib)in which R5is a (C6-12)aryl(C1-6)alkyl. In particular, examples of the compounds of formula (Ib)in which R5represents.

A preferred group of compounds according to the invention are the compounds of formula (Ib)in which: R1is an R13C(O)- (in particular,); R3represents H, (C6-12)aryl(C1-6)alkyl (in particular, ) or (C1-6)alkyl (in particular, CH3-CH2-);

R4represents H or methyl, and R5is a (C6-12)aryl(C1-6)alkyl (in particular,).

Another preferred group of compounds according to the invention are the compounds of formula (Ic):

where R1, R3, R4, R5and R6defined above, and their corresponding N-oxides, prodrugs, protected derivatives, individual isomers and mixtures of these isomers, and pharmaceutically acceptable salt and solvate (e.g., hydrates) of compounds of formula (Ic) and their N-oxides, prodrugs, protected derivatives, individual isomers and mixtures of these isomers.

Examples are the compounds of formula (Ic)in which R1is an R13C(O)-, and R13represents a hetero(C5-12)cycloalkyl. In particular, examples of the compounds of formula (Ic)in which R1represents.

Examples are the compounds of formula (Ic)in which R3is a (C1-6)alkyl, which is optionally substituted by-X6OR9[where X6represents a bond, and R9is a (C1-6)alkyl]. In particular, example and can serve as the compounds of formula (Ic), in which R3represents CH3-CH2-, CH3-CH2-CH2or CH3-O-CH2-.

Examples are the compounds of formula (Ic)in which R4represents H or methyl. Examples are the compounds of formula (Ic)in which R4represents H.

Examples are the compounds of formula (Ic)in which R5is a (C1-9)alkyl or (C6-12)aryl(C1-6)alkyl. In particular, examples of the compounds of formula (Ic)in which R5represents CH3CH2CH2CH3CH2CH3or. Examples are the compounds of formula (Ic)in which R5represents.

Examples are the compounds of formula (Ic)in which R6represents a hetero(C5-13)aryl, optionally substituted (C1-9)alkyl, (C3-12)cycloalkyl, (C6-12)aryl or hetero(C5-13)aryl. Examples of the optionally substituted hetero - (C5-13)aryl groups are optionally substituted benzoxazolyl, oxadiazolyl, isoxazolyl or oxazolyl. As examples of compounds of formula (Ic)in which R6is benzoxazol-2-yl, 5-tert-butyl[1,2,4]oxadiazol-3-yl, 3-cyclopropyl-1,2,4-OK is diazol-5-yl, 5-cyclopropyl-1,2,4-oxadiazol-2-yl, 5-cyclopropyl-1,3,4-oxadiazol-2-yl, 5-ethyl-1,3,4-oxadiazol-2-yl, 5-(4-forfinal)-1,2,4-oxadiazol-3-yl, 5-isopropylthiazole-3-yl, 5-(5-methylisoxazol-3-yl)oxazol-2-yl, 5-(5-methyltin-2-yl)oxazol-2-yl, oxazol-2-yl, 3-phenyl-1,2,4-oxadiazol-5-yl, 5-phenyl-1,2,4-oxadiazol-3-yl, 5-thiophene-2-isoxazol-2-yl, 5-(4-trifloromethyl)-1,3,4-oxadiazol-2-yl and the like, In particular, may serve as examples of compounds of formula (Ic)in which R6is benzoxazol-2-yl, 3-cyclopropyl-1,2,4-oxadiazol-5-yl, oxazol-2-yl.

One of the preferred groups of compounds according to the invention are the compounds of formula (Ic)in which: R1is an R13C(O)- (in particular,);

R3is a (C1-6)alkyl, which is optionally substituted by-X6OR9(in particular, CH3-CH2-, CH3-CH2-CH2or CH3-O-CH2-); R4represents H, and R5is a (C1-9)alkyl or (C6-12)aryl(C1-6)alkyl (in particular,); R6represents a hetero(C5-13)aryl, optionally substituted (C1-9)alkyl, (C3-12)cycloalkyl, hetero(C5-12)cycloalkyl, (C6-12)aryl or hetero(C5-13)aryl (in particular, benzoxazol-2-yl, 3-cyclopropyl-1,2,4-about sedesol-5-yl, oxazol-2-yl and 5-(5-methylisoxazol-3-yl)oxazol-2-yl).

Another preferred group of compounds according to the invention are the compounds of formula (Id):

where R1, R5, R11and X5defined above, and their corresponding N-oxides, prodrugs, protected derivatives, individual isomers and mixtures of these isomers, and pharmaceutically acceptable salt and solvate (e.g., hydrates) of compounds of formula (Id) and their N-oxides, prodrugs, protected derivatives, individual isomers and mixtures of these isomers.

Examples are the compounds of formula (Id)in which R1is an R13C(O)-, and R13represents a hetero(C5-12)cycloalkyl. In particular, examples of the compounds of formula (Id)in which R1represents.

Examples are the compounds of formula (Id)in which R5is a (C6-12)aryl(C1-6)alkyl. In particular, examples of the compounds of formula (Id)in which R5represents.

Examples are the compounds of formula (Id)in which R11represents-C(O)OR13or-S(O)2R13where R13represents alkyl or (C6-12)aryl. In particular, examples of logit the compounds of formula (Id), in which R11represents-C(O)OC(CH3)3or.

Examples are the compounds of formula (Id)in which X1represents propylene.

One of the preferred groups of compounds according to the invention are the compounds of formula (Id)in which: R1is an R13C(O)- (in particular,); R5is a (C6-12)aryl(C1-6)alkyl (in particular,);

R11represents-C(O)OR13[in particular, -C(O)OC(CH3)3] or-S(O)2R13(in particular,), and X1represents propylene.

Preferred compounds according to the invention are

{(S)-1-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-carbonyl)propellerblades]-3,3-divergence}amide morpholine-4-carboxylic acid,

{(S)-1-[(S)-1-(5-cyclopropyl-1,3,4-oxadiazol-2-carbonyl)propellerblades]-3,3-divergence}amide morpholine-4-carboxylic acid,

((S)-3,3-debtor-1-{(S)-1-[5-(4-trifloromethyl)-1,3,4-oxadiazol-2-carbonyl]propellerblades}hexyl)amide morpholine-4-carboxylic acid,

{(S)-1-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-carbonyl)propellerblades]-3,3-debtor-4-phenylbutyl}amide morpholine-4-carboxylic acid,

{1-[1-(3-cyclopropyl[1,2,4]oxadiazol-5-carbonyl)PDEC is carbamoyl]-3,3-debtor-5-methylhexan}amide morpholine-4-carboxylic acid,

{(S)-1-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-carbonyl)propellerblades]-3,3-deformaty}amide morpholine-4-carboxylic acid,

{(S)-3,3-debtor-1-[(S)-1-(3-phenyl-1,2,4-oxadiazol-5-carbonyl)propellerblades]butyl}amide morpholine-4-carboxylic acid,

{(S)-3,3-debtor-1-[(S)-1-(5-phenyl-1,2,4-oxadiazol-3-carbonyl)propellerblades]butyl}amide morpholine-4-carboxylic acid,

{1-[1-(5-cyclopropyl[1,3,4]oxadiazol-2-carbonyl)propellerblades]-3,3-debtor-4-phenylbutyl}amide morpholine-4-carboxylic acid,

{3,3-debtor-1-[1-(5-isopropylthiazole-3-carbonyl)propellerblades]hexyl}amide morpholine-4-carboxylic acid,

((S)-3,3-debtor-1-{1-[5-(5-methylisoxazol-3-yl)oxazol-2-carbonyl]propellerblades}hexyl)amide morpholine-4-carboxylic acid,

{(S)-3,3-debtor-1-[(S)-1-(oxazol-2-carbonyl)propellerblades]-4-phenylbutyl}amide morpholine-4-carboxylic acid,

{(S)-3,3-debtor-4-phenyl-1-[(S)-1-(5-thiophene-2-isoxazol-2-carbonyl)propellerblades]butyl}amide morpholine-4-carboxylic acid,

{(S)-1-[(S)-1-(benzoxazol-2-carbonyl)butylcarbamoyl]-3,3-debtor-4-phenylbutyl}amide morpholine-4-carboxylic acid,

[1-(2-benzoxazol-2-yl-1-methoxymethyl-2-oxoethylidene)-3,3-debtor-4-phenylbutyl]amide morpholine-4-carboxylic acid,

{(S)-1-[(S)-1-(benzoxazol-2-carbonyl)-1-methylbutanoyl]-3,3-debtor-4-phenylbutyl}amide morpholine-4-carboxylic acid,

[(S)-1-((S)-1-cyano-3-phenylpropionyl)-3,3-debtor-phenylbutyl]amide morpholine-4-carboxylic acid,

[(S)-1-(cyanomethylene)-3,3-debtor-4-phenylbutyl]amide morpholine-4-carboxylic acid,

[(S)-3,3-debtor-1-((S)-1-formyl-1-methylbutanoyl)-4-phenylbutyl]amide morpholine-4-carboxylic acid,

{(S)-1-[1-(5-ethyl[1,3,4]oxadiazol-2-carbonyl)propellerblades]-3,3-debtor-4-phenylbutyl}amide morpholine-4-carboxylic acid,

{(S)-1-[1-(5-tert-butyl[1,2,4]oxadiazol-3-carbonyl)propellerblades]-3,3-debtor-4-phenylbutyl}amide morpholine-4-carboxylic acid,

{(S)-3,3-debtor-4-phenyl-1-[(S)-1-(5-phenyl[1,2,4]oxadiazol-3-yl)propellerblades]butyl}amide morpholine-4-carboxylic acid,

complex benzyl ester [(S)-1-(cyanomethylene)-3,3-debtor-4-phenylbutyl]carbamino acid,

cyanomethylene (S)-4,4-debtor-5-phenyl-2-(tetrahydropyran-4-ylamino)pentanol acid,

cyanomethylene (S)-4,4-debtor-2-isobutylamino-5-phenylpentane acid,

[(S)-1-((S)-1-benzazolyl-3-oxazepan-4-ylcarbonyl)-3,3-debtor-4-phenylbutyl]amide morpholine-4-carboxylic acid,

complex tert-butyl ether (S)-4-{(S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]-5-phenylenediamine}-3-oxazepan-1-carboxylic acid,

((S)-1-{(S)-1-[(5-ethyl-1,3,4-oxadiazol-2-yl)hydroxymethyl]propellerblades}-3,3-divergence}amide morpholine-4-carboxylic acid,

{(S)-1-[1-(5-cyclopropyl-1,3,4-oxadiazol-2-carbonyl)propellerblades]-3,3-deformaty}amide morpholine-4-carboxylic acid,

{(S)-1-[1-(5-cyclopropyl-1,2,4-about sedesol-3-carbonyl)propellerblades]-3,3-divergence}amide morpholine-4-carboxylic acid,

((S)-3,3-debtor-1-{(S)-1-[5-(4-forfinal)-1,2,4-oxadiazol-3-carbonyl]propellerblades}butyl)amide morpholine-4-carboxylic acid,

((S)-3,3-debtor-1-{1-[5-(4-forfinal)-1,2,4-oxadiazol-3-carbonyl]propellerblades}butyl)amide morpholine-4-carboxylic acid,

((S)-3,3-debtor-1-{(R)-1-[5-(4-forfinal)-1,2,4-oxadiazol-3-carbonyl]propellerblades}butyl)amide morpholine-4-carboxylic acid,

{(S)-1-[(S)-1-(benzoxazol-2-carbonyl)propellerblades]-3,3-deformaty}amide morpholine-4-carboxylic acid,

[(S)-1-(cyanomethylene)-3,3-divergence]amide morpholine-4-carboxylic acid,

((S)-3,3-debtor-1-{(R)-1-[5-(5-methylthiophene-2-yl)oxazol-2-carbonyl]propellerblades}hexyl)amide morpholine-4-carboxylic acid,

((S)-3,3-debtor-1-{(S)-1-[5-(5-methylthiophene-2-yl)oxazol-2-carbonyl]propellerblades}hexyl)amide morpholine-4-carboxylic acid,

and their corresponding N-oxides, prodrugs, protected derivatives, individual isomers and mixtures of these isomers, and pharmaceutically acceptable salt and solvate (e.g., hydrates) of compounds of formula (Ia), their N-oxides, prodrugs, protected derivatives, individual isomers and mixtures of these isomers.

Pharmacology and use

Compounds according to the invention are inhibitors of cathepsin S and, as such, can be used to treat diseases in which the activity of cathepsin S is involved in the pathogenesis and/or is in the induction of disease symptoms. For example, the compounds according to the invention can be used to treat autoimmune diseases, including, but not limited to: juvenile diabetes, multiple sclerosis, vulgar disease, graves disease, malignant gravis, systemic lupus erythematosus, irritable bowel syndrome, rheumatoid arthritis and autoimmune thyroiditis; allergic disorders, including, but not limited to, asthma and allogeneic immune responses, including, but not limited to, reactions by transplantation of organs or tissues.

Cathepsin S also associated with disorders involving excessive elastolin, for example, chronic obstructive pulmonary disease (eg, emphysema), bronchiolitis, excessive elastosis of the Airways in asthma and bronchitis, pneumonitis and cardiovascular disease, such as the destruction of plaques and atheroma. Cathepsin S involved in the formation of fibrils, and, consequently, inhibitors of cathepsin S may be used for the treatment of systemic amyloidosis.

Activity inhibition of cysteinate compounds according to the invention can be determined by methods known to experts in this field. Known appropriate testsin vitrothat allows you to measure the activity of protease and inhibition of the test compounds. Typically, when Taco is the analysis determine the degree induced by protease hydrolysis of the peptide substrate. Detailed information about the tests for measuring the activity of inhibiting the protease are described below in examples 31, 32, 33, 34.

Compounds according to the invention are also inhibitors of cathepsin K and B and, as such, can be used to treat diseases in which the activity of cathepsin K and B involved in the pathogenesis and/or symptomatology of the disease. For example, the compounds according to the invention can be used for the treatment of osteoarthritis, osteoporosis or cancer, such as lung cancer, leukemia (B - and T-cell acute leukaemia), ovarian cancer, sarcoma, Kaposi's sarcoma, colon cancer, cancer of the lymph nodes, brain tumor, breast cancer, pancreatic cancer, prostate cancer or skin cancer.

Introduction and pharmaceutical composition

In General, the compounds according to the invention can be introduced in therapeutically effective quantities of any of the traditional and acceptable methods known to experts in the field, or separately, or in combination with one or more therapeutic agents. therapeutically effective amount can vary widely depending on the severity of the disease, the age and General health of the patient, the effectiveness of the connection you use, and other factors. For example, terapeuticas the effective amount of the compounds according to the invention may be in the range from about 1 microgram per kilogram of body weight (mcg/kg) per day to about 60 milligrams per kilogram of body weight (mg/kg) per day, usually from about 1 μg/kg/day to about 20 mg/kg/day. Therefore, a therapeutically effective amount for a person weighing 80 kg can be from about 80 μg/day to about 4.8 g/day, typically from about 80 μg/day to about 1.6 g/day. In General, the person skilled in the art, based on their knowledge and the information given in the present description, can determine therapeutically effective amount of the compounds according to the invention for the treatment of this disease.

Compounds according to the invention can be put into the form of pharmaceutical compositions by one of the following ways: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g. intramuscular, intravenous or subcutaneous). Compositions can take the form of tablets, pills, capsules, semi-solid substances, powders, sustained release formulations release, solutions, suspensions, elixirs, aerosols, or any other suitable drugs, and may consist essentially of the compounds according to the invention in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, facilitate the administration of a medicinal product and has no negative impact on therapeutic effect is aktivnosti active ingredient. Such a filler may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is available to professionals in this field.

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dry the separated milk and other Liquid and semi-solid fillers can be selected from water, ethanol, glycerin, propylene glycol and various oils, including liquid paraffin, oil of animal or vegetable origin or synthetic oil (such as peanut oil, soybean oil, mineral oil, sesame oil and the like). Preferred liquid carriers, particularly carriers for injection solutions are water, saline, aqueous dextrose, and glycols.

The number of compounds according to the invention in the composition can vary widely depending on the type of composition, size uniform dose, type of filler and other factors known to experts in the field of pharmacology. In General, a composition comprising a compound according to the invention and intended for the treatment of this disease, may contain the active ingredient is in the range from 0.01 wt.% up to 10 wt.%, preferably from 0.3 wt.% up to 1 wt.%, and the rest will be one or more fillers. The pharmaceutical composition is preferably administered in a single unified doses for prolonged treatment or as one unified dose, administered by the desire to relieve specific symptoms. A representative pharmaceutical composition containing the compound according to the invention, described in example 35.

Chemistry

Methods for producing compounds according to the invention

Compounds according to the invention can be obtained by application or adaptation of the methods described previously or known from the literature, for example, described in R.C. Larock in Comprehensive Organic Transformations, VCH publishers, 1989.

The following reactions may be necessary to protect reactive functional groups, for example, hydroxy-, amino-, imino-, thio - or carboxypropyl, to avoid their unwanted participation in the reactions in cases where it is desirable that their presence in the final product. This can be used a standard protective groups in accordance with common practice, see, for example, by T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991.

Compounds according to the invention can be obtained in accordance with reaction scheme 1:

where each of X1, R1, R3, R4, R5and R6defined in the brief description of the invention. For example, in stage 1, the acid may be condensed with aminoguanidinium specified formula with education β-hydroxyamide. The condensation reaction may be conducted in the presence of an appropriate Vasudeva reagent combinations (for example, hexaflurophosphate benzotriazol-1-electroparadise (PyBOP®), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), hexaflurophosphate O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium (HBTU), 1,3-dicyclohexylcarbodiimide (DCC) or the like), with the addition of, but not necessarily, an appropriate catalyst (for example, 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-isobenzofuranone (HOAt), hexaflurophosphate O-(7-asobancaria-1-yl)-1,1,3,3 - tetramethyluronium (HATU) or etc) and dinucleophiles base (e.g. triethylamine, N-methylmorpholine and the like, or any suitable combination thereof) at ambient temperature; however, to complete the reaction requires from 2 to 10 hours. Then β-hydroxyamide can be oxidized in stage 2 with obtaining the compounds of formula (Ic). The oxidation reaction is usually carried out using periodinane dess-Martin in an inert solvent, such as dichloromethane, at a temperature of from about 0°C to about ControlTemplate.

In addition, the compounds according to the invention can be obtained in accordance with reaction scheme 2:

where each of X1, R1, R3, R4, R5and R6defined in the brief description of the invention, and PG represents a suitable protective group. For example, in stage 1, the acid may be condensed with aminoguanidinium specified formula with education β-hydroxyamide. After removal of the protective group (stage 2), followed by the introduction of the group R1(stage 3) and oxidation (stage 4) get the connection formula (Ic).

Examples

The present invention, also illustrated, but not limited to, the following examples, which describe the formation of compounds of formula (I) (examples) and intermediate compounds (reference examples) according to the invention.

The spectra of nuclear magnetic resonance1H (NMR) were recorded on instruments Varian Mercury-300, Unity-400, UnityPlus-500 or Inova-500. In the spectra of nuclear magnetic resonance (NMR) magnitude of chemical shift (δ) are expressed in ppm relative to tetramethylsilane. Abbreviations have the following meanings: s = singlet; d = doublet; t = triplet; m = multiplet; q = Quartet; DD = doublet of doublets; DDD = doublet of double doublets.

Liquid chromatography high pressure (ghvd) was performed on a column of Komasil 10 microns, 100A silica gel, 4.6 mm EXT. dia. ×250 mm with a mixture of heptane/THF/1,2-dichloroethane as the mobile phase. Mass spectra were recorded on the instrument Agilent 1100 series or MICROMASS LCT-TOF MS. In thin-layer chromatography (TLC), retention time RFdetermined on tablets with silica Merck.

Reduction

CBZ - benzyloxycarbonyl

DAST - TRIFLUORIDE (diethylamino)sulfur

DCM (DHM) - dichloromethane

DMF (DMF - dimethylformamide

DMSO (DMSO) dimethyl sulfoxide

DTT (DTT) - dithiotreitol

EDCI hydrochloride N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide

EDTA (EDTA) - ethylenediaminetetraacetic acid

EtOAc - ethyl acetate

HOBT - hydrate of 1-hydroxybenzotriazole

MeOH - methanol

MES - 2-morpholinobutyrophenone acid

PyBOP - hexaphosphate (benzotriazol-1 yloxy)triprolidine

THF (THF - tetrahydrofuran

REFERENCE EXAMPLE 1

Methyl ester (S)-2-benzyloxycarbonylamino-4-oxo-5-phenylpentane acid

To a suspension of copper bromide(I) (4.26 deaths mmol, 611,1 mg) in 3 ml of dry THF in an atmosphere of N2solution was added lithium bromide (charged 8.52 mmol, 740 mg) in 5 ml of dry THF. The resulting mixture was stirred at room temperature for 20 minutes and then was cooled to -78°C. After this solution was added chloride benzylamine (20 wt.% in THF, 4.26 deaths IMO the e l e C of 3.25 ml), and then the solution is complicated methyl ester (S)-2-benzyloxycarbonylamino-3-chlororesorcinol acid [see Synth. Comm. 1993, 23(18), 2511-2526] (3,59 mmol) in 7 ml of dry THF. The resulting mixture was stirred at -78°C for 30 minutes and then the reaction was suppressed saturated NH4Cl (50 ml). Mixture two times were extracted with ethyl acetate (30 ml). The organic layers were dried over magnesium sulfate, and then concentrated in vacuum. The residue was purified over 35 g of silica gel, elwira a mixture of EtOAc:heptane (1:1), and receivedmethyl ester (S)-2-benzyloxycarbonylamino-4-oxo-5-phenylpentane acid(1.07 g, 84%).

1H-NMR (CDCl3): δ 7,4-7,17 (m, 10H), 5,73 (d, J=8,2 Hz, 1H), 5,11 (s, 2H), 4,57 (m, 1H), 3,7 (2×s, 5H), 3,24 (DD, J=18,5, and 4.4 Hz, 1H), 3,0 (DD, J=18.2, and a 4.1 Hz, 1H).

LC/MS: 100% 378 (M+Na).

REFERENCE EXAMPLE 2

Methyl ester (S)-2-benzyloxycarbonylamino-4-exogamous acid

In a manner analogous to that described above in reference example 1, but using propylchloride magnesium instead of benzylchloride magnesium receivedmethyl ester (S)-2-menthoxycarbonyl-4-exogamous acid.

1H-NMR (CDCl3): δ 7,35 (m, 5H), 5,78 (d, J=8.5 Hz, 1H), 5,13 (s, 2H), 4,58 (m, 1H, in), 3.75 (s, 3H), 3,2 (DD, J=18,3, 4,2 Hz, 1H), 2,96 (DD, J=18,3, a 4.1 Hz, 1H), 2,4 (m, 2H), 1,6 (m, 2H), to 0.92 (t, J=7.4 Hz, 3H).

LC/MS: 330 (M+Na).

REFERENCE EXAMPLE 3

The complex mixture of methyl ester of 2-benzyloxycarbonylamino-4-oxo-5-phenylpentane acid (3,310 g, 9,31 mmol) and DAST (7 ml) was stirred at room temperature for 3 days. The resulting mixture was diluted with dichloromethane (100 ml) and carefully added to a solution of 0.5 N. NaOH (150 ml). The aqueous layer was extracted with dichloromethane (50 ml). The organic phase was dried over magnesium sulfate, and then concentrated in vacuum. The residue was purified on 110 g of silica gel, elwira a mixture of EtOAc:heptane (1:4, then 1:3), and receivedmethyl ester (S)-2-benzyloxycarbonylamino-4,4-debtor-5-phenylpentane acid(1,797 g, 51.1 percent).

1H-NMR (CDCl3): δ and 7.3 (m, 10H), 5,43 (d, J=7,6 Hz, 1H), 5,14 (s, 2H)and 4.65 (m, 1H), 3,74 (s, 3H), 3,2 (t, J=16.5 Hz, 2H), 2,4 (m, 2H).

LC/MS: 97% 400 (M+Na).

REFERENCE EXAMPLE 4

Hydrochloride difficult methyl ester (S)-2-amino-4,4-debtor-5-phenylpentane acid

The complex solution of the methyl ester of (S)-2-benzyloxycarbonylamino-4,4-debtor-5-phenylpentane acid (7,806 g, 20,68 mmol) in 120 ml of methanol and 4 M HCl in dioxane (41,4 mmol, 10.3 ml) was first made over 10% Pd/C (1.0 g) at a pressure of 50 psig. After 8 hours was added another portion of 10% Pd/C (1.0 g). After 24 hours the catalyst was removed by filtration through celite, and the filtrate was concentrated in vacuum. The obtained light yellow t ardoe substance was dissolved in minimum amount of methanol and slowly added to ether (150 ml). The obtained suspension was kept for 30 minutes and then filtered. The obtained white solid was dried in vacuum and receivedhydrochloride difficult methyl ester (S)-2-amino-4,4-debtor-5-phenylpentane acid(4,950 g, 85,5%).

1H-NMR (DMSO-d6): δ 8,6 (width, 3H), and 7.3 (m, 5H), 4.26 deaths (t, J=6 Hz, 1H), of 3.73 (s, 3H), 3,3 (t, J=17.5 Hz, 2H), by 2.55 (m, 2H).

LC/MS: 100% 244 (M+1).

REFERENCE EXAMPLE 5

Methyl ester of (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]-5-phenylpentane acid

To a mixture of the hydrochloride difficult methyl ester (S)-2-amino-4,4-debtor-5-phenylpentane acid (2.50 g, to 8.94 mmol) and Diisopropylamine (22,3 mmol, 2,89 g) in dry dichloromethane (40 ml) in an atmosphere of N2was added dropwise morpholinylcarbonyl region (13.4 mmol, 2.0 g). The resulting mixture was stirred at room temperature for 15 hours and then was diluted with water (50 ml). The aqueous layer was extracted with dichloromethane (30 ml). The organic layers were dried over magnesium sulfate, and then concentrated in vacuum. After purification on 110 g of silica gel with elution with a mixture of EtOAc:heptane (1:1, then 2:1) was receivedmethyl ester of (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]-5-phenylpentane acid(2,82 g, 88.5 percent).

1H-NMR (CDCl3): δ and 7.3 (m, 5H), 5,16 (d, J=7.5 Hz, 1H), and 4.75 (DD, J=13, 6 Hz, 1H), of 3.73 (s, 3H), and 3.7 (m, 4H), 3,4 (m, 4H), 3,2 (t, J=16,7 Hz, 2H), 2,4 (who, 2H).

LC/MS: 100% 357 (M+1).

REFERENCE EXAMPLE 6

(S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]-5-phenylpentane acid

To a solution of complex methyl ester (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]-5-phenylpentane acid (2,81 g, 7,88 mmol) in MeOH:H2O (2:1 vol., 40 ml) was added LiOH monohydrate (662 mg, 15,76 mmol). The resulting mixture was stirred at room temperature for 2.5 hours and then was diluted with water (30 ml). The methanol was removed in vacuum. the pH was adjusted to 1 by addition of 6 N. HCl, and the aqueous layer was extracted with dichloromethane (2×30 ml). The organic layers were dried over magnesium sulfate and concentrated in vacuum to obtain(S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]-5-phenylpentane acid(2,509 g, 93%).

1H-NMR (CDCl3): δ 8,2 (width, 1H), and 7.3 (m, 5H), to 5.3 (m, 1H), 4,6 (m, 1H), the 3.65 (m, 4H), 3,4 (m, 4H), 3,2 (t, J=16.5 Hz, 2H), 2,4 (m, 2H).

LC/MS: 94% 343 (MH+)

REFERENCE EXAMPLE 7

Complex 1-tert-butyl-6-methyl ether (S)-5-benzyloxycarbonylamino-2-isopropyl-3-oxohexanoate acid

To a cooled to -78°C solution Diisopropylamine (3,53 g, 34,88 mmol) in dry THF (20 ml) in an atmosphere of N2was added dropwise a solution of n-utility (2.5 M in hexane, 34,88 mmol, 13,95 ml). The resulting mixture was stirred at -78°C for 30 minutes, and then to allali the complex solution of tert-butyl methyl ether 3-methylmalonic acid (34,88 mmol, 5,52 g) in THF (40 ml). The resulting mixture was stirred at -78°C for 30 minutes and then was added dropwise a solution of methyl (S)-2-benzyloxycarbonylamino-3-chlororesorcinol acid (see Synth. Comm 1993, 23(18), 2511-2526] (of 16.6 mmol) in 30 ml of dry THF. After stirring for a further 2 hours at -78°C reaction extinguished 50 ml of 1 N. HCl and heated to room temperature. the pH was adjusted to 3 by adding 1 N. NaOH and THF was removed in vacuum. The organic layer was extracted with EtOAc (C ml). The organic phase was dried over magnesium sulfate, and then concentrated in vacuum. The residue was purified on 90 g of silica gel, elwira a mixture of EtOAc:heptane (1:3, then 1:2), and receivedcomplex 1-tert-butyl-6-methyl ether (S)-5-benzyloxycarbonylamino-2-isopropyl-3-oxohexanoate acid(2,417 g, 34.5 per cent).

1H-NMR (CDCl3): δ to 7.4 (m, 5H), 5,73 (d, J=8,4 Hz, 1H), 5,12 (s, 2H), 4,6 (m, 1H), 3,74 (s, 3H), 3,39-of 3.06 (m, 3H), 2,4 (m, 1H), of 1.45 (2s, 9H), and 0.98 (d, J=6.6 Hz, 3H), from 0.88 (d, J=6,7 Hz, 3H).

LC/MS: 100% 422 (M+1).

REFERENCE EXAMPLE 8

Complex 6-tert-butyl-1-methyl ester (S)-2-benzyloxycarbonylamino-4-oxohexanoate acid

To a solution of complex 1-methyl ester N-CBZ-L-aspartic acid (1,00 g, 3,55 mmol) in dry tetrahydrofuran (17 ml) was added carbonyldiimidazole (634,1 mg, 3,91 mmol). The resulting mixture was stirred at room temperature during the 6 hours, and then added a magnesium salt of mono-tert-butylmalonate (1,339 g, 3,91 mmol) (obtained as described in Angew. Chem. Int. Ed. Engl. 1979, 18(1), 72-74). The mixture was stirred at room temperature for 20 hours and then concentrated in vacuum. The residue was divided between ether (60 ml) and 0.5 N. HCl (60 ml). The organic layer was washed with saturated solution of NaHCO3(50 ml), then dried over magnesium sulfate and concentrated in vacuum. The residue was purified over 35 g of silica gel, elwira a mixture of EtOAc:heptane (1:1), and receivedcomplex 6-tert-butyl-1-methyl ester (S)-2-benzyloxycarbonylamino-4-oxohexanoate acid(1,17 g, 87%).

1H-NMR (CDCl3): δ to 7.4 (m, 5H), 5,73 (d, J=8,3 Hz, 1H), 5,1 (s, 2H), 4,6 (m, 1H, in), 3.75 (s, 3H), 3,37 (s, 2H), 3,32 (DD, J=18,7, a 4.3 Hz, 1H), 3,13 (DD, J=18,5, a 4.1 Hz, 1H), 1,47 (s, 9H).

LC/MS: 93% 402 (M+Na).

REFERENCE EXAMPLE 9

Methyl ester (S)-2-benzyloxycarbonylamino-6-methyl-4-exogamous acid

A solution of complex 1-tert-butyl-6-methyl ester 5-benzyloxycarbonylamino-2-isopropyl-3-oxohexanoate acid (1.06 g, 2.51 mmol) and monohydrate p-toluensulfonate acid (35,8 mg, 0,19 mmol) in toluene (20 ml) was boiled under reflux in an atmosphere of N2within 6.5 hours. The resulting mixture was cooled to room temperature and concentrated in vacuum. The residue was purified over 35 g of silica gel, Elya is the ROI with a mixture of EtOAc:heptane (1:4), and receivedmethyl ester (S)-2-benzyloxycarbonylamino-6-methyl-4-exogamous acid(727 mg, 90%).

1H-NMR (CDCl3): δ to 7.4 (m, 5H), 5,78 (d, J=9.1 Hz, 1H), 5,13 (s, 2H), 4,6 (m, 1H), 3,74 (s, 3H), 3,2 (DD, J=18,3, and 4.4 Hz, 1H), 2,95 (DD, J=18.2, and 4.0 Hz, 1H), 2,3 (m, 2H), 2,1 (m, 1H), 0,92 (d, J=6,7 Hz, 6H).

LC/MS 77% 322 (MH+).

REFERENCE EXAMPLE 10

Methyl ester (S)-2-benzyloxycarbonylamino-4-oxopentanoic acid

In a manner analogous to that described above in reference example 9, but using complex 6-tert-butyl-1-methyl ester 2-benzyloxycarbonylamino-4-oxohexanoate acid, was receivedmethyl ester (S)-2-benzyloxycarbonylamino-4-oxopentanoic acid.

1H-NMR (CDCl3): δ to 7.4 (m, 5H), USD 5.76 (d, J=8,1 Hz, 1H), 5,14 (s, 2H), 4,57 (m, 1H, in), 3.75 (s, 3H), 3,23 (DD, J=18,4, a 4.3 Hz, 1H), 3,0 (DD, J=18,4, a 4.3 Hz, 1H), 2,18 (s, 3H).

LC/MS >85% 280 (MH+).

An alternative way

To a cooled to 0° (C) suspension of copper iodide(I) in ether (20 ml) in an atmosphere of N2was slowly added motility (solution of 1.6 M in ether, is 21.3 mmol, 13.3 ml). The resulting mixture was stirred at 0°C for 10 minutes and then was cooled to -78°C. then was added dropwise a solution 3,55 mmol difficult methyl ester (S)-2-benzyloxycarbonylamino-3-chlororesorcinol acid (see Synth. Comm 1993, 23(18), 2511-2526) in 12 ml of ugogo THF. The resulting mixture was stirred at -78°C for 30 minutes and then the reaction was suppressed by the addition of methanol (2 ml). The mixture was poured into saturated NH4Cl (80 ml) and was extracted with ether (2×40 ml). The organic layers were dried over magnesium sulfate and concentrated in vacuum. The residue was purified over 35 g of silica gel, elwira a mixture of EtOAc:heptane (1:1), and receivedmethyl ester (S)-2-benzyloxycarbonylamino-4-oxopentanoic acid(261 mg, 26%).

REFERENCE EXAMPLE 11

Methyl ester (S)-2-benzyloxycarbonylamino-4,4-debtor-6-methylheptanoic acid

The complex mixture of methyl ester (S)-2-benzyloxycarbonylamino-6-methyl-4-exogamous acid (915 mg, 2,85 mmol) and DAST (3 ml, excess) was stirred at 35°C for 47 hours. The mixture was diluted with dichloromethane (50 ml) and carefully added to a saturated solution of NaHCO3(150 ml). The aqueous layer was extracted with dichloromethane (30 ml). The organic layers were dried over magnesium sulfate and concentrated in vacuum. The residue was purified over 35 g of silica gel, elwira a mixture of EtOAc:heptane (1:4), and receivedmethyl ester (S)-2-benzyloxycarbonylamino-4,4-debtor-6-methylheptanoic acid(156 mg, 16%).

1H-NMR (CDCl3): δ to 7.4 (m, 5H), of 5.48 (d, J=7.9 Hz, 1H), further 5.15 (s, 2H), br4.61 (kV, J=5,9 Hz, 1H), of 3.78 (s, 3H), 2,4 (m, 2H), 1,95 (m, 1H), 1.8 m (m, 2H), and 0.98 (d, J=6.6 Hz, 6H).

LC/MS 98 366 (M+Na).

REFERENCE EXAMPLE 12

Methyl ester (S)-2-benzyloxycarbonylamino-4,4-differentyou acid

In a manner analogous to that described above in reference example 11, but using sophisticated methyl ester (S)-2-menthoxycarbonyl-4-oxopentanoic acid was receivedmethyl ester (S)-2-benzyloxycarbonylamino-4,4-differentyou acid.

1H-NMR (CDCl3): δ to 7.4 (m, 5H), 5,46 (d, J=7,1 Hz, 1H), further 5.15 (s, 2H), br4.61 (kV, J=7,3 Hz, 1H), of 3.78 (s, 3H), of 2.45 (m, 2H), 1,67 (t, J=18,8 Hz, 3H).

LC/MS: 94% 324 (M+Na).

REFERENCE EXAMPLE 13

Methyl ester (S)-2-benzyloxycarbonylamino-4,4-differetnly acid

In a manner analogous to that described above in reference example 11, but using sophisticated methyl ester (S)-2-benzyloxycarbonylamino-4-exogamous acid was receivedmethyl ester (S)-2-benzyloxycarbonylamino-4,4-differetnly acid.

LC/MS: 96% 330 (MH+), 352 (M+Na).

REFERENCE EXAMPLE 14

Hydrochloride difficult methyl ester (S)-2-amino-4,4-debtor-6-methylheptanoic acid

The complex solution of the methyl ester of (S)-2-benzyloxycarbonylamino-4,4-debtor-6-methylheptanoic acid (333 mg, 0.97 mmol) in methanol (10 ml) and 4 M HCl in dioxane (4 mmol, 1 is l) was first made over 10% Pd/C (150 mg) under a pressure of 55 pounds per square the inch. After 7 hours was added another portion of 10% Pd/C (200 mg), and continued hydrogenation. After 5.5 hours the reaction was stopped. The catalyst was filtered, and the filtrate was concentrated in vacuum and placed in conditions of hydrogenation. After 6.5 hours the catalyst was removed by filtration through celite, and the filtrate was concentrated in vacuum, and receivedhydrochloride difficult methyl ester (S)-2-amino-4,4-debtor-6-methylheptanoic acidas a yellow sticky solid (240 mg, Quant.).

1H-NMR (CDCl3): δ 4,8 (width, 3H), 4,35 (width, 1H), 3,84 (s, 3H), and 2.6 (m, 2H), and 1.9 (m, 3H), 0,99 (d, J=6.2 Hz, 6H).

LC/MS: 90% 210 (M+1).

REFERENCE EXAMPLE 15

Hydrochloride difficult methyl ester (S)-2-amino-4,4-differentyou acid

In a manner analogous to that described above in reference example 14, but using sophisticated methyl ester (S)-2-benzyloxycarbonylamino-4,4-differentyou acid was receivedhydrochloride difficult methyl ester (S)-2-amino-4,4-differentyou acid.

1H-NMR (CDCl3): δ and 4.8 (s, 3H), 4,37 (m, 1H), 3,86 (s, 3H), 2.4 to 2.8 (m, 2H), 1,73 (t, J=18,9 Hz, 3H).

LC/MS: 100% 168 (M+1).

REFERENCE EXAMPLE 16

Hydrochloride difficult methyl ester (S)-2-amino-4,4-differetnly acid

In a manner analogous to that described above in reference Primera, but using sophisticated methyl ester (S)-2-benzyloxycarbonylamino-4,4-differetnly acid was receivedhydrochloride difficult methyl ester (S)-2-amino-4,4-differetnly acid.

LC/MS: 100% 196 (MH+).

REFERENCE EXAMPLE 17

Methyl ester of (S)-4,4-debtor-6-methyl-2-[(morpholine-4-carbonyl)amino]heptane acid

To a mixture of the hydrochloride difficult methyl ester (S)-2-amino-4,4-debtor-6-methylheptanoic acid (238 mg, 0.97 mmol) and Diisopropylamine (2,42 mmol, 313 mg) in dry dichloromethane (5 ml) in an atmosphere of N2was added dropwise morpholinylcarbonyl (1,45 mmol, 218 mg). The resulting mixture was stirred at room temperature for 23 hours and then was diluted with dichloromethane (25 ml) and washed with dilute HCl (30 ml) and saturated NaHCO3(30 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuum. After purification on 12 g of silica gel with elution with a mixture of EtOAc:heptane (1:1, then 2:1) was receivedmethyl ester of (S)-4,4-debtor-6-methyl-2-[(morpholine-4-carbonyl)amino]heptane acid(206 mg, 66%).

1H-NMR (CDCl3): δ 5,2 (d, J=7,4 Hz, 1H), 4.72 in (DD, J=13,6 Hz, 1H), of 3.78 (s, 3H), and 3.7 (m, 4H), 3,4 (m, 4H), 2,4 (m, 2H), 1,95 (m, 1H), 1.8 m (m, 2H), 0,99 (d, J=6.4 Hz, 6H).

LC/MS: 90% 345 (M+Na).

REFERENCE EXAMPLE 18

Methyl ester of (S)-4,4-debtor-2-[(morpholin-carbonyl)amino]pentanol acid

In a manner analogous to that described above in reference example 17, but using hydrochloride difficult methyl ester (S)-2-amino-4,4-differentyou acid was receivedmethyl ester of (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]pentanol acid.

1H-NMR (CDCl3): δ by 5.18 (d, J=7.5 Hz, 1H), 4,71 (kV, J=7 Hz, 1H), of 3.78 (s, 3H), 3,71 (m, 4H), 3,4 (m, 4H), 2,37 is 2.55 (m, 2H), 1,67 (t, J=18.7 Hz, 3H).

LC/MS: 100% 303 (M+Na).

REFERENCE EXAMPLE 19

Methyl ester of (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]heptane acid

In a manner analogous to that described above in reference example 17, but using hydrochloride difficult methyl ester (S)-2-amino-4,4-differetnly acid was receivedmethyl ester of (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]heptane acid.

LC/MS: 100% 309 (MH+).

REFERENCE EXAMPLE 20

(S)-4,4-debtor-6-methyl-2-[(morpholine-4-carbonyl)amino]heptane acid

To a solution of complex methyl ester (205 mg, to 0.63 mmol) in MeOH:H2O (2:1 vol., 4 ml) was added LiOH monohydrate (80 mg, 1.9 mmol). The resulting mixture was stirred at room temperature for 21 hours and then was diluted with water (15 ml) and was extracted with ether (20 ml). the pH of the aqueous phase was adjusted to 1 the user is receiving 1 N. HCl, and was extracted with dichloromethane (2×20 ml). The organic layers were dried over magnesium sulfate and concentrated in vacuum, and received(S)-4,4-debtor-6-methyl-2-[(morpholine-4-carbonyl)amino]heptane acid(168 mg, 86%).

1H-NMR (CDCl3): δ 6,4 (width, 1H), 5,3 (d, J=6.2 Hz, 1H), 4,6 (m, 1H), and 3.7 (m, 4H), 3,4 (m, 4H), 2,5 (m, 2H), 2.0 (m, 1H), 1.8 m (m, 2H), 1,0 (d, J=6.6 Hz, 6H).

LC/MS: 90% 309 (M+1).

REFERENCE EXAMPLE 21

(S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]pentane acid

In a manner analogous to that described above in reference example 20, but using sophisticated methyl ester (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]pentanol acid was received(S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]pentane acid.

1H-NMR (CDCl3): δ 5,9 (width, 1H), from 5.29 (d, J=6.3 Hz, 1H), 4,6 (m, 1H), 3,71 (m, 4H), 3,4 (m, 4H), 2,38-to 2.65 (m, 2H), 1,70 (t, J=18,9 Hz, 3H).

LC/MS: 100% 267 (M+1).

REFERENCE EXAMPLE 22

(S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]heptane acid

In a manner analogous to that described above in reference example 20, but using sophisticated methyl ester (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]heptane acid was received(S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]heptane acid.

1H-NMR (CDCl3): δ 5,3 (width, 1H, in), 5.25 (d, J=5.4 Hz, 1H), 4,6 (m, 1H), 3,71 (m, 4H), 3,4 (who, 4H), 2,6-2,3 (m, 2H), and 1.9 (m, 2H), 1.55V (m, 2H), 1,0 (t, J=7,3 Hz, 3H).

LC/MS: 83% 295 (M+1).

REFERENCE EXAMPLE 23

5-thiophene-2-isoxazol

To a solution of p-toluensulfonate (3.0 g, 15,36 mmol) and thiophene-2-carboxaldehyde (1,72 g, 15,36 mmol) in methanol (45 ml) in an atmosphere of N2was added potassium carbonate (2,12 g, 15,36 mmol). The resulting mixture was boiled under reflux for 5 hours, then cooled and concentrated in vacuum (cold water bath). The residue was distributed between ether (100 ml) and water (100 ml). The organic layer was washed with water (100 ml), dried over magnesium sulfate, and then concentrated in vacuum. The residue was purified over 35 g of silica gel, elwira a mixture of ethyl acetate:heptane (1:5), and received5-thiophene-2-isoxazol(0,852 g, 37%).

1H-NMR (CDCl3): δ and 7.9 (s, 1H), and 7.3 (m, 2H), 7,2 (s, 1H), and 7.1 (DD, J=5, 3.8 Hz, 1H).

LC/MS: 100% 152 (M+1).

REFERENCE EXAMPLE 24

Complex tert-butyl ester {(S)-1-[hydroxy-(5-thiophene-2-yl-oxazol-2-yl)methyl]propyl}carbamino acid

To a solution of 5-thiophene-2-isoxazol of 0.85 g, 5,62 mmol) in dry THF (4 ml) was added triethylborane of (1.0 M in THF, 5,62 mmol, 5,62 ml). The resulting mixture was stirred at room temperature for 45 minutes and then was cooled to -78°C and to it was added dropwise n-utility (a 1.6 M in hexane, 5,62 mmol who, 3,51 ml). The mixture was stirred at -78°C for 45 minutes, and then thereto was slowly added a solution of complex tert-butyl methyl ether (1-formylpropyl)carbamino acid (2,81 mmol, 0,526 g) in dry THF (3 ml). The resulting mixture was stirred at -78°C for 4 hours and then was heated to 0°C and extinguished the addition of 30 ml of 10% (vol.) of HOAc solution in ethanol. The mixture was stirred at room temperature for 18 hours and then concentrated in vacuum. The residue was purified on 90 g of silica gel with elution with a mixture of ethyl acetate:heptane (1:2, then 1:1) and receivedcomplex tert-butyl ester {(S)-1-[hydroxy-(5-thiophene-2-yl-oxazol-2-yl)methyl]propyl}carbamino acid(363 mg, 38%) as a yellow oil.

1H-NMR (CDCl3): δ (mixture of isomers) 7,35 (m, 2H), and 7.1 (m, 2H), 4,9 (m, 2H), 4,0 (width, 1H), 3,6 (m, 1H), 1,8-of 1.55 (m, 2H), 1,4 and 1,3 (2s, 9H), 1.0 and 0.9 (2T, J=7.4 Hz, 3H).

LC/MS: 100% 339 (M+1).

REFERENCE EXAMPLE 25

Hydrochloride (S)-2-amino-1-(5-thiophene-2-isoxazol-2-yl)butane-1-ol

To a solution of complex tert-butyl ester {(S)-1-[hydroxy-(5-thiophene-2-yl-oxazol-2-yl)methyl]propyl}carbamino acid (361 mg, 1.07 mmol) in dry dichloromethane (3 ml) was added 4 N. HCl in dioxane (3.0 ml, wt.). The resulting mixture was stirred at room temperature for 16 hours and then concentrated in vacuum, and receivedhydrochloride (S)-2-amino-1-(5-type the-2-isoxazol-2-yl)butane-1-ol in the form of a yellow-brown solid (Quant.).

1H-NMR (CDCl3): δ 7,5 (DD, J=5,2, 1.2 Hz, 1H), and 7.4 (DD, J=3,6, 1.1 Hz, 1H), and 7.3 (s, 1H), and 7.1 (DD, J=5, 3.6 Hz, 1H), 4,8 (m, 3H), 3,6 (m, 2H), 3,3 (width, 1H), a 1.75 (m, 2H), 1,0 (t, J=7.5 Hz, 3H).

LC/MS: 100% 239 (M+1).

REFERENCE EXAMPLE 26

Complex tert-butyl methyl ether (1-ethyl-2-hydroxy-3-nitropropyl)carbamino acid

The complex solution of tert-butyl methyl ether (1-formylpropyl)carbamino acid (1.0 g, of 5.34 mmol) in dry THF (10 ml) and ethanol were added nitromethane (3,91 g, 64,09 mmol)and then triethylamine (2.70 g, to 26.7 mmol). The mixture was stirred at room temperature for 22 hours and then concentrated in vacuum. The residue was diluted with ether (50 ml) and washed with concentrated NH4Cl (60 ml). The ether layer was dried over magnesium sulfate and concentrated in vacuum. The residue was purified over 35 g of silica gel, elwira a mixture of ethyl acetate:heptane (1:3), and received the desired alcohol (1,09 g, 82%) as a pale yellow oily solid.

1H-NMR (CDCl3): δ 4,2-4,8 (m, 4H), 3,15 to 3.8 (m, 2H), 1,69 to 1.6 (m, 2H), 1,47 (2×s, 9H), 1,02 and 1.0 (2×t, J=7,1 Hz, 3H).

LC/MS: 2 isomer, just 100% 149 (M-BOC+1).

REFERENCE EXAMPLE 27

Complex tert-butyl methyl ether (1-ethyl-3-nitro-2-trimethylsilyloxy)carbamino acid

To a complex mixture of tert-BU is silt ether (1-ethyl-2-hydroxy-3-nitropropyl)carbamino acid (1,83 g, 7,37 mmol) and triethylamine (1,49 g, 14,75 mmol) in dry dichloromethane (25 ml) in an atmosphere of N2added trimethylsilane (1.20 g, 11,05 mmol). The resulting mixture was stirred at room temperature for 24 hours and then diluted with 40 ml of dichloromethane and washed with water (40 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuum. The residue was purified on 110 g of silica gel, elwira a mixture of ethyl acetate:heptane (1:4) and receivedcomplex tert-butyl methyl ether (1-ethyl-3-nitro-2-trimethylsilyloxy)carbamino acid(1,505 g, 86%) as a colourless oil.

1H-NMR (CDCl3): δ 4,4-the 4.65 (m, 4H), 3,55 (m, 1H), 1,2-1,7 (m, 11H), and 0.98 (2×t, J=7.4 Hz, 3H), 0,13 (2s, 9H).

LC/MS: 2 isomer, just 100% 221 (M-BOC+1).

REFERENCE EXAMPLE 28

Complex tert-butyl ester {1-[(5-isopropylthiazole-3-yl)-trimethylsilylmethyl]propyl}carbamino acid

The complex solution of tert-butyl methyl ether (1-ethyl-3-nitro-2-trimethylsilyloxy)carbamino acid (918 mg, of 2.86 mmol), 1,4-phenylenediamine (1,38 g, 8.5 mmol) and 3-methyl-1-butyne (586 mg, 8.5 mmol) in dry toluene (15 ml) in an atmosphere of N2was added triethylamine (10 drops). The mixture was heated to 50°C in a sealed flask for 28 hours and then cooled to room temperature. After this was added water (1 ml) and the mixture was stirred is another 2 hours, and then was filtered. The filtrate was concentrated in vacuo and the residue was purified over 35 g of silica gel and was suirable a mixture of ethyl acetate:heptane (1:5), resulting in the receivedcomplex tert-butyl ester {1-[(5-isopropylthiazole-3-yl)trimethylsilylmethyl]propyl}carbamino acid(764 g, 72%) as a colourless oil.

1H-NMR (CDCl3): δ 6,0 (2s, 1H), 4,4-4,9 (m, 2H), and 3.7 (m, 1H), 3.0 a (m, 1H), of 1.2-1.6 (m, 17H), 1,0 (m, 3H), 0.11 and 0,1 (2×s, 9H).

LC/MS: 2 isomer, only 67% 271 (M-BOC+1).

REFERENCE EXAMPLE 29

Hydrochloride of 2-amino-1-(5-isopropylthiazole-3-yl)butane-1-ol

To a solution of complex tert-butyl ester {1-[(5-isopropylthiazole-3-yl)trimethylsilylmethyl]propyl}carbamino acid in dry dichloromethane (5 ml) in an atmosphere of N2solution was added 4 M HCl in dioxane (5.0 ml, wt.). The mixture was stirred at room temperature for 22 hours and then concentrated in vacuum to obtain amine salt (475 mg, 99%) as a yellowish brown solid.

1H-NMR (CDCl3): δ 6,25 (2×s, 1H), 5.0mm (d, J=3,9 Hz, 1H), 4.8V (d, J=6,8 Hz, 1H), 3,4 (m, 1H), 3,1 (m, 1H), 1.5 and 1.7 (m, 2H), 1,3 (d, J=6.8 Hz, 6H); 1,0 (t, J=6,7 Hz, 3H).

LC/MS: 100% 199 (M+1).

REFERENCE EXAMPLE 30

5-methyl-3-oxazol-5-yl-isoxazol

Hydride diisobutylaluminum (1,0 M in DHM, of 25.5 ml, 25.5 mmol) was added p who drops in for 20 minutes to a solution of methyl-5-methylisoxazol-3-carboxylate (3.0 g, of 21.3 mmol) in 35 ml of dry methylene chloride with stirring at -78°C, and the reaction mixture was stirred at -78°C for 5.5 hours. The reaction mixture was heated to -40°C and the reaction was suppressed by ice (60 g). After heating the obtained two-phase mixture to room temperature, was added tartrate tetrahydrate potassium-sodium (100 ml saturated aqueous solution). Double layer was separated and the aqueous layer was extracted with methylene chloride. The organic extracts were dried over sodium sulfate and concentrated under reduced pressure to get5-methylisoxazol-3-carbaldehydein the form of a white solid (1.3 g).

P-toluensulfonate (1.75 g, 8,97 mmol) and potassium carbonate (1.24 g, 8,97 mmol) was added to a solution of 5-methylisoxazol-3-carbaldehyde (1.0 g, 8,97 mmol) in 35 ml of dry methanol, and the reaction mixture is boiled under reflux (90°C) for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was distributed in diethyl ether (100 ml) and water (200 ml). The organic layer was separated and the aqueous layer was extracted with diethyl ether. The organic extracts were washed with salt solution and water, dried over sodium sulfate and concentrated under reduced pressure to obtain specified in the title compound as a yellowish solid substances is TBA (to 1.25 g).

LC/MS: 87%, 238 (M+1)

REFERENCE EXAMPLE 31

Complex tert-butyl ester ((S)-1-{hydroxy-[5-(5-methylisoxazol-3-yl)oxazol-2-yl]methyl}propyl)carbamino acid

Triethylborane (1 M in THF, 12 ml, 12 mmol) was added to a solution of 5-methyl-3-oxazol-5-isoxazole (1.8 g, 12 mmol) in 40 ml of dry tetrahydrofuran, and the resulting mixture was stirred at room temperature for 15 minutes. The mixture was cooled to -78°C, was added dropwise n-BuLi (2.5 M in hexane, 4.8 ml, 12 mmol)and the mixture was stirred at -78°C for 15 minutes. Then was added dropwise a solution of complex tert-butyl ether (S)-1-formylpropyl)carbamino acid (898,7 mg, 4.8 mmol) in 15 ml of dry tetrahydrofuran and the reaction mixture was stirred at -78°C for 3 hours and then was heated to -30°C, and the reaction was suppressed acetic acid in ethanol (4%, 250 ml), after which stirring was continued for another 2 hours while heating the mixture to room temperature. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in diethyl ether (250 ml) and was stirred for 1.5 hours at room temperature. The precipitate was filtered, and the filtrate was concentrated under reduced pressure. After chromatography on a column of silica with elution with a mixture of methylene chloride and ethyl acetate has been specified in sagola the ke compound as a pale yellow solid (830 mg).

LC/MS 100%, 338 (M+1)

REFERENCE EXAMPLE 32

Hydrochloride (S)-2-amino-1-[5-(5-methylisoxazol-3-yl)oxazol-2-yl]butane-1-ol

Hydrogen chloride (4 M in 1,4-dioxane, and 3.3 ml) was added dropwise to a solution of complex tert-butyl ester ((S)-1-{hydroxy-[5-(5-methylisoxazol-3-yl)oxazol-2-yl]methyl}propyl)carbamino acid (0.75 g, 2.22 mmol) in 10 ml of methylene chloride and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with diethyl ether (50 ml) and was stirred for another hour at room temperature, and then concentrated under reduced pressure, resulting in the received specified in the title compound as a yellowish solid (0.75 g).

1H NMR [(CD)3SO]: δ 8,18 (m, 3H), to 7.84 (s, 1H), 6,70 (s, 1H), 4,90 (m, 1H), to 3.58 (m, 2H), 2,50 (s, 3H), 1,60 (m, 2H), of 0.90 (t, 3H).

LC/MS 100%, 238 (M+1)

REFERENCE EXAMPLE 33

(S)-2-amino-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)butane-1-ol

A solution of (S)-3-tert-butoxycarbonylamino-2-hydroxypentanal acid (2.00 g, to 8.57 mmol) and N-hydroxycyclohexanecarboxylate (1,03 g, 10,29 mmol) in dichloromethane (20 ml) was stirred at 0°and portions were added to 1.25 equivalents of N-cyclohexylcarbodiimide-N'-metropolitical (1.70 mmol/g, 6,30 g, 10.72 mmol). The reaction mixture was stirred the nitrogen atmosphere for three hours while heating up to 15° C. Then the reaction mixture was filtered, the resin washed with dichloromethane, and the filtrate was evaporated in vacuum to dryness [LC/MS m/z=338 (M+H+Na)].

The residue was dissolved in tetrahydrofuran (20 ml) and heated in a microwave reactor (Smith Creator) at 160°C for three minutes, and then cooled to room temperature and evaporated in vacuum to dryness [LC/MS m/z=320 (M+H+Na)]. The residue was dissolved in dichloromethane (50 ml) and stirred at room temperature with added dropwise 50 ml of 50% triperoxonane acid in dichloromethane. After three hours the reaction mixture was evaporated in vacuum to dryness, and again dissolved in 50 ml of dichloromethane. Then added three equivalents of Silicycle silica gel triamine-3, and the mixture was stirred at room temperature overnight. The mixture was filtered and washed with dichloromethane. After evaporation in vacuo was obtained 1.04 g (61%).

[LC/MS m/z=198 (M+H)].

Alternatively, the removal of the protective group BOC was carried out by addition of HCl in dioxane, resulting in received hydrochloride (S)-2-amino-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)butane-1-ol.

REFERENCE EXAMPLE 34

(S)-2-amino-1-(3-phenyl-1,2,4-oxadiazol-5-yl)butane-1-ol

A solution of (S)-3-tert-butoxycarbonylamino-2-hydroxypentanal acid (2.00 g, to 8.57 mmol) and N-hydroxybenzamide (1.3 g, 9.5 mmol) in dichloromethane (40 ml) was stirred at 0� C. Then portions were added N-cyclohexylcarbodiimide-N'-metropolitical (1,90 mmol/g, 6 g, of 11.4 mmol). The reaction mixture was stirred in nitrogen atmosphere for one hour. Then the reaction mixture was filtered, the resin washed with dichloromethane, and the filtrate was evaporated in vacuum to dryness [LC/MS m/z=352 (M+H+), 296 (M+H+-isobutan)]. The residue was dissolved in tetrahydrofuran (20 ml) and heated in a microwave reactor (Smith Creator) at 180°C for three minutes, cooled to room temperature and evaporated in vacuum to dryness. The residue was purified flash chromatography (gradient elution with a mixture of from 5% to 65% ethyl acetate in heptane) and received the product in the form of a white solid [LC/MS m/z=356 (M+Na+), 234 (M+H+-Boc)].

The product was dissolved in dichloromethane (45 ml) was added triperoxonane acid (5 ml). After two hours the reaction mixture was evaporated in vacuum to dryness. The residue was again dissolved in 50 ml of dichloromethane. Then added Silicycle silica gel triamine-3 (9,9 g, 39 mmol) and the mixture was stirred at room temperature overnight. The mixture was filtered and washed with dichloromethane. The filtrate was concentrated in vacuum to obtain(S)-2-amino-1-(3-phenyl-1,2,4-oxadiazol-5-yl)butane-1-ol(775 mg, 38%) as a white solid.

1H-NMR (CDCl3): δ 8,12-of 8.06 (m, 2H), 7,54 was 7.45 (m, 3H), 4,93 and 4,75 (2×d, J=5 Hz and 3.5 Hz, 1H), 3.25 and 3,11 (2×m, 1H), 1,7-1,42 (2× m, 2H), 1.04 million and 1.01 (2×t, J=7.5 Hz, 3H).

[LC/MS m/z=234 (M+H)].

REFERENCE EXAMPLE 35

(S)-2-amino-1-(5-phenyl[1,2,4]oxadiazol-3-yl)butane-1-ol

This compound was synthesized as described in the following reaction scheme:

Complex tert-butyl ester {(S)-1-[hydroxy-(N-hydroxycarbamoyl)methyl]propyl}carbamino acid (2)

The complex solution of tert-butyl methyl ether (2-cyano-1-ethyl-2-hydroxyethyl)carbamino acid (at 9.53 g, 44 mmol) in methanol (80 ml) was cooled to 0°C and successively treated with hydroxylamine hydrochloride (3,05 g, 44 mmol) in methanol (80 ml) and 25% solution of sodium methoxide in methanol (10,2 ml). After stirring at 0°C for 5 minutes the reaction mixture was stirred at room temperature for 5 hours and then evaporated. The residue was distributed between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate, and then evaporated under reduced pressure. The residual yellow oil was subjected to liquid chromatography, medium-pressure chromatography with a mixture of ethyl acetate and heptane, resulting in the receivedcomplex tert-butyl ester {(S)-1-[hydroxy-(N-hydroxycarbamoyl)methyl]propyl}carbamino acid(3.5 g) as a white solid.

MS: MH+248.

The complex is th tert-butyl ester {1-[hydroxy-(N-benzyloxycarbonylamino)methyl]propyl}carbamino acid (3)

The complex solution of tert-butyl methyl ether {1-[hydroxy-(N-hydroxycarbamoyl)methyl]propyl}carbamino acid (2) (2.5 g, 10 mmol) in dichloromethane (125 ml) was treated with benzoic acid (1,36 g, 11 mmol), EDCI (2.14 g, 11 mmol), HOBT (of 1.37 g, 10 mmol) and triethylamine (1.35 ml, 11 mmol) and stirred at room temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate solution, then water, then dried over Na2SO4and evaporated under reduced pressure. The residue was chromatographically liquid medium pressure chromatography with elution with 1% of triethylamine in a mixture of 2:3 V/V ethyl acetate and heptane and receivedcomplex tert-butyl ester {1-[hydroxy-(N-benzyloxycarbonylamino)methyl]propyl}carbamino acid(850 g) as a yellow solid.

MS: MH+352.

2-amino-1-(5-phenyl[1,2,4]oxadiazol-3-yl)butane-1-ol (5)

Solution (3) (1.5 g, 4.3 mmol) in diglyme was heated at 150°C in a microwave reactor (Smith Creator, S00219) for 40 minutes. The solvent was evaporated in vacuum Genevac evaporator at 80°C for 3 hours to obtain a brown solid. The resulting material was dissolved in dichloromethane (40 ml) and treated triperoxonane acid at room temperature for 2 hours. The solvent was evaporated to dryness under reduced pressure, the raw is, the product was dissolved in water, washed DHM, the aqueous layer was podslushivaet a solution of 1 M NaOH and was extracted with dichloromethane. The organic layer was dried over Na2SO4and evaporated under reduced pressure to get2-amino-1-(5-phenyl[1,2,4]oxadiazol-3-yl)butane-1-ol(300 mg) as a pale brown solid.

1H-NMR (CDCl3): δ 8,14-8,10 (m, 2H), to 7.59-7,47 (m, 3H), of 4.83 and the 4.65 (d, J=5 Hz, 1H), 3,18-3,05 (2m, 1H), 1,71-1,20 (m, 2H), 1,05-0,97 (2×t, J=7.2 Hz, 3H).

REFERENCE EXAMPLE 36

(S)-2-acetoxy-3-tert-butoxycarbonylamino acid

Pyridine (5 ml), 4-(dimethylamino)pyridine (0.01 g) and acetic anhydride (11 mmol, 1.12 g) was dissolved in dichloromethane (150 ml)and the resulting solution was cooled to 0°C. thereafter, it was added (S)-3-tert-butoxycarbonylamino-2-hydroxypentanal acid (10 mmol, 2,33 g, A) and the resulting reaction mixture was stirred for 5 hours. Then added 1 M hydrochloric acid (250 ml) and the mixture was transferred into a separating funnel. The phases were separated and the aqueous phase three times were extracted with ethyl acetate (200 ml). The combined organic phase is twice washed with water (200 ml) and saturated salt solution (100 ml). The organic phase was dried with magnesium sulfate and the solvent was evaporated under reduced pressure to get(S)-2-acetoxy-3-tert-butoxycarbonylamino acid(2,535 g, 92%).

MS: m/z=298 (+Na +), 276 (M+H+)

REFERENCE EXAMPLE 37

Complex (S)-2-tert-butoxycarbonylamino-1-[N'-(4-trifloromethyl)hydrazinecarboxamide]butyl ether acetic acid

(S)-2-acetoxy-3-tert-butoxycarbonylamino acid (1.82 mmol, 0.5 g, A) was dissolved in 30 ml of dichloromethane. Then was added N-cyclohexylcarbodiimide-N'-metropolitical (of 3.64 mmol, 1.92 g, B), and the resulting reaction mixture was stirred for 2 minutes. After this was added hydrazide 4-(triptoreline)benzoic acid (1,65 mmol, 0,363 g, C), and the reaction mixture was stirred over night. After 16 hours analysis by LC/MS is still indicated the presence of hydrazide. Then added politicalmilitary (1,65 mmol, 1,15 g) and stirring continued for another eight hours. The reaction mixture was filtered under vacuum and the filtrate was concentrated under reduced pressure. The result has beencomplex (S)-2-tert-butoxycarbonylamino-1-[N'-(4-trifloromethyl)hydrazinecarboxamide]butyl ether acetic acidas a yellow foam (0.5 g, 64%). According to analysis by LC/MS were remnants of the hydrazide.

MS: m/z=500 (M+Na+), 478 (M+H+)

REFERENCE EXAMPLE 38

Complex (S)-2-tert-butoxycarbonylamino-1-[5-(4-trifloromethyl)-1,3,4-oxadiazol-2-yl]butyl ether acetic acid

Complex (S)-2-tert-butoxycarbonylamino-1-[N'-(4-trifloromethyl)hydrazinecarboxamide]butyl ester acetic acid, obtained as described above was divided into 5 portions, which were separately used in the following reactions:

Complex (S)-2-tert-butoxycarbonylamino-1-[N'-(4-trifloromethyl)hydrazinecarboxamide]butyl ether acetic acid (0.21 mmol, 0.1 g) was dissolved in THF (5 ml) and the resulting solution was placed in a microwave reactor for synthesis of Smith Microwave. Then added 2-tert-butylamino-2-diethylamino-1,3-dimethylpyridine-1,2,3-datafactory polystyrene (1.05 mmol, 0,456 g, 2.3 mmol/g loading), p-toluenesulfonyl chloride (0.25 mmol, 0,048 g) and the reaction mixture was heated at 150°C for 10 minutes (fixed time) in the microwave synthesizer.

The combined reaction mixture was filtered under vacuum and the resin was washed with 300 ml of ethyl acetate. The combined filtrates were concentrated under reduced pressure. The crude product was purified flash chromatography (column (Biotage Horizon, 25m, the crude product was applied to a small column, the flow rate of 17 ml/min, 12 ml per fraction, 120 ml gradient from 0% of ethyl acetate in heptane to 30% ethyl acetate in heptane, 240 ml of 30% ethyl acetate in heptane, 60 ml gradient of 30-50% ethyl acetate in heptane, 300 ml of 50% ethyl acetate in heptane) and gotcomplex (S)-2-tert-butoxy is ebonyline-1-[5-(4-trifloromethyl)-1,3,4-oxadiazol-2-yl]butyl ether acetic acid (0.28 g, 58%).

MS: m/z=460 (M+H+)

REFERENCE EXAMPLE 39

Complex tert-butyl ester ((S)-1-{hydroxy-[5-(4-trifloromethyl)-1,3,4-oxadiazol-2-yl]methyl}propyl)carbamino acid

Complex (S)-2-tert-butoxycarbonylamino-1-[5-(4-trifloromethyl)-1,3,4-oxadiazol-2-yl]butyl ether acetic acid (0.61 mmol, 0.28 g) was dissolved in a mixture of THF (10 ml) and water (10 ml). Then hydrate was added lithium hydroxide (1,22 mmol, 0,051 g) and the reaction mixture was stirred for 2 hours. The solvents are evaporated under reduced pressure and the residue was transferred into a separating column with 300 ml of ethyl acetate and 50 ml of water. The phases were separated and the organic phase is washed with saturated salt solution (100 ml). Then the organic phase was dried over magnesium sulfate. The solvent is evaporated under reduced pressure, dried in high vacuum and receivedcomplex tert-butyl ester ((S)-1-{hydroxy-[5-(4-trifloromethyl)-1,3,4-oxadiazol-2-yl]methyl}propyl)carbamino acidin the form of a yellow oil (0,225 g, 89%).

MS: m/z=440 (M+Na+), 418 (M+H+)

REFERENCE EXAMPLE 40

(S)-2-amino-1-[5-(4-trifloromethyl)-1,3,4-oxadiazol-2-yl]butane-1-ol

Complex tert-butyl ester ((S)-1-{hydroxy-[5-(4-trifloromethyl)-1,3,4-oxadiazol-2-yl]methyl}propyl)carbamino to the slots (0.54 mmol, 0,225 g) was dissolved in dichloromethane (9 ml) and treated triperoxonane acid (1 ml). The reaction mixture was stirred for four hours. The solvent was evaporated under reduced pressure. The residue was again dissolved in dichloromethane (20 ml) was added Silicycle silica gel Triamine (5.4 mmol, 1.47 g). The reaction mixture was stirred for 60 hours (over a weekend). The reaction mixture was filtered under vacuum, and the solvent evaporated, and received(S)-2-amino-1-[5-(4-trifloromethyl)-1,3,4-oxadiazol-2-yl]butane-1-ol(0,164 g, 96%).

MS: m/z=318 (M+H+)

REFERENCE EXAMPLE 41

2-cyclopropyl[1,3,4]oxadiazol

The complex mixture of methyl ester cyclopropanecarbonyl acid (10 g, 0.1 mol) and hydrazine hydrate (7.3 ml, 0.15 mol) was boiled under reflux for 28 hours and then cooled to room temperature. The mixture was evaporated under reduced pressure, and then dried by azeotropic removal of the solvent with toluene. The residue was dissolved in dichloromethane and washed with saturated NaCl. The organic phase was dried over anhydrous MgSO4and the solvent evaporated under reduced pressure to gethydrazide cyclopropanecarbonyl acid(4,36 g, 44%).

A mixture of hydrazide cyclopropanecarbonyl acid (31,35 g, 0.31 mol), triethylorthoformate (300 ml) and monohydrate p-toluols Lanovoy acid (200 mg) was boiled under reflux overnight. Excess triethylorthoformate and methanol was removed by distillation. After vacuum distillation of the residue was received2-cyclopropyl[1,3,4]oxadiazol(22 g, 64%).

1H-NMR (CDCl3): δ 8,24 (s, 1H), 2,2 (m, 1H)and 1.15 (m, 4H).

LC/MS: 100%, 111 (MH+).

REFERENCE EXAMPLE 42

Complex tert-butyl ester {1-[(5-cyclopropyl[1,3,4]oxadiazol-2-yl)-hydroxymethyl]propyl}carbamino acid

A solution of 2-cyclopropyl[1,3,4]oxadiazole (2.16 g, a 19.6 mmol) in dry THF (100 ml) was cooled to -78°C. Then was added dropwise n-BuLi (1.6 M in hexane, to 12.3 ml and 19.6 mmol). The reaction mixture was stirred at -78°C for 40 minutes. Then added MgBr2·OEt2(5,0692 g and 19.6 mmol). The reaction mixture was left to warm to -45°C, and then stirred at this temperature for 1.5 hours. After this solution was added to complex tert-butyl methyl ether (1-formylpropyl)carbamino acid (3.7 g, a 19.6 mmol) in THF (40 ml). The reaction mixture was heated to -20°C and stirred at this temperature for 3.5 hours. The reaction was suppressed with saturated solution of NH4Cl and the mixture was extracted with ethyl acetate. The combined organic extrate washed with saturated solution of NaCl and dried over MgSO4. The solvent is evaporated under reduced pressure and the crude product was purified column chromatograph is her elwira a mixture of ethyl acetate and heptane, resulting in the receivedcomplex tert-butyl ester {1-[(5-cyclopropyl[1,3,4]oxadiazol-2-yl)hydroxymethyl]propyl}carbamino acid(2.83 g, 49%).

LC/MS: 298 (MH+).

REFERENCE EXAMPLE 43

(S)-2-amino-1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)butane-1-ol; compound with triperoxonane acid

The complex mixture of tert-butyl methyl ether {1-[(5-cyclopropyl[1,3,4]oxadiazol-2-yl)hydroxymethyl]propyl}carbamino acid (2.83 g, for 9.95 mmol) and triperoxonane acid (5 ml) in dichloromethane (20 ml) was stirred at room temperature for 2 hours and concentrated to dryness under reduced pressure, and was received(S)-2-amino-1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)butane-1-ol; compound with triperoxonane acid.

LC/MS: 100% 198 (MH+).

REFERENCE EXAMPLE 44

Methyl ester of (S)-4,4-debtor-2-[(perhydro-1,4-oxazepine-4-carbonyl)amino]pentanol acid

Triphosgene was dissolved in dichloromethane (10 ml) and the resulting solution via syringe pump over 1 hour was added to a mixture of the hydrochloride of S-2-amino-4,4-differentyou acid (1,00 g of 4.90 mmol) (see reference example 15) and diisopropylethylamine (of 1.88 ml, 10,80 mmol)dissolved in dichloromethane (10 ml). After stirring for 15 mine is, to this solution was added a solution of hydrochloride homomorpholine (0,67 g of 4.90 mmol) and diisopropylethylamine (1.90 ml, 10,90 mmol) in dichloromethane (10 ml). The resulting solution was stirred at room temperature for 2 hours. The solvent is evaporated, and the residue was diluted with ethyl acetate (100 ml)and then washed with 1 M KHSO3(2×10 ml), saturated NaHCO3and a saturated solution of salt. The organic phase was dried (Na2SO4), filtered and concentrated to obtain a light yellow oil. The crude product was purified on 20 g of silica gel, elwira a mixture of ethyl acetate:heptane gradient of 50-100%. The result has beenmethyl ester of (S)-4,4-debtor-2-[(perhydro-1,4-oxazepine-4-carbonyl)amino]pentanol acidin the form of a white solid (0.40 g, 28%).

1H-NMR (CDCl3): δ 5,12 (d, J=7.5 Hz, 1H), 4.72 in (DD, J=12,0, 7.2 Hz, 1H, in), 3.75 (m, 7H), 3,55 (m, 4H), of 2.45 (m, 2H), up to 1.98 (m, 2H), of 1.66 (t, J=18.7 Hz, 3H).

LC/MS: 295, 100%, (M+H), 317 (M+Na)

REFERENCE EXAMPLE 45

(S)-4,4-debtor-2-[(perhydro-1,4-oxazepine-4-carbonyl)amino]pentane acid

Methyl ester of (S)-4,4-debtor-2-[(perhydro-1,4-oxazepine-4-carbonyl)amino]pentanol acid (0,38 g, 1,29 mmol) was dissolved in a mixture of tetrahydrofuran/methanol (15 ml/10 ml) was added lithium hydroxide (35 mg, of 1.40 mmol)dissolved in water (5 ml). The reaction mixture was stirred pikantnoi temperature for 18 hours, and then a mixture of methanol/tetrahydrofuran was removed in vacuum. The residue was acidified using 6 M hydrochloric acid (0.25 ml) and was extracted with dichloromethane (3×20 ml), dried (Na2SO4) and concentrated, and received(S)-4,4-debtor-2-[(perhydro-1,4-oxazepine-4-carbonyl)amino]pentane acidin the form of a white solid (0.36 g, 99%).

1H-NMR (DMSO-d6): δ 12,6 (Sirs, 1H), 6,60 (d, J=8,3 Hz, 1H), 4,30 (DD, J=14,5, 7,0 Hz, 1H), only 3.57 (m, 4H), 3.43 points (m, 4H), of 2.38 (m, 2H), 1.77 in (m, 2H), 1,61 (t, J=19.2 Hz, 3H).

LC/MS: 100% 281 (M+H).

REFERENCE EXAMPLE 46

Methyl ester of (S)-4,4-debtor-2-[(perhydro-1,4-oxazepine-4-carbonyl)amino]heptane acid

To a mixture of sodium bicarbonate (5,25 g), p-nitroformate (of 5.03 g, 25 mmol) in acetonitrile (130 ml) under nitrogen atmosphere was addedhydrochloride difficult methyl ester (S)-2-amino-4,4-differetnly acid (5,79 g 0,025 mol)and the mixture was stirred at room temperature for 5 hours. Then was added the hydrochloride homomorpholine (3,61 g, 26,25 mmol) and triethylamine (12.5 ml) and the reaction mixture was stirred over night at room temperature. The solvent is evaporated under reduced pressure and the crude product was distributed between water (150 ml) and ethyl acetate (200 ml). The organic layer was separated, washed with a solution of K2CO3(150 ml), HCl (150 ml) and saturated R is the target salt (150 ml). The organic layer was separated, dried (MgSO4) and evaporated under reduced pressure. The crude product was purified column chromatography, elwira a mixture of from 1:1 to 8:2 V/V ethyl acetate and heptane, and then with ethyl acetate, and receivedmethyl ester of (S)-4,4-debtor-2-[(perhydro-1,4-oxazepine-4-carbonyl)amino]heptane acid(4.8 g) as a pale yellow oil.

LC/MS: 323 (M+H)

REFERENCE EXAMPLE 47

(S)-4,4-debtor-2-[(perhydro-1,4-oxazepine-4-carbonyl)amino]heptane acid

In a manner analogous to that described above in reference example 45, but using sophisticated methyl ester (S)-4,4-debtor-2-[(perhydro-1,4-oxazepine-4-carbonyl)amino]heptane acid was received(S)-4,4-debtor-2-[(perhydro-1,4-oxazepine-4-carbonyl)amino]heptane acid.

LC/MS: 309 (M+H)

REFERENCE EXAMPLE 48

(S)-2-amino-1-(3-isopropyl[1,2,4]oxadiazol-5-yl)butane-1-ol

This compound was obtained by a method similar to that described in reference example 33.

LC/MS: 200 (M+H)

REFERENCE EXAMPLE 49

Complex tert-butyl ester {(S)-1-[(5-tert-butyl-1,2,4-oxadiazol-3-yl)hydroxymethyl]propyl}carbamino acid

Complex tert-butyl ester {(S)-1-[hydroxy-(N-hydroxycarbamoyl)methyl]propyl}carbonintensity (235 mg, 0.95 mmol) in diglyme (2 ml) was treated trimethyloxonium anhydride (0,212 ml, 1.04 mmol)and the reaction mixture was heated at 170°C for 5 minutes in a microwave reactor Emrys Optimizer company Personal Chemistry. The solvent is evaporated under high vacuum. The crude product was purified flash chromatography, elwira a mixture of ethyl acetate and heptane (1:4) and receivedcomplex tert-butyl ester {(S)-1-[(5-tert-butyl-1,2,4-oxadiazol-3-yl)hydroxymethyl]propyl}carbamino acidin the form of a brown oil (100 mg) (mixture of diastereoisomers).

1H-NMR (CDCl3): δ 4,92-4,69 (m, 2H), 4,05-of 3.85 (m, 1H), 3,57-3,41 and of 3.32-3.15 in (2×Sirs, 1H), 1,73 is 1.48 (m, 2H), 1,45, and 1.44 (2×s, 9H), 1,43, and 1,39 (2×s, 9H), of 0.99 and 0.96 (2×t, J=7.5 Hz, 3H).

MS: 314 (M+H).

REFERENCE EXAMPLE 50

(S)-2-amino-1-(5-tert-butyl-1,2,4-oxadiazol-3-yl)butane-1-ol

The complex solution of tert-butyl ester {(S)-1-[(5-tert-butyl-1,2,4-oxadiazol-3-yl)hydroxymethyl]propyl}carbamino acid (2,11 g, 6,72 mmol) in methylene chloride (20 ml) was treated triperoxonane acid (5,18 ml, 67,25 mmol) and stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure. The residue was dissolved in methylene chloride (100 ml) and treated with trisamine on a polymer substrate (Argonaut Technologies) (download 5,38 g, 20,18 mmol, 3.75 mmol/g), then p is a promotional mixture was stirred at room temperature for 4 hours, was filtered, and the filtrate was evaporated and received(S)-2-amino-1-(5-tert-butyl-1,2,4-oxadiazol-3-yl)butane-1-olas an orange oil (975 mg) (mixture of diastereoisomers).

1H-NMR (CDCl3): δ 4,73 and 4,58 (2×d, J=5 Hz, 1H), 3,12-3,00 (m, 1H), 2,64-2,31 (Sirs, 3H), 1,69-of 1.44 (m, 2H), USD 1.43 (s, 9H), of 0.99 and 0.97 (2×t, J=7.5 Hz, 3H).

MS: 214 (M+H).

REFERENCE EXAMPLE 51

Complex tert-butyl ether (S)-1-{[5-(4-forfinal)-1,2,4-oxadiazol-3-yl]hydroxymethyl}propyl)carbamino acid

A suspension of 4-fermenting acid (1.70 g, 0.012 mol) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2,12 g to 0.011 mol) in methylene chloride (80 ml) was treated with complex tert-butyl ether (S)-1-[hydroxy-(N-hydroxycarbamoyl)methyl]propyl}carbamino acid (3 g, 0.012 mol) and triethylamine (1,54 ml, to 0.011 mol). The reaction mixture was stirred at room temperature overnight. Then it was diluted with 40 ml of methylene chloride, washed with saturated aqueous bicarbonate (30 ml), water (30 ml) and saturated salt solution (30 ml), dried over Na2SO4and the solvent evaporated under reduced pressure. The residue was purified flash chromatography, elwira a mixture of ethyl acetate and heptane (2:1), and were not quite white solid (2.20 g).

1H-NMR (CDCl3): δ 8,10-to 7.95 (m, 2H), 7,16-7,00 (m, 2H), 5,43-5,24 (m, 2H), 5,22-of 5.05 (m, 1H), 5,01-is 4.85 (m, 1H), 4,5-4,39 (m, 1H), 3,80-of 3.60 (m, 1H), 1,90-of 1.78 (m, 2H), 1,40 (s, 9H), and 0.98 (t, J=7.5 Hz, 3H).

MS: 370 (M+H).

240 mg of a solid (of 0.65 mmol), obtained as described above was dissolved in diglyme (5 ml) and boiled at 160°C in a microwave reactor (Smith Creator, S00219) for 18 minutes. The solvent is evaporated in a high vacuum. The crude product was purified flash chromatography, elwira a mixture of ethyl acetate and heptane (1:4), and receivedcomplex tert-butyl ether (S)-1-{[5-(4-forfinal)-1,2,4-oxadiazol-3-yl]hydroxymethyl}propyl)carbamino acidin the form of a white solid (148 mg).

1H-NMR (CDCl3): δ 8,16-of 8.09 (m, 2H), 7,25 for 7.12 (m, 2H), 4,98-to 4.73 (m, 2H), 4,13-a 3.87 (m, 1H), 3,82-to 3.35 (m, 1H), 1,80-of 1.52 (m, 2H), 1.46 and of 1.34 (2×s, 9H), of 1.02 and 0.99 (2×t, J=7.5 Hz, 3H).

MS: 352 (M+H).

REFERENCE EXAMPLE 52

(S)-2-amino-1-[5-(4-forfinal)-1,2,4-oxadiazol-3-yl]butane-1-ol

The compound was obtained in a manner analogous to that described above in reference example 50, but using complex tert-butyl ether (S)-1-{[5-(4-forfinal)-1,2,4-oxadiazol-3-yl]hydroxymethyl}propyl)carbamino acid.

1H-NMR (CDCl3): δ 8,18-with 8.05 (m, 2H), 7,26 for 7.12 (m, 2H), 4.92 in and 4.73 (2×d, J=5 Hz, 1H), 3.27 to 3,05 (m, 1H), 1,75-of 1.62 (m, 1H), 1,59-of 1.41 (m, 1H), of 1.02 and 1.00 (2×t, J=7.5 Hz, 3H).

MS: 252 (M+H).

REFERENCE EXAMPLE 53

Complex tert-butyl ester {(S)-1-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)hydroximate is]propyl}carbamino acid

A suspension of complex tert-butyl ether (S)-1-[hydroxy-(N-hydroxycarbamoyl)methyl]propyl}carbamino acid (6,12 g, 24,78 mmol) in methylene chloride (150 ml) was treated with triethylamine (3.46 in ml, 24,82 mmol), and then was cooled to 0°C. then was added dropwise cyclopropanecarbonitrile (2.25 ml, 24,79 mmol). The reaction mixture was stirred at room temperature for 1 hour and 45 minutes and was diluted with 150 ml of methylene chloride, washed with water (40 ml), saturated aqueous bicarbonate (20 ml), water (20 ml), dried over Na2SO4and the solvent evaporated under reduced pressure to obtain white solids (7,16 g).

MS: 338 (M+Na).

A solution of the compound obtained as described above (7,45 g 0,024 mol) in dioxane (150 ml) was boiled under reflux for 15 hours. The solvent is evaporated under reduced pressure and the residue was purified flash chromatography, elwira a mixture of ethyl acetate and heptane, and receivedcomplex tert-butyl ether (S)-1-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)hydroxymethyl]propyl}carbamino acidin the form of a pale yellow solid (5 g).

1H-NMR (CDCl3): δ 4,94-4,74 (m, 2H), 3,97 and 3.85 (2×m, 1H), 3,62, and 3,48 (2×Sirs, 1H), 2,19 (m, 1H), 1,72-of 1.42 (m, 2H), 1.44MB and 1,39 (2×s, 9H), 1,26-of 1.18 (m, 4H), 0.98 and 0.95 to (2×t, J=7.4 Hz, 3H).

MS: 298 (M+H).

REFERENCE EXAMPLE 54

p> HCl-salt (S)-2-amino-1-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)butane-1-ol

The complex solution of tert-butyl ester {(S)-1-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)hydroxymethyl]propyl}carbamino acid (3,41 g to 0.011 mmol) in 4 BC, HCl in dioxane (43 ml, 0,172 mmol) was stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure. The residue is triturated with a mixture of ethyl acetate and ether. Then it was filtered and receivedHCl-salt (S)-2-amino-1-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)butane-1-olin the form of a brown solid (2,47 g).

1H-NMR (CDCl3): δ 8,21 (Sirs, 2H), and lower than the 5.37 5,14 (2×d, 1H), 3,88, and to 3.73 (2×m, 1H), of 2.21 (m, 1H), 1,92 of 1.50 (m, 2H), 1,24 (m, 4H), 1.08 and 1.06 a (2×t, J=7.4 Hz, 3H).

MS: 198 (M+H).

EXAMPLE 1

{(S)-1-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-carbonyl)propellerblades]-3,3-divergence}amide morpholine-4-carboxylic acid

To a mixture of (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]heptane acid (104 mg, 0.35 mmol), hydrochloride (S)-2-amino-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)butane-1-ol (86,7 mg of 0.37 mmol) and Diisopropylamine (219 mg, 0.42 mmol) in dry dichloromethane (5 ml) was added PyBOP (113 mg, 0.87 mmol). The resulting mixture was stirred at room temperature for 16 hours and evaporated in vacuum. The residue was diluted with ethyl acetate (25 ml), washed with h Sydenham NaHCO 3(30 ml)and then diluted HCl (30 ml) and saturated NaHCO3(30 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuum. The residue was purified on 12 g of silica gel, elwira a mixture of ethyl acetate:heptane (2:1, then 1:0), and received(1-{1-[(3-cyclopropyl[1,2,4]oxadiazol-5-yl)hydroxymethyl]propellerblades}-3,3-divergence)amide morpholine-4-carboxylic acid(146 mg, 88%) as a white solid. Analysis by LC/MS revealed 2 isomer, just 100% M+1 474.

To a solution of (1-{1-[(3-cyclopropyl[1,2,4]oxadiazol-5-yl)hydroxymethyl]propellerblades}-3,3-divergence)amide morpholine-4-carboxylic acid (145 mg, 0.31 mmol) in dry dichloromethane (3 ml) in an atmosphere of N2added periodinane dess-Martin (15 wt.% solution in dichloromethane, 1.73 g, 0.061 mmol). The reaction mixture was stirred at room temperature for 2 hours and then the reaction was suppressed by a solution of Na2S2O3(193 mg, 1,22 mmol) in a saturated NaHCO3(30 ml). The aqueous layer was extracted with dichloromethane (2×30 ml). The organic layers were dried over magnesium sulfate and concentrated in vacuum. The residue was purified on 12 g of silica gel, elwira a mixture of ethyl acetate:heptane (1:1, then 2:1), to obtain the desired ketone (119 mg, 81%) as a yellowish brown solid.

1H-NMR (CDCl3): δ 7,4 (d, J=7,0 Hz, 1H), 5,27 (m, 1H), 5,13 (d, J=6,9 Hz, 1H)and 4.65 (DD, J=13,1, 6,9 Hz, 1H), and 3.7 (m, 4H) 3,4 (m, 4H), 2,4 (m, 2H), 2,2 (m, 1H), 2.05 is (m, 1H), 1.8 m (m, 3H), of 1.55 (m, 2H)and 1.15 (m, 4H), and 0.98 (t, J=7.4 Hz, 6H).

LC/MS: 28% 512 (M+H2O+Na) and 68% 494 (M+Na).

EXAMPLE 2

{(S)-1-[(S)-1-(5-cyclopropyl-1,3,4-oxadiazol-2-carbonyl)propellerblades]-3,3-divergence}amide morpholine-4-carboxylic acid

PyBOP (171,73 mg, 0.33 mmol), diisopropylethylamine (0,0575 ml, 0.33 mmol) and (S)-2-amino-1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)butane-1-ol, compound with triperoxonane acid (0.30 mmol)was added to a solution of (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]heptane acid (88,29 mg, 0.30 mmol) in dry methylene chloride (4 ml)and the reaction mixture was stirred over night at room temperature. The reaction extinguished aqueous sodium bicarbonate, twice were extracted with methylene chloride, and the organic extracts were dried over sodium sulfate and evaporated under reduced pressure. After column chromatography on silica gel with elution with a mixture of methylene chloride and ethyl acetate was received((S)-1-{(S)-1-[(5-cyclopropyl-1,3,4-oxadiazol-2-yl)hydroxymethyl]propellerblades}-3,3-forhekset)amide morpholine-4-carboxylic acidin the form of a white solid (87 mg).

LC/MS 97%, 474 (M+1).

Periodinane dess-Martin (15 wt.% in DHM, 0,79 g, 0.28 mmol) was added to a solution of ((S)-1-{(S)-1-[(5-cyclopropyl-1,3,4-oxadiazol-2-yl)hydroxymethyl]propellerblades}-3,3-divergence)amide morpholine-4-carbon is acid (67 mg, 0.14 mmol) in dry methylene chloride (10 ml)and the mixture was stirred at room temperature for 2.5 hours. The reaction was suppressed by a solution of Na2S2O3(110,68 mg, 0.70 mmol) in aqueous NaHCO3. The organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic extracts were dried over sodium sulfate and concentrated under reduced pressure. After column chromatography on silica with elution with a mixture of methylene chloride and ethyl acetate was received{(S)-1-[(S)-1-(5-cyclopropyl-1,3,4-oxadiazol-2-carbonyl)propellerblades]-3,3-divergence}amide morpholine-4-carboxylic acidin the form of a white powder (48 mg).

1H-NMR (CDCl3): δ 7,52 (d, J=7.5 Hz, 1H), of 5.34 (m, 1H), 5,18 (d, J=7.5 Hz, 1H)and 4.65 (m, 1H), and 3.72 (m, 4H), 3,40 (m, 4H), 2,50-2,22 (m, 3H), 2,18-of 2.08 (m, 1H), 1,96-of 1.78 (m, 3H), 1.60-to a 1.45 (m, 2H), 1,30 (m, 4H), and 0.98 (t+t, 6H).

LC/MS 95%, 472 (M+1).

EXAMPLE 3

((S)-3,3-debtor-1-{(S)-1-[5-(4-trifloromethyl)-1,3,4-oxadiazol-2-carbonyl]propellerblades}hexyl)amide morpholine-4-carboxylic acid

PyBOP (68,69 mg, 0.13 mmol), diisopropylethylamine (is 0.023 ml, 0.13 mmol) and (S)-2-amino-1-[5-(4-trifloromethyl)-1,3,4-oxadiazol-2-yl]butane-1-ol (38,0 mg, 0.12 mmol) was added to a solution of (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]heptane acid (34 mg, 0.12 mmol) in dry methylene chloride (4 ml)and the reaction mixture was stirred during the night when to the room temperature. The reaction is extinguished in an aqueous solution of NaHCO3mixture two times were extracted with methylene chloride and the organic extracts were dried over Na2SO4and evaporated under reduced pressure. After column chromatography on silica gel with elution with a mixture of methylene chloride and ethyl acetate was received[(S)-3,3-debtor-1-((S)-1-{hydroxy-[5-(4-trifloromethyl)-1,3,4-oxadiazol-2-yl]methyl}propellerblades)hexyl]amide morpholine-4-carboxylic acidin the form of a white solid (61 mg).

LC/MS 71%, M+1=594.

Periodinane dess-Martin (15 wt.% in DHM, of 0.58 g, 0.21 mmol) was added to a solution of [(S)-3,3-debtor-1-((S)-1-{hydroxy-[5-(4-trifloromethyl)-1,3,4-oxadiazol-2-yl]methyl}propellerblades)hexyl]amide morpholine-4-carboxylic acid (61 mg, 0.10 mmol) in dry methylene chloride (8 ml) and the mixture was stirred at room temperature for 3 hours. The reaction was suppressed by a solution of Na2S2O3(81,43 mg, 0.50 mmol) in aqueous NaHCO3. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic extracts were dried over sodium sulfate and concentrated under reduced pressure. After chromatography on a column of silica with elution with a mixture of methylene chloride and ethyl acetate was received((S)-3,3-debtor-1-{(S)-1-[5-(4-trifloromethyl)-1,3,4-oxadiazol-2-carbonyl]propellerblades}hexyl)amide morpholine-4-carboxylic acid in the form of a white powder (39 mg).

1H-NMR (CDCl3): δ of 8.25 (d, J=7.5 Hz, 2H), 7,60 (d, J=7.5 Hz, 1H), 7,42 (d, J=7.5 Hz, 2H), are 5.36 (m, 1H), 5,16 (d, J=7.5 Hz, 1H), 4,70 (m, 1H), 3,74 (m, 4H), 3,42 (m, 4H), 2,54 of-2.32 (m, 2H), 2,28 with 2.14 (m, 1H), 2,02 and 1.80 (m, 3H), 1.60-to a 1.45 (m, 2H), 1.06 a (t, J=7 Hz, 3H), of 0.96 (t, J=7 Hz, 3H).

LC/MS: 96%, 592 (M+1).

EXAMPLE 4

{(S)-1-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-carbonyl)propellerblades]-3,3-debtor-4-phenylbutyl}amide morpholine-4-carboxylic acid

In a manner analogous to that described above in example 1, but using (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]-5-phenylpentane acid and (S)-2-amino-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)butane-1-ol was received{(S)-1-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-carbonyl)propellerblades]-3,3-debtor-4-phenylbutyl}amide morpholine-4-carboxylic acid.

1H-NMR (CDCl3): δ and 7.3 (m, 6H), 5.25 in (m, 1H), 5,08 (d, J=6,9 Hz, 1H), 4,7 (DD, J=12,8, 7,4 Hz, 1H), and 3.7 (m, 4H), 3,4 (m, 4H), 3,2 (t, J=16,8 Hz, 2H), 2,4-2,1 (m, 3H), of 2.05 (m, 1H), 1.8 m (m, 1H), 1,1 (m, 4H), of 0.95 (t, J=7.5 Hz, 3H).

LC/MS: 35% 560 (M+H2O+Na) and 65% 542 (M+Na).

EXAMPLE 5

{1-[1-(3-cyclopropyl[1,2,4]oxadiazol-5-carbonyl)propellerblades]-3,3-debtor-5-methylhexan}amide morpholine-4-carboxylic acid

In a manner analogous to that described above in example 1, but using (S)-4,4-debtor-6-methyl-2-[(morpholine-4-carbonyl)amino]heptane acid and (S)-2-amino-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)butane-1-ol floor is made {1-[1-(3-cyclopropyl[1,2,4]oxadiazol-5-carbonyl)propellerblades]-3,3-debtor-5-methylhexan}amide morpholine-4-carboxylic acid.

1H-NMR (CDCl3): δ and 7.6 (d, J=6,8 Hz, 1H), 5,2 (m, 2H), of 4.66 (DD, J=13, 7.2 Hz, 1H), and 3.7 (m, 4H), 3,4 (m, 4H), 2,3 (m, 2H), 2,2 (m, 1H), 2.05 is (m, 1H), 1,95 (m, 1H), 1.8 m (m, 3H), 1,1 (m, 4H), of 0.97 (d, J=6,6 Hz, 6H), is 0.96 (t, J=7.4 Hz, 3H).

LC/MS: 26%, 526 (M+H2O+Na) and 74%, 508 (M+Na).

EXAMPLE 6

{(S)-1-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-carbonyl)propellerblades]-3,3-deformaty}amide morpholine-4-carboxylic acid

In a manner analogous to that described above in example 1, but using (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]pentanol acid and (S)-2-amino-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)butane-1-ol was received{(S)-1-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-carbonyl)propellerblades]-3,3-deformaty}amide morpholine-4-carboxylic acid.

1H-NMR (CDCl3): δ 7,47 (d, J=6,8 Hz, 1H), 5,3 (m, 1H), 5,16 (d, J=6,9 Hz, 1H)and 4.65 (DD, J=13, 7,4 Hz, 1H), and 3.7 (m, 4H), 3,4 (m, 4H), 2,4 (m, 2H), 2,2 (m, 1H), 2.05 is (m, 1H), 1.8 m (m, 1H), 1,67 (t, J=18,7 Hz, 3H), 1,1 (m, 4H), of 0.97 (t, J=7.5 Hz, 3H).

LC/MS: 37% 484 (M+H2O+Na) and 63% 484 (M+CH3CN).

EXAMPLE 7

{(S)-3,3-debtor-1-[(S)-1-(3-phenyl-1,2,4-oxadiazol-5-carbonyl)propellerblades]butyl}amide morpholine-4-carboxylic acid

In a manner analogous to that described above in example 1, but using (S)-4,4-debtor-2-[(morpholine-4-arbonyl)amino]pentanol acid and (S)-2-amino-1-(3-phenyl-1,2,4-oxadiazol-5-yl)butane-1-ol was received {(S)-3,3-debtor-1-[(S)-1-(3-phenyl-1,2,4-oxadiazol-5-carbonyl)propellerblades]butyl}amide morpholine-4-carboxylic acidin the form of a light brown solid.

1H-NMR (CDCl3): δ 8,15 (DD, J=7,7, 1.5 Hz, 2H), to 7.61 (d, J=6,4 Hz, 1H), 7.5 (m, 3H), to 5.35 (m, 1H), and 5.2 (d, J=6,9 Hz, 1H), and 4.68 (DD, J=13,2, and 7.8 Hz, 1H), and 3.7 (m, 4H), 3,4 (m, 4H), 2,4 (m, 2H), 2,2 (m, 1H), of 1.95 (m, 1H), of 1.66 (t, J=18.7 Hz, 3H), of 1.03 (t, J=7.5 Hz, 3H).

LC/MS: 37% 520 (M+H2O+Na) and 63% 502 (M+Na).

EXAMPLE 8

{(S)-3,3-debtor-1-[(S)-1-(5-phenyl-1,2,4-oxadiazol-3-carbonyl)propellerblades]butyl}amide morpholine-4-carboxylic acid

In a manner analogous to that described above in example 1, but using (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]pentanol acid and (S)-2-amino-1-(5-phenyl[1,2,4]oxadiazol-3-yl)butane-1-ol was received{(S)-3,3-debtor-1-[(S)-1-(5-phenyl-1,2,4-oxadiazol-3-carbonyl)propellerblades]butyl}amide morpholine-4-carboxylic acid

1H-NMR (CDCl3): δ 8,2 (d, J=7,1 Hz, 2H), 7,65 (d, J=7,4 Hz, 1H), 7,55 (m, 3H), 5,4 (DD, J=12,2, 7 Hz, 1H), 5,3 (d, J=7,4 Hz, 1H), 4,7 (DD, J=13, 7,3 Hz, 1H), and 3.7 (m, 4H), 3,4 (m, 4H), 2,4 (m, 2H), 2,1 (m, 1H), and 1.9 (m, 1H), 1,67 (t, J=18.7 Hz, 3H), 1,0 (t, J=7.4 Hz, 3H).

LC/MS: 6% 520 (M+H2O+Na) and 94% 502 (M+Na).

EXAMPLE 9

{1-[1-(5-cyclopropyl[1,3,4]oxadiazol-2-carbonyl)propellerblades]-3,3-debtor-4-phenylbutyl}amide morpholine-4-carboxylic acid

In a manner analogous to that described above in the example is 1, but using (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]-5-phenylpentane acid and salts triperoxonane acid (S)-2-amino-1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)butane-1-ol was received{1-[1-(5-cyclopropyl[1,3,4]oxadiazol-2-carbonyl)propellerblades]-3,3-debtor-4-phenylbutyl}amide morpholine-4-carboxylic acid.

1H-NMR (CDCl3): δ and 7.3 (m, 6H), 5,27 (m, 1H), 5.0mm (d, J=7,0 Hz, 1H major), of 4.95 (d, J=7,3 Hz, 1H minor), 4,7 (m, 1H), and 3.7 (m, 4H), 3,4 (m, 4H), 3,2 (t, J=16,3 Hz, 2H), 2,4-2,2 (m, 3H), of 2.05 (m, 1H), 1.8 m (m, 1H), 1,2 (m, 4H), of 0.95 (t, J=7.5 Hz, 3H).

LC/MS: 12% 560 (M+H2O+Na) and 83% 542 (M+Na).

EXAMPLE 10

{3,3-debtor-1-[1-(5-isopropylthiazole-3-carbonyl)propellerblades]hexyl}amide morpholine-4-carboxylic acid

In a manner analogous to that described above in example 1, but using the hydrochloride of 2-amino-1-(5-isopropylthiazole-3-yl)butane-1-ol instead of hydrochloride of (S)-2-amino-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)butane-1-ol was received{3,3-debtor-1-[1-(5-isopropyl-isoxazol-3-carbonyl)propilkki]hexyl}amide morpholine-4-carboxylic acidin the form of a white solid.

1H-NMR (CDCl3): δ mixture of isomers of about 2:1 to 7.4 (width, 1H), 6,37 (s, 1H), 5,4 (m, 1H), 5,26 (d, J=6,9 Hz, 1H major), and 5.2 (d, J=7,2 Hz, 1H minor), 4,7 (m, 1H), and 3.7 (m, 4H), 3,4 (m, 4H), 3.15 in (m, 1H), 2,4 (m, 2H), 2,1 (m, 1H), 1.8 m (m, 4H), 1,5 (m, 1H), 1,35 (d, J=7,0 Hz, 6H), of 0.95 (m, 6H).

LC/MS: 100% 473 (M+1).

EXAMPLE 11

((S)-3,3-d is fluoro-1-{1-[5-(5-methylisoxazol-3-yl)oxazol-2-carbonyl]propellerblades}hexyl)amide morpholine-4-carboxylic acid

In a manner analogous to that described above in example 3, but using (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]heptane acid hydrochloride and (S)-2-amino-1-[5-(5-methylisoxazol-3-yl)oxazol-2-yl]butane-1-ol was received((S)-3,3-debtor-1-{1-[5-(5-methylisoxazol-3-yl)oxazol-2-carbonyl]propellerblades}hexyl)amide morpholine-4-carboxylic acidin the form of a white solid.

1H-NMR (CDCl3): δ for 7.78 (s, 1H), 7,40 (m, 1H), 6,44 (s, 1H), 5,48 (m, 1H), 5,22-5,10 (m, 1H), and 4.68 (m, 1H), and 3.72 (m, 4H), 3,40 (m, 4H), of 2.54 (s, 3H), 2,50-of 2.30 (m, 2H), 2,22-of 2.08 (m, 1H), 1,94-of 1.78 (m, 3H), 1.60-to of 1.46 (m, 2H), 1,08-0,94 (2×t, 6H).

LC/MS: 99%, 512 (M+1).

EXAMPLE 12

{(S)-3,3-debtor-1-[(S)-1-(oxazol-2-carbonyl)propellerblades]-4-phenylbutyl}amide morpholine-4-carboxylic acid

In a manner analogous to that described above in example 2, but using (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]-5-phenylpentane acid hydrochloride and (S)-2-amino-1-oxazol-2-ivatan-1-ol was received{(S)-3,3-debtor-1-[(S)-1-(oxazol-2-carbonyl)propellerblades]-4-phenylbutyl}amide morpholine-4-carboxylic acid.

1H-NMR (CDCl3): δ 7,86 (s, 1H), 7,37 (s, 1H), 7,30 (m, 5H), from 7.24 (m, 1H), the 5.45 (m, 1H), 5,08 (d, J=9 Hz, 1H), 4,70 (m, 1H), and 3.72 (m, 4H), to 3.38 (m, 4H), up 3.22 (t, J=17 Hz, 2H), 2,35 (m, 2H), 2,12 (m, 1H), of 1.85 (m, 1H), of 0.95 (t, J=9 Hz, 3H).

LC/MS: 97%, 479 (M+1).

EXAMPLE 13

{(S)-3,3-debtor-4-phenyl-1-[(S)-1-(5-thiophene-2-ylox the evils-2-carbonyl)propellerblades]butyl}amide morpholine-4-carboxylic acid

In a manner analogous to that described above in example 1, but using (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]-5-phenylpentane acid hydrochloride and (S)-2-amino-1-(5-thiophene-2-isoxazol-2-yl)butane-1-ol was received{(S)-3,3-debtor-4-phenyl-1-[(S)-1-(5-thiophene-2-isoxazol-2-carbonyl)propellerblades]butyl}amide morpholine-4-carboxylic acid.

1H-NMR (CDCl3): δ 7,53 (DD, J=3,6, 1 Hz, 1H), of 7.48 (DD, J=5, 1 Hz, 1H), and 7.4 (s, 1H), and 7.3 (m, 6H), to 7.15 (DD, J=5, 3.6 Hz, 1H), 5,4 (m, 1H), 5,15 (d, J=7,1 Hz, 1H), 4,7 (DD, J=13, 7,4 Hz, 1H), and 3.7 (m, 4H), 3,4 (m, 4H), 3,2 (t, J=16,7 Hz, 2H), 2,4 (m, 2H), 2,1 (m, 1H), 1.8 m (m, 1H), of 0.96 (t, J=7.5 Hz, 3H).

LC/MS: 100% 561 (M+1).

EXAMPLE 14

{(S)-1-[(S)-1-(benzoxazol-2-carbonyl)butylcarbamoyl]-3,3-debtor-4-phenylbutyl}amide morpholine-4-carboxylic acid

In a manner analogous to that described above in example 1, but using (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]-5-phenylpentane acid and (S)-2-amino-1-benzoxazol-2-alpental-1-ol was received{(S)-1-[(S)-1-(benzoxazol-2-carbonyl)butylcarbamoyl]-3,3-debtor-4-phenylbutyl}amide morpholine-4-carboxylic acid.

1H-NMR (CDCl3): δ 7,9 (d, J=8.0 Hz, 1H), 7,66 (d, J=8 Hz, 1H), 7,56 (t, J=7.2 Hz, 1H), 7,47 (t, J=8 Hz, 1H), 7,2 (m, 6H), 5,6 (m, 1H), of 5.05 (d, J=7 Hz, 1H), 4,71 (DD, J=12,8, 7,4 Hz, 1H), and 3.7 (m, 4H), to 3.35 (m, 4H), 3,18 (t, J=16,8 Hz, 2H), 2,3 (m, 2H), 2,1 (m, 1H), 1.8 m (m, 1H), 1,4 (m, 2H), were 0.94 (t, J=7,3 Hz, 3H).

LC/MS: 100% 543 (M+1).

EXAMPLE 15

[1-(2-benzoxazol-2-yl-1-methoxymethyl-2-oxoethylidene)-3,3-debtor-4-phenylbutyl]amide morpholine-4-carboxylic acid

In a manner analogous to that described above in example 1, but using (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]-5-phenylpentane acid and (S)-2-amino-1-benzoxazol-2-yl-3-methoxypropan-1-ol was received[1-(2-benzoxazol-2-yl-1-methoxymethyl-2-oxoethylidene)-3,3-debtor-4-phenylbutyl]amide morpholine-4-carboxylic acid.

1H-NMR (CDCl3): δ 7,9 (d, J=7.7 Hz, 1H), to 7.67 (d, J=8 Hz, 1H), 7,56 (t, J=8 Hz, 1H), of 7.48 (t, J=8 Hz, 1H), 7,2 (m, 6H), 5,7 (m, 1H), 5,1 (d, J=7 Hz, 1H major), of 5.05 (d, J=7,3 Hz, 1H minor), and 4.8 (m, 1H), 4.26 deaths (DD, J=9,7, 3.5 Hz, 1H), and 3.8 (m, 1H), and 3.7 (m, 4H), to 3.35 (m, 4H), of 3.27 (s, 3H), up 3.22 (t, J=16.2 Hz, 2H), 2,4 (m, 2H).

LC/MS: 94% 545 (M+1).

EXAMPLE 16

{(S)-1-[(S)-1-(benzoxazol-2-carbonyl)-1-methylbutanoyl]-3,3-debtor-4-phenylbutyl}amide morpholine-4-carboxylic acid

A mixture of the hydrochloride of (S)-2-amino-1-benzoxazol-2-yl-2-methylpentan-1-it (80,6 mg, 0.3 mmol), (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]-5-phenylpentane acid (is 0.102 mg, 0.3 mmol), EDCI (69 mg, 0.36 mmol), HOBT (48.6 mg, 0.36 mmol) and diisopropylethylamine (0.2 ml) in DMF was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with cold 1 N. HCl, saturated NaHCO3and then saturated NaCl. The organic phase was dried over magnesium sulfate, and the solvent evaporated under reduced pressure to get crude product. After purification column chromatography on silica gel with elution with a mixture of ethyl acetate and heptane received{(S)-1-[(S)-1-(benzoxazol-2-carbonyl)-1-methylbutanoyl]-3,3-debtor-4-phenylbutyl}amide morpholine-4-carboxylic acid(82%).

1H-NMR (CDCl3): δ 7,8 (d, J=7, 8.0 Hz, 1H), to 7.64 (d, J=7.8 Hz, 1H), 7,53 (dt, J=7,2, 1.2 Hz, 1H), 7,43 (dt, J=8, 1.2 Hz, 1H), 7,2 (m, 6H), 4,9 (d, J=7,3 Hz, 1H)and 4.65 (m, 1H), and 3.7 (m, 4H), 3,3 (m, 4H), 3,1 (t, J=16,8 Hz, 2H), 2,2 (m, 3H), 2,1 (m, 1H), 1,74 (s, 3H), 1,25 (m, 2H), and 0.9 (t, J=7,3 Hz, 3H).

LC/MS: 100% 557 (M+1).

EXAMPLE 17

[(S)-1-((S)-1-cyano-3-phenylpropionyl)-3,3-debtor-4-phenylbutyl]amide morpholine-4-carboxylic acid

In accordance with a method similar to the method of combination of PyBOP described in example 1, but using (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]-5-phenylpentane acid andhydrochloride (S)-2-amino-4-phenylbutyramide received [(S)-1-((S)-1-cyano-3-phenylpropionyl)-3,3-debtor-4-phenylbutyl]amide morpholine-4-carboxylic acid.

1H-NMR (CDCl3): δ 7,9 (d, J=7,6 Hz, 1H), 7,2 (m, 10H), 5,1 (d, J=7,3 Hz, 1H), 4,6 (m, 2H), 3,6 (m, 4H), 3,3 (m, 4H), 3,2 (t, J=16.5 Hz, 2H), 2,74 (t, J=7.2 Hz, 2H), 2,3 (m, 2H), 2,1 (m, 2H).

LC/MS: 100% 485 (M+1).

EXAMPLE 18

[(S)-1-(cyanomethylene)-3,3-debtor-4-phenylbutyl]amemorial-4-carboxylic acid

In accordance with a method similar to the method of combination of PyBOP described in example 1, but using (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]-5-phenylpentane acid and hydrochloride aminoacetonitrile received[(S)-1-(cyanomethylene)-3,3-debtor-4-phenylbutyl]amide morpholine-4-carboxylic acid.

1H-NMR (CDCl3): δ 7,95 (width, 1H), and 7.3 (m, 5H), 5.25-inch (d, J=7,0 Hz, 1H), 4,7 (DD, J=12,7, 7.2 Hz, 1H), 4,1 (m, 2H), and 3.7 (m, 4H), to 3.35 (m, 4H), 3,2 (t, J=16,3 Hz, 2H), 2,4 (m, 2H).

LC/MS: 83% 403 (M+Na).

EXAMPLE 19

[(S)-3,3-debtor-1-((S)-1-formyl-1-methylbutanoyl)-4-phenylbutyl]amide morpholine-4-carboxylic acid

A mixture of the hydrochloride of (S)-2-amino-2-methylpentan-1-ol (104,4 mg, 0.67 mmol), (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]-5-phenylpentane acid (231 mg, 0.67 mmol), EDCI (154 mg, 0.8 mmol), HOBT (108 mg, 0.8 mmol) and diisopropylethylamine (0,23 ml) in DMF (2 ml) was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with cold 1 N. HCl, saturated NaHCO3and then a saturated solution of NaCl. The organic phase was dried over MgSO4and the solvent evaporated under reduced pressure to get crude product. After purification through column chromatography with silica gel and elution with a mixture of ethyl acetate and heptane received[(S)-3,3-debtor-1-((S)-1-HYDR shall kemetyl-1-methylbutanoyl)-4-phenylbutyl]amide morpholine-4-carboxylic acid (223 mg, 75%).

The mixture of[(S)-3,3-debtor-1-((S)-1-hydroxymethyl-1-methylbutanoyl)-4-phenylbutyl]amide morpholine-4-carboxylic acid(217 mg) and periodinane dess-Martin (15% in DHM, 2 EQ.) in DHM (5 ml) was stirred at room temperature for 3 hours, and the reaction was suppressed by a solution of sodium thiosulfate in saturated NaHCO3. The product was extracted with ethyl acetate and washed with saturated solution of NaCl. The organic phase was dried over anhydrous MgSO4the solvent is evaporated under reduced pressure. After purification through column chromatography with silica gel and elution with a mixture of ethyl acetate and heptane received[(S)-3,3-debtor-1-((S)-1-formyl-1-methylbutanoyl)-4-phenylbutyl]amide morpholine-4-carboxylic acid(83 mg, 38%).

1H-NMR (CDCl3): δ and 9.3 (s, 1H), 7,2 (m, 5H), 7,0 (s, 1H), 5.0mm (d, J=7 Hz, 1H), with 4.64 (DD, J=13, 7,3 Hz, 1H), and 3.7 (m, 4H), 3,4 (m, 4H), 3,2 (t, J=16.5 Hz, 2H), 2,3 (m, 2H), and 1.9 (m, 1H), 1,65 (m, 1H), of 1.35 (s, 3H), 1,2 (m, 2H), and 0.9 (t, J=7,3 Hz, 3H).

LC/MS: 100% 440 (M+1)

EXAMPLE 20

{(S)-1-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-carbonyl)propellerblades]-3,3-deformaty}amide of perhydro-1,4-oxazepine-4-carboxylic acid

To a mixture of (S)-4,4-debtor-2-[(perhydro-1,4-oxazepine-4-carbonyl)amino]pentanol acid (97 mg, 0.35 mmol), hydrochloride (S)-2-amino-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)butane-1-ol (83 mg, 0.36 mmol) and diisopropylethylamine (121 μl, 0.70 mm is l) in dry dichloromethane (12 ml) were added hydrochloride 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (66 mg, 0.35 mmol) and the hydrate of 1-hydroxybenzotriazole (47 mg, 0.35 mmol). The mixture was stirred at room temperature for 16 hours, then was diluted with dichloromethane (20 ml) and washed with dilute HCl (30 ml)and then saturated NaHCO3(30 ml). The organic layer was dried (Na2SO4) and concentrated in vacuum. The residue was purified on 12 g of silica gel, elwira a mixture of ethyl acetate:heptane (gradient 50-100%), and received((S)-1-{(S)-1-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)hydroxymethyl]propellerblades}-3,3-deformaty)amide, perhydro-1,4-oxazepine-4-carboxylic acid(120 mg, 75%) as a colourless glassy solid.

LC/MS 100% 460 (M+H).

To a solution of ((S)-1-{(S)-1-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)hydroxymethyl]propellerblades}-3,3-deformaty)amide, perhydro-1,4-oxazepine-4-carboxylic acid (110 mg, 0.24 mmol) in dry dichloromethane (20 ml) in an atmosphere of N2added periodinane dess-Martin (143 mg, 0.34 mmol). The reaction mixture was stirred at room temperature for 2 hours, and then was added dichloromethane (20 ml). The reaction was suppressed by a solution of Na2S2O3(0,26 M, 2 ml) and the reaction mixture was washed with saturated NaHCO3(20 ml). The aqueous layer was extracted with dichloromethane (2×30 ml). The organic layers were dried (Na2SO4) and concentrated in vacuum. The residue was purified on 12 g of silica gel, elwira a mixture of ethyl acetate:hepta the (gradient 50-100%) and received {(S)-1-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-carbonyl)propellerblades]-3,3-deformaty}amide of perhydro-1,4-oxazepine-4-carboxylic acid(82 mg, 75%) as a white solid.

1H-NMR (CDCl3) δ 7,52 (d, 6,2H), 5,28 (m, 1H), of 5.05 (d, J=7 Hz, 1H), of 4.66 (m, 1H), 3,78 (m, 4H)and 3.59 (m, 4H), 2,42 (m, 2H), 2,23 (m, 1H), 2,07 (m, 1H), up to 1.98 (m, 1H), of 1.85 (m, 1H), 1.69 in (t, J=18,8 Hz, 3H)and 1.15 (m, 4H), and 0.98 (t, J=7.5 Hz, 3H).

LC/MS: 97% 458 (M+H).

EXAMPLE 21

{(S)-1-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-carbonyl)propellerblades]-3,3-divergence}amide of perhydro-1,4-oxazepine-4-carboxylic acid

In a manner analogous to that described above in example 20, but using (S)-4,4-debtor-2-[(perhydro-1,4-oxazepine-4-carbonyl)amino]heptane acid hydrochloride and (S)-2-amino-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)butane-1-ol was received{(S)-1-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-carbonyl)propellerblades]-3,3-divergence}amide of perhydro-1,4-oxazepine-4-carboxylic acid(98 mg, 65%) as a white solid.

1H-NMR (CDCl3): δ and 7.6 (d, J=7.5 Hz, 1H), 5.25 in (m, 1H), 5,10 (d, J=7.5 Hz, 1H)and 4.65 (DD, J=14, J=7.5 Hz, 1H, in), 3.75 (m, 6H), 3,55 (m, 4H), 2,4 (m, 2H), 2,2 (m, 2H), 1,95 (m, 1H), 1.8 m (m, 3H), of 1.55 (m, 2H,), 1,10 (m, 4H), of 0.95 (t, J=7.5 Hz, 6H).

LC/MS: 70% 486 (M+1) and 30% 504 (M+1+H2O).

EXAMPLE 22

{(S)-1-[(S)-1-(3-isopropyl-1,2,4-oxadiazol-5-carbonyl)propellerblades]-3,3-divergence}amide morpholine-4-carboxylic acid

In a manner analogous to that described above in example 20, but using(S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]heptane acidand (S)-2-amino-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)butane-1-ol was received{(S)-1-[(S)-1-(3-isopropyl-1,2,4-oxadiazol-5-carbonyl)propellerblades]-3,3-divergence}amide morpholine-4-carboxylic acid(122 mg, 71%) as a white solid.

1H-NMR (CDCl3): δ 7.5 (d, J=7,0 Hz, 1H), 5,3 (m, 1H), 5.25-inch (d, J=7,0 Hz, 1H)and 4.65 (DD, J=13, 7,0 Hz, 1H), and 3.7 (m, 4H), 3,4 (m, 4H), 3,2 (m, 1H), 2,35 (m, 2H), 2,1 (m, 1H), 1.8 m (m, 3H), of 1.55 (m, 2H), of 1.40 (d, J=7 Hz, 6H), and 0.9 (t, J=7.0 Hz, 6H).

LC/MS: 72% 474 (M+1) and 28% 492 (M+1+H2O).

EXAMPLE 23

{(S)-1-[(S)-1-(5-tert-butyl-1,2,4-oxadiazol-3-carbonyl)propellerblades]-3,3-divergence}amide morpholine-4-carboxylic acid

A solution of (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]heptane acid (175 mg, of 0.60 mmol) in dimethylformamide (6 ml) was sequentially treated with (S)-2-amino-1-(5-tert-butyl-1,2,4-oxadiazol-3-yl)butane-1-I (240 mg, 1.13 mmol), hexaflurophosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (226 mg, 0.59 mmol) and diisopropylethylamine (0.104 g ml of 0.60 mmol). The reaction mixture was stirred at room temperature overnight. The solvent is evaporated under high vacuum. The residue was dissolved in ethyl acetate and washed with 1 N. hydrochloric acid, saturated podnimetsia bicarbonate and water, dried over Na2SO4and the solvent evaporated under reduced pressure. The crude product was purified flash chromatography on silica (column, 10 g), elwira a mixture of ethyl acetate and heptane (2:1), and received((S)-1-{(S)-1-[(5-tert-butyl-1,2,4-oxadiazol-3-yl)hydroxymethyl]propellerblades}-3,3-divergence)amide morpholine-4-carboxylic acidin the form of a brown oil (60 mg).

MS: 490 (M+H).

A solution of ((S)-1-{(S)-1-[(5-tert-butyl-1,2,4-oxadiazol-3-yl)hydroxymethyl]propellerblades}-3,3-divergence)amide morpholine-4-carboxylic acid (57 mg, 0,117 mmol) in methylene chloride (3 ml) was treated with periodinane dess-Martin (59 mg, 0,139 mmol) and stirred at room temperature for 90 minutes. The reaction mixture was washed with a solution of Na2S2O3in water (0,26 M), saturated aqueous bicarbonate and water, dried over Na2SO4and the solvent evaporated under reduced pressure. The residue was purified flash chromatography, elwira a mixture of ethyl acetate and heptane (1:1), and received {(S)-1-[(S)-1-(5-tert-butyl-1,2,4-oxadiazol-3-carbonyl)propellerblades]-3,3-divergence}amide morpholine-4-carboxylic acid in the form of not-quite-white solid (41 mg).

MS: 488 (M+H).

EXAMPLE 24

{(S)-1-[1-(5-tert-butyl-1,2,4-oxadiazol-3-carbonyl)propellerblades]-3,3-debtor-4-phenylbutyl}amide morpholine-4-carboxylic acid

In a manner analogous to that described above in example 23, but using (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]-5-phenylpentane acid and (S)-2-amino-1-(5-tert-butyl-1,2,4-oxadiazol-3-yl)butane-1-ol was received{(S)-1-[1-(5-tert-butyl-1,2,4-oxadiazol-3-carbonyl)propellerblades]-3,3-debtor-4-phenylbutyl}amide morpholine-4-carboxylic acidin a mixture of 7:3 diastereoisomers.

1H-NMR (CDCl3): δ of 7.36-7,19 (m, 5H), to 7.15 (d, J=7,1 Hz, 1H), 5,31 (m, 1H), 5.03 and 4,96 (2×d, J=7 Hz, 1H), and 4.68 (m, 1H), 3,76-3,59 (m, 4H), 3,45-3,26 (m, 4H), 3,18 (t, J=16,8 Hz, 2H), 2,52-to 2.18 (m, 2H), 2,17-was 1.94 (m, 1H), 1,88 is 1.70 (m, 1H), 1,47 (s, 9H), of 0.93 (t, J=7.4 Hz, 3H).

MS: 536 (M+H).

EXAMPLE 25

((S)-3,3-debtor-1-{(S)-1-[5-(4-propenyl)-1,2,4-oxadiazol-3-carbonyl]propellerblades}butyl)amide morpholine-4-carboxylic acid

In a manner analogous to that described above in example 23, but using (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]pentanol acid and (S)-2-amino-1-[5-(4-forfinal)-1,2,4-oxadiazol-3-yl]butane-1-ol was received((S)-3,3-debtor-1-{(S)-1-[5-(4-forfinal)-1,2,4-oxadiazol-3-carbonyl]propellerblades}butyl)amide morpholine-4-carboxylic acid

1H-NMR (CDCl3): δ 8,21 (m, 2H), 7,31 (d, J=6,8 Hz, 1H), 7,30-7,20 (m, 2H), 5,38 (m, 1H), 5,07 (d, J=6,8 Hz, 1H), 4,63 (m, 1H), 3.75 to to 3.64 (m, 4H), 3,44-to 3.33 (m, 4H), 2,58-of 2.28 (m, 2H), 2,22-2,04 (m, 1H), 1,96-1,79 (m, 1H), of 1.66 (t, J=18,8 Hz, 3H), of 0.97 (t, J=7.4 Hz, 3H).

MS: 498 (M+H).

EXAMPLE 26

{(S)-1-[1-(5-cyclopropyl-1,2,4-xavator-3-carbonyl)propellerblades]-3,3-debtor-4-phenylbutyl}amide morpholine-4-carboxylic acid

In a manner analogous to that described above in example 23, but using (S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]-5-phenylpentane acid and (S)-2-amino-1-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)butane-1-ol was obtained {(S)-1-[1-(5-cyclopropyl-1,2,4-oxadiazol-3-carbonyl)propellerblades]-3,3-debtor-4-phenylbutyl}amide morpholine-4-carboxylic acid in the form of a mixture of diastereoisomers 3:1.

1H-NMR (CDCl3): δ of 7.36-7,20 (m, 5H), 7,14 (d, J=7,1 Hz, 1H), 5,26 (m, 1H), 5.02 and 4,96 (2×d, J=7 Hz, 1H), 4,70 (m, 1H), of 3.73-3,61 (m, 4H), 3.43 points of 3.28 (m, 4H), 3,18 (t, J=16.5 Hz, 2H), 2,48-of 2.21 (m, 3H), 2,14-to 1.98 (m, 1H), 1.85 to to 1.70 (m, 1H), 1,38-to 1.21 (m, 4H), of 0.91 (t, J=7.5 Hz, 3H).

MS: 520 (M+H).

EXAMPLE 27

{(S)-1-[1-(5-cyclopropyl-1,2,4-oxadiazol-3-carbonyl)propellerblades]-3,3-divergence}amide of perhydro-1,4-oxazepine-4-carboxylic acid

In a manner analogous to that described above in example 23, but using (S)-4,4-debtor-2-[(perhydro-1,4-oxazepine-4-carbonyl)amino]heptane acid and (S)-2-amino-1-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)butane-1-ol was received{(S)-1-[1-(5-cyclopropyl-1,2,4-oxadiazol-3-carbonyl)propellerblades]-3,3-divergence}amide of perhydro-1,4-oxazepine-4-carboxylic acidin the form of a mixture of diastereoisomers 5:1.

1H-NMR (CDCl3): δ 7,44 and 7,39 (2×d, J=7,3 Hz, 1H), and 5.30 (m, 1H), of 5.05 and to 4.98 (2×d, J=6,5 Hz, 1H), 4,63 (m, 1H), 3,79-to 3.73 (m, 4H), 3,59-of 3.53 (m, 4H), 2,47-of 2.23 (m, 3H), 2,15 to 1.76 (m, 6H), 157-1,43 (m, 2H), 1,38-of 1.26 (m, 4H), of 0.95 (t, J=7,3 Hz, 3H), of 0.93 (t, J=7.2 Hz, 3H).

MS: 486 (M+H).

EXAMPLE 28

[(S)-1-(cyanomethylene)-3,3-divergence]amide of perhydro-1,4-oxazepine-4-carboxylic acid

The suspension associated with the polystyrene carbodiimide (570 mg, 0.73 mmol) and (S)-4,4-debtor-2-[(perhydro-1,4-oxazepine-4-carbonyl)amino]heptane acid (135 mg) in DHM (10 ml) was stirred for 10 minutes. Then was added HOBT (60 mg)and the mixture was stirred for another 10 minutes. After this was added a suspension of the hydrochloride aminoacetonitrile (34 mg) and triethylamine (52 μl) in DHM (5 ml)and the mixture was stirred over night at room temperature. Then added trisamine polystyrene (493 mg)and the mixture was stirred at room temperature for 2 hours and 30 minutes. After filtration, the filtrate was diluted DHM, washed with water, evaporated under reduced pressure and was purified column chromatography, elwira a mixture of ethyl acetate and heptane, resulting in the received[(S)-1-(cyanomethylene)-3,3-divergence]amide of perhydro-1,4-oxazepine-4-carboxylic acidin the form of a white solid.

LC/MS: 100% 347 (M+H)

EXAMPLE 29

[(S)-1-((S)-1-cyanopropionic)-3,3-divergence]amide of perhydro-1,4-oxazepine-4-carboxylic acid

In a manner analogous to that described above in example 28, but using EQ is whether the 4,4-debtor-2-[([1,4]oxazepan-4-carbonyl)amino]heptane acid hydrochloride and (S)-2-aminomalononitrile received [(S)-1-((S)-1-cyanopropionic)-3,3-divergence]amide of perhydro-1,4-oxazepine-4-carboxylic acid.

LC/MS: 100% 375 (M+H).

EXAMPLE 30

[(S)-1-(1-cyanocyclohexane)-3,3-divergence]amide morpholine-4-carboxylic acid

The specified connection was obtained in the reaction(S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]heptane acidand hydrochloride of 1-aminocyclopropane using TOTU as a reagent combination and diisopropylethylamine as a base.

LC/MS: 359 (M+H)

EXAMPLE 31

Analysis of cathepsin S

Solutions of test compounds in varying concentrations were obtained in 10 μl of dimethyl sulfoxide (DMSO)and then diluted analytical buffer (40 μl, comprising: MES, 50 mm (pH 6.5); EDTA, 2.5 mm; and NaCl, 100 mm, 0.5 mm DTT, 0.01% of Triton X-100).

To the diluted solutions were added to human cathepsin S (final concentration in well 1,74 nm). Solutions for analysis was stirred for 5-10 seconds on a plate shaker, covered, and incubated for 30 minutes at room temperature. The analytical solutions were added Z-Val-Val-Arg-AMC (final concentration in well 0.08 mm) and the hydrolysis was monitored by spectrophotometry (at λ 460 nm) for 5 minutes. Apparent inhibition constants (Ki) was calculated on the basis of the curves is modify the concentration of the enzyme, built using standard mathematical models.

EXAMPLE 32

Analysis of cathepsin B

Solutions of test compounds in varying concentrations were obtained in 10 μl of dimethyl sulfoxide (DMSO)and then diluted analytical buffer (containing: 50 mm MES (pH 6); 2.5 mm EDTA, 2% DMSO and dithiothreitol (DTT), 2.5 mm).

To the diluted solutions were added to human cathepsin B (final concentration of 0.3 ng/µl). Analytical solutions were stirred for 5-10 seconds on a plate shaker, covered, and incubated for 30 minutes at room temperature. The analytical solutions were added Z-FR-pNa (final concentration 100 μm) and the hydrolysis was monitored by spectrophotometry (at λ 405 nm) for 60 minutes. Apparent inhibition constants (Ki) was calculated based on the curves of changes in the concentration of the enzyme, built using standard mathematical models.

EXAMPLE 33

Analysis of cathepsin K

Solutions of test compounds in varying concentrations were obtained in 10 μl of dimethyl sulfoxide (DMSO)and then diluted analytical buffer (40 μl, comprising: MES, 50 mm (pH 5.5); EDTA, 2.5 mm; and DTT, 0.5 mm).

To the diluted solutions were added to human cathepsin K (0,0906 pmol 25 ál analytical buffer). Analytical solutions were stirred for 5-10 seconds on PLA is Satnam shaker, covered and incubated for 30 minutes at room temperature. The analytical solutions were added Z-Phe-Arg-AMC (4 nmol in 25 ál analytical buffer) and hydrolysis was monitored by spectrophotometry (at λ 460 nm) for 5 minutes. Apparent inhibition constants (Ki) was calculated from the curves of changes in the concentration of the enzyme using standard mathematical models.

EXAMPLE 34

Analysis of cathepsin L

Solutions of test compounds in varying concentrations were obtained in 10 μl of dimethyl sulfoxide (DMSO)and then diluted analytical buffer (40 μl, comprising: MES, 50 mm (pH 6,0); EDTA, 2.5 mm; and DTT, 2.5 mm).

To the diluted solutions were added to human cathepsin L (10 ál 0.2 ng/ál, final concentration of 0.02 ng/ál). Analytical solutions were stirred for 5-10 seconds on a plate shaker, covered, and incubated for 30 minutes at room temperature. The analytical solutions were added Z-Phe-Arg-AMC (10 μl of 0.1 mm, final concentration 10 μm) and hydrolysis was monitored by spectrophotometry (at λ 460 nm) for 30 minutes. Apparent inhibition constants (Ki) was calculated from the curves of changes in the concentration of the enzyme using standard mathematical models.

Compounds according to the invention was tested in accordance with the above EN what lizama for inhibition of the protease, and these analyses indicated on the selective inhibition of cathepsin S. the Apparent inhibition constants (Kifor compounds according to the invention, inhibiting cathepsin S was in the range of about 10-10M to 10-7M.

EXAMPLE 35

Representative pharmaceutical compositions containing a compound of the formula (I):

COMPOSITION FOR ORAL administration
The compound of the formula I10-100 mg
Citric acid monohydrate105 mg
Sodium hydroxide18 mg
Perfume
Watera sufficient amount of to 100 ml

COMPOSITION FOR INTRAVENOUS INJECTION
The compound of the formula I0,1-10 mg
Dextrose monohydrateenough to give isotonicity
Citric acid monohydrate1,05 mg
Sodium hydroxide0.18 mg
Water for injectionssufficient to 1.0 ml

COM IS AZIZIA IN TABLET FORM
The compound of the formula I1%
Microcrystalline cellulose73%
Stearic acid25%
Colloidal silicon dioxide1%

Although in the present application is described and demonstrated new fundamental features of the invention are used in preferred embodiments of the invention, however, it should be noted that the present invention can be made of different abbreviations, substitutions and changes relating to the form, to the specific compositions and methods that are not beyond the merits of the invention. For example, it is obvious that replacement of chemical radicals and/or replacement of the stages of the methods, which are, essentially, the same procedure is carried out essentially in the same way with similar results, and these modifications are also included in the scope of the present invention.

The present invention is not limited to the above variants of its implementation, which are given here only as examples and can be modified in various ways without going beyond the scope of the invention protected by the attached claims.

1. The compound having the structure the PN formula (I)

where a represents

X1represents methylene;

X2represents CN, CHO, C(O)R6;

X6represents a bond;

R1is an R13C(O)-;

R2represents hydrogen;

R3selected from the group consisting of H, phenyl-(C0-6)alkyl, (C1-6)alkyl, optionally substituted by a group-X6OR9;

R4represents H or (C1-6)alkyl; or R3and R4together with the carbon atom, which is associated with R3and R4form (C3-8)cycloalkyl;

R5is a (C1-9)alkyl, benzyl;

R6represents a 5-membered heteroaryl with 2 or 3 heteroatoms, represents N, O, where R6may be optionally substituted by a radical independently selected from the group consisting of (C1-9)alkyl, (C3-7)cycloalkyl, phenyl, optionally substituted halogen-substituted (C1-6)alkoxyl or halogen, 5-membered heteroaryl with 1 or 2 heteroatoms selected from N, O, S, optionally substituted (C1-6)alkyl; or a bicyclic 9-membered heteroaryl 2 heteroatoms, represents N, O;

R9pre is is a (C 1-6)alkyl;

R13is a 6-7 membered heterocyclyl 2 heteroatoms, represents N, O,

and its related isomers and mixtures of isomers; as well as pharmaceutically acceptable salts.

2. The compound according to claim 1, where R3represents H, phenyl(C2-6)alkyl or (C1-6)alkyl, which is optionally substituted by-X6OR9where X6represents a bond, a R9is a (C1-6)alkyl.

3. The compound according to claim 1 or 2, in which R4represents H or (C1-6)alkyl.

4. The compound of formula (Ia)

where R1, R3, R4and R5defined above,

and its related isomers and mixtures of isomers; as well as pharmaceutically acceptable salts.

5. The compound of formula (Ib)

where R1, R3, R4and R5defined above,

and its related isomers and mixtures of isomers; as well as pharmaceutically acceptable salts.

6. The compound of formula (Ic)

where R1, R3, R4, R5and R6defined above,

and its related isomers and mixtures of isomers; as well as pharmaceutically acceptable salts.

7. The compound according to claim 4, in which R1pre is is a R 13C(O)-, where R13is a 6-7 membered heterocyclyl 2 heteroatoms, represents N, O.

8. The connection according to claim 7, in which R1represents.

9. The compound according to claim 4, in which R3represents H, phenyl(C1-6)alkyl or (C1-6)alkyl.

10. The connection according to claim 9, in which R3represents H,or CH3CH2CH2-.

11. The connection according to claim 6, in which R3is a (C1-6)alkyl, which is optionally substituted by-X6OR9where X6represents a bond, a R9is a (C1-6)alkyl.

12. Connection by claim 11, in which R3represents CH3-CH2-, CH3-CH2-CH2or CH3-O-CH2-.

13. The compound according to claim 4, in which R4represents H or methyl.

14. The compound according to claim 4, in which R5represents benzyl.

15. The connection according to claim 6, in which R5is a (C1-9)alkyl or benzyl.

16. The connection indicated in paragraph 15, in which R5represents CH3CH2CH2CH3CH2CH3or.

17. The connection according to claim 6, in which R6represents a 5-membered heteroaryl with 2 or 3 heteroatoms, representing the Wallpaper N, Oh, optionally substituted (C1-9)alkyl, (C3-7)cycloalkyl, phenyl, optionally substituted halogen-substituted (C1-6)alkoxyl or halogen, or a 5-membered heteroaryl with 1 or 2 heteroatoms selected from N, O, S.

18. The connection 17 in which R6represents oxadiazolyl, isoxazolyl or oxazolyl, each of which may be substituted by one or more phenyl or alkyl groups.

19. The connection 17 in which R6represents 5-tert-butyl[1,2,4]oxadiazol-3-yl, 3-cyclopropyl-1,2,4-oxadiazol-5-yl, 5-cyclopropyl-1,2,4-oxadiazol-3-yl, 5-cyclopropyl-1,3,4-oxadiazol-2-yl, 5-ethyl-1,3,4-oxadiazol-2-yl, 5-(4-forfinal)-1,2,4-oxadiazol-3-yl, 5-isopropylthiazole-3-yl, 5-(5-methylisoxazol-3-yl)oxazol-2-yl, 5-(5-methyltin-2-yl)oxazol-2-yl, oxazol-2-yl, 3-phenyl-1,2,4-oxadiazol-5-yl, 5-phenyl-1,2,4-oxadiazol-3-yl, 5-thiophene-2-isoxazol-2-yl or 5-(4-trifloromethyl)-1,3,4-oxadiazol-2-yl.

20. The connection according to claim 19, in which R6is a 3-cyclopropyl-1,2,4-oxadiazol - 5-yl, oxazol-2-yl or 5-cyclopropyl-1,2,4-oxadiazol-3-yl.

21. The compound according to claim 1, selected from the group consisting of

{(S)-1-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-carbonyl)propellerblades]-3,3-divergence}amide morpholine-4-carboxylic acid,

{(S)-1-[(S)-1-(5-cyclopropyl-1,3,4-oxadiazol-2-carbonyl)propellerblade is]-3,3-divergence}amide morpholine-4-carboxylic acid,

((S)-3,3-debtor-1-{(S)-1-[5-(4-trifloromethyl)-1,3,4-oxadiazol-2-carbonyl]propellerblades}hexyl)amide morpholine-4-carboxylic acid,

{(S)-1-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-carbonyl)propellerblades]-3,3-debtor-4-phenylbutyl}amide morpholine-4-carboxylic acid,

{1-[1-(3-cyclopropyl[1,2,4]oxadiazol-5-carbonyl)propellerblades]-3,3-debtor-5-methylhexan}amide morpholine-4-carboxylic acid,

{(S)-1-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-carbonyl)propellerblades]-3,3-deformaty}amide morpholine-4-carboxylic acid,

{(S)-3,3-debtor-1-[(S)-1-(3-phenyl-1,2,4-oxadiazol-5-carbonyl)propellerblades]butyl}amide morpholine-4-carboxylic acid,

{(S)-3,3-debtor-1-[(S)-1-(5-phenyl-1,2,4-oxadiazol-3-carbonyl)propellerblades]butyl}amide morpholine-4-carboxylic acid,

{1-[1-(5-cyclopropyl[1,3,4]oxadiazol-2-carbonyl)propellerblades]-3,3-debtor-4-phenylbutyl}amide morpholine-4-carboxylic acid,

{3,3-debtor-1-[1-(5-isopropylthiazole-3-carbonyl)propellerblades]hexyl}amide morpholine-4-carboxylic acid,

((S)-3,3-debtor-1-{1-[5-(5-methylisoxazol-3-yl)oxazol-2-carbonyl]propellerblades}hexyl)amide morpholine-4-carboxylic acid,

{(S)-3,3-debtor-1-[(S)-1-(oxazol-2-carbonyl)propellerblades]-4-phenylbutyl}amide morpholine-4-carboxylic acid,

{(S)-3,3-debtor-4-phenyl-1-[(S)-1-(5-thiophene-2-isoxazol-2-carbonyl)propilkki the oil]butyl}amide morpholine-4-carboxylic acid,

{(S)-1-[(S)-1-(benzoxazol-2-carbonyl)butylcarbamoyl]-3,3-debtor-4-phenylbutyl}amide morpholine-4-carboxylic acid,

[1-(2-benzoxazol-2-yl-1-methoxymethyl-2-oxoethylidene)-3,3-debtor-4-phenylbutyl]amide morpholine-4-carboxylic acid,

{(S)-1-[(S)-1-(benzoxazol-2-carbonyl)-1-methylbutanoyl]-3,3-debtor-4-phenylbutyl}amide morpholine-4-carboxylic acid,

[(S)-1-((S)-1-cyano-3-phenylpropionyl)-3,3-debtor-4-phenylbutyl]amide morpholine-4-carboxylic acid,

[(S)-1-(cyanomethylene)-3,3-debtor-4-phenylbutyl]amide morpholine-4-carboxylic acid,

[(S)-3,3-debtor-1-((S)-1-formyl-1-methylbutanoyl)-4-phenylbutyl]amide morpholine-4-carboxylic acid,

{(S)-1-[1-(5-ethyl[1,3,4]oxadiazol-2-carbonyl)propellerblades]-3,3-debtor-4-phenylbutyl}amide morpholine-4-carboxylic acid,

{(S)-1-[1-(5-tert-butyl[1,2,4]oxadiazol-3-carbonyl)propellerblades]-3,3-debtor-4-phenylbutyl}amide morpholine-4-carboxylic acid,

{(S)-3,3-debtor-4-phenyl-1-[(S)-1-(5-phenyl[1,2,4]oxadiazol-3-yl)propellerblades]butyl} amide morpholine-4-carboxylic acid,

complex benzyl ester [(S)-1-(cyanomethylene)-3,3-debtor-4-phenylbutyl]carbamino acid,

cyanomethylene (S)-4,4-debtor-5-phenyl-2-(tetrahydropyran-4-ylamino)pentanol acid,

cyanomethylene (S)-4,4-debtor-2-isobutylamino-5-phenylpentane acid,

[(S)-1-((S)-1-benzazolyl-3-oxazepan-4-ylcarbonyl)-3,3-debtor-4-phenylbutyl]amide morpholine-4-carboxylic acid,

complex tert-butyl ether (S)-4-{(S)-4,4-debtor-2-[(morpholine-4-carbonyl)amino]-5-phenylenediamine}-3-oxazepan-1-carboxylic acid,

((S)-1-{(S)-1-[(5-ethyl-1,3,4-oxadiazol-2-yl)hydroxymethyl]propellerblades}-3,3-divergence}amide morpholine-4-carboxylic acid,

{(S)-1-[1-(5-cyclopropyl-1,3,4-oxadiazol-2-carbonyl)propellerblades]-3,3-deformaty}amide morpholine-4-carboxylic acid,

{(S)-1-[l-(5-cyclopropyl-1,2,4-oxadiazol-3-carbonyl)propellerblades]-3,3-divergence}amide morpholine-4-carboxylic acid,

((S)-3,3-debtor-1-{(S)-1-[5-(4-forfinal)-1,2,4-oxadiazol-3-carbonyl]propellerblades}butyl)amide morpholine-4-carboxylic acid,

((S)-3,3-debtor-1-{1-[5-(4-forfinal)-1,2,4-oxadiazol-3-carbonyl]propellerblades}butyl)amide morpholine-4-carboxylic acid,

((S)-3,3-debtor-1-{(R)-1-[5-(4-forfinal)-1,2,4-oxadiazol-3-carbonyl]propellerblades}butyl)amide morpholine-4-carboxylic acid,

{(S)-1-[(S)-1-(benzoxazol-2-carbonyl)propellerblades]-3,3-deformaty}amide morpholine-4-carboxylic acid,

[(S)-1-(cyanomethylene)-3,3-divergence]amide morpholine-4-carboxylic acid,

((S)-3,3-debtor-1-{(R)-1-[5-(5-methylthiophene-2-yl)oxazol-2-carbonyl]propellerblades}hexyl)amide morpholine-4-carboxylic acid

((S)-3,3-debtor-1-{(S)-1-[5-(5-methylthiophene-2-yl)oxazol-2-carbonyl]propellerblades}hexyl)amide morpholine-4-carboxylic acid and its related isomers and mixtures of isomers, and pharmaceutically acceptable salts.

22. Pharmaceutical composition having the properties of an inhibitor of cathepsin containing an effective amount of a compound according to claim 1 and a pharmaceutically acceptable filler.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: description is given of a piperidine derivative with general formula (I) , where L represents CH or N; M represents CH or N; under the condition that, L and M both do not represent CH; R1 represents phenyl (possibly substituted with a halogen or C1-4alkyl), S(O)2(C1-4alkyl), S(O)2(C1-4fluroalkyl), S(O)2phenyl (possibly substituted with CF3 or OCF3), benzyl, benzoyl (possibly substituted with a halogen) or C(O)NHphenyl (possibly substituted with a halogen); R2 represents phenyl, possibly substituted with a halogen; R3 represents hydrogen or C1-4alkyl; R4 represents methyl or ethyl; R5 represents phenyl-NH, phenyl (C1-2alkyl), phenyl(C1-C2)alkyl-NH or pyridyl(C1-2alkyl). The phenyl can be substituted with a halogen, cyano, C1-4alkyl, C1-4alkoxy, S(O)k(C1-4alkyl) or S(O)2NR8R9; k is equal to 2; R8 and R9 represent hydrogen or its pharmaceutical salts. The compound is a modulator of the activity of the CCR5 receptor. Description is given of the method of obtaining the compound, where L represents N, and the pharmaceutical composition based on a compound with formula (I).

EFFECT: design of a method of obtaining a compound, where L represents N, and a pharmaceutical composition based a compound with formula (I).

7 cl, 7 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns to new diamides of pyrimidine-4,6-dicarboxylic acid of I formula, selective inhibitors of collagenases possessing properties which concern to the metalloproteinase superfamily and the matrix metalloproteinases. The bonds render influence on hyperactivity of the matrix metalloproteinase-13 (MMP-13) and thus do not render influence on MMP-3 and MMP-8. In the formula I R1 means an atom of hydrogen, R2 means - (C1-C6)-alkyl where alkyl is unitary replaced by phenyl where phenyl is replaced 1) -(C0-C6)-alkyl-C(O)-N(R9)-(R10), where R9 and R10 identical or different and independently from each other mean i) atom of hydrogen or ii) - (C1-C6)-alkyl or R9 and R10 together with atom of nitrogen to which they are bound, form 5, 6-links the sated cycle, and instead of one or two other atoms of carbon there can be also a heteroatom from an oxygen row, sulphur and nitrogen, and in case of nitrogen atoms of nitrogen independently from each other can be unsubstituted or substituted with (C1-C6)-alkyl, 2) -(C0-C6)-alkyl-C(O)-NH-SN, 3) -O-(C0-C6)-alkyl-C(O)-N(R9)-(R10) where R9 and R10 have the specified above value, 4) -(C0-C6)-alkyl-C(O)-N (R8)-(C0-C6)-alkyl-N(R9)-(R10) where R8 means hydrogen, R9 and R10 have the specified above value, 5) -(C0-C6)-alkyl-C(O)-N(R8)-(C0-C6)-alkyl-Het, and R8 has the specified above value, and Het means the sated or nonsaturated monocyclic heterocyclic system with number of links from 3 to 6 which contains in a cycle of 1 or 2 identical or different heteroatoms from a number nitrogen, oxygen and sulphur and unsubstituted or one-, two- or triple independently from each other is replaced by halogen, b) hydroxy,) -(C1-C6)-alkyl, and alkyl is unsubstituted or one-, two- or triple is substituted by halogen, d)=0,e)-Het, R4 and R5 or R5 and R6 together with atom of Carboneum to which they are bound, independently from each other form 5 or 6-unit cycle which is sated and contains one or two heteroatoms from an oxygen row.

EFFECT: obtaining of bonds which can find application for treatment of degenerate diseases of joints, such as osteoarthritis, rheumatic disease.

7 cl, 3 tbl, 117 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to derivatives of 4-[1-arylimidazol-4-yl ethynyl]-2-alkylpyridine and 4-[1-heteroarylimidazol-4-yl ethynyl]-2-alkylpyridine of general formula I having general formula I in which R1 stands for C1-C6alkyl; R2 stands for C1-C6alkyl or C3-C12cycloalkyl; R3 stands for aryl or heteroaryl, where aryl or heteroaryl are unsubstituted or contain substituents, selected from group, including halogen, C1-C6alkyl, S-C1-C6alkyl, C1-C6alkylhlogen, C1-C6alkoxygroup, halogen- C1-C6lkoxygroup, C3-C12cycloalkyl, C2-C11heterocycloakyl, C1-C6alkylminogroup,di- C1-C6alkylaminogroup, C1-C6alkoxyaminogroup, (C1-C6 alkoxy) C1-C6alkylaminogroup, C3-C12cycloalkylaminogroup, benzylaminogroup and cyanogroup, where said "aryl" represents phenyl, and said " heteroaryl" represents aromatic 5- or 6- member ring or one or more condensed rings, containing one or more heteroatoms, selected from group, which includes nitrogen, oxygen and sulfur; and R4 stands for hydrogen, C(O)H or CH2R5 , where R stands for hydrogen or its pharmaceutically acceptable salt. Invention also relates to method of obtaining compounds of general formula I, their application as anxiolytic, to based on them pharmaceutical composition and method of treatment or prevention of disorders, fully or partly mediated by metabotropic glutamate receptor of subtype 5.

EFFECT: obtaining novel heterocyclic compounds possessing useful biological properties.

15 cl, 18 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to agonist of receptor of glucagone-like peptide-1, which can be applied for treatment of diseases, caused by disturbance of glycometabolism, such as type II diabetes, insensibility to insulin or obesity. In structural formula each of Ar1 and Ar2 independently represents substituted phenyl, and group-substituents represent one, two or three groups selected from C1-C6alkoxyl, C1-C6-alkanoylamino, which is substituted with hydroxyl (which contains groups-substituents, including hydroxyl); C3-C6-cyclolkanoylamino, C2-C6-lkenoylamino; banzoylamino, banzyloxy C1-C6-alkanoylamino, thenoyloxy, tret-butoxyformamido, adamantanformamido; and mandeloylamino; X represents O; Y represents O. Invention also relates to method of obtaining agonist, and to its application for obtaining medication for treatment of diseases caused by disturbance of glycometabolism.

EFFECT: obtaining medication for treatment of diseases caused by disturbance of glycometabolism.

8 cl, 4 ex, 2 tbl, 2 dwg

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to novel compounds of formula (I), its pharmaceutically acceptable salts, possessing qualities of chemokine receptor modulators. Compounds can be applied for asthma, allergic rhinitis, COLD, inflammatory intestinal disease, irritated intestine syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis, psoriasis or cancer. In compound of formula (I) , R1 represents group selected from C1-8alkyl, said group is possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4 , -NR5R6 , phenyl, phenyl is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4,-NR5R6,-SR10,C1-6alkyl and trifluoromethyl; R2 represents group selected from C1-8alkyl, said group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-(C1-6alkyl)-N-(phenyl)amino; R3 represents hydrogen, R4 represents hydrogen or group selected from C1-6alkyl and phenyl, R5 and R6, independently, represent hydrogen or group selected from C1-6alkyl and phenyl, said group being probably substituted with 1, 2 or 3 substituents, independently selected from -OR14, -NR15R16, -COOR14,-CONR15R16, or R5 and R6 together with nitrogen atom, to which they are bound, form 4-7-member saturated heterocyclic ring system, possibly containing additional heteroatom, selected from oxygen and nitrogen atoms, ring possibly being substituted with 1, 2 or 3 substituents, independently selected from -OR14, -COOR14,-NR15R16,CONR15R16 and C1-6alkyl; R10 represents hydrogen or group selected from C1-6alkyl or phenyl; and each from R7, R8, R9, R14, R15, R16 independently represents hydrogen, C1-6alkyl or phenyl; X represents hydrogen, halogeno; Rx represents trifluoromethyl, -NR5 R6 , phenyl, naphtyl, heteroaryl, heteroring can be partly or fully saturated, and one or more ring carbon atoms can form carbonyl group, each phenyl or heteroaryl group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR4, -NR5R6, -CONR5R6, -COR7, -COOR7, -NR8COR9, -SR10, -SO2R10, -SO2NR5R6, -NR8SO2R9, C1-6alkyl or trifluoromethyl; or Rx represents group selected from C1-6alkyl, said group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6, phenyl or heteroaryl, where heteroaryl represents monocyclic or bicyclic aryl ring, containing from 5 to 10 ring atoms, from which 1, 2 or 3 ring atoms are selected from nitrogen, sulfur or oxygen. Invention also relates to methods of obtaining compounds, versions, pharmaceutical composition and application for manufacturing medications using compounds of invention.

EFFECT: obtaining novel compounds of formula (I), its pharmaceutically acceptable salts, possessing properties of chemokine receptor moduators.

25 cl, 138 ex

FIELD: medicine; pharmacology.

SUBSTANCE: in formula (I) V represents -N (R1) (R2) or OR4; R4 represents H, C1-6alkyl, C1-6halogenalkyl or (C1-6alkylen)0-1R4' R4' represents C3-7cycloalkyl, phenyl, pyridyl, piperidinyl; and R4' is optionally substituted with 1 or 2 identical or different substitutes chosen from group consisting of C1-4alkyl, amino, C1-3alkylamino, C1-3dialkylamino, phenyl and benzyl; and each R1 and R2 independently represents L1, where L1 is chosen from group consisting from H, C1-6alkyl, C2-6alkenyl, C2-6alkinyl, - adamantyl, pyrrolidinyl, pyridyl, or R1 and R2 together with nitrogen atom to which attached, form X, where X represents pyrrolidinyl, piperazinyl, piperidinyl, morpholino; where X is optionally substituted with Y, where Y represents dioxolanyl, C1-9alkyl, phenyl, furanyl, pyrrolyl, pyridyl, pyrrolidinyl; and where X and Y are optionally split with Z, where Z represents -C1-3alkylen-, C1-3alkylen-. Other radical values are specified in formula of invention.

EFFECT: effective application for treatment of migraine and other headache mediated by action of CGRP-receptors.

34 cl, 11 dwg, 6 tbl, 201 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

Crystal form // 2339634

FIELD: chemistry.

SUBSTANCE: (E)-2-(5-Chlorothiene-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl} ethensulfonamide in essentially crystal form has powder radiograph, expressed in angle values 20, and obtained by means of difractometer, including peaks, located in the following positions expressed in angles 2θ: 9.1-9.2 (±0.1), 16.0-16.1(±0.1), 18.0-18.2 (±0.1) and 18.3-18.4 (±0.1) degrees, and term "essentially crystal form" means that said form is mainly free from amorphous form of (E)-2-(5-Chlorothiene-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl} ethensulfonamide, and by term "mainly free from" content of amorphous form less than 50% is meant.

EFFECT: increased activity.

15 cl, 2 dwg, 5 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new derivatives of 2-pyridinecarboxamide and their pharmaceutical salts, which have glucokinase activating properties. In formula (I): D represents O or S; R2 and R3 each represents a hydrogen atom; formula (II) represents triazole group, imidazole group, thiazole group and pyridine group, which can have in the ring, 1 or 2 substitutes; formula (III) represents a thiazole group, thiadiazole group, isoxazolyl group, pyrazine group, pyridothiazolyl group or pyridyl group, ring B can have 1 or 2 substitutes. The invention also relates to pharmaceutical compositions based on the invented compounds.

EFFECT: new derivatives can be used for treating such diseases as sugar diabetes.

19 cl, 5 tbl, 165 ex

FIELD: chemistry.

SUBSTANCE: new compounds with formula Ia are proposed, where: P represents pyridine or pyrimidine; R1 represents hydrogen; R2 is chosen from halogen, nitro, C0-6alkylheteroaryl, (CO)OR4, trifluoromethyl, C0-6alkylcyano, C0-6alkylNR4R5, OC1-6alkylNR4R5, C0-6alkylCONR4R5, C0-6alkyl(SO2)NR4R5 and X1R6 group, where X1 represents a direct link; R6 represents a 5- or 6-member heterocyclic group, containing one or two heteroatoms, independently chosen from N, O, and S, for which the given heterocyclic group can be unsaturated and can be substituted with by one substitute, chosen from W; m equals 0, 1, or 2; R3 is chosen from CO(OR4), C0-6alkylNR4R5, C0.6alkylCONR4R5, OC1-6alkylNR4R5 C1-6alkyl(SO2)NR4R5; n equals 1 or 2; R4 is chosen from hydrogen, C1-6alkyl; R5 is chosen from hydrogen, C1-6 alkyl, C0-6 alkyl C3-6 cycloalkyl, C0-6 alkylaryl, C0-6alkylheteroaryl and C1-6alkylNR14R15 or R4 and R5 together can form a 4-, 5-, 6- or 7-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O, where the given heterocyclic group can be substituted by group Y; and where any C1-6alkyl, indicated in defining R2-R5, can be substituted with one or more one Z group; R14 and R15 together can form a 5-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O; W and Z are independently chosen from halogen, CN, OR16, C1-6alkyl, trifluoromethyl, trifluoromethoxy, 5-member heterocyclic group, containing one heteroatom, independently chosen from N, for which the given heterocyclic group can be substituted with group Y; Y is chosen from oxo, halogen, C1-6alkyl, C0-6alkylaryl, NR16R17, phenyl, C0-6alkylaryl, where the phenyl and C0-6alkylaryl groups can be substituted with nitro, trifluoromethyl; R16 and R17 are independently chosen from hydrogen and C1-6alkyl, or where R16 and R17 together can form a 5-member heterocyclic group, containing one heteroatom, chosen from N; in form of a free base or pharmaceutical salt. Formula Ia compounds have inhibiting effect to glycogen-synthase-kinase-3 (GSK3). The invention also relates to the method of obtaining the proposed compounds and to new intermediate compounds, used in them, pharmaceutical compositions, containing the given therapeutically active compounds, and use of the given active compounds in therapy for treating conditions, related to GSK3.

EFFECT: new method of obtaining indole derivatives.

33 cl, 1 tbl, 112 ex

FIELD: chemistry.

SUBSTANCE: invention claims derivatives of pyridazin-3(2H)-one of formula (I), where R1, R2 and R4 are organic radicals described in the claim 1, R3 is cyclic group described in the claim, and R5 is phenyl or heteroaryl group described in the claim. Compounds of formula (I) inhibit phosphodiesterase 4 (PDE-4) and can be applied in treatment of various diseases or pathological states alleviated by PDE-4 inhibition, and in medicine production for treatment of aforesaid diseases. Also invention claims method of obtaining these compounds and intermediate compounds for their obtainment.

EFFECT: obtaining compounds which can be used in treatment of various diseases or pathological states and in medicine production for treatment of aforesaid diseases.

25 cl, 28 tbl, 243 ex

FIELD: chemistry.

SUBSTANCE: invention concerns method of obtaining heterocycles of formula I , where X, A, R10-R17 are as defined in point 1 of the claim, while a) isothiocyanate of formula II is transformed into thiourea of formula IV by interaction with primary amine of formula III, and b) thiourea of formula IV is transformed into compound of formula I by interaction with sulfochloride R6SO2Cl in the presence of a base, where A, X, n, m and R10 to R17 in compounds of formulae II, III and IV are as defined in formula I, and R6 is (C1-C4)-alkyl, trifluoromethyl or phenyl non-sustituted or substituted by methyl, trifluoromethyl, F, CI, Br or polymer carreir. The transportation is shown by combination formulae

EFFECT: new multipurpose synthesis technique for heterocyclic compounds of the general formula I.

8 cl, 31 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: claimed invention relates to novel compounds of formula (I) and their pharmaceutically acceptable salts. Compounds of claimed invention possess properties of agonists of mGlu 1 receptors and can find application in treatment of such diseases as psychosis, schizophrenia, Alzheimer's disease, etc. In general formula (I) one of R1 and R2 stands for trifluoromethyl, the other stands for hydrogen; R3, R3' independently on each other stand for hydrogen or halogen.

EFFECT: obtaining medication which possesses properties of agonists of mGlu 1 receptors.

7 cl, 2 tbl, 2 dwg, 17 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns to new diamides of pyrimidine-4,6-dicarboxylic acid of I formula, selective inhibitors of collagenases possessing properties which concern to the metalloproteinase superfamily and the matrix metalloproteinases. The bonds render influence on hyperactivity of the matrix metalloproteinase-13 (MMP-13) and thus do not render influence on MMP-3 and MMP-8. In the formula I R1 means an atom of hydrogen, R2 means - (C1-C6)-alkyl where alkyl is unitary replaced by phenyl where phenyl is replaced 1) -(C0-C6)-alkyl-C(O)-N(R9)-(R10), where R9 and R10 identical or different and independently from each other mean i) atom of hydrogen or ii) - (C1-C6)-alkyl or R9 and R10 together with atom of nitrogen to which they are bound, form 5, 6-links the sated cycle, and instead of one or two other atoms of carbon there can be also a heteroatom from an oxygen row, sulphur and nitrogen, and in case of nitrogen atoms of nitrogen independently from each other can be unsubstituted or substituted with (C1-C6)-alkyl, 2) -(C0-C6)-alkyl-C(O)-NH-SN, 3) -O-(C0-C6)-alkyl-C(O)-N(R9)-(R10) where R9 and R10 have the specified above value, 4) -(C0-C6)-alkyl-C(O)-N (R8)-(C0-C6)-alkyl-N(R9)-(R10) where R8 means hydrogen, R9 and R10 have the specified above value, 5) -(C0-C6)-alkyl-C(O)-N(R8)-(C0-C6)-alkyl-Het, and R8 has the specified above value, and Het means the sated or nonsaturated monocyclic heterocyclic system with number of links from 3 to 6 which contains in a cycle of 1 or 2 identical or different heteroatoms from a number nitrogen, oxygen and sulphur and unsubstituted or one-, two- or triple independently from each other is replaced by halogen, b) hydroxy,) -(C1-C6)-alkyl, and alkyl is unsubstituted or one-, two- or triple is substituted by halogen, d)=0,e)-Het, R4 and R5 or R5 and R6 together with atom of Carboneum to which they are bound, independently from each other form 5 or 6-unit cycle which is sated and contains one or two heteroatoms from an oxygen row.

EFFECT: obtaining of bonds which can find application for treatment of degenerate diseases of joints, such as osteoarthritis, rheumatic disease.

7 cl, 3 tbl, 117 ex

FIELD: chemistry.

SUBSTANCE: compound of formula I , its diastereomers or salts, where dot line represents optional double bond, m and p independently stand for 0, 1, 2 or 3; R1 stands for H, -N(R8)-C(O)-NR6R7, -N(R8)-S(O)2-NR6R7, -N(R8)-C(O)-N(R8a)-S(O)2-NR6R7, etc.; R1a stands for H or group OH; or R1 or R1a together form oxo; or R1 and R1a together with carbon atom, to which they are bound, form optionally substituted oxo spiro-condensed heterocyclic group, representing fully saturated 5-member monocyclic group, containing 2 nitrogen atoms; R2 stands for heteroaryl, (heteroary)alkyl, representing 5-6-member aromatic ring, contaning 1 nitrogen atom and/or 1 atom of oxygen and/or sulphur, and optionally condensed with aryl ring; aryl, (aryl)alkyl, alkyl, alkenyl or cycloalkyl, representing partly or fully saturated C3-C6 monocyclic structure, any of which can be optionally, independently, substituted with one or more groups T1, T2 or T3; J stands for bond, C1-4 alkylene, R3 stands for -R5, -C(Z1)-R5, -N(R8a1)-C(Z1)-R5, -N(R8a1)-C(Z1)-O-R5, -N(R8a1)-S(O)2-R5; R4 stands for alkyl, halogenalkyl, cycloalkyl, aryl, which can be optionally condensed with heteroaryl 6-member ring, containing 1-2 heteroatoms, selected from group SO2, N, etc.; R5 stands for -NR6aR7a or heteroaryl, (heteroaryl)alkyl, representing 5-6-member aromatic ring, which contains 1-3 nitrogen atoms and/or 1 or 2 atoms of oxygen or sulphur, optionally condensed with heteroaryl ring, representing 6-member aromatic ring, containing 1 nitrogen atom, etc.; R6a, R7a independently represent H, alkyl, aryl, (aryl)alkyl, heteroaryl, representing 5-6-member aromatic ring, which contains 1-2 nitrogen atoms, optionally condensed with aryl or heteroaryl ring, representing 6-member aromatic ring with 1 nitrogen atom; any of which can be optionally, independently, substituted with one or more groups T1c, T2c or T3c; R6, R7, R8, R8a, R8a1 R8a2, and R9, independently, represent H, alkyl, hydroxy, alkoxy, (hydroxy)alkyl, (alkoxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, -NR12R13, cycloalkyl, (cycloalkyl)alkyl, optionally condensed with aryl; aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, etc.; R10, R10a, R11 and R11a, independently, represent H, alkyl, aryl, (aryl)alkyl, , hydroxy, (hydroxy)alkyl; heteroaryl, (heteroaryl)alkyl, representing 5-member aromatic ring, which contains 2 nitrogen atoms, or R11 and R11a can together form oxogroup, or R10a can together with R11a form bond, or R10 can together with R9 form saturated 3-4-member cycle; R12 and R13, independently, represent H, alkyl; W represents =NR8a2, =N- CO2R8a2, =N- CN; X represents C(=O), C=N-CN; Z1represents =O, or =N-CN; RX represents one optional substituent, bound with any suitable carbon atom in cycle, independently selected from T1g, T2g or T3g. Compounds of formula I are applied for manufacturing medication for treatment of IKur-mediated disorders.

EFFECT: cycloalkyl compounds, useful as inhibitors of potassium channels function.

13 cl, 694 ex, 1 tbl

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to agonist of receptor of glucagone-like peptide-1, which can be applied for treatment of diseases, caused by disturbance of glycometabolism, such as type II diabetes, insensibility to insulin or obesity. In structural formula each of Ar1 and Ar2 independently represents substituted phenyl, and group-substituents represent one, two or three groups selected from C1-C6alkoxyl, C1-C6-alkanoylamino, which is substituted with hydroxyl (which contains groups-substituents, including hydroxyl); C3-C6-cyclolkanoylamino, C2-C6-lkenoylamino; banzoylamino, banzyloxy C1-C6-alkanoylamino, thenoyloxy, tret-butoxyformamido, adamantanformamido; and mandeloylamino; X represents O; Y represents O. Invention also relates to method of obtaining agonist, and to its application for obtaining medication for treatment of diseases caused by disturbance of glycometabolism.

EFFECT: obtaining medication for treatment of diseases caused by disturbance of glycometabolism.

8 cl, 4 ex, 2 tbl, 2 dwg

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to novel compounds of formula (I), its pharmaceutically acceptable salts, possessing qualities of chemokine receptor modulators. Compounds can be applied for asthma, allergic rhinitis, COLD, inflammatory intestinal disease, irritated intestine syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis, psoriasis or cancer. In compound of formula (I) , R1 represents group selected from C1-8alkyl, said group is possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4 , -NR5R6 , phenyl, phenyl is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4,-NR5R6,-SR10,C1-6alkyl and trifluoromethyl; R2 represents group selected from C1-8alkyl, said group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-(C1-6alkyl)-N-(phenyl)amino; R3 represents hydrogen, R4 represents hydrogen or group selected from C1-6alkyl and phenyl, R5 and R6, independently, represent hydrogen or group selected from C1-6alkyl and phenyl, said group being probably substituted with 1, 2 or 3 substituents, independently selected from -OR14, -NR15R16, -COOR14,-CONR15R16, or R5 and R6 together with nitrogen atom, to which they are bound, form 4-7-member saturated heterocyclic ring system, possibly containing additional heteroatom, selected from oxygen and nitrogen atoms, ring possibly being substituted with 1, 2 or 3 substituents, independently selected from -OR14, -COOR14,-NR15R16,CONR15R16 and C1-6alkyl; R10 represents hydrogen or group selected from C1-6alkyl or phenyl; and each from R7, R8, R9, R14, R15, R16 independently represents hydrogen, C1-6alkyl or phenyl; X represents hydrogen, halogeno; Rx represents trifluoromethyl, -NR5 R6 , phenyl, naphtyl, heteroaryl, heteroring can be partly or fully saturated, and one or more ring carbon atoms can form carbonyl group, each phenyl or heteroaryl group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR4, -NR5R6, -CONR5R6, -COR7, -COOR7, -NR8COR9, -SR10, -SO2R10, -SO2NR5R6, -NR8SO2R9, C1-6alkyl or trifluoromethyl; or Rx represents group selected from C1-6alkyl, said group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6, phenyl or heteroaryl, where heteroaryl represents monocyclic or bicyclic aryl ring, containing from 5 to 10 ring atoms, from which 1, 2 or 3 ring atoms are selected from nitrogen, sulfur or oxygen. Invention also relates to methods of obtaining compounds, versions, pharmaceutical composition and application for manufacturing medications using compounds of invention.

EFFECT: obtaining novel compounds of formula (I), its pharmaceutically acceptable salts, possessing properties of chemokine receptor moduators.

25 cl, 138 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to compounds of formula (I) or their pharmaceutically acceptable salts, where Q represents optionally substituted with 1-3 substituents, determined in formula, phenyl or pyridyl or pyrodazinyl; R2 represents C1-6alkyl or aminogroup, determined in item 1 of formula or C1-6alkyl, substituted with said aminogroup; bond between oxygen atom O* and adjacent carbon atom C1 or (i) is double bond, which determines carbonyl group [C(=O)], where R6 represents C1-6alkyl or cyclopropyl; or (ii) represents simple bond, where, in case of simple bond, said oxygen atom O*, is in addition bound to group R6 and, taken together with R6 and with adjacent nitrogen atom, determines optionally substituted with C1-6alkyl, oxadiazolyl ring, bond between C1 and adjacent nitrogen atom being double bond.

EFFECT: obtaining medications which are useful in obtaining medications for treatment of conditions connected with p38 kinase and/or in obtaining medications for treatment of inflammatory diseases or conditions in patient.

8 cl, 6 tbl, 88 ex

FIELD: medicine; pharmacology.

SUBSTANCE: presented are anilides of nicotinic acid of general formula I , where R means atom of hydrogen, halogen or benzyloxy-group, R' means atom of hydrogen or halogen, X means 2-furyl, 2-pyridyl, 3-pyridyl unsubstituted or substituted with phenyl halogen atom with fungicidal activity.

EFFECT: new compound are effective for hazardous fungi.

3 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: in pyridylmethylanilides of heterocyclic acids of general formula I R stands for atom of hydrogen halogen or benzyloxy-group, R' stands for atom of hydrogen or halogen, X stands for 2-phuryl or 2-pyridyl.

EFFECT: increase of compound efficiency against harmful fungi.

1 cl, 3 tbl, 5 ex

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