Human protein tyrosine phosphatase inhibitors and application methods thereof

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R denotes a thiazolyl group of formula R2 and R3 are selected from: hydrogen, C1-C3linear alkyl; R4 is selected from: C1-C3linear or C3cyclic alkyl, phenyl and thiophenyl; Z denotes a group of formula: -(L)n-R1; R1 is selected from: i) C1-C3linear or branched alkyl, optionally substituted with C1-C4alkoxycarbonyl, halogen; ii) substituted phenyl or substituted with one or two substitutes selected from halogen, methoxy- or hydroxy group, C1-C4alkoxycarbonyl; iii) dioxopiperazinyl and 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl, substituted with C1-C3alkyl; or iv) heteroaryl rings containing 5-10 atoms selected from thiazole, triazole, 1H-imidazole, thiadiazole, oxazole, isoxazole, oxadiazole, benzodioxole, benzo(1,4)dioxepanyl, pyridine, pyrimidine, 1H-indole, 2,3-dihydrobenzo[b][1,4]dioxynil, which can be substituted with oine or two substitutes selected from: a) hydroxy; b) C1-C3alkyl (which can be substituted with one more two substitutes selected from: ) phenyl; ii) C1-C4alkoxycarbonyl; iii) naphthalenyl; iv) 2-methylthiazolyl) ; c) NHC(O)C1-C3alkyl; d) C1-C4alkoxycarbonyl; e) 1 -(tert-butoxycarbonyl)-2-phenylethyl; f) methoxybenzyl; g) phenyl which can be substuted with C1-C4alkoxy, halogen, methoxycarbonyl or >NHC(O)CH3; h) (methoxy-2-oxoethyl)carbamoyl; L denotes a group selected from: i) C(O)NH[C(R5aR5b)]w-; ii) -C(O)[C(R6aR6b)]x-; iii) -C(O)[C(R7aR7b)]yC(O)-; iv) -SO2[C(R8aR8b)]z-; R5a, R5b, R6a, R6b, R7a, R7b, R8a and R8b, each independently denotes: i) hydrogen; ii) C1-C3 linear alkyl which can be substituted with 1 or 2 halogen atoms; iii) phenyl which can be substituted with 1-2 substitutes selected from halogen and lower alkoxy; iv) heteroaryl rings selected from imidazolyl, imidazolyl substituted with methyl, benzo(1,4)oxazinyl, oxadiazolyl substituted with methyl; index n equals 0 or 1; indices w, x, y and z are each independently equal to a number from 1 to 3. The invention also relates to pharmaceutically acceptable salts of compounds of formula (I) and use of compounds of formula (I) to prepare a medicinal agent for treating protein tyrosine phosphatase beta-mediated conditions.

EFFECT: obtaining compounds of formula (I) as human protein tyrosine phosphatase beta (HPTP-β) inhibitors.

15 cl, 17 dwg, 13 tbl, 16 ex

 

The present invention relates to compounds useful as inhibitors of beta-tyrosinosis protein human (NRTR-β) through the regulation of angiogenesis. The present invention also relates to compositions containing one or more inhibitors of beta-tyrosinosis protein human (NRTR-β), and the regulation of angiogenesis.

Angiogenesis, the development of new blood vessels from preexisting vasculature, plays a crucial role in a large number of physiological and pathological processes (Nguyen L.L. et al., Int. Rev. Cytol.,204, 1-48 (2001)). Angiogenesis is a complex process mediated by communication between the endothelial cells that lie on the border between the walls of blood vessels and their liquid content, and their environment. In the early stages of angiogenesis tissue or tumor cells produce and secrete Pro-angiogenic growth factors in response to environmental stimuli, such as hypoxia. These factors diffuse near endothelial cells and stimulate the receptors, which leads to the production and secretion of proteases that destroy the surrounding extracellular matrix. Activated endothelial cells begin to migrate and proliferate into the surrounding tissue in the direction of the source of these growth factors (Bussolino F., Trends Biochem. Sci.,22, 251-256(1997). Endothelial cells then stop proliferation and differentiation in the tubular structure, which represents the first phase in the formation of stable developed blood vessels. Then pericytoma cells, such as pericyte and smooth muscle cells are recruited into the newly formed vessel at a later stage towards full development.

Angiogenesis is regulated by a balance of naturally occurring Pro-angiogenic and antiangiogenic factors. Vascular endothelial growth factor, fibroblast growth factor and angiopoietin represent a small number of the many potential Pro-angiogenic growth factors. Such ligands are linked through their respective tyrosine kinase receptors with the surface of endothelial cells and transducer signals that promotirovat cell migration and proliferation. While many regulatory factors have been identified, the molecular mechanisms of this process are completely incomprehensible.

There are many conditions of disease caused by constantly unregulated or improperly regulated angiogenesis. In the case of such disease States unregulated or improperly regulated angiogenesis may or induce a specific disease or exacerbate existing pathological status is E. For example, ocular neovascularization refers to as the most common causes of blindness and underlies the pathology of approximately 20 eye diseases. In the case of some, above existing conditions such as arthritis, the newly formed capillary blood vessels invade the joint and destroy cartilage. In diabetes, new capillaries formed in the retina, penetrate into the vitreous humor, causing bleeding and blindness. As the development and metastasis of solid tumors are dependent on angiogenesis (Folkman et al., "Tumor Angiogenesis", Chapter 10, 206-232, in The Molecular Basis of Cancer, Mendelsohn et al., eds., W.B. Saunders (1995)). It is shown that tumors that grow to more than 2 mm in diameter, must obtain their own blood supply and, thus, to meet the requirements by inducing the development of new capillary blood vessels. After these new blood vessels become embedded in the tumor, they provide nutrients and growth factors required for tumor development, as well as a way for tumor cells to enter the circulation and metastasize to distant sites such as liver, lung or bone (Weidner, New Eng. J. Med.,324, 1, 1-8 (1991)). When they are used as medicines in tumor bearing animals, natural inhibitors of any the Genesis can prevent the growth of small tumors (O'reilly et al., Cell79, 315-28 (1994)). According to some protocols, the use of such inhibitors leads to regression and education "dormant" tumor even after cessation of treatment (O'reilly et al., Cell88, 277-85 (1997)). In addition, satisfying inhibitors of angiogenesis in the case of some tumors can potentiate their response in relation to other medical schemes (Teischer et al., Int. J. Cancer,57, 920-25 (1994)).

Although many state of the disease provoked constantly unregulated or improperly regulated angiogenesis, some state of the disease can be treated by increasing angiogenesis. Growth and tissue repair are biological events, where cell proliferation and angiogenesis. Thus, an important aspect of wound healing is revascularization of damaged tissue by angiogenesis.

Chronic, non-healing wounds are a major cause prolonged pain in the defined age of the human population. This particularly applies to bedridden or diabetic patients who develop severe, non-healing skin ulcers. In many of these cases the delay in healing is a result of inadequate blood supply or as a result of continuous pressure or clogged blood vessels. Insufficient capillary blood is the treatment because of the small arterial atherosclerosis or venous stasis promotes failure repair damaged tissue. Such fabrics are often exposed to infection by microorganisms that undeniable proliferate due to innate protective systems of the body that require well vascularization fabric for effective removal of pathogenic organisms. In the greatest therapeutic effect is concentrated on the restoration of blood flow in ischemic tissues, providing nutrients and immunological factors access to the site of the wound.

Atherosclerotic lesions in large vessels can cause ischemia of the tissue, which can be reduced in intensity due to the modulation of the development of blood vessels in the damaged tissue. For example, atherosclerotic lesions in the coronary arteries can cause angina and myocardial infarction, which can be prevented if it is possible to restore blood flow by stimulating the development of collateral arteries. Similarly atherosclerotic lesions in large arteries that supply the lower limbs can cause ischemia in skeletal muscle, which limits mobility and in some cases necessitates the amputation, which can also be prevented by improving blood flow using angiogenic therapy.

Other diseases such as diabetes and hypertension, are characterized by the mind is Ishenim number and density of small blood vessels, such as the arteries and capillaries. These small blood vessels are important for the delivery of oxygen and nutrients. The decrease in the number and density of these vessels contributes to adverse effects of hypertension and diabetes, including claudication, ischemic ulcers, progressive option hypertensive disease and renal failure. Such General disorders and many other less common ailments, such as Buerger's disease, can be reduced in intensity by increasing the number and density of small blood vessels, using angiogenic therapy.

Suggest that one way of regulation of angiogenesis is the treatment of patients with inhibitor beta-tyrosinosis protein human (NRTR-β) (Kruegar et al., EMBO J.9, (1990)), and, consequently, to meet this need were the compounds of the present invention.

The present invention relates to compounds of formula (I), as shown below:

or their pharmaceutically acceptable salts, where the groups R and Z can be determined by any of various alternative descriptions offered below. It was found that the compounds of formula (I) and/or their pharmaceutically acceptable salts are inhibitors of the beta-tyrosinosis protein human (NRTR-β) and, therefore, capable of R is to guluronate angiogenesis in humans, in order to treat various diseases, which include, but are not limited to, diabetic retinopathy, macular degeneration, cancer, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum, Paget's disease, vein occlusion, arterial occlusion, carotid obstructive disease, chronic uveitis/vitric, mycobacterial infections, Lyme disease, systemic lupus erythematosus, retrolateral fibroplasia, disease ILSA, Behcet's disease, caused by retinitis or chorioidea infection, presumed ocular histoplasmosis, a disease best, myopia, congenital pit of the optic nerve disc disease Stargardt, including inflammation of the peripheral retina and ciliary circle, clinical syndrome, chronic retinal detachment, a syndrome of increased viscosity, toxoplasmosis, trauma and postlapsaria complications associated with redness of the disease and the proliferative vitreoretinopathy, Crohn's disease and ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis, hemangioma, disease Randy-Osler-Weber, hereditary haemorrhagic telangiectasia, solid tumor or blood tumor on the head in infants and acquired immunodeficiency syndrome, ischemia of skeletal muscle and myocardial ischemia, stroke, peripheral vascular disease and Corot is ary arterial disease.

The present invention also relates to pharmaceutical compositions containing one or more compounds of the formula (I) and their pharmaceutically acceptable salts.

The present invention also relates to a method of controlling angiogenesis and, thus, provide treatment of diseases caused by angiogenesis, and these methods include introduction to the human an effective amount of one or more compounds of the formula (I) and their pharmaceutically acceptable salts, as described in this specification.

These and other objects, features and advantages will become apparent to the person skilled in the art upon reading the following detailed description and the accompanying claims. All documents cited in relevant part, incorporated in this description by reference; reference to any document should not be construed as an admission that the prior art is in accordance with the present invention.

In accordance with this description and the following claims will be made reference to a number of terms that must be defined as having the following values:

All percentages, ratios and proportions herein are mass, unless otherwise noted. All temperatures are given in degrees Celsius (°C)if not ukazaniya.

The term "pharmaceutically acceptable" means a material that is not biologically or otherwise undesirable, i.e., the substance can be administered to the individual together with the corresponding active compound without causing clinically unacceptable biological effects or interacting harmful way with any of the other components of the pharmaceutical composition in which it is contained.

Throughout the description and claims of this specification the word "include" and other forms of words, such as "comprising" and "comprises", mean inclusion without limitation, and does not imply the exclusion of, for example, other additives, components, integers operations or stages.

As used in the description and the attached claims, the singular number include the plural instructions, if this description clearly does not prescribe otherwise. So, for example, reference to "a composition" includes mixtures of two or more such compositions, reference to "phenylsulfinyl acid" includes mixtures of two or more such phenylalaninol acids, reference to "a compound" includes mixtures of two or more such compounds, etc.

The term "optional" or "optionally" means that the described subsequently, the event or event can occur or not, and what the description includes examples, where an event or incident occur, and examples where this is not true.

Ranges can be expressed, according to this description, as from "about" one particular value and/or to "about" another particular value. When this range is clearly marked, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of a prior "about", it should be clear that the specific value is another aspect. Further, it should be clear that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also clear that there are a number disclosed in this description and values, and that each is also described in this description as "about" specified values in addition to the value itself. For example, if you specify a value of "10", then also specify a value of "about 10". It is also clear that, when a value is specified, then also disclosed "less than or equal to the value greater than or equal to the value and possible ranges between values, respectively as is clear to a person skilled in the art. For example, if you specify a value of "10", then also disclosed "less than or equal to 10", and "more chamili is 10". It is also understood that throughout the description data are provided by a number of different formats and that these data represent endpoints and starting points and ranges for any combination of values. For example, if you specify a specific value of "10" and the value "15", it is clear that discusses open specify greater than, greater than or equal, less than, less than, or equal to, or equal to 10 and 15, and between 10 and 15. It is also understood that each unit between two specific units of measurement are also disclosed. For example, if you specify 10 and 15, then also disclosed 11, 12, 13 and 14.

The organic radical can be, for example, 1-26 carbon atoms of 1-18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, or 1-4 carbon atoms. Organic radicals often have hydrogen associated at least with a certain number of carbon atoms of the organic radical. One example of an organic radical which does not include inorganic atoms, a is a radical 5,6,7,8-tetrahydro-2-naphthyl. In some embodiments, the implementation of the organic radical can contain 1-10 inorganic atoms, connected with, or in, including the atoms of halogen, oxygen, sulfur, nitrogen, phosphorus, etc. are Examples of organic radicals include, but are not limited to, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mo is samewindow the amino group, disubstituted by an amino group, alloctype, cyano, carboxyl, carbalkoxy, alkylcarboxylic, replaced alkylcarboxylic, dialkylimidazolium, replaced dialkylimidazolium, alkylsulfonyl, alkylsulfanyl, thioalkyl, tyokalupalkin, alkoxy, substituted alkoxy, halogenated, halogenoalkane, aryl, substituted aryl, heteroaryl, heterocyclic group or substituted heterocyclic group, where the terms are defined elsewhere in this description. Some non-limiting examples of organic radicals which contain heteroatoms, include alkoxygroup, cryptometer, acetochlor, dimethylaminopropyl etc.

Substituted and unsubstituted, linear, branched or cyclic alkyl groups include the following, non-limiting examples: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), cyclopropyl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (C4), tert-butyl (C4), cyclobutyl (C4), cyclopentyl (C5), cyclohexyl (C6and so on; whereas the substituted linear, branched or cyclic alkyl, non-limiting examples of which include hydroxymethyl (C1), chloromethyl (C1), trifluoromethyl (C1), aminomethyl (C1), 1-chloroethyl (C2), 2-hydroxic is l (C 2), 1,2-dottorati (C2), 2,2,2-triptorelin (C3), 3-carboxypropyl (C3), 2,3-dihydroxycinnamate (C4and so on

Substituted and unsubstituted, linear, branched or cyclic alkenyl include ethynyl (C2), 3-propenyl (C3), 1-propanyl (2-methylethenyl) (C3), isopropanol (2-mutilated-2-yl) (3), butene-4-yl (C4and the like; substituted linear or branched alkenyl, non-limiting examples of which include 2-chloranil (2-vinyl chloride) (2), 4-hydroxybutane-1-yl (C4), 7-hydroxy-7-Metalock-4-EN-2-yl (C9), 7-hydroxy-7-Metalock-3,5-Dien-2-yl (C9and so on

Substituted and unsubstituted, linear or branched quinil includes ethinyl (C2), prop-2-inyl (also propargyl) (C3), propyne-1-yl (C3) and 2-metrex-4-in-1-yl (C7); substituted linear or branched quinil, non-limiting examples of which include 5-hydroxy-5-metrex-3-inyl (C7), 6-hydroxy-6-methylhept-3-in-2-yl (C8), 5-hydroxy-5-amilhat-3-inyl (C9and so on

The term "aryl", as used herein, means an organic ring consisting of a conjugated ring system of planar carbon atoms with delocalized PI-electrons, non-limiting examples of which include phenyl (C6), naphtalen-1-yl (C 10), naphtalen-2-yl (C10). Aryl ring may have one or more hydrogen atoms replaced with another organic or inorganic radical. Non-limiting examples of substituted aryl rings include 4-forfinal (C6), 2-hydroxyphenyl (C6), 3-were (C6), 2-amino-4-forfinal (C6), 2-(N,N-diethylamino)phenyl (C6), 2-cyanophenyl (C6), 2,6-di-tert-butylphenyl (C6), 3-methoxyphenyl (C6), 8-hydroxynaphthalene-2-yl (C10), 4,5-dimethoxyaniline-1-yl (C10) and 6-cyanonaphthalene-1-yl (C10).

The term "heteroaryl" means an aromatic ring system containing 5 to 10 atoms. Rings can be a single ring, such as ring containing 5 or 6 atoms, where at least one atom of the ring is a heteroatom, but not limited to, nitrogen, oxygen or sulfur. Or heteroaryl" can mean a condensed ring system with 8-10 atoms, where at least one of the rings is an aromatic ring, and at least one atom of the aromatic ring is a heteroatom, but not limited to nitrogen, oxygen or sulfur.

Below are non-limiting examples of heteroaryl rings of the present invention:

The term "heterocycle" means a ring system with the number of atoms of from 3 to 10, where at least one of the ring atoms is a heteroatom, but not limited to, nitrogen, oxygen or sulfur. Rings can be a single ring, condensed ring or Bicycle. Non-limiting examples of heterocycles include:

All of the above heteroaryl rings or heterocyclic rings optionally may be substituted by one or more substituents hydrogen, as described in this description below.

Throughout the description of the present description, the terms having the spelling "thiophene-2-yl and thiophene-3-yl", used to describe heteroaryl residues corresponding to the formula:

whereas in the case of the names of the compounds of the present invention the chemical nomenclature for these fragments usually written "thiophene-2-yl and thiophene-3-yl respectively. In this description, the terms "thiophene-2-yl and thiophene-3-yl" is used in the description of such rings as groups or fragments that make up the compounds of the present invention, for the sole purpose of giving an unambiguous description for a specialist in this area in relation to rings that are referenced by this specification.

The term "substituted" used throughout the description. The term "substituted" according to the nexto defined as "hydrocarbon fragment, alicyclic or cyclic, which contains one or more hydrogen atoms is replaced by a Deputy or more substituents as described herein below. These groups, with the substitution of hydrogen atoms, capable of replacing one hydrogen atom, two hydrogen atoms or three hydrogen atoms of the hydrocarbon fragment immediately. In addition, these substituents can replace two hydrogen atoms from two adjacent carbon atoms with the formation of the above substituent, a new fragment or group. For example, substituted fragment that requires replacement of one hydrogen atom, include halogen, hydroxyl, etc. Replacement of two hydrogen atoms include carbonyl, oxymyoglobin etc. Replacement of two hydrogen atoms from two adjacent carbon atoms includes apachegroup etc. Replacing three carbon atoms includes the cyano and the like, the Term "substituted" is used throughout this description to indicate that hydrocarbon fragment, such as an aromatic ring, the alkyl chain may contain one or more hydrogen atoms replaced by a substituent. When the balance is described as "substituted"may be replaced by any number of hydrogen atoms. For example, 4-hydroxyphenyl represents a substituted aromatic carbocycle", (N,N-dimethyl-5-amino)octanol is a "someseni the 8alkyl", 3-guanidinopropionic represents a substituted C3alkyl and 2-carboxyphenyl represents a substituted heteroaryl".

Below are non-limiting examples of groups that can replace hydrogen atoms in the fragment:

i) linear, branched or cyclic With1-C12alkyl, -alkenyl and-quinil; for example, methyl (C1), ethyl (C2), ethynyl (C2), ethinyl (C2), n-propyl (C3), isopropyl (C3), cyclopropyl (C3), 3-propenyl (C3), 1-propanyl (2-methylethenyl) (C3), isopropanol (2-mutilated-2-yl) (3), prop-2-inyl (also propargyl) (C3), prop-1-yl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (C4), tert-butyl (C4), cyclobutyl (C4), butene-4-yl (C4), cyclopentyl (C5), cyclohexyl (C6);

ii) substituted or unsubstituted With6- or10aryl; for example, phenyl, naphthyl (also described in this description as naphtalen-1-yl (C10or naphtalen-2-yl (C10);

iii) substituted or unsubstituted With1-C9heterocyclic ring, as described herein below;

iv) substituted or unsubstituted With1-C9heteroaryl ring, as described herein below;

v) -(CR14aR14b)zOR13; for example, -OH, -CH2HE-core 3, -CH2Och3, -Och2CH3, -CH2Och2CH3, -Och2CH2CH3and CH2Och2CH2CH3;

vi) -(CR14aR14b)zC(O)R13; for example, the PINES3, -CH2PINES3, -Och2CH3, -CH2PINES2CH3-The PINES2CH2CH3and CH2PINES2CH2CH3;

vii) -(CR14aR14b)zC(O)OR13; for example, -CO2CH3, -CH2CO2CH3, -CO2CH2CH3, -CH2CO2CH2CH3, -CO2CH2CH2CH3and CH2CO2CH2CH2CH3;

viii) -(CR14aR14b)zC(O)N(R13)2; for example, -CONH2, -CH2CONH2, -CONHCO3, -CH2CONHCO3, -CON(CH3)2and-CH2CON(CH3)2;

ix) -(CR14aR14b)zN(R13)2; for example, -NH2, -CH2NH2, -NHCH3, -N(CH3)2, -NH(CH2CH3), -CH2NHCH3, -CH2N(CH3)2and-CH2NH(CH2CH3);

x) halogen; -F, -Cl, -Br and-I;

xi) -(CR14aR14b)zCN;

xii) -(CR14aR14b)zNO2;

xiii) -CHjXk; where X means halogen, j is equal to from 0 to 2, j+k=3; for example, -CH2F, -CHF2, -CF3, -CCl3or-CBr ;

xiv) -(CR14aR14b)zSR13; -SH, -CH2SH, -SCH3, -CH2SCH3, -SC6H5and-CH2SC6H5;

xv) -(CR14aR14b)zSO2R13; -SO2H, -CH2SO2H, -SO2CH3, -CH2SO2CH3, -SO2C6H5and-CH2SO2C6H5;

xvi) -(CR14aR14b)zSO3R13; -SO3H, -CH2SO3H, -SO3CH3, -CH2SO3CH3, -SO3C6H5and-CH2SO3C6H5;

where R13each independently mean hydrogen, substituted or unsubstituted, linear, branched or cyclic With1-C4alkyl, phenyl, benzyl; or two groups R13taken together, may form a ring containing 3-7 atoms; R14aand R14beach independently mean hydrogen or a linear or branched C1-C4alkyl; the index z is from 0 to 4.

The present invention is directed to some unmet medical needs, among other things:

1) providing compositions effective as inhibitors of beta-tyrosinosis protein human (NRTR-β); and, thus, providing a method of regulating angiogenesis in case of violation, illness, disease or condition where an increased angiogenesis;

2) provision of com is Azizi, effective as inhibitors of beta-tyrosinosis protein human (NRTR-β); and, thus, providing a method of regulating angiogenesis in case of violation, illness, disease or condition; and

3) providing compositions effective as inhibitors of beta-tyrosinosis protein human (NRTR-β); and, thus, providing a method of regulating angiogenesis in case of violation, illness, disease or condition, where reduced angiogenesis.

These and other unmet medical needs are met by using inhibitors of beta-tyrosinosis protein human (NRTR-β) of the present invention are able to regulate angiogenesis and, thus, serve as a treatment for elevated or reduced angiogenesis in humans or in the treatment of diseases that are the result of insufficient regulation of beta-tyrosinosis protein human (NRTR-β).

Compounds disclosed herein, include all pharmaceutically acceptable salt forms, for example salt as major groups, among others, amines, and salts of acid groups, among other things, sulfamic acids and carboxylic acids. Below are non-limiting examples of anions that can form salts with basic groups such as amines: chloride, bromide, iodide, sulfate, bisulfate, carbon is t, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, citrate, etc. Below are non-limiting examples of cations that can form salts with acid groups, such as groups, carboxylic acid/carboxylate groups: sodium, lithium, potassium, calcium, magnesium, bismuth, etc.

Compounds of the present invention are Ethylenediamine phenylalaninamide acid or their pharmaceutically acceptable salts, having the Central structure of the compound (I)represented as shown below:

where the groups R and Z can be any of the alternatives identified below and cited as examples in the description below. In such compounds of formula (I), the carbon atom bearing the amino group has the absolute stereochemistry of (S)as indicated in the above picture, which usually corresponds to (S)-configuration of the same, bearing the amino group of a carbon atom, but which may depend on the nature of the substituting groups R and resulting priority changes.

Group R

In some embodiments, the implementation of the group R of the compounds of formula (I) can be substituted or unsubstituted heterocycle or heteroaryl rings with the number of atoms in the ring from 3 to 15. Replace the military or unsubstituted heterocyclic or heteroaryl ring group R of the compounds of formula (I) can be represented below by using the shared rings And, as shown below:

These heterocyclic or heteroaryl ring And may be optionally substituted by one, two or three independently selected substituents, represented by groups of the General formula R15. Non-limiting examples of substituting groups, R15include:

i) linear, branched or cyclic alkyl, alkenyl and quinil; for example, methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), cyclopropyl (C3), propylene-2-yl (C3), propargyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), cyclobutyl (C4), n-pentyl (C5), cyclopentyl (C5), n-hexyl (C6) and cyclohexyl (C6);

ii) substituted or unsubstituted aryl; for example, phenyl, 2-forfinal, 3-chlorophenyl, 4-were, 2-AMINOPHENYL, 3-hydroxyphenyl, 4-triptoreline and biphenyl-4-yl;

iii) substituted or unsubstituted heterocycles, examples of which are shown in this description below;

iv) substituted or unsubstituted, heteroaryl, examples of which are given in the description below;

v) -(CR17aR17b)qOR16; for example, -OH, -CH2HE, -och3, -CH2Och3, -Och2CH3, -CH2Och2CH3, -Och2CH2CH3and CH2Och2SN 2CH3;

vi) -(CR17aR17b)qC(O)R16; for example, the PINES3, -CH2PINES3, -Och2CH3, -CH2PINES2CH3-The PINES2CH2CH3and CH2PINES2CH2CH3;

vii) -(CR17aR17b)qC(O)OR16; for example, -CO2CH3, -CH2CO2CH3, -CO2CH2CH3, -CH2CO2CH2CH3, -CO2CH2CH2CH3and CH2CO2CH2CH2CH3;

viii) -(CR17aR17b)qC(O)N(R16)2; for example, -CONH2, -CH2CONH2, -CONHCO3, -CH2CONHCO3, -CON(CH3)2and-CH2CON(CH3)2;

ix) -(CR17aR17b)qOC(O)N(R16)2; for example, -OC(O)NH2, -CH2OC(O)NH2, -OC(O)NHCH3, -CH2OC(O)NHCH3, -OC(O)N(CH3)2and-CH2OC(O)N(CH3)2;

x) -(CR17aR17b)qN(R16)2; for example, -NH2, -CH2NH2, -NHCH3, -N(CH3)2, -NH(CH2CH3), -CH2NHCH3, -CH2N(CH3)2and-CH2NH(CH2CH3);

xi) halogen; -F, -Cl, -Br and-I;

xii) -CHmXn; where X is halogen, m is from 0 to 2, m+n=3; for example, -CH2F, -CHF2, -CF3, -CCl3or-CBr3;

xiii) -(CR17aR17b )qCN; for example, -CN, -CH2CN and CH2CH2CN;

xiv) -(CR17aR17b)qNO2; for example, -NO2, -CH2NO2and-CH2CH2NO2;

xv) -(CR17aR17b)qSO2R16; for example, -SO2H, -CH2SO2H, -SO2CH3, -CH2SO2CH3, -SO2C6H5and-CH2SO2C6H5; and

xvi) -(CR17aR17b)qSO3R16; for example, -SO3H, -CH2SO3H, -SO3CH3, -CH2SO3CH3, -SO3C6H5and-CH2SO3C6H5;

where R16each independently mean hydrogen, substituted or unsubstituted linear, branched or cyclic With1-C4alkyl; or two groups R16taken together, may form a ring containing 3 to 7 ring atoms; R17aand R17beach independently mean hydrogen or a linear or branched C1-C4alkyl; the index q is from 0 to 4.

When the group R15include linear, branched or cyclic With1-C12alkyl, -alkenyl; substituted or unsubstituted With6- or10aryl; substituted or unsubstituted With1-C9a heterocycle; or a substituted or unsubstituted With1-C9heteroaryl, group, R15can also have one or more atom is in hydrogen, substituted groups R18. Non-limiting examples of groups R18include:

i) linear, branched or cyclic alkyl, alkenyl and quinil; for example, methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), cyclopropyl (C3), propylene-2-yl (C3), propargyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), cyclobutyl (C4), n-pentyl (C5), cyclopentyl (C5), n-hexyl (C6) and cyclohexyl (C6);

ii) -(CR20aR20b)qOR19; for example, -OH, -CH2HE, -och3, -CH2Och3, -Och2CH3, -CH2Och2CH3, -Och2CH2CH3and CH2Och2CH2CH3;

iii) -(CR20aR20b)qC(O)R19; for example, the PINES3, -CH2PINES3, -Och2CH3, -CH2PINES2CH3-The PINES2CH2CH3and CH2PINES2CH2CH3;

iv) -(CR20aR20b)qC(O)OR19; for example, -CO2CH3, -CH2CO2CH3, -CO2CH2CH3, -CH2CO2CH2CH3, -CO2CH2CH2CH3and CH2CO2CH2CH2CH3;

v) -(CR20aR20b)qC(O)N(R19)2; for example, -CONH 2, -CH2CONH2, -CONHCO3, -CH2CONHCO3, -CON(CH3)2and-CH2CON(CH3)2;

vi) -(CR20aR20b)qOC(O)N(R19)2; for example, -OC(O)NH2, -CH2OC(O)NH2, -OC(O)NHCH3, -CH2OC(O)NHCH3, -OC(O)N(CH3)2and-CH2OC(O)N(CH3)2;

vii) -(CR20aR20b)qN(R19)2; for example, -NH2, -CH2NH2, -NHCH3, -N(CH3)2, -NH(CH2CH3), -CH2NHCH3, -CH2N(CH3)2and-CH2NH(CH2CH3);

viii) halogen; -F, -Cl, -Br and-I;

ix) -CHmXn; where X is halogen, m is from 0 to 2, m+n=3; for example, -CH2F, -CHF2, -CF3, -CCl3or-CBr3;

x) -(CR20aR20b)qCN; for example, -CN, -CH2CN and CH2CH2CN;

xi) -(CR20aR20b)qNO2; for example, -NO2, -CH2NO2and-CH2CH2NO2;

xii) -(CR20aR20b)qSO2R19; for example, -SO2H, -CH2SO2H, -SO2CH3, -CH2SO2CH3, -SO2C6H5and-CH2SO2C6H5; and

xiii) -(CR20aR20b)qSO3R19; for example, -SO3H, -CH2SO3H, -SO3CH3, -CH2SO3CH3, -SO3C6H5and-CH2SO3C6H5;

where R19 each independently mean hydrogen, substituted or unsubstituted linear, branched or cyclic With1-C4alkyl; or two groups R19taken together, may form a ring containing 3-7 atoms; R20aand R20beach independently mean hydrogen or a linear or branched C1-C4alkyl; the index q is from 0 to 4.

In the following description, the groups R15and R18can be represented by a Deputy concrete rings, such as ring, included in the definition of R, can be given as or corresponding to the formula:

or corresponding to the formula:

Both of the above formulas are equally fully valid for optionally substituted thiazolidine rings.

Group R

Group R include ring containing from 3 to 15 atoms in the ring.

The group R may include 5-membered heteroaryl ring. Below are non-limiting examples of 5-membered heteroaryl rings:

i)

ii)

iii)

iv)

v)

vi)

vii)

viii)

ix)

x)

xi)

xii)

xiii)

xiv)

xv)and

xvi)

As described herein, a 5-membered heteroaryl ring can be substituted by one or more substituents hydrogen, such as methyl group:

or Deputy hydrogen, which itself is substituted, for example:

Examples of groups R 5-membered ring include thiazolidine group having the formula:

One example thiazolidine group R includes thiazol-2-ilen group having the formula:

where R2and R3each independently chosen from:

i) hydrogen;

ii) substituted or unsubstituted linear, branched or cyclic With1-C6of alkyl;

iii) substituted or unsubstituted phenyl;

iv) substituted or unsubstituted With1-C9heteroaryl; or

R2and R3taken together, may form a saturated or unsaturated ring containing from 5 to 7 atoms.

One note is R. the group R refers to groups of the formula:

where R3means hydrogen, and R2means a group selected from methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (C4) and tert-butyl (C4).

Another example refers to the group R groups, where R2means a group selected from methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (C4) and tert-butyl (C4); and R3means a group selected from methyl (C1) or ethyl (C2). Non-limiting examples of a specified aspect of R include 4,5-dimethylthiazol-2-yl, 4-ethyl-5-methylthiazole-2-yl, 4-methyl-5-utiltity-2-yl and 4,5-dietitians-2-yl.

The following example refers to the group R groups, where R3means hydrogen, and R2means substituted alkyl group, and the substituents are selected from:

i) halogen,- F, -Cl, -Br and-I;

ii) -N(R11)2and

iii) -OR11;

where R11each independently mean hydrogen or a linear or branched C1-C4alkyl. Non-limiting examples of groups that include this variant implementation of R include: -CH2F, -CHF2, -CF3, -CH2CF3, -CH2Cl, -CH2OH, -CH2OCH3, -CH2CH2OH, -CH2CH 2Och3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2and-CH2NH(CH2CH3).

Another further example of the R groups includes groups, where R3means hydrogen, and R2means phenyl.

Another further example of the R groups includes groups, where R3means hydrogen, and R2means a heteroaryl group selected from 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5-yl, [1,2,3]triazole-4-yl, [1,2,3]triazole-5-yl, [1,2,4]triazole-4-yl, [1,2,4]triazole-5-yl, imidazol-2-yl, imidazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, [1,2,4]oxadiazol-3-yl, [1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazole-5-yl, [1,2,4]thiadiazole-3-yl, [1,2,4]thiadiazole-5-yl, and [1,3,4]thiadiazole-2-yl.

One example of R include groups, where R2means thiophene-2-yl or thiophene-3-yl.

Another example of R groups include thiazole-4-ilen group of the formula:

where R4represents a group chosen from:

i) hydrogen;

ii) substituted or unsubstituted linear, branched or cyclic With1-C6of alkyl;

iii) substituted or unsubstituted phenyl; or

iv) substituted or what zameshannogo 1-C9heteroaryl.

One example of R groups include compounds where R4means hydrogen.

Another example of R groups include compounds where R4means a group selected from methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (C4) and tert-butyl (C4). Non-limiting examples of this aspect of R include 2-methylthiazole-4-yl, 2-utiltity-4-yl, 2-(n-propyl)thiazol-4-yl and 2-(isopropyl)thiazol-4-yl.

A further example of R groups include compounds where R4represents a substituted or unsubstituted phenyl, non-limiting examples of which include phenyl, 2-forfinal, 2-chlorophenyl, 2-were, 2-methoxyphenyl, 3-forfinal, 3-chlorophenyl, 3-were, 3-methoxyphenyl, 4-forfinal, 4-chlorophenyl, 4-were and 4-methoxyphenyl.

Another another example of R groups include compounds where R4represents a substituted or unsubstituted heteroaryl, non-limiting examples of which include thiophene-2-yl, thiophene-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 2,5-dimethylthiazol-4-yl, 2,4-dimethylthiazol-5-yl, 4-utiltity-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl and 3-methyl-1,2,4-oxadiazol-5-yl.

The following example groups R 5-membered ring include substituted or unsubstituted imidazolidine group of the formula:

One example thiazolidine group R includes imidazol-2-ilen group having the formula:

where R2and R3each independently chosen from:

i) hydrogen;

ii) substituted or unsubstituted linear, branched or cyclic With1-C6of alkyl;

iii) substituted or unsubstituted phenyl;

iv) substituted or unsubstituted With1-C9heteroaryl; or

R2and R3taken together, may form a saturated or unsaturated ring containing from 5 to 7 atoms.

One example of R groups include compounds where groups R have the formula:

where R3means hydrogen, and R2means a group selected from methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (C4) and tert-butyl (C4).

Another example of R groups include compounds where R2means a group selected from methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (C4) and tert-butyl (C4); and R3means a group selected from methyl (C1) or ethyl (C2). Non-limiting examples of this aspect of R include 4,5-dimethylimidazole-2-yl, 4-ethyl-5-meth is imidazol-2-yl, 4-methyl-5-ethylimidazole-2-yl and 4,5-diethylamido-2-yl.

One example of R groups include compounds where R3means hydrogen, and R2means substituted alkyl group, and the substituents are selected from:

i) halogen,- F, -Cl, -Br and-I;

ii) -N(R11)2and

iii) -OR11;

where R11each independently mean hydrogen or a linear or branched C1-C4alkyl. Non-limiting examples of groups that include this variant implementation of R include: -CH2F, -CHF2, -CF3, -CH2CF3, -CH2Cl, -CH2OH, -CH2OCH3, -CH2CH2OH, -CH2CH2Och3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2and-CH2NH(CH2CH3).

Another further example of the R groups includes groups, where R3means hydrogen, and R2means phenyl.

Another further example of the R groups includes groups, where R3means hydrogen, and R2means a heteroaryl group selected from 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5-yl, [1,2,3]triazole-4-yl, [1,2,3]triazole-5-yl, [1,2,4]triazole-4-yl, [1,2,4]triazole-5-yl, imidazol-2-yl, imidazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, [1,2,4]oxadiazol-3-yl, [1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, furan-2-yl, furan-3-yl, t is the dryer-2-yl, thiophene-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, [1,2,4]thiadiazole-3-yl, [1,2,4]thiadiazole-5-yl, and [1,3,4]thiadiazole-2-yl.

One example of R include groups, where R2means thiophene-2-yl or thiophene-3-yl.

Another example of the R groups includes imidazol-4-ilen group of the formula:

where R4represents a group chosen from:

i) hydrogen;

ii) substituted or unsubstituted linear, branched or cyclic With1-C6of alkyl;

iii) substituted or unsubstituted phenyl or

iv) substituted or unsubstituted With1-C9heteroaryl.

One example of this variant implementation of the groups R refers to compounds where R4means hydrogen.

One example of R groups include compounds where R4means hydrogen.

Another example of R groups include compounds where R4means a group selected from methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (C4) and tert-butyl (C4). Non-limiting examples of this aspect of R include 2-Mei-4-yl, 2-ethylimidazole-4-yl, 2-(n-propyl)imidazol-4-yl and 2-(isopropyl)imidazol-4-yl.

A further example of R groups include compounds where R4represents C is displaced or unsubstituted phenyl, non-limiting examples of which include phenyl, 2-forfinal, 2-chlorophenyl, 2-were, 2-methoxyphenyl, 3-forfinal, 3-chlorophenyl, 3-were, 3-methoxyphenyl, 4-forfinal, 4-chlorophenyl, 4-were and 4-methoxyphenyl.

Another another example of R groups include compounds where R4represents a substituted or unsubstituted heteroaryl, non-limiting examples of which include thiophene-2-yl, thiophene-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 2,5-dimethylthiazol-4-yl, 2,4-dimethylthiazol-5-yl, 4-utiltity-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl and 3-methyl-1,2,4-oxadiazol-5-yl.

The following examples of groups R 5-membered ring are substituted or unsubstituted oxazoline group of the formula:

One example oxazolidine group R includes oxazol-2-ilen group having the formula:

where R2and R3each independently chosen from:

i) hydrogen;

ii) substituted or unsubstituted linear, branched or cyclic With1-C6of alkyl;

iii) substituted or unsubstituted phenyl;

iv) substituted or unsubstituted With1-C9heteroaryl; or

R2and R3taken together, may form a saturated or unsaturated ring containing from 5 to 7 atoms.

One example of the R groups includes connection, hidegroup R have the formula:

where R3means hydrogen, and R2means a group selected from methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (C4) and tert-butyl (C4).

Another example of the R groups includes groups, where R2means a group selected from methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (C4) and tert-butyl (C4); and R3means a group selected from methyl (C1) or ethyl (C2). Non-limiting examples of this aspect of R include 4,5-dimethyloxazole-2-yl, 4-ethyl-5-methoxazole-2-yl, 4-methyl-5-ethyloxazole-2-yl and 4,5-diethyl-oxazol-2-yl.

A further example of R groups include groups wherein R3means hydrogen, and R2means substituted alkyl group, and the substituents are selected from:

i) halogen,- F, -Cl, -Br and-I;

ii) -N(R11)2and

iii) -OR11;

where R11each independently mean hydrogen or a linear or branched C1-C4alkyl. Non-limiting examples of groups that include this variant implementation of R include: -CH2F, -CHF2, -CF3, -CH2CF3, -CH2Cl, -CH2OH, -CH2OCH3, -CH2CH2OH, -CH2CH2The CH 3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2and-CH2NH(CH2CH3).

Another further example of the R groups includes groups, where R3means hydrogen, and R2means phenyl.

Another further example of the R groups includes groups, where R3means hydrogen, and R2means a heteroaryl group selected from 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5-yl, [1,2,3]triazole-4-yl, [1,2,3]triazole-5-yl, [1,2,4]triazole-4-yl, [1,2,4]triazole-5-yl, imidazol-2-yl, imidazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, [1,2,4]oxadiazol-3-yl, [1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazole-5-yl, [1,2,4]thiadiazole-3-yl, [1,2,4]thiadiazole-5-yl, and [1,3,4]thiadiazole-2-yl.

One example of R include groups, where R2means thiophene-2-yl or thiophene-3-yl.

Another example of the R groups includes oxazol-4-ilen group of the formula:

where R4represents a group chosen from:

i) hydrogen;

ii) substituted or unsubstituted linear, branched or cyclic With1-C6of alkyl;

iii) substituted or unsubstituted phenyl or

iv) substituted or asamese the s 1-C9heteroaryl.

One example of this variant implementation of the groups R refers to compounds where R4means hydrogen.

One example of R groups include compounds where R4means hydrogen.

Another example of R groups include compounds where R4means a group selected from methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (C4) and tert-butyl (C4). Non-limiting examples of this aspect of R include 2-methoxazole-4-yl, 2-ethyloxazole-4-yl, 2-(n-propyl)oxazol-4-yl and 2-(isopropyl)-oxazol-4-yl.

A further example of R groups include compounds where R4represents a substituted or unsubstituted phenyl, non-limiting examples of which include phenyl, 2-forfinal, 2-chlorophenyl, 2-were, 2-methoxyphenyl, 3-forfinal, 3-chlorophenyl, 3-were, 3-methoxyphenyl, 4-forfinal, 4-chlorophenyl, 4-were and 4-methoxyphenyl.

Another another example of R groups include compounds where R4represents a substituted or unsubstituted heteroaryl, non-limiting examples of which include thiophene-2-yl, thiophene-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 2,5-dimethylthiazol-4-yl, 2,4-dimethylthiazol-5-yl, 4-utiltity-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl and 3-methyl-1,2,4-oxadiazol-5-yl.

Future prospect the measures groups R refers to oxazol-5-ilen groups of the formula:

where R4represents a group chosen from:

i) hydrogen;

ii) substituted or unsubstituted linear, branched or cyclic With1-C6of alkyl;

iii) substituted or unsubstituted phenyl or

iv) substituted or unsubstituted With1-C9heteroaryl.

One example of R groups include compounds where R4means hydrogen.

Another example of R groups include compounds where R4means a group selected from methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (C4) and tert-butyl (C4). Non-limiting examples of R include 2-methoxazole-4-yl, 2-ethyloxazole-4-yl, 2-(n-propyl)oxazol-4-yl and 2-(isopropyl)-oxazol-4-yl.

A further example of R groups include compounds where R4represents a substituted or unsubstituted phenyl, non-limiting examples of which include phenyl, 2-forfinal, 2-chlorophenyl, 2-were, 2-methoxyphenyl, 3-forfinal, 3-chlorophenyl, 3-were, 3-methoxyphenyl, 4-forfinal, 4-chlorophenyl, 4-were and 4-methoxyphenyl.

Another another example of R groups include compounds where R4represents a substituted or unsubstituted heteroaryl, non-limiting examples of which include thiophene-2-yl, t is the dryer-3-yl, the thiazole-2-yl, thiazol-4-yl, thiazol-5-yl, 2,5-dimethylthiazol-4-yl, 2,4-dimethylthiazol-5-yl, 4-utiltity-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl and 3-methyl-1,2,4-oxadiazol-5-yl.

Another another example of the R groups with a 5-membered ring include substituted or unsubstituted [1,2,4]oxadiazolidine group of the formula:

One example [1,2,4]oxadiazolidine groups R include [1,2,4]oxadiazol-3-ilen group of the formula:

where R2choose from:

i) hydrogen;

ii) substituted or unsubstituted linear, branched or cyclic With1-C6of alkyl;

iii) substituted or unsubstituted phenyl or

iv) substituted or unsubstituted With1-C9heteroaryl.

One example of the R groups includes groups, where R2means hydrogen.

Another example includes a group R, where R2represents a group selected from methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (C4) and tert-butyl (C4); and R3means a group selected from methyl (C1) or ethyl (C2). Non-limiting examples of this aspect of R include 5-methyl[1,2,4]oxadiazol-2-yl, 5-ethyl[1,2,4]oxadiazol-2-yl, 5-propyl[1,2,4]oxadiazol-2-yl and 5-cyclopropyl[1,2,4]oxadiazol-2-yl.

Further primegroup R includes a group where R2means substituted alkyl group, and the above substituents chosen from:

i) halogen,- F, -Cl, -Br and-I;

ii) -N(R11)2and

iii) -OR11;

where R11each independently mean hydrogen or a linear or branched C1-C4alkyl. Non-limiting examples of groups that include this variant implementation of R include: -CH2F, -CHF2, -CF3, -CH2CF3, -CH2Cl, -CH2OH, -CH2OCH3, -CH2CH2OH, -CH2CH2Och3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2and-CH2NH(CH2CH3).

Another further example of the R groups includes groups, where R2means phenyl.

Another further example of the R groups includes groups, where R2means a heteroaryl group selected from 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5-yl, [1,2,3]triazole-4-yl, [1,2,3]triazole-5-yl, [1,2,4]triazole-4-yl, [1,2,4]triazole-5-yl, imidazol-2-yl, imidazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, [1,2,4]oxadiazol-3-yl, [1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazole-5-yl, [1,2,4]thiadiazole-3-yl, [1,2,4]thiadiazole-5-yl, and [1,3,4]thiadiazole-2-the La.

Specific examples of R groups include groups wherein R2means thiophene-2-yl or thiophene-3-yl.

Another example of R groups include [1,2,4]oxadiazol-5-ilen group of the formula:

where R4means a group selected from:

i) hydrogen;

ii) substituted or unsubstituted linear, branched or cyclic With1-C6of alkyl;

iii) substituted or unsubstituted phenyl or

iv) substituted or unsubstituted With1-C9heteroaryl.

One example of R groups include compounds where R4means hydrogen.

Another example of R groups include compounds where R4represents a group selected from methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (C4) and tert-butyl (C4). Non-limiting examples of this aspect of R include 3-methyl[1,2,4]oxadiazol-5-yl, 3-ethyl[1,2,4]oxadiazol-5-yl, 3-(n-propyl)[1,2,4]oxadiazol-5-yl and 3-(isopropyl)[1,2,4]oxadiazol-5-yl.

A further example of R groups include compounds where R4represents a substituted or unsubstituted phenyl, non-limiting examples of which include phenyl, 2-forfinal, 2-chlorophenyl, 2-were, 2-methoxyphenyl, 3-forfinal, 3-chlorophenyl, 3-were, 3-methoxyphenyl, 4-forfinal, 4-chlorophenyl, 4-were is 4-methoxyphenyl.

Another another example of R groups include compounds where R4represents a substituted or unsubstituted heteroaryl, non-limiting examples of which include thiophene-2-yl, thiophene-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 2,5-dimethylthiazol-4-yl, 2,4-dimethylthiazol-5-yl, 4-utiltity-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl and 3-methyl-1,2,4-oxadiazol-5-yl.

Further, non-limiting examples of 5-membered heteroaryl rings include:

i)

ii)

iii)

iv)

v)

vi)

vii)and

viii)

The group R may include 5-membered heterocyclic ring. Non-limiting examples of 5-membered heterocyclic rings include:

i)

ii)

iii)

iv)

v)

vi)and

vii)

The group R may include 6-membered heterocyclic ring. Non-limiting examples of 6-membered heterocyclic rings include:

i)

ii)

iii) and

iv)

The group R may include 6-membered heteroaryl ring. Non-limiting examples of 6-membered heteroaryl rings include:

i)

ii)

iii)and

iv)

Example 6-membered heteroaryl rings include pyrimidine-2-ilen group of the formula:

where R2, R3and R4each independently chosen from:

i) hydrogen;

ii) substituted or unsubstituted linear, branched or cyclic With1-C6of alkyl;

iii) substituted or unsubstituted phenyl or

iv) substituted or unsubstituted With1-C9heteroaryl; or

R2and R3or R3and R4taken together, may form a saturated or unsaturated ring containing from 5 to 7 atoms.

Another example of R groups include groups of the formula:

where R3and R4both represent hydrogen, and R2means a group selected from methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (C4) and tert-butyl (C4).

Further examples of R groups include groups wherein R2and R3choose from methyl ( 1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (C4) and tert-butyl (C4); and R4means hydrogen. Non-limiting examples of this aspect of R include 4,5-dimethylpyrimidin-2-yl, 4,5-diarylpyrimidine-2-yl, 4-methyl-5-ethylpyrimidine-2-yl and 4-ethyl-5-methylpyrimidin-2-yl.

Another further example of the R groups includes groups, where R4means hydrogen, and R2and R3choose from:

i) halogen,- F, -Cl, -Br and-I;

ii) -N(R11)2and

iii) -OR11;

where R11each independently mean hydrogen or a linear or branched C1-C4alkyl. Non-limiting examples of groups that include this variant implementation of R include: -CH2F, -CHF2, -CF3, -CH2CF3, -CH2Cl, -CH2OH, -CH2OCH3, -CH2CH2OH, -CH2CH2Och3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2and-CH2NH(CH2CH3).

Another further example of the R groups includes groups, where R2or R3means substituted phenyl, and R4means hydrogen.

Another further example of the R groups includes groups, where R4means hydrogen, and R2or R3means a heteroaryl group selected from 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5-yl, [1,2,3]triazol-Il, [1,2,3]triazole-5-yl, [1,2,4]triazole-4-yl, [1,2,4]triazole-5-yl, imidazol-2-yl, imidazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, [1,2,4]oxadiazol-3-yl, [1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, [1,2,4]thiadiazole-3-yl, [1,2,4]thiadiazole-5-yl, and [1,3,4]thiadiazole-2-yl.

Below are non-limiting examples of R groups, where R2means thiophene-2-yl, and R2means thiophene-3-yl, thus providing the groups R, which are 4-(thiophene-2-yl)pyrimidine-2-yl, 5-(thiophene-2-yl)pyrimidine-2-yl, 4-(thiophene-3-yl)pyrimidine-2-yl and 5-(thiophene-2-yl)pyrimidine-3-yl.

Non-limiting examples of 6-membered heteroaryl rings include:

i)and

ii).

The group R may also include a condensed ring heteroaryl group. Non-limiting examples of R groups include:

i);

ii)

iii)

iv);

v)

vi)and

vii)

Group R, which represent Conde is lirovannye heteroaryl ring, optionally can be substituted by one or more independently selected substituents hydrogen, as described above in this specification.

Group Z

Z means a group of the formula:

-(L)n-R1,

where R1choose from:

i) hydrogen;

ii) substituted or unsubstituted linear, branched or cyclic With1-C6of alkyl;

iii) substituted or unsubstituted With6or10aryl;

iv) substituted or unsubstituted With1-C9heterocyclic rings or

v) substituted or unsubstituted With1-C9heteroaryl rings.

One example of the groups R1includes substituted or unsubstituted phenyl (C6aryl) groups, where each Deputy independently selected from: halogen, linear, branched or cyclic With1-C4of alkyl, -OR11, -CN, -N(R11)2, -CO2R11, -C(O)N(R11)2, -NR11C(O)R11, -NO2and-SO2R11; where R11each independently mean hydrogen; substituted or unsubstituted, linear, branched or cyclic With1-C4alkyl, alkenyl or quinil; substituted or unsubstituted phenyl or benzyl; or two groups R11taken together, may form a ring containing from 3 to 7 atoms.

Another example of the groups R1on the em substituted C 6aryl group selected from phenyl, 2-ftoheia, 3-ftoheia, 4-ftoheia, 2,3-dipthera, 3,4-dipthera, 3,5-dipthera, 2-chlorphenyl, 3-chlorphenyl, 4-chlorphenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-acid, 3,4-acid and 3,5-acid.

The following example groups R1includes substituted or unsubstituted With6aryl group selected from phenyl, 2-ftoheia, 3-ftoheia, 4-ftoheia, 2,3-dipthera, 2,4-dipthera, 2,5-dipthera, 2,6-dipthera, 3,4-dipthera, 2,3,4-tryptophanyl, 2,3,5-tryptophanyl, 2,3,6-tryptophanyl, 2,4,5-tryptophanyl, 2,4,6-tryptophanyl, 2-chlorphenyl, 3-chlorphenyl, 4-chlorphenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 2,3,4-trichlorophenol, 2,3,5-trichlorophenol, 2,3,6-tryptophanyl, 2,4,5-trichlorophenyl, 3,4,5-trichlorophenol and 2,4,6-trichlorophenyl.

Another another example of the groups R1includes substituted C6aryl group selected from 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,3-dimetilfenil, 2,4-dimetilfenil, 2,5-dimetilfenil, 2,6-dimetilfenil, 3,4-dimetilfenil, 2,3,4-trimetilfenil, 2,3,5-trimetilfenil, 2,3,6-trimetilfenil, 2,4,5-trimetilfenil, 2,4,6-trimetilfenil, 2-ethylphenyl, 3-ethylphenyl, 4-this is phenyl, 2,3-diethylphenyl, 2,4-diethylphenyl, 2,5-diethylphenyl, 2,6-diethylphenyl, 3,4-diethylphenyl, 2,3,4-triterpene, 2,3,5-triterpene, 2,3,6-triterpene, 2,4,5-triterpene, 2,4,6-triethylene, 2-isopropylphenyl, 3-isopropylphenyl and 4-isopropylphenyl.

Another further example of the groups R1includes substituted C6aryl group selected from 2-AMINOPHENYL, 2-(N-methylamino)phenyl, 2-(N,N-dimethylamino)phenyl, 2-(N-ethylamino)phenyl, 2-(N,N-diethylamino)phenyl, 3-AMINOPHENYL, 3-(N-methylamino)phenyl, 3-(N,N-dimethylamino)phenyl, 3-(N-ethylamino)phenyl, 3-(N,N-diethylamino)phenyl, 4-AMINOPHENYL, 4-(N-methylamino)phenyl, 4-(N,N-dimethylamino)phenyl, 4-(N-ethylamino)phenyl and 4-(N,N-diethylamino)phenyl.

R1may include heteroaryl groups. Non-limiting examples of heteroaryl groups include:

i)

ii)

iii)

iv)

v)

vi)

vii)

viii)

ix)

x)

xi)

xii)

xiii)and

xiv)

Heteroaryl groups of R1may be substituted or not unesennymi. Non-limiting examples of groups that can be Deputy hydrogen, include groups selected from:

i) linear, branched and cyclic1-C6of alkyl;

ii) substituted or unsubstituted phenyl and benzyl;

iii) substituted or unsubstituted With1-C9heteroaryl;

iv) -C(O)R9and

v) -NHC(O)R9;

where R9means a linear or branched C1-C6alkyl; linear or branched C1-C6alkoxy; or-NHCH2C(O)R10; where R10selected from hydrogen, methyl, ethyl and tert-butyl.

One example of R1refers to groups substituted alkyl group selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

Another example of R1includes group, which is substituted by substituted or unsubstituted phenyl and benzyl, where the substituents of the phenyl and benzyl are selected from one or more groups such as:

i) halogen;

ii)1-C3alkyl;

iii)1-C3alkoxy;

iv) -CO2R11and

v) -NHCOR16;

where R11and R16each independently mean hydrogen, methyl or ethyl.

Another example of R1refers to phenyl and benzyl groups, substituted carboxypropyl formula-C(O)R9; where R9selected from methyl, metoxygroup, E. the sludge and ethoxypropan.

The following example R1includes phenyl and benzyl groups, substituted amide group of the formula-NHC(O)R9; where R9selected from methyl, metoxygroup, ethyl, ethoxypropan, tert-butyl and tert-butoxypropyl.

One further example of R1includes phenyl and benzyl groups substituted by one or more fluorine atoms or chlorine.

L is a bridging group selected from:

i) -C(O)NH[C(R5aR5b)]w-;

ii) -C(O)[C(R6aR6b)]x-;

iii) -C(O)[C(R7aR7b)]yC(O)-;

iv) -SO2[C(R8aR8b)]z-;

where R5a, R5b, R6a, R6b, R7a, R7b, R8aand R8b, each independently, means:

i) hydrogen;

ii) substituted or unsubstituted linear or branched C1-C4alkyl;

iii) substituted or unsubstituted aryl;

iv) substituted or unsubstituted heterocyclic ring;

v) substituted or unsubstituted With1-C9heteroaryl ring;

and the index w, x, y and z, each independently, is from 1 to 4. The linking group may be present, i.e., the index n is equal to 1, or absent, when the index n is equal to 0, for example, the linking group is not in the connections category V, described later in this description.

One example of group L includes a connecting group of the formula:

-C(O)[C(R6a R6b)]x-,

where R6ameans hydrogen, substituted or unsubstituted phenyl and substituted or unsubstituted heteroaryl, moreover, the above substituents for phenyl and heteroaryl choose from:

i) linear, branched and cyclic1-C6of alkyl;

ii) substituted or unsubstituted phenyl and benzyl;

iii) substituted or unsubstituted With1-C9heteroaryl;

iv) -C(O)R16and

v) -NHC(O)R16;

where R16means a linear or branched C1-C6alkyl; linear and branched C1-C6alkoxy; or-NHCH2C(O)R17; where R17selected from hydrogen, methyl, ethyl and tert-butyl; the index x is 1 or 2.

Another example of groups L include groups where the first group of R6aselected from phenyl, 2-ftoheia, 3-ftoheia, 4-ftoheia, 2,3-dipthera, 3,4-dipthera, 3,5-dipthera, 2-chlorphenyl, 3-chlorphenyl, 4-chlorphenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-acid, 3,4-acid and 3,5-acid; the second group, R6Arepresents hydrogen, and the group R6bmean hydrogen. For example, the linking group has the formula:

Further applying the L includes the first group of R 6aas described herein above, which is substituted or unsubstituted heteroaryl group, as described in the description above.

Another another example L includes groups of the formula:

-C(O)[C(R6aR6b)]x-,

where R6aand R6bmean hydrogen, and the index x is 1 or 2; the above groups can choose from:

i) -C(O)CH2and

ii) -C(O)CH2CH2-.

Another example of groups L include groups of the formula:

-C(O)[C(R7aR7b)]yC(O)-,

where R7aand R7bmean hydrogen, and the index x is 1 or 2; the above groups can choose from:

i) -C(O)CH2C(O)- and

ii) -C(O)CH2CH2C(O)-.

Another another example of groups L include groups of the formula:

-C(O)NH[C(R5aR5b)]w-,

where R5aand R5bmean hydrogen, and the index w is equal to 0, 1 or 2; the above groups can choose from:

i) -C(O)NH;

ii) -C(O)NHCH2and

iii) -C(O)NHCH2CH2-.

Another further example of the group L comprises a group of the formula:

-SO2[C(R8aR8b)]z-,

where R8aand R8bmean hydrogen, and the index z is 0, 1 or 2; the above groups can choose from:

i) -SO2-;

ii) -SO2CH2and

iii) -SO2CH2CH2-.

Describes the s above in the description of the compounds of the present invention include all pharmaceutically acceptable salt forms. The compound of the formula:

may form a salt, such as salt of sulfonic acid:

and

.

The connection can also be twittervision form, for example:

or in the form of salts of strong acids, for example:

Analogues (compounds) of the present invention are classified into several categories to help you practice in the application of synthetic strategy to obtain analogues, which are not specifically shown in the examples described in this way. Classification into categories does not imply increased or decreased efficiency in respect of any of the compositions described in this description of the substances.

The first aspect of category I of the present invention relates to 2-(thiazol-2-ilen) compounds of the formula:

where R1, R2, R3and L have the meanings as defined in table I below in this description.

-CH3 30
Table I
No.LR1R2 R3
1-C(O)CH2-phenyl-CH3-H
2-C(O)CH2-2-forfinal-CH3-H
3-C(O)CH2-3-forfinal-CH3-H
4-C(O)CH2-4-forfinal-CH3-H
5-C(O)CH2-2,3-differenl-CH3-H
6-C(O)CH2-3,4-differenl-CH3-H
7-C(O)CH2-3,5-differenl-CH3-H
8 -C(O)CH2-2-chlorophenyl-CH3-H
9-C(O)CH2-3-chlorophenyl-CH3-H
10-C(O)CH2-4-chlorophenyl-CH3-H
11-C(O)CH2-2,3-dichlorophenyl-CH3-H
12-C(O)CH2-3,4-dichlorophenyl-CH3-H
13-C(O)CH2-3,5-dichlorophenyl-CH3-H
14-C(O)CH2-2-hydroxyphenyl-CH3-H
15-C(O)CH2-3-hydroxyphenyl-H
16-C(O)CH2-4-hydroxyphenyl-CH3-H
17-C(O)CH2-2-methoxyphenyl-CH3-H
18-C(O)CH2-3-methoxyphenyl-CH3-H
19-C(O)CH2-4-methoxyphenyl-CH3-H
20-C(O)CH2-2,3-acid-CH3-H
21-C(O)CH2-3,4-acid-CH3-H
22-C(O)CH2-3,5-acid-CH3-H
23-C(O)CH2-phenyl-CH2CH3-H
24-C(O)CH2-2-forfinal-CH2CH3-H
25-C(O)CH2-3-forfinal-CH2CH3-H
26-C(O)CH2-4-forfinal-CH2CH3-H
27-C(O)CH2-2,3-differenl-CH2CH3-H
28-C(O)CH2-3,4-differenl-CH2CH3-H
29-C(O)CH2-3,5-differenl-CH2CH3-H
-C(O)CH2-2-chlorophenyl-CH2CH3-H
31-C(O)CH2-3-chlorophenyl-CH2CH3-H
32-C(O)CH2-4-chlorophenyl-CH2CH3-H
33-C(O)CH2-2,3-dichlorophenyl-CH2CH3-H
34-C(O)CH2-3,4-dichlorophenyl-CH2CH3-H
35-C(O)CH2-3,5-dichlorophenyl-CH2CH3-H
36-C(O)CH2-2-hydroxyphenyl-CH2CH3-H
37 -C(O)CH2-3-hydroxyphenyl-CH2CH3-H
38-C(O)CH2-4-hydroxyphenyl-CH2CH3-H
39-C(O)CH2-2-methoxyphenyl-CH2CH3-H
40-C(O)CH2-3-methoxyphenyl-CH2CH3-H
41-C(O)CH2-4-methoxyphenyl-CH2CH3-H
42-C(O)CH2-2,3-acid-CH2CH3-H
43-C(O)CH2-3,4-acid-CH2CH3-H
44 -C(O)CH2-3,5-acid-CH2CH3-H
45-C(O)CH2CH2-phenyl-CH3-H
46-C(O)CH2CH2-2-forfinal-CH3-H
47-C(O)CH2CH2-3-forfinal-CH3-H
48-C(O)CH2CH2-4-forfinal-CH3-H
49-C(O)CH2CH2-2,3-differenl-CH3-H
50-C(O)CH2CH2-3,4-differenl-CH3-H
51-C(O)C 2CH2-3,5-differenl-CH3-H
52-C(O)CH2CH2-2-chlorophenyl-CH3-H
53-C(O)CH2CH2-3-chlorophenyl-CH3-H
54-C(O)CH2CH2-4-chlorophenyl-CH3-H
55-C(O)CH2CH2-2,3-dichlorophenyl-CH3-H
56-C(O)CH2CH2-3,4-dichlorophenyl-CH3-H
57-C(O)CH2CH2-3,5-dichlorophenyl-CH3-H
58-C(O)CH 2CH2-2-hydroxyphenyl-CH3-H
59-C(O)CH2CH2-3-hydroxyphenyl-CH3-H
60-C(O)CH2CH2-4-hydroxyphenyl-CH3-H
61-C(O)CH2CH2-2-methoxyphenyl-CH3-H
62-C(O)CH2CH2-3-methoxyphenyl-CH3-H
63-C(O)CH2CH2-4-methoxyphenyl-CH3-H
64-C(O)CH2CH2-2,3-acid-CH3-H
65 -C(O)CH2CH2-3,4-acid-CH3-H
66-C(O)CH2CH2-3,5-acid-CH3-H
67-C(O)CH2CH2-phenyl-CH2CH3-H
68-C(O)CH2CH2-2-forfinal-CH2CH3-H
69-C(O)CH2CH2-3-forfinal-CH2CH3-H
70-C(O)CH2CH2-4-forfinal-CH2CH3-H
71-C(O)CH2CH2-2,3-differenl-CH2CH3-H
72-C(O)CH2CH2-3,4-differenl-CH2CH3-H
73-C(O)CH2CH2-3,5-differenl-CH2CH3-H
74-C(O)CH2CH2-2-chlorophenyl-CH2CH3-H
75-C(O)CH2CH2-3-chlorophenyl-CH2CH3-H
76-C(O)CH2CH2-4-chlorophenyl-CH2CH3-H
77-C(O)CH2CH2-2,3-dichlorophenyl-CH2CH3-H
78-C(O)CH2CH2-3,4-dichlorophenyl-CH2CH3 -H
79-C(O)CH2CH2-3,5-dichlorophenyl-CH2CH3-H
80-C(O)CH2CH2-2-hydroxyphenyl-CH2CH3-H
81-C(O)CH2CH2-3-hydroxyphenyl-CH2CH3-H
82-C(O)CH2CH2-4-hydroxyphenyl-CH2CH3-H
83-C(O)CH2CH2-2-methoxyphenyl-CH2CH3-H
84-C(O)CH2CH2-3-methoxyphenyl-CH2CH3-H
85-C(O)CH2CH2- 4-methoxyphenyl-CH2CH3-H
86-C(O)CH2CH2-2,3-acid-CH2CH3-H
87-C(O)CH2CH2-3,4-acid-CH2CH3-H
88-C(O)CH2CH2-3,5-acid-CH2CH3-H

Compounds included in the first aspect of category I of the present invention can be obtained by the method presented in scheme I and described below in example 1 of this specification.

Scheme I

Reagents and conditions: (a) (i) (isobutyl)Cl, NMM, DMF; 0°C, 20 min; (ii) NH3; 0°C for 30 minutes

Reagents and conditions:

(b) a reagent Lawesson, THF, room temperature, 3 hours.

Reagents and conditions: (C) CH3CN; boiling under reflux for 2 hours.

Reagents and conditions the Oia: (d) C 6H4CO2H, EDCI, HOBt, DIPEA, DMF; room temperature, 18 hours

Reagents and conditions: (e) (i) H2:Pd/C, CH3OH; (ii) SO3-pyridine, NH4OH, room temperature, 18 hours.

Example 1

{4-[2-(S)-(4-Utiltity-2-yl)-2-(2-phenylacetamido)ethyl]phenyl}sulfamic acid (5)

(S) - tert-Butyl-1-amino-3-(4-nitrophenyl)-1-oxoprop-2-ylcarbamate

Obtain (S)-tert-butyl 1-amino-3-(4-nitrophenyl)-1-oxoprop-2-ylcarbamate (1):

It cooled down to 0°C solution of 2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)propionic acid and N-methylmorpholine (1.1 ml, 9,65 mmol) in DMF (10 ml) added dropwise isobutylparaben (1.25 ml, 9,65 mmol). The mixture is stirred at 0°C for 20 minutes, then through the reaction mixture for 30 minutes at a temperature of 0°With miss NH3(gas). The reaction mixture was concentrated and the residue is dissolved in ethyl acetate, washed sequentially with 5%citric acid, water, 5% solution of NaHCO3, water and saturated salt solution, dried (Na2SO4), filtered and concentrated in vacuo, obtaining a residue, which is triturated in a mixture of ethyl acetate/petroleum ether, obtaining 2.2 g (yield 74%) of the desired product as a white solid.

Obtain tert-butyl ester [2-(4-nitrophenyl)-1-(S)thiocarbamoylation]karbaminovoi acid (2):

To a solution of (S)-tert-butyl 1-amino-3-(4-nitrophenyl)-1-oxoprop-2-ylcarbamate 1 (0.400 g, 1,29 mmol) in THF (10 ml) is added a reagent Lawesson (0,262 g of 0.65 mmol). The reaction mixture is stirred for 3 hours and concentrated, obtaining a residue, which is purified using silica, getting 0,350 g (yield 83%) of the desired product.

1H NMR (300 MHz, CDCl3) δ 8,29 (s, 1H), 8,10 (d, J=8,4 Hz, 2H), 8,01 (s, 1H), 7,42 (d, J=8,4 Hz, 2H), 5,70 (d, J=7.2 Hz, 1H), around 4.85 (d, J=7.2 Hz, 1H), 3,11-3,30 (m, 1H), 1,21 (s, N).

Getting hydrobromide 1-(S)-4-utiltity-2-yl)-2-(4-nitrophenyl)ethylamine (3):

A mixture of tert-butyl methyl ether [2-(4-nitrophenyl)-1-(S)thiocarbamoylation]carbamino acid 2 (10 g, 30.7 mmol) and 1-bromo-2-butanone (90%, 3.8 ml, 33.8 mmol) in CH3CN (500 ml) is refluxed for 18 hours. The reaction mixture is cooled to room temperature, to the solution was added diethyl ether and the precipitated precipitate is removed by filtration, getting 7,4 7 g of the desired product.

MS (ESI+) MS: 278 (M+1).

Obtaining N-[1-(4-utiltity-2-yl)-2-(4-nitrophenyl)ethyl]-2-phenylacetamide (4):

To a solution of the hydrobromide 1-(S)-4-utiltity-2-yl)-2-(4-nitrophenyl)ethylamine 3 (0,393 g, 1.1 mmol), phenylacetic acid (0,190 g, 1.4 mmol) and 1-hydroxybenzotriazole (t) (0,094 g, 0.70 mmol) in DMF (10 ml) at a temperature of 0°C was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0,268 g, 1.4 mmol), then trie the ylamine (of 0.60 ml, 4.2 mmol). The mixture is stirred at 0°C for 30 minutes, then at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phase was washed with 1 N. aqueous solution of HCl, 5%aqueous solution of NaHCO3, water and saturated salt solution and dried over Na2SO4. The solvent is removed in vacuum, obtaining is 0.260 g (yield 60%) of the desired product which is used without further purification.

MS (ESI+): 396 (M+1).

Obtain {4-[2-(S)-(4-utiltity-2-yl)-2-(2-phenylacetamido)ethyl]phenyl}sulfamic acid (5):

N-[1-(4-Utiltity-2-yl)-2-(4-nitrophenyl)ethyl]-2-phenylacetamide 4 (0,260 g) dissolved in methanol (4 ml). Add a catalytic amount of Pd/C (10% wt./wt.) and the mixture is stirred in hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a layer of CELITETMand the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 ml) and treated SO3-pyridine (0,177 g of 1.23 mmol). The reaction mixture was stirred at room temperature for 5 minutes, then add the 7%solution of NH4OH (10 ml). The mixture was then concentrated and the resulting residue purified by chromatography with reversed phase, receiving 0,136 g of the desired product in the form of ammonium salt.

1H NMR (CD3OD) δ at 8.60 (d, 1H, J=8.1 Hz), 7,33-of 7.23 m, 3H), 7,16-7,00 (m, 6H), 5,44-5,41 (m, 1H), or 3.28 (1H, A of ABX, masked by solvent), 3,03 (1H, B of ABX, J=14.1 to, and 9.6 Hz), 2,80 (q, 2H, J=10,5, 7,8 Hz) is 1.31 (t, 3H, J=4,6 Hz).

Below is a General methodology for the selection of the final connection in the form of free acid.

The restoration of the aryl nitro group to the free amine:

In the vessel for hydrogenation Parra download nitrosoaniline [for example, the intermediate compound 4] (1.0 EQ.) and Pd/C (10% Pd on C, 50% humidity, the type E101 NE/W, Degussa, 2,68 g, 15% of the mass.) in the form of solids. Add methanol (15 mg/g) to obtain a suspension. The vessel was placed in an apparatus for the hydrogenation Parra. The vessel is subjected to the process of filling/degassing N2(3×20 lbs/inch2) to "inertia", then the same process, using H2(3×40 lb/in2). The vessel is filled N2and shaken for about 40 hours at a pressure of H240 lb/in2. The vacuum vessel and purge N2(5×20 lbs/inch2). The sample was filtered and analyzed HPLC to establish completion of the conversion. The suspension is filtered through a layer of CELITETMremoval of the catalyst and homogeneous yellow filtrate concentrated by evaporation on a rotary evaporator, obtaining the desired product which is used without further purification.

Free sulfamic acid:

In RBF with a capacity of 100 ml is loaded is tons of free amine (1.0 EQ.), obtained at the stage described above. Add acetonitrile and the suspension is yellow, which is usually yellow to orange, stirred at room temperature. In the second three-neck RBF with a capacity of 500 ml load SO3-pyridine (1.4 EQ.) and acetonitrile (5 ml/g) and the suspension is stirred at room temperature. Both the suspension is gently heated to until the reaction solution containing the amine will not become colored from orange to red-orange (usually at a temperature of about 40-45°C). Received containing the substrate solution was poured in one portion into a stirred suspension of SO3-pyridine at a temperature of 35°C. the Obtained opaque mixture is intensively stirred, allowing slow cooling to room temperature. After stirring for 45 minutes, or after determining the full completion of the reaction by HPLC, the painted suspension add water (20 ml)to give a homogeneous solution having a pH of approximately 2.4. Slowly add concentrated H3RHO4to reduce the pH to approximately 1.4. While such regulation of pH is usually precipitation is not entirely white, and the solution was stirred at room temperature for an additional hour. The suspension is filtered and the filter cake washed with filtrate. The precipitate on the filter is dried in air overnight, obtaining the desired product in the form of the free acid.

Below are non-limiting examples according to the first aspect of category I of the present invention.

(S)-4-(2-(4-Utiltity-2-yl)-2-(2-(2-forfinal)acetamido)ethyl)phenyl)sulfamic acid

1H NMR (CD3OD) δ 8,65 (d, 1H, J=8,4 Hz), 7,29-to 7.15 (m, 1H), 7,13-7,03 (m, 7H), 5,46-5,42 (m, 1H), 3,64-3,51 (m, 2H), 3,29 (1H), 3.04 from (1H, B of ABX, J=13,8, 9.6 Hz), of 2.81 (q, 2H, J=15,6, 3,9 Hz)is 1.31 (t, 3H, J=7,8 Hz).19F NMR (CD3OD) δ 43,64.

(S)-4-(2-(4-Utiltity-2-yl)-2-(2-(3-forfinal)acetamido)ethyl)phenyl)sulfamic acid

1H NMR (CD3OD) δ total of 8.74 (d, 1H, J=8,4 Hz), 7,32 (kV, 1H, J=6,6, of 14.2 Hz), 7,10-6,91 (m, 8H), 5,47-of 5.40 (m, 1H), 3,53 (s, 2H), 3,30 (1H), 3,11 (1H, B of ABX, J=9,6, 14.1 Hz), 2,80 (q, 2H, J=6,6, and 15.1 Hz), is 1.31 (t, 3H, J=7,8 Hz).19F NMR δ 47,42.

(S)-4-(2-(2-(2,3-Differenl)acetamido)-2-(4-utiltity-2-yl)ethyl)phenyl)sulfamic acid

1H NMR (CD3OD) δ 7,16-7,05 (m, 5H), 6,85-to 6.80 (m, 1H), 5,48-5,43 (m, 1H), 3,63 (s, 2H), 3,38 (1H, A of ABX, masked by solvent), 3,03 (1H), 2,80 (kV, H, J=15,1, and 7.8 Hz), is 1.31 (t, 3H, J=7.5 Hz).

(S)-4-(2-(2-(3,4-Differenl)acetamido)-2-(4-utiltity-2-yl)ethyl)phenyl)sulfamic acid

1H NMR (CD3OD) δ is 8.75 (d, 1H, J=7.8 Hz), 7.23 percent? 7.04 baby mortality (m, 6H), 6,88-6,84 (m, 1H), 5,44-of 5.40 (m, 1H), 3,49 (s, 2H), 3,34 (1H), to 3.02 (1H, B of ABX, J=14,1, 9.9 Hz), 2,80 (q, 2H, J=15,1, and 7.8 Hz), 1,31 (t, 1H, J=7.5 Hz).19F NMR (CD 3OD) δ 22,18, 19,45.

(S)-4-(2-(2-(2-Chlorophenyl)acetamido)-2-(4-utiltity-2-yl)ethyl)phenyl)sulfamic acid

1H NMR (CD3OD) δ 7,39 was 7.36 (m, 1H), 7,27-7,21 (m, 2H), 7,15-6,98 (m, 5H), 5,49-5,44 (m, 1H), 3,69 (d, 2H, J=11.7 Hz), 3,32 (1H), 3.04 from (1H, B of ABX, J=9,3, a 13.9 Hz), 2,80 (q, 2H, J=7,8, 15.3 Hz), is 1.31 (t, 3H, J=7.5 Hz).

(S)-4-(2-(2-(3-Chlorophenyl)acetamido)-2-(4-utiltity-2-yl)ethyl)phenyl)sulfamic acid

1H NMR (CD3OD) δ 7,33-of 7.23 (m, 3H) , 7,13-7,03 (m, 5H) , 5,43 (kV, 1H, J=5,1, 9.6 Hz), 3,51 (s, 2H), 3,29 (1H), 3,03 (1H, from avj, J=9,9, 14.1 Hz), 2,80 (q, 2H, J=7,5, 15 Hz), is 1.31 (t, 3H, J=7,8 Hz).

(S)-4-(2-(4-Utiltity-2-yl)-2-(2-(3-hydroxyphenyl)acetamido)ethyl)fenilalanina acid

1H NMR (CD3OD) δ 7,16-was 7.08 (m, 3H) , 7.03 is-7,00 (m, 3H) , 6,70-6,63 (m, 2H), 5,42-of 5.40 (m, 1H) , 3,44 (s, 2H) , OR 3.28 (1H, BUT from AVH, masked by solvent), 3.04 from (from AVG, J=14,1, 9.6 Hz), 2,89 (q, 2H, J=15, 7.5 Hz), is 1.31 (t, 3H, J=7.5 Hz).

(S)-4-(2-(4-Utiltity-2-yl)-2-(2-(2-methoxyphenyl)acetamido)ethyl)fenilalanina acid

1H NMR (CD3OD) δ of 8.00 (d, 1H, J=7.8 Hz), 7,26 (t, 1H, J=13,2 Hz), 7,09-7,05 (m, 4H), 7,01 (s, 1H) , 6,91-6,89 (m, 4H) , 5,44 of 5.39 (m, 1H) , 3,71 (s, 3H) , 3,52 (s, 2H) , 3,26 (1H, BUT from avj, J=14,1, 5,1 Hz), 3,06 (1H IN from avj, J=13,8, and 8.4 Hz), 2,80 (q, 2H, J=8,1, the 15.6 Hz), is 1.31 (t, 3H, J=1.2 Hz).

(S)-4-{2-(4-Utiltity-2-yl)-2-[2-(3-methoxyphenyl)acetamido]ethyl}fenilalanina KIS the PTA

1H NMR (CD3OD) δ 8,58 (d, 1H, J=8.1 Hz), 7,21 (t, 1H, J=7.8 Hz), 7,12-7,02 (m, 4H), for 6.81 (s, 2H), 6,72 (d, 1H, J=7.5 Hz), the 5.45 to 5.40 (m, 1H), 3,79 (s, 3H), 3,50 (s, 2H), 3,29 (1H, A of ABX, masked by solvent), is 3.08 (1H, B of ABX, J=11,8, 5,1 Hz), 2,80 (q, 2H, J=15, 7.5 Hz), is 1.31 (t, 3H, J=6.6 Hz).

(S)-4-(2-(4-Utiltity-2-yl)-2-(3-phenylpropanamide)ethyl)fenilalanina acid

1H NMR (CD3OD) δ 8,56 (d, 1H, J=8,4 Hz), 7,25-6,98 (m, 9H), 5,43 is 5.38 (m, 1H), 3,26 (1H, A of ABX, J=14.1 to, and 9.6 Hz), 2,97 (1H, B of ABX, J=10,9, 3 Hz), 2,58 was 2.76 (m, 3H), 2,98 (q, 2H, J=13,8, 7,2 Hz)of 1.29 (t, 3H, J=8.7 Hz).

(S)-4-(2-(2-(3,4-Acid)acetamido)-2-(4-utiltity-2-yl)ethyl)fenilalanina acid

1H NMR (CD3OD) δ 7,12-7,03 (m, 3H), 6,91 (d, 1H, J=8,4 Hz), PC 6.82 (s, 1H), 6,66 (d, 1H, J=2.1 Hz), 6,63 (d, 1H, J=2.1 Hz), 5,43 (m, 1H), 3,84 (s, 3H), of 3.80 (s, 3H), of 3.45 (s, 2H), 3,30 (1H), 3,03 (1H, B of ABX, J=14,1, 9.6 Hz), and 2.79 (q, 2H, J=15,1, 7,2 Hz), of 1.30 (t, 3H, J=7.2 Hz).

(S)-4-(2-(2-(2,3-Acid)acetamido)-2-(4-utiltity-2-yl)ethyl)fenilalanina acid

1H NMR (CD3OD) δ 8,31 (d, 1H, J=7.8 Hz), 7,11-6,93 (m, 6H), of 6.68 (d, 1H, J=7.5 Hz), 5,49-of 5.40 (m, 1H), a 3.87 (s, 3H), 3,70 (s, 3H), 3,55 (s, 2H), 3,26 (1H, A of ABX, masked by solvent), 3,06 (1H, B of ABX, J=13,9, 9 Hz), 2,80 (q, 2H, J=14,8, 7.5 Hz), is 1.31 (t, 3H, J=7.5 Hz).

(S)-4-(2-(3-(3-Chlorophenyl)propanamide)-2-(4-utiltity-2-yl)ethyl)fenilalanina acid

1H NMR (CD3OD) δ 7,27-to 7.18 (m, 3H), 7,13-was 7.08 (m, 5H), 7,01 (s, 1H), 5,3 (kV, 1H, J=5,1, 9.4 Hz), or 3.28 (1H, A of ABX, J=5,1, 14.1 Hz), 2,97 (1H, B of ABX, J=9,3, a 13.9 Hz), 2,88 was 2.76 (m, 4H), of 2.50 (t, 2H, J=8.1 Hz), is 1.31 (t, 3H, J=7,8 Hz).

(S)-4-(2-(4-Utiltity-2-yl)-2-(3-(2-methoxyphenyl)propanamide)ethyl)fenilalanina acid

1H NMR (CD3OD) δ 7.18 in-was 7.08 (m, 6H), 6,92 (d, 1H, J=8.1 Hz), PC 6.82 (t, 1H, J=7.5 Hz), 5.40 to to 5.35 (m, 1H), 3,25 (1H, A of ABX, J=15, 5,4 Hz)of 3.00 (1H, B of ABX, J=a 10.5, 7.5 Hz), 2,88 was 2.76 (m, 4H), 2,47 (q, 2H, J=9,1, 6 Hz), of 1.31 (t, 3H, J=7,8 Hz).

(S)-4-(2-(4-Utiltity-2-yl)-2-(3-(3-methoxyphenyl)propanamide)ethyl)fenilalanina acid

1H NMR (CD3OD) δ 7,19-7,00 (m, 5H), 6.75 in (s, 1H), 6.73 x (s, 1H), 5,42 lower than the 5.37 (m, 1H), 3,76 (s, 3H), of 3.25 (1H, A of ABX, J=13,9, a 5.4 Hz), 2,98 (1H, B of ABX, J=14.1 to, and 9.6 Hz), 2,86 is 2.75 (m, 4H), 2,48 (q, 2H, J=11,7, 1.2 Hz), 1,31 (t, 3H, J=7.5 Hz).

(S)-4-(2-(4-Utiltity-2-yl)-2-(3-(4-methoxyphenyl)propanamide)ethyl)fenilalanina acid

1H NMR (CD3OD) δ 7,13-6,99 (m, 7H), 6,82-of 6.78 (m, 2H), 5,42 lower than the 5.37 (m, 1H), 3.33 and (s, 3H), 3,23 (1H), 2,97 (1H, B of ABX, J=13,3, and 11.4 Hz), 2,83 is 2.75 (m, 4H), 2.49 USD (kV, 2H, J=6,4, and 3.3 Hz), is 1.31 (t, 3H, J=7.5 Hz).

(S)-4-{2-[2-(4-Ethyl-2,3-dioxopiperazinyl-1-yl)acetamido]-2-(4-utiltity-2-yl)ethyl}fenilalanina acid

1H NMR (CD3OD) δ 7,14 (s, 4H), was 7.08 (s, 1H), 5,56-the 5.51 (m, 1H), 4,34 (d, 2H, J=16.2 Hz), 3,88 (d, 2H, J=17.6 Hz), 3,59 is 3.40 (m, 3H), 3,26-3,14 (m, 3H), 2,98 (1H, B of ABX, J=10,8, a 13.9 Hz), 2,82 (q, 2H, J=6,9, 15 Hz), 1,32 (t, 3H, J=7.5 Hz), to 1.21 (t, 3H, J=7.2 Hz).

(S)-4-{2-(4-Atillia the ol-2-yl)-2-[2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamido]ethyl}fenilalanina acid

1H (CD3OD): δ 7,13 (s, 1H), 7,06-7,02 (m, 4H), to 6.95 (s, 1H), 5,42-5,31 (m, 1H), 4,43-4,18 (DD, 2H, J=16.5 Hz), 3,24-of 2.93 (m, 2H), 2,74-2,69 (q, 2H, J=7,3 Hz)to 1.79 (s, 3H), 1,22 (t, 3H, J=7.5 Hz).

(S)-4-[2-(benzo[d][1,3]dioxol-5-carboxamido)-2-(4-utiltity-2-yl)ethyl]fenilalanina acid

1H NMR (CD3OD) δ of 7.25 (d, 1H, J=6.5 Hz), 7,13 (s, 1H), 7,06 (d, 2H, J=8.5 Hz), 7,00 (d, 2H, J=8.5 Hz), 6,91 (s, 1H), 6,76 (d, 1H, J=8.1 Hz), 5,90 (s, 2H), 5,48 (kV, 1H, J=5.0 Hz), 3,32-3,24 (m, 2H), 3,07-to 2.99 (m, 2H,), of 2.72 (q, 2H, J=7.5 Hz), to 1.21 (t, 3H, J=7.5 Hz).

(S)-4-{2-[2-(2,5-Dimethylthiazol-4-yl)acetamido]-2-(4-utiltity-2-yl)ethyl}fenilalanina acid

1H (CD3OD): δ 7,10-7,01 (m, 5H), 5,41 (t, 1H, J=6,9 Hz)to 3.58 (s, 2H), 3.33 and-a 3.01 (m, 2H), 2,82 is 2.75 (q, 2H, J=7.5 Hz), at 2.59 (s, 3H), of 2.23 (s, 3H), of 1.30 (t, 3H, J=7.5 Hz).

(S)-4-{2-[2-(2,4-Dimethylthiazol-5-yl)acetamido]-2-(4-methylthiazole-2-yl)ethyl}fenilalanina acid

1H (CD3OD): δ 8,71-8,68 (d, 1H, J=8,4 Hz), 7,10-7,03 (m, 4H), 7,01 (s, 1H), 5,41 (m, 1H)and 3.59 (s, 1H), 3,34-2,96 (m, 2H), 2,59 (s, 3H), 2.40 a (s, 3H), of 2.23 (s, 3H).

(S)-4-{2-(4-Utiltity-2-yl)-2-[3-(thiazol-2-yl)propanamide]-ethyl}fenilalanina acid

1H (CD3OD): δ to 7.67-the 7.65 (m, 1H), 7,49-7,47 (m, 1H), 7,14-was 7.08 (m, 4H),? 7.04 baby mortality (s, 1H), 5,46-5,41 (kV, 1H, J=5,1 Hz)to 3.58 (s, 2H), 3,30-of 3.25 (m, 3H), 3,02-to 2.67 (m, 5H), is 1.31 (t, 3H, J=7.5 Hz).

(S)-4-{2-(4-Utiltity-2-yl)-2-[2-(4-utiltity-2-yl)acetamido]ethyl}fenilalanina acid

1H(CD3OD): δ? 7.04 baby mortality-6,91 (m, 6H), 5,32 (t, 1H, J=5.4 Hz), 3,25-2,90 (m, 2H), 2.71 to 2,61 (m, 4H) 1,93 (s, 2H), 1,22-to 1.14 (m, 6H).

The second aspect of category I of the present invention relates to 2-(thiazole-4-ilen) compounds of the formula:

where R1, R4and L have the meanings as defined in table II below.

td align="center"> 146 163
Table II
No.LR1R4
89-C(O)CH2-phenylmethyl
90-C(O)CH2-phenylethyl
91-C(O)CH2-phenylphenyl
92-C(O)CH2-phenylthiophene-2-yl
93-C(O)CH2-phenylthe thiazole-2-yl
94 -C(O)CH2-phenyloxazol-2-yl
95-C(O)CH2-phenylisoxazol-3-yl
96-C(O)CH2-3-chlorophenylmethyl
97-C(O)CH2-3-chlorophenylethyl
98-C(O)CH2-3-chlorophenylphenyl
99-C(O)CH2-3-chlorophenylthiophene-2-yl
100-C(O)CH2-3-chlorophenylthe thiazole-2-yl
101-C(O)CH2-3-chlorophenyloxazol-2-yl
102-C(O)CH2-isoxazol-3-yl
103 -C(O)CH2-methyl
104-C(O)CH2-ethyl
105-C(O)CH2-phenyl
106-C(O)CH2-3-chlorophenylthiophene-2-yl
107-C(O)CH2-3-methoxyphenylthe thiazole-2-yl
108-C(O)CH2-3-methoxyphenyloxazol-2-yl
109-C(O)CH2-3-methoxyphenylisoxazol-3-yl
110-C(O)CH2-3-forfinalmethyl
111-C(O)CH2-3-forfinalethyl
112-C(O)H 2-3-forfinalphenyl
113-C(O)CH2-3-forfinalthiophene-2-yl
114-C(O)CH2-3-forfinalthe thiazole-2-yl
115-C(O)CH2-3-forfinaloxazol-2-yl
116-C(O)CH2-3-forfinalisoxazol-3-yl
117-C(O)CH2-2.5-dimethylthiazol-4-ylmethyl
118-C(O)CH2-2.5-dimethylthiazol-4-ylethyl
119-C(O)CH2-2.5-dimethylthiazol-4-ylphenyl
120-C(O)CH2-2.5-dimethylthiazol-4-ylthiophene-2-yl
121-C(O)CH2-2.5-dimethylthiazol-4-ylthe thiazole-2-yl
122-C(O)CH2-2.5-dimethylthiazol-4-yloxazol-2-yl
123-C(O)CH2-2.5-dimethylthiazol-4-ylisoxazol-3-yl
124-C(O)CH2-2,4-dimethylthiazol-5-ylmethyl
125-C(O)CH2-2,4-dimethylthiazol-5-ylethyl
126-C(O)CH2-2,4-dimethylthiazol-5-ylphenyl
127-C(O)CH2-2,4-dimethylthiazol-5-ylthiophene-2-yl
128-C(O)CH2-2,4-dimethylthiazol-5-ylthe thiazole-2-yl
129 -C(O)CH2-2,4-dimethylthiazol-5-yloxazol-2-yl
130-C(O)CH2-2,4-dimethylthiazol-5-ylisoxazol-3-yl
131-C(O)CH2-4-utiltity-2-ylmethyl
132-C(O)CH2-4-utiltity-2-ylethyl
133-C(O)CH2-4-utiltity-2-ylphenyl
134-C(O)CH2-4-utiltity-2-ylthiophene-2-yl
135-C(O)CH2-4-utiltity-2-ylthe thiazole-2-yl
136-C(O)CH2-4-utiltity-2-yloxazol-2-yl
137-C(O)CH2-4-utiltity-2-yl isoxazol-3-yl
138-C(O)CH2-3-methyl-1,2,4-oxadiazol-5-ylmethyl
139-C(O)CH2-3-methyl-1,2,4-oxadiazol-5-ylethyl
140-C(O)CH2-3-methyl-1,2,4-oxadiazol-5-ylphenyl
141-C(O)CH2-3-methyl-1,2,4-oxadiazol-5-ylthiophene-2-yl
142-C(O)CH2-3-methyl-1,2,4-oxadiazol-5-ylthe thiazole-2-yl
143-C(O)CH2-3-methyl-1,2,4-oxadiazol-5-yloxazol-2-yl
144-C(O)CH2-3-methyl-1,2,4-oxadiazol-5-ylisoxazol-3-yl
145-C(O)CH2CH2-phenylmethyl
-C(O)CH2CH2-phenylethyl
147-C(O)CH2CH2-phenylphenyl
148-C(O)CH2CH2-phenylthiophene-2-yl
149-C(O)CH2CH2-phenylthe thiazole-2-yl
150-C(O)CH2CH2-phenyloxazol-2-yl
151-C(O)CH2CH2-phenylisoxazol-3-yl
152-C(O)CH2CH2-3-chlorophenylmethyl
153-C(O)CH2CH2-3-chlorophenylethyl
154-C(O)CH2CH2-3-chlorophenyl phenyl
155-C(O)CH2CH2-3-chlorophenylthiophene-2-yl
156-C(O)CH2CH2-3-chlorophenylthe thiazole-2-yl
157-C(O)CH2CH2-3-chlorophenyloxazol-2-yl
158-C(O)CH2CH2-3-chlorophenylisoxazol-3-yl
159-C(O)CH2CH2-3-methoxyphenylmethyl
160-C(O)CH2CH2-3-methoxyphenylethyl
161-C(O)CH2CH2-3-methoxyphenylphenyl
162-C(O)CH2CH2-3-methoxyphenylthiophene-2-yl
-C(O)CH2CH2-3-methoxyphenylthe thiazole-2-yl
164-C(O)CH2CH2-3-methoxyphenyloxazol-2-yl
165-C(O)CH2CH2-3-methoxyphenylisoxazol-3-yl
166-C(O)CH2CH2-3-forfinalmethyl
167-C(O)CH2CH2-3-forfinalethyl
168-C(O)CH2CH2-3-forfinalphenyl
169-C(O)CH2CH2-3-forfinalthiophene-2-yl
170-C(O)CH2CH2-3-forfinalthe thiazole-2-yl
171-C(O)CH2C 2-3-forfinaloxazol-2-yl
172-C(O)CH2CH2-3-forfinalisoxazol-3-yl
173-C(O)CH2CH2-2.5-dimethylthiazol-4-ylmethyl
174-C(O)CH2CH2-2.5-dimethylthiazol-4-ylethyl
175-C(O)CH2CH2-2.5-dimethylthiazol-4-ylphenyl
176-C(O)CH2CH2-2.5-dimethylthiazol-4-ylthiophene-2-yl
177-C(O)CH2CH2-2.5-dimethylthiazol-4-ylthe thiazole-2-yl
178-C(O)CH2CH2-2.5-dimethylthiazol-4-yloxazol-2-yl
179-C(O)CH2 CH2-2.5-dimethylthiazol-4-ylisoxazol-3-yl
180-C(O)CH2CH2-2,4-dimethylthiazol-5-ylmethyl
181-C(O)CH2CH2-2,4-dimethylthiazol-5-ylethyl
182-C(O)CH2CH2-2,4-dimethylthiazol-5-ylphenyl
183-C(O)CH2CH2-2,4-dimethylthiazol-5-ylthiophene-2-yl
184-C(O)CH2CH2-2,4-dimethylthiazol-5-ylthe thiazole-2-yl
185-C(O)CH2CH2-2,4-dimethylthiazol-5-yloxazol-2-yl
186-C(O)CH2CH2-2,4-dimethylthiazol-5-ylisoxazol-3-yl
187 -C(O)CH2CH2-4-utiltity-2-ylmethyl
188-C(O)CH2CH2-4-utiltity-2-ylethyl
189-C(O)CH2CH2-4-utiltity-2-ylphenyl
190-C(O)CH2CH2-4-utiltity-2-ylthiophene-2-yl
191-C(O)CH2CH2-4-utiltity-2-ylthe thiazole-2-yl
192-C(O)CH2CH2-4-utiltity-2-yloxazol-2-yl
193-C(O)CH2CH2-4-utiltity-2-ylisoxazol-3-yl
194-C(O)CH2CH2-3-methyl-1,2,4-oxadiazol-5-ylmethyl
195-C(O)CH CH2-3-methyl-1,2,4-oxadiazol-5-ylethyl
196-C(O)CH2CH2-3-methyl-1,2,4-oxadiazol-5-ylphenyl
197-C(O)CH2CH2-3-methyl-1,2,4-oxadiazol-5-ylthiophene-2-yl
198-C(O)CH2CH2-3-methyl-1,2,4-oxadiazol-5-ylthe thiazole-2-yl
199-C(O)CH2CH2-3-methyl-1,2,4-oxadiazol-5-yloxazol-2-yl
200-C(O)CH2CH2-3-methyl-1,2,4-oxadiazol-5-ylisoxazol-3-yl

Compounds included in the second aspect of category I of the present invention can be obtained by the method presented in scheme II and described below in example 2 of this specification.

Scheme II

Reagents and conditions: (a) (i) (isobutyl)Cl, Et3N, THF; 0°C, 20 min; (ii) CH2N2; at room temperature the tour, within 30 hours.

Reagents and conditions: (b) 48%HBr, THF; 0°C, 1.5 hours.

Reagents and conditions: (C) CH3CN; boiling under reflux, 5 hours.

Reagents and conditions: (d) (3-Cl)C6H4CO2H, EDCI, HOBt, DIPEA, DMF; room temperature, 18 hours.

Reagents and conditions: (e) (i) H2:Pd/C, CH3OH; (ii) SO3-pyridine, NH4OH, room temperature, 18 hours.

Example 2

4-((S)-2-(2-(3-Chlorophenyl)acetamido)-2-(2-(thiophene-2-yl)thiazol-4-yl)ethyl)fenilalanina acid (10)

Obtain tert-butyl ether (S)-[3-diazo-1-(4-nitrobenzyl)-2-oxopropyl]carbamino acid (6):

It cooled down to 0°C solution of 2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)propionic acid (1.20 g, 4.0 mmol) in THF (20 ml) was added drop wise addition of triethylamine (and 0.61 ml, 4.4 mmol), then isobutylparaben (or 0.57 ml, 4.4 mmol). The reaction mixture was stirred at 0°C for 20 minutes and filtered. The filtrate is treated with a solution of diazomethane in diethyl ether (approximately 16 mmol) at 0°C. the Reaction mixture was stirred at room temperature for 3 hours, then concentrated in vacuo. The resulting residue is dissolved in ethyl acetate and washed with serial is Ino water and saturated salt solution, dried (Na2SO4), filtered and concentrated. The residue is purified using silica (hexane/ethyl acetate in the ratio 2:1)to give 1.1 g (yield 82%) of the desired product as a slightly yellowish solid.

1H NMR (300 MHz, CDCl3) δ is 8.16 (d, J=8.7 Hz, 2H), 7,39 (d, J=8.7 Hz, 2H), 5,39 (s, 1H), 5,16 (d, J=6.3 Hz, 1H), 4,49 (s, 1H), 3,25 (DD, J=13.8 and 6,6, 1H), 3,06 (DD, J=13.5 and 6.9 Hz, 1H), of 1.41 (s, 9H).

Obtain (S)-tert-butyl-4-bromo-1-(4-nitrophenyl)-3-oxobutyl-2-ylcarbamate (7):

It cooled down to 0°C. a solution of tert-butyl methyl ether (S)-[3-diazo-1-(4-nitrobenzyl)-2-oxopropyl]carbamino acid 6 (0,350 g, 1.04 mmol) in THF (5 ml) is added dropwise 48%aqueous HBr solution (of 0.14 ml, 1.25 mmol). The reaction mixture was stirred at 0°C for 1.5 hours, then the reaction is quenched at 0°With a saturated solution of Na2CO3. The mixture is extracted with ethyl acetate (3×25 ml) and the combined organic extracts washed with saturated salt solution, dried (Na2SO4), filtered and concentrated, obtaining 0.400 g of product, which is used in the next stage without further purification.

1H NMR (300 MHz, CDCl3) δ to 8.20 (d, J=8,4 Hz, 2H), 7,39 (d, J=8,4 Hz, 2H), is 5.06 (d, J=7.8 Hz, 1H), 4,80 (kV, J=6.3 Hz, 1H), Android 4.04 (s, 2H), of 1.42 (s, 9H).

Getting hydrobromide (S)-2-(4-nitrophenyl)-1-[(thiophene-2-yl)thiazol-4-yl]ethanamine (8):

A mixture of (S)-tert-butyl-4-bromo-1-(4-n is trienyl)-3-oxobutyl-2-ylcarbamate 7 (7,74 g, 20 mmol) and amide thiophene-2-carbothiolate (3,14 g, 22 mmol) in CH3CN (200 ml) is refluxed for 5 hours. The reaction mixture is cooled to room temperature and the solution was added diethyl ether (50 ml). Dropped the precipitate was separated by filtration. The solid is dried in vacuum, obtaining 7,14 g (yield 87%) of the desired product.

MC (ESI+): 322 (M+1).

Getting 2-(3-chlorophenyl)-N-{(S)-2-(4-nitrophenyl)-1-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}ndimethylacetamide (9):

To a solution of 2-(4-nitrophenyl)-1-(2-thiophene-2-iltiazem-4-yl)ethylamine 8 (0,41 g, 1 mmol), 3-chlorophenylalanine acid (0,170 g, 1 mmol) and 1-hydroxybenzotriazole (HOBt) (0,070 g, 0.50 mmol) in DMF (5 ml) at a temperature of 0°C was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0,190 g, 1 mmol), then triethylamine (0,42 ml, 3 mmol). The mixture is stirred at 0°C for 30 minutes, then at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phase was washed with 1 N. aqueous solution of HCl, 5%aqueous solution of NaHCO3, water and saturated salt solution and dried over Na2SO4. The solvent is removed in vacuum, obtaining 0,290 g (yield 60%) of the desired product which is used without further purification.

MS (ESI-): 482 (M-1).

Obtain {4-[2-(3-chlorophenyl)atsetamino)-2-(2-(thiophene-2-yl)thiazol-4-yl)ethyl]phenyl}self mirovoi acid (10):

2-(3-Chlorophenyl)-N-{(S)-2-(4-nitrophenyl)-1-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}ndimethylacetamide 9 (0,290 g) dissolved in methanol (4 ml). Add a catalytic amount of Pd/C (10% wt./wt.) and the mixture is stirred in hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a layer of CELITETMand the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 ml) and treated SO3-pyridine (of) 0.157 g). The reaction mixture was stirred at room temperature for 5 minutes, then add the 7%solution of NH4OH. The mixture was then concentrated and the resulting residue purified by chromatography with reversed phase, receiving 0,078 g of the desired product in the form of ammonium salt.

1H NMR (CD3OD) δ to 7.61 (d, 1H, J=3.6 Hz), 7,58 (d, 1H, J=5,1 Hz), 7,41-7,35 (m, 1H), 7,28-7,22 (m, 2H), 7.18 in-6,98 (m, 6H), 5,33 (t, 1H, J=6.6 Hz), 3,70 (d, 2H, J=3,9 Hz), 3,23 (1H, A of ABX, J=6,6, of 13.8 Hz), of 3.07 (1H, B from ABX, J=8,1, and 13.5 Hz).

Below are non-limiting examples of compounds included in the second aspect of category I of the present invention.

4-((S)-2-(2-(3-Methoxyphenyl)acetamido)-2-(2-(thiophene-2-yl)thiazol-4-yl)ethyl)fenilalanina acid

1H NMR (CD30D) δ 8,35 (d, 1H, J=8.7 Hz), to 7.61-EUR 7.57 (m, 2H), 7,25-7,20 (m, 2H), 7,25-7,20 (m, 2H), to 7.09 (s, 1H), 7,05 (d, 2H, J=4, 2 Hz), of 6.99 (d, 1H, J=8.7 Hz), for 6.81 (d, 1H, J=7.8 Hz), 6,77 (s, 1H), 5,30 is 5.28 (m, 1H), 3,76 (s, 3H), 3,51 (s, 2H), 3,20 (1H, A of ABX, J=6,3, to 13.6 Hz), 3,06 (1H, B of ABX, J=8,1, to 13.8 Hz).

p>

4-{(S)-2-(3-Phenylpropanamide)-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}fenilalanina acid

1H NMR (CD3OD) δ 8.30 to (d, 1H, J=9 Hz), to 7.61-7,56 (m, 2H), 7,26-7,14 (m, 7H), 7,12 (d, 1H, J=1.5 Hz), to 7.09 (d, 1H, J=2.1 Hz), 6.89 in (s, 1H), 5,28-of 5.26 (m, 1H), 3,18 (1H, A of ABX, J=6,2, to 13.8 Hz), 2,96 (1H, B of ABX, J=8.4 and, to 13.6 Hz).

4-{(S)-2-(3-(3-Chlorophenyl)propanamide)-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}fenilalanina acid

1H NMR (CD3OD) δ to 7.61-7,56 (m, 3H), 7,22-7,14 (m, 6H), was 7.08 (d, 1H), 7,00 (d, 1H, J=77,5 Hz), 6,870 (s, 1H), 5.25 in (t, 1H, J=7.8 Hz), 3,18 (1H, A of ABX, J=6,6, of 13.8 Hz), 2,97 (1H, B of ABX, J=7,8, or 13.8 Hz), 2,87 (t, 2H, J=7,5 Hz), of 2.51 (t, 2H, J=7,2 Hz).

4-{(S)-2-(2-(3-Forfinal)propanamide)-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}fenilalanina acid

1H NMR (CD3OD) δ to 7.61-EUR 7.57 (m, 2H), 7,32-7,28 (m, 1H), 7,19-7,16 (m, 2H), was 7.08 (t, 1H, J=4.5 Hz), 7,02-to 6.95 (m, 6H), from 5.29 (t, 1H, J=8.1 Hz), 3,53 (s, 2H), up 3.22 (1H, A of ABX, J=6,6, a 13.9 Hz), 3,06 (1H, B of ABX, J=8,4, to 13.6 Hz).

(S)-4-{2-[2-(3-Methyl-1,2,4-oxadiazol-5-yl)acetamido]-2-(2-(phenylthiazol-4-yl)ethyl}fenilalanina acid

1H (CD3OD): δ 7,98-to 7.95 (m, 2H), of 7.48-7,46 (m, 3H), of 7.23 (s, 1H), 7,09-7,05 (m, 4H), 5,33 (t, 1H, J=7,2 Hz), 3.33 and-a 3.06 (m, 2H), 2,35 (s, 3H).

4-{(S)-2-[2-(4-Ethyl-2,3-dioxopiperazinyl-1-yl)acetamido]-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}fenilalanina acid

1H NMR (CD3OD) δ a 7.62 (d, 1H, J=3 Hz), 7,58 (d, 1H, J=15.6 Hz), 7,27 (s, 1H), 7,16 (t, 1H, J=15 Hz), 5,42-5,32 (m, 1H), or 4.31 (d, 1H, J=15.6 Hz), 3,91 (d, 1H, J=15,9 Hz), 3,60-to 3.50 (m, 4H), 3,30 is 3.23 (m, 2H), 2,98 (1H, B of ABX, J=9,9, to 13.8 Hz), to 1.21 (t, 3H, J=6.9 Hz).

The third aspect of category I of the present invention relates to compounds of the formula:

where the linking group L include phenyl group, with the above linking group has the formula:

-C(O)[(CR6aH)][(CH2)]-,

R5ameans phenyl or substituted phenyl, and non-limiting examples of groups R2, R3and R6ain table III, below.

Table III
No.R2R3R6a
201methylhydrogenphenyl
202methylhydrogen2-forfinal
203methylhydrogen3-forfinal
204methylin the location 4-forfinal
205methylhydrogen3,4-differenl
206methylhydrogen2-chlorophenyl
207methylhydrogen3-chlorophenyl
208methylhydrogen4-chlorophenyl
209methylhydrogen3,4-dichlorophenyl
210methylhydrogen2-methoxyphenyl
211methylhydrogen3-methoxyphenyl
212methylhydrogen4-methoxyphenyl
213ethylhydrogenFe is Il
214ethylhydrogen2-forfinal
215ethylhydrogen3-forfinal
216ethylhydrogen4-forfinal
217ethylhydrogen3,4-differenl
218ethylhydrogen2-chlorophenyl
219ethylhydrogen3-chlorophenyl
220ethylhydrogen4-chlorophenyl
221ethylhydrogen3,4-dichlorophenyl
222ethylhydrogen2-methoxyphenyl
223 ethylhydrogen3-methoxyphenyl
224ethylhydrogen4-methoxyphenyl

Compounds included in the third aspect of category I of the present invention can be obtained by the method presented in scheme III and described below in example 3 of this specification.

Scheme III

Reagents and conditions: (a) diphenylpropionic acid, EDCI, HOBt, TEA, DMF; temperature from 0°C to room temperature 18 hours.

Reagents and conditions: (b) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH; room temperature, 18 hours.

Example 3

(S)-4-(2-(2,3-Diphenylpropanoic)-2-(4-utiltity-2-yl)ethyl)fenilalanina acid (12)

Obtain (S)-N-[1-(4-utiltity-2-yl)-2-(4-nitrophenyl)ethyl]-2,3-diphenylpropylamine (11):

To a solution of the hydrobromide 1-(S)-(4-utiltity-2-yl)-2-(4-nitrophenyl)ethylamine 3 (0.95 g, to 2.65 mmol), diphenylpropionic acid (0,60 g, to 2.65 mmol) and 1-hydroxybenzotriazole (HOBt) (0,180 g of 1.33 mmol) in DMF (10 ml) at a temperature of 0°C was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0,502 g, 2,62 mmol), then triethylamine (1.1 ml, 7,95 mmol). The mixture is stirred at 0°C for 30 minutes, then at room temp is the atur during the night. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phase was washed with 1 N. aqueous solution of HCl, 5%aqueous solution of NaHCO3, water and saturated salt solution and dried over Na2SO4. The solvent is removed in vacuum, obtaining of 0.903 g (yield 70%) of the desired product which is used without further purification.

Obtain (S)-4-(2-(2,3-diphenylpropanoic)-2-(4-utiltity-2-yl)ethyl)phenylalaninol acid (12):

(S)-N-[1-(4-Utiltity-2-yl)-2-(4-nitrophenyl)ethyl]-2,3-diphenylpropanoic 11 (of 0.903 g) dissolved in methanol (10 ml). Add a catalytic amount of Pd/C (10% wt./wt.) and the mixture is stirred in hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a layer of CELITETMand the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (30 ml) and treated SO3-pyridine (0,621 g). The reaction mixture was stirred at room temperature for 5 minutes, then add a solution of NH4OH. The mixture was then concentrated and the resulting residue purified by chromatography with reversed phase, receiving 0,415 g of the desired product in the form of ammonium salt.

1H NMR (CD3OD) δ 8,59-charged 8.52 (m, 1H), 7,37? 7.04 baby mortality (m, 9H), 6,97-6,93 (m, 1H), 6.89 in-6,85 (m, 2H), are 5.36-5,32 (m, 1H), 3,91-a 3.83 (m, 1H), 3,29 (1H, A of ABX, masked by solvent)and 3.15 (1H, B of ABX, J=5,4, 33,8 Hz), 2,99-is 2.88 (m, 2H), 2,81-2,69 (m, 2H), 1.32 to 1,25 (m, 3H).

Predecessors of many of the groups Z, which includes the third aspect of category I, are readily available. The following method illustrates an example method that can be used for different groups of R6aof the present invention. Using the method presented in scheme IV and described in example 4, the person skilled in the art can make modifications without undue experimentation to obtain groups of R5awith reference to the present description.

Scheme IV

13

Reagents and conditions: (a) methyl-2-(2-methoxyphenyl)acetate, LDA, THF; temperature from 0°C to room temperature 18 hours.

Reagents and conditions: (b)

Example 4

2-(2-Methoxyphenyl)-3-phenylpropane acid (14)

Obtaining methyl-2-(2-methoxyphenyl)-3-phenylpropanoate (13):

In a round bottom flask with a capacity of 500 ml make methyl-2-(2-methoxyphenyl)acetate (8,496 g, 47 mmol, 1 EQ.) and THF (200 ml). Homogeneous mixture is cooled to a temperature of 0°C in an ice bath. Add diisopropylamide lithium (23,5 ml of 2.0m solution in a mixture of heptane/THF), keeping the temperature below 3°C. the Reaction mixture is stirred for 45 minutes at this low temperature. Added dropwise benzylbromide (5.6 ml, 47 mmol, 1 EQ.). The reaction mixture is left to gradually warm up to anatoy temperature and stirred for 18 hours. The reaction is quenched with 1 N. HCl and extracted 3 times with equal portions of ethyl acetate. The combined extracts washed with N2O and saturated salt solution, dried over Na2SO4filter and concentrate. The residue is purified using silica, getting 4,433 g (yield 35%) of the desired compound.

MS (ESI+): 293 (M+Na).

Obtaining 2-(2-methoxyphenyl)-3-phenylpropane acid (14):

Methyl-2-(2-methoxyphenyl)-3-phenylpropanoate (4,433 g, 16 mmol, 1 EQ.) dissolve in 100 ml of a mixture of THF and methanol in the ratio of 1:1 (vol./vol.). Add sodium hydroxide (3.28 g, 82 mmol, 1 EQ.) and the reaction mixture stirred for 18 hours at room temperature. The reaction mixture was then poured into water and the pH adjusted to 2 by adding 1 N. HCl. Roll a white precipitate, which is removed by filtration. The resulting solution was extracted with 3 portions of diethyl ether. The extracts are combined washed with N2O and saturated salt solution, dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue is purified using silica, getting 2,107 g (51%) of the desired compound.

MS (ESI-): 255 (M-1); 211 (M-CO2N).

The intermediate product 14 can be obtained in accordance with methods described in scheme III and described in example 3 to obtain the following compounds according to the third aspect of category the AI I.

(S)-4-{2-(4-Utiltity-2-yl)-2-[2-(2-methoxyphenyl)-3-phenylpropanamide]ethyl}fenilalanina acid

1H NMR (CD3OD) δ 7,32 for 7.12 (m, 7H), 7,05-7,02 (m, 1H), 6,99-6,83 (m, 4H), 6,80 to 6.75 (m, 2H), 5,35-5,31 (m, 1H), or 4.31-4.26 deaths (m, 1H, in), 3.75 (s, 3H), 3,20-2,90 (m, 4H), 2,79-to 2.74 (m, 2H), 1.32 to 1,25 (m, 3H).

Below is a further, non-limiting examples of compounds according to the third aspect of category I of the present invention.

(S)-4-{2-(4-Utiltity-2-yl)-2-[2-(3-forfinal)-3-phenylpropanamide]ethyl}fenilalanina acid

1H NMR (CD3OD) δ 7,33-6,87 (m, 14H), 5,39-a 5.25 (m, 1H), 3.95 to a 3.83 (m, 1H), 3,31-3,10 (m, 1H), 3,05-is 2.88 (m, 2H), 2,80-2,70 (m, 2H), 1,32 is 1.23 (m, 3H).19F NMR δ 47,59.

(S)-4-{2-(4-Utiltity-2-yl)-2-[2-(3-methoxyphenyl)-3-phenylpropanamide]ethyl}fenilalanina acid

1H NMR (CD3OD) δ a 7.85 (d, 1H, J=8,4 Hz), 7,25-7,20 (m, 1H), 7,11-7,02 (m, 4H), 7,01 (s, 1H), 6.90 to-6,79 (m, 2H), the 5.45 to 5.40 (m, 1H), 4.09 to (s, 2H), 3,79 (s, 3H), 3,12-is 3.08 (m, 2H), 1,10 (s, 9H).

The fourth aspect of category I of the present invention relates to compounds of the formula:

where the linking group L include phenyl group, with the above linking group has the formula:

-C(O)[(CR6aH)][(CH2)]-,

R5ameans substituted or unsubstituted heteroaryl, and examples of the groups R2, R3and R5agiven neither the e in table IV.

Table IV
No.R2R3R6a
225methylhydrogen3-methyl-1,2,4-oxadiazol-5-yl
226methylhydrogenthiophene-2-yl
227methylhydrogenthe thiazole-2-yl
228methylhydrogenoxazol-2-yl
229methylhydrogenisoxazol-3-yl
230ethylhydrogen3-methyl-1,2,4-oxadiazol-5-yl
231ethylhydrogenthiophene-2-yl
232 ethylhydrogenthe thiazole-2-yl
233ethylhydrogenoxazol-2-yl
234ethylhydrogenisoxazol-3-yl
235ethylmethyl3-methyl-1,2,4-oxadiazol-5-yl
236ethylmethylthiophene-2-yl
237ethylmethylthe thiazole-2-yl
238ethylmethyloxazol-2-yl
239ethylmethylisoxazol-3-yl
240thiophene-2-ylhydrogen3-methyl-1,2,4-oxadiazol-5-yl
241iophen-2-yl hydrogenthiophene-2-yl
242thiophene-2-ylhydrogenthe thiazole-2-yl
243thiophene-2-ylhydrogenoxazol-2-yl
244thiophene-2-ylhydrogenisoxazol-3-yl
245isoxazol-3-ylhydrogen3-methyl-1,2,4-oxadiazol-5-yl
246isoxazol-3-ylhydrogenthiophene-2-yl
247isoxazol-3-ylhydrogenthe thiazole-2-yl
248isoxazol-3-ylhydrogenoxazol-2-yl
249isoxazol-3-ylhydrogenisoxazol-3-yl

Compounds are included the in the fourth aspect of category I of the present invention, can be obtained by the method presented in scheme V and described below in example 5 of this specification.

Scheme V

Reagents and conditions: (a) 2-benzyl-3-ethoxy-3-oxopropanoic acid, EDCI, HOBt, DIPEA, DMF; room temperature, 18 hours.

Reagents and conditions: (b) CH3C(=NOH)NH2, K2CO3, toluene; boiling under reflux, 18 hours.

Reagents and conditions: (C) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH; room temperature, 18 hours.

Example 5

4-{(S)-2-(4-Utiltity-2-yl)-2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-phenylpropanamide]ethyl}fenilalanina acid (17)

Getting ethyl-2-benzyl-3-[(S)-1-(4-utiltity-2-yl)-2-(4-nitrophenyl)ethylamino]-3-oxopropanoic (15):

To a solution of the hydrobromide 1-(S)-(4-utiltity-2-yl)-2-(4-nitrophenyl)ethylamine 3 (0,406 g, 1.13 mmol), 2-benzyl-3-ethoxy-3-oxopropanoic acid (0,277 g) and 1-hydroxybenzotriazole (HOBt) (0,191 g of 1.41 mmol) in DMF (10 ml) at a temperature of 0°C was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0,240 g, 1.25 mmol), then diisopropylethylamine (DIPEA) (0,306 g). The mixture is stirred at 0°C for 30 minutes, then at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. United organicheskoi the phase is washed with 1 N. aqueous solution of HCl, 5%aqueous solution of NaHCO3, water and saturated salt solution and dried over Na2SO4. The solvent is removed in vacuum, obtaining 0,169 g (yield 31%) of the desired product which is used without further purification.

Obtaining N-[(S)-1-(4-utiltity-2-yl)-2-(4-nitrophenyl)ethyl]-2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-phenylpropanamide (16):

Ethyl-2-benzyl-3-((S)-1-(4-utiltity-2-yl)-2-(4-nitrophenyl)ethylamino)-3-oxopropanoic dissolved in toluene (5 ml) and heated to the boiling temperature under reflux. Add potassium carbonate (80 mg) and oxiracetam (43 mg) and treated with 80 mg of potassium carbonate and 43 mg of oxiracetam at the boiling point under reflux. The reaction mixture is cooled to room temperature, filtered and concentrated. The remainder chromatographic using silicon dioxide, getting 0,221 g (yield 94%) of the desired product as a yellow oil.

Getting 4-{(S)-2-(4-utiltity-2-yl)-2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-phenylpropanamide]ethyl}phenylalaninol acid (17):

N-[(S)-1-(4-Utiltity-2-yl)-2-(4-nitrophenyl)ethyl]-2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-phenylpropanamide 16 (0,221 g) and tin chloride(II) (507 mg, 2.2 mmol) dissolved in ethanol (25 ml) and the solution refluxed for 4 hours. The solvent is removed in vacuo and the resulting residue is dissolved in etelaat the E. Add a saturated solution of NaHCO3(50 ml) and the solution stirred for 1 hour. The organic layer is separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers are dried (Na2SO4), filtered and concentrated, obtaining a residue which is dissolved in pyridine (0,143 g) and treated SO3-pyridine (0,143 g). The reaction mixture was stirred at room temperature for 5 minutes, then add the 7%solution of NH4OH. The mixture was then concentrated and the resulting residue purified by chromatography with reversed phase, receiving 0,071 g of the desired product in the form of ammonium salt.

1H (CD3OD): δ 7.29 trend-6,87 (m, 10H), 5,38-and 5.30 (m, 1H), 4,37-4,30 (m, 1H), 3,42-to 2.74 (m, 6H), 2,38 is 2.33 (m, 3H), 1,34 of 1.28 (m, 3H).

Category II of the present invention relates to 2-(thiazol-2-ilen) compounds of the formula:

where R1, R2, R3and L have the meanings as defined in table V.

Table V
No.R2R3R1
250ethylhydrogenthiophene-2-yl
251ethylhydrogenthe thiazole-2-yl
252ethylhydrogenoxazol-2-yl
253ethylhydrogenisoxazol-3-yl
254ethylhydrogenthiophene-2-yl
255ethylhydrogenthe thiazole-2-yl
256ethylhydrogenoxazol-2-yl
257ethylhydrogenisoxazol-3-yl
258ethylhydrogenthiophene-2-yl
259ethylhydrogenthe thiazole-2-yl
260 ethylmethylmethyl
261ethylmethylethyl
262ethylmethylcut
263ethylmethylisopropyl
264ethylmethylbutyl
265ethylmethylphenyl
266ethylmethylbenzil
267ethylmethyl2-forfinal
268ethylmethyl3-forfinal
269ethylmethyl4-forfinal
270phenylhydrogenmethyl
271phenylhydrogenethyl
272phenylhydrogencut
273phenylhydrogenisopropyl
274phenylhydrogenbutyl
275phenylhydrogenphenyl
276phenylhydrogenbenzil
277phenylhydrogen2-forfinal
278phenylhydrogen3-forfinal
279phenylhydrogen 4-forfinal
280thiophene-2-ylhydrogenmethyl
281thiophene-2-ylhydrogenethyl
282thiophene-2-ylhydrogencut
283thiophene-2-ylhydrogenisopropyl
284thiophene-2-ylhydrogenbutyl
285thiophene-2-ylhydrogenphenyl
286thiophene-2-ylhydrogenbenzil
287thiophene-2-ylhydrogen2-forfinal
288thiophene-2-ylhydrogen3-forfinal
289thiophene-2-ylhydrogen4-forfinal

Compounds included in category II of the present invention can be obtained by the method presented in scheme VI and described below in example 6 of this specification.

Scheme VI

Reagents and conditions: (a) 3-benzoylpropionic acid, TsCl, N-Mei, CH2Cl2, room temperature, 18 hours.

Reagents and conditions: (b) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH.

Example 6

(S)-4-[2-(4-Utiltity-2-yl)-2-(4-oxo-4-phenylbutyramide)ethyl]fenilalanina acid (19)

Obtain (S)-N-[1-(4-utiltity-2-yl)-2-(4-nitrophenyl)ethyl]-4-oxo-4-phenylbutyramide (18):

3-Benzoylpropionic acid (0,250 g) dissolved in CH2Cl2(5 ml), add N-Mei (of 0.333 ml) and the resulting solution is cooled to a temperature of 0°C., then added dropwise a solution of p-toluensulfonate (0,320 g) in CH2Cl2(2 ml). After 0.5 hours add (S)-1-(4-utiltity-2-yl)-2-(4-nitrophenyl)ethanamine 3 (0,388 g). The reaction mixture is stirred for 18 hours at room temperature and then concentrated in vacuo. The resulting residue is dissolved in ethyl acetate and washed with 1 N. hydrochloric acid and saturated salt solution. Rest the R dried over Na 2SO4, filtered, concentrated and the crude substance is purified using silica, getting 0,415 g of the desired product.

Obtain (S)-4-[2-(4-utiltity-2-yl)-2-(4-oxo-4-phenylbutyramide)ethyl]phenylalaninol acid (19):

(S)-N-[1-(4-Utiltity-2-yl)-2-(4-nitrophenyl)ethyl]-4-oxo-4-phenylbutane 18 (0.2 g) dissolved in methanol (15 ml). Add a catalytic amount of Pd/C (10% wt./wt.) and the mixture is stirred in hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a layer of CELITETMand the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (5 ml) and treated SO3-pyridine (0,153 g). The reaction mixture was stirred at room temperature for 5 minutes, then add the 7%solution of NH4OH. The mixture was then concentrated and the resulting residue purified by chromatography with reversed phase, receiving 0,090 g of the desired product in the form of ammonium salt.

1H NMR (CD3OD) δ 8,68 (d, 1H, J=8,2 Hz), 8,00 (d, 2H, J=7,2 Hz), 7,80 is 7.50 (m, 3H), 7,12 (s, 4H), 7,03 (s, 1H), 5,46 is 5.38 (m, 1H), 3,29-3,14 (m, 2H), 3,06-to 2.99 (m, 2H), and 2.83 (q, 2H, J=7.5 Hz), 2,69-of 2.54 (m, 2H), 1,33 (t, 3H, J=7.5 Hz).

Below are non-limiting examples of compounds included in category II of the present invention. The intermediate nitro compounds can also be obtained by reacting the corresponding 4-oxocarbons acid with p is megalocnus product 3 in terms described above in this description to obtain an intermediate product 4 according to scheme I.

(S)-4-(2-(4-Utiltity-2-yl)-2-(5-methyl-4-oxohexanoate)ethyl)fenilalanina acid

1H NMR (CD3OD) δ 8,59 (d, 1H, J=8.1 Hz), 7,14 (s, 4H), was 7.08 (t, 1H, J=13,0 Hz), 5.40 to to 5.35 (m, 1H), 3,37-of 3.27 (m, 2H), 3.04 from-of 2.97 (m, 1H), 2,83-2,61 (m, 4H), 2,54-of 2.36 (m, 3H), of 1.33 (t, 2H, J=7,3 Hz), 1,09 (DD, 6H, J=7,0 and 2.2 Hz).

(S)-4-{2-[4-(3,4-Dihydro-2H-benzo[b][1,4]dioxan-7-yl)-4-oxobutanamide]-2-(4-utiltity-2-yl)ethyl}fenilalanina acid

1H NMR(CD3OD) δ 8,64 (d, 1H, J=8,4 Hz), 7,60 (d, 2H, J=a 10.6 Hz), 7,11 (s, 3H),? 7.04 baby mortality (d, 2H, J=5.5 Hz), 5,42-of 5.40 (m, 1H), 4,30-4,22 (m, 4H), 3,20 are 2.98 (m, 4H), 2,82 (q, 2H, J=7,3 Hz), 2,67-2,48 (m, 2H), 2,23 (t, 2H, J=5.5 Hz), 1,32(t, 3H, J=7,3 Hz).

(S)-4-{2-[4-(2,3-Acid)-4-oxobutanamide]-2-(4-utiltity-2-yl)ethyl}fenilalanina acid

1H NMR (CD3OD), δ 8,64,(d, 1H, J=8.1 Hz), 7,21-7,11 (m, 7H), 7,02 (s, 1H), 5,42 (kV, 1H, J=5,9 Hz), 3,90 (d, 3H, J=3.3 Hz), 3,88 (d, 3H, J=2,9 Hz), 3,22-3,18 (m, 2H), 3,07-to 2.99 (m, 2H), and 2.83 (q, 2H, J=7,3 Hz), 2.63 in-to 2.54 (m, 2H), of 1.34 (t, 3H, J=7,69 Hz).

(S)-4-{2-[4-Utiltity-2-yl)-2-[4-oxo-4-(pyridin-2-yl)butanamide]ethyl}fenilalanina acid

1H NMR (CD3OD) δ at 8.60 (d, 1H, J=12,8 Hz), to $ 7.91-7,81 (m, 2H), of 7.48-7,44 (m, 1H), 7,22-7,21 (m, 1H), 6,99 (s, 3H), 6,91 (s, 1H), and 5.30 (q, 1H, J=5.4 Hz), to 3.36 (q, 2H, J=7.0 Hz), 3,21 is 3.15 (m, 1H), 2.91 in-2,85 (m, 1H), 2,74 (kV, 2H, J=10.4 Hz), 2.57 m-2,50 (m, 2H), 1,20 (t, 3H, J=7.5 Hz).

img src="https://img.russianpatents.com/1094/10948421-s.jpg" height="27" width="62" />

(S)-4-{2-[4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-4-oxobutanamide]-2-(4-utiltity-2-yl)ethyl}fenilalanina acid

1H NMR (CD3OD) δ 7,52-7,47 (m, 2H), 7,11 (s, 4H), 7,03 (s, 1H), 6,95 (d, 1H, J=8,4 Hz), 5,41 (kV, 1H, J=3,7 Hz), or 4.31 (d, 4H, J=5.5 Hz), 3,24-of 3.12 (m, 2H), 3,06 are 2.98 (m, 2H), and 2.83 (q, 2H, J=7,3 Hz), 2,62 of $ 2.53 (m, 2H), of 1.33 (t, 3H, J=7,3 Hz).

(S)-4-[2-(4-tert-Butoxy-4-oxobutanamide)-2-(4-utiltity-2-yl)ethyl]fenilalanina acid

1H NMR (CD3OD), δ 7,10 (s, 4H), 7,02 (s, 1H), 5,41 (kV, 1H, J=3,7 Hz), 3,30-of 3.25 (m, 1H), 3,06-2,99 (m, 1H), and 2.83 (q, 2H, J=7,3 Hz), 2,52-to 2.40 (m, 4H), of 1.42 (s, 9H), of 1.33 (t, 3H, J=7,3 Hz).

(S)-4-[2-(4-Ethoxy-4-oxobutanamide)-2-(4-utiltity-2-yl)ethyl]fenilalanina acid

1H NMR (CD3OD) δ to 8.62 (d, 1H, J=8,4 Hz), 7,10 (s, 4H), 7,02 (s, 1H), of 5.40 (q, 1H, and 3.7 Hz), is 4.15 (q, 2H, J=7,3 Hz), 3,28-of 3.25 (m, 1H), 3,05-to 3.02 (m, 1H), 2,82 (q, 2H, J=4.4 Hz), 2,54-2,48 (m, 2H), 1,33 (t, 3H, J=7,3 Hz), of 1.24 (t, 3H, J=7,0 Hz).

The first aspect of category III of the present invention relates to 2-(thiazol-2-ilen) compounds of the formula:

where non-limiting examples of R1, R2and R3below in table VI of this specification.

Table VI
No.R2R3 R1
290methylhydrogenphenyl
291methylhydrogenbenzil
292methylhydrogen2-forfinal
293methylhydrogen3-forfinal
294methylhydrogen4-forfinal
295methylhydrogen2-chlorophenyl
296methylhydrogen3-chlorophenyl
297methylhydrogen4-chlorophenyl
298ethylhydrogenphenyl
299 ethylhydrogenbenzil
300ethylhydrogen2-forfinal
301ethylhydrogen3-forfinal
302ethylhydrogen4-forfinal
303ethylhydrogen2-chlorophenyl
304ethylhydrogen3-chlorophenyl
305ethylhydrogen4-chlorophenyl
306Tien-2-ylhydrogenphenyl
307Tien-2-ylhydrogenbenzil
308Tien-2-ylhydrogen 2-forfinal
309Tien-2-ylhydrogen3-forfinal
310Tien-2-ylhydrogen4-forfinal
311Tien-2-ylhydrogen2-chlorophenyl
312Tien-2-ylhydrogen3-chlorophenyl
313Tien-2-ylhydrogen4-chlorophenyl

Compounds included in category III of the present invention can be obtained by the method presented in scheme VII and described below in example 7 of this specification.

Scheme VII

320

Reagents and conditions: (a) basilidians, Thea, CH2Cl2, room temperature, 18 hours.

Reagents and conditions: (b) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH.

Example 7

<> (S)-4-(2-(3-Benzylamino)-2-(4-utiltity-2-yl)ethyl)fenilalanina acid (21)

Obtain (S)-1-benzyl-3-[1-(4-utiltity-2-yl)-2-(4-nitrophenyl)ethyl]urea (20):

To a solution of the hydrobromide 1-(S)-(4-utiltity-2-yl)-2-(4-nitrophenyl)ethylamine 3 (0,360 g, 1 mmol) and Et3N (of 0.42 ml, 3 mmol) in 10 ml of CH2Cl2add benzylsuccinic (of 0.12 ml, 1 mmol). The mixture is stirred at room temperature for 18 hours. The product distinguish filtering, receiving 0,425 g (yield 96%) of the desired product which is used without further purification.

Obtain (S)-4-(2-(3-benzylamino)-2-(4-utiltity-2-yl)ethyl)phenylalaninol acid (21):

(S)-1-Benzyl-3-[1-(4-utiltity-2-yl)-2-(4-nitrophenyl)ethyl]urea, 20, (0,425 g) dissolved in methanol (4 ml). Add a catalytic amount of Pd/C (10% wt./wt.) and the mixture is stirred in hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a layer of CELITETMand the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 ml) and treated SO3-pyridine (0,220 g). The reaction mixture was stirred at room temperature for 5 minutes, then add the 7%solution of NH4OH. The mixture was then concentrated and the resulting residue purified by chromatography with reversed phase, receiving 0,143 g of the desired product in the form of ammonium salt.

1H NMR (CD3/sub> OD) δ 7,32-7,30 (m, 2H), 7,29-7,22 (m, 3H), 7,12-7,00 (m, 4H), at 6.84 (d, 1H, J=8.1 Hz), 5,35-and 5.30 (m, 1H), 4,29 (s, 2H), 3.27 to up 3.22 (m, 3H), 3,11 totaling 3.04 (m, 3H), of 2.81 (q, 2H, J=10,2, 13,0 Hz)is 1.31 (t, 3H, J=4.5 Hz).

Below are non-limiting examples of compounds included in the first aspect of category III of the present invention.

4-{[(S)-2-(2-Utiltity-4-yl)-2-(3-(R)-methoxy-1-oxo-3-phenylpropane-2-yl)ureido]ethyl}fenilalanina acid

1H NMR (CD3OD) δ of 7.36-7,26 (m, 3H), 7,19-7,17 (m, 2H), 7,10-7,06 (m, 2H), 6.90 to-6,86 (m, 3H), 5,12-of 5.06 (m, 1H), 4,60-4,55 (m, 1H), 3,69 (s, 3H), 3,12 are 2.98 (m, 6H), 1,44-to 1.38 (m, 3H).

The second aspect of category III of the present invention relates to 2-(thiazole-4-ilen) compounds of the formula:

where non-limiting examples of R1and R4below in table VII of this specification.

Table VII
No.R1R4
314methylmethyl
315ethylmethyl
316n-propylmethyl
317isopropylmethyl
318phenylmethyl
319benzilmethyl
3202-forfinalmethyl
3212-chlorophenylmethyl
322thiophene-2-ylmethyl
323the thiazole-2-ylmethyl
324oxazol-2-ylmethyl
325isoxazol-3-ylmethyl
326methylethyl
327ethylethyl
328 n-propylethyl
329isopropylethyl
330phenylethyl
331benzilethyl
3322-forfinalethyl
3332-chlorophenylethyl
334thiophene-2-ylethyl
335the thiazole-2-ylethyl
336oxazol-2-ylethyl
337isoxazol-3-ylethyl
338methylthiophene-2-yl
339ethyl thiophene-2-yl
340n-propylthiophene-2-yl
341isopropylthiophene-2-yl
342phenylthiophene-2-yl
343benzilthiophene-2-yl
3442-forfinalthiophene-2-yl
3452-chlorophenylthiophene-2-yl
346thiophene-2-ylthiophene-2-yl
347the thiazole-2-ylthiophene-2-yl
348oxazol-2-ylthiophene-2-yl
349isoxazol-3-ylthiophene-2-yl
350mate the the thiazole-2-yl
351ethylthe thiazole-2-yl
352n-propylthe thiazole-2-yl
353isopropylthe thiazole-2-yl
354phenylthe thiazole-2-yl
355benzilthe thiazole-2-yl
3562-forfinalthe thiazole-2-yl
3572-chlorophenylthe thiazole-2-yl
358thiophene-2-ylthe thiazole-2-yl
359the thiazole-2-ylthe thiazole-2-yl
360oxazol-2-ylthe thiazole-2-yl
361 isoxazol-3-ylthe thiazole-2-yl
362methyloxazol-2-yl
363ethyloxazol-2-yl
364n-propyloxazol-2-yl
365isopropyloxazol-2-yl
366phenyloxazol-2-yl
367benziloxazol-2-yl
3682-forfinaloxazol-2-yl
3692-chlorophenyloxazol-2-yl
370thiophene-2-yloxazol-2-yl
371the thiazole-2-yloxazol-2-yl
372oxazol-2-yloxazol-2-yl
373isoxazol-3-yloxazol-2-yl

Compounds included in the second aspect of category III of the present invention, can be obtained as described herein below in scheme VIII and described in example 8.

Scheme VIII

Reagents and conditions: (a) basilidians, Thea, CH2Cl2; room temperature, 18 hours.

Reagents and conditions: (b) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH.

Example 8

4-{(S)-2-(3-Benzylamino)-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}fenilalanina acid (23)

Obtain 1-benzyl-3-{(S)-2-(4-nitrophenyl)-1-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}urea (22):

To a solution of the hydrobromide (S)-2-(4-nitrophenyl)-1-[(2-thiophene-2-yl)thiazol-4-yl)ethanamine 8 and Et3N (of 0.42 ml, 3 mmol) in 10 ml of dichloromethane add benzylsuccinic (of 0.12 ml, 1 mmol). The mixture is stirred at room temperature for 18 hours. The product distinguish filtering, receiving 0,445 g (yield 96%) of the desired product which is used without further purification.

Getting 4-{(S)-2-(3-benzylamino)-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}phenylalaninol key is lots (23):

1-Benzyl-3-{(S)-2-(4-nitrophenyl)-1-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}urea 22 (0,445 g) dissolved in methanol (10 ml) and CH2Cl2(5 ml). Add a catalytic amount of Pd/C (10% wt./wt.) and the mixture is stirred in hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a layer of CELITETMand the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 ml) and treated SO3-pyridine (0,110 g). The reaction mixture was stirred at room temperature for 5 minutes, then add the 7%solution of NH4OH. The mixture was then concentrated and the resulting residue purified by chromatography with reversed phase, receiving 0,080 g of the desired product in the form of ammonium salt.

1H NMR (CD3OD) δ to 7.61 (d, 1H, J=2.1 Hz), 7,58 (d, 1H, J=6 Hz), 7,33-7,22 (m, 4H), 7,17-7,14 (m, 1H), 7,09-6,94 (m, 6H), 5,16 (t, 1H, J=6.6 Hz), 4,13 (s, 2H), 3,14-3,11 (m, 2H).

Category IV of the present invention relates to 2-(thiazole-4-ilen) compounds of the formula:

where R1, R4and L have the meanings as defined below in table VIII of this specification.

374
Table VIII
No.R4LR1
methyl-SO2-methyl
375ethyl-SO2-methyl
376phenyl-SO2-methyl
377thiophene-2-yl-SO2-methyl
378methyl-SO2-trifluoromethyl
379ethyl-SO2-trifluoromethyl
380phenyl-SO2-trifluoromethyl
381thiophene-2-yl-SO2-trifluoromethyl
382methyl-SO2-ethyl
383ethyl -SO2-ethyl
384phenyl-SO2-ethyl
385thiophene-2-yl-SO2-ethyl
386methyl-SO2-2,2,2-triptorelin
387ethyl-SO2-2,2,2-triptorelin
388phenyl-SO2-2,2,2-triptorelin
389thiophene-2-yl-SO2-2,2,2-triptorelin
390methyl-SO2-phenyl
391ethyl-SO2-phenyl
392phenyl-SO2 -phenyl
393thiophene-2-yl-SO2-phenyl
394methyl-SO2-4-forfinal
395ethyl-SO2-4-forfinal
396phenyl-SO2-4-forfinal
397thiophene-2-yl-SO2-4-forfinal
398methyl-SO2-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl
399ethyl-SO2-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl
400phenyl-SO2-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl
401t is open-2-yl -SO2-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl
402methyl-SO2-1-methyl-1H-imidazol-4-yl
403ethyl-SO2-1-methyl-1H-imidazol-4-yl
404phenyl-SO2-1-methyl-1H-imidazol-4-yl
405thiophene-2-yl-SO2-1-methyl-1H-imidazol-4-yl
406methyl-SO2-4-acetamidophenyl
407ethyl-SO2-4-acetamidophenyl
408phenyl-SO2-4-acetamidophenyl
409thiophene-2-yl-SO2-4-acetamidophenyl/td>
410methyl-SO2CH2-phenyl
411ethyl-SO2CH2-phenyl
412phenyl-SO2CH2-phenyl
413thiophene-2-yl-SO2CH2-phenyl
414methyl-SO2CH2-(4-methylcarbamoyl)methyl
415ethyl-SO2CH2-(4-methylcarbamoyl)methyl
416phenyl-SO2CH2-(4-methylcarbamoyl)methyl
417thiophene-2-yl-SO2CH2-(4-methylcarbamoyl)methyl
418 methyl-SO2CH2-(2-methylthiazole-4-yl)methyl
419ethyl-SO2CH2-(2-methylthiazole-4-yl)methyl
420phenyl-SO2CH2-(2-methylthiazole-4-yl)methyl
421thiophene-2-yl-SO2CH2-(2-methylthiazole-4-yl)methyl
422methyl-SO2CH2CH2-phenyl
423ethyl-SO2CH2CH2-phenyl
424phenyl-SO2CH2CH2-phenyl
425thiophene-2-yl-SO2CH2CH2-phenyl

Compounds included in category IV of the present invention, can be is obtained by the method presented herein below in scheme IX and described in example 9.

Scheme IX

Reagents and conditions: (a)6H4CH2SO2Cl, DIP, CH2Cl2; 0°C for 14 hours.

Reagents and conditions: (b) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH.

Example 9

{4-(S)-[2-Phenylmethanesulfonyl-2-(2-thiophene-2-iltiazem-4-yl)ethyl]phenyl}sulfamic acid (25)

Obtain (S)-N-{2-(4-nitrophenyl)-1-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}-1-phenylmethanesulfonyl (24):

To a suspension of 2-(4-nitrophenyl)-1-(2-thiophene-2-iltiazem-4-yl)ethylamine 8 (330 mg, 0.80 mmol) in CH2Cl2(6 ml) at 0°With add diisopropylethylamine (0,30 ml, 1.6 mmol), then phenylmethanesulfonyl (167 mg, 0.88 mmol). The reaction mixture was stirred at room temperature for 14 hours. The mixture was diluted with CH2Cl2and washed with saturated solution of NaHCO3then a saturated solution of salt, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is purified using silica, getting 210 mg of the desired product as a white solid.

Obtain {4-(S)-[2-phenylmethanesulfonyl-2-(2-thiophene-2-iltiazem-4-yl)ethyl]phenyl}sulfamic acid (25):

(S)-N-{2-(4-nitrophenyl)-1-[2-(thiophene-2-yl)thiazol-4-yl]the Tyl}-1-phenylmethanesulfonyl 24 (210 mg, 0.41 mmol) was dissolved in methanol (4 ml). Add a catalytic amount of Pd/C (10% wt./wt.) and the mixture is stirred in hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a layer of CELITETMand the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 ml) and treated SO3-pyridine (197 mg, of 1.23 mmol). The reaction mixture was stirred at room temperature for 5 minutes, then add the 7%solution of NH4OH. The mixture was then concentrated and the resulting residue purified by chromatography with reversed phase, getting to 0.060 g of the desired product in the form of ammonium salt.

1H NMR (300 MHz, MeOH-d4) δ 7,52-7,63 (m, H)6,70-7,28 (m, 11H), and 4.75 (t, J=7.2 Hz, 1H), 3.95 to 4.09 to (m, 2H), 3,20 (DD, J=13.5 and 7.8 Hz, 1H), 3,05 (DD, J=13.5 and 7.8 Hz, 1H).

Intermediate products for use in stage (a) of scheme IX can be obtained by the conventional method presented in this description and in the following scheme X and described in example 10.

Scheme X

Reagents and conditions: (a) Na2SO3H2O; microwave irradiation; 200°C, 20 minutes

2627

Reagents and conditions: (b) PCl5, POCl3; 50°C, 3 hours.

Example 10

(2-Methylthiazole-yl)methanesulfonamide (27)

Receive (2-methylthiazole-4-yl)methanesulfonate sodium (26):

4-Chloromethyl-2-methylthiazole (250 mg, was 1.69 mmol) was dissolved in N2About (2 ml) and treated with sodium sulfite (224 mg, 1.78 mmol). The reaction mixture was subjected to microwave irradiation for 20 minutes at 200°C. the Reaction mixture was diluted with H2O (30 ml) and washed with ethyl acetate (2 x 25 ml). The aqueous layer was concentrated, receiving 0,368 g of the desired product as a yellow solid.

LC/MS (ESI+): 194 (M+1, free acid).

Receive (2-methylthiazole-4-yl)methanesulfonamide (27):

(2-Methylthiazole-4-yl)methanesulfonate sodium (357 mg, of 1.66 mmol) was dissolved in phosphorus oxychloride (6 ml) and treated with pentachloride phosphorus (345 mg, of 1.66 mmol). The reaction mixture was stirred at 50°C for 3 hours, then allowed to cool to room temperature. The solvent is removed under reduced pressure, the residue is again dissolved in CH2Cl2(40 ml) and washed with a saturated solution Panso3and a saturated solution of salt. The organic layer is dried over MgSO4, filtered and the solvent is removed in vacuum, obtaining 0,095 g of the desired product as brown oil.

LC/MS (ESI+): 211 (M+1).

Intermediate products are obtained with sufficient purity for subsequent use in accordance with the scheme IX without whom neobhodimosti further purification.

(S)-{4-[2-(2-Utiltity-4-yl)-2-(2-methylthiazole-4-sulphonamido)ethyl]phenyl}sulfamic acid

1N (CD3OD): δ 7,71-7,66 (m, 2H), 7,27-7,10 (m, 7H), to 4.87 (t, 1H, J=7,3 Hz), 4,30-of 4.16 (q, 2H, J=13,2 Hz), 3,34-3,13 (m, 2H), 2,70 (s, 3H).

Below are non-limiting examples of compounds included in category IV of the present invention.

{4-(S)-[2-Phenylmethanesulfonyl-2-(2-utiltity-4-yl)ethyl]phenyl}sulfamic acid

1H NMR (300 MHz, MeOH-d4) δ 7,27-to 7.32 (m, 3H), 7,16-7,20 (m, 3H), 7,05 and 7.6 (m, 2H), of 6.96 (d, J=8,4 Hz, 2H), 4,70 (t, J=9.0 Hz, 1H), 3,91-was 4.02 (m, 2H), 2.95 and-3,18 (m, 4H), of 1.41 (t, J=7.5 Hz, 3H).

(S)-(4-(2-(2-(2-utiltity-4-yl)-2-(3-methoxyphenyl)methylsulfonylamino)ethyl)phenyl)sulfamic acid.

1H NMR (300 MHz, MeOH-d4) δ 7,20 (t, J=8,1 Hz. 1H), 6,94-was 7.08 (m, 4H), 6,88-6,94 (m, 3H), 6.75 in-to 6.80 (m, 1H), 4,67 (t, J=7.2 Hz, 1H), 3,90 to 4.0 (m, 2H), 3,76 (s, 3H), 2.95 and-and 3.16 (m, 4H), of 1.40 (t, J=7.5 HZ, 3H).

Methyl ester of (S)-4-{[1-(2-utiltity-4-yl)-2-(4-sulfonylarenes)ethylsulfanyl]methyl}benzoic acid

1H NMR (300 MHz, MeOH-d4) δ of 7.90-7,94 (m, 2H), 7,27-7,30 (m, 2H), 7,06-7,11 (m, 3H), 6,97-7,00 (m, 2H), 4,71 (t, J=7.2 Hz, 1H), 3.95 TO 4,08 (4, 2H), 3,92 (s, 3H), 2,80-to 3.50 (m, 4H), 1,38-of 1.44 (m, 3H).

(S)-4-[2-(2-Utiltity-4-yl)-2-(1-methyl-1H-imidazol-4-methylsulfonylamino)ethyl]fenilalanina acid

1H NMR (300 MHz, MeOH-d4) δ rate of 7.54 (s, 1H), 7,20 (s, 1H),to 7.09 (s, 1H), 6,92-7,00 (m, 4H), to 4.62 (t, J=5.4 Hz, 1H), 3,70 (s, 3H), 2,98-3,14 (m, 3H), and 2.79 (DD, J=9,3 and 15.0 Hz, 1H), 1,39 (kV, J=7.5 Hz, 3H).

4-{(3)-2-[2-(Thiophene-2-yl)thiazol-4-yl]-2-(2,2,2-cryptgethashparam]ethyl}fenilalanina acid

1N (CD3OD): δ 7,62-7,56 (m, 2H), 7,22 (s, 1H), 7,16-7,06 (m, 5H), 4,84 (t, 1H, J=7,6 Hz), 3,71-3,62 (m, 2H), 3,32-3,03 (m, 2H).

{4-(S)-[2-(Phenylethanolamine)-2-(2-thiophene-2-iltiazem-4-yl)ethyl]phenyl}sulfamic acid

1H NMR (300 MHz, MeOH-d4) δ 7,56 to 7.62 (m, 2H),? 7.04 baby mortality-7,19 (m, N), 6,94-6,97 (m, 2H), 4,78 (t, J=7.8 Hz, 1H), 3,22-3,30 (m, 2H), 3,11 (DD, J=13.5 and 7.8 Hz, 1H), 2,78-2,87 (m, 4H).

(S)-(4-(2(3(Phenylpropanolamine)-2-[(2-thiophene-2-yl)thiazol-4-yl}phenyl)sulfamic acid

1H NMR (300 MHz, MeOH-d4) δ 7,56 to 7.62 (m, 2H), 6,99-7,17 (m, 10H), 4.72 in (t, J=7.8 Hz, 1H), 3,21 (DD, J=13.5 and 7.2 Hz, 1H), to 3.02 (DD, J=13.5 and 7.2 Hz, 1H), 2,39-of 2.64 (m, 4H), 1,65 is 1.86 (m, 2H).

(S)-{4-[2-(4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-sulfonylamino)-2-(2-thiophene-2-iltiazem-4-yl)ethyl]phenyl}sulfamic acid

1H NMR (300 MHz, MeOH-d4) δ 7,53 (d, J=5,1 Hz, 1H) of 7.48 (d, J=5,1 Hz, 1H), 7,13-7,10 (m, 1H),? 7.04 baby mortality (d, J=8,4 Hz, 2H), 6,93-to 6.88 (m, 3H), of 6.75 (d, J=8,1 Hz, 1H), is 6.54 (d, J=8,1 Hz, 1H), br4.61 (t, J=7.5 Hz, 1H), 4,20-4,08 (m, 2H), 3,14-3,00 (m, 4H), 2,69 (s, 3H).

4-{(S)-2-(4-Acetamidobenzenesulfonyl)-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}fenilalanina acid

1H CD 3OD): δ to 7.67-7,52 (m, 6H), 7.24 to of 7.23 (m, 1H), 7,12-to 7.09 (m, 3H), 7,02-of 6.99 (m, 2H), 4,70 (t, 1H, J=7,3 Hz), 3.25 to about 3.00 (m, 2H), 2,24 (s, 3H).

The first aspect of category V of the present invention relates to compounds of the formula:

where R1means substituted or unsubstituted heteroaryl, and R4means linear, branched or cyclic With1-C6alkyl, as defined below in table IX of this specification.

4-(4-forfinal)thiazol-2-yl
Table IX
No.R4R1
426-CH34-(methoxycarbonyl)thiazol-5-yl
427-CH34-[(2-methoxy-2-oxoethyl)carbarnoyl]thiazol-5-yl
428-CH35-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl]oxazol-2-yl
429-CH35-(2-methoxyphenyl)oxazol-2-yl
430-CH35-[(5)-1-(tert-butoxycarbonyl)-2-phenylethyl]about Sasol-2-yl
431-CH35-[4-(methylcarbonate)phenyl]oxazol-2-yl
432-CH35-(3-methoxybenzyl)oxazol-2-yl
433-CH35-(4-phenyl)oxazol-2-yl
434-CH35-(2-methoxyphenyl)thiazol-2-yl
435-CH35-(3-methoxyphenyl)thiazol-2-yl
436-CH35-(4-forfinal)thiazol-2-yl
437-CH35-(2,4-differenl)thiazol-2-yl
438-CH35-(3-methoxybenzyl)thiazol-2-yl
439-CH34-(3-methoxyphenyl)thiazol-2-yl
440-CH34-(4-forfinal)thiazol-2-yl
441 -CH2CH34-(methoxycarbonyl)thiazol-5-yl
442-CH2CH34-[(2-methoxy-2-oxoethyl)carbarnoyl]thiazol-5-yl
443-CH2CH35-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl]oxazol-2-yl
444-CH2CH35-(2-methoxyphenyl)oxazol-2-yl
445-CH2CH35-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl
446-CH2CH35-[4-(methylcarbonate)phenyl]oxazol-2-yl
447-CH2CH35-(3-methoxybenzyl)oxazol-2-yl
448-CH2CH35-(4-phenyl)oxazol-2-yl
449-CH2CH35-(2-methoxyphenyl)thiazol-2-yl
450-CH2CH3 5-(3-methoxyphenyl)thiazol-2-yl
451-CH2CH35-(4-forfinal)thiazol-2-yl
452-CH2CH35-(2,4-differenl)thiazol-2-yl
453-CH2CH35-(3-methoxybenzyl)thiazol-2-yl
454-CH2CH34-(3-methoxyphenyl)thiazol-2-yl
455-CH2CH34-(4-forfinal)thiazol-2-yl
456cyclopropyl4-(methoxycarbonyl)thiazol-5-yl
457cyclopropyl4-[(2-methoxy-2-oxoethyl)carbarnoyl]thiazol-5-yl
458cyclopropyl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl]oxazol-2-yl
459cyclopropyl5-(2-methoxyphenyl)oxazol-2-yl
460C is chlorophil 5-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl
461cyclopropyl5-[4-(methylcarbonate)phenyl]oxazol-2-yl
462cyclopropyl5-(3-methoxybenzyl)oxazol-2-yl
463cyclopropyl5-(4-phenyl)oxazol-2-yl
464cyclopropyl5-(2-methoxyphenyl)thiazol-2-yl
465cyclopropyl5-(3-methoxyphenyl)thiazol-2-yl
466cyclopropyl5-(4-forfinal)thiazol-2-yl
467cyclopropyl5-(2,4-differenl)thiazol-2-yl
468cyclopropyl5-(3-methoxybenzyl)thiazol-2-yl
469cyclopropyl4-(3-methoxyphenyl)thiazol-2-yl
470cyclopropyl

Compounds according to the first aspect of category V, which include substituted or an unsubstituted thiazole-4-ilen group in the case of R1can be obtained by the method presented in scheme XI and described herein below in example 11.

Scheme XI

Reagents and conditions: (a) CH3CN, boiling under reflux for 24 hours.

Reagents and conditions: (b) thiophosgene, caso3, CCl4H2O; room temperature, 18 hours.

Reagents and conditions: (C) tert-butyl potassium, THF, room temperature, 2 hours.

Reagents and conditions: (d) (i) SnCl2-2H2O, EtOH; boiling under reflux, 4 h; (ii) SO3-pyridine, NH4OH.

Example 11

(S)-4-(2-(2-Phenylthiazol-4-yl)-2-(4-methoxycarbonyl)thiazole-5-ylamino)ethyl)fenilalanina acid (31)

Getting hydrobromide (S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanamine (28):

A mixture of (S)-tert-butyl-4-bromo-1-(4-nitrophenyl)-3-oxobutyl-2-ylcarbamate 7 (1,62 g of 4.17 mmol) and thiobenzamide (0,63 g, 4,60 mmol) in CH3CN (5 ml) is refluxed for 24 hours. The reaction mixture is cooled to room temperature and the solution was added diethyl ether. Dropped out OS the iPod is separated by filtration. The solid is dried in vacuum, obtaining 1.2 g (yield 67%) of the desired product.

LC/MS (ESI+): 326 (M+1).

Obtain (S)-4-(1-isothiocyanato-2-(4-nitrophenyl)ethyl)-2-phenylthiazole (29):

To a solution of the hydrobromide (S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanamine 28 (726 mg, to 1.79 mmol) and caso3(716 mg, 7,16 mmol) in N2About (2 ml) is added CCl4(3 ml), then thiophosgene (of 0.28 ml, 3.58 mmol). The reaction mixture was stirred at room temperature for 18 hours, then diluted with CH2Cl2and water. The layers are separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers washed with saturated salt solution, dried (Na2SO4) and concentrated in vacuo, obtaining a residue, which is purified using silica (CH2Cl2)to give 480 mg (yield 73%) of the desired product as a yellow solid.

1H NMR (300 MHz, CDCl3) δ of 8.15 (d, J=8.7 Hz, 2H), 7,97-to 7.99 (m, 2H), 7,43-to 7.50 (m, 3H), 7,34 (d, J=8.7 Hz, 2H), 7,15 (d, J=0.9 Hz, 1H), 5.40 to-5,95 (m, 1H), 3,60 (DD, J=13.8 and 6.0 Hz, 1H), 3.46 in (DD, J=13.8 and 6,0 Hz).

Obtain (S)-methyl-5-[1-(2-phenylthiazol-4-yl)-2-(4-nitrophenyl)ethylamino]thiazole-4-carboxylate (30):

To a suspension of tert-butoxide potassium (80 mg, 0.75 mmol) in THF (3 ml) add methylisocyanate (65 μl, of 0.68 mmol), then (S)-2-phenyl-4-(1-isothiocyanato-2-(4-nitrophenyl)ethyl)thiazole 29 (250 mg, of 0.68 mmol). The mixture is extracted with ethyl acetate (3 the Aza 25 ml), the combined organic layers washed with saturated salt solution, dried (Na2SO4) and concentrated in vacuo. The crude residue purified using silica, getting 323 mg (yield about 100%) of the desired product as a slightly yellowish solid.

1H NMR (300 MHz, CDCl3) δ 8,09-8,13 (m, 2H), 7.95 is-7,98 (m, 3H), to 7.84 (d, J=1.2 Hz, 1H), 7,44 is 7.50 (m, 3H), 7,28-7,31(m, 2H), of 7.96 (d, J=0.6 Hz, 1H), 4,71-4,78 (m, 1H), 3,92 (s, 3H), of 3.60 (DD, J=13.8 and 6.0 Hz, 1H), of 3.45 (DD, J=13.8 and 6,0 Hz, 1H).

Obtain (S)-4-(2-(2-phenylthiazol-4-yl)-2-(4-methoxycarbonyl)thiazole-5-ylamino)ethyl)phenylalaninol acid (31):

(S)-Methyl-5-[1-(2-phenylthiazol-4-yl)-2-(4-nitrophenyl)ethylamino]thiazole-4-carboxylate 30 (323 mg, of 0.68 mmol) and tin chloride(II) (612 mg, of 2.72 mmol) is dissolved in ethanol and the solution is brought to the boiling temperature under reflux. The solvent is removed in vacuo and the resulting residue is dissolved in ethyl acetate. Add a saturated solution of NaHCO3and the solution is stirred for 1 hour. The organic layer is separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers are dried (Na2SO4), filtered and concentrated, obtaining a residue which is dissolved in pyridine (10 ml) and treated SO3-pyridine (130 mg, 0.82 mmol). The reaction solution was stirred at room temperature for 5 minutes , then add 7%-n is th solution of NH 4OH. The mixture was then concentrated and the resulting residue purified by chromatography with reversed phase, receiving 0,071 g of the desired product in the form of ammonium salt.

1H NMR (300 MHz, MeOH-d4) δ 7,97-of 8.00 (m, 3H), of 7.48-7,52 (m, 3H), 7,22 (s, 1H), 7.03 is-7,13 (m, 4H), 4,74 (t, J=6,6 Hz, 1H), 3,88 (s, 3H), 3,28-of 3.42 (m, 2H).

Compounds according to the first aspect of category V, which include substituted or an unsubstituted thiazole-2-strong group in the case of R1can be obtained by the method presented in scheme XII and described herein below in example 12. The intermediate product 32 can be obtained according to scheme II and example 2 by replacing the amide thiophene-2-carbothiolate amidon cyclopropanecarboxylate.

Scheme XII

Reagents and conditions: (a) thiophosgene, caso3, CCl4/H2O; room temperature, 18 hours.

Reagents and conditions: (b)

Reagents and conditions: (C) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH.

Example 12

4-{(S)-2-(2-Cyclopropylmethyl-4-yl)-2-[4-(3-methoxyphenyl)thiazol-2-ylamino]ethyl}fenilalanina acid (35)

Obtain (S)-1-(1-(2-cyclopropylmethyl-4-yl)-2-(4-nitrophenyl)ethyl)thiourea (33):

To a solution of the hydrobromide (S)-1-(2-cyclopropylmethyl-4-yl)-2-(4-nitrophenyl)ethanamine 32 (Android 4.04 g, 10.9 mmol) and caso3(2,18 g, 218 mmol) in a mixture of CCl 4/water (25 ml/20 ml) add thiophosgene (1.5 g, of 13.1 mmol). The reaction mixture was stirred at room temperature for 18 hours, then diluted with CH2Cl2and water. The layers are separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers washed with saturated salt solution, dried (Na2SO4) and concentrated in vacuo, receiving the remainder, which is then treated with ammonia (0.5 m solution in 1,4-dioxane, 120 ml) and purified using silica, getting 2,90 g of the desired product as a red-brown solid.

LC/MS (ESI-): 347 (M-1).

Obtain (S)-4-(3-methoxybenzyl)-N-(1-(2-cyclopropylmethyl-4-yl)-2-(4-nitrophenyl)ethyl)thiazol-2-amine (34):

(S)-1-(1-(2-Cyclopropylmethyl-4-yl)-2-(4-nitrophenyl)ethyl)thiourea 33 (350 mg, 1.00 mmol) and 2-bromo-3'-methoxyacetophenone (253 mg, 1.10 mmol) are mixed in 3 ml of CH3CN and refluxed for 24 hours. The mixture of concentrate and chromatographic getting 0.172 g of product as a yellow solid.

LC/MS (ESI+): 479 (M+1).

Getting 4-{(S)-2-(2-cyclopropylmethyl-4-yl)-2-[4-(3-methoxyphenyl)thiazol-2-ylamino]ethyl}phenylalaninol acid (35):

(S)-4-(3-Methoxybenzyl)-N-(1-(2-cyclopropylmethyl-4-yl)-2-(4-nitrophenyl)ethyl)thiazol-2-amine 34 (0.172 g) dissolved in 10 ml of methanol. Add a catalytic amount of Pd/C (10% wt./wt.) and mesh stirred in an atmosphere of hydrogen for 18 hours. The reaction mixture was filtered through a layer of CELITETMand the solvent is removed under reduced pressure. The crude product is dissolved in 5 ml of pyridine and treated SO3-pyridine (114 mg). The reaction mixture was stirred at room temperature for 5 minutes, then add 10 ml of 7%aqueous solution of NH4OH. The mixture was then concentrated and the resulting residue purified by chromatography with reversed phase, receiving 0,033 g of the desired product in the form of ammonium salt.

1H (CD3OD): δ 7,33-7,22 (m, 3H), 7,10-6,97 (m, 5H), 6,84-to 6.80 (m, 2H), 5,02 (t, 1H, J=6.9 Hz), 3,82 (s, 1H), 3,18 (q, 2H, J=7,1 Hz), a 2.36 (q, 1H, J=4,6 Hz), 1,20-of 1.13 (m,2H), 1.04 million is 0.99 (m, 2H).

Below are non-limiting examples of compounds included in the first aspect of category V

(S)-4-(2-(4-((2-Methoxy-2-oxoethyl)carbarnoyl)thiazole-5-ylamino)-2-(2-utiltity-4-yl)ethyl)fenilalanina acid

1H NMR (300 MHz, MeOH-d4) δ to $ 7.91 (s, 1H), 7,08-7,10 (m, 3H), of 6.99 (d, J=8.7 Hz, 2H), 4,58 (t, J=6,9 Hz, 1H), 4,11 (d, J=2.7 Hz, 2H), of 3.78 (s, 3H), 3,14 of 3.28 (m, 2H), 3,06 (kV, J=7.5 Hz, 2H), 1,41 (t, J=7.5 Hz, 3H).

(S)-4-(2-((3-((2-Methoxy-2-oxoethyl)carbarnoyl)-1-H-indol-2-yl)amino)-2-(2-methylthiazole-4-yl)ethyl)fenilalanina acid

1H NMR (300 MHz, MeOH-d4) δ 7,63 (d, J=7.8 Hz, 1H), 7,37 (s, 1H), 7.18 in-7,29 (m, 4H), 7,02-7,16 (m, 4H), 6,85 (s, 1H), 5,04-5,09 (m, 1H), 4,85 (s, 3H), of 3.27 (DD, J=13.5 and 8.1 Hz, 1H), 3,10 (m, J=13.5 and 8.1 Hz, 1H), 2,69 (s, 3H).

4-((S)-2-(5-(2-Methoxyphenyl)oxazol-2-ylamino)-2-(2-methylthiazole-4-yl)ethyl)fenilalanina acid

1H NMR (300 MHz, MeOH-d4) 5 7,52 (DD, J=7.5 and 1.2 Hz, 1H), 6,95-of 1.24 (m, 10H), 5,04-5,09 (m, 1H), 3,92 (s, 3H), 3,26 (DD, J=13.8 and an 8.4 Hz, 1H), 3,10(DD, J=13.8 and an 8.4 Hz, 1H), 2,72 (s, 3H).

4-((S)-2-(5-((S)-1-(tert-Butoxycarbonyl)-2-phenylethyl)oxazol-2-ylamino)-2-(2-methylthiazole-4-yl)ethyl)fenilalanina acid

1H NMR (300 MHz, MeOH-d4) δ 7.03 is-7,27 (m, 10H), of 6.50 (s, 1H), 4.95 points-of 5.00 (m, 1H), amounts to 4.76 (t, J=6,9 Hz, 1H), up 3.22 (DD, J=14.1 and 6.9 Hz, 1H), 3.00 and-3,10 (m, 2H), 2,90 (DD, J=14.1 and 6.9 Hz, 1H), 2,72 (s, 3H), of 1.37 (s, 9H).

(S)-{4-{2-[5-(4-Methoxycarbonyl)phenyl]oxazol-2-ylamino}-2-(2-methylthiazole-4-yl)ethyl}fenilalanina acid

1H NMR (300 MHz, MeOH-d4) δ to 7.99 (d, J=7.5 Hz, 2H), 7,56-to 7.59 (m, 2H), 7.23 percent-of 7.24 (m, 1H), 7,08-7,14 (m, 4H), 6,83 (d, J=10,2 Hz, 1H), 5,08 (t, J=6.0 Hz, 1H), 3,91 (s, 3H), of 3.25 to 3.35 (m, 1H), 3,09-3,13 (m, 1H), 2,73 (s, 3H).

(S)-4-(2-(5-(3-Methoxybenzyl)oxazol-2-ylamino}-2-(2-methylthiazole-4-yl)ethyl)fenilalanina acid

1H NMR (300 MHz, MeOH-d4) δ 7.03 is-7,28 (m, 8H), 6,79-6,83 (m, 1H), 5,70 (s, 1H), 4,99-of 5.06 (m, 2H), to 4.41 (d, J=2.1 Hz, 2H), 3,80 (s, 3H), 3.27 to 3,37 (m, 1H), 3,03 is 3.15 (m, 1H), 2,71 (s, 3H).

(S)-4-(2-(2-Methylthiazole-4-yl)-2-(5-phenyloxazol-2-ylamino)ethyl)fenilalanina acid

1H NMR (300 MHz, MeOH-d4) δ was 7.45 (d, J=8.7 Hz, 2H), 7,33 (t, J=7.8 Hz, 2H), 7.18 in-7,22 (m, 1H), 7,10-7,14 (m, 6H),? 7.04 baby mortality (s, 1H), 5,4-5,09 (m, 1H), 3,26 (DD, J=13.8 and 6.3 Hz, 1H), 3,10 (DD, J=13.8 and 6.3 Hz, 1H), 2,70 (s, 3H).

4-((S)-2-(2-Cyclopropylmethyl-4-yl)-2-(4-(3-methoxyphenyl)thiazol-2-ylamino)ethyl)fenilalanina acid

1H (CD3OD): δ 7,33-7,22 (m, 3H), 7,10-6,97 (m, 5H), 6,84-to 6.80 (m, 2H), 5,02 (t, 1H, J=6.9 Hz), 3,82 (s, 1H), 3,18 (q, 2H, J=7,1 Hz), a 2.36 (q, 1H, J=4,6 Hz), 1,20-of 1.13 (m, 2H), 1.04 million is 0.99 (m, 2H).

(S)-4-(2-(2-Cyclopropylmethyl-4-yl)-2-(4-(4-forfinal)thiazol-2-ylamino)ethyl)fenilalanina acid

1H (CD3OD): δ 7,79-7,74 (m, 2H), 7,14-7,03 (m, 7H), 7,21 (s, 1H), 6,79 (s, 1H), 5,08 (t, 1H, J=6.6 Hz), 3,29-of 3.12 (m, 2H), 2.40 a (q, 2H, J=5,1 Hz), 1,23-of 1.18 (m, 2H), 1,08-1,02 (m, 2H).

4-((S)-2-(2-Cyclopropylmethyl-4-yl)-2-(4-(2-methoxyphenyl)thiazol-2-ylamino)ethyl)fenilalanina acid

1H (CD3OD): δ 7,89-7,87 (d, 1H, J=7,6 Hz), 7,28 (t, 1H, J=7,0 Hz), 7,10-of 6.96 (m, 8H), to 5.03 (t, 1H, J=6.9 Hz), 3,90 (s, 1H), 3,19 (q, 2H, J=6.6 Hz), of 2.38 (q, 1H, J=4,8 Hz), 1,21-to 1.14 (m, 2H), 1,06 of 1.00 (m, 2H).

4-((S)-2-(2-Cyclopropylmethyl-4-yl)-2-(4-(2,4-differenl)thiazol-2-ylamino)ethyl)fenilalanina acid

1H (CD3OD): δ 8,06-8,02 (q, 2H, J=6.9 Hz), 7,12-to 6.95 (m, 7H), to 6.88 (s, 1H), 5,11 (t, 1H, J=6.9 Hz), 3,22 is 3.15 (m, 2H), 2,38 (kV, 1H, J=4,8 Hz), 1,22-of 1.15 (m, 2H), 1.06 a-1,02 (m, 2H).

(S)-4-(2-(4-(3-Methoxybenzyl)thiazol-2-ylamino)-2-(2-cyclopropylmethyl-4-yl)ethyl)fenilalanina acid

1H (CD3OD): δ 7,22-7,17 (m, 3H), 7,09-6,97 (m, 5H), 6,78-,66 (m, 3H), of 3.77 (s, 2H, in), 3.75 (s, 3H), 3,20-of 3.07 (m, 2H), 2,35 (kV, 1H, J=4,8 Hz), 1,19-of 1.13 (m, 2H), of 1.03 to 1.00 (m,2H).

Methyl ester of (S)-{5-[1-(2-utiltity-4-yl)-2-(4-sulfonylarenes)ethylamino]-2-methyl-2H-[1,2,4]triazole-3-yl}carbamino acid

1H NMR (300 MHz, MeOH-d4) δ 6,97-was 7.08 (m, 5H), 3,71 (s, 3H), 3,51 (s, 3H), 3.15 in (DD, J=13.5 and 6.3 Hz, 1H), 3,02-of 3.07 (m, 3H), of 1.40 (t, J=6.6 Hz, 3H).

The second aspect of category V of the present invention relates to compounds of the formula:

where R1means substituted or unsubstituted heteroaryl, and R4means substituted or unsubstituted phenyl and substituted or unsubstituted heteroaryl, as described below in table X of this specification.

Table X
No.R4R1
471phenyl4-(methoxycarbonyl)thiazol-5-yl
472phenyl4-[(2-methoxy-2-oxoethyl)carbarnoyl]thiazol-5-yl
473phenyl5-[1-N-(2-methoxy-2-oxoethyl)-1-N-indol-3-yl]oxazol-2-yl
474phenyl5-(2-methoxyphenyl)oxazol-2-yl
475phenyl5-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl
476phenyl5-[4-(methylcarbonate)phenyl]oxazol-2-yl
477phenyl5-(3-methoxybenzyl)oxazol-2-yl
478phenyl5-(4-phenyl)oxazol-2-yl
479phenyl5-(2-methoxyphenyl)thiazol-2-yl
480phenyl5-(3-methoxyphenyl)thiazol-2-yl
481phenyl5-(4-forfinal)thiazol-2-yl
482phenyl5-(2,4-differenl)thiazol-2-yl
483phenyl5-(3-methoxybenzyl)thiazol-2-yl
484phenyl4-(3-m is toxigenic)thiazol-2-yl
485phenyl4-(4-forfinal)thiazol-2-yl
486thiophene-2-yl4-(methoxycarbonyl)thiazol-5-yl
487thiophene-2-yl4-[(2-methoxy-2-oxoethyl)carbarnoyl]thiazol-5-yl
488thiophene-2-yl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl]oxazol-2-yl
489thiophene-2-yl5-(2-methoxyphenyl)oxazol-2-yl
490thiophene-2-yl5-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl
491thiophene-2-yl5-[4-(methylcarbonate)phenyl]oxazol-2-yl
492thiophene-2-yl5-(3-methoxybenzyl)oxazol-2-yl
493thiophene-2-yl5-(4-phenyl)oxazol-2-yl
494thiophene-2-yl5-(2-methoxide the yl)thiazol-2-yl
495thiophene-2-yl5-(3-methoxyphenyl)thiazol-2-yl
496thiophene-2-yl5-(4-forfinal)thiazol-2-yl
497thiophene-2-yl5-(2,4-differenl)thiazol-2-yl
498thiophene-2-yl5-(3-methoxybenzyl)thiazol-2-yl
499thiophene-2-yl4-(3-methoxyphenyl)thiazol-2-yl
500thiophene-2-yl4-(4-forfinal)thiazol-2-yl
501cyclopropyl4-(methoxycarbonyl)thiazol-5-yl
502cyclopropyl4-[(2-methoxy-2-oxoethyl)carbarnoyl]thiazol-5-yl
503cyclopropyl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl]oxazol-2-yl
504cyclopropyl5-(2-methoxyphenyl)oxazol-2-yl
505cyclopropyl5-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl
506cyclopropyl5-[4-(methylcarbonate)phenyl]oxazol-2-yl
507cyclopropyl5-(3-methoxybenzyl)oxazol-2-yl
508cyclopropyl5-(4-phenyl)oxazol-2-yl
509cyclopropyl5-(2-methoxyphenyl)thiazol-2-yl
510cyclopropyl5-(3-methoxyphenyl)thiazol-2-yl
511cyclopropyl5-(4-forfinal)thiazol-2-yl
512cyclopropyl5-(2,4-differenl)thiazol-2-yl
513cyclopropyl5-(3-methoxybenzyl)thiazol-2-yl
514cyclopropyl4-(3-methoxyphenyl)thiazol-2-yl
515cyclopropyl4-(4-forfinal)thiazol-2-yl

Connection according to the second aspect of category V, which include substituted or an unsubstituted thiazole-4-ilen group in the case of R1can be obtained by the method presented in schemes XIII, XIV and XV and described herein below in examples 13, 14 and 15.

Scheme XIII

Reagents and conditions: (a) (i) (isobutyl)OCOCH3Et3N, THF; 0°C, 20 min; (ii) CH2N2; temperature from 0°C to room temperature for 3 hours.

Reagents and conditions: (b) 48% HBr, THF; 0°C, 1.5 hours.

Reagents and conditions: (C) CH3CN; boiling under reflux for 2 hours.

Reagents and conditions: (d) thiophosgene, caso3, CCl4H2O; room temperature, 18 hours.

Reagents and conditions: (e) (i) CH3C(O)NHNH2, EtOH; boiling under reflux, 2 h; (ii) POCl3, room temperature, 18 h; 50°C, 2 hours.

Reagents and conditions: (f) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH.

Example 13

(S)-4-(2-((5-Methyl-1,3,4-thiadiazole-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl)fenilalanina KIS the PTA (41)

Obtain tert-butyl ester [3-diazo-1-(4-nitrobenzyl)-2-oxopropyl]carbamino acid (36):

It cooled down to 0°C solution of 2-(S)-(tert-butoxycarbonylamino-3-(4-nitrophenyl)propionic acid (1.20 g, 4.0 mmol) in THF (20 ml) was added drop wise addition of triethylamine (and 0.61 ml, 4.4 mol), then isobutylparaben (or 0.57 ml, 4.4 mmol). The reaction mixture was stirred at 0°C for 20 minutes, then filtered. The filtrate is treated with a solution of diazomethane in diethyl ether (approximately 16 mmol) at 0°C. the Reaction mixture was stirred at room temperature for 3 hours and concentrated. The residue is dissolved in ethyl acetate and washed successively with water and saturated salt solution, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is purified using silica (hexane/ethyl acetate in the ratio 2:1)to give 1.1 g (yield 82%) of the desired product as a slightly yellowish solid.

1H NMR (300 MHz, CDCl3) δ is 8.16 (d, J=8.7 Hz, 2H), 7,39 (d, J=8.7 Hz, 2H), 5,39 (s, 1H), 5,16 (d, J=6.3 Hz, 1H), 4,49 (s, 1H), 3,25 (DD, J=13.8 and 6,6, 1H), 3,06 (DD, J=13.5 and 6.9 Hz, 1H), of 1.41 (s, 9H).

Obtain tert-butyl ester [3-bromo-1-(4-nitrobenzyl)-2-oxopropyl]carbamino acid (37):

It cooled down to 0°C solution of [3-diazo-1-(4-nitrobenzyl)-2-oxopropyl]carbamino acid 36 (0,30 g, 1.04 mmol) in THF (5 ml) is added dropwise 48%aqueous HBr solution (of 0.14 ml, 1.25 mmol). The reaction mixture was stirred at 0°C for 1.5 hours and quenched at 0°With saturated aqueous Na2CO3. The mixture is extracted with ethyl acetate (3 times 25 ml) and the combined organic extracts washed with saturated salt solution, dried (Na2SO4), filtered and concentrated in vacuo, getting 0.400 g of the desired product, which is used in the next stage without further purification.

1H NMR (300 MHz, CDCl3) δ to 8.20 (d, J=8,4 Hz, 2H), 7,39 (d, J=8,4 Hz, 2H), is 5.06 (d, J=7.8 Hz, 1H), 4,80 (kV, J=6.3 Hz, 1H), Android 4.04 (s, 2H), of 1.42 (s, 9H).

Getting hydrobromide (S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanamine (38):

A mixture of tert-butyl methyl ether [3-bromo-1-(4-nitrobenzyl)-2-oxopropyl]carbamino acid 37 (1,62 g of 4.17 mmol) and benzothioate (0,630 g, 4,59 mmol) in CH3CN (5 ml) is refluxed for 24 hours. The reaction mixture is cooled to room temperature, to the solution was added diethyl ether (50 ml) and precipitated precipitate was separated by filtration. The solid is dried in vacuum, obtaining 1,059 g (yield 63%) of the desired product.

MS (ESI+): 326 (M+1).

Obtain (S)-4-[1-isothiocyanato-2-(4-nitrophenyl)ethyl]-2-phenylthiazole (39):

To a solution of the hydrobromide (S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanamine 38 (2,03 g, 5 mmol who) and caso 3(1 g, 10 mmol) in a mixture of CCl4/water (10 ml:7.5 ml) add thiophosgene ones (0.46 ml, 6 mmol). The reaction mixture was stirred at room temperature for 18 hours, then diluted with CH2Cl2and water. The layers are separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers washed with saturated salt solution, dried (Na2SO4) and concentrated in vacuo, obtaining a residue, which is purified using silica (CH2Cl2), receiving 1,71 g (yield 93%) of the desired product.

MS (ESI+): 368 (M+1).

Obtain (S)-5-methyl-N-[2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethyl]-1,3,4-thiadiazole-2-amine (40):

A solution of (S)-4-[1-isothiocyanato-2-(4-nitrophenyl)ethyl]-2-phenylthiazole 39 (332 mg, 0,876 mmol) and acetic hydrazide (65 mg, 0,876 mmol) in ethanol (5 ml) is refluxed for 2 hours. The solvent is removed under reduced pressure, the residue is dissolved in POCl3(3 ml) and the resulting solution was stirred at room temperature for 18 hours, then the solution is heated at 50°C for 2 hours. The solvent is removed in vacuum, the residue is dissolved in ethyl acetate (40 ml) and the resulting solution was treated with 1 N. NaOH solution to achieve a pH of approximately 8. The solution is extracted with ethyl acetate. The combined aqueous layers washed with ethyl acetate, the organic layers of the volume of inaut, washed with saturated salt solution, dried over MgSO4, filtered and concentrated in vacuo, getting 0,345 g (yield 93%) of the desired product as a yellow solid.

1H NMR (CDCl3) of 8.09 (d, J=8,4 Hz, 2H), to $ 7.91 (m, 2H), 7,46 (m, 4H), 7,44 (s, 1H), 5,23 (m, 1H)and 3.59 (m, 2H), 2.49 USD (C, ZN). ESI+MS 424 (M+1).

Obtain (S)-4-(2-(5-methyl-1,3,4-thiadiazole-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl]phenylalaninol acid (41):

(S)-5-Methyl-N-[2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethyl]-1,3,4-thiadiazole-2-amine 40 (0,404 g, 0,954 mmol) dissolved in methanol (5 ml). Add Pd/C (50 mg, 10% wt./wt.) and the mixture is stirred in hydrogen atmosphere until the establishment of the completeness of the completion of the reaction. The reaction mixture was filtered through a layer of CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (4 ml) and treated SO3-pyridine (0,304 g, at 1.91 mmol). The reaction mixture was stirred at room temperature for 5 minutes, then add the 7%solution of NH4OH (50 ml). The mixture was then concentrated and the resulting residue purified preparative HPLC with reversed phase, receiving 0,052 g (yield 11%) of the desired product in the form of ammonium salt.

1H (CD3OD): δ 8,00-of 7.97 (m, 2H), 7,51-7,47 (m, ZN), of 7.23 (s, 1H), 7,11? 7.04 baby mortality (q, 4H, J=9.0 Hz), 5,18 (t, 1H, J=7,2 Hz), 3,34-up 3.22 (m, 2H), 2,50 (s, 3H). ESI-MC 472 (M-1).

Reagents and conditions: (a) thiophosgene, CAC is 3, CCl4/H2O; room temperature, 18 hours.

Reagents and conditions: (b) CH3CN; boiling under reflux, 5 hours.

Reagents and conditions: (C) (i) H2:PD/C, Meon; (ii) SO3-pyridine, NH4OH; room temperature, 18 hours.

Example 14

(S)-[4-(2-{[4-(3-Methoxyphenyl)thiazol-2-ylamino]-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}fenilalanina acid (44)

Obtain (S)-1-[1-(thiophene-2-iltiazem-4-yl)-2-(4-nitrophenyl)ethyl]thiourea (42):

To a solution of the hydrobromide (S)-2-(4-nitrophenyl)-1-(thiophene-2-iltiazem-4-yl)ethanamine 8 (1,23 g, 2,98 mmol) and caso3(0,597 g, 5,96 mmol) in a mixture of CCL4/water (10 ml/5 ml) add thiophosgene (0,412 g, 3.58 mmol). The reaction mixture was stirred at room temperature for 18 hours, then diluted with CH2Cl2and water. The layers are separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers washed with saturated salt solution, dried (Na2SO4) and concentrated in vacuo, receiving the remainder, which is then treated with ammonia (0.5 m solution in 1,4-dioxane, to 29.4 ml, 14.7 mmol) and purified using silica, getting 0,490 g of the desired product as a red-brown solid.

MS (ESI+): 399 (M+1).

Getting 4-(2-methoxyphenyl)-N-{(S)-2-(4-nitrophenyl)-1-[2-(iophen-2-yl)thiazol-4-yl]ethyl}thiazol-2-amine (43):

(S)-1-[1-(Thiophene-2-iltiazem-4-yl)-2-(4-nitrophenyl)ethyl]thiourea 42 (265 mg, 0,679 mmol) is treated with bromo-2'-methoxyacetophenone (171 mg, 0,746 mmol), receiving 0,221 g of the product as a yellow solid.

MS (ESI+): 521 (M+1).

Obtain (S)-[4-(2-{[4-(3-methoxyphenyl)thiazol-2-ylamino]-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}phenylalaninol acid (44):

4-(2-Methoxyphenyl)-N-{(S)-2-(4-nitrophenyl)-1-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}thiazol-2-amine 43 (0,229 g) dissolved in 12 ml of methanol. Add a catalytic amount of Pd/C (10% wt./wt.) and the mixture is stirred in hydrogen atmosphere for 18 hours. The reaction mixture was filtered through CELITETMand the solvent is removed under reduced pressure. The crude product is dissolved in 6 ml of pyridine and treated SO3-pyridine (140 mg). The reaction mixture was stirred at room temperature for 5 minutes, then add 10 ml of 7%aqueous solution of NH4OH. The mixture was then concentrated and the resulting residue purified by chromatography with reversed phase, receiving 0,033 g of the desired product in the form of ammonium salt.

1H (CD3OD): δ of 7.96-to 7.93 (m, 1H), 7,60-of 7.55 (m, 2H), 7,29-of 7.23 (m, 1H), 7.18 in-to 6.95 (m, 9H), of 5.15 (t, 1H, J=6.9 Hz), 3,90 (s, 3H), 3,35-3,24 (m,2H).

Connection according to the second aspect of category V, which include substituted or unsubstituted oxazol-2-strong group in the case of R1can be obtained by the method presented is passed in scheme XV and described herein below in example 15. Intermediate 39 can be obtained according to scheme XIII and example 13.

Scheme XV

Reagents and conditions: (a) 1 azido-1-(3-methoxyphenyl)Etalon, PPh3, dioxane, 90°C, 20 minutes.

Reagents and conditions: (b) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH; room temperature, 18 hours.

Example 15

4-{(S)-2-[5-(3-Methoxyphenyl)oxazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}fenilalanina acid (46)

Obtain [5-(3-methoxyphenyl)oxazol-2-yl]-[2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethyl]amine (45):

A mixture of (S)-4-(1-isothiocyanato-2-(4-nitrophenyl)ethyl)-2-phenylthiazole 39 (300 mg, 0.81 mmol), 1-azido-1-(3-methoxyphenyl)ethanone (382 mg, 2.0 mmol) and PPh3(0.8 g, associated with the polymer, about 3 mmol/g) in dioxane (6 ml) is heated at 90°C for 20 minutes. The reaction solution is cooled to room temperature and the solvent is removed in vacuo and the resulting residue purified using silica, receiving 300 mg (yield 74%) of the desired product as a yellow solid.

1H NMR (300 MHz, MeOH-d4) δ 8,02 (d, J=7.2 Hz, 2H), 7,92-to 7.99 (m, 2H), 7,42-7,47 (m, 3H), 7,22-7,27 (m, 3H), 6,69-7,03 (m, 4H), 6.75 in-is 6.78 (m, 1H), 5,26 (t, J=6.3 Hz, 1H), 3,83 (s, 4H), 3,42 is-3.45 (m, 2H).

Getting 4-{(S)-2-[5-(3-methoxyphenyl)oxazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}phenylalaninol acid (46):

[5-(3-Methoxyphenyl)oxazol-2-yl]-[2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethyl]amine 45 (300 mg, of 0.60 mmol) dissolved in methanol (15 ml). Add a catalytic amount of Pd/C (10% wt./wt.) and the mixture is stirred in hydrogen atmosphere for 18 hours. The reaction mixture was filtered through CELITETMand the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (10 ml) and treated SO3-pyridine (190 mg, 1.2 mmol). The reaction mixture was stirred at room temperature for 5 minutes, then add the 7%solution of NH4OH. The mixture was then concentrated and the resulting residue purified by chromatography with reversed phase, receiving 0,042 g of the desired product in the form of ammonium salt.

1H NMR (300 MHz, MeOH-d4) δ to 7.99 (d, J=7.5 Hz, 2H), 7,46 is 7.50 (m, 3H),7.23 percent-7,29 (m, 3H),? 7.04 baby mortality for 7.12 (m, 6H), is 6.78 (DD, J=8.4 and 2.4 Hz, 1H), 5,16 (t, J=6,6 Hz, 1H), 3,81 (s, 3H), 3,29-3,39 (m, 1H), 3,17 (DD, J=13.8 and 8.1 Hz, 1H).

Further, in the case of obtaining compounds that belong to the category V of the present invention, the compounds of the present invention, including the group R1having not illustrated in the group, can be obtained by modification of the methods described herein above. For example, the compounds of category V, including substituted or unsubstituted [1,2,4]triazole-3-ilen group, can be obtained by s......

Below are neogranichena the following examples according to the second aspect of category V of the present invention.

(S)-4-(2-(5-Phenyl-1,3,4-thiadiazole-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl)fenilalanina acid

1H (CD3OD): δ 7,97-7,94 (m, 2H), 7,73-of 7.70 (m, 2H), 7,44-7,39 (m, 6H), 7,25 (s, 1H), 7,12 (s, 4H), from 5.29 (t, 1H, J=6.9 Hz), 3,35-3,26 (m, 2H).

4-((S)-2-(5-Propyl-1,3,4-thiadiazole-2-ylamino)-2-(2-(thiophene-2-yl)thiazol-4-yl)ethyl)fenilalanina acid

1H (CD3OD): δ to 7.59-rate of 7.54 (m, 2H), 7,17-7,03 (m, 6H), 5,13 (t, 1H, J=7,2 Hz), 3,32-3,13 (m, 2H), of 2.81 (t, 2H, J=7.4 Hz), 1,76-1,63 (t, 6H, J=7,4 Hz)to 0.97 (t, 3H, J=7,3 Hz).

4-((S)-2-(5-Benzyl-1,3,4-thiadiazole-2-ylamino)-2-(2-(thiophene-2-yl)thiazol-4-yl)ethyl)fenilalanina acid

1H (CD3OD): δ (m, 2H), 7,49 was 7.45 (m, 2H), 7,26-7,16 (m, 5H), 7,05-6,94 (m, 6H), 5,04 (t, 1H, J=7,1 Hz), 4,07 (s, 2H), 3,22 totaling 3.04 (m, 2H).

4-((S)-2-(5-(Naphthalene-1-ylmethyl)-1,3,4-thiadiazole-2-ylamino)-2-(2-(thiophene-2-yl)thiazol-4-yl)ethyl)fenilalanina acid

1H (CD3OD): δ 8,08-with 8.05 (m, 1H), 7,89-7,80 (m, 2H), 7,55-the 7.43 (m, 6H), 7,11-7,00 (m, 6H), to 5.08 (t, 1H, J=7,1 Hz), 4,63 (s, 2H), 3,26-is 3.08 (m, 2H).

4-((S)-2-(5-((Methoxycarbonyl)methyl)-1,3,4-thiadiazole-2-ylamino)-2-(2-(thiophene-2-yl)thiazol-4-yl)ethyl)fenilalanina acid

1H (CD3OD): δ of 7.48-7,44 (m, 2H), 7.03 is-6,92 (m, 6H), 5,02 (t, 1H, J=7,2 Hz), 4,30 (s, 2H), 3,55 (s, 3H), 3,22-to 3.02 (m, 2H).

4-((S)-2-(5-((2-Methylthiazole-4-yl)methyl)-1,3,4-thiadiazole-2-ylamino)-2-(2-(thiophene-2-yl)thiazo the-4-yl)ethyl)fenilalanina acid

1H (CD3OD): δ 7,60-7,56 (m, 2H), 7,19 (s, 1H), 7,15 for 7.12 (m, 2H), to 7.09-7.03 is (q, 4H, J=8.7 Hz), 5,14 (t, 1H, J=7,2 Hz), 4,28 (s, 2H), 3.33 and-3,14 (m, 2H), to 2.67 (s, 3H).

4-{(S)-2-[4-(2,4-Differenl)thiazol-2-ylamino]-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}fenilalanina acid

1H (CD3OD): δ 8,06-8,02 (kV, 1H, J=6, 8 Hz), to 7.59-rate of 7.54 (m, 2H), 7,16-was 7.08 (m, 6N), 7,01-to 6.88 (m, 4H), 5,20 (t, 1H, J=7,0 Hz), 3,36-3,17 (m, 2H).

(S)-4-{2-[4-(Etoxycarbonyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}fenilalanina acid

1N (CD3OD): δ 8,02-to 7.99 (m, 2H), 7,54 was 7.45 (m, 4H), 7,26 (s, 1H), was 7.08 (s, 4H), of 5.26 (t, 1H, J=6, 9 Hz), 4,35-to 4.28 (q, 2H, J=6.9 Hz), 3,38-3,18 (m, 2H), of 1.36 (t, 3H, J=7.2 Hz).

(S)-4-{2-[4-(2-Ethoxy-2-oxoethyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}fenilalanina acid

1N (CD3OD): δ of 7.96 (m, 2H), 7,50-7,46 (m, 3H), 7,21 (s, 1H), 7,10? 7.04 baby mortality (m, 4H), 6,37 (s, 1H), 5,09 (t, 1H, J=6, 9 Hz), 4,17-4,10 (q, 2H, J=7,1 Hz), of 3.54 (s, 2H), 3,35-3,14 (m, 2H), 1,22 (t, 3H, J=7,1 Hz).

(S)-4-{2-[4-(4-Acetamidophenyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}fenilalanina acid

1H (CD3OD): δ 8,11 (m, 2H), 7,82-7,80 (m, 2H), 7,71-to 7.61 (m, 6H), 7,40 (s, 1H), 7.23 percent (s, 4H), 5,32 (t, 1H, J=7,0 Hz), 3,51-to 3.35 (m, 2H), 2,28 (s, 3H).

(S)-4-[2-(4-Phenylthiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl]fenilalanina acid

1H (CD3OD): δ 8,03-to 7.99 (m, 2H), 7,75-7,72 (d, 2H, J=8,4 Hz), 7,53-of 7.48 (m,3H), 7,42 (m, 4H), 7,12 (s, 4H), 6,86 (s, 1H), 5,23 (t, 1H, J=7,2 Hz), 3,40-of 3.27 (m, 2H).

(S)-4-{2-[4-(4-(Methoxycarbonyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}fenilalanina acid

1H (CD3OD): δ 8,04-of 8.00 (m, 4H), 7,92-7,89 (d, 2H, J=9.0 Hz), 7,53-7,49 (m, 3H), 7,30 (s, 1H), 7,15 (s, 4H), 7,05 (s, 1H), 5,28 (t, 1H, J=6.9 Hz), 3,93 (s, 3H), 3,35-3,24 (m,2H).

4-{(S)-2-[4-(Etoxycarbonyl)thiazol-2-ylamino]-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}fenilalanina acid

1H (CD3OD): δ 7,43-7,38 (m, 2H), 7,26 (s, 1H), 7,00-6,94 (m, 3H), 6.89 in (s, 4H), 5,02 (t, 1H, J=7,0 Hz), 4,16-4.09 to (q, 2H, J=7,1 Hz), 3,14-to 2.94 (m, 2H), by 1.17 (t, 3H, J=7,1 Hz).

(S)-4-[2-(4-(Methoxycarbonyl)thiazole-5-ylamino)-2-(2-phenylthiazol-4-yl)ethyl]fenilalanina acid

1H NMR (300 MHz, MeOH-d4) δ 7,97-of 8.00 (m, 3H), of 7.48-7,52 (m, 3H), 7,22 (s, 1H), 7.03 is-7,13 (m, 4H), 4,74 (t, J=6,6 Hz, 1H), 3,88 (s, 3H), 3,28-of 3.42 (m, 2H).

(S)-4-[2-(5-Phenyloxazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl]fenilalanina acid

1H NMR (300 MHz, MeOH-d4) δ 7,94-of 7.96 (m, 2H), 7,45-7,49 (m, 5H), 7,32 (t, J=7.8 Hz, 2H), 7,12 (s, 1H), 7,19 (t, J=7.2 Hz, 1H), 7,12 (s, 4H), 7,05 (s, 1H), 5,15 (t, J=6,4 Hz, 1H), 3,34 (DD, J=14.1 and an 8.4 Hz, 1H), 3,18 (DD, J=14.1 and 8,4 Hz, 1H).

(S)-4-{2-[5-(4-Acetamidophenyl)oxazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}fenilalanina acid

1H NMR (300 MHz, MeOH-d4) δ 7,92-7,94 (m, 2H), 7,55-7,58 (m, 2H), 7,39-to 7.50 (m, 5H), 7,26 (s, 1H), 7,12 (C, 4), 7,02 (s, 1H0), 5,14 (t, J=7.8 Hz, 1H), 3,13-to 3.38 (m, 2H), 2,11 (s, 3H).

4-((S)-2-(5-(2,4-Differenl)oxazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl)fenilalanina acid

1H NMR (300 MHz, MeOH-d4) δ 7,97-to 7.99 (m, 2H), 7,54 to 7.62 (m, 1H), 7,45 is 7.50 (m, 3H), 7,28 (s, 1H), 7,12 (s, 4H), 6,97-7,06 (m, 3H), 5,15-5,20 (m, 1H), 3,28 is 3.40 (m, 1H), 3,20 (DD, J=13.8 and an 8.4 Hz, 1H).

4-{(S)-2-[5-(3-Methoxyphenyl)oxazol-2-ylamino]-2-[(2-thiophene-2-yl)thiazol-4-yl]ethyl}fenilalanina acid

1H NMR (300 MHz, MeOH-d4) δ 7,55-of 7.60 (m, 2H), 7,26 (t, J=8,1 Hz, 1H), 7,21 (s, 1H),? 7.04 baby mortality-to 7.15 (m, 8H), 6,77-for 6.81 (m, 1H), 5,10 (t, J=6.3 Hz, 1H), 3,81 (s, 3H), 3,29-to 3.36(m, 1H), 3.15 in (DD, J=14.1 and an 8.4 Hz, 1H).

(S)-4-[2-(4,6-Dimethylpyrimidin-2-ylamino]-2-(2-methylthiazole-4-yl)ethyl]fenilalanina acid

1H NMR (300 MHz, MeOH-d4) δ 7,00-7,10 (m, 5H), 6,44 (s, 1H), 5,50 (t, J=7.2 Hz, 1H), 3.04 from-3,22 (m, 2H), by 2.73 (s, 3H), and 2.27 (s, 6H).

(S)-4-[2-(4-Hydroxy-6-methylpyrimidin-2-ylamino)-2-(2-methylthiazole-4-yl)ethyl]fenilalanina acid

1H NMR (300 MHz, MeOH-d4) δ 7,44 (d, J=8,4 Hz, 2H), 6,97-7,10 (m, 4H), 5,61 (s, 1H), 5.40 to-5,49 (m, 1H), 3,10-up 3.22 (m, 2H), by 2.73 (s, 3H) ,2.13 and(s,3H).

The first aspect of category VI-the present invention relates to compounds of the formula:

where R1means heteroaryl, and R4matter, as described further below in table XI of this specification.

Table XI
No.R4R1
516phenyl4-(methoxycarbonyl)thiazol-5-yl
517phenyl4-[(2-methoxy-2-oxoethyl)carbarnoyl]thiazol-5-yl
518phenyl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl]oxazol-2-yl
519phenyl5-(2-methoxyphenyl)oxazol-2-yl
520phenyl5-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl
521phenyl5-[4-(methylcarbonate)phenyl]oxazol-2-yl
522phenyl5-(3-methoxybenzyl)oxazol-2-yl
523phenyl5-(4-phenyl)oxazol-2-yl
524phenyl 5-(2-methoxyphenyl)thiazol-2-yl
525phenyl5-(3-methoxyphenyl)thiazol-2-yl
526phenyl5-(4-forfinal)thiazol-2-yl
527phenyl5-(2,4-differenl)thiazol-2-yl
528phenyl5-(3-methoxybenzyl)thiazol-2-yl
529phenyl4-(3-methoxyphenyl)thiazol-2-yl
530phenyl4-(4-forfinal)thiazol-2-yl
531thiophene-2-yl4-(methoxycarbonyl)thiazol-5-yl
532thiophene-2-yl4-[(2-methoxy-2-oxoethyl)carbarnoyl]thiazol-5-yl
533thiophene-2-yl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl]oxazol-2-yl
534thiophene-2-yl5-(2-methoxyphenyl)oxazol-2-yl
535thiophene-2-yl5-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl
536thiophene-2-yl5-[4-(methylcarbonate)phenyl]oxazol-2-yl
537thiophene-2-yl5-(3-methoxybenzyl)oxazol-2-yl
538thiophene-2-yl5-(4-phenyl)oxazol-2-yl
539thiophene-2-yl5-(2-methoxyphenyl)thiazol-2-yl
540thiophene-2-yl5-(3-methoxyphenyl)thiazol-2-yl
541thiophene-2-yl5-(4-forfinal)thiazol-2-yl
542thiophene-2-yl5-(2,4-differenl)thiazol-2-yl
543thiophene-2-yl5-(3-methoxybenzyl)thiazol-2-yl
544thiophene-2-yl4-(3-methoxyphenyl)thiazol-2-yl
545 thiophene-2-yl4-(4-forfinal)thiazol-2-yl
546cyclopropyl4-(methoxycarbonyl)thiazol-5-yl
547cyclopropyl4-[(2-methoxy-2-oxoethyl)carbarnoyl]thiazol-5-yl
548cyclopropyl5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl]oxazol-2-yl
549cyclopropyl5-(2-methoxyphenyl)oxazol-2-yl
550cyclopropyl5-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl
551cyclopropyl5-[4-(methylcarbonate)phenyl]oxazol-2-yl
552cyclopropyl5-(3-methoxybenzyl)oxazol-2-yl
553cyclopropyl5-(4-phenyl)oxazol-2-yl
554cyclopropyl5-(2-methoxyphenyl)thiazol-2-yl
555cyclopropyl5-(3-methoxyphenyl)thiazol-2-yl
556cyclopropyl5-(4-forfinal)thiazol-2-yl
557cyclopropyl5-(2,4-differenl)thiazol-2-yl
558cyclopropyl5-(3-methoxybenzyl)thiazol-2-yl
559cyclopropyl4-(3-methoxyphenyl)thiazol-2-yl
560cyclopropyl4-(4-forfinal)thiazol-2-yl

Compounds according to the first aspect of category VI can be obtained by the method presented in scheme XVI and described herein below in example 16.

Scheme XVI

Reagents and conditions: (a) CH3CN; boiling under reflux for 2 hours.

Reagents and conditions: (b) (3-Cl)C6H4CO2H, EDCI, HOBt, DIPEA, DMF; room temperature, 18 hours.

Reagents and conditions: (C) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH, room temperature, 18 hours.

Example 16

4-((S)-2-(2-(3-Chlorophenyl)acetamido)-2-(2-(thiophene-2-yl)oxazol-4-yl)ethyl)fenilalanina acid (49)

Getting hydrobromide (S)-2-(4-nitrophenyl)-1-[(thiophene-2-yl)oxazol-4-yl]ethanamine (47):

A mixture of (S)-tert-butyl-4-bromo-1-(4-nitrophenyl)-3-oxobutyl-2-ylcarbamate 7 (of 38.7 g, 100 mmol) and thiophene-2-carboxamide (14 g, 110 mmol) (available from Alfa Aesar) in CH3CN (500 ml) is refluxed for 5 hours. The reaction mixture is cooled to room temperature and the solution was added diethyl ether (200 ml). Dropped the precipitate was separated by filtration. The solid is dried in vacuum, obtaining the desired product, which can be used in the next stage without further purification.

Getting 2-(3-chlorophenyl)-N-{(S)-2-(4-nitrophenyl)-1-[2-(thiophene-2-yl)oxazol-4-yl]ethyl}ndimethylacetamide (48):

To a solution of (S)-2-(4-nitrophenyl)-1-[(thiophene-2-yl)oxazol-4-yl]ethanamine 47 (3.15 g, 10 mmol) 3-chlorophenylalanine acid (1.70 g, 10 mmol) and hydroxybenzotriazole (HOBt) (0,70 g, 5.0 mmol) in DMF (50 ml) at a temperature of 0°C was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.90 g, 10 mmol), then triethylamine (of 4.2 ml, 30 mmol). The mixture is stirred at 0°C for 30 minutes, then at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phase was washed with 1 N. water is the first solution of HCl, a 5%aqueous solution of NaHCO3, water and saturated salt solution and dried over Na2SO4. The solvent is removed in vacuum, obtaining the desired product which is used without further purification.

Getting 4-((S)-2-(2-(3-chlorophenyl)acetamido)-2-(2-(thiophene-2-yl)oxazol-4-yl)ethyl)phenylalaninol acid (49):

2-(3-Chlorophenyl)-N-{(S)-2-(4-nitrophenyl)-1-[2-(thiophene-2-yl)oxazol-4-yl]ethyl}ndimethylacetamide 48 (3 g) dissolved in methanol (4 ml). Add a catalytic amount of Pd/C (10% wt./wt.) and the mixture is stirred in hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a layer of CELITETMand the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 ml) and treated SO3-pyridine (of) 0.157 g). The reaction mixture was stirred at room temperature for 5 minutes, then add the 7%solution of NH4OH. The mixture was then concentrated and the resulting residue may be purified by chromatography with reversed phase, obtaining the desired product in the form of ammonium salt.

The second aspect of category VI of the present invention relates to compounds of the formula:

where R1means aryl, and R2and R3have the meanings as defined below in table XII of this specification.

Table XII
No.R2R3R1
561methylhydrogenphenyl
562methylhydrogenbenzil
563methylhydrogen2-forfinal
564methylhydrogen3-forfinal
565methylhydrogen4-forfinal
566methylhydrogen2-chlorophenyl
567methylhydrogen3-chlorophenyl
568methylhydrogen4-chlorophenyl
569ethylhydrogenphenyl
570ethylhydrogenbenzil
571ethylhydrogen2-forfinal
572ethylhydrogen3-forfinal
573ethylhydrogen4-forfinal
574ethylhydrogen2-chlorophenyl
575ethylhydrogen3-chlorophenyl
576ethylhydrogen4-chlorophenyl
577Tien-2-ylhydrogenphenyl
578Tien-2-ylhydrogen benzil
579Tien-2-ylhydrogen2-forfinal
580Tien-2-ylhydrogen3-forfinal
581Tien-2-ylhydrogen4-forfinal
582Tien-2-ylhydrogen2-chlorophenyl
583Tien-2-ylhydrogen3-chlorophenyl
584Tien-2-ylhydrogen4-chlorophenyl

Connection according to the second aspect of category VI can be obtained by the method presented in scheme XVII and described herein below in example 17.

Scheme XVII

Reagents and conditions: (a) CH3CN; boiling under reflux for 2 hours.

Reagents and conditions: (b) C6H4CO2H, EDCI, HOBt, DIPEA, DMF; room so the temperature value, 18 hours.

Reagents and conditions: (C) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH, room temperature, 18 hours.

Example 17

{4-[2-(S)-(4-Ethyloxazole-2-yl)-2-phenylacetylamino]phenyl}sulfamic acid (52)

Obtain (S)-1-(4-ethyloxazole-2-yl)-2-(4-nitrophenyl)ethanamine (50):

A mixture of tert-butyl methyl ether [1-(S)-carbarnoyl-2-(4-nitrophenyl)ethylcarbamate acid 1 (10 g, and 32.3 mmol) and 1-bromo-2-butanone (90%, to 4.1 ml, 36 mmol) in CH3CN (500 ml) is refluxed for 18 hours. The reaction mixture is cooled to room temperature, to the solution was added diethyl ether, the precipitated precipitate is removed by filtration and used without further purification.

Obtaining N-[1-(4-ethyloxazole-2-yl)-2-(4-nitrophenyl)ethyl]-2-phenylacetamide (51):

To a solution of (S)-1-(4-ethyloxazole-2-yl)-2-(4-nitrophenyl)ethanamine 50 (2.9 g, 11 mmol), phenylacetic acid (1.90 g, 14 mmol) and 1-hydroxybenzotriazole (HOBt) (0,94 g, 7.0 mmol) in DMF (100 ml) at a temperature of 0°C was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (2,68 g, 14 mmol), then triethylamine (6.0 ml, 42 mmol). The mixture is stirred at 0°C for 30 minutes, then at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phase was washed with 1 N. aqueous solution of HCl, 5%-n the m aqueous solution of NaHCO 3, water and saturated salt solution and dried over Na2SO4. The solvent is removed in vacuum, obtaining the desired product which is used without further purification.

Obtain {4-[2-(S)-(4-ethyloxazole-2-yl)-2-phenylacetylamino]phenyl}sulfamic acid (52):

N-[1-(4-Ethyloxazole-2-yl)-2-(4-nitrophenyl)ethyl]-2-phenylacetamide 51 (0,260 g) dissolved in methanol (4 ml). Add a catalytic amount of Pd/C (10% wt./wt.) and the mixture is stirred in hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a layer of CELITETMand the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 ml) and treated SO3-pyridine (0,177 g of 1.23 mmol). The reaction mixture was stirred at room temperature for 5 minutes, then add the 7%solution of NH4OH (10 ml). The mixture was then concentrated and the resulting residue purified by chromatography with reversed phase, obtaining the desired product in the form of ammonium salt.

Regulation NRTR-β provides a method of modulating the activity angiopoietin receptor tyrosinekinase type of Tie-2, and, thus, to mediate, to influence or otherwise control the state of a disease associated with angiogenesis, where angiogenesis is wrong is regulated by the human body. Compounds of the present invention are used in kachestvennostju ensure the regulation of angiogenesis. As such, the present invention is directed to some unmet medical needs, among other things:

1) providing compositions effective as inhibitors of beta-tyrosinosis protein human (NRTR-β); and, thus, ensuring the implementation of the method of regulation of angiogenesis in case of violation, where angiogenesis is promoted;

2) providing compositions effective as inhibitors of beta-tyrosinosis protein human (NRTR-β); and, thus, ensuring the implementation of the method of regulation of angiogenesis in violation;

3) providing compositions effective as inhibitors of beta-tyrosinosis protein human (NRTR-β); and, thus, ensuring the implementation of the method of regulation of angiogenesis in case of violation, where angiogenesis is reduced.

For the purposes of the present invention, the term "regulate" is defined as including, but not limited to, the regulation regarding the increase or regulation in respect of reduction, to fix, bring "order" or to uniformity, direction or targeting a variety of means. In one aspect, the antibody can be used in the method of treatment of disorders with increased angiogenesis" or "disorders with reduced angiogenesis". As used in this description, "violation with increased angiogenesis" to depict the place of a violation, which is involved in the pathological process of unwanted or increased angiogenesis in the case of the biological manifestations of the disease, disorders and/or conditions; in the case of a biological cascade leading to the violation; or as a symptom of disturbance. Similarly, the "violation reduced angiogenesis is a violation, which is involved in the pathological process of unwanted or reduced angiogenesis in the case of the biological manifestations of the disease. This "involvement in the pathological process of angiogenesis in case of violation of increased/decreased angiogenesis include, but are not limited to, the following:

1) angiogenesis as "causes" of the violation or biological manifestations of the disease, increased or decreased level of angiogenesis genetically, by infection, autoimmunity, trauma, biomechanical reasons, lifestyle, or some other reason;

2) angiogenesis as part of the observable symptoms of disease or disorders. That is, the disease or disorder is defined in terms of increased or reduced angiogenesis. From a clinical point of view, angiogenesis indicate disease; however, angiogenesis should not be a "hallmark" of the disease or disorder;

3) angiogenesis is part of the biochemical or cellular cascade that results in the disease or disorder. In this regard, due to the regulation of angiogenesis is possible to interrupt the cascade and you can control the disease. Non-limiting examples of disorders regulated angiogenesis, which can be treated using the present invention, described herein below.

Drugs

The present invention also relates to compositions or preparations that contain one or more inhibitors of beta-tyrosinosis protein human (NRTR-β), as described in this description. As a rule, proposed according to the invention the compositions contain:

a) an effective amount of one or more phenylalaninol acids or their salts of the present invention are effective as inhibitors of beta-tyrosinosis protein human (NRTR-β); and

b) one or more excipients.

For the purposes of the present invention the terms "excipient" and "media" use equivalent throughout the description of the present invention, and the above terms in this description is defined as "the ingredients that are used in the practice of obtaining safe and effective pharmaceutical compositions.

Specialist in the field of technology of reception of medicines will be clear that the excipients used mainly to perform the function of delivering a safe, stable the CSOs and functional pharmaceuticals, moreover, they serve not only as part of the whole filler for delivery, but also as a means to achieve efficient absorption recipient of the active ingredient. Excipient may also act as a simple and direct inert filler, or excipient, as used in this description, may be part of stabilizing the pH of the system or coverage for "insurance" delivery safe ingredients in the stomach. Specialist in the field of production of medicines can also take advantage of the fact that the compounds of the present invention improve cellular potency, pharmacokinetic properties, and also improve oral bioavailability.

In non-limiting examples of proposed according to the invention the compositions contain:

a) from about 0.001 mg to 1000 mg of one or more phenylalaninol acids or their salts of the present invention; and

b) one or more excipients.

In another example, compositions according to the invention contain:

a) from about 0.01 mg to 100 mg of one or more phenylalaninol acids or their salts of the present invention; and

b) one or more excipients.

In the following example compositions according to the invention contain:

a) from about 0.1 mg to 10 mg of one or more phenylalaninol acids or the x salts of the present invention; and

b) one or more excipients.

The term "effective amount", as used herein, means an amount of one or more phenylalaninol acids, effective at dosages and for periods of time necessary to achieve the desired therapeutic result." The effective amount may vary according to factors known in the field, such as the disease state, age, sex and weight of the human or animal being treated. Although specific schemes medicines can be described in below in this description and the examples, the person skilled in the art it will be clear that the scheme is the introduction of a medicinal product may be modified for optimal therapeutic response. Thus, there is no need to specify an exact "effective amount". For example, several separate doses may be administered daily or the dose may be proportionally reduced as required due to the extreme need of therapeutic situation. In addition, the compositions of the present invention can enter as often as necessary to achieve a therapeutic amount.

Method of use

The present invention relates to a method of regulating angiogenesis in humans, including introduced the e person of one or more proposed according to the invention compounds.

One example method according to the invention includes a method of treating disorders regulated angiogenesis in the subject, where the violation with adjustable angiogenesis is a disorder with increased angiogenesis, and the above violations are selected from diabetic retinopathy, macular degeneration, cancer, sickle cell anemia, sarcoid, pseudoxanthoma elasticum, Paget's disease, vein occlusion, carotid obstructive disease, chronic uveitis/vitrite, mycobacterial infections, Lyme disease, systemic lupus erythematosus, retrolateral fibroplasia, disease ILSA, disease behceta causing retinitis or chorionic infections, the intended ocular histoplasmosis, a disease of the best, myopia, congenital holes in the optic nerve, diseases of Stargardt, including inflammation of the peripheral retina and ciliary mug clinical syndrome, chronic retinal detachment, syndrome of increased viscosity, toxoplasmosis, trauma and postlagernd complications associated with redness diseases and proliferative vitreoretinopathy.

Another example of the methods according to the invention includes a method of treating disorders regulated angiogenesis in the subject, where the violation with adjustable angiogenesis is a disorder with increased angiogenesis, and videocasinoonline choose from inflammatory intestinal diseases, such as Crohn's disease and ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis, hemangiomas, illness Randy-Osler-Weber or hereditary hemorrhagic telangiectasia, solid tumor or blood tumor on the head of the infant and acquired immunodeficiency syndrome.

Further, the example methods according to the invention includes a method of treating disorders regulated angiogenesis in the subject, where the violation with adjustable angiogenesis is a violation of reduced angiogenesis, and the above violations are selected from ischemia of skeletal muscle and myocardial ischemia, stroke, peripheral vascular disease, coronary arterial disease.

One other example methods according to the invention includes a method of vascularization of ischemic tissue. As used herein, the term "ischemic tissue" means tissue that has lost adequate blood flow. Examples of ischemic tissue include, but are not limited to, cloth, lacking adequate supply of blood that occurs as a result of myocardial infarction or stroke, mesenterina ischemia or ischemia of the extremities, or is the result of vascular occlusion or stenosis. According to one example, the interruption of the supply of oxygenated blood can be caused by vascular occlusion. This is vascular occlusion may be provoked by arteriosclerosis, trauma, surgery, disease and/or other etiology. Also included in the treatment methods of the present invention is the treatment of ischemic skeletal muscle and myocardial ischemia, stroke, peripheral vascular disease, coronary arterial disease.

One other example methods according to the invention includes a method of restoring tissue. As used herein, "tissue repair" means the promotion of regeneration, growth and/or maintain tissue, including, but not limited to, wound healing or tissue engineering. The person skilled in the art it will be clear that to restore tissue requires the formation of new blood vessels. In turn, the fabric may be damaged, including, but not limited to, due to traumatic injuries or conditions, including arthritis, osteoporosis and other skeletal disorders and burns. The fabric may also be compromised due to damage by surgical intervention, radiation, rupture, toxic chemicals, viral or bacterial infections or burns. The fabric that needs restoration, it also includes non-healing wounds. Examples of non-healing wounds include non-healing ulcers on the skin resulting from diabetic pathology, or fractures, which is trudnoizlechimykh.

Compounds according to the invention are also suitable for use when carrying out repair tissue in the context of methods directed tissue regeneration (GTR). Such methods are currently used by specialists in this area to accelerate healing of wounds after invasive surgery.

Another further example of the methods according to the invention includes a method of promotion restore tissue, characterized by increased tissue growth during the process of tissue engineering. As used herein, the term "tissue engineering" is defined as the formation, construction and manufacturing of biological prostheses in combination with synthetic or natural materials for growth or replacement of tissues and organs of the body. Thus, these methods can be used to enhance the design and growth of human tissues outside the body in order to carry out later implantation to repair or replace diseased tissues. For example, antibodies may be useful in case of promotion of the development of graft-substitutes, which are used as therapy in the treatment of burns.

Other examples of tissue engineering example methods according to the invention includes a containing cells, or not containing cells "device"to the e induce the regeneration of functional human tissues, when implanted at the site, requiring regeneration. As discussed herein, directed by biomaterial tissue regeneration can be used for promotion of renewed growth in bone, for example, in the case of periodontal disease. Thus, antibodies can be used for growth promotion reconstructed tissues, entered into a three-dimensional configurations at the site of the wound or other tissue, requiring such restoration.

According to yet another another example of tissue engineering, the example methods according to the invention, the compounds disclosed herein, can be included in external or internal devices containing human tissue, designed to replace the functions of the internal tissues of patients. This method comprises selecting cells from the body, placing them in a structured matrices and implantation of a new system inside the body or the use of the system outside the body. For example, antibodies can be included in a vascular graft cell lines for promotion of development of cells contained in the graft. It is envisaged that the methods according to this invention can be used to enhance the recovery of tissue regeneration and engineering "products", such as cartilage and bone tissue of the Central nerve of the second system, muscle, liver and cells of the islet of Langerhans (insulinproducing cells).

The present invention also relates to the application of the proposed according to the invention phenylalaninol acids to obtain drugs for the promotion of the development of graft-substitutes.

The present invention also relates to the application of the proposed according to the invention phenylalaninol acids in accordance with the present invention for obtaining a medicinal product for use in the implementation of the repair tissue in the context of methods directed tissue regeneration (GTR).

Proposed according to the invention compounds can be used to obtain one or more drugs, non-limiting examples of which include:

drugs for treatment of disorders regulated angiogenesis in the subject, where the violation with adjustable angiogenesis is a disorder with increased angiogenesis;

drugs for treatment of disorders regulated angiogenesis in the subject, where the violation with adjustable angiogenesis is a disorder with a high angiogensis selected from Crohn's disease and ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis, hemangiomas, illness Randy-Osler-Weber, or hereditary is hemorrhagic telangiectasia, solid tumors and blood tumors on the head in infants and acquired immune deficiency syndrome;

drugs suitable for the purposes of tissue engineering, thus inducing an overdevelopment of tissue;

drugs for treatment of disorders regulated angiogenesis in the subject, where the violation with adjustable angiogenesis is a violation of reduced angiogenesis.

Methods

Screening tests using in vitro and in vivo models of angiogenesis

Antibodies of the compounds according to this invention can be subjected to screening tests on angiogenesis, which are known in this field. Such tests include in vitro assays, which determine the development of substitutes blood vessels in cultured cells or the formation of vascular structures from tissue explants and in vivo analyses, which determine the development of blood vessels direct or indirect way (Auerbach R. et al., Clin Chem.,49, 32-40 (2003); Vailhe B. et al., Lab. Invest.,81, 439-452 (2001)).

1. In vitro models of angiogenesis

In the case of in vitro models that are appropriate for application of the present invention, use of cultured endothelial cells or tissue explants and determine the impact of agents on the "angiogenic" cellular responses or obrazovatelnyh blood capillary structures. Non-limiting examples of in vitro tests on angiogenesis include, but are not limited to, migration and proliferation of endothelial cells, the formation of capillaries, endothelial "germination", analysis of Explant rings of aorta and analysis of the aortic arch of a chicken.

2. In vivo models of angiogenesis

In vivo agents or antibodies that are suitable for applying the present invention was administered locally or systemically in the presence or in the absence of growth factors (e.g., VEGF or angiopoietin), and the development of new blood vessel was determined by direct observation or by defining a surrogate marker, such as hemoglobin or fluorescent indicator. Non-limiting examples of in vivo tests on angiogenesis include, but are not limited to, analysis chorioallantoic membrane of a chicken, a test for corneal angiogenesis and test against the MATRIGEL tubeTM.

3. Methods for determining the vascularization of ischemic tissue

Standard routine methods are suitable for determining the inherent tissue, the risk of ischemic damage from unwanted vascular occlusion. For example, if the disease of the myocardium such methods include a variety of imaging techniques (e.g., methodology of radioactive labels, x-rays and MRI) and physiological tests. Therefore, the induction of angiogenesis as an effective means of preventing or reducing ischemia in the tissues, damaged or risk of damage due to vascular occlusion, can be easily defined.

The person skilled in the art using standard methods will be able to determine the vascularization of tissue. Non-limiting examples of definitions of vascularization in a subject include SPECT (CT emission of a proton), PET (emission tomography positron), MRI (magnetic resonance imaging) and their combination, by determining the blood flow in the tissue before and after treatment. Angiography can be used as a macroscopic evaluation of the presence of blood vessels. Histological assessment can be used to calculate the availability of the blood vessels at the level of small vessels. These and other methods are discussed Simons et al., "Clinical trials in coronary angiogenesis", Circulation,102, 73-86 (2000).

Below are non-limiting examples of activity against NRTR-β (IC50microns) and RTRW (IC50microns), are given below in table a of this specification.

Table a
ConnectionNRTR-β IC50, mcmRTRV IC50, mcm

(S)-{4-[2-(4-utiltity-2-yl)-2-(phenyl which ethylamino)ethyl]phenyl}sulfamic acid
0,0522,9

(S)-4-(2-(4-utiltity-2-yl)-2-(2-(2-forfinal)acetamido)ethyl)fenilalanina acid
0,012are 5.36

(S)-4-(2-(4-utiltity-2-yl)-2-(2-(3-forfinal)acetamido)ethyl)fenilalanina acid
0,00032,85

(S)-4-(2-(2-(2,3-differenl)acetamido)-2-(4-utiltity-2-yl)ethyl)fenilalanina acid
0,028are 5.36

(S)-4-(2-(2-(3,4-differenl)acetamido)-2-(4-utiltity-2-yl)ethyl)fenilalanina acid
0,07523,9

(S)-4-(2-(2-(2-chlorophenyl)acetamido)-2-(4-utiltity-2-yl)ethyl)fenilalanina acid
0,05622,8

(S)-4-(2-(2-(3-chlorophenyl)acetamido)-2-(4-utiltity-2-yl)ethyl)fenilalanina acid
0,03313,6

(S)-4-(2-(4-utiltity-2-yl)-2-(2-(3-hydroxyphenyl)acetamido)ethyl)fenilalanina acid
0,04to 6.57

(S)-4-(2-(4-utiltity-2-yl)-2-(2-(2-methoxyphenyl)acetamido)ethyl)fenilalanina acid
0,01411,7

(S)-4-(2-(4-utiltity-2-yl)-2-(2-(3-methoxyphenyl)acetamido)ethyl)fenilalanina acid
0,0084,05

(S)-4-(2-(4-utiltity-2-yl)-2-(3-phenylpropanamide)ethyl)fenilalanina acid
0,00210,4

(S)-4-(2-(2-(3,4-acid)acetamido)-2-(4-utiltity-2-yl)ethyl)fenilalanina acid
0,02815,5

(S)-4-(2-(2-(2,3-acid)acetamido)-2-(4-utiltity-2-yl)ethyl)fenilalanina acid
0,03725,4

(S)-4-(2-(3-(3-chlorophenyl)propanamide)-2-(4-ethyl shall eazol-2-yl)ethyl)fenilalanina acid
is 0.000215,3

(S)-4-(2-(4-utiltity-2-yl)-2-(3-(2-methoxyphenyl)propanamide)ethyl)fenilalanina acid
0,00316,9

(S)-4-(2-(4-utiltity-2-yl)-2-(3-(3-methoxyphenyl)propanamide)ethyl)fenilalanina acid
0,0120,6

(S)-4-(2-(4-utiltity-2-yl)-2-(3-(4-methoxyphenyl)propanamide)ethyl)fenilalanina acid
0,00616,0

(S)-4-{2-[2-(4-ethyl-2,3-dioxopiperazinyl-1-yl)acetamido]-2-(4-utiltity-2-yl)ethyl}fenilalanina acid
0,0020,53

(S)-4-{2-(4-utiltity-2-yl)-2-[2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ndimethylacetamide]ethyl}fenilalanina acid
0,0020,254

(S)-4-[2-(benzo[d][1,3]dioxol-5-carboxamido)-2-(4-utiltity-2-yl)ethyl]fenilalanina acid
0,04219

Values and the values given in this description should not be construed as strictly limited to the above precise numeric values. Instead, unless otherwise stated, assume that each such value is a specified value and a functionally equivalent range surrounding that value. For example, assume that the value that is specified as "40 mm"mean "about 40 mm".

All documents cited in the detailed description of the invention, in relevant part, incorporated in this description by reference; the citation of any document should not be construed as an admission that it is prior art in regard to the present invention. To the extent that any meaning or definition of the term in this description is inconsistent with any meaning or definition of the same term in a document incorporated by reference, should be guided by value or by definition, intended for this term in this document.

Although specific embodiments of the present invention is illustrated and described, therefore the person skilled in the art it will be obvious that various other changes and modifications may be made without departing from the substance of iobama invention. Thus imply the inclusion in the appended claims all such changes and modifications that are included in the scope of this invention.

1. The compound of the formula:

where R is substituted or unsubstituted thiazolino group of the formula:
or
R2and R3each independently chosen from:
i) hydrogen; or
ii)1-C3linear alkyl;
R4means a group selected from:
i)1-C3linear or3cyclic alkyl;
ii) phenyl; and
iii) thiophenyl;
Z means a group of the formula:

R1choose from:
i)1-C3linear or branched alkyl, optionally substituted C1-C4alkoxycarbonyl, halogen;
(ii) unsubstituted phenyl or substituted by one or two substituents selected from halogen, methoxy or hydroxy-group, With1-C4alkoxycarbonyl;
iii) dioxopiperazinyl and 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl, substituted C1-C3by alkyl; or
iv) heteroaryl rings containing 5 to 10 atoms selected from thiazole, triazole, 1H-imidazole, thiadiazole, oxazole, isoxazol, oxadiazole, benzodioxole, benzo(1,4)dioxane, pyridine, pyrimidine, 1H-indole and 2,3-dihydr the benzo[b][1,4]dioxine, which may be substituted by one or two substituents selected from:
(a) hydroxy;
(b) (C1-C3the alkyl which may be substituted by one or two substituents selected from:
i) phenyl;
ii)1-C4alkoxycarbonyl;
iii) naphthalenyl;
iv) 2-methylthiazolyl;
c) NHC(O)C1-C3of alkyl;
d)1-C4alkoxycarbonyl;
e) 1-(tert-butoxycarbonyl)-2-phenylethyl;
f) methoxybenzyl;
(g) phenyl, which may be substituted With1-C4alkoxy, halogen, methoxycarbonyl or NHC(O)CH3;
h) (methoxy-2-oxoethyl)carbamoyl;
L is a bridging group selected from:
i) -C(O)NH[C(R5aR5b)]w-;
ii) -C(O)[C(R6aR6b)]x-;
iii) -C(O)[C(R7aR7b)]yC(O)-;
iv) -SO2[C(R8aR8b)]z-;
R5a, R5b, R6a, R6b, R7a, R7b, R8aand R8beach independently means:
i) hydrogen;
ii) C1-C3linear alkyl which may be substituted by 1 or 2 halogen atoms;
iii) phenyl which may be substituted by 1-2 substituents selected from halogen and lower alkoxy;
iv) heteroaryl ring selected from imidazolyl, imidazolyl, replaced by stands, benzo(1,4)oxazine and oxadiazolyl, replaced by stands;
the index n is 0 or 1; the indices w, x, y, and z, each independently, is equal to from 1 to 3,
and the and its pharmaceutically acceptable salt.

2. The compound according to claim 1, where R2and R3each means hydrogen or C1-C3linear alkyl.

3. The compound according to claim 1, where R4means phenyl.

4. The compound according to claim 1, where R4means thiophenyl.

5. The compound according to claim 1, where L has the formula:
-C(O)[C(R6aR6b)]x-,
R6ameans hydrogen, substituted or unsubstituted phenyl and substituted or unsubstituted heteroaryl; the index x is 1 or 2.

6. The compound according to claim 5, where R1selected from phenyl, 2-ftoheia, 3-ftoheia, 4-ftoheia, 2,3-dipthera, 3,4-dipthera, 3,5-dipthera, 2-chlorphenyl, 3-chlorphenyl, 4-chlorphenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-acid, 3,4-acid and 3,5-acid.

7. The compound according to claim 1 of the formula:
i)

where R2means methyl or ethyl, R3means hydrogen, R6aselected from phenyl, 2-ftoheia, 3-ftoheia, 4-ftoheia, 2,3-dipthera, 3,4-dipthera, 3,5-dipthera, 2-chlorphenyl, 3-chlorphenyl, 4-chlorphenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-acid, 3,4-acid and 3,5-acid;
ii)

where R means methyl, ethyl, phenyl or thiophene-2-yl, R6aselected from phenyl, 2-ftoheia, 3-ftoheia, 4-ftoheia, 2,3-dipthera, 3,4-dipthera, 3,5-dipthera, 2-chlorphenyl, 3-chlorphenyl, 4-chlorphenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-acid, 3,4-acid and 3,5-acid;
iii)

where R2selected from methyl, ethyl, R3means hydrogen or methyl; R1selected from phenyl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl and isoxazol-3-yl.

8. The compound according to claim 1, where R represents:

and where Z means a substituted or unsubstituted heteroaryl group selected from:
i) imidazol-2-yl and imidazol-4-yl, corresponding to the formula:

ii) oxazol-2-yl, oxazol-4-yl and oxazol-5-yl, corresponding to the formula:

iii) isoxazol-3-yl, isoxazol-4-yl and isoxazol-5-yl, corresponding to the formula:

iv) [1,2,4]oxadiazol-3-yl and [1,2,4]oxadiazol-5-yl, corresponding to the formula:

v) [1,3,4]oxadiazol-2-yl of the formula:

vi) thiazol-2-yl, thiazol-4-yl and thiazol-5-yl, corresponding to the formula:

vii) [1,2,4]thiadiazole-3-yl and [1,2,4]thiadiazole-5-yl, corresponding to the formula:

9. The connection of claim 8, where Z is chosen from 4-(methoxycarbonyl) thiazol-5-yl, 4-[(2-methoxy-2-oxoethyl)carbarnoyl]thiazol-5-yl, 5-(2 - methoxyphenyl)oxazol-2-yl, 5-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl, 5-[4-(methoxycarbonyl)phenyl]oxazol-2-yl, 5-(3-methoxybenzyl)oxazol-2-yl, 5-(4-phenyl)oxazol-2-yl, 5-(2-methoxyphenyl)thiazol-2-yl, 5-(3-methoxyphenyl)thiazol-2-yl, 5-(4-forfinal)thiazol-2-yl, 5-(2,4-differenl)thiazol-2-yl, 5-(3-methoxybenzyl)thiazol-2-yl, 4-(3-methoxyphenyl)thiazol-2-yl and 4-(4-forfinal)thiazol-2-yl.

10. A compound selected from:
{4-[2(S)-(4-utiltity-2-yl)-2-phenylacetamido)ethyl]phenyl}sulfamic acid;
(S)-(4-(2-(4-utiltity-2-yl)-2-(2-(2-forfinal)acetamido)ethyl)phenylalaninol acid;
(S)-(4-(2-(4-utiltity-2-yl)-2-(2-(3-forfinal)acetamido)ethyl)phenylalaninol acid;
(S)-4-(2-(2-(2,3-differenl)acetamido)-2-(4-utiltity-2-yl)ethyl)phenylalaninol acid;
(S)-4-(2-(2-(3,4-differenl)acetamido)-2-(4-utiltity-2-yl)-ethyl)phenylalaninol acid;
(S)-4-(2-(2-(2-chlorophenyl)acetamido)-2-(4-utiltity-2-yl)-ethyl)peninsul mirovoi acid;
(S)-4-(2-(2-(3-chlorophenyl)acetamido)-2-(4-utiltity-2-yl)-ethyl)phenylalaninol acid;
(S)-4-(2-(4-utiltity-2-yl)-2-(2-(3-hydroxyphenyl)acetamido)ethyl)phenylalaninol acid;
(S)-4-(2-(4-utiltity-2-yl)-2-(2-(2-methoxyphenyl)acetamido)ethyl)phenylalaninol acid;
(S)-4-(2-(4-utiltity-2-yl)-2-(2-(3-methoxyphenyl)acetamido)ethyl)phenylalaninol acid;
(S)-4-(2-(4-utiltity-2-yl)-2-(3-phenylpropanamide)ethyl)phenylalaninol acid;
(S)-4-(2-(2-(3,4-acid)acetamido)-2-(4-utiltity-2-yl)-ethyl)phenylalaninol acid;
(S)-4-(2-(2-(2,3-acid)acetamido)-2-(4-utiltity-2-yl)-ethyl)phenylalaninol acid;
(S)-4-(2-(3-(3-chlorophenyl)propanamide)-2-(4-utiltity-2-yl)-ethyl)phenylalaninol acid;
(S)-4-(2-(4-utiltity-2-yl)-2-(3-(2-methoxyphenyl)propanamide)ethyl)phenylalaninol acid;
(S)-4-(2-(4-utiltity-2-yl)-2-(3-(3-methoxyphenyl)propanamide)ethyl)phenylalaninol acid;
(S)-4-(2-(4-utiltity-2-yl)-2-(3-(4-methoxyphenyl)propanamide)ethyl)phenylalaninol acid;
(S)-4{2-[2-(4-ethyl-2,3-dioxopiperazinyl-1-yl)ndimethylacetamide]-2-(4-utiltity-2-yl)ethyl} phenylalaninol acid;
(S)-4-{2-(4-utiltity-2-yl)-2-[2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ndimethylacetamide]ethyl}phenylalaninol acid;
(S)-4-[2-(benzo[d][1,3]dioxol-5-carboxamido)-2-(4-utiltity-2-yl)-ethyl]phenylalaninol acid;
4-((S)-2-(2-(3-chlorophenyl)acetamido)-2-(2-what iophen-2-yl)thiazol-4-yl)-ethyl)phenylalaninol acid;
4-((S)-2-(2-(3-methoxyphenyl)acetamido)-2-(thiophene-2-yl)thiazol-4-yl)-ethyl)phenylalaninol acid;
4-{(S)-2-(3-phenylpropanamide)-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}phenylalaninol acid;
4-{(S)-2-(3-(3-chlorophenyl)propanamide)-2-[2-(thiophene-2-yl)thiazol-4-yl]-ethyl}phenylalaninol acid;
4-{(S)-2-(2-(3-forfinal)acetamido)-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}phenylalaninol acid;
(S)-4-{2-[2-(2,5-dimethylthiazol-4-yl)acetamido]-2-(4-utiltity-2-yl]ethyl}phenylalaninol acid;
(S)-4-{2-[2-(2,4-dimethylthiazol-5-yl)acetamido]-2-(4-methylthiazole-2-yl)ethyl}phenylalaninol acid;
(S)-4-{2-(4-utiltity-2-yl)-2-[3-(thiazol-2-yl)propanamide]ethyl}phenylalaninol acid;
(S)-4-{2-(4-utiltity-2-yl)-2-[2-(4-utiltity-2-yl)acetamido]-ethyl}phenylalaninol acid;
(S)-4-{2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)ndimethylacetamide]-2-(2-phenylthiazol-4-yl)ethyl}phenylalaninol acid;
4-{(S)-2-[2-(4-ethyl-2,3-dioxopiperazinyl-1-yl)acetamido]-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl} phenylalaninol acid;
(S)-4-(2-(2,3-diphenylpropanoic)-2-(4-utiltity-2-yl)-ethyl)phenylalaninol acid;
(S)-4-{2-(4-utiltity-2-yl)-2-[2-(2-methoxyphenyl)-3-phenylpropanamide]ethyl}phenylalaninol acid;
(S)-4-{2-(4-utiltity-2-yl)-2-[2-(3-forfinal)-3-phenylpropanamide]ethyl}phenylalaninol acid;
(S)-4-{2-(4-utiltity-2-yl)-2-[2-(3-methoxyphenyl)-3-phenylpropanamide]ethyl}phenylalaninol acid;
4-(S)-2-(4-utiltity-2-yl)-2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-phenylpropanamide]ethyl}phenylalaninol acid;
(S)-4-[2-(4-utiltity-2-yl)-2-(4-oxo-4-phenylbutyramide)ethyl]phenylalaninol acid;
(S)-4-(2-(4-utiltity-2-yl)-2-(5-methyl-4-oxohexanoate)ethyl)phenylalaninol acid;
(S)-4-{2-[4-(3,4-dihydro-2H-benzo[b][1,4]doxepin-7-yl)-4-oxobutanamide]-2-(4-utiltity-2-yl)ethyl}phenylalaninol acid;
(S)-4-{2-[4-(2,3-acid)-4-oxobutanamide]-2-(4-utiltity-2-yl)ethyl}phenylalaninol acid;
(S)-4-{2-(4-utiltity-2-yl)-2-[4-oxo-4-(pyridin-2-yl)butanamide]-ethyl}phenylalaninol acid;
(S)-4-{2-[4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-oxobutanamide]-2-(4-utiltity-2-yl)ethyl}phenylalaninol acid;
(S)-4-[2-(4-tert-butoxy-4-oxobutanamide)-2-(4-utiltity-2-yl)-ethyl]phenylalaninol acid;
(S)-4-[2-(4-ethoxy-4-oxobutanamide)-2-(4-utiltity-2-yl)-ethyl]phenylalaninol acid;
(S)-4-(2-(3-benzylamino)-2-(4-utiltity-2-yl)ethyl)phenylalaninol acid;
4-{(S)-2-(3-benzylamino)-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}-phenylalaninol acid;
4-{(S)-2-[(2-methylthiazole-4-yl)methylsulfonyl]-2-[2-(thiophene-2-yl)-thiazol-4-yl]ethyl}phenylalaninol acid;
{4-(S)-[2-phenylmethanesulfonyl-2-(2-utiltity-4-yl)ethyl]-phenyl}sulfamic acid;
{4-(S)-[2-(3-methoxyphenyl)methanesulfonamide-2-(2-utiltity-4-yl)-ethyl]phenyl}sulfamic acid;
methyl ester (S)-4-{[1-(2-utiltity-4-yl)-2-(4-sulfamidate)ethylsulfanyl]methyl}benzoic acid the acid;
(S)-4-[2-(2-utiltity-4-yl)-2-(1-methyl-1H-imidazol-4-sulphonamido)ethyl]phenylalaninol acid;
4-{(S)-2-[2-(thiophene-2-yl)thiazol-4-yl]-2-(2,2,2-cryptgethashparam)ethyl}phenylalaninol acid;
{4-(S)-[2-(phenylethanolamine)-2-(2-thiophene-2-iltiazem-4-yl)ethyl]-phenyl}sulfamic acid;
{4-(S)-[3-(phenylpropionylamino)-2-(2-thiophene-2-iltiazem-4-yl)-ethyl]phenyl}sulfamic acid;
(S)-{4-[2-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-sulfonylamino)-2-(2-thiophene-2-iltiazem-4-yl)ethyl]phenyl}sulfamic acid;
4-{(S)-2-(4-acetamidobenzenesulfonyl)-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}phenylalaninol acid;
4-{(S)-2-(2-cyclopropylmethyl-4-yl)-2-[4-(3-methoxyphenyl)thiazol-2-ylamino]ethyl}phenylalaninol acid;
(S)-4-(2-(4-((2-methoxy-2-oxoethyl)carbarnoyl)thiazole-5-ylamino)-2-(2-utiltity-4-yl)ethyl)phenylalaninol acid;
4-((S)-2-(5-(1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl)oxazol-2-ylamino)-2-(2-methylthiazole-4-yl)ethyl)phenylalaninol acid;
4-((S)-2-(5-(2-methoxyphenyl)oxazol-2-ylamino)-2-(2-methylthiazole-4-yl)-ethyl)phenylalaninol acid;
4-((S)-2-(5-((S)-1-(tert-butoxycarbonyl)-2-phenylethyl)oxazol-2-ylamino)-2-(2-methylthiazole-4-yl)ethyl)phenylalaninol acid;
(S)-4-(2-(5-(4-methoxycarbonyl)phenyl)oxazol-2-ylamino)-2-(2-methylthiazole-4-yl)ethyl)phenylalaninol acid;
(S)-4-(2-(5-(3-methoxybenzyl)oxazol-2-ylamino)-2-(2-methylthiazole-4-yl)et the l)phenylalaninol acid;
(S)-4-(2-(2-methylthiazole-4-yl)-2-(5-phenyloxazol-2-ylamino)ethyl)-phenylalaninol acid;
4-((S)-2-(2-cyclopropylmethyl-4-yl)-2-(4-(3-methoxyphenyl)thiazol-2-ylamino)ethyl)phenylalaninol acid;
(S)-4-(2-(2-cyclopropylmethyl-4-yl)-2-(4-(4-forfinal)thiazol-2-ylamino)ethyl)phenylalaninol acid;
4-((S)-2-(2-cyclopropylmethyl-4-yl)-2-(4-(2-methoxyphenyl)thiazol-2-ylamino)ethyl)phenylalaninol acid;
4-((S)-2-(2-cyclopropylmethyl-4-yl)-2-(4-(2,4-differenl)thiazol-2-ylamino)ethyl)phenylalaninol acid;
(S)-4-(2-(4-(3-methoxybenzyl)thiazol-2-ylamino)-2-(2-cyclopropylmethyl-4-yl)ethyl)phenylalaninol acid;
methyl ester (S)-{5-[1-(2-utiltity-4-yl)-2-(4-sulfamidate)ethylamino]-2-methyl-2H-[1,2,4]triazole-3-yl}-carbamino acid;
4-{(S)-2-[4-(2-methoxyphenyl)thiazol-2-ylamino)-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}phenylalaninol acid;
4-{(S)-2-[5-(3-methoxyphenyl)oxazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl}phenylalaninol acid;
4-{(S)-2-[4-(2,4-differenl)thiazol-2-ylamino)-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}phenylalaninol acid;
(S)-4-{2-[4-(etoxycarbonyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl-ethyl}phenylalaninol acid;
(S)-4-{2-[4-(2-ethoxy-2-oxoethyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}phenylalaninol acid;
(S)-4-{2-[4-(4-acetamidophenyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}phenylalaninol acid;
(S)-4-[2-(4-Fe is iltiazem-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl]-phenylalaninol acid;
(S)-4-{2-[4-(4-(methoxycarbonyl)phenyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}phenylalaninol acid;
4-{(S)-2-[4-(etoxycarbonyl)thiazol-2-ylamino]-2-[2-(thiophene-2-yl)thiazol-4-yl]ethyl}phenylalaninol acid;
(S)-4-[2-(4-(methoxycarbonyl)thiazole-5-ylamino]-2-(2-phenylthiazol-4-yl)-ethyl]phenylalaninol acid;
(S)-4-[2-(5-phenyloxazol-2-ylamino)]-2-(2-phenylthiazol-4-yl)-phenylalaninol acid;
(S)-4-{2-[5-(4-acetamidophenyl)oxazol-2-ylamino]-2-(2-phenylthiazol-4-yl)ethyl}phenylalaninol acid;
4-((S)-2-(5-(2,4-differenl)oxazol-2-ylamino)-2-(2-phenylthiazol-4-yl)-ethyl)phenylalaninol acid;
4-{(S)-2-[5-(3-methoxyphenyl)oxazol-2-ylamino]-2-[(2-thiophene-2-yl)thiazol-4-yl]ethyl} phenylalaninol acid;
(S)-4-[2-(4,6-dimethylpyrimidin-2-ylamino)-2-(2-methylthiazole-4-yl)ethyl]phenylalaninol acid and
(S)-4-[2-(4-hydroxy-6-methylpyrimidin-2-ylamino)-2-(2-methylthiazole-4-yl)ethyl]phenylalaninol acid, or its pharmaceutically acceptable salt.

11. The compound according to any one of claims 1 to 10, where compounds are salts comprising anions selected from chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarata citrate, or a cation selected from sodium, lithium, potassium, calcium, magnesium, and bismuth.

12. Applied the e compound according to any one of claims 1 to 10 for the manufacture of a medicine for treatment status, selected from diabetic retinopathy, macular degeneration, cancer, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum, Paget's disease, vein occlusion, arterial occlusion, carotid obstructive disease, chronic uveitis/vitrite, mycobacterial infections, Lyme disease, systemic lupus erythematosus, retrolateral fibroplasia, disease ILSA, disease behceta causing retinitis or chorionic infections, the intended ocular histoplasmosis, a disease of the best, myopia, congenital holes in the optic nerve, diseases of Stargardt, including inflammation of the peripheral retina and ciliary mug clinical syndrome, chronic retinal detachment, syndrome high viscosity, toxoplasmosis, trauma and postlagernd complications associated with redness diseases and proliferative vitreoretinopathy; Crohn's disease and ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis, hemangiomas, illness Randy-Osler-Weber, or hereditary hemorrhagic telangiectasia, solid tumors or blood tumours on the head in infants and acquired immune deficiency syndrome; ischemic skeletal muscle and myocardial ischemia, stroke, peripheral vascular disease, coronary arterial disease.

13. Primeministerial according to any one of claims 1 to 10 for the manufacture of a medicine for the regulation of angiogenesis, vascularization of ischemic tissue growth promotion graft substitutes, promotion restore tissue in the context of methods directed tissue regeneration (GTR).

14. The compound according to any one of claims 1 to 10, used for the treatment of a condition selected from diabetic retinopathy, macular degeneration, cancer, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum, Paget's disease, vein occlusion, arterial occlusion, carotid obstructive disease, chronic uveitis/vitrite, mycobacterial infections, Lyme disease, systemic lupus erythematosus, retrolateral fibroplasia, disease ILSA, disease behceta causing retinitis or chorionic infections, the intended ocular histoplasmosis, a disease of the best, myopia, congenital holes in the optic nerve, diseases of Stargardt, including inflammation the peripheral retina and ciliary mug clinical syndrome, chronic retinal detachment, syndrome of increased viscosity, toxoplasmosis, trauma and postlagernd complications associated with redness diseases and proliferative vitreoretinopathy; Crohn's disease and ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis, hemangiomas, illness Randy-Osler-Weber, or hereditary hemorrhagic telangiectasia, solid the tumor or blood tumor on the head in infants and acquired immune deficiency syndrome; ischemia of skeletal muscle and myocardial ischemia, stroke, peripheral vascular disease, coronary arterial disease.

15. The compound according to any one of claims 1 to 10 for application to the regulation of angiogenesis, vascularization of ischemic tissue growth promotion graft substitutes, promotion restore tissue in the context of methods directed tissue regeneration (GTR).



 

Same patents:

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of azabicyclo{3,1,0}hexane of general formula (I) or pharmaceutically acceptable salts thereof (values of radicals are given in the claim), synthesis method thereof, intermediate compounds, a pharmaceutical composition and use of the novel compounds in therapy as dopamine receptor D3 modulators, for example, for treating drug dependence or as antipsychotic agents.

EFFECT: improved properties of the derivatives.

34 cl, 122 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and salts thereof (I), where T is a tetrazolyl group which is not substituted or substituted with [C1-C8]alkyl; L1 denotes (CR1R2)n-, where n equals 1, 2, 3 or 4; R1 and R2 denote hydrogen; L2 denotes a direct bond; A is selected from a group comprising A2, A8 and A20 , where Z1, Z2, Z3 and Z4 are independently selected from a group comprising hydrogen, -NR5R6, -N(R5)C(=O)R6, -N(R5)C(=O)OR6, -N(R5)C(=O)NR6R7, -N(R5)C(=S)NR6R7; Q is selected from a group comprising , where X1, X2 and X3 are independently selected from a group comprising hydrogen, halogen, [C1-C8]alkyl, phenyl or phenyl which is substituted by 1-5 halogen atoms; R5-R7 are independently selected from a group comprising hydrogen, [C1-C8]alkyl, [C1-C8]halogenalkyl, [C2-C8]alkenyl, [C3-C6]cycloalkyl, phenyl and phenyl [C1-C8]alkyl.

EFFECT: invention also relates to a fungicide composition containing an active ingredient in form of an effective amount of the disclosed compound, use of the disclosed compound or fungicide composition thereof for treatment or prophylactic control of phytopathogenic fungi of plants or agricultural crops and a method for treatment or prophylactic control of phytopathogenic fungi of plants or agricultural crops.

14 cl, 3 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel carbostyril compounds of general formula (1) or salts thereof with common pharmaceutically acceptable acids or pharmaceutically acceptable basic compounds, having activity on promotion of TFF2 production, a pharmaceutical composition based on said compounds, an agent based on disclosed compounds used in case of a disorder where up-regulation of TFF has a prophylactic and/or therapeutic effect, use of disclosed compounds to prepare said agent and a method of producing disclosed compounds. The invention also relates to novel specific carbostyril compounds or salts thereof with common pharmaceutically acceptable acids or pharmaceutically acceptable basic compounds. In structural formula (1), A is a direct bond, a lower alkylene group or lower alkylidene group, X is an oxygen or sulphur atom, the bond between positions 3 and 4 of the carbostyril backbone is a single bond or a double bond, R4 and R5 each denotes a hydrogen atom provided that, when the bond between positions 3 and 4 of the carbostyril backbone is a double bond, R4 and R5 can instead be bonded to each other in form of a -CH=CH-CH=CH- group, and R1, R2 and R3 assume values given in the claims.

EFFECT: high efficiency of compositions based on said compounds.

32 cl, 23 dwg, 184 tbl, 1535 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

, where R is a group selected from: i) hydrogen; ii) phenyl and iii) thiophenyl; Z is a substituted or unsubstituted [1,3,4]thiadiazol-2-yl group, R1 is selected from: i) hydrogen; ii) straight C1-C6alkyl; iii) C6 or C10 aryl; iv) C(O)OR5; and v) 2-methylthiazol-4-yl; R5 denotes a straight or branched C1-C6alkyl; and index x equals 0 or 1. The invention also relates to use of compounds of formula (I) to prepare a medicinal agent having human protein tyrosine phosphatase beta (HPTP-β) inhibiting action and use in treatment.

EFFECT: compounds can be used as human protein tyrosine phosphatase beta inhibitors.

11 cl, 1 dwg, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I or pharmaceutically acceptable salts thereof, which have receptor tyrosine kinase type I inhibiting properties and can be used in treating hyperproliferative disorders in mammals. In general formula

,

A is O or S; G is N; B is a 6-member aryl or 5-6-member heteroaryl ring containing a sulphur atom as a heteroatom; E is

, , , , , X is N or CH; D1, D2 and D3 independently denote N or CR19; D4 and D5 independently denote N or CR19 and D6 is O, S or NR20, where at least one of D4 and D5 is CR19; D7, D8, D9 and D10 independently denote N or CR19, where at least one of D7, D8, D9 and D10 is N; R1 is H or C1-C6 alkyl; each R2 independently denotes halogen, cyano, nitro etc, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR15R14, -NR15C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14, C1-C12alkyl, C2-C12 alkenyl, alkynyl, saturated or partially unsaturated C3-C10cycloalkyl, C3-C10cycloalkyl-C1-C12alkyl, -S(O)p(C1-C6alkyl), -S(O)p(CR13R14)q-phenyl, phenyl, phenyl-C1-3-alkyl, 5-6-member heteroaryl, 5-6-member heteroaryl-C1-C3-alkyl, saturated or partially unsaturated 3-8-member heterocyclyl, 5-6-member heterocyclyl-C1-C3-alkyl, -O(CR13R14)q-phenyl, NR15(CR13R14)q-phenyl, O(CR13R14)q-(5-6-member heteroaryl), NR13(CR13R14)q-(5-6-member heteroaryl, -O(CR13R14)q-(3-8-member heterocyclyl) or -NR15(CR13R14)q-3-8-member heterocyclyl), each R3 denotes Z, where Z is selected from and , W is O or S; W2 is O or S;V is CR8R9, R8b is H or C1-C6alkyl; each of R6, R8, R8a and R9 independently denotes hydrogen, trifluoromethyl, C1-C12alkyl etc.

EFFECT: improved properties and high efficiency of using the compounds.

25 cl, 13 dwg, 1 tbl, 36 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof. In formula (I) Y is C-R4 and Z is CH; or Y is C-R4 and Z is N; or Y is N and Z is CH; R1 is a 5- or 6-member ring of formula (II) or (III): R2 is H, C1-C7-alkyl; R3 is phenyl, pyrazolyl, isoxazolyl, pyridinyl, pyrimidinyl or pyrazinyl, which can possibly be substituted with one, two or three substitutes selected from a group consisting of: CN, CI, F, Br, CF3, CHF2, C1-C7-alkyl, -O-C1-C7-alkyl, -(CH2)m-Rc, -O-CH2F, -O-CHF2, -O-CF3, -S(O)2-Rd; R4 is H, C1-C7-alkyl; R5 is H, CI, F, Br, CN, CF3, CHF2, C1-C7-alkyl, -C3-C6-cycloalkyl, -(CH2)m-Re or -(CO)-NRiRj; R6 is C1-C7-alkyl; R7 is H, CI, F, CN or C1-C7-alkyl; Rc is -OH; Rd is C1-C7-alkyl; Re is -CH2F, -CHF2, -CF3, CN, C1-C7-alkoxy; Ri, Rj independently denote H or C1-C7-alkyl; m equals 1-4. The invention also relates to a medicinal agent having mGluR5a receptor antagonist properties, containing one or more of the disclosed compounds as an active component.

EFFECT: high efficiency of the medicinal agent.

24 cl, 208 ex

FIELD: chemistry.

SUBSTANCE: disclosed compounds have activity and selectivity towards the GABA A receptor subunit α5. In formula I , R1 denotes hydrogen, halogen, phenyl, a 6-member heterocycyl with 2 heteroatoms selected from N, O, a 5-member heteroaryl with 1-2 heteroatoms selected from S, N, cyano, lower alkyl, -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-N(R)2, -(CH2)n-O-lower alkyl or -(CH2)n-OH; equals 0, 1 or 2; R denotes hydrogen or lower alkyl; R2 denotes C3-C7-cycloalkyl, phenyl, 5-6-member heteroaryl with 1 heteroatom selected from N, S or a 9-10-member bicyclic heteroaryl with 1-3 heteroatoms selected from N, which are possibly substituted with one or more substitutes selected from a group comprising halogen, cyano, nitro, oxo group, lower alkyl, lower alkyl substituted with a halogen, lower alkoxy, lower alkoxy substituted with a halogen, -C(O)O-lower alkyl, lower alkylsulphonyl, -NRaRb, -C(O)-NRaRb, -C(O)-(6-member heterocyclyl with 2 heteroatoms selected from N, O), benzyloxy, 6-member heterocyclyl with 1-2 heteroatoms selected from N, S, O, possibly substituted with hydroxy, 1-2 oxo-groups, halogen or lower alkyl, or selected from a 5-6-member heteroaryl with 1-3 heteroatoms selected from N, possibly substituted with lower alkyl; Ra and Rb independently denote hydrogen, lower alkylsulphonyl, -C(O)H, -(CH2)n-N(R)2, -(CH2)n-O-lower alkyl, -(CH2)n-S-lower alkyl, -(CH2)n-S(O)2-lower alkyl, (5-member heteroaryl with 1 heteroatom selected from S)-sulphonyl, lower alkyl, -(CH2)n-(5-6-member heterocyclyl with 1 heteroatom selected from O, N), possibly substituted with lower alkyl, oxo group, or denotes -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-(5-6-member heteroaryl with 1-2 heteroatoms selected from N), possibly substituted with an oxo group, -(CH2)n-OH, -(CO)-R', where R' denotes C3-C7-cycloalkyl, a 5-member heteroaryl with 1 heteroatom selected from S, or lower alkyl; R' denotes a phenyl or a 6-member heteroaryl with 1 heteroatom selected from N which are possibly substituted with a halogen or lower alkyl, optionally substituted with a halogen. The invention also relates to a medicinal agent containing one or more compounds of formula I and use of the disclosed compounds to prepare a medicinal agent.

EFFECT: high effectiveness of derivatives.

16 cl, 145 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where R3 has any

of the formulae , where R1 is selected from

,

where each R2 independently denotes hydrogen, halogen, C1-C8alkyl, C1-C8alkoxy- C1-C8alkyl, C1-C8alkoxy; R4 denotes a five- or six-member monocyclic ring system, having two heteroatoms selected from O, N and S, such as pyrazinyl, isoxazole or thiazolyl, each of which can be optionally substituted with one or more of the following substitutes: C1-C8alkyl or C1-C8alkoxy; R5 and R6 independently denote hydrogen or C1-C8alkyl; R7 and R8 together form a cyclopentyl ring; R9 independently denotes C1-C8alkyl; R9a independently denotes C1-C8alkylcarbonyl or phenylcarbonyl; R10 denotes hydrogen; R11 independently denotes C1-C8alkyl or C1-C8alkoxy; R12 denotes hydrogen or -COOR17; R13 independently denotes hydrogen, phenyl and a 6-member heteroaryl containing one heteroatom selected from N; R17 denotes hydrogen; R23 denotes (a) C1-C8alkyl, phenyl, a 5-member heteroaryl containing 1-2 heteroatoms selected from S and N, where any phenyl or heteroaryl residue is optionally substituted with a halogen, C1-C8alkyl or C1-C8alkoxy; R24 denotes C1-C8alkyl; R27 denotes H, C1-C8alkyl, C1-C8alkoxy, O-phenyl, S-phenyl; R29 denotes -(CH2)w-COOR17; where w=0; R31 denotes hydrogen; and pharmaceutically acceptable salts thereof. The invention also relates to a method of producing the disclosed compounds, a pharmaceutical composition, having dual acting ATI and ETA receptor antagonist properties, containing the disclosed compound as an active component, use of the compound in preparing a medicinal agent and methods of treating arterial hypertension.

EFFECT: high effectiveness of the compounds.

8 cl, 1 dwg, 39 ex

FIELD: chemistry.

SUBSTANCE: compound of formula (I) has antiviral activity toward the human cytomegalovirus (HCMV) or some other representative of the Herpes virida group. In formula (I)

, R1 is a group of formula , where * denotes the point of bonding to a carbonyl group, R3 denotes a pyridyl which can be substituted with a substitute independently selected from a group comprising C1-C6alkyl or a cyano group, R5 and R6 independently denote hydrogen, R2 denotes a phenyl which can be substituted with a substitute selected from a group comprising a trifluoromethoxy group, a difluoromethoxy group and a monofluoromethoxy group, A is a group of formula

or , where * denotes the point of bonding to the carbonyl group, # denotes the point of bonding to the nitrogen atom of urea, R7 denotes C1-C6alkyl which can be substituted with a substitute selected from a group comprising C3-C6cycloalkyl, R8 and R9 independently denote hydrogen, halogen or C1-C6alkyl. The invention also relates to a method of producing a compound of formula (I) from a compound of formula , a method of producing a compound of formula (V), a medicinal agent containing the disclosed compound, use of the compound in preparing a medicinal agent and a method of fighting viral infections, among them human cytomegalovirus (HCMV) or some other representative of the Herpes viridae group.

EFFECT: high antiviral activity.

9 cl, 1 tbl, 39 ex

FIELD: chemistry.

SUBSTANCE: formula (I) compound has antibacterial activity and can be used as a medicinal agent. In formula ,

R1 is hydrogen, halogen, C1-4alkyl; R2 is selected from hydrogen, halogen, C1-4alkyl; R3 is selected from hydrogen, halogen, cyano, C1-4alkyl; W is -N(R6)-; X is a single bond; ring A is an unsaturated or partially saturated ring containing 5-6 atoms, one or two of which are independently selected from nitrogen and sulphur; or an unsaturated or partially saturated bicyclic ring containing 9-10 atoms, one, two or three of which are selected from nitrogen and sulphur; R4 and R5 are substitutes on a carbon atom and are independently selected from a halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, formyl, hydroxy iminomethyl, C1-4alkoxyminomethyl, C1-4alkyl, C1-4alkoxy, C1-4alkanoyl, C1-4alkoxy)carbamoyl, N-(C1-4alkyl)-N-(C1-4alkoxy)carbamoyl, C1-4alkylS(O)a, where a equals 0-2, C1-4alkoxycarbonyl, C1-4alkoxycarbonylamino, C1-4alkylsulphonylamino, (saturated or unsaturated carbocycle containing 3-7 atoms)-R10- or (saturated, partially saturated or unsaturated ring containing 5-6 atoms, one or two of which are selected from nitrogen, oxygen and sulphur)-R11-; where R4 and R5 can independently and optionally substituted at the carbon atom with one or more R12; R6 is hydrogen; n equals 1-4; where values of R4 can be identical or different; m equals 0-4; where values of R5 can be identical or different; R12 is selected from azido, halogen, cyano, hydroxy, amino, carboxy, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, C1-4alkanoyl, N-(C1-4alkyl)amino, N,N-(C1-4alkyl)2amino, C1-4alkylS(O)a, where a equals 0-2, (saturated or unsaturated cabocycle containing 3-7 atoms)-R14- or (saturated, partially saturated or unsaturated ring containing 5 or 6 atoms, one or two of which are selected from nitrogen, oxygen and sulphur)-R15-; where R12 can independently and optionally be substituted at the carbon atom with one or more R9; R10, R11, R14 and R15 are independently selected from a single bond, -C(O)-, -N(R19)C(O)- or -C(O)N(R20)-; where R19 and R20 are independently selected from hydrogen or C1-4alkyl; R16 is selected from halogen, cyano, hydroxy, carboxy, methyl and methoxy. The invention also relates to a pharmaceutical composition, having antibacterial activity, containing the disclosed compound as an active ingredient, use of the disclosed compound to prepare a medicinal agent and a method of producing the compound of formula (I).

EFFECT: high activity of the compounds.

22 cl, 52 tbl, 721 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an isoxazoline-substituted benzamide derivative of formula or salt thereof, where A1 denotes a carbon or nitrogen atom, A2 and A3 independently denote a carbon atom, G denotes a benzene ring, W denotes an oxygen or sulphur atom, X denotes a halogen atom or C1-C6alkyl, arbitrarily substituted with a radical R4, Y denotes a halogen atom, cyano, nitro, C1-C6alkyl, C1-C6alkyl arbitrarily substituted with radical R4, -OR5, -N(R7)R6, phenyl, D-41, when n equals 2, each Y can be identical or different from each other, R1 denotes -C(R1b)=NOR1a, M-5, -C(O)OR1c, -C(O)SR1c, -C(S)OR1c, -C(S)SR1c, -C(O)N(R1e)R1d, -C(S)N(R1e)R1d, -C(R1d)=NN(R1e)R1lf, phenyl, phehnyl substituted with (Z)p1, or D-3, D-8, D-13-D-15, D-21, D-35, D-52-D-55 or D-57-D-59, R2 denotes C1-C6alkyl, -CH2R14a, E-5, C3-C6alkynyl, -C(O)R15, -C(O)OR15, -C(O)C(O)OR15 or -SR15, where, when R1 denotes -C(R1b)=NOR1a, M-5, or -C(R1b)=NN(R1e)R1f, R2 can denote a hydrogen atom, when R1 denotes -C(O)OR1c, -C(O)SR1c, -C(S)OR1c or -C(S)SR1c, R2 can denote hydrogen, when R denotes -C(O)N(R1e)R1d or -C(S)N(R1c)R1d, R2 can denote a hydrogen atom, when R1 denotes phenyl, phenyl substituted with (Z)p1, or D-3, D-8, -D-13-D-15, D-21, D-35, D-52-D-55 or D-57-D-59 R2 can denote C1-C6halogenalkyl, C1-C6alkyl arbitrarily substituted with a radical R14a, C3-C6alkenyl, -C(O)NH2, -C(O)N(R16)R15, or R2 together with R1 can form =C(R2b)R2a, R3 denotes C1-C6alkyl arbitrarily substituted with radical R4, D-1, D-3, D-8, D-13-D-15, D-21, D-35, D-41, D-52-D-55, D-57-D-59 denote aromatic heterocyclic rings, m equals an integer from 2 to 3, n equals an integer from 0 to 2.

EFFECT: isoxazoline-substituted benzamide derivative and salt thereof are used in pest control, against harmful arthropods in agriculture and horticulture or in livestock farming and in the field of hygiene.

12 cl, 18 tbl, 73 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 1,7-bis[4(5)-methyl-1,3-thiazol-2-yl]-3,5-dithia-1,7-diazaheptanes of general formula (1), which can be used in organic synthesis to produce macro-heterocyclic rings, as well as sorbents and extraction agents for precious and rare-earth metals. The method is realised by reacting hydrogen sulphide-saturated aqueous formaldehyde solution (37%) with 2-amino-4(5)-methylthiazole with molar ratio of initial reagents 2-amino-4(5)-methylthiazole: formaldehyde: hydrogen sulphide equal to 20:30:20, at temperature -5-5°C and atmospheric pressure for 8-12 hours.

EFFECT: improved method.

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

, where R is a group selected from: i) hydrogen; ii) phenyl and iii) thiophenyl; Z is a substituted or unsubstituted [1,3,4]thiadiazol-2-yl group, R1 is selected from: i) hydrogen; ii) straight C1-C6alkyl; iii) C6 or C10 aryl; iv) C(O)OR5; and v) 2-methylthiazol-4-yl; R5 denotes a straight or branched C1-C6alkyl; and index x equals 0 or 1. The invention also relates to use of compounds of formula (I) to prepare a medicinal agent having human protein tyrosine phosphatase beta (HPTP-β) inhibiting action and use in treatment.

EFFECT: compounds can be used as human protein tyrosine phosphatase beta inhibitors.

11 cl, 1 dwg, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a use of N-(2-thiazolyl)amide derivatives of formula

,

where R1 and R2 are independently selected from H, -NO2, halogen, C1-C6 alkyl with a straight chain, where at least one of R1 and R2 is different from H; m equals 0, 1, 2 or 3; X is selected from a group consisting of: indole of formula (A) bound in position 2, indole of formula (B) bound in position 3 and indazole of formula (C) bound in position 3:

, , ,

where R3 is selected from H and C1-C6 alkyl with a straight chain; R4, R5, R6 and R7 are independently selected from H and C1-C6 alkoxy group; R8 is selected from H and C1-C6 alkyl, or any of its pharmaceutically acceptable salts to obtain a medicinal agent for treating or preventing diseases or conditions mediated by GSK-3, especially neurodegenerative diseases such as Alzheimer's disease or insulin-independent sugar diabetes. The invention also relates to a compound of formula (I), a pharmaceutical composition based on said compound and synthesis method thereof.

EFFECT: high efficiency of using said derivatives.

30 cl, 3 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I or pharmaceutically acceptable salts thereof, which have receptor tyrosine kinase type I inhibiting properties and can be used in treating hyperproliferative disorders in mammals. In general formula

,

A is O or S; G is N; B is a 6-member aryl or 5-6-member heteroaryl ring containing a sulphur atom as a heteroatom; E is

, , , , , X is N or CH; D1, D2 and D3 independently denote N or CR19; D4 and D5 independently denote N or CR19 and D6 is O, S or NR20, where at least one of D4 and D5 is CR19; D7, D8, D9 and D10 independently denote N or CR19, where at least one of D7, D8, D9 and D10 is N; R1 is H or C1-C6 alkyl; each R2 independently denotes halogen, cyano, nitro etc, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR15R14, -NR15C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14, C1-C12alkyl, C2-C12 alkenyl, alkynyl, saturated or partially unsaturated C3-C10cycloalkyl, C3-C10cycloalkyl-C1-C12alkyl, -S(O)p(C1-C6alkyl), -S(O)p(CR13R14)q-phenyl, phenyl, phenyl-C1-3-alkyl, 5-6-member heteroaryl, 5-6-member heteroaryl-C1-C3-alkyl, saturated or partially unsaturated 3-8-member heterocyclyl, 5-6-member heterocyclyl-C1-C3-alkyl, -O(CR13R14)q-phenyl, NR15(CR13R14)q-phenyl, O(CR13R14)q-(5-6-member heteroaryl), NR13(CR13R14)q-(5-6-member heteroaryl, -O(CR13R14)q-(3-8-member heterocyclyl) or -NR15(CR13R14)q-3-8-member heterocyclyl), each R3 denotes Z, where Z is selected from and , W is O or S; W2 is O or S;V is CR8R9, R8b is H or C1-C6alkyl; each of R6, R8, R8a and R9 independently denotes hydrogen, trifluoromethyl, C1-C12alkyl etc.

EFFECT: improved properties and high efficiency of using the compounds.

25 cl, 13 dwg, 1 tbl, 36 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (11) given below and pharmaceutically acceptable salts thereof: chemical formula 1

in which: each of G1, G2, G3 and G8 independently denotes -N=, -CR1= or -C(-G9-X)=; one of G1, G2, G3 and G8 is-C(-G9-X)=; X is C1-6 alkyl (where C1-6 can be optionally substituted with a group selected from a halogen atom, hydroxy, cyano and -NR56R57), aryl, heterocycle (where the heterocycle denotes a 5-9-member saturated or unsaturated cyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulphur atoms, and can be a monocycle or condensed ring, and can be optionally substituted with a halogen atom, C1-6 alkyl; C1-6 alkoxy, R33R34NCS-, R3R4NCO-); G9 denotes a single bond, an oxygen atom, a sulphur atom, ring G6 denotes a divalent aryl group or divalent pyridyl group (where the divalent pyridyl group can be optionally substituted with a halogen atom); A is a group of formula (2) given below, or a group of formula (3) given below. Chemical formula 2

, chemical formula 3 , G4 is an oxygen atom or sulphur atom; G5 is an oxygen atom or sulphur atom; G7 is an oxygen atom, -CR42R43-, -CONR44-, -NR44CO, -NR45-, CR42R43NR45-, -S-, -NR44S(=O)2-; R1 is a hydrogen atom, a halogen atom, cyano, C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a halogen atom), carbamoyl or C2-7 alkynyl (where C2-7 alkynyl can be optionally substituted with C1-4 acyl); when G2 or G3 denotes -CR1=, then G8 is -C(-G9-X)=, and X is R3R4NCO-, R33R34NCS-; when G8 is -CR1=, then G3 denotes -C(-G9-X)=, and X is R3R4NCO, or R33R34NCS-; when G1 or G8 denotes -CR4 then G2 is -C(-G9-X)=, and X denotes R3R4NCO-, or R33R34NCS-; or when G2 is -CR1=, then G1 denotes -C(-G9-X)=, and X denotes R3R4NCO-, or R33R34NCS-; R1 can form a single bond or -CH2- with R4 or R34; R2 denotes hydroxy or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from a halogen atom, hydroxy, C1-6 alkoxy, formyl and -CO2R50); R3, R4, R9 and R10 each independently denotes a hydrogen atom, C3-8 cycloalkyl or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from cyano, a halogen atom, hydroxy, C1-6 alkoxy, -NR13R14, and CONR28R29); R6 and R7 each independently denotes a hydrogen atom, C1-6 alkoxy, C3-8 cycloalkyl or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from cyano, halogen atom, hydroxy, C1-6 alkoxy, -NR13R14, and CONR28R29); R33 and R34 each independently denotes a hydrogen atom, C1-6 alkyl, the combination of R3 and R4 together with a nitrogen atom to which they are bonded can form a 5-6-member heterocyclic group containing at least one nitrogen atom (where the 5-6-member heterocyclic group which contains at least one nitrogen atom is a saturated or unsaturated heterocyclic group containing 5-6 atoms in the ring and which, in addition to one or more nitrogen atoms, can contain one or more heteroatoms selected from oxygen and sulphur atoms (where the 5-6-member heterocyclic group can be optionally condensed with a benzene ring); and which can be optionally substituted with a halogen atom or C1-6 alkyl; the combination of R6 and R7 together with the nitrogen atom to which they are bonded can form a 5-6-member heterocyclic group containing at least one nitrogen atom (where the 5-6-member heterocyclic group which contains at least one nitrogen atom is a saturated or unsaturated heterocyclic group containing 5-6 atoms in the ring and which, in addition to one or more nitrogen atoms, can contain one or more heteroatoms selected from oxygen and sulphur atoms (where the 5-6-member heterocyclic group can be optionally condensed with a benzene ring); and which can be optionally substituted with a halogen atom, C1-6 alkyl or an oxo group; R45 is a hydrogen atom, R13 and R14 each independently denotes a hydrogen atom, C1-6 alkyl or COR32; R56 and R57 each independently denotes a hydrogen atom or C1-6 alkyl, and R5, R8, R28, R29, R32, R42, R43, R44, and R50 each independently denotes a hydrogen atom or C1-6 alkyl. The invention also relates to a pharmaceutical composition, as well as to a medicinal agent for treating cell proliferative disorder.

EFFECT: obtaining novel biologically active compounds having inhibitory effect on cell proliferation.

15 cl, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof. In formula (I) Y is C-R4 and Z is CH; or Y is C-R4 and Z is N; or Y is N and Z is CH; R1 is a 5- or 6-member ring of formula (II) or (III): R2 is H, C1-C7-alkyl; R3 is phenyl, pyrazolyl, isoxazolyl, pyridinyl, pyrimidinyl or pyrazinyl, which can possibly be substituted with one, two or three substitutes selected from a group consisting of: CN, CI, F, Br, CF3, CHF2, C1-C7-alkyl, -O-C1-C7-alkyl, -(CH2)m-Rc, -O-CH2F, -O-CHF2, -O-CF3, -S(O)2-Rd; R4 is H, C1-C7-alkyl; R5 is H, CI, F, Br, CN, CF3, CHF2, C1-C7-alkyl, -C3-C6-cycloalkyl, -(CH2)m-Re or -(CO)-NRiRj; R6 is C1-C7-alkyl; R7 is H, CI, F, CN or C1-C7-alkyl; Rc is -OH; Rd is C1-C7-alkyl; Re is -CH2F, -CHF2, -CF3, CN, C1-C7-alkoxy; Ri, Rj independently denote H or C1-C7-alkyl; m equals 1-4. The invention also relates to a medicinal agent having mGluR5a receptor antagonist properties, containing one or more of the disclosed compounds as an active component.

EFFECT: high efficiency of the medicinal agent.

24 cl, 208 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazole derivatives of general formula I and pharmaceutically acceptable salts thereof, where R1 is selected from a group comprising aryl and alkyl, optionally substituted hydroxy; R2 is selected from a group comprising hydrogen and alkyl; R3 is selected from a group comprising hydrogen and -X-A, where X is selected from a group comprising -C(O)- and -S(O)2-; and A is selected from a group comprising hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle and optionally substituted cycloalkyl, where the optionally substituted groups are substituted with 1-2 substitutes selected from a group comprising alkyl, substituted alkyl, alkoxy, substituted amine which is a -NRR group, substituted aryloxy, heteroaryl, heterocycle, halogen, hydroxy and -S(O)2-R9, where R9 is an alkyl; or R1 and R3 together with a carbon atom bonded to R1 and a nitrogen atom bonded to R3 form a heterocyclic or substituted heterocyclic group; R4 is selected from a group comprising hydrogen, linear alkyl, -alkylene-aminoacyl-, -alkylene-hydroxy-, -[alkylene]p-nitrogen-containing heterocycle, -[alkylene]p-nitrogen-containing substituted heterocycle, -[alkylene]p-nitrogen-containing heteroaryl, -[alkylene]p-nitrogen-containing substituted heteroaryl and -[alkylene]p-NR10R11, where p equals 0 or 1, the alkylene contains 1-5 carbon atoms and can have 1 or 2 substitutes selected from a group comprising amine, hydroxy and halogen, aminoacyl relates to a group -C(O)NRR, where each R is independently selected from a group comprising hydrogen and alkyl, R10 and R11 are independently selected from a group comprising hydrogen, alkyl, substituted alkyl, -S(O)2-alkyl, substituted aryl, substituted heteroaryl, cycloalkyl, or when R10 is hydrogen, R11 is hydroxy, alkoxy or substituted alkoxy; or when R1 and R3 together with carbon and nitrogen atoms respectively bonded to them do not form a heterocyclic or a substituted heterocyclic group, R3 and R4 together with a nitrogen atom to which they are bonded form a spiro-condensed heterocyclic group; R5 is selected from a group comprising L-A1, where L is selected from a group comprising C1-C5alkylene, where the alkylene is defined above; and A1 is selected from a group comprising aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle; and one of R6 or R7 is selected from a group comprising aryl and heteroaryl, each of which can optionally be substituted with -(R8)m, where m equals a whole number from 1 to 2, and the other of R6 or R7 is selected from a group comprising hydrogen, halogen and alkyl; or R6 as well as R7 denotes hydrogen; R8 is selected from a group comprising cyano, alkyl, -CF3, alkoxy, halogen, where alkyl, aryl, aryloxy, cycloalkyl, heterocycle, heteraryl and substituted alkyl, aryl, aryloxy, cycloalkyl, heterocycle and heteroaryl are described in claim 1. The invention also relates to specific compounds, a pharmaceutical composition based on the compound of formula I, a method of inhibiting KSP and use of the composition to prepare a medicinal agent.

EFFECT: novel imidazole derivatives are useful as kinesin spindle protein inhibitors for treating cancer.

25 cl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula as well as separate enantiomers, diastereomers, racemic mixures and pharmaceutically acceptable salts thereof, having mitotic kinesin KSP inhibiting activity, as well as inhibitory action on tumour cells, use thereof in preparing a medicinal agent and a pharmaceutical composition based on said compounds. In said formula, R denotes Z-NR2R3, Z-OH, Ar1 and Ar2 independently denote a phenyl which, if needed, is substituted with one or more groups independently selected from: F, CI, Br, I, OH, Z denotes an alkylene having 1-6 carbon atoms which, if needed, is substituted with C1-6alkyl, and R1 assumes values given in the claim.

EFFECT: improved method.

16 cl, 3 dwg, 124 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to their pharmaceutically acceptable salts exhibiting P2X3 receptor antagonist activity. In formula (I), X represents -O-; Y represents -NRdRe where one of radicals Rd and Re means hydrogen, and the other means hydrogen; C1-C12alkyl; C5-C7cycloalkyl; C5-C7cycloalky-C1-C12alkyl; hydroxy-C1-C12alkyl; acetyl; aminocarbonyloxy- C1-C12alkyl or heterocyclyl representing a 6-members saturated ring containing heteroatom S substituted by two oxo groups; D represents optional oxygen; R1 represents isopropyl; R2 represents hydrogen; R5 represents hydrogen or C1-C12alkyl; R4 means hydrogen; C1-C12alkyl; halogen; halogen- C1-C12alkyl; C1-C12alkoxy; hydroxy; halogen- C1-C12alkoxy; nitro; amino; hydroxy- C1-C12alkyl; C1-C12alkoxyalkyl; hydroxy- C1-C12alkoxy; C1-C12alkylsulphonyl; cyano; heteroaryl representing a 5-members aromatic ring containing one, two or three heteroatoms selected from O, S and N which can be optionally substituted by a thio group, C1-C12alkyl or C1-C12alkylsulphonyl; heterocyclyl representing a 6-members saturated ring containing two heteroatoms N, one of which is substituted C1-C12alkylsulphonyl; -(CH2)m-(Z)n-(CO)-Rf or -(CH2)m-(Z)n-SO2-(NRg)n-Rf where each m and n independently represents 0 or 1, Z means NR8, Rf means C1-C12alkyl, hydroxy, amino or hydroxy- C1-C12alkyl, and Rg means hydrogen; R3 represents methoxy; R6 represents hydrogen; and one of radicals R7 and R8 represents hydrogen, and the other represents hydrogen, acetyl or phenyl.

EFFECT: also, the invention refers to a pharmaceutical composition and to an application of the compound of formula (I) for preparing a drug.

8 cl, 3 tbl, 70 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to derivatives of 5-amino-3-(2-nitroxipropyl)-1,2,4-thiadiazoles of general formula , where R1, R2 can be similar or different and independently represent hydrogen, substituted or non-substituted aryl or heteroaryl or aralkyl, alkyl, cycloalkyl, and R1 + R2 can represent heteroaryl (optionally substituted piperasin and piperidin).

EFFECT: obtained are novel compounds, which can be applied in medicine for treatment of neurodegenerative diseases.

1 cl, 3 ex

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