Melanocortin receptor agonists

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula 1, its pharmaceutically acceptable salts and stereoisomers: $ (1), where: R1 means H, amidino, C1-C4-alkyl amidino, C1-C4alkanoylamidino, C1-C10-alkyl, C3-C7-cycloalkyl, C6-C10-aryl, 6-members heterocycle with O atom, 5-members heterocycle with two N atoms, 6-members heteroaryl with one or two N atoms, 5-members heteroaryl with two heteroatoms, one of which is N, and the other is S, C1-C6-alkylcarbonyl, C3-C7-cycloalkylcarbonyl, C1-C4-alkoxycarbonyl, C6-C10-aryl-C1-C4-alkoxycarbonyl, -SO2-C1-C4-alkyl, -C(O)-N(R6)(R7) or -C(S)-N(R6)(R7); and, R6, R7 means H, C1-C6-alkyl, C3-C7-cycloalkyl; alkyl, cycloalkyl, heterocycle, aryl or heteroaryl are unsubstituted or substituted; R2 means C6-C10-aryl which is unsubstituted or mono- or disubstituted; R3 means H, CN, C1-C6-alkyl, C3-C7-cycloalkyl, C2-C6-alkenyl, monocyclic 5-members heterocycle with N and O, monocyclic 5-members heteroaryl with two heteroatoms, one of which is N, and the other is O or S, C(O)-R8 or -C(S)-R8; and R8 means OH, C1-C4-alkyl, C1-C4-alkyloxy or N(R9)(R10); R9, R10 mean N, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C4-alkyloxy, phenyl or 5-members heteroaryl with two heteroatoms, one of which is N, and the other is S, 6-members heteroaryl with N; R9, R10 together with N whereto attached can form a single 4-6-members ring which can include in addition O or S; and alkyl, cycloalkyl, heterocycle, phenyl or heteroaryl are unsubstituted or substituted. R4 means C3-C8-cycloalkyl, C6-C10-aryl, 5-members heteroaryl with two heteroatoms, one of which is N, and the other is S, 6-members heteroaryl with N, 6-members heterocycle with O, and C6-C10-aryl or heteroaryl are unsubstituted or mono- or polysubstituted. R5 means N, C1-C6-alkyl, -C(O)-R11, C1-C6-alkylsulphonyl, C6-C10-arylsulphonyl, -(CH2)p-C6-C10-aryl, -(CH2)p-heteroaryl or -(CH2)p-C3-C8-cycloalkyl where heteroaryl means 5-members heteroaryl with O or with N or with S which can contain in addition N. p is equal to 1 or 2; R11 means C1-C10-alkyl, C1-C6-alkenyl, C3-C8-cycloalkyl, C3-C8-cycloalkenyl, NH2, C1-C4alkylamino, (C1-C4-alkyl)(C1-C4-alkyl)amino, C6-C10-aryl, 5-members heteroaryl with N or with O or with 8 which can contain in addition N, 6-members heterocycle with N and O, 5- or 6-members heterocycle with O, and alkyl is unsubstituted or substituted with one substitute. Aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycle are unsubstituted or mono- or disubstituted.

EFFECT: compounds are melanocortin receptor agonists so presented to be used in a pharmaceutical composition for treatment and prevention of obesity, diabetes, inflammation, erectile dysfunction.

19 cl, 18 tbl

 

The technical field

The present invention relates to a compound of the following formula 1, its pharmaceutically acceptable salt or isomer, effective as an agonist for receptor melanocortin:

in which R1, R2, R3, R4and R5have some lower values.

The present invention also relates to a method for obtaining compounds of the indicated formula 1.

The present invention also relates to agonistic towards the receptor melanocortin compositions containing a compound of a specified formula 1 as an active ingredient, in particular to compositions for the prevention and treatment of obesity, diabetes, inflammation, or erectile dysfunction.

The LEVEL of TECHNOLOGY

Five receptor subtypes in melanocarcinoma family were, were cloned and characterized. These are associated with G-protein receptors (GPCR) stimulate the transmission of signal currents in many different tissues, Poreba a wide range of physiological functions. Receptor melanocortin 1 (MC1R) is mainly expressed in melanocytes, monocytes and mast cells and mediates the pigmentation of hair and skin and prevents inflammation. MC2R is expressed in adipocytes and cells of the adrenal glands and mediates the steroidogeneza in the adrenal gland. MC3R is present in the brain, and the hypothesis is Alamosa, heart, intestine and placenta, and is associated with energy homeostasis and inflammation. MC4R is uniquely expressed in the brain and controls food behavior, energy homeostasis and erectile function. Mouse knockout for MC4R showed the phenotype hyperpathia and obesity. MC5R is found in different tissues and is thought to be important for system exocrine glands.

In search of potent agonists and antagonists in respect of multiple physiological functions melanocortin receptors were designed and synthesized a large number of compounds. Early examples of such compounds are synthetic peptides and peptide analogs, which were identified on the basis of the endogenous agonist, such as MSH. These agonists peptides were used to characterize the function of these receptors. NDP-MSH is a very powerful and non-selective agonist MC1R, 3R, 4R and 5R and, as reported, it reduces food intake and increased body weight in the rat models. Cyclic heptapeptide MT-II is an agonist with similar non-selective profile, and its therapeutic use has been proven in clinical trials for the treatment of erectile dysfunction.

Small molecule agonists for melanocortin receptors, as reported, had significant activity in the drug trials for Leche is of obesity, sexual dysfunction or inflammation. For example, have identified a series of potent and selective MC4R agonists, one of which showed a significant effect of enhancing erectile response in mice (J. Med. Chem. 2002, 45, 4589). It was also identified many of MC4R agonists, which showed pituitary activity and effect against obesity in model rats (Bioorg. Med. Chem. Lett. 2005, 15, 171, Bioorg. Med. Chem. Lett. 2005, 15, 3430, Bioorg. Med. Chem. Lett. 2005, 15, 3501). Discovered a very potent and selective agonist MC1R, which showed efficacy in acute models of inflammation in mice (J. Med. Chem. 2003, 46, 1123). In addition, various small molecules as MCR agonists, have been described in patent applications (WO 01/55109, WO 01/70337, WO 01/70708, WO 02/018327, WO 02/059095, WO 02/059107, WO 02/059117, WO 02/059108, WO 02/081443, WO 02/085925, WO 02/15909, WO 02/067869, WO 02/068387, WO 02/068388, WO 03/009847, WO 03/009850, WO 2004/087159, WO 2004/078716, WO 2004/078717, WO 2005/040109, WO 2005/047251, WO. 2005/077935, WO 2005/077935, WO 2006/019787, WO 2006/020277, WO 2007/041052, WO 2007/041061, WO 2007/047496, WO 2006/072393, WO 2007/015157, WO 2007/015162).

In view of the unsolved problems of lack of various pharmaceutical compounds, as discussed above, in the art, there remains a need in small molecules-MCR agonists and pharmaceutical compositions that would have improved pharmacological profiles. Therefore, the aim of the present invention is to provide new compounds which are useful for the treatment of the Irene, diabetes, sexual dysfunction and inflammation.

DISCLOSURE of INVENTION

Technical solution

The present invention relates to the compound of formula 1, having agonistic effect against MCR, in particular selective agonistic effect against MC4R, its pharmaceutically acceptable salt or isomer.

Another object of the present invention relates to a method for obtaining compounds of formula 1.

Another object of the present invention relates to agonistic towards the receptor melanocortin compositions containing the compound of formula 1, its pharmaceutically acceptable salt or isomer as active ingredients together with pharmaceutically acceptable carrier.

In particular, the composition according to the present invention has a powerful effect for the prevention and treatment of obesity, diabetes, inflammation, or erectile dysfunction.

Description of the INVENTION

The present invention relates to a compound of the following formula 1, its pharmaceutically acceptable salt or isomer:

in which

R1denotes hydrogen, amidino, C1-C4-alkylamino, C1-C4-alkanolamide, C1-C10-alkyl, C3-C7-cycloalkyl, C6-C10aryl, heterocycle, heteroaryl, C1-C6-alkylsulphonyl, C3 -C7-cycloalkylcarbonyl, C1-C4-alkoxycarbonyl, C6-C10-aryl-C1-C4-alkoxycarbonyl, -SO2-C1-C4-alkyl, -C(O)-N(R6)(R7or-C(S)-N(R6)(R7),

and

R6and R7each independently represents hydrogen, C1-C6-alkyl or C3-C7-cycloalkyl,

alkyl, cycloalkyl, heterocycle, aryl or heteroaryl unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, amino, C1-C4-alkyl, trifloromethyl, hydroxy, C1-C4-alkoxy and oxo,

R2represents C6-C10-aryl or heteroaryl, each of which is unsubstituted or mono - or Disaese Deputy selected from the group consisting of halogen, hydroxy, C1-C4-alkyl, C1-C4-alkoxy, cyano, amino,

R3denotes hydrogen, cyano, C1-C6-alkyl, C3-C7-cycloalkyl, C2-C6alkenyl, monocyclic heterocycle, a monocyclic heteroaryl, -C(O)-R8or-C(S)-R8,

and R8denotes hydroxy, C1-C4-alkyl, C1-C4-alkyloxy or N(R9)(R10),

R9and R10each independently represents hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C4-alkylic and, phenyl or heteroaryl, or

R9and R10may together form a single ring or two rings, or optionally include an oxygen atom or a sulfur atom,

moreover alkyl, cycloalkyl, heterocycle, phenyl or heteroaryl unsubstituted or substituted by a Deputy selected from the group consisting of methyl, trifloromethyl, hydroxy, hydroxyimino, amino, acetylamino, amino(C1-C4-alkyl) and (C1-C4-alkyl)(C1-C4-alkyl)amino,

R4represents C3-C8-cycloalkyl, C6-C10-aryl, heteroaryl or heterocycle,

and C6-C10-aryl or heteroaryl unsubstituted or mono - or polyamidine Deputy selected from the group consisting of halogen, hydroxy, C1-C4-alkyl, trifloromethyl, C1-C4-alkoxy, amino,

cycloalkyl or heterocycle unsubstituted or mono - or polyamidine Deputy selected from the group consisting of halogen, hydroxy, C1-C4-alkyl, trifloromethyl, C1-C4-alkoxy and oxo,

R5denotes hydrogen, C1-C6-alkyl, -C(O)-R11C1-C6-alkylsulfonyl, C6-C10-arylsulfonyl, -(CH2)p-C6-C10-aryl, -(CH2)p-heteroaryl or -(CH2)p-C3-C8-cycloalkyl,

and p denotes 1 or 2,

R11oznachaet C 1-C10-alkyl, C2-C6alkenyl, C3-C8-cycloalkyl, C3-C8-cycloalkenyl, amino, C1-C4-alkylamino, (C1-C4-alkyl)(C1-C4-alkyl)amino, C6-C10-aryl, heteroaryl or heterocycle,

moreover, the alkyl is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy, mercapto, C1-C4-alkoxy, C1-C3-alkylcarboxylic, amino, dimethylamino, C1-C4-alkylcarboxylic, cyano, carbamoyl, dimethylcarbamoyl, hydroxyimino and oxo,

aryl or heteroaryl unsubstituted or mono - or tizamidine Deputy selected from the group consisting of halogen, hydroxy, C1-C4-alkyl, trifloromethyl, C1-C4-alkoxy, amino,

cycloalkyl, cycloalkenyl or heterocycle unsubstituted or mono - or tizamidine Deputy selected from the group consisting of halogen, hydroxy, amino, C1-C4-alkyl, trifloromethyl, C1-C4-alkoxy and oxo.

In the definitions of the radicals of the compounds of formula (1) according to the present invention, the term "alkyl", used alone or in combination with alkyloxy"refers to a hydrocarbon radical straight or branched chain. The term "cycloalkyl" means an unsaturated aliphatic Kohl is about, including cyclohexyl.

The term "aryl" means a 6-10-membered aromatic radical including phenyl, naphthyl, etc.

The term "heteroaryl includes 1-2 heteroatoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, and means aromatic 3-6-membered ring which may be condensed with benzene or C3-C8-cycloalkyl. Examples of monocyclic heteroaryl include, but are not limited to, thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazol, pyrazole, triazole, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazin and stuff like that. Examples of bicyclic heteroaryl include, but are not limited to, indole, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzothiadiazole, benzotriazole, quinoline, isoquinoline, purine, properidine and similar groups.

The term "heterocycle" includes 1-2 heteroatoms from the group consisting of nitrogen atom, oxygen atom and sulfur atom, and means 4-8-membered ring which may be condensed with benzene or C3-C8-cycloalkyl, and which is saturated or has 1 or 2 double bonds. His examples include, but are not limited to, piperidine, tetrahydrooxazolo, thiomorpholine, pyrrolidine, imidazolidine, tetrahydrofuran, piperazine, and the like groups.

Preferred the nutrient compounds among the compounds of formula 1, described above are compounds in which

i) R1denotes hydrogen, amidino, C1-C4-alkylamino, C1-C4-alkanolamide, C1-C6-alkyl, C3-C7-cycloalkyl, phenyl, monocyclic heterocycle, a monocyclic heteroaryl, C1-C6-alkylsulphonyl, TRIFLUOROACETYL, C1-C4-alkoxycarbonyl, C6-C10-aryl-C1-C4-alkoxycarbonyl, -SO2-C1-C4-alkyl, carbarnoyl, C1-C6-allylcarbamate, (C1-C6-alkyl)(C1-C6-alkyl)carbarnoyl, thiocarbamoyl, C1-C6-alkylthiomethyl or (C1-C6-alkyl)(C1-C6-alkyl)thiocarbamoyl,

more preferably, R1denotes hydrogen, amidino, methylamino, ethylamide, acetylamino, methyl, ethyl, triptorelin, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxazolyl, imidazolyl, thiazolyl, piperidinyl, tetrahydropyranyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, pyridinyl, acetyl, TRIFLUOROACETYL, propionyl, butyryl, isobutyryl, pivaloyl, methoxycarbonyl, etoxycarbonyl, benzyloxycarbonyl, methylsulphonyl, carbarnoyl, methylcarbamoyl, ethylcarbitol, triptoreline, propellerblades, isopropylcarbamate, butylcarbamoyl, tert-bout carbamoyl, thiocarbamoyl, methylthiocarbamate, etildiocolmain or methylethylketon,

ii) R2denotes phenyl, unsubstituted or mono - or disubstituted by a Deputy selected from the group consisting of F, Cl, and methyl,

more preferably, R2denotes phenyl, 4-forfinal, 4-chlorophenyl, 4-were or 2,4-differenl,

iii) R3denotes hydrogen, cyano, C1-C4-alkyl, C2-C4alkenyl , -CH2C(CH3)2CH2OH, oxazolyl, thiazolyl, oxazolyl, thiazolyl, carboxy, C1-C4-alkylsulphonyl, C1-C4-allyloxycarbonyl, carbarnoyl, thiocarbamoyl, C1-C4-allylcarbamate, (C1-C4-alkyl)(C1-C4-alkyl)carbarnoyl, (C1-C4-alkyl)(C1-C4-alkyloxy)carbarnoyl, C1-C4-alkylthiomethyl or (C1-C4-alkyl)(C1-C4-alkyl)thiocarbamoyl, phenylcarbamoyl, heteroarylboronic, azetidinone, pyrrolidinecarbonyl, piperidinylcarbonyl or morpholinylcarbonyl,

moreover, the alkyl is unsubstituted or substituted by a Deputy selected from the group consisting of hydroxy, hydroxyimino, amino, amino(C1-C4-alkyl) and (C1-C4-alkyl)(C1-C4-alkyl)amino,

more preferably, R3denotes hydrogen, cyano, methyl, ethyl, propyl, allyl, -CHNOH, hydroxymet is l, -CH(CH3)OH, aminomethyl, dimethylaminomethyl, oxazolyl, thiazolyl, oxazolyl, thiazolyl, carboxy, acetyl, propanol, methoxycarbonyl, etoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, carbarnoyl, thiocarbamoyl, ethylcarbitol, tert-butylcarbamoyl, dimethylcarbamoyl, methylethylketon, metrotextual, diethylthiocarbamoyl, phenylcarbamoyl, heteroarylboronic, -C(O)NH(CH2)2NH2azetidinone, pyrrolidinecarbonyl, piperidinylcarbonyl or morpholinylcarbonyl.

iv) R4represents C4-C7-cycloalkyl or monocyclic heterocycle, unsubstituted or mono - or politeley Deputy selected from the group consisting of halogen, hydroxy, C1-C4-alkyl, trifloromethyl, C1-C4-alkoxy and oxo; or phenyl, or monocyclic heteroaryl, unsubstituted or mono-or disubstituted by a Deputy selected from the group consisting of halogen, hydroxy, C1-C4-alkyl, trifloromethyl, C1-C4-alkoxy, amino,

more preferably, R4denotes cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 4,4-dimethylcyclohexyl, 4,4-diverticulosis, 4-cryptometrics, 3,4-tetramethylcyclobutane, tetrahydropyranyl, pyridinyl, N-methylpyridine or phenyl,

and phenyl unsubstituted or mono - or d is substituted by the Deputy, selected from the group consisting of F, Cl, methyl and methoxy.

v) R5denotes hydrogen, C1-C5-alkyl, trifluoromethyl, C1-C6-alkylsulphonyl, TRIFLUOROACETYL, acryloyl, methacryloyl, C3-C8-cycloalkylcarbonyl, C3-C8-cycloalkylcarbonyl, carbarnoyl, C1-C4-allylcarbamate, (C1-C4-alkyl)(C1-C4-alkyl)carbarnoyl, methanesulfonyl, econsultancy, propanesulfonyl, benzoyl, hydroxybenzoyl, aminobenzoyl, monocyclic heteroarylboronic, heterocyclicamines, benzoyl, -CH2-monocyclic heteroaryl or-CH2-C3-C8-cycloalkyl,

more preferably, R5denotes hydrogen, methyl, ethyl, propyl, isobutyl, -hydroxyethyl, -CH2C(CH3)2CH2OH, -CH2C(CH3)2CH(CH3)OH, -CH2CH2NHC(O)CH3aminoethyl, acetyl, TRIFLUOROACETYL, hydroxyacetic, methoxyacetyl, ethoxyacetic, propionyl, ethoxypropanol, isobutyryl, cyanocobalamin, hydroxyisobutyryl, carbamoylethyl, 3,3-dimethylbutanol, pivaloyl, Perevalov, giftacular, hydroxypivalic, mercaptoethanol, dihydroxybiphenyl, metaxopoulos, ethoxyethanol, aminodialkyl, dimethylaminoethanol, hydroxyaminobuteroyl, acetylserotonin, -C(O)C(CH3)2CH(CH3)OH, -C(O)C(CH3)2C(CH3) OH, acryloyl, methacryloyl, cyclopentanecarbonyl, cyclohexanecarbonyl, carbarnoyl, dimethylcarbamoyl, methysulfonylmethane, benzoyl, thiofentanyl, furoyl, oxazolidinyl, diazocarbonyl, imidazolidinyl, pyrazolinones, tetrahydrofuroyl, dihydrouracil, tetrahydropyranyl, morpholinylcarbonyl, methanesulfonyl, benzoyl, furanosyl, thiazolyl or imidazolyl.

Compounds according to the present invention may also form pharmaceutically acceptable salts. These pharmaceutically acceptable salts include salts of accession of acid, which is formed with acid, which contains a pharmaceutically acceptable anion, with the formation of non-toxic salt of Association with an acid, for example, with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, Hydrobromic acid, itestosterone acid and the like; organic carboxylic acids such as tartaric, formic, citric, acetic, trichloroacetic, triperoxonane, gluconic, benzoic, lactic, fumaric, maleic, and the like; sulfonic acid, such as methanesulfonate acid, benzolsulfonat acid, p-toluensulfonate acid or naphthalenesulfonate acid and the like; and more preferably, salts of accession with the acid formed with sulfuric KIS is Auteuil, methanesulfonic acid or halogenation acid and other Compounds of formula 1 according to the present invention can be converted into their salts in the usual way.

In addition, the compounds according to the present invention may have asymmetric carbon center and, thus, may be present as R or S isomer forms, racemates, diastereomeric mixtures and individual diastereomers. The present invention covers all of these isomeric forms and mixtures.

In addition, the present invention relates to a method for obtaining compounds of formula 1, comprising the reaction of an amide of a combination of compounds of formula 2 with a compound of formula 3:

in which R1, R2, R3, R4and R5have the meanings given above.

In addition, the present invention relates to a method for obtaining compounds of formula 1, comprising the reaction of an amide of a combination of compounds of formula 2' with the compound of the formula 3 with the formation of the compounds of formula 1'; and removing the protective group of the compound of formula 1':

in which R1denotes hydrogen,

R2, R3, R4and R5have the meanings set is installed above

P denotes a protective group for amino group, preferably tert-butoxycarbonyl (Vos), benzyloxycarbonyl (Cbz) or fluorenylmethoxycarbonyl (Fmoc).

In addition, the present invention relates to a method for obtaining compounds of formula 1, including the removal of the protective group of the compounds of formula 1' in the specified method with the following (i) amide combination with C1-C6-alkyl-CO2H, or (ii) by reaction with isocyanate, C1-C4-alkylsulfonates, isothiocyanato or C1-C4-allylisothiocyanate:

in which R1represents C1-C6-alkylsulphonyl, carbarnoyl, thiocarbamoyl, C1-C4-allylcarbamate or C1-C4-thiocarbamoyl,

moreover, the alkyl is unsubstituted or substituted by a Deputy selected from the group consisting of halogen, amino, C1-C4-alkyl, trifloromethyl, hydroxy, C1-C4-alkoxy and oxo;

R2, R3, R4and R5have the meanings given above.

Preferably each stage of these methods is carried out in a conventional solvent which does not have a significant adverse effect on the reaction, and particularly preferable to use one or more solvents selected from the group consisting of, but not limited, and is, and of dimethylformamide, dimethylacetamide, tetrahydrofuran, methylene chloride and chloroform.

The reaction of removing the protective group for the amino group can be performed in the presence of a strong acid, such as hydrochloric acid (HCl), triperoxonane acid (TFA), etc. in the presence of an amine base, such as triethylamine, diisopropylethylamine (DIPEA), etc. or by hydrogenation. Specific reaction conditions described in T.W. Green & G.M. Wuts Protective Groups in Organic Synthesis, Chapter 7, pp.309-405.

Known agents combination suitable for use in the reaction combinations include, but are not limited to, carbodiimide, such as dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), 1,1'-dicarbonitriles (CDI), etc. that are used in a mixture with 1-hydroxybenzotriazole (HOBT) or 1-hydroxy-7-isobenzofuranone (HOAT); the acid chloride of bis-(2-oxo-3-oxazolidinyl)phosphinic acid (BOP-Cl), diphenylphosphoryl (DPPA), N-[dimethylamino-1H-1,2,3-triazole[4,5-b]pyridine-1-ylmethylene]-N-methylmethanamine (HATU), etc.

The compounds of formula 1 obtained by the method according to the present invention, can be converted into their salts in the usual way.

After completion of the above reaction method according to the present invention, the products can be isolated and purified by usual methods such as chromatography, recrystallization, etc.

Compounds according to the present invention have potent agonistic effect against melanocortin receptors, and thus the present invention relates to agonistic respect to receptor melanocortin compositions containing the compound of formula 1 as an active ingredient together with a pharmaceutically acceptable carrier. In particular, the composition according to the present invention has a powerful effect for the prevention and treatment of, but not limited to, diabetes, erectile dysfunction, obesity and inflammation.

When the compounds according to the present invention is injected with clinical purpose, the preferred daily dose is within the range of 0.01~10 mg/kg of body weight in a single dose or a single dose. However, the level of doses specified for individual patients may be different depending on the specific connection, body weight, sex, health status, diet, time and route of administration of the medicinal product, rate of excretion, the mixture of drug and the severity of the condition.

Any way depending on the purpose can be used to administer the compounds according to the present invention. Injection and oral and nasal introduction are preferred, however, the introduction can be carried out skin, nutriplus is authorized, retroperitoneal and rectal route.

The preparation for injection, for example, aqueous or oily suspension for sterile injections, can be obtained according to a known method with the use of appropriate dispersing agents, wetting agents or suspendida agents. Solvents suitable for this purpose are water, ringer's solution and isotonic NaCl solution, and also as a solvent or suspendida environment is traditionally used sterilized non-volatile oil. This purpose can be any non-irritating non-volatile oil, including mono-, diglycerides, and aliphatic acid such as oleic acid, can be used for injectable drug.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules, in particular capsules and tablets. Pills and tablets preferably prepared with intersolubility coating. Solid dosage forms may be obtained by mixing the compounds of formula 1 according to the present invention with one or more inert diluents such as sucrose, lactose, starch, etc. and the media, for example, lubricants such as magnesium stearate, dezinfeciruyuhimi, binders, etc.

Examples of compounds of formula 1 according to Nast is Adamu invention include the following compounds:

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-{(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-N,N-ethylmethyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-{(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-N-ethyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]-N-ethyl-N-methyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-diverticulosis)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-diverticulosis)(2.2-dimethylpropanoyl)amino]-N-ethyl-L-prolinamide

(4S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-methylpyrrolidine-3-yl]carbonyl}-4-[(2,2-dimethylpropanoyl)(CIS-4-methylcyclohexyl)amino]-L-prolinamide

N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-dimethylpropanamide

N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]arbonyl}-4-[(4,4-dimethylcyclohexyl)(methylsulphonyl)amino]-N,N-dimethyl-L-prolinamide

N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl](4,4-dimethylcyclohexyl)amino}-2,2-DIMETHYLPROPANE-1-ol

(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-N-isobutyl-N-(CIS-4-methylcyclohexyl)pyrrolidin-3-amine

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(CIS-4-methylcyclohexyl)(tetrahydro-2H-Piran-4-ylcarbonyl)amino]-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-diferenciales-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(3-thienylboronic)amino]-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(isobutyryl)amino]-N,N-dimethyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(2,2-dimethylpropanoyl)(CIS-4-methylcyclohexyl)amino]-N,N-dimethyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N-ethyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N-ethyl-N-methyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-DIMET propanol)amino]-N-isopropyl-L-prolinamide

N-[(3S,5S)-5-(azetidin-1-ylcarbonyl)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(2,5-dihydrofuran-3-ylcarbonyl)(4,4-dimethylcyclohexyl)amino]-N,N-dimethyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino]-N,N-dimethyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-diverticulosis)(3-hydroxy-2,2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]-N-ethyl-N-methyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(3-furoyl)amino]-N,N-dimethyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(3-furoyl)amino]-N-ethyl-N-methyl-L-prolinamide

N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-[(4,4-diverticulosis)(3-hydroxy-2,2-dimethylpropanoyl)am is but]-N-ethyl-N-methyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino]-N-ethyl-N-methyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-diverticulosis)(2.2-dimethylpropanoyl)amino]-N-ethyl-N-methyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-N-ethyl-4-[(3-hydroxy-2,2-dimethylpropanoyl)(CIS-4-methylcyclohexylamine]-N-methyl-L-prolinamide

N-[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-{[ethyl(methyl)amino]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide

N-[(3S,5S-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-(pyrrolidin-1-ylcarbonyl)pyrrolidin-3-yl]-N-(4,4-diverticulosis)-2,2-dimethylpropanamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-]-N-ethyl-N-methyl-4-{Spiro[2,5]Oct-6-yl[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-L-prolinamide

N-[(3S,5S-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-(morpholine-4-ylcarbonyl)pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)ndimethylacetamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)[(2R)-tetrahydrofuran-2-ylcarbonyl]amino]-N-ethyl-N-methyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropyl is Noel)amino]-N-ethyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N-phenyl-L-prolinamide

(2S)-N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)tetrahydrofuran-2-carboxamide

N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-2-methyl-N-[CIS-4-(trifluoromethyl)cyclohexyl]propanamide

(2S)-N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)tetrahydrofuran-2-carboxamide

N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)tetrahydrofuran-3-carboxamide

N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-dimethylpropanamide

N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-cycloheptyl-3-hydroxy-2,2-dimethylpropanamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-{(4,4-dimethylcyclohexyl)[(methylsulphonyl)amino}-N-ethyl-N-methyl-L-prolinamide

(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-N-(4,4-dimethylcyclohexyl)-N-3-furylfuramide-Amin

N-[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-(4,5-dihydro-1,3-oxazol-2-yl)pyrrolidin-3-yl]N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide

N-{(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-[(dimethylamino)carbonothioyl]pyrrolidin-3-yl}-N-(4,4-dimethylcyclohexyl)-2-methylpropanamide

N-[(3S,5R)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-5-(1,3-thiazol-2-yl)pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide

N-[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-(hydroxymethyl)pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide

N-[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-methylpyrrolidine-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide

N-{(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-5-[(E)-(hydroxyimino)methyl]pyrrolidin-3-yl}-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide

N-[(3S,5S)-5-(aminoethyl)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide

N-[(3S,5S)-5-[(acetylamino)methyl]-1-{[(3S,4R)-1-tert-butyl-4-(2,4-dichlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide

N-[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-dichlorophenyl)pyrrolidin-3-yl]carbonyl}-5-[(dimethylamino)methyl]pyrrolidin-3-yl}-]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide

N-[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-5-cyanopyrrolidine-3-yl]-2,2-dimethyl-N-(CIS-4-metallic hexil)propanamide

N-[(3S,5R)-5-acetyl-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide

N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-(1-hydroxymethyl)pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide

(4S)-4-[acetyl - (4,4-dimethylcyclohexyl)amino]-N-(2-amino-ethyl)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]methyl-L-prolinate have been obtained

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-L-Proline

N-[(3S,5R)-5-(aminocarbonyl-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide

N-{(3S,5R)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-5-[(dimethylamino)carbonothioyl]pyrrolidin-3-yl}-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide

N-[(3S,5R)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-5-propionylthiocholine-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide

N-[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-propionylthiocholine-3-yl]-N-(4,4-diverticulosis)-2,2-dimethylpropanamide

N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrole the Jn-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-diethylmalonate

N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-methoxy-2,2-dimethylpropanamide

(3E)-N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-(hydroxyimino)-2,2-dimethylpropanamide

N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-Dimethylbutane

N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethyl-3-oxobutanamide

N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2,3-trimethylbutane

N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-fluoro-2,2-dimethylpropanamide

N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3,3-debtor-2,2-dimethylpropanamide

N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-[(4,4-diverticulosis)(3-methoxy-2,2-dimethylpropanoyl)amino]-N-ethyl-N-methyl-L-prolinamide

(4S)-4-[(3-amino-2,2-dimethylpropanoyl)(4,4-dimethylcyclohexyl)amino]-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-N,N-dimethyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)p is Raiden-3-yl]carbonyl}-4-{[3-(dimethylamino)-2,2-dimethylpropanoyl](4,4-dimethylcyclohexyl)amino}-N,N-dimethyl-L-prolinamide

N-{(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-[(dimethylamino)carbonyl]pyrrolidin-3-yl}-N-(4,4-dimethylcyclohexyl)-2,2-diethylmalonate

S-(3-{[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-5-{[ethyl(methyl)amino]carbonyl}pyrrolidin-3-yl](4,4-dimethylcyclohexyl)amino}-2,2-dimethyl-3-oxopropyl)attentioin

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(3-mercapto-2,2-dimethylpropanoyl)amino]-N-ethyl-N-methyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-diverticulosis)(3-methoxy-2,2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-diverticulosis)(3 ethoxy-2,2-dimethylpropanoyl)amino]-N-ethyl-N-methyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(2,4-differenl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(2,2-dimethylpropanoyl)(4-methoxyphenyl)amino]-N,N-dimethyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-{(2,2-dimethylpropanoyl)[4-(trifluoromethyl)phenyl]amino}-N,N-dimethyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(2,2-dimethylpropanoyl)(4-were)amino]-N,N-dimethyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-{(2,4-differenl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino]-N-N-dimethyl-L-prolinamide

(4S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide

(2S)-N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)tetrahydrofuran-2-carboxamide

N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(CIS-4-methylcyclohexyl)3-furamide

N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(CIS-4-methylcyclohexyl)-2,5-dihydrofuran-3-carboxamide

(4S)-N-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(2,2-dimethylpropanoyl)(CIS-4-methylcyclohexyl)amino]-D-prolinamide

N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-(1-hydroxymethyl)pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide

(4S)-1-{[(3S,4R)-1-(aminocarbonyl)-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide

(3R,4S)-3-(4-chlorophenyl)-4-({(3S)-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]pyrrolidin-1-yl}carbonyl)pyrrolidin-1-carboxamid

(3R,4S)-3-(4-chlorophenyl)-4-({(3S)-3-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidin-1-yl}carbonyl)pyrrolidin-1-carboxamid

(4S)-1-({[(3S,4R)-4-(4-chlorophenyl)-1-(e is ylamino)carbonyl]pyrrolidin-3-yl}carbonyl)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide

N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-[(ethylamino)carbonothioyl]pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-diverticulosis)-3-hydroxy-2,2-dimethylpropanamide

(3R,4S)-3-(4-chlorophenyl)-4-({(3S)-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]pyrrolidin-1-yl}carbonyl)-N-ethylpyrrolidin-1-carboxamid

(3R,4S)-3-(4-chlorophenyl)-4-({(3S)-3-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidin-1-yl}carbonyl)-N-ethylpyrrolidin-1-carboxamid

(3R,4S)-3-(4-chlorophenyl)-4-({(3S)-3-[(2,4-differenl)(2.2-dimethylpropanoyl)amino]pyrrolidin-1-yl}carbonyl)-N-ethylpyrrolidin-1-carboxamid

(3R,4S)-3-(4-chlorophenyl)-N-ethyl-4-({(3S)-3-[isobutyryl(CIS-4-methylcyclohexyl)amino]pyrrolidin-1-yl}carbonyl)-N-methylpyrrolidine-1-carboxamid

(4S)-1-({[(3S,4R)-1-acetyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide

N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-isobutylpyrazine-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide

(4S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-isobutylpyrazine-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-L-prolinamide

(4S)-1-({[(3S,4R)-4-(4-chlorophenyl)1-cyclopropylboronic-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide

(4S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-(tetrahydro-2H-Piran-4-yl)pyrrolidin-3-yl]carbonyl}-4-{(4,4-dimethyl clohessy)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-N-ethyl-N-methyl-L-prolinamide

N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-(2,2,2-triptorelin)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide

(4S)-1-{[(3S,4R)-4-(2,4-differenl)-1-isobutylpyrazine-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide

(4S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-cyclobutylmethyl-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide

(4S)-1-{[(3S,4R)-1-cyclopentyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide

N-{(3S,5S)-1-{[(3S,4R)-4-(2,4-differenl)-1-isobutylpyrazine-3-yl]carbonyl}-5-[(dimethylamino)carbonato]pyrrolidin-3-yl}-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide

N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-(methylsulphonyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-2-methyl-N-(CIS-4-methylcyclohexyl)propanamide

(3R,4S)-3-(4-chlorophenyl)-4-({(3S)-3-[(CIS-4-methylcyclohexyl)(2-methylpropanoyl)amino]pyrrolidin-1-yl}carbonyl)-N-(2,2,2-triptorelin)pyrrolidin-1-carboxamid

(3R,4S)-3-(4-chlorophenyl)-4-({(3S)-3-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidin-1-yl}carbonyl)-N-(2,2,2-trifluoromethyl)pyrrolidin-1-carboxamid

(3R,4S)-3-(4-chlorophenyl)-4-({(3S)-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]pyrrolidin-1-yl}carbonyl)pyrrolidin-1-methylcarbamoyl

N-[(3S)1-{[(3S,4R)-1-[amino(imino)methyl]-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-2-methyl-N-(CIS-4-methylcyclohexyl)propanamide

N-[(3S)-1-({(3S,4R)-4-(4-chlorophenyl)-1-[(ethylamino)(imino)methyl]pyrrolidin-3-yl}carbonyl)pyrrolidin-3-yl]-2-methyl-N-(CIS-4-methylcyclohexyl)propanamide

N-[(3S)-1-{[(3S,4R)-1-[(acetylamino)(imino)methyl]-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-2-methyl-N-(CIS-4-methylcyclohexyl)propanamide

N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-phenylpyrrolidine-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-propanamide

N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-pyridin-2-iparralde-3-yl]carbonyl}pyrrolidin-3-yl]-2,2-dimethyl-N-(CIS-4-methylcyclohexyl)propanamide

N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-(4,5-dihydro-1H-imidazol-2-yl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-dimethylpropanamide

N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-(4,5-dihydro-1H-imidazol-2-yl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-dimethylpropanamide.

The present invention is described in more detail the connections illustrated in the following examples, but the scope of the invention is not limited to them.

Abbreviations used in the following examples of the preparation and in the examples are as follows:

Ac: acetyl

AcOH: acetic acid

Bn: benzoyl

n-Bu n-butyl

t-Bu: tert-butyl

THIEF: (benzotriazol-1-yl-oxy)Tris(dimethylamino)phosphonium hexaflurophosphate

Bu: butyl

CBZ(Cbz): benzyloxycarbonyl

VOS(Vos): tert-butoxycarbonyl

C-Hex: cyclohexyl

c-Bu cyclobutyl

s-Pen: cyclopentyl

c-Pr: cyclopropyl

DAST: trichotillomania

DCC: dicyclohexylcarbodiimide

DCE: dichloroethane

DCM: dichloromethane

diMe dimethyl

diF: debtor

DIPEA: diisopropylethylamine

DMAP: 4-dimethylaminopyridine

DMF: N,N-dimethylformamide

DMSO: dimethyl sulfoxide

DPPA: diphenylphosphoryl

EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

EDTA: ethylenediaminetetraacetic acid

Et: ethyl

EtOAc: ethyl acetate

Et2O: easy diethyl ether

Fmoc: 9-fluorenylmethoxycarbonyl

Hex: normal hexane

HATU: N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridine-3-yloxy)methylene]-N-methylenediamine hexaphosphate

HOAT: 1-hydroxy-7-asobancaria

HOBT: hydroxybenzotriazole

HBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate

i-Pr: isopropyl

i-Bu: isobutyl

KOCN: potassium cyanate

K2CO3: potassium carbonate

LiBH4: borohydride lithium

Me: methyl

MeOH methanol

MTBE: methyl tert-butyl ether

MgSO4: magnesium sulfate

NaBH4: sodium borohydride

NaBH(OAc)3: triacetoxyborohydride sodium

NaOtBu: tert-piperonyl sodium

NaOH: sodium hydroxide

NaN3: sodium azide

NaH: sodium hydride

Pyr: pyridine

Ph: phenyl

Pr: propyl

TBAF: tetrabutylammonium fluoride

Tea: triethylamine

TFA: triperoxonane acid

TFAA: anhydride triperoxonane acid

THF: tetrahydrofuran

t-Bu: tert-butyl

Compounds according to the present invention can be obtained according to the following procedures (schemes A, B, C, D, E and so on).

Scheme A

Intermediate compound A1 can be obtained in the following way:

Example of getting A1-1: (2S,4S)-1-Boc-4-aminopyrrolidine-2-methylcarbamoyl

Stage A: (4R)-1-Boc-4-hydroxy-L-Proline

To a solution of (4R)-hydroxy-L-Proline (5,08 g, 38,77 mmol) in 1N NaOH (40 ml) and 1,4-dioxane (40 ml) at 0°C was added dropwise di-tert-butylboronic (9.3 g, is 42.6 mmol). The reaction mixture was stirred at ambient temperature for 8 hours, concentrated in vacuo, acidified 1H. HCl and was extracted with EtOAc. The organic extracts were washed with saline, dried over MgSO4, filtered and concentrated in vacuum, obtaining the target compound (8.8 g, 99%).

MC[M+H] = 232(M+1)

Stage B: (2S,4R)-1-Boc-4-hydroxypyrrolidine-2-methylcarbamoyl

To a solution of (4R)-1-Boc-4-hydroxy-L-Proline (8 g, 34,63 mmol)obtained in stage A, in DMF was added K2CO3(14 g, 101 mmol) and methyliodide (2,6 ml, with 51.9 mmol). The reaction mixture was stirred at ambient temperature for 5 hours, concentrated in vacuo and extracted tOAc. The organic extracts were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuum, obtaining the target compound (8.0 g, 95%).

MC[M+H] = 246(M+1)

Stage C: (2S,4R)-1-Boc-4-[(methylsulphonyl)oxy]pyrrolidin-2-methylcarbamoyl

To a solution of (2S,4R)-1-Boc-4-hydroxypyrrolidine-2-methylcarbamate (8 g, 32,65 mmol)obtained in stage B, in DCM at 0°C was added dropwise tea (11,99 ml, 81,56 mmol) and methanesulfonamide (3.77 ml, for 48.9 mmol). After the reaction mixture was stirred at ambient temperature for 3 hours, the organic extracts washed with saturated aqueous NaHCO3, 1H. HCl and brine, dried over MgSO4, filtered and concentrated in vacuum, obtaining the target compound (9.4 g, 90%).

MC[M+H] = 324(M+1)

Stage D: (2S,4S)-1-Boc-4-azidopyridine-2-methylcarbamoyl

To a solution of (2S,4R)-1-Boc-4-[(methylsulphonyl)oxy]pyrrolidin-2-methylcarbamate (9 g, 27,86 mmol)obtained in stage C in DMF was added NaN3(2.7 g, 41,79 mmol) and stirred at 90°C for 10 hours. The reaction mixture was concentrated in vacuo, extracted with EtOAc. The organic extracts were washed with saline, dried over MgSO4, filtered and concentrated in vacuum. The residue was purified by chromatography on columns (eluent, EtOAc/Hex = 1/4)to give the target compound (6 g, 80%.

MC[M+H] = 271(M+1)

Stage E: (2S,4S)-1-Boc-4-aminopyrrolidine-2-methylcarbamoyl

To a solution of (2S,4S)-1-Boc-4-azidopyridine-2-methylcarbamate (6 g, 22,22 mmol)obtained in stage D, in dioxane (10 ml) was added Pd/C (800 mg). The reaction mixture was stirred in the atmosphere of hydrogen for 24 hours, Filtered through Celite, and the filtrate was concentrated in vacuum, obtaining the target compound in the form of oil (5.34 g, 98.5 per cent).

MC[M+H] = 245(M+1)

Example of getting A1-2: (2S,4R)-1-Boc-4-aminopyrrolidine-2-methylcarbamoyl

The target compound was obtained according to the procedure described in example obtain A1-1, using (4S)-hydroxy-L-Proline.

MC[M+H] = 245(M+1)

Example of getting A1-3: (2R,4S)-1-Boc-4-aminopyrrolidine-2-methylcarbamoyl

The target compound was obtained according to the procedure described in example obtain A1-1, using (4R)-hydroxy-D-Proline.

MC[M+H] = 245(M+1)

Example of getting A1-4: (2S,4S)-1-Boc-2-allyl-4-aminopyrrolidine

Stage A: (2S,4R)-1-Boc-2-allyl-4-hydroxypyrrolidine

(3R)-1-BOC-3-hydroxypyrrolidine (1 g, of 5.34 mmol) was dissolved in simple diethyl ether (50 ml), and filled with nitrogen. The reaction mixture was cooled to -78°C, was added N,N,N',N'-tetramethylethylenediamine (620 mg, of 5.34 mmol) and slowly added second-utility (1,4M solution of cyclohexane of 4.45 ml, 6,23 mmol). After stirring for 30 minutes at the same temperature dimethyls lift (1.44 g, for 10.68 mmol) was dissolved in simple diethyl ether (10 ml). The reaction solution was slowly heated to ambient temperature, diluted with water (12 ml)and was extracted with simple diethyl ether. The organic extracts were dried over MgSO4and the residue was purified by chromatography on columns (eluent, EtOAc/Hex = 1/4)to give the target compound (840 mg, 70%).

MC[M+H] = 228(M+1)

Stage B: (2S,4S)-1-Boc-2-allyl-4-azidopyridine

The target compound was obtained according to the procedure described in stage C~D of example obtaining A1-1, using the product of stage A, (2S,4S)-1-Boc-2-allyl-4-hydroxypyrrolidine.

MC[M+H] = 253(M+1)

Stage C: (2S,4R)-1-Boc-2-allyl-4-aminopyrrolidine

To a solution of (2S,4R)-1-Boc-2-allyl-4-azidopyridine (450 mg, 1.78 mmol), obtained in stage B in THF was added dropwise trimethylphosphine (135 mg, 1.78 mmol). After the reaction mixture was stirred at ambient temperature for 5 hours, adding water (0,03 ml)and was stirred for additional 20 minutes, the Reaction mixture was concentrated in vacuo, extracted with EtOAc, washed with water and brine and concentrated in vacuum. The residue was purified by chromatography on columns (eluent, MeOH/DCM = 1/9)to give the target compound (280 mg, 70%).

MC[M+H] = 227(M+1)

Example of getting A1-5: (2S,4S)-1-Boc-2-propyl-4-aminopyrrolidine

To a solution of (2S,4S)-1-Boc-2-allyl-4-aminophe is alidina (450 mg, 1.78 mmol)obtained in example obtain A1-4, in dioxane (5 ml) was added Pd/C (40 mg). The reaction mixture was stirred in the atmosphere of hydrogen for 24 hours, Filtered through celite, and the filtrate was concentrated in vacuum, obtaining the target compound in the form of oil (390 mg, 98.5 per cent).

MC[M+H] = 229(M+1)

Example of getting A1-6: (2R,4S)-1-Boc-2-propyl-4-aminopyrrolidine

The target compound was obtained according to the procedure described in example obtain A1-5, using (2R,4R)-1-Boc-2-allyl-4-hydroxypyrrolidine as source material.

MC[M+H] = 229(M+1)

Intermediate A2 can be obtained in the following way:

Example obtain A2-1: 4,4-dimethylcyclohexanone

4,4-Dimethylcyclohexane-1-he (5 g, of 40.3 mmol) and n-pentane (15 ml) were placed in the hydrogen reactor was added Pd/C (500 mg). In the hydrogen reactor was maintained pressure of hydrogen (25 psi), and reaction was performed for 30 minutes After completion of the reaction, the reaction mixture was filtered through celite, and the filtrate was concentrated in vacuum, obtaining the target compound (5 g, 98%).

MC[M+H] = 127(M+1)

Example obtain A2-2: 4-cryptometrics

Stage A: 4-cryptometrics

4-Hydroxybenzotriazole (5 g, 30,8 mmol) were placed in the hydrogen reactor was dissolved in acetic acid (15 ml) was added Pt2O (500 mg). In the hydrogen reactor supported Yes the separation of hydrogen (50 psi), and reaction was performed for 16 hours. After completion of the reaction, the reaction mixture was filtered through celite and to the filtrate was added 1N. NaOH was extracted with simple diethyl ether, dried over MgSO4, and concentrated in vacuum at ambient temperature, obtaining the target compound (4.5 g, 87%).

MC[M+H] = 169(M+1)

Stage B: 4-cryptometrics

To a solution of 4-triftormetilfullerenov (4.5 g, to 26.7 mmol) in DCM (100 ml) was added periodinane dessa-Martin (13,6 g, 32 mmol), and stirred at ambient temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under vacuum, was added an aqueous solution of sodium thiosulfate and simple diethyl ether and stirred at ambient temperature for 30 minutes and was extracted with simple diethyl ether. The organic layer was dried over MgSO4concentrated in vacuum at ambient temperature, obtaining the target compound (4,2 g, a 94.6%).

MC[M+H] = 167(M+1)

Example obtain A2-3: 4,4-dipertikaikan

Stage A: 8,8-debtor-1,4-dioxaspiro [4.5] Decan

To a solution of commercially available 1,4-cyclohexanedione-mono-atelectasia (25 g, 160 mmol) in DCM (500 ml) was added dropwise at 0°C. DAST (52 g, 2.0 mmol). The reaction mixture was slowly heated to ambient temperature and was stirred until end the of the reaction. After confirmation of disappearance of the entire reaction mixture, the reaction solution was added to saturated aqueous solution of NaHCO3(700 ml)to complete the reaction, and was extracted with DCM. The organic extracts were washed with saturated aqueous solution of NaHCO3and brine, dried over MgSO4, filtered and concentrated in vacuum. The obtained residue was used for next reaction without further purification.

Stage B: 4,4-dipertikaikan

The product of stage A, 8,8-debtor-1,4-dioxaspiro[4.5]decane was dissolved in acetone (90 ml) and 3n. HCl (900 ml), and stirred to complete the reaction. Then the reaction mixture was extracted with DCM, washed with saline, dried over MgSO4, filtered and concentrated in vacuum. The obtained residue was used for next reaction without further purification.

Example obtain A2-4: Spiro[2,5]octane-6-he

Stage A: 4,4-methylene-1,1-atlantal-4-Spiro[2,5]octane

To a solution of dimethyl sulfoxide (15 ml), filled with nitrogen, was added NaH (60%suspension in mineral oil, 0,42 g, 10,50 mmol)and the reaction mixture was stirred at 50-60°C for 2 hours, was added methyltriphenylphosphonium (MeP(Ph)3Br)(3,76 g, 10,50 mmol), and stirred at ambient temperature for 1 hour. Added cyclohexandione monoethylether (1 g, 6,40 mmol), and eremetical at 40°C for 2 hours. The reaction solution was cooled to ambient temperature, water with ice{meltwater} was added and was extracted with Et2O. the Organic extracts were dried over MgSO4, filtered and concentrated in vacuum. The residue was purified by chromatography on columns (eluent, EtOAc/Hex = 1/5)to give the target compound (0.74 g, 74,95%).

Stage B: Spiro[2,5]octane-6-he

The product of stage A, 4,4-methylene-1,1-atlantal-4-Spiro[2,5]octane (0.74 g, 4,80 mmol) and diiodomethane (1,93 ml, 24,00 mmol) were placed in Et2O (45 ml)was added Zn-Cu (1,96 g, 30 mmol) and was heated under reflux for 12 hours. The reaction solution was cooled to ambient temperature, was again added diiodomethane (1,93 ml, 24,00 mmol) and Zn-Cu (1,96 g, 30 mmol), and heated under reflux for 20 hours. The reaction solution was cooled to ambient temperature, filtered and washed with Et2O. the filtrate was added 1M HCl (100 ml)was subjected to reaction at ambient temperature for 1 hour, and was extracted with four (4) times Et2O. the Organic extracts were dried over MgSO4, filtered and concentrated in vacuum (0.28 g, 46,99%).

The intermediate A4 can be obtained in the following way:

An example of obtaining A4-1: 2,2-dimethyl-3-acetylaminophenol

Stage A: 2,2-dimethyl-3-acetylaminophenol acid

22-Dimethyl-3-hydroxypropionic acid (11.8 g, 100 mmol) was dissolved in pyridine (30 ml), and the reaction solution was cooled to 0°C. acetylchloride (11.8 g, 15.0 mmol) was added slowly dropwise, the temperature was raised to ambient temperature, and the reaction solution was stirred at ambient temperature for 3 hours. After completion of the reaction was added 1N. HCl (30 ml), was established pH 3-4, the reaction mixture was extracted with EtOAc. The organic extracts were washed for 1H. HCl 4-5 times, dried over MgSO4concentrated in vacuum, obtaining the target compound (15.2 g, 95,0%).

MC[M+H] = 161(M+1)

Stage B: 2,2-dimethyl-3-acetylaminophenol

The product of stage A, 2,2-dimethyl-3-acetylaminophenol acid (11,76 g, 80 mmol) was dissolved in benzene (100 ml), the reaction solution was cooled to 0°C, was slowly added dropwise to the acid chloride oxalic acid (15.0 g, 120 mmol). After 3 hours the solvent was removed in vacuum and the person to distil under vacuum, obtaining the target compound.

MC[M+H] = 179(M+1)

An example of obtaining A4-2: 2.5-dihydrofuran-3-carboxylate

Stage A: 4-oxitetraciclina-3-tert-butylcarbamoyl acid

Sodium hydride (55%suspension in mineral oil, 0.5 g, 11,46 mmol) were placed in the anhydride Et2O (8 ml) and stirred, was added dropwise at ambient temperature ethylglycol (0.9 ml, being 9.61 mmol). The reaction solution was stirred during the 1 hour, concentrated in vacuo, and was added at 0-5°C tert-butyl acrylate (1,68 ml, 11,46 mmol) in anhydride DMSO (8 ml). The reaction solution was stirred for 15 minutes at 0-5°C, was stirred at ambient temperature for an additional 1 hour and filtered. At 0-5°C, the filtrate was placed in a solution of sulfuric acid (5%, 5.6 ml) and was extracted with Et2O 3 times. The organic extracts were washed with saline, dried over MgSO4, filtered and concentrated in vacuum. The residue was purified by chromatography on columns (eluent, EtOAc/Hex = 1/5)to give the target compound (0.95 g, 53,11%).

Stage B: 4-hydroxymitragynine-3 - tert-butylcarbamoyl

The product of stage A, 4-oxitetraciclina-3-tert-butylcarbamoyl, (0.95 g, 5,10 mmol) were placed in isopropyl alcohol (14 ml) at 0-5°C, was added NaBH4(77 mg, 2.04 mmol) and was stirred for 2 hours. Again, were added NaBH4(77 mg, 2.04 mmol) and stirred at ambient temperature for 1 hour, was added NaBH4(39 mg, of 1.02 mmol) and was stirred for 30 minutes, the Reaction mixture was treated with Et2O, diluted, washed with saline solution and was extracted with Et2O twice. The organic layer was collected, were extracted in an aqueous solution of NaHCO3, dried over MgSO4, filtered and concentrated in vacuum. The residue was purified by chromatography on to the ankah (eluent, EtOAc/Hex = 1/3)to give the target compound (0,83 g, 86,56%).

Stage C: 2.5-dihydrofuran-3-tert-butylcarbamoyl

The product of stage B, 4-hydroxymitragynine-3-tert-butylcarbamoyl, (0,83 g, to 4.41 mmol) and PPh3(1,74 g, 6,63 mmol) were placed in THF (5 ml), the solution was cooled to 0-5°C, was added dropwise DIAD (1.13 ml, 5,74 mmol). After reaction at ambient temperature for 12 hours, the reaction mixture was filtered, washed with a solution of EtOAc/Hex = 1/4, and the filtrate was concentrated in vacuo, the residue was purified by chromatography on columns (eluent, EtOAc/Hex = 1/7)to give the target compound (0.39 g, 51,34%).

Stage D: 2.5-dihydrofuran-3-carboxylic acid

To a solution of 2,5-dihydrofuran-3-tert-BUTYLCARBAMATE (0.39 g, to 2.29 mmol)obtained in stage C in DCM (2 ml) was added TFA (6 ml) and stirred at ambient temperature for 12 hours. The reaction solution was concentrated in vacuo, the residue was treated with N-hexane, stirred at ambient temperature for 30 minutes and filtered, obtaining the target compound (0,19 g, 72.3 per cent).

Stage E: 2.5-dihydrofuran-3-carboxylicacid

The product of stage D, 2.5-dihydrofuran-3-carboxylic acid (0,19 g of 1.66 mmol) was dissolved in benzene (3 ml), the reaction solution was cooled to 0°C and slowly added dropwise to the acid chloride oxalic acid (0.4 g, of 3.32 mmol). After 3 hours, the solvent prowess and in vacuum and person to distil under vacuum, receiving the target connection.

An example of obtaining A4-3: 2-cyano-2-methylpropanoate

To a solution of commercially available ethyl-2-cyano-2-methylpropanoate (3.5 g, 24,8 mmol) in methanol (10 ml) was added LiOH (900 mg, or 37.2 mmol) and water (0.5 ml), and reaction was performed at ambient temperature for 1 hour. After completion of the reaction the solvent was concentrated under vacuum, was added 1N. HCl (50 ml) and was extracted with EtOAc. Extracted organic layer was dried over MgSO4concentrated in vacuum, obtaining 2-cyano-2-methylpropionic acid (2.67 g, 95%). This compound (2.5 g, 22 mmol) was dissolved in DCM (7 ml), and reaction was performed according to the procedure described in stage B of example obtaining A4-1, obtaining the target compound (2.5 g, 86,3%).

MC[M+H] = 132(M+1)

An example of obtaining A4-4~9

The following acylchlorides received according to the procedure described in example obtaining A4-1 and A4-3, using commercially available carboxylic acid.

Table 1
An example of receivingR5MC(M+1)An example of receivingR5MC(M+1)
A44 135A4-5135
A4-6149A4-7147
A4-8135A4-9131

Example of getting A9-1: (3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-carboxylic acid

The target compound was obtained according to the procedure described in WO 2004/09126.

Example of getting A9-2~7

Compounds in the following table were obtained according to the procedure described in example receiving the A9-1, using commercially available compounds alpha-haloketones.

Table 2
An example of receivingAR2'M+l
A9-2t-Bu4-C1282
A9-3t-Bu4-Me262
A9-4t-Bu4-F266
A9-6Me4-C1240
A9-7Me2,4-diF242

Example of getting A9-8: (3S,4R)-1-Boc-4-(2,4-differenl)pyrrolidin-3-carboxylic acid

Stage A: (4R)-4-(2,4-differenl)pyrrolidin-3-carbonitril

To a solution of (4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-carbonitrile (4 g, br15.15 mmol), obtained according to the procedure described in WO 2004/09126 in DCE (10 ml) at 0°C was added dropwise 1-chloroethylphosphonic (at 2.45 ml, 22,68 mmol). The reaction solution was heated to 70°C and maintaining this temperature, was added dropwise within 2 hours of 1,8-bis(dimethylamino)naphthalene (4,87 g, 22,72 mmol) in DCE (10 ml). After completion of the reaction was added methanol (10 ml) and maintaining the temperature, the reaction mixture was stirred for additional 1 hour, concentrated in vacuo is e, and the following reaction was carried out without further purification.

MC[M+1] = 209(M+1)

Stage B: (4R)-1-BOC-4-(2,4-differenl)pyrrolidin-3-carbonitril

To a solution of (4R)-4-(2,4-differenl)pyrrolidin-3-carbonitrile obtained at stage A, DMAP (1.8 g, br15.15 mmol) and tea (5.56 ml, 15.15 mmol) in DCM (10 ml) at 0°C was added dropwise di-tert-butyl bicarbonate (4.9 g, 22.7 mmol). The reaction mixture was stirred at ambient temperature for 8 hours, concentrated in vacuo and extracted with EtOAc. The organic extracts were washed for 1H. HCl and brine, dried over MgSO4concentrated in vacuo and purified by chromatography on columns (eluent: EtOAc/Hex = 1/6)to give the target compound (3.3 grams, the total number of stages A and B: 72%).

MC[M+H] = 309(M+1)

Stage C: (3S,4R)-1-Boc-4-(2,4-differenl)pyrrolidin-3-carboxylic acid

To a solution of (4R)-1-BOC-4-(2,4-differenl)pyrrolidin-3-carbonitrile (3,3 g, 10.6 mmol), obtained in stage B in ethanol (10 ml) was added 6N NaOH solution (5 ml), and stirred at 70°C for 4 hours. After completion of the reaction the solvent was removed, the reaction mixture was diluted simple ether, the organic solution was acidified using 6N. HCl and washed. The organic solution was washed with saline, dried over MgSO4and concentrated in vacuum, obtaining the target compound (3,43 g, 99,0%).

MC[M+1] = 328(M+1)

Example of getting A9-9~11

Compounds in the following table were obtained according to the procedure described in example receiving the A9-8, using the intermediate phenylpyrrolidine-3-carbonitrile received in the sample receiving the A9-2~4.

Table 3
An example of receivingM+l
A9-94-C1326
A9-104-Me306
A9-114-F310

Examples synthesized in accordance with the procedure of scheme A are as follows.

Example A1: (4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide Salt HCl

HCl

Stage A: (2S,4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)amino]pyrrolidin-2-methylcarbamoyl

To (2S,4S)-1-Boc-4-aminopyrrolidine-2-methylcarbamate (1.07 g, of 4.38 mmol) and dimethylcyclohexanone (0.66 g, a 5.25 mmol) in DCE (20 ml) at ambient temperature was added dropwise NaBH(OAc)3(1.39 g, to 6.57 mmol). The reaction is mesh was stirred at ambient temperature for 4 hours, was added a saturated aqueous solution of NaHCO3and was extracted with DCM (50 ml × 2) and EtOAc. The organic extracts were washed with saline, dried over MgSO4, filtered and concentrated in vacuum. The obtained residue was purified by chromatography on columns (eluent, EtOAc/Hex = 1/2)to give the target compound (1,16 g, 75%).

MC[M+H] = 355(M+1)

Stage B: 1-BOC-2-methyl-(2S,4S)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl) amino]pyrrolidin-2-carboxylate

To a solution of (2S,4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)amino]pyrrolidin-2-methylcarbamate (1.01 g, 2,84 mmol)obtained in stage A, in DCE (5 ml) was added dropwise tea (5 ml) and DMAP (0.34 g, 2,84 mmol), was added commercially available pivaloate (1.01 g, charged 8.52 mmol). The reaction solution was heated to 90°C and was stirred for 24 hours. After completion of the reaction the solvent was removed in vacuo, the residue was treated with saturated aqueous NaHCO3and was extracted with EtOAc. The organic extracts were washed for 1H. HCl, dried over MgSO4concentrated in vacuo and purified by chromatography on columns (eluent: EtOAc/Hex = 1/4)to give the target compound (1,02 g, 82%).

MC[M+H] = 439(M+1)

Stage C: (4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-L-Proline

To a solution of 1-BOC-2-methyl-(2S,4S)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidine-2-carboxylate (1,02 g, 2.32 mmol), who received at stage B, in methanol (7 ml) and water (7 ml) was added LiOH (0.15 g, of 6.99 mmol). The reaction mixture was stirred at ambient temperature for 3 hours, concentrated in vacuo and extracted with EtOAC. The organic extracts were washed with saline, dried over MgSO4and concentrated in vacuum, obtaining the target compound (0,93 g, 95%).

MC[M+H] = 425(M+1)

Stage D: BOC (2S,4S)-2-[(dimethylamino)carbonyl]-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidin

To a solution of (4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-L-Proline (0,93 g, 2.2 mmol)obtained in stage C in DMF (10 ) was added dropwise DIPEA (0.95, and 5.5 mmol), then salt dimethylamine-HCl (0.21 g, 2.57 mmol) and HBTU (0,83 g, 2.2 mmol). The reaction solution was stirred at ambient temperature for 2 h and concentrated in vacuum. The residue was diluted with EtOAc, washed with saturated aqueous NaHCO3, water and 1N. HCl. The organic solution was dried over MgSO4concentrated in vacuo, and the residue was purified by chromatography on a column (eluent: EtOAc:Hex = 2/1)to give the target compound (0,92 g, 93%).

MC[M+H] = 452(M+1)

Stage E: (4S)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N, N-dimethyl-L-prolinamide

To a solution of BOC(2S,4S)-2-[(dimethylamino)carbonyl]-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidine (0,92 g, 2.0 mmol)obtained in the process D, in DCM (1 ) was added dropwise 4M HCl (1 ml). The reaction mixture was stirred at ambient temperature for 1 h and concentrated in vacuum. The residue was concentrated in vacuum, obtaining the target compound (705 mg, 99.9%uptime)

MC[M+H] = 352(M+1)

Stage F: (4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide TFA Salt

To a solution of (4S)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide (0.70 g, 2.0 mmol)obtained in stage E in DMF (5 ml) was added dropwise DIPEA (0.95 ml, 5.5 mmol). Then was added dropwise (3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-carboxylic acid (or 0.57 g, 2.0 mmol)obtained in example obtaining A-9-1, then HBTU (0,76 g, 2.0 mmol). The reaction mixture was stirred at ambient temperature for 2 h and the solution was concentrated in vacuum. The residue was diluted with EtOAc and washed with saturated aqueous NaHCO3and water. The organic solution was dried over MgSO4concentrated in vacuo and the residue was purified HPLC, obtaining the target compound (TFA salt, 1.04 g, 85%)

MC[M+H] = 617(M+1)

Stage G: (4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide Salt HCl

The TFA salt of the compound obtained in stage F, Padme acively 1H. NaOH and was extracted with EtOAc. The organic solution was dried over MgSO4concentrated under vacuum, was treated with 4M HCl/dioxane and stirred at ambient temperature for 1 hour. The reaction solution was concentrated in vacuo without further purification, receiving the HCl salt.

1H NMR (400 MHz, CDCl3) δ 8,10-of 8.04 (m, 1H), 6,97-6,93 (m, 1H), 6,79-6,74 (m, 1H), 4,70 (t, 1H), 4,35-4,22 (m, 2H), 3.95 to 3,90 (m, 2H), 3,81 at 3.69 (m, 1H), 3,67-of 3.54 (m, 2H), 3,42 be 3.29 (m, 2H), 3,22-3,11 (m, 1H), 2,99 (c, 3H), 2.95 and (c, 3H), 2,82 of 2.68 (m, 1H), 2,19-of 1.97 (m, 1H), 1,61-of 1.39 (m, 4H), 1,49 (c, 9H), 1,31-of 1.15 (m, 4H), 1,22 (c, 9H), 0,95 (c, 3H), 0,91 (c, 3H).

Example A2: (4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-{(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-N,N-ethylmethyl-L-prolinamide Salt HCl

HCl

Stage A: 1-boc-2-methyl (2S,4S)-4-{(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}pyrrolidin-carboxylate

To a solution of (2S,4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)amino]pyrrolidin-2-methylcarbamate (1.01 g, 2,84 mmol)obtained in stage a in example A1, in DCE (5 ml) was added dropwise tea (5 ml) and DMAP (0.34 g, 2,84 mmol). Then was added (S)-tetrahydrofuran-2-carbonylchloride (1,14 g, charged 8.52 mmol)obtained in example obtaining A4-5. The reaction solution was heated at 90°C and was stirred for 24 hours. After completion of the reaction the solvent was removed in vacuo and to the residue was added saturated aqueous shall actor NaHCO 3, and was extracted with EtOAc. The organic extracts were washed for 1H. HCl, dried over MgSO4concentrated in vacuo and purified by chromatography on columns (eluent: EtOAc/Hex = 1/4)to give the target compound (1,05 g, 82%).

MC[M+H] = 453(M+1)

Stage B: (4S)-1-BOC-4-{(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-L-Proline

The target compound was obtained according to the procedure described in stage C of example A1, using 1-BOC-2-methyl (2S,4S)-4-{(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}pyrrolidin-carboxylate (1,05 g, 2.32 mmol)obtained in stage A, (0.96 g, 95%).

MC[M+H] = 439(M+1)

Stage C: BOC-(2S,4S)-4-{(4,4-dimethylcyclohexyl) [(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-2-{[ethyl(methyl)amino]carbonyl}pyrrolidin

The target compound was obtained according to the procedure described in stage D of example A1, using (4S)-1-BOC-4-{(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-L-Proline (0.96 g, 2.2 mmol), obtained in stage B, and commercially available N-methylethylamine (0,92 g, 93%).

MC[M+H] = 480(M+1)

Stage D: (4S)-4-[(4,4-dimethylcyclohexyl)(tetrahydrofuran-2-ylcarbonyl)amino]-N-ethyl-N-methyl-L-prolinamide

To a solution of BOC-(2S,4S)-4-{(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-2-{[ethyl(methyl)amino]carbonyl}pyrrolidine (0,92 g, 2.0 mmol)obtained in stage C in DCM (1 ml) was added dropwise 4M HCl (1 ml). The reaction is th the mixture was stirred at ambient temperature for 1 h and concentrated in vacuum. The residue was concentrated in vacuum, obtaining the target compound (750 mg, 99.9%uptime)

MC[M+H] = 380(M+1)

Stage E: (4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-{(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-N,N-ethylmethyl-L-prolinamide Salt HCl

To a solution of (4S)-4-[(4,4-dimethylcyclohexyl)(tetrahydrofuran-2-ylcarbonyl)amino]-N-ethyl-N-methyl-L-prolinamide (0,76 g, 2.0 mmol)obtained in stage D in DMF (5 ml) was added dropwise DIPEA (0.95 ml, 5.5 mmol). Then added dropwise to the product of example obtaining A9-2, (3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-carboxylic acid (0.56 g, 2.0 mmol), and then HBTU (0,76 g, 2.0 mmol). The reaction mixture was stirred at ambient temperature for 2 h, the solution was concentrated in vacuum. The residue was diluted with EtOAc and washed with saturated aqueous NaHCO3and water. The organic solution was dried over MgSO4concentrated in vacuo and the residue was purified HPLC, receiving TFA salt of compound (1,09 g, 85%). This compound was treated according to the procedure described in stage G of example A1, receiving the target connection.

MC[M+H] = 643(M+1)

1H NMR (400 MHz, CDCl3) δ 7,51 (d, 2H), 7,33 (d, 2H), and 4.68 (t, 1H), 4,48 (t, 1H), 4,40-is 4.21 (m, 1H), 4,03-3,90 (m, 3H), 3,90-3,81 (m, 2H), 3,80-3,70 (m, 2H), 3,66-of 3.46 (m, 3H), 3.45 points-of 3.12 (m, 3H), of 2.97 (d, 3H), 2,86-2,62 (m, 1H), 2,41-of 2.28 (m, 1H), 2,13-to 1.82 (m, 4H), 1,64-of 1.40 (m, 4H), 1,52 (c, 9H), 1,40-1,22 (m, 2H), 1.26 in (t, 3H), 1,20-1,08 (m, 2H), 0,97 (c, 3H), were 0.94 (s, H).

Example A3: (4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-{(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-N-ethyl-L-prolinamide Salt HCl

HCl

Stage A: 1-BOC-(2S,4S)-4-{(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-2-[(ethylamino)carbonyl}pyrrolidin

The target compound was obtained according to the procedure described in stage D of example A1, using (4S)-1-BOC-4-{(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-L-Proline (0.96 g, 2.2 mmol), obtained in stage B of example A2, and commercially available ethylamine (0.95 g, 93%).

MC[M+H] = 466(M+1)

Stage B:(4S)-4-[(4,4-dimethylcyclohexyl)(tetrahydrofuran-2-ylcarbonyl)amino]-N-ethyl-L-prolinamide

To a solution of 1-BOC-(2S,4S)-4-{(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-2-[(ethylamino)carbonyl}pyrrolidine (0.95 g, 2.0 mmol), obtained at the stage in DCM (1 ml) was added dropwise 4M HCl (1 ml). The reaction mixture was stirred at ambient temperature for 1 h and concentrated in vacuum. The residue was concentrated in vacuum, obtaining the target compound (730 mg, 99.9%uptime)

MC[M+H] = 366(M+1)

Stage C: (4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-{(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-N-ethyl-L-prolinamide Salt HCl

To a solution of (4S)-4-[(4,4-dimethylcyclohex the KSIL)(tetrahydrofuran-2-ylcarbonyl)amino]-N-ethyl-L-prolinamide (0.73 g, 2.0 mmol), obtained in stage B in DMF (5 ml) was added dropwise DIPEA (0.95 ml, 5.5 mmol). Then added dropwise to the product of example obtaining A9-2, (3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-carboxylic acid (0.56 g, 2.0 mmol), and then HBTU (0,76 g, 2.0 mmol). The reaction mixture was stirred at ambient temperature for 2 h, the solution was concentrated in vacuum. The residue was diluted with EtOAc and washed with saturated aqueous NaHCO3and water. The organic solution was dried over MgSO4concentrated in vacuo and the residue was purified HPLC, receiving TFA salt of compound (1.06 g, 85%). This compound was treated according to the procedure described in stage G of example A1, receiving the target connection.

MC[M+H] = 629(M+1)

1H NMR (400 MHz, CDCl3) δ of 7.55 (d, 2H), 7,33 (d, 2H), 4,51-4,43 (m, 1H), 4.26 deaths (t, 1H), 4,06-3,98 (m, 1H), 3,97 of 3.56 (m, 7H), 3,49-to 3.02 (m, 4H), 2,83-to 2.74 (m, 1H), 2,49-of 2.38 (m, 1H), 2,32-2,22 (m, 1H), 2.21 are 2,11 (m, 1H), 2,02-1,82 (m, 4H), 1,61-of 1.15 (m, 8H), 1,49 (c, 9H), 1,10 (t, 3H), 0,93 (c, 3H), 0,91 (c, 3H).

Example A4: (4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]-N-ethyl-N-methyl-L-prolinamide Salt HCl

HCl

Stage A: 1-boc-2-methyl-(2S,4S)-4-{[3-(atomic charges)-2,2-dimethylpropanoyl](4,4-dimethylcyclohexyl)amino}pyrrolidin-2-carboxylate

To a solution of (2S,4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)amino]pyrrolidin-2-metalcarbon elata (1.01 g, 2,84 mmol)obtained under example A1 in DCE (5 ml) was added dropwise tea (5 ml) and DMAP (0.34 g, 2,84 mmol). Then was added the product of example obtaining A4-1, 2,2-dimethyl-3-acetylaminophenol (1.01 g, of 5.68 mmol). The reaction solution was heated to 90°C and was stirred for 48 hours. After completion of the reaction the solvent was removed in vacuo, to the residue was added a saturated aqueous solution of NaHCO3and was extracted with EtOAc. The organic extracts were washed for 1H. HCl, dried over MgSO4concentrated in vacuo and purified by chromatography on columns (eluent: EtOAc/Hex = 1/4)to give the target compound (0.88 g, 63%).

MC[M+H] = 497(M+1)

Stage B: (4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]-L-Proline

To a solution of 1-BOC-2-methyl-(2S,4S)-4-{[3-(atomic charges)-2,2-dimethylpropanoyl](4,4-dimethylcyclohexyl)amino}pyrrolidin-2-carboxylate (1,02 g, 2.05 mmol)obtained in stage A, in methanol (10 ml) and water (10 ml) was added NaOH (246 mg, 6,15 mmol) and was stirred for 12 hours. After completion of the reaction, the reaction solution was concentrated in vacuo, acidified 1H. HCl and was extracted with EtOAc. The organic extracts were washed for 1H. HCl, dried MgSO4and concentrated in vacuum, obtaining the target compound of 0.85 g, 95%).

MC[M+H] = 441(M+1)

Stage C: BOC-(2S,4S)-4-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]-2-{[ethyl(methyl)amine is]carbonyl}pyrrolidin

The target compound was obtained according to the procedure described in stage D of example A, using A1 (4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]-L-Proline (0,85 g, 1.94 mmol), obtained in stage B, and commercially available N-methylethylamine (0,86 g, 93%).

MC[M+H] = 482(M+1)

Stage D: (4S)-4-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]-N-ethyl-N-methyl-L-prolinamide

The target compound was obtained according to the procedure described in stage E of example A1, using BOC-(2S,4S)-4-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]-2-{[ethyl(methyl)amino]carbonyl}pyrrolidin (0,86 g, 1.8 mmol)obtained in stage C (0.68 g, 99.9 percent).

MC[M+H] = 382(M+1)

Stage E: (4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]-N-ethyl-N-methyl-L-prolinamideSalt HCl

The TFA salt of the compounds were obtained according to the procedure described in stage G of example A1, using (4S)-4-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]-N-ethyl-N-methyl-L-prolinamide (0.68 g, 2.0 mmol)obtained in stage D (1 g, 89%). This compound was treated according to the procedure described in stage G of example A1, receiving the target connection.

MC[M+H] = 645(M+1)

1H NMR (400 MHz, CDCl3) a 7.62 (d, 2H), 7,31 (d, 2H), and 4.68 (t, 1H), 4,36-4,19 (m, 1H), 3.96 points-with 3.79 (m, 3H), of 3.77-to 3.52 (m, 4H), 3.43 points-is 3.08 (m, 6H), 2,94 (c, 3H), 2,74-2,62 (m, 1H), 2,11-of 1.97 (m, 1H), 1,67-of 1.36 (m, 14N), 1,35-of 1.15 (m, 9H), 1,10 (t, 3H), 0,95 (c, 3H), 0,92 (c, 3H).

Example A5: (4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-diverticulosis)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide Salt HCl

HCl

Stage A: 2-methyl-(2S,4S)-1-BOC-4-[(4',4'-diverticulosis)amino]pyrrolidinecarboxylic

To a solution of 4,4-Diverticulectomy obtained in example obtain A2-3, and (2S,4S)-1-Boc-4-aminopyrrolidine-2-methylcarbamate (29 g, 120 mmol)obtained in example obtain A1-1 in DCE was added NaBH(OAc)3(37 g, 180 mmol), and stirred at ambient temperature for 6 hours. After completion of the reaction the solvent was concentrated under vacuum, was added an aqueous solution of NaHCO3, was extracted with EtOAc, and the organic layer was dried over MgSO4concentrated in vacuum. The residue was purified by chromatography on columns (eluent: EtOAc/Hex = 1/4)to give 2-methyl-(2S,4S)-1-BOC-4-[(4'-forcelogix-3-EN-1-yl)amino]pyrrolidinecarboxylic, whereby obtaining the target compound (23 g, 55%).

MC[M+H] = 363(M+1)

Stage B: 1-SUN 2-methyl(2S,4S)-4-[(4,4-diverticulosis)(2.2-dimethylpropanoyl)amino]pyrrolidine-2-carboxylate

The target compound was obtained according to the procedure described in stage B of example A1 using 2-methyl-(2S,4S)-1-BOC-4-[(4',4'-diverticulosis)amino]pyrrolidinyloxy is at (1,03 g, 2,84 mmol)obtained in stage (1,02 g, 82%).

MC[M+H] = 447(M+1)

Stage C: (4S)-1-BOC-4-[(4,4-diverticulosis)(2.2-dimethylpropanoyl)amino]-L-Proline

The target compound was obtained according to the procedure described in stage C of example A1, using 1-BOC-2-methyl (2S,4S)-4-[(4,4-diverticulosis)(2.2-dimethylpropanoyl)amino]pyrrolidine-2-carboxylate (1,02 g, 2.32 mmol), obtained in stage B (0.95 g, 95%).

MC[M+H] = 433(M+1)

Stage D: BOC-(2S,4S)-4-[(4,4-diverticulosis)(2.2-dimethylpropanoyl)amino]-2-[(dimethylamino)carbonyl]pyrrolidin

The target compound was obtained according to the procedure described in stage D of example A1, using (4S)-1-BOC-4-[(4,4-diverticulosis)(2.2-dimethylpropanoyl)amino]-L-Proline (0.95 g, 2.2 mmol)obtained in stage C (0,93 g, 93%).

MS[M+H] = 460(M+1)

Stage E: (4S)-4-[(4,4-diverticulosis)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide

The target compound was obtained according to the procedure described in stage E of example A1, using BOC-(2S,4S)-4-[(4,4-diverticulosis)(2.2-dimethylpropanoyl)amino]-2-[(dimethylamino)carbonyl]pyrrolidine (0,93 g, 2.0 mmol)obtained in stage D (710 mg, 99.9 percent).

MS[M+H] = 360(M+1)

Stage F: (4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-diverticulosis)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide Salt HCl

The target compound was obtained according to the procedure described in the study is x F~G of example A1, using (4S)-4-[(4,4-diverticulosis)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide (0,70 g, 2.0 mmol)obtained in stage E, and (3S,4R)-1-tert-butyl-4-(4-dichlorophenyl)pyrrolidin-3-carboxylic acid obtained in example receiving the A9-2 (1.06 g, 85%).

MS[M+H] = 623(M+1)

1H NMR (400 MHz, CDCl3) 7,60 (d, 2H), 7,31 (d, 2H), 4,69 (t, 1H), 4,33-4,11 (m, 1H), 4,00-3,51 (m, 6H), 3,37-is 3.08 (m, 3H), 2,99 (d, 6H), 2,45 is 1.96 (m, 5H), 1,90-of 1.56 (m, 5H), 1,48 (c, 9H), 1,21 (c, 9H).

Example A6: (4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-diverticulosis)(2.2-dimethylpropanoyl)amino]-N-ethyl-L-prolinamide Salt HCl

HCl

Stage A: BOC-(2S,4S)-4-[(4,4-diverticulosis)(2.2-dimethylpropanoyl)amino]-2-[(ethylamino)carbonyl]pyrrolidin

The target compound was obtained according to the procedure described in stage D of example A1, using (4S)-1-BOC-4-[(4,4-diverticulosis)(2.2-dimethylpropanoyl)amino]-L-Proline (0.95 g, 2.2 mmol)obtained in stage C of example A5, and commercially available ethylamine (0,93 g, 93%).

MS[M+H] = 460(M+1)

Stage B: (4S)-4-[(4,4-diverticulosis)(2.2-dimethylpropanoyl)amino]-N-ethyl-L-prolinamide

The target compound was obtained according to the procedure described in stage E of example A1, using BOC-(2S,4S)-4-[(4,4-diverticulosis)(2.2-dimethylpropanoyl)amino]-2-[(ethylamino)carbonyl]pyrrolidin (0,93 g, 2.0 mmol)obtained in stage (710 mg, 99.9 percent).

MS[M+H] = 360(M+1)

Stage C: (4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-diverticulosis)(2.2-dimethylpropanoyl)amino]-N-ethyl-L-prolinamide Salt HCl

The target compound was obtained according to the procedure described in stage F~G of example A1, using (4S)-4-[(4,4-diverticulosis)(2.2-dimethylpropanoyl)amino]-N-ethyl-L-prolinamide (0,70 g, 2.0 mmol)obtained in stage B and (3S,4R)-1-tert-butyl-4-(4-dichlorophenyl)pyrrolidin-3-carboxylic acid obtained in example receiving the A9-2 (1.06 g, 85%).

MS[M+H] = 623(M+1)

1H NMR (400 MHz, CDCl3) 7,56 (d, 2H), 7,35 (d, 2H), 4.26 deaths (t, 1H), 4.04 the is 3.57 (m, 6H), 3,57 is 3.40 (m, 1H), 3,40 was 3.05 (m, 3H), 2,70-of 2.50 (m, 1H), 2,43-of 2.15 (m, 3H), 1,95-1,22 (m, 8H), 1,49 (c, 9H), 1,22 (c, 9H), is 1.11 (t, 3H).

Example A7: (4S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-methylpyrrolidine-3-yl]carbonyl}-4-[(2,2-dimethylpropanoyl)(CIS-4-methylcyclohexyl)amino]-L-prolinamide Salt HCl

HCl

Stage A: 1-SUN 2-methyl (2S,4S)-4-[(CIS-4-methylcyclohexyl)amino]pyrrolidin-2-carboxylate

To a solution of (2S,4S)-1-Boc-4-aminopyrrolidine-2-methylcarbamate (1.07 g, of 4.38 mmol)obtained in example obtain A1-1, and 4-methylcyclohexanone series in DCE (30 ml) was added dropwise at ambient temperature NaBH(OAc)3(1.39 g, to 6.57 mmol). The reaction mixture was stirred at ambient temperature for 4 hours, was added a saturated aqueous solution of NaHCO3and was extracted with DCM (50 ml × 2) and EtOAc. Organizes the e extracts were washed with saline, dried over MgSO4, filtered and concentrated in vacuum. The residue was purified by chromatography on columns (eluent, EtOAc/Hex = 1/2), highlighting the CIS - and Transmediale, whereby was obtained target compound (0.84 g, 57%).

MS[M+H] = 341(M+1)

Stage B: 1-SUN 2-methyl (2S,4S)-4-[(2,2-dimethylpropanoyl)(CIS-4-methylcyclohexyl)amino]pyrrolidin-2-carboxylate

The target compound was obtained according to the procedure described in stage B of example A1, using 1-BOC-2-methyl (2S,4S)-4-[(CIS-4-methylcyclohexyl)amino]pyrrolidin-2-carboxylate (0.84 g, 2.49 mmol)obtained in stage (0,92 g, 87%).

MS[M+H] = 425(M+1)

Stage C: (4S)-1-BOC-4-[(2,2-dimethylpropanoyl)(CIS-4-methylcyclohexyl)amino]-L-Proline

The target compound was obtained according to the procedure described in stage C of example A1, using 1-BOC-2-methyl (2S,4S)-4-[(2,2-dimethylpropanoyl)(CIS-4-methylcyclohexyl)amino]pyrrolidin-2-carboxylate (0,92 g of 2.16 mmol), obtained in stage B (0.84 g, 95%).

MS[M+H] = 411(M+1)

Stage D: BOC-(2S,4S)-2(aminocarbonyl)-4-[(2,2-dimethylpropanoyl)(CIS-4-methylcyclohexyl)amino]pyrrolidin

To a solution of (4S)-1-BOC-4-[(2,2-dimethylpropanoyl)(CIS-4-methylcyclohexyl)amino]-L-Proline (0,83 g, 2.05 mmol), obtained in stage C, in THF was added dropwise tea (0,32 ml of 2.27 mmol). Then slowly added dropwise at 0°C ethylchloride (0.24 g, of 2.27 mmol)and the reaction solution was stirred at the same temp is the temperature for 1 hour. Was slowly added dropwise at 0°C 28% aqueous ammonia solution (1 equivalent)and stirred at the same temperature for additional 1 hour. After completion of the reaction, the reaction mixture was concentrated in vacuo and extracted with EtOAC. The organic extracts were washed with saline, dried over MgSO4concentrated in vacuo and purified by chromatography on columns (eluent: EtOAc/Hex = 2/1)to give the target compound (0,62 g, 74%).

MS[M+H] = 410(M+1)

Stage E: (4S)-4-[(2,2-dimethylpropanoyl)(CIS-4-methylcyclohexyl)amino]L-prolinamide

The target compound was obtained according to the procedure described in stage E of example A1, using BOC-(2S,4S)-2(aminocarbonyl)-4-[(2,2-dimethylpropanoyl)(CIS-4-methylcyclohexyl)amino]pyrrolidine (0,62 g, 1.53 mmol), obtained in stage D (0.45 g, 95%).

MS[M+H] = 310(M+1)

Stage F: (4S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-methylpyrrolidine-3-yl]carbonyl}-4-[(2,2-dimethylpropanoyl)(CIS-4-methylcyclohexyl)amino]-L-prolinamide Salt HCl

The target compound was obtained according to the procedure described in stage F~G of example A1, using (4S)-4-[(2,2-dimethylpropanoyl)(CIS-4-methylcyclohexyl)amino]L-prolinamide (0.45 g, 1,45 mmol)obtained in stage E, and (3S,4R)-1-tert-methyl-4-(4-chlorophenyl)pyrrolidin-3-carboxylic acid obtained in example receiving the A9-6 (0,67 g, 88%).

MS[M+H] = 531(M+1)

1H NMR (400 MHz, CDCl3) δ 7,51 (d, 2H), 7,33 (who, 2H), 4,69 (t, 1H), 4,35-4,22 (m, 2H), 3.95 to 3,90 (m, 2H), 3,81 at 3.69 (m, 1H), 3,67-of 3.54 (m, 2H), 3,42 be 3.29 (m, 2H), 3,22-3,11 (m, 1H), 2,82 of 2.68 (m, 1H), 2,68-of 2.56 (m, 3H), 2,19-of 1.97 (m, 1H), 1,61-of 1.39 (m, 5H), 1,31-of 1.15 (m, 4H), 1,22 (c, 9H), of 0.90 (d, 3H).

Example A8: N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-dimethylpropanamide Salt HCl

HCl

Stage A: (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)amino]pyrrolidin

To a solution of 4,4-dimethylcyclohexanone (3.8 g, 30 mmol) in DCM (200 ml) was added commercially obtained (3S)-1-Boc-3-aminopyrrolidine (5.6 g, 30 mmol) was added NaBH(OAc)3(12.7 g, 60 mmol), and stirred at ambient temperature for 6 hours. After completion of the reaction the solvent was concentrated under vacuum, was added an aqueous solution of NaHCO3and was extracted with EtOAc. The organic layer was dried over MgSO4concentrated in vacuo and purified by chromatography on columns (eluent: EtOAc/Hex = 2/1)to give the target compound (8,4 g, 94.5%of).

MS[M+H] = 297(M+1)

Stage B: (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]pyrrolidin

To a solution of (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)amino]pyrrolidine (2 g, 6.7 mmol)obtained in stage A, in anhydrous THF was added tea (2,03 g of 20.1 mmol) and DMAP (818 mg, 6.7 mmol). Then was added the product of example obtaining A4-1, 2,2-dimethyl-3-acetylaminophenol (3.6 g, 20 mmol), and the solution was stirred at 80°C for 14 hours. After completion of the reaction the solvent was concentrated in vacuo, and the residue was diluted with EtOAc, and was washed for 1H. NaOH and 1N. HCl. The organic layer was dried over MgSO4concentrated in vacuo and purified by chromatography on columns (eluent: EtOAc/Hex = 1/3)to give (3S)-1-Boc-3-{[3-(atomic charges)-2,2-dimethylpropanoyl](4,4-dimethylcyclohexyl)amino}pyrrolidine (2.3 g, 78%). This compound was dissolved in methanol (10 ml) was added LiOH (187 mg, 7.8 mmol) and water (0.3 ml), and stirred at ambient temperature for 3 hours. After completion of the reaction the solvent was removed in vacuo, diluted with water (50 ml) and was extracted with EtOAc. The organic layer was washed for 1H. HCl, dried over MgSO4concentrated in vacuum, obtaining the target compound (1,95 g, 94.5%of).

MS[M+H] = 397(M+1)

Stage C: N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-dimethyl-N-[(3S)-pyrrolidin-3-yl]propanamide

The target compound was obtained according to the procedure described in stage E of example A1 using (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]pyrrolidine (484 mg, 1,22 mmol)obtained in stage B (500 mg, 99.9 percent).

Stage D: N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-dimethylpropanamide Salt HCl

The target compound was obtained agreement is but the procedure described in stage F~G of example A1, using N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-dimethyl-N-[(3S)-pyrrolidin-3-yl]propanamide (500 mg, 1,21 mmol)obtained in stage B and (3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-carboxylic acid obtained in example receiving the A9-2 (672 mg, 91,9%).

MS[M+H] = 560(M+1)

1H NMR (500 MHz, CDCl3) 7,55-of 7.48 (m, 2H), was 7.36-7,28 (m, 2H), 3.95 to 3,20 m, N), 3,01-of 2.93 (m, 0,5H), 2,75 of 2.68 (m, 0,5H), 2,48-of 2.38 (m, 0,5H), 2,18-of 2.08 (m, 0,5H), 1,86 by 1.68 (m, 1H), 1,67-of 1.53 (m, 6H), 1,53-of 1.35 (m, 10H), 1,32-1,14 (m, 8H), 0,94 (c, 3H), 0,91 (c, 3H).

Example A9: N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide Salt HCl

HCl

Stage A: (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidin

The target compound was obtained according to the procedure described in stage B of example A1, using (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)amino]pyrrolidine (2 g, 6.7 mmol), obtained at the stage of example A8 (2.4 g, 94.5%of).

MS[M+H] = 381(M+1)

Stage B: N-(4,4-dimethylcyclohexyl)-2,2-dimethyl-N-[(3S)-pyrrolidin-3-yl]propanamide

The target compound was obtained according to the procedure described in stage E of example A1 using (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidine (460 mg, 1.22 mmol)obtained in stage (0.33 g, 97%).

MS[M+H] = 281(M+1)

Stage C: N-[(3S)-1-{[(3S,4R)-1-tert-is util-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide Salt HCl

The target compound was obtained according to the procedure described in stage F~G of example A1, using N-(4,4-dimethylcyclohexyl)-2,2-dimethyl-N-[(3S)-pyrrolidin-3-yl]propanamide (300 mg, 1.06 mmol)obtained in stage B and (3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-carboxylic acid obtained in example receiving the A9-2 (510 mg, 90%).

MS[M+H] = 544(M+1)

1H NMR (400 MHz, CDCl3) 7,58-7,47 (m, 2H), 7,37-7,30 (m, 2H), 3,92-of 3.48 (m, 7H), 3,47-up 3.22 (m, 3H), 2.77-to 2,69 (m, 1H), 2,53 is 2.33 (m, 1H), 1,78-of 1.57 (m, 8H), 1,52-to 1.38 (m, 10H), 1,32 is 1.20 (m, 10H), 0,94 (c, 3H), 0,92 (c, 3H).

Example A10: (4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(methylsulphonyl)amino]-N,N-dimethyl-L-prolinamide Salt HCl

HCl

Stage A: (2S,4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)(methylsulphonyl)amino]pyrrolidin-2-methylcarbamoyl

To a solution of (2S,4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)amino]pyrrolidin-2-methylcarbamate (2.37 g, 6.7 mmol)obtained in stage a of example A1, in DCM (10 ml) was added tea (1,36 g, a 13.4 mmol), at 0°C was slowly added dropwise methanesulfonanilide (104 mg, of 0.91 mmol) and stirred at ambient temperature for 30 minutes After completion of the reaction the solvent was concentrated in vacuo, the residue was extracted with water and EtOAc. The organic layer was dried over MgSO4concentrated in vacuo and purified by chromatography on columns (eluent: EOAc/Hex = 1/1), receiving the target connection (2,08 g, 72%).

MS[M+H] = 433(M+1)

Stage B: (4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)(methylsulphonyl)amino]-L-Proline

The target compound was obtained according to the procedure described in stage C of example A1, using (2S,4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)(methylsulphonyl)amino]pyrrolidin-2-methylcarbazole (500 mg, 1,19 mmol)obtained in stage A, (470 mg, 95%).

MS[M+H] = 419(M+1)

Stage C: 1-BOC-(2S,4S)-2-[(dimethylaminobenzoyl)-4-[(4,4-dimethylcyclohexyl)(methylsulphonyl)amino]pyrrolidin

The target compound was obtained according to the procedure described in stage D of example A1, using (4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)(methylsulphonyl)amino]-L-Proline (470 mg, 1.13 mmol)obtained in stage B (402 mg, 80%).

MS[M+H] = 446(M+1)

Stage D: (4S)-4-[(4,4-dimethylcyclohexyl)(methylsulphonyl)amino]-N,N-dimethyl-L-prolinamide

The target compound was obtained according to the procedure described in stage E of example A1 using 1-BOC-(2S,4S)-2-[(dimethylaminobenzoyl)-4-[(4,4-dimethylcyclohexyl)(methylsulphonyl)amino]pyrrolidine (402 mg, 0.90 mmol), obtained in stage C (310 mg, 97%).

MS[M+H] = 346(M+1)

Stage E: (4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(methylsulphonyl)amino]-N,N-dimethyl-L-prolinamide Salt HCl

The target compound was obtained according to the procedure described in stage F~G of example A1, the IP is the use of (4S)-4-[(4,4-dimethylcyclohexyl)(methylsulphonyl)amino]-N,N-dimethyl-L-prolinamide (300 mg, 0.86 mmol)obtained in stage D (370 mg, 70%).

MS[M+H] = 611(M+1)

1H NMR (400 MHz, CDCl3) δ a 7.85-7,76 (m, 1H), of 6.96-6,92 (m, 1H), 6,85-6,79 (m, 1H), of 4.66 (t, 1H), 4,21-4,00 (m, 2H), 4,00-of 3.80 (m, 2H), 3,71-to 3.52 (m, 2H), 3,48 be 3.29 (m, 2H), is 3.08 (c, 3H), 2,99 (c, 3H), 2,86 (c, 3H), 2,43 is 2.33 (m, 1H), 2,22-2,11 (m, 1H), 1,99-of 1.78 (m, 2H), 1,57-of 1.18 (m, 8H), 1,48 (c, 9H), 0,91 (c, 6H).

Example A11: N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl](4,4-dimethylcyclohexyl)amino}-2,2-DIMETHYLPROPANE-1-ol HCl Salt

HCl

Stage A: (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropyl)amino]pyrrolidin

To a solution of (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]pyrrolidine (210 mg, of 0.53 mmol)obtained in stage B of example A8 in THF was added dropwise borane complex-metilsulfate (in THF, 2.0M, 0.4 ml, 0.8 mmol), and stirred at 80°C for 3 hours. After completion of the reaction the solvent was concentrated in vacuo, added water, was extracted with EtOAc. The organic layer was dried over MgSO4concentrated in vacuo and purified by chromatography on columns (eluent: DCM/MeOH = 9/1)to give the target compound (140 mg, 75%).

MS[M+H] = 382(M+1)

Stage B: N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl](4,4-dimethylcyclohexyl)amino}-2,2-DIMETHYLPROPANE-1-ol HCl Salt

The target compound was obtained according to the procedure described in a hundred is the s E~G of example A1, using (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropyl)amino]pyrrolidine (140 mg, 0.36 mmol)obtained in stage (156 mg, 78%).

MS[M+H] = 546(M+1)

1H NMR (500 MHz, CDCl3) 7,55-of 7.48 (m, 2H), was 7.36-7,28 (m, 2H), 3.95 to 3.15 in (m, 11H), 2,85-2,78 (m, 1H), 2,58-of 2.38 (m, 2H), 2,28-of 2.08 (m, 2H), 1.85 to 1,53 (m, 7H), 1,53-of 1.35 (m, 10H), 1,32-1,14 (m, 8H), 0,94 (c, 3H), 0,91 (c, 3H).

Example A12: (3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-N-isobutyl-N-(CIS-4-methylcyclohexyl)pyrrolidin-3-amine HCl Salt

HCl

Stage A: (3S)-1-Boc-3-[isobutyl(CIS-4-methylcyclohexyl)amino]pyrrolidin

Commercially obtained (3S)-1-Boc-3-aminopyrrolidine (5.6 g, 30 mmol) was introduced into the reaction according to the procedure described in stage a of example A7, receiving (3S)-1-Boc-3-CIS-(4'-methylcyclohexyl)aminopyrrolidine. Then, the target compound was obtained from this compound and Isobutyraldehyde by reductive amination, as described in stage a of example A1.

MS[M+H] = 339(M+1)

Stage B: (3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-N-isobutyl-N-(CIS-4-methylcyclohexyl)pyrrolidin-3-amine HCl Salt

The target compound was obtained according to the procedure described in stages E, F, G of example A1, using (3S)-1-Boc-3-[isobutyl(CIS-4-methylcyclohexyl)amino]pyrrolidine (100 mg, 0.30 mmol)obtained in stage A (115 mg, 78%).

MS[M+H] = 502(M+1)

1H NMR (400 MHz, CDCl3/sub> ) to 7.59-of 7.48 (m, 2H), 7,35-7,28 (m, 2H), 3,91-3,47 (m, 7H), 3,47-up 3.22 (m, 3H), 2,80-2,69 (m, 2H), 2,53 is 2.33 (m, 1H), 1,78-of 1.57 (m, 8H), 1,52-to 1.38 (m, 11H), 1,28-of 1.18 (m, 7H), of 0.95 (d, 3H).

Example A13~172

The following examples were obtained according to the procedure described in example A1~A7, A9, using suitable connections from the sample receiving A1, A2, A4, A9 and commercially available amine.

Salt

Table 4

(A44) (TFUC salt)

1H NMR (500 MHz, CDCl3) 7,60-7,52 (m, 1H), 6,92-6,85 (m, 1H), 6,82-6,74 (m, 1H), 4.72 in (t, 1H), 4,23-4,10 (m, 2H), 4,06-3,93 (m, 2H), 3,74 is 3.40 (m, 5H), 3,35-of 3.25 (m, 1H), 2,99 (c, 3H), 2.95 and (c, 3H), 2,81-of 2.66 (m, 2H), 2,17-to 2.06 (m, 1H), 1,68-to 1.14 (m, 6H), 1,44 (c, 9H), 1,14-1,00 (m, 2H), 1,07 (DD, 6H), 0,95 (c, 3H), 0,92 (c, 3H)

(A50) (TFUC salt)

1H NMR (500 MHz, CDCl3) to 7.61-rate of 7.54 (m, 1H), 6,92-6,86 (m, 1H), for 6.81-6.75 in (m, 1H), 4,71 (t, 1H), 4,25-4,07 (m, 2H), 4.04 the-3,93 (m, 2H), 3,84-3,71 (m, 1H), 3,70-3,55 (m, 2H), 3,55 is-3.45 (m, 1H), 3.45 points-to 3.35 (m, 1H), 3,35-of 3.25 (m, 1H), 3,11(c, 6H), 2,81-2,70 (m, 1H), 2,01-1,90 (m, 1H), 1.60-to of 1.39 (m, 5H), 1,44 (c, 9H), 1,28-of 1.13 (m, 4H), 1,21 (c, 9H), of 0.97 (d, 3H)

(A52) (HCl salt)

1H NMR (400 MHz, CDCl3) 8,10-of 8.04 (m, 1H), 6,97-6,93 (m, 1H), 6,79-6,74 (m, 1H), 4,70 (t, 1H), 4,35-4,22 (m, 2H), 3,95 is 3.40 (m, 2H), 3,81 at 3.69 (m, 1H), 3,67-of 3.54 (m, 2H), 3,42 be 3.29 (m, 2H), 3,26-3,11 (m, 3H), 2,82 of 2.68 (m, 1H), 2,19-of 1.97 (m, 1H), 1,61-of 1.39 (m, 4H), 1,49 (c, 9H), 1.32 to to 1.15 (m, 7H), 1,22 (c, 9H), 0,95 (c, 3H), 0,91 (c, 3H)

(A53) (HCl salt)

1H NMR (400 MHz, CDCl3) 8,10-of 8.04 (m, 1H), 6,97-6,93 (m, 1H), 6,79-6,74 (m, 1H), 4,70 (t, 1H), 4,35-4,22 (m, 2H), 3,95 is 3.40 (m, 2H), 3,81 at 3.69 (m, 1H), 3,67-of 3.54 (m, 2H), 3,42 be 3.29 (m, 2H), 3,26-3,11 (m, 3H), 2,99 (c, 3H), 2,82 of 2.68 (m, 1H), 2,19-of 1.97 (m, 1H), 1,61-of 1.39 (m, 4H), 1,49 (c, 9H), 1.32 to to 1.15 (m, 7H), 1,22 (c, 9H), 0,95 (c, 3H), 0,91 (c, 3H)

(A54) (HCl salt)

1H NMR (400 MHz, CDCl3) 8,10-of 8.04 (m, 1H), 6,97-6,93 (m, 1H), 6,79-6,74 (m, 1H), 4,70 (t, 1H), 4,35-4,22 (m, 2H), 3,98-3,93 (m, 1H), 3.95 to 3,81 (m, 2H), 3,81 at 3.69 (m, 1H), 3,67-of 3.54 (m, 2H), 3,42 be 3.29 (m, 2H), 3,26-3,11 (m, 1H), 2,82-of 2.68 (m, 1H), 2,19-of 1.97 (m, 1H), 1,61-of 1.39 (m, 4H), 1,49 (c, 9H), 1,34-of 1.15 (m, 10H), 1,22 (c, 9H), 0,95 (c, 3H), 0,91 (c, 3H)

(A55) (HCl salt)

1H NMR (400 MHz, CDCl3) 8,10-of 8.04 (m, 1H), 6,97-6,93 (m, 1H), 6,79-6,74 (m, 1H), 4,70 (t, 1H), 4,35-4,22 (m, 2H), 3,97-3,81 (m, 6H), 3,81 at 3.69 (m, 1H), 3,67-of 3.54 (m, 2H), 3,42 be 3.29 (m, 2H), 3,22-3,11 (m, 1H), 2,82 of 2.68 (m, 1H), 2,35-of 2.20 (m, 2H), 2,19-of 1.97 (m, 1H), 1,61-of 1.39 (m, 4H), 1,49 (c, 9H), 1,31-of 1.15 (m, 4H), 1,22 (c, 9H), 0,95 (c, 3H), 0,91 (c, 3H)

(A60) (HCl salt)

1H NMR (400 MHz, CDCl3) 8,14-of 8.00 (m, 1H), 7.03 is-6,91 (m, 1H), 6,83-6,72 (m, 1H), 5,94 (c, 1H), 4,89-of 4.66 (m, 5H), 4,30-4,12 (m, 2H), 4,12-to 3.99 (m, 1H), 3,99-3,88 (m, 1H), 3,74-3,47 (m, 4H), 3,42-3,26 (m, 2H), 3.00 and (c, 3H), 2.95 and (c, 3H), was 2.76-2,52 (m, 1H), 2,24-of 2.09 (m, 1H), 1,57 is 1.34 (m, 4H), 1,49 (c, 9H), 1,34 is 1.16 (m, 4H), 0,93 (c, 3H), 0,90 (c, 3H)

A62) (HCl salt)

1H NMR (400 MHz, CDCl3a 7.62 (d, 2H), 7,31 (d, 2H), 4,70 (t, 1H), 4,36-4,19 (m, 1H), 3,97-of 3.80 (m, 3H), 3,78-to 3.64 (m, 2H), 3,63-to 3.52 (m, 2H), 3,39-is 3.21 (m, 3H), 3,19-3,10 (m, 1H), 2,99 (c, 6H), 2,74-2,62 (m, 1H), 2,11-of 1.97 (m, 1H), 1,67-1,36 (m, 14H), 1,35-of 1.15 (m, 9H), 0,95 (c, 3H), 0,92 (c, 3H)

(A63) (HCl salt)

1H NMR (400 MHz, CDCl3) 8,08-8,02 (m, 1H), of 6.96-6,92 (m, 1H), 6,78-of 6.73 (m, 1H), and 4.68 (t, 1H), 4,48 (t, 1H), 4,40-is 4.21 (m, 1H), 4.04 the-3,81 (m, 5H), 3,80-3,71 (m, 2H), 3,66-of 3.46 (m, 3H), 3,22-of 3.12 (m, 1H), 2,97 (c, 6H), 2,86-2,62 (m, 1H), 2,41-of 2.28 (m, 1H), 2,13-to 1.82 (m, 4H), 1,64-of 1.39 (m, 4H), 1,49 (c, 9H), 1,39-1,22 (m, 2H), 1,20-1,08 (m, 2H), 0,97 (c, 3H), 0,94 (c, 3H)

(A67) (HCl salt)

1H NMR (400 MHz, CDCl3) 8,10-of 8.04 (m, 1H), 6,97-6,93 (m, 1H), 6,79-6,74 (m, 1H), 4,69 (t, 1H), to 4.38-4,19 (m, 2H), 4,03-of 3.80 (m, 2H), 3,76-to 3.50 (m, 4H), 3.43 points-is 3.08 (m, 6H), 2,94 (c, 3H), 2,74-2,62 (m, 1H), 2,11-of 1.97 (m, 1H), 1,67-1,36 (m, 14H), 1,35-of 1.15 (m, 9H), 1,10 (t, 3H), 0,95 (c, 3H), 0,92 (c, 3H)

(A68) (HCl salt)

1H NMR (500 MHz, CDCl3) 8,13-8,03 (m, 1H), 7.62mm (c, 1H), 7,40 (c, 1H), 6,99-6,92 (m, 1H), 6,78-of 6.71 (m, 1H), gold 6.43 (c, 1H), 4.75 V-of 4.67 (m, 1H), or 4.31-4,18 (m, 2H), 4,11-4,01 (m, 1H), 3.96 points-to 3.89 (m, 1H), 3,78-3,66 (m, 1H), 3,66-of 3.48 (m, 4H), 3,42-3,24 (m, 4H), of 2.93 (d, 3H), 2.23 to-2,12 (m, 1H), 1,88 was 1.06 (m, 8H), 1,48 (c, 9H), of 1.20 (t, 3H), 0,91 (c, 3H), 0,90 (c, 3H)

(A72) (HCl salt)

1H NMR (500 MHz, CDCl3) to 7.64-7,56 (m, 2H), 7,35-7,29 (m, 2H), 4,70-br4.61 (m, 1H), 4,32-4,16 (m, 1H), 3,97-to 3.50 (m, 7H), 3,41-3,14 (m, 5H), 2,93 (c, 3H), was 2.76-of 2.56 (m, 1H), 2,40-of 2.28 (m, 1H), 2,23-2,12 (m, 1H), 1.70 to 1.14 in (m, 8H), 1,48 (c, 9H), 1.30 and of 1.16 (m, 6H), 1,10 (t, 3H)

(A73) (HCl salt)

1H NMR (400 MHz, CDCl3) 8,08-8,02 (m, 1H), of 6.96-6,92 (m, 1H), 6,78-of 6.73 (m, 1H), and 4.68 (t, 1H), 4,48 (t, 1H), 4,40-is 4.21 (m, 1H), 4.04 the-3,81 (m, 5H), 3,80-3,71 (m, 2H), 3,66-of 3.46 (m, 3H), 3.45 points-of 3.12 (m, 3H), of 2.97 (d, 3H), 2,86-2,62 (m, 1H), 2,41-of 2.28 (m, 1H), 2,13-to 1.82 (m, 4H), 1,64-of 1.39 (m, 4H), 1,49 (c, 9H), 1,39-1,22 (m, 2H), 1.26 in (t, 3H), 1,20-1,08 (m, 2H), 0,97 (c, 3H), 0,94 (c, 3H)

<> (A75) (HCl salt)

1H NMR (400 MHz, CDCl3) 7,60 (d, 2H), 7,31 (d, 2H)and 4.65 (t, 1H), 4,33-4,1 l (m, 1H), 4,00-3,51 (m, 5H), 3,37-is 3.08 (m, 6H), 2.95 and (d, 3H), 2,45 is 1.96 (m, 5H), 1,90-of 1.56 (m, 5H), 1,48 (c, 9H), 1,21 (c, 9H), 1,10 (t, 3H)

(A83) (TFUC salt)

1H NMR (500 MHz, CDCl3) of 7.36 (d, 2H), 7,29 (d, 2H), 4,60 (t, 1H), to 4.38-4.25 in (m, 1H), 4,25-to 4.14 (m, 1H), 3,92-of 3.78 (m, 1H), 3.72 points-of 3.27 (m, 8H), 3,19-of 3.12 (m, 1H), 2,96 (d, 3H), 2,85 of 2.68 (m, 1H), 2.13 and of 1.99 (m, 1H), 1,62-1,11 (m, 11H), 1,43 (c, 9H), 1.39 in (c, 3H), 1,33 (c, 3H), 0,90 (c, 3H), 0,87 (c, 3H)

(A90) (HCl salt)

1H NMR (400 MHz, CDCl3) to 7.50 (d, 2H), 7,32 (d, 2H), and 4.68 (t, 1H), 4,48 (t, 1H), 4,40-is 4.21 (m, 1H), 4,03-3,90 (m, 3H), 3,90-3,81 (m, 2H), 3,80-3,70 (m, 2H), 3,66-of 3.46 (m, 3H), 3.45 points-of 3.12 (m, 3H), of 2.97 (d, 3H), 2,86-2,62 (m, 1H), 2,41-of 2.28 (m, 1H), 2,13-to 1.82 (m, 4H), 1,64-of 1.40 (m, 4H), 1,52 (c, 9H), 1,40-1,22 (m, 2H), 1.26 in (t, 3H), 1,20-1,08 (m, 2H), 0.39 to-0,11 (m, 4H)

(A96) (TFUC salt)

1H NMR (500 MHz, CDCl3) 7,40 (d, 2H), 7,29 (d, 2H), 4,69 (t, 1H), 4,12-4,00 (m, 2H), 3,89 of 3.75 (m, 2H), 3,74-of 3.53 (m, 9H), 3,51-3,30 (m, 4H), 3,28-3,18(M, 1H), 2,72 2.63 in (m, 1H), 2,07 (c, 3H), 1.60-to to 1.38 (m, 15H), 1,32-to 1.21 (m, 3H), 0,92 (c, 3H), 0,90 (c, 3H)

(A97) (TFUC salt)

1H NMR (400 MHz, CDCl3) 7,40 (d, 2H), 7,31 (d, 2H), of 4.66 (t, 1H), 4,51 (t, 1H), 4.26 deaths is 4.13 (m, 1H), 4.09 to of 3.96 (m, 1H), 3.96 points-of 3.65 (m, 5H), 3,65-is 3.21 (m, 7H), to 2.94 (d, 3H), 2,88-of 2.27 (m, br, 2H), 2,19-to 1.82 (m, 4H), 1,62-of 1.39 (m, 4H), 1.44MB (c, 9H), 1 ,35-1,12 (m, br, 2H), of 1.23 (t, 3H), 1,12-of 1.06 (m, 2H), 0,94 (c, 3H), 0,91 (c, 3H)

(A98 motorway) (TFUC salt)

1H NMR (500 MHz, CDCl3) 7,37 (d, 2H), 7,32 (d, 2H), 4,34-is 4.21 (m, 1H), was 4.02-3,86 (m, 2H), 3,85-of 3.12 (m, 11H), 2,95-and 2.83 (m, 1H), 2,53-to 2.40 (m, 1H), 2,31-2,19 (m, 1H), 1.60-to 1.14 in (m, 8H), 1,44 (c, 9H), 1,21 (c, 6H), is 1.11 (t, 3H), 0,94 (c, 3H), 0,91 (c, 3H)

(A99) (TFUC salt)

1H NMR (500 MHz, CDCl3) 7,66 (d, 2H), 7,39-7,22 (m, 6H), 7,06 (t, 1H), 4,34 (t, 1H), 3,93-,84 (m, 2H), 3,84 of 3.75 (m, 2H), 3,74-to 3.35 (m, 4H), 3,32 is 3.23 (m, 1H), 3.04 from-2,96 (m, 1H), 2,56 is 2.46 (m, 1H), 2,35 was 2.25 (m, 1H), 1,68-1,17 (m, 8H), 1,40 (c, 9H), 1,25 (c, 9H), 0,95 (c, 3H), 0,93 (c, 3H)

(A158) (TFUC salt)

1H NMR (500 MHz, CDCl3) EUR 7.57-7,41 (m, 1H), 6,95-6,86 (m, 1H), 6,86 to 6.75 (m, 1H), 4,17-and 3.72 (m, 9H), 3,72-to 3.36 (m, 6H), 3,36-3,26 (m, 1H), 3,26-to 3.09 (m, 2H), 2,55-to 2.41 (m, 1H), 2,22-to 1.98 (m, 2H), 1,94-to 1.77 (m, 1H), 1,73 is 1.23 (m, 7H), 1.44MB (c, 9H), 0,95 (c, 3H), 0,92 (c, 3H)

Example A173~177

The following examples were obtained according to the procedure described in example A10, using suitable connections from the sample receiving A1, A2, A4, A9 and commercially available amine.

Table 5

Example A177~188

The following examples were obtained according to the procedure described in example A11, A12, using the appropriate compound of example obtaining A1, A2, A4, A9 and commercially available amine.

Table 6

Scheme B

The way to obtain the intermediate compounds B1, and examples were synthesized in accordance with the procedure of scheme B are as follows.

Example B1: N-[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-(4,5-dihydro-1,3-oxazol-2-yl)pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide Salt HCl

HCl

Stage A: (2S,4S)-1-Boc-2-{[(2-hydroxyethyl)amino]carbonyl}-4-[dim is dipropenyl(4,4-dimethylcyclohexyl)amino]pyrrolidin

The target compound was obtained according to the procedure described in stage D of example A1, using (4S)-1-BOC-4-[(4,4-diverticulosis)(2.2-dimethylpropanoyl)amino]-L-Proline (410 mg, 0.9 mmol), obtained in stage C of example A1, and hydroxyethylamine (273 mg, 65%).

MS[M+H] = 468(M+1)

Stage B: (2S,4S)-1-Boc-2-(4,5-dihydro-1,3-oxazol-2-yl)-4-[dimethylpropanoyl(4,4-dimethylcyclohexyl)amino]pyrrolidin

The product of stage A, (2S,4S)-1-Boc-2-{[(2-hydroxyethyl)amino]carbonyl}-4-[dimethylpropanoyl(4,4-dimethylcyclohexyl)amino]pyrrolidine, (410 mg, of 0.58 mmol) with DMAP (70,7 mg of 0.58 mmol) and DIPEA (of 0.39 ml, 2.32 mmol) was dissolved in toluene (3 ml)and added dropwise phosgene (20% in toluene, at 0.31 ml, 0.87 mmol). After the reaction solution was stirred at 30~40°C for 48 hours, the solution was concentrated in vacuum. The residue was diluted with EtOAc and washed with saturated aqueous NaHCO3, water and 1N. HCl. The organic solution was dried over MgSO4concentrated in vacuo, and the residue was purified by chromatography on columns (eluent: EtOAc)to give the target compound (160 mg, 62%).

MS[M+H] = 450(M+1)

Stage C: N-[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-(4,5-dihydro-1,3-oxazol-2-yl)pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide Salt HCl

The target compound was obtained according to the procedure described in stage E~G of example A1, used the eat (2S,4S)-1-Boc-2-(4,5-dihydro-1,3-oxazol-2-yl)-4-[dimethylpropanoyl(4,4-dimethylcyclohexyl)amino]pyrrolidine (100 mg, 0.2 mmol), obtained in stage B (95 mg, 82%).

MS[M+H] = 613(M+1)

1H NMR (400 MHz, CDCl3) δ of 7.36 (d, 2H), 7,29 (d, 2H), 4,35-4,22 (m, 2H), 3.95 to 3,90 (m, 2H), 3,80-3,51 (m, 6H), 3,42 be 3.29 (m, 2H), 3,22-3,11 (m, 1H), 2,82 of 2.68 (m, 1H), 2,19-of 1.97 (m, 1H), 1,61-of 1.39 (m, 6H), 1,49 (c, 9H), 1,31-1,15 (m, 4H), 1,22 (c, 9H), 0,95 (c, 3H), 0,91 (c, 3H)

Example B2: N-{(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-[(dimethylamino)carbonothioyl]pyrrolidin-3-yl}-N-(4,4-dimethylcyclohexyl)-2-methylpropanamide TFA Salt

TFA

Stage A: 1-BOC-2-methyl (2S,4S)-4-[(4,4-dimethylcyclohexyl)(isobutyryl)amino]pyrrolidin-2-carboxylate

The target compound was obtained according to the procedure described in stage B of example A1, using (2S,4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)amino]pyrrolidin-2-methylcarbazole (1 g, 2.82 mmol), obtained under example A1

MS[M+H] = 425(M+1)

Stage B: (4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)(isobutyryl)amino]-L-Proline

The target compound was obtained according to the procedure described in stage C of example A1, using 1-BOC-2-methyl (2S,4S)-4-[(4,4-dimethylcyclohexyl)(isobutyryl)amino]pyrrolidin-2-carboxylate (1.1 g, 2,62 mmol)obtained in stage (1.0 g, 93%).

MS[M+H] = 411(M+1)

Stage C: BOC-(2S,4S)-2-[(dimethylamino)carbonyl]-4-[(4,4-dimethylcyclohexyl)(isobutyryl)amino]pyrrolidin

The target compound was obtained according to the procedure described in stage D of example A1, using (4S)-1-BOC-4[(4,4-dimethylcyclohexyl)(isobutyryl)amino]-L-Proline (1.0 g, 2,43 mmol)obtained in stage B (0.97 g, 92%).

MS[M+H] = 438(M+1)

Stage D: BOC(2S,4S)-2-[(dimethylamino)carbonothioyl]-4-[(4,4-dimethylcyclohexyl)(isobutyryl)amino]pyrrolidin

To a solution of BOC-(2S,4S)-2-[(dimethylamino)carbonyl]-4-[(4,4-dimethylcyclohexyl)(isobutyryl)amino]pyrrolidine (615 mg, of 1.41 mmol)obtained in stage C in benzene (3 ml) was added reagents Lawson (570 mg, about 1.47 mmol). The reaction solution was heated up to 80°C and was stirred for 1 hour. After completion of the reaction the solution was concentrated in vacuum. The residue was diluted with EtOAc and washed with saline. The organic solution was dried over MgSO4concentrated in vacuo, and the residue was purified by chromatography on columns (eluent: EtOAc:Hex = 1/2)to give the target compound (409 mg, 64%).

MS[M+H] = 454(M+1)

Stage E: N-{(3S,5S)-5-[(dimethylamino)carbonothioyl]pyrrolidin-3-yl}-N-(4,4-dimethylcyclohexyl)-2-methylpropanamide

The target compound was obtained according to the procedure described in stage E of example A1 using BOC(2S,4S)-2-[(dimethylamino)carbonothioyl]-4-[(4,4-dimethylcyclohexyl)(isobutyryl)amino]pyrrolidine (50 mg, 0.11 mmol)obtained in stage D (38 mg, 98%).

MS[M+H] = 354(M+1)

Stage F: N-{(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-[(dimethylamino)carbonothioyl]pyrrolidin-3-yl}-N-(4,4-dimethylcyclohexyl)-2-methylpropanamide TFA Salt

The target was soedineniya according to the procedure described in stage F of example A1, using N-{(3S,5S)-5-[(dimethylamino)carbonothioyl]pyrrolidin-3-yl}-N-(4,4-dimethylcyclohexyl)-2-methylpropanamide (38 mg, 0.10 mmol)obtained in stage E, and (3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-carboxylic acid obtained in example receiving the A9-2 (55 mg, 89%).

MS[M+H] = 617(M+1)

1H NMR (500 MHz, CDCl3) 7,55 is 7.50 (m, 1H), 6,92-6,85 (m, 1H), 6,82 to 6.75 (m, 1H), 5,02-of 4.95 (t, 1H), 4,20-4,08 (m, 1H), 4,08-3,90 (m, 2H), 3,68-3,26 (m, 5H), 3.46 in (c, 3H), 3,31 (c, 3H), 3,15-is 2.88 (m, 3H), 2,79 of 2.68 (m, 1H), 2,20-2,00 (m, 1H), 1,75-to 1.60 (m, 1H), 1.60-to of 1.52 (m, 1H), 1,52-to 1.38 (m, 4H), 1,44 (c, 9H), 1,38-1,25 (m, 2H), 1,10 (DD, 6H), 0,94 (c, 3H), 0,92 (c, 3H).

Example B3: N-[(3S,5R)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-5-(1,3-thiazol-2-yl)pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide Salt HCl

HCl

Stage A: VOS(2R,4S)-2-(iminocarbonothioyl)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)aminopyrrolidine

The target compound was obtained according to the procedure described in stages A~C of example A1 and stage D of example B2 using (2R,4S)-1-Boc-4-aminopyrrolidine-2-methylcarbamoyl received in the sample receiving A1-3 as a source material (880 mg, 2 mmol).

MS[M+H] = 440(M+1)

Stage B: VOS(2R,4S)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-2-(1,3-thiazol-2-yl)pyrrolidin

To a solution of BOC(2R,4S)-2-(iminocarbonothioyl)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino is rolidone (880 mg, 2 mmol)obtained in stage A, in dimethoxyethane (10 ml) was added 50 wt.% chloroacetaldehyde (range 0.38 ml, 3 mmol) and NaHCO3(504 mg, 6 mmol), and stirred at ambient temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated under vacuum and extracted with EtOAC. The organic extracts were washed with water and brine, dried over MgSO4concentrated in vacuo, and the residue was purified by chromatography on columns (eluent: EtOAc:Hex = 1/1). This compound (510 mg, 1,24 mmol) was dissolved in pyridine (0.9 ml, 11.1 mmol) was added dropwise at 0°C TFAA (1.0 g, 4,96 mmol). At the same temperature, the solution was stirred for 1.5 hours, concentrated in vacuo and extracted with EtOAc. The organic extracts were washed 0,5N HCl solution and brine, dried over MgSO4and concentrated in vacuum. The residue was purified by chromatography on columns (eluent: EtOAc/Hex = 2/1)to give the target compound (249 mg, 51,0%).

MS[M+H] = 464(M+1)

Stage C: N-(4,4-dimethylcyclohexyl)-2,2-dimethyl-N-[(3S,5R)-5-(1,3-thiazol-2-yl)pyrrolidin-3-yl]propanamide

The target compound was obtained according to the procedure described in stage E of example A1 using VOS(2R,4S)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-2-(1,3-thiazol-2-yl)pyrrolidine (80 mg, 0,17 mmol)obtained in stage B (60 mg, 98%).

MS[M+H] = 364(M+1)

Stage D: N-[(3S,5R)1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-5-(1,3-thiazol-2-yl)pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide Salt HCl

The target compound was obtained according to the procedure described in stage F, G of example A1, using N-(4,4-dimethylcyclohexyl)-2,2-dimethyl-N-[(3S,5R)-5-(1,3-thiazol-2-yl)pyrrolidin-3-yl]propanamide (60 mg, 0.16 mmol)obtained in stage C (55 mg, 89%).

MS[M+H] = 629(M+1)

1H NMR (400 MHz, CDCl3) δ 8,10-of 8.04 (m, 1H), 7,92-7,86 (m, 1H), 7,21-to 7.15 (m, 1H), 6,97-6,93 (m, 1H), 6,79-6,74 (m, 1H), 4,94 (t, 1H), 4,35-4,22 (m, 2H), 3.95 to 3,90 (m, 2H), 3,81 at 3.69 (m, 1H), 3,67-of 3.54 (m, 2H), 3,42 be 3.29 (m, 2H), 3,22-3,11 (m, 1H), 2,82 of 2.68 (m, 1H), 2,19-of 1.97 (m, 1H), 1,61-of 1.39 (m, 4H), 1,49 (c, 9H), 1,31-of 1.15 (m, 4H), 1,22 (c, 9H), 0,95 (c, 3H), 0,91 (c, 3H)

Example B4: N-[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-(hydroxymethyl)pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide TFA Salt

TFA

Stage A: BOC(2S,4S)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-2-(hydroxymethyl)pyrrolidin

To a solution of 1-BOC-2-methyl-(2S,4S)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidine-2-carboxylate (1.18 g, a 2.71 mmol)obtained in stage B of example A1, in THF (10 ml) was added LiBH4(177 mg, 8,13 mmol). The solution was stirred at 70°C for 2 hours, concentrated in vacuo and extracted with EtOAc. The organic extracts were washed with saturated aqueous solution of NaHCO3and brine, dried over MgSO4and concentrated in vacuum, obtaining the target compound (0.88 g, 81%).

MS[M+H] = 411(M+1)

Stage B: N-(4,dimethylcyclohexyl)-N-[(3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl]-2,2-dimethylpropanamide

The target compound was obtained according to the procedure described in stage E of example A1 using BOC(2S,4S)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-2-(hydroxymethyl)pyrrolidine (120 mg, 0.29 mmol)obtained in stage (89 mg, 98%).

MS[M+H] = 311(M+1)

Stage C: N-[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-(hydroxymethyl)pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide TFA Salt

The target compound was obtained according to the procedure described in stage F of example A1, using N-(4,4-dimethylcyclohexyl)-N-[(3S, 5S)-5-(hydroxymethyl)pyrrolidin-3-yl]-2,2-dimethylpropanamide (60 mg, 0.28 mmol)obtained in stage B and (3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-carboxylic acid obtained in example receiving the A9-2 (144 mg, 90%).

MS[M+H] = 574(M+1)

1H NMR (400 MHz, CDCl3) δ 7,49-7,21 (m, 4H), 4,28-is 3.21 (m, N), 3,17 totaling 3.04 (m, 1H), 2,46-to 2.29 (m, 1H), 2.06 to of 1.92 (m, 1H), 1,72 of-1.04 (m, 8H), 1,45 (c, 9H), 1,21 (c, 9H), 0,93 (c, 3H), 0,90 (c, 3H).

Example B5: N-[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-methylpyrrolidine-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide TFA Salt

TFA

Stage A: BOC-(2R,4S)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-2-(hydroxymethyl)pyrrolidin

The target compound (1.11 g) was obtained according to the procedure described in stage A~C of example A1 and stage a of example B4, using (R,4S)-1-Boc-4-aminopyrrolidine-2-methylcarbamoyl, received in the sample receiving A1-3 as a source material.

MS[M+H] = 411(M+1)

Stage B: BOC-(2R,4S)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-2-{[(methylsulphonyl)oxy]methyl}pyrrolidin

The target compound was obtained according to the procedure described in stage C of example obtaining A1-1A, using BOC-(2R,4S)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-2-(hydroxymethyl)pyrrolidine (1,11 g, a 2.71 mmol)obtained in stage (1.1 g, 85%).

MS[M+H] = 489(M+1)

Stage C: BOC-(2R,4S)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-2-methylpyrrolidine

To a solution of BOC-(2R,4S)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-2-{[(methylsulphonyl)oxy]methyl}pyrrolidine (580 mg, 1,19 mmol)obtained in stage B in THF (5 ml) was added dropwise at 70°C LiBH4(77 mg, of 3.57 mmol). The solution was stirred at 70°C for 5 hours, concentrated in vacuo and extracted with EtOAC. The organic extracts were washed with saturated aqueous solution of NaHCO3and brine, dried over MgSO4and concentrated in vacuum. The residue was purified by chromatography on columns (eluent: EtOAc:Hex = 1/4)to give the target compound (258 mg, 53%).

MS[M+H] = 395(M+1)

Stage D: N-(4,4-dimethylcyclohexyl)-2,2-dimethyl-N-[(3S,5S)-5-methylpyrrolidine-3-yl]propanamide

The target compound was obtained according to the procedure described in stage E of PR is a measure A1, using BOC-(2R,4S)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-methylpyrrolidine (50 mg, 0.12 mmol)obtained in stage C (36 mg, 98%).

MS[M+H] = 295(M+1)

Stage E:N-[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-methylpyrrolidine-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide TFA Salt

The target compound was obtained according to the procedure described in stage F of example A1, using N-(4,4-dimethylcyclohexyl)-2,2-dimethyl-N-[(3S,5S)-5-methylpyrrolidine-3-yl]propanamide (36 mg, 0.12 mmol)obtained in stage D, and (3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-carboxylic acid obtained in example receiving the A9-2 (144 mg, 90%).

MS[M+H] = 558(M+1)

1H NMR (400 MHz, CDCl3) of 7.48 δ-7,20 (m, 4H), 4,28-of 3.25 (m, 10H), 3,17 totaling 3.04 (m, 1H), 2,46-to 2.29 (m, 1H), 2.06 to of 1.92 (m, 1H), 1,72 of-1.04 (m, 8H), 1,45 (c, 9H), 1.27mm (m, 3H), 1,21 (c, 9H), 0,93 (c, 3H), 0,90 (c, 3H).

Example B6: N-{(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-5-[(E)-(hydroxyimino)methyl]pyrrolidin-3-yl}-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide Salt HCl

HCl

Stage A: (2S,4S)-1-Boc-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-2-formylpyridine

To a solution of BOC(2S,4S)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-2-(hydroxymethyl)pyrrolidine (602 mg, about 1.47 mmol)obtained in stage a of example B4, in DCM (5 ml) at 70°C was added dropwise 15 wt.% reagent D is CCA-Martin/DCM (2.2 mmol). The solution was stirred at ambient temperature for 3 hours, concentrated in vacuo and extracted with EtOAC. The organic extracts were washed with water and brine, dried over MgSO4and concentrated in vacuum. The residue was purified by chromatography on columns (eluent: EtOAc:Hex = 1/4)to give the target compound (312 mg, 60%).

MS[M+H] = 423(M+1)

Stage B: BOC(2S,4S)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-2-[(E)-(hydroxyimino)methyl]pyrrolidin

To a solution of (2S,4S)-1-Boc-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-2-formylpyridine (312 mg, 0.88 mmol)obtained in stage A, in methanol (5 ml) and tea (of 0.64 ml, 4.4 mmol) was added hydroxylamine hydrochloride (305 mg, 4.4 mmol), and stirred at ambient temperature for 2 hours. After completion of the reaction the solution was concentrated in vacuo and extracted with EtOAC. The organic extracts were washed with water and brine, dried over MgSO4and concentrated in vacuum. The residue was purified by chromatography on columns (eluent: EtOAc:Hex = 1/2)to give the target compound (208 mg, 67%).

MS[M+H] = 424(M+1)

Stage C: N-(4,4-dimethylcyclohexyl)-N-{(3S,5S)-5-[(E)-(hydroxyimino)methyl]pyrrolidin-3-yl}-2,2-dimethylpropanamide

The target compound was obtained according to the procedure described in stage E of example A1 using BOC(2S,4S)-4-[(4,4-dimethylcyclohexyl)(22-dimethylpropanoyl)amino]-2-[(E)-(hydroxyimino)methyl]pyrrolidine (200 mg, 0.47 mmol)obtained in stage B (150 mg, 98%).

MS[M+H] = 324(M+1)

Stage D: N-{(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-5-[(E)-(hydroxyimino)methyl]pyrrolidin-3-yl}-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide Salt HCl

The target compound was obtained according to the procedure described in stage F, G of example A1, using N-(4,4-dimethylcyclohexyl)-N-{(3S,5S)-5-[(E)-(hydroxyimino)methyl]pyrrolidin-3-yl}-2,2-dimethylpropanamide (150 mg, 0.46 mmol)obtained in stage C (144 mg, 90%).

MS[M+H] = 589(M+1)

1H NMR (500 MHz, CDCl3) δ 8,06 shed 8.01 (m, 1H), was 7.36-7,30 (m, 1H), 6,97-6,93 (m, 1H), 6,79-6,74 (m, 1H), 4,34-of 4.25 (m, 1H), 3,82 at 3.69 (m, 3H), 3,69-3,44 (m, 3H), 3,19-3,10 (m, 2H), is 3.08 are 2.98 (m, 1H), 2,88 (d, 1H), 2,34 was 2.25 (m, 1H), 2.13 and-2,03 (m, 1H), 1,61 to 1.37 (m, 4H), 1,45 (c, 9H), 1,36-1,17 (m, 4H), 1,23 (c, 9H), 0,94 (c, 3H), 0,90 (c, 3H).

Example B7: N-[(3S,5S)-5-(aminoethyl)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide TFA Salt

TFA

Stage A: (2S,4S)-1-BOC-2-(aminomethyl)4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidin

The target compound was obtained according to the procedure described in stage C~E of example obtaining A1-1, using a BOC(2S,4S)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-2-(hydroxymethyl)pyrrolidine (2 g, to 4.87 mmol), obtained at the stage of example B4

MS[M+H] = 410(M+1)

Stage B: (2S,4S)-1-BOC-2-({[(benzo is lexi)carbonyl]amino}methyl)4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidin

To a solution of (2S,4S)-1-BOC-2-(aminomethyl)4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidine (410 mg, 1 mmol)obtained in stage A, in DCM (10 ml) at 0°C was slowly added dropwise benzoylchloride (200 mg, 1.2 mmol), and stirred at ambient temperature for 3 hours. After completion of the reaction the solvent was concentrated in vacuo, the residue was extracted with water and EtOAc, and the organic layer was dried over MgSO4concentrated in vacuo and purified by chromatography on columns (eluent: EtOAc/Hex = 1/1)to give the target compound (310 g, 72%).

MS[M+H] = 544(M+1)

Stage C: ({(2S,4S)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidin-2-yl}methyl)benzylcarbamoyl

The target compound was obtained according to the procedure described in stage E of example A1 using (2S,4S)-1-BOC-2-({[(benzoyloxy)carbonyl]amino}methyl)4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidine (150 mg, 0.27 mmol)obtained in stage B (120 mg, 98%).

MS[M+H] = 444(M+1)

Stage D: ({(2S,4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidin-2-yl}methyl)benzylcarbamoyl

The target compound was obtained according to the procedure described in stage F of example A1 using ({(2S,4S)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidin-2-yl}methyl)shall ensorcelant (120 mg, 0.27 mmol)obtained in stage C (170 mg, 90%). However, the next stage of the reaction was performed without additional purification, as in stage E for cleaning used HPLC.

MS[M+H] = 709(M+1)

Stage E: N-[(3S,5S)-5-(aminoethyl)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide TFA Salt

The target compound was obtained according to the procedure described in stage E of example obtaining A1-1, using ({(2S,4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidin-2-yl}methyl)benzylcarbamoyl (170 mg, 0.27 mmol)obtained in stage D, and HPLC purification (108 mg, 70%).

MS[M+H] = 575(M+1)

1H NMR (500 MHz, CDCl3) to 7.61 δ is the rate of 7.54 (m, 1H), 6,92-6,86 (m, 1H), for 6.81-6.75 in (m, 1H), 4,34-4,24 (m, 1H), 3,84 at 3.69 (m, 4H), 3,69-of 3.54 (m, 2H), 3,19-3,10 (m, 2H), is 3.08-2,90 (m, 3H), 2,88 (d, 1H), 2,34 was 2.25 (m, 1H), 2,13-2,03 (m, 1H), 1,61 to 1.37 (m, 4H), 1,45 (c, 9H), 1,36-1,17 (m, 4H), 1,23 (c, 9H), 0,94 (c, 3H), 0,90 (c, 3H).

Example B8: N-[(3S,5S)-5-[(acetylamino)methyl]-1-{[(3S,4R)-1-tert-butyl-4-(2,4-dichlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide TFA Salt

TFA

Stage A: (2S,4S)-1-BOC-2-[(acetylamino)methyl] 4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidin

To a solution of (2S,4S)-1-BOC-2-(aminomethyl)4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidine (500 is g, to 1.21 mmol)obtained in stage a of example B7, in DMF was added dropwise acetic acid (80 mg, 1.3 mmol), HBTU (490 mg, 1.28 mmol) and DIPEA (of 0.56 ml, up 3.22 mmol) in that order. After the reaction mixture was stirred at ambient temperature for 5 hours, the solution was concentrated in vacuum. The residue was diluted with EtOAc and washed with saturated aqueous NaHCO3, water and 1N. HCl. The organic solution was dried over MgSO4and concentrated in vacuum. The residue was purified by chromatography on columns (eluent: EtOAc:Hex = 1/2)to give the target compound (508 mg, 93%).

MS[M+H] = 452(M+1)

Stage B:N-{(3S,5S)-5-[(acetylamino)methyl]pyrrolidin-3-yl}-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide

The target compound was obtained according to the procedure described in stage E of example A1 using (2S,4S)-1-BOC-2-[(acetylamino)methyl]4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidine (100 mg, 0.22 mmol)obtained in stage (75 mg, 98%).

MS[M+H] = 352(M+1)

Stage C: N-[(3S,5S)-5-[(acetylamino)methyl]-1-{[(3S,4R)-1-tert-butyl-4-(2,4-dichlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide TFA Salt

The target compound was obtained according to the procedure described in stage F of example A1, using N-{(3S,5S)-5-[(acetylamino)methyl]pyrrolidin-3-yl}-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide (75 mg, 0.21 m is ol), obtained in stage B and (3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-carboxylic acid obtained in example receiving the A9-2 (113 mg, 89%).

MS[M+H] = 615(M+1)

1H NMR (500 MHz, CDCl3) δ 7,41 (d, 2H), 7,30 (m, 2H), 4,34-4,24 (m, 2H), 3,82 at 3.69 (m, 3H), 3,69-of 3.54 (m, 2H), 3,42-of 3.27 (m, 2H), 3,19-3,10 (m, 2H), is 3.08 are 2.98 (m, 1H), 2,88 (d, 1H), 2,34 was 2.25 (m, 1H), 2,13-2,03 (m, 1H), 2,08 (c, 3H), 1,61 to 1.37 (m, 4H), 1,45 (c, 9H), 1,36-1,17 (m, 4H), 1,23 (c, 9H), 0,94 (c, 3H), 0,90 (c, 3H).

Example B9: N-[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-dichlorophenyl)pyrrolidin-3-yl]carbonyl}-5-[(dimethylamino)methyl]pyrrolidin-3-yl}-]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide Salt HCl

HCl

Stage A: (2S,4S)-1-Boc-2-[(dimethylamino)methyl]-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidin

The target compound was obtained according to the procedure described under example A1, using (2S,4S)-1-BOC-2-(aminomethyl) 4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidine (440 mg, 1 mmol), obtained at the stage of example B7, and formaldehyde by reductive amination (300 mg, 70%).

MS[M+H] = 438(M+1)

Stage B: N-{(3S,5S)-5-[(dimethylamino)methyl]pyrrolidin-3-yl}-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide

The target compound was obtained according to the procedure described in stage E of example A1 using (2S,4S)-1-Boc-2-[(dimethylamino)methyl]-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidine (100 mg, 0.22 mmol), poluchennogo is on stage (75 mg, 98%).

MS[M+H] = 338(M+1)

Stage C: N-[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-dichlorophenyl)pyrrolidin-3-yl]carbonyl}-5-[(dimethylamino)methyl]pyrrolidin-3-yl}-]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide Salt HCl

The target compound was obtained according to the procedure described in stage F, G of example A1, using N-{(3S,5S)-5-[(dimethylamino)methyl]pyrrolidin-3-yl}-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide (75 mg, 0.21 mmol)obtained in stage B (113 mg, 89%).

MS[M+H] = 603(M+1)

1H NMR (500 MHz, CDCl3) δ 8,05-of 7.90 (m, 1H), 6,97-6,93 (m, 1H), 6,79-6,74 (m, 1H), 4,67-4,48 (m, 1H), 3,84 at 3.69 (m, 4H), 3,69-of 3.54 (m, 2H), 3,19-3,10 (m, 2H), is 3.08-of 2.97 (m, 1H), 2,88-of 2.58 (m, 3H), 2,34-of 2.27 (m, 1H), 2,25 (c, 3H), 2.23 to (c, 3H), 2,13-2,03 (m, 1H), 1,61 to 1.37 (m, 4H), 1,45 (c, 9H), 1,36-1,17 (m, 4H), 1,23 (c, 9H), 0,94 (c, 3H), 0,90 (c, 3H).

Example B10: N-[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-5-cyanopyrrolidine-3-yl]-2,2-dimethyl-N-(CIS-4-methylcyclohexyl)propanamide Salt HCl

HCl

Stage A: 1-BOC(2S,4S)-2-cyano-4-[(2,2-dimethylpropanoyl)(CIS-4-methylcyclohexyl)amino]pyrrolidin

To a solution of BOC-(2S,4S)-2(aminocarbonyl)-4-[(2,2-dimethylpropanoyl)(CIS-4-methylcyclohexyl)amino]pyrrolidine (576 mg, of 1.41 mmol)obtained in stage D of example A7 in DCM (5 ml) was added dropwise TFAA (0.2 ml, of 1.41 mmol)and the solution was stirred at ambient temperature for 2 hours. After completion of the reaction the solution was concentrated in vacuum. Estato is diluted with EtOAc and washed with saline. The organic solution was dried over MgSO4and concentrated in vacuum. The residue was purified by chromatography on columns (eluent: EtOAc:Hex = 1/2)to give the target compound (514 mg, 93%).

MS[M+H] = 392(M+1)

Stage B: N-[(3S,5S)-5-cyanopyrrolidine-3-yl]-2,2-dimethyl-N-(CIS-4-methylcyclohexyl)propanamide

The target compound was obtained according to the procedure described in stage E of example A1 using 1-BOC(2S,4S)-2-cyano-4-[(2,2-dimethylpropanoyl)(CIS-4-methylcyclohexyl)amino]pyrrolidine (50 mg, 0.13 mmol)obtained in stage (37 mg, 98%).

MS[M+H] = 292(M+1)

Stage C: N-[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-5-cyanopyrrolidine-3-yl]-2,2-dimethyl-N-(CIS-4-methylcyclohexyl)propanamide Salt HCl

The target compound was obtained according to the procedure described in stage F, G of example A1, using N-[(3S,5S)-5-cyanopyrrolidine-3-yl]-2,2-dimethyl-N-(CIS-4-methylcyclohexyl)propanamide (37 mg, 0.12 mmol)obtained in stage B (58 mg, 89%).

MS[M+H] = 557(M+1)

1H NMR (400 MHz, CDCl3) δ 8,10-of 8.04 (m, 1H), 6,97-6,93 (m, 1H), 6,79-6,74 (m, 1H), amounts to 4.76 (t, 1H), 4,35-4,22 (m, 2H), 3.95 to 3,90 (m, 2H), 3,81 at 3.69 (m, 1H), 3,67-of 3.54 (m, 2H), 3,42 be 3.29 (m, 2H), 3,22-3,11 (m, 1H), 2,82 of 2.68 (m, 1H), 2,28 is 2.10 (m, 1H), 1,61-of 1.39 (m, 5H), 1,49 (c, 9H), 1,31-of 1.15 (m, 4H), 1,22 (c, 9H), 0,86 (d, 3H).

Example B11: N-[(3S, 5R)-5-acetyl-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide TFA Salt

TFA

Stage A: (4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-L-Proline

The target compound was obtained according to the procedure described in stage A~C of example A1, using the example of getting A1-3 as a source material.

Stage B: VOS(2R,4S)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-2-{[methoxy(methyl)amino]carbonyl}pyrrolidin

To a solution of (4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-L-Proline (1.08 g, 2.57 mmol), obtained at the stage in DMF (10 ml) was added dropwise DIPEA (1,15 ml, 6,70 mmol), was added dropwise N,O-dimethylhydroxylamine hydrochloride (292 mg, 3 mmol) and HBTU (1.1 g, 3 mmol) in that order. After stirring the reaction mixture at ambient temperature for 1 h, the solution was concentrated in vacuum. The residue was diluted with EtOAc and washed with saturated aqueous NaHCO3, water and 1N. HCl. The organic solution was dried over MgSO4and concentrated in vacuum. The residue was purified by chromatography on a column (eluent: EtOAc:Hex = 3/1)to give the target compound (600 mg, 50%).

MS[M+H] = 468(M+1)

Stage C: 1-VOS(2R,4S)-2-acetyl-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidin

To a solution of BOC(2R,4S)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-2-{[methoxy(methyl)amino]carbonyl}pyrrolidine (670 mg, 1.44 mmol)obtained in stage B in THF (5 ml) EXT is ulali solution 3M methylacrylamide simple ether (1.2 ml, 3,66 mmol)and the solution was stirred for 3 hours. After completion of the reaction the solution was concentrated in vacuum. The residue was diluted with EtOAc and washed with water and brine. The organic solution was dried over MgSO4and concentrated in vacuum. The residue was purified by chromatography on columns (eluent: EtOAc:Hex = 3/1)to give the target compound (280 mg, 46%).

MS[M+H] = 423(M+1)

Stage D: N-[(3S,5R)-5-acetylpyrrolidine-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide

The target compound was obtained according to the procedure described in stage E of example A1 using 1-BOC-(2R,4S)-2-acetyl-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidine (200 mg, 0.47 mmol)obtained in stage C (149 mg, 98%).

MS[M+H] = 323(M+1)

Stage E: N-[(3S,5R)-5-acetyl-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide TFA Salt

The target compound was obtained according to the procedure described in stage F of example A1, using N-[(3S,5R)-5-acetylpyrrolidine-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide (149 mg, 0.46 mmol)obtained in stage D, and (3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-carboxylic acid obtained in example receiving the A9-2 (230 mg, 89%).

MS[M+H] = 587(M+1)

1H NMR (500 MHz, CDCl3) δ 7,44-7,37 (m, 2H), was 7.36-7,28 (m, 2H), 4.80 to 4,74 (m, 1H), 4,01-3,26 (m, 10H), 2,81-a 2.71 (m, 1H), 2,64 (t, 1H), 2,11 (c, 3H), 1.70 to of 1.13 (m, 8H), 1,45 (, 9H), 1,20 (c, 9H), 0,93 (c, 3H), 0,91 (c, 3H).

Example B12: N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-(1-hydroxymethyl)pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide TFA Salt

TFA

Stage A: 1-BOC-(4S)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-2-(1-hydroxymethyl)pyrrolidin

To a solution of 1-BOC-(2R,4S)-2-acetyl-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidine (270 mg, 0.66 mmol)obtained in stage C of example B11, in methanol (5 ml) was added NaBH4(to 49.9 mg, of 1.32 mmol). The solution was stirred at ambient temperature for 2 hours, concentrated in vacuo and ekstragirovanie EtOAC. The organic extracts were washed with saline, dried over MgSO4and concentrated in vacuum, obtaining the target compound (225 mg, 80%).

MS[M+H] = 425(M+1)

Stage B: N-(4,4-dimethylcyclohexyl)-N-[(3S)-5-(1-hydroxyethyl)pyrrolidin-3-yl]-2,2-dimethylpropanamide

The target compound was obtained according to the procedure described in stage E of example A1 using 1-BOC-(4S)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-2-(1-hydroxymethyl)pyrrolidine (100 mg, 0.23 mmol)obtained in stage (75 mg, 98%).

MS[M+H] = 325(M+1)

Stage C: N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-(1-hydroxymethyl)pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethy propanamide TFA Salt

The target compound was obtained according to the procedure described in stage F of example A1, using N-(4,4-dimethylcyclohexyl)-N-[(3S)-5-(1-hydroxyethyl)pyrrolidin-3-yl]-2,2-dimethylpropanamide (75 mg, 0.22 mmol)obtained in stage B and (3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-carboxylic acid obtained in example receiving the A9-2 (113 mg, 88%).

MS[M+H] = 588(M+1)

1H NMR (400 MHz, CDCl3) δ 7,49-7,21 (m, 4H), 4,30-3,24 (m, 11H), 3,17 totaling 3.04 (m, 1H), 2,46-to 2.29 (m, 1H), 2.06 to of 1.92 (m, 1H), 1,72 of-1.04 (m, 8H), 1,45 (c, 9H), 1,21 (c, 9H), of 1.18 (d, 3H), 0,93 (c, 3H), 0,90 (c, 3H).

Example B13: (4S)-4-[acetyl - (4,4-dimethylcyclohexyl)amino]-N-(2-amino-ethyl)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-L-prolinamide TFA Salt

TFA

Stage A: 1-BOC(2S,4S)-4-[acetyl - (4,4-dimethylcyclohexyl)amino]-2-{[(2-{[(benzoyloxy)carbonyl]amino}ethyl)amino]carbonyl}pyrrolidin

(2S,4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)amino]pyrrolidin-2-methylcarbazole (1.77 g, 5 mmol), obtained at the stage of the example, A1 and acetylchloride was introduced into the reaction according to the procedure described in stage B~C of example A1, and then introduced into the reaction according to the procedure described in stage D of example A1, using CBZ-ethylamine, obtaining the target compound (1.5 g, 55%).

MS[M+H] = 559(M+1)

Stage B: (4S)-4-[acetyl - (4,4-dimethylcyclohexyl)amino]-N-(2-{[(benzoyloxy)carbonyl]amino}ethyl)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbon is l}-L-prolinamide

The target compound was obtained according to the procedure described in stage E~F of example A1, using 1-BOC(2S,4S)-4-[acetyl - (4,4-dimethylcyclohexyl)amino]-2-{[(2-{[(benzoyloxy)carbonyl]amino}ethyl)amino]carbonyl}pyrrolidin (560 mg, 1 mmol)obtained in stage (0.56 g, 78%).

MS[M+H] = 724(M+1)

Stage C: 4S)-4-[acetyl - (4,4-dimethylcyclohexyl)amino]-N-(2-amino-ethyl)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-L-prolinamide TFA Salt

The target compound was obtained according to the procedure described in stage E of example obtaining A1-1, using (4S)-4-[acetyl - (4,4-dimethylcyclohexyl)amino]-N-(2-{[(benzoyloxy)carbonyl]amino}ethyl)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-L-prolinamide (100 mg, 0.13 mmol)obtained in stage B and purification through HPLC (65 mg, 80%).

MS[M+H] = 590(M+1)

1H NMR (500 MHz, CDCl3) δ 7,71-to 7.61 (m, 1H), 6,99-6,79 (m, 2H), 4,67-4,48 (m, 1H), 4,22-of 3.94 (m, 2H), 3,94-a-3.84 (m, 1H), 3,83-3,00 (m, 11H), 2,59-to 2.29 (m, 2H), 1,99 (d, 3H), 1,69-1,17 (m, 8H), 1,43 (c, 9H), 0,94 (c, 3H), 0,91 (c, 3H).

Example B14: (4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]methyl-L-prolinate have been obtained Sol HCl

HCl

The target compound was obtained according to the procedure described in stage E~G of example A1, using 1-BOC-2-methyl-(2S,4S)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidine-2-carboxylate (200 mg, 0.45 IMO the b) obtained in stage B of example A1 (230 mg, 87%).

MS[M+H] = 602(M+1)

1H NMR (500 MHz, CDCl3) δ EUR 7.57 (d, 2H), 7,32 (d, 2H), 4,45 (t, 1H), 4,05-of 3.94 (m, 1H), 3,89-of 3.54 (m, 6H), 3.72 points (c, 3H), 3,39-is 3.21 (m, 2H), 3.04 from-2,95 (m, 1H), 2,74-2,62 (m, 1H), 2,15-2,05 (m, 1H), 1,54-of 1.35 (m, 4H), 1,48 (c, 9H), 1,27-1,12 (m, 4H), 1,19 (c, 9H), 0,93 (c, 3H), 0,90 (c, 3H).

Example B15: (4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-L-Proline SaltTFA

TFA

The target compound was obtained according to the procedure described in stage C of example A1, using (4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-methyl-L-prolinate have been obtained TFA salt obtained in example B14 (230 mg, 82%).

MS[M+H] = 588(M+1)

1H NMR (500 MHz, CDCl3) 7,38 (d, 2H), 7,30 (m, 2H), 4,37 (t, 1H), 4,10-of 3.56 (m, 8H), 3,36-3,18 (m, 2H), of 2.51-to 2.42 (m, 1H), 2.40 a-2,30 (m, 1H), 1,61 to 1.37 (m, 5H), 1.50 in (c, 9H), 1.32 to a 1.08 (m, 3H), 1,22 (c, 9H), 0,94 (c, 3H), 0,90 (c, 3H).

Example B16~41

The following examples were obtained according to the procedure described in example B1~15 using intermediate compounds that are received in a series of examples And reactions between the appropriate compounds of example, obtain A1, A2, A4, A9 and the corresponding amines.

Table 7

Scheme C

Example C1: N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-diethylmalonate TFA Salt

TFA

Stage A: (3S)-1-BOC[(2-cyano-2-methylpropanoyl)(4,4-dimethylcyclohexyl)amino]pyrrolidin

The target compound was obtained according to the procedure described in stage B of example A1, using (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)amino]pyrrolidine (1.5 g, 5 mmol), obtained at the stage of example A8, and 2-cyano-2-methylpropanoate (2 g, 15 mmol)obtained in example obtaining A4-3 (1.5 g, 76.6 per cent).

MS[M+H] = 392(M+1)

Stage B: (3S)-1-Boc-3-[(3-amino-2,2-dimethyl-3-oxopropanoic)(4,4-dimethylcyclohexyl)amino]pyrrolidin

To a solution of (3S)-1-BOC[(2-cyano-2-methylpropanoyl)(4,4-dimethylcyclohexyl)amino]pyrrolidine (900 mg, 2.3 mmol)obtained in stage A, in methanol (10 ml) was added 10h. NaOH (5 ml)and the solution was stirred at 80°C for 2 hours. After completion of the reaction the solvent was concentrated in vacuum, diluted with water and was extracted with EtOAc. Extracted organic layer was dried over MgSO4concentrated in vacuo and purified by chromatography on columns (eluent: EtOAc/Hex = 3/1)to give the target compound (828 mg, 88%).

MS[M+H] = 410(M+1)

Stage C: N-(4,4-dimethylcyclohexyl)-2,2-dimethyl-N-[(3S)-pyrrolidin-3-yl]malonamic

The target compound was obtained agreement is but the procedure described in stage E of example A1 using (3S)-1-Boc-3-[(3-amino-2,2-dimethyl-3-oxopropanoic)(4,4-dimethylcyclohexyl)amino]pyrrolidine (192 mg, 0.47 mmol)obtained in stage B (142 mg, 98%).

MS[M+H] = 310(M+1)

Stage D: N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-diethylmalonate TFA Salt

The target compound was obtained according to the procedure described in stage F of example A1, using N-(4,4-dimethylcyclohexyl)-2,2-dimethyl-N-[(3S)-pyrrolidin-3-yl]malonamic (142 mg, 0.46 mmol)obtained in stage C, and (3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-carboxylic acid obtained in example receiving the A9-2 (234 mg, 89%).

MS[M+H] = 573(M+1)

1H NMR (500 MHz, CDCl3) 7,29-7,25 (m, 4H), 4,58 ñ 4.50 (m, 1H), 4,34-4.26 deaths (m, 1H), 4,20-to 4.14 (m, 1H), 4.04 the-of 3.96 (m, 1H), 3,84 of 3.75 (m, 1H), 3,69-of 3.60 (m, 1H), 3,55 is 3.40 (m, 2H), 3,40-of 3.32 (m, 1H), 3,19-3,10 (m, 2H), 2,96-2,87 (m, 1H), 2,28-2,17 (m, 1H), 1,87-of 1.78 (m, 1H), 1,72-of 1.56 (m, 2H), 1,53-to 1.38 (m, 3H), 1,43 (c, 9H), 1,40 (c, 3H), 1,36-to 1.21 (m, 3H), 1,30 (c, 3H), 0,89 (c, 3H), 0,87 (c, 3H).

Example C2: N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-methoxy-2,2-dimethylpropanamide TFA Salt

TFA

Stage A: (3S)-1-Boc-3-{[3-(methoxy)-2,2-dimethylpropanoyl] (4,4-dimethylcyclohexyl)amino}pyrrolidin

To a solution of (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]pyrrolidine (800 mg, 2.0 mmol), obtained in stage B of example A8 in THF was added at 0°C, NaH (73 mg, 3.03 mmol) and iodomethane (430 mg, 3.03 mmol)and the solution was stirred at ambient temperature for 2 hours. After completion of the reaction the solution was concentrated in vacuum, were extracted 1H. HCl and EtOAc. The organic layer was washed with saline, dried over MgSO4and concentrated in vacuum. The residue was purified by chromatography on columns (eluent: EtOAc/Hex = 1/2)to give the target compound (784 mg, 94,6%).

MS[M+H] = 411(M+1)

Stage B: N-(4,4-dimethylcyclohexyl)-3-methoxy-2,2-dimethyl-N-[(3S)-pyrrolidin-3-yl]propanamide

The target compound was obtained according to the procedure described in stage E of example A1 using (3S)-1-Boc-3-{[3-(methoxy)-2,2-dimethylpropanoyl](4,4-dimethylcyclohexyl)amino}pyrrolidine (193 mg, 0.47 mmol)obtained in stage A (141 mg, 98%).

MS[M+H] = 311(M+1)

Stage C: N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-methoxy-2,2-dimethylpropanamide TFA Salt

The target compound was obtained according to the procedure described in stage F of example A1, using N-(4,4-dimethylcyclohexyl)-3-methoxy-2,2-dimethyl-N-[(3S)-pyrrolidin-3-yl]propanamide (141 mg, 0.46 mmol)obtained in stage B and (3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-carboxylic acid obtained in example receiving the A9-2 (232 mg, 89%).

MS[M+H] = 574(M+1

1H NMR (500 MHz, CDCl3) 7,37-7,33 (d, 2H), 7,31-of 7.25 (d, 2H), 3,91-3,81 (m, 2H), 3,80-the 3.65 (m, 4H), 3,64-3,55 (m, 2H), 3,54-of 3.46 (m, 1H), 3,44-3,26 (m, 3H), 3,29 (c, 3H), 3,24-3,17 (m, 1H), is 3.08-a 3.01 (m, 0,3H), 2,94-is 2.88 (m, 0,7H), 2,42 of-2.32 (m, 1H), 1,80-1,71 (m, 1H), 1,65 of 1.50 (m, 2H), 1,49-1,32 (m, N), 1,30-of 1.15 (m, 9H), 0,95-of 0.85 (m, 6H).

Example C3: (3E)-N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-(hydroxyimino)-2,2-dimethylpropanamide Salt HCl

HCl

Stage A: (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(2,2-dimethyl-3-oxopropanoic)amino]pyrrolidin

To a solution of (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]pyrrolidine (1,05 g, 2.7 mmol), obtained in stage B of example A8 in DCM was added periodinane dessa-Martin (1.35 g, 3,17 mmol) and stirred at ambient temperature for 2 hours. After completion of the reaction the solvent was concentrated under vacuum, was added aqueous sodium thiosulfate solution and EtOAc and stirred at ambient temperature for 30 minutes and was extracted with EtOAc. The organic layer was dried over MgSO4concentrated in vacuum at ambient temperature and was purified by chromatography on columns (eluent: EtOAc/Hex = 1/3)to give the target compound (960 mg, 90%).

MS[M+H] = 395(M+1)

Stage B: 1-BOC-(3S)-3-[(4,4-dimethylcyclohexyl)(2,2-dimethyl-3-oxopropanoic)amino]pyrrolidin

K R is the target (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(2,2-dimethyl-3-oxopropanoic)amino]pyrrolidine (250 mg, to 0.63 mmol)obtained in stage A, in methanol (5 ml) was added hydroxynonenal (49 mg, of 1.27 mmol) and tea (127 mg, of 1.26 mmol)and the solution was stirred at 80°C for 1 hour. After completion of the reaction the solvent was concentrated in vacuum, diluted with water (20 ml) and was extracted with EtOAc. The organic layer was washed for 1H. HCl, dried over MgSO4concentrated in vacuo and purified by chromatography on columns (eluent: EtOAc/Hex = 1/2)to give the target compound (206 mg, 80%).

MS[M+H] = 410(M+1)

Stage C: (3E)-N-(4,4-dimethylcyclohexyl)-3-(hydroxyimino)-2,2-dimethyl-N-[(3S)-pyrrolidin-3-yl]propanamide

The target compound was obtained according to the procedure described in stage E of example A1 using 1-BOC-(3S)-3-[(4,4-dimethylcyclohexyl)(2,2-dimethyl-3-oxopropanoic)amino]pyrrolidine (192 mg, 0.47 mmol)obtained in stage B (142 mg, 98%).

MS[M+H] = 310(M+1)

Stage D: (3E)-N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-(hydroxyimino)-2,2-dimethylpropanamide Salt HCl

The target compound was obtained according to the procedure described in stage F, G of example A1, using (3E)-N-(4,4-dimethylcyclohexyl)-3-(hydroxyimino)-2,2-dimethyl-N-[(3S)-pyrrolidin-3-yl]propanamide (142 mg, 0.46 mmol)obtained in stage C, and (3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-carboxylic acid obtained in example receiving the A9-2 (234 mg, 89%).

MS[M+H] = 573(M+1)

1H NMR (400 MHz, CDCl3) 7,45-7,39 (m, 2H), 7,37-7,30 (m, 2H), 6,72 (c, 1H), 4,12-to 3.52 (m, 7H), 3,40-3,19 (m, 3H), 2.77-to 2,69 (m, 1H), 2,53 is 2.33 (m, 1H), 1,78-of 1.57 (m, 8H), 1,55-of 1.41 (m, 10H), 1,35-1,22 (m, 7H), 0,94 (c, 3H), 0,92 (c, 3H).

Example C4: N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-Dimethylbutane Salt HCl

HCl

Stage A: (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylbutanol)amino]pyrrolidin

To a solution of (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(2,2-dimethyl-3-oxopropanoic)amino]pyrrolidine (250 mg, 0.63 mmol), obtained at the stage of example C3 in THF, at 0°C was slowly added dropwise methylmagnesium (simple diethyl ether, 3,0M, 0.25 ml, from 0.76 mmol)and the solution was stirred at ambient temperature for 2 hours. After completion of the reaction solution at 0°C was added 1N. HCl and was extracted with EtOAc. The organic layer was dried over MgSO4concentrated in vacuo and purified by chromatography on columns (eluent: EtOAc/Hex = 1/2)to give the target compound (238 mg, 92%).

MS[M+H] = 425(M+1)

Stage B: N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-dimethyl-N-[(3S)-pyrrolidin-3-yl]butanamide

The target compound was obtained according to the procedure described in stage E of example A1 using (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylbutanol)amino]Pirro is Idina (100 mg, 0.23 mmol)obtained in stage (73 mg, 98%).

MS[M+H] = 325(M+1)

Stage C: N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-Dimethylbutane Salt HCl

The target compound was obtained according to the procedure described in stage F, G of example A1, using N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-dimethyl-N-[(3S)-pyrrolidin-3-yl]butanamide (73 mg, 0.23 mmol)obtained in stage B and (3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-carboxylic acid obtained in example receiving the A9-2 (232 mg, 89%).

MS[M+H] = 574(M+1)

1H NMR (400 MHz, CDCl3) 7,58-of 7.48 (m, 2H), 7,37-7,29 (m, 2H), 3,92-of 3.48 (m, 7H), 3,47-up 3.22 (m, 4H), 2.77-to 2,69 (m, 1H), 2,53 is 2.33 (m, 1H), 1,80-of 1.55 (m, 8H), 1,52-to 1.38 (m, 10H), 1,32 is 1.20 (m, 10H), 0,94 (c, 3H), 0,92 (c, 3H).

Example C5: N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethyl-3-oxobutanamide Salt HCl

HCl

Stage A: (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(2,2-dimethyl-3-oxobutyl)amino]pyrrolidin

To a solution of (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylbutanol)amino]pyrrolidine (150 mg, 0.36 mmol), obtained at the stage of example C4 in DCM was added periodinane dessa-Martin (230 mg, 0.54 mmol), and stirred at ambient temperature for 2 hours. After completion of the reaction the solvent was concentrated in vacuo is e, was added an aqueous sodium thiosulfate solution and EtOAc and stirred at ambient temperature for 30 minutes and was extracted with EtOAc. The organic layer was dried over MgSO4concentrated in vacuum at ambient temperature and was purified by chromatography on columns (eluent: EtOAc/Hex = 1/3)to give the target compound (132 mg, 90%).

MS[M+H] = 409(M+1)

Stage B: N-(4,4-dimethylcyclohexyl)-2,2-dimethyl-3-oxo-N-[(3S)-pyrrolidin-3-yl]butanamide

The target compound was obtained according to the procedure described in stage E of example A1 using (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(2,2-dimethyl-3-oxobutyl)amino]pyrrolidine (50 mg, 0.12 mmol)obtained in stage (36 mg, 98%).

MS[M+H] = 309(M+1)

Stage C: N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethyl-3-oxobutanamide Salt HCl

The target compound was obtained according to the procedure described in stage F, G of example A1, using N-(4,4-dimethylcyclohexyl)-2,2-dimethyl-3-oxo-N-[(3S)-pyrrolidin-3-yl]butanamide (50 mg, 0.11 mmol)obtained in stage B and (3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-carboxylic acid obtained in example receiving the A9-2 (56 mg, 89%).

MS[M+H] = 572(M+1)

1H NMR (500 MHz, CDCl3) 7,60-7,51 (m, 2H), 7,35-7,30 (m, 2H), 3.95 to 3,48 (m, 7H), 3,47-up 3.22 (m, 3H), 2.77-to 2,69 (m, 1H), 2,53 is 2.33 (m, 1H), 2,11 (c, 3H), 1,78-of 1.57 (m, 8H), 1,50 to 1.37 (m, 10H), 1,35-1,25 (m, 7H), 0,94 (c, 3), 0,92 (c, 3H).

Example C6: N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2,3-trimethylbutane Salt HCl

HCl

Stage A: (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2,3-trimethylbutane)amino]pyrrolidin

To a solution of (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(2,2-dimethyl-3-oxobutyl)amino]pyrrolidine (100 mg, 0.25 mmol), obtained at the stage of example C5, in THF at 0°C was slowly added dropwise methylmagnesium (simple diethyl ether, 3,0M, 0.1 ml, 0.3 mmol)and the solution was stirred at ambient temperature for 2 hours. After completion of the reaction solution at 0°C was added 1N. HCl, and was extracted with EtOAc. The organic layer was dried over MgSO4concentrated in vacuo and purified by chromatography on columns (eluent: EtOAc/Hex = 1/3)to give the target compound (97 mg, 92%).

MS[M+H] = 425(M+1)

Stage B: N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2,3-trimethyl-N-[(3S)-pyrrolidin-3-yl]butanamide

The target compound was obtained according to the procedure described in stage E of example A1 using (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2,3-trimethylbutane)amino]pyrrolidine (80 mg, 0,19 mmol)obtained in stage (60.5 mg, 98%).

MS[M+H] = 325(M+1)

Stage C: N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolic the n-3-yl]-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2,3-trimethylbutane Salt HCl

The target compound was obtained according to the procedure described in stage F, G of example A1, using N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2,3-trimethyl-N-[(3S)-pyrrolidin-3-yl]butanamide (62 mg, 0,19 mmol)obtained in stage B and (3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-carboxylic acid obtained in example receiving the A9-2 (99 mg, 89%).

MS[M+H] = 588(M+1)

1H NMR (400 MHz, CDCl3) 7,60-7,49 (m, 2H), 7,39-7,30 (m, 2H), 3,93-of 3.48 (m, 7H), 3,47-is 3.21 (m, 3H), 2.77-to 2,69 (m, 1H), 2,53 is 2.33 (m, 1H), 1,80-of 1.55 (m, 8H), 1,52-to 1.38 (m, 10H), 1,34-to 1.21 (m, 13H), 0,94 (c, 3H), 0,92 (c, 3H).

Example C7: N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-fluoro-2,2-dimethylpropanamide Salt HCl

HCl

Stage A: (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(3-fluoro-2,2-dimethylpropanoyl)amino]pyrrolidin

To a solution of (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]pyrrolidine (300 mg, from 0.76 mmol)obtained in stage B of example A8 in DCM was added tea (192 mg, 1.9 mmol)was slowly added dropwise at 0°C methanesulfonanilide (104 mg, of 0.91 mmol)and the solution was heated to ambient temperature and was stirred for 1 hour. After completion of the reaction the solvent was concentrated in vacuo and washed with water and EtOAc. The organic layer was dried over MgSO4concentrated in vacuo and purified by chromatography on columns (eluent: EOAc/Hex = 1/2), receiving (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl){2,2-dimethyl-3-[(methylsulphonyl)oxy]propanoic}amino]pyrrolidine (250 mg, 75%). To a solution of this compound (200 mg, 0.42 mmol) in THF was added dropwise TBAF (in THF, 1,0M 0.5 ml, 0.5 mmol)and the solution was stirred at 80°C for 3 hours. After completion of the reaction the solvent was concentrated in vacuo and was extracted with 1N. HCl and EtOAc. The organic layer was dried over MgSO4concentrated in vacuo and purified by chromatography on columns (eluent: EtOAc/Hex = 1/4)to give the target compound (147 mg, 89%).

MS[M+H] = 399(M+1)

Stage B: N-(4,4-dimethylcyclohexyl)-3-fluoro-2,2-dimethyl-N-[(3S)-pyrrolidin-3-yl]propanamide

The target compound was obtained according to the procedure described in stage E of example A1 using (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(3-fluoro-2,2-dimethylpropanoyl)amino]pyrrolidine (147 mg, and 0.37 mmol)obtained in stage (108 mg, 98%).

MS[M+H] = 299(M+1)

Stage C: N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-fluoro-2,2-dimethylpropanamide Salt HCl

The target compound was obtained according to the procedure described in stage F, G of example A1, using N-(4,4-dimethylcyclohexyl)-3-fluoro-2,2-dimethyl-N-[(3S)-pyrrolidin-3-yl]propanamide (100 mg, 0.47 mmol)obtained in stage B and (3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-carboxylic acid obtained in example receiving the Oia A9-2 (230 mg, 89%).

MS[M+H] = 562(M+1)

1H NMR (400 MHz, CDCl3) 7,58-7,47 (m, 2H), 7,37-7,30 (m, 2H), 4,39-to 4.28 (m, 2H), 3,92-of 3.48 (m, 7H), 3,47-up 3.22 (m, 3H), 2.77-to 2,69 (m, 1H), 2,53 is 2.33 (m, 1H), 1,78-of 1.57 (m, 8H), 1,52-to 1.38 (m, 10H), 1,35 is 1.23 (m, 7H), 0,94 (c, 3H), 0,92 (c, 3H).

Example C8: N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3,3-debtor-2,2-dimethylpropanamide Salt HCl

HCl

Stage A: (3S)-1-BOC[(3,3-debtor-2,2-dimethylpropanoyl)(4,4-dimethylcyclohexyl)amino]pyrrolidin

To (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(2,2-dimethyl-3-oxopropanoic)amino]pyrrolidine (1 g, of 2.53 mmol), obtained at the stage of example C3 was added DCM (20 ml)was cooled to -78°C and slowly added dropwise DAST (of 0.67 ml of 5.06 mmol). The mixture was stirred at -78°C for 1 hour and was stirred at ambient temperature for 10 hours. After completion of the reaction the solvent was concentrated in vacuo and was extracted with water and EtOAc. The organic layer was dried over MgSO4concentrated in vacuo and purified by chromatography on columns (eluent: EtOAc/Hex = 1/1)to give the target compound (630 mg, 60%).

MS[M+H] = 417(M+1)

Stage B: N-(4,4-dimethylcyclohexyl)-3,3-debtor-2,2-dimethyl-N-[(3S)-pyrrolidin-3-yl]propanamide

The target compound was obtained according to the procedure described in stage E of example A1 using (3S)-1-BOC [(3,3-debtor-2,2-dimethylpropanoyl)(4,4-di is ethylcyclohexyl)amino]pyrrolidine (100 mg, 0.24 mmol)obtained in stage (73 mg, 98%).

MS[M+H] = 317(M+1)

Stage C: N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3,3-debtor-2,2-dimethylpropanamide Salt HCl

The target compound was obtained according to the procedure described in stage F, G of example A1, using N-(4,4-dimethylcyclohexyl)-3,3-debtor-2,2-dimethyl-N-[(3S)-pyrrolidin-3-yl]propanamide (73 mg, 0.23 mmol)obtained in stage B and (3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-carboxylic acid obtained in example receiving the A9-2 (118 mg, 89%).

MS[M+H] = 580(M+1)

1H NMR (400 MHz, CDCl3) to 7.59-7,49 (m, 2H), 7,38-7,31 (m, 2H), 5,59 (c, 1H), 3,92-of 3.48 (m, 7H), 3,47-up 3.22 (m, 3H), 2.77-to 2,69 (m, 1H), 2,53 is 2.33 (m, 1H), 1,78-of 1.57 (m, 8H), 1,52-to 1.38 (m, 10H), 1,34 is 1.23 (m, 7H), 0,94 (c, 3H), 0,92 (c, 3H).

Example C9: N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-[(4,4-diverticulosis)(3-methoxy-2,2-dimethylpropanoyl)amino]-N-ethyl-N-methyl-L-prolinamide TFA Salt

TFA

Stage A: 2-methyl-(2S,4S)-1-BOC-4-{[3-(atomic charges)-2,2-dimethylpropanoyl](4,4-diverticulosis)amino}pyrrolidinecarboxylic

To a solution of 2-methyl-(2S,4S)-1-BOC-4-[(4',4'-diverticulosis)amino]pyrrolidinecarboxylic (1.01 g, 2,84 mmol)obtained in stage a of example A5, in DCE (5 ml) was added dropwise tea (5 ml) and DMAP (0.34 g, 2,84 mmol), was added 2,2-dimethyl-3-acetylaminophenol (1.01 g, of 5.68 mmol), is received in the sample receiving A4-1. The reaction solution was heated to 90°C and was stirred for 48 hours. After completion of the reaction the solvent was removed in vacuo and to the residue was added a saturated aqueous solution of NaHCO3, and was extracted with EtOAc. The organic extracts were washed for 1H. HCl, dried over MgSO4concentrated in vacuo and purified by chromatography on columns (eluent: EtOAc/Hex = 1/4)to give the target compound (0,89 g, 62.9 per cent).

MS[M+H] = 505(M+1)

Stage B: (4S)-1-BOC-4-(4,4-diverticulosis)amino(3-hydroxy-2,2-dimethylpropanoyl)amino]-L-Proline

To a solution of 2-methyl-(2S,4S)-1-BOC-4-{[3-(atomic charges)-2,2-dimethylpropanoyl](4,4-diverticulosis)amino}of pyrrolidinecarboxylic (0,89 g, 1.78 mmol)obtained in stage A, in 1N NaOH (5 ml) and water (5 ml), and stirred to complete the reaction. The reaction solution was concentrated in vacuo, acidified 1H. HCl and was extracted with EtOAc. The organic extracts were washed for 1H. HCl, dried over MgSO4concentrated in vacuum, obtaining the target compound (1.1 g, 90%).

MS[M+H] = 449(M+1)

Stage C: (2S,4S)-1-BOC-4-[(4,4-diverticulosis)(3-hydroxy-2,2-dimethylpropanoyl)amino]-2-[(dimethylethylamine)carbonyl]pyrrolidin

To a solution of (4S)-1-BOC-4-(4,4-diverticulosis)amino(3-hydroxy-2,2-dimethylpropanoyl)amino]-L-Proline (1.1 g, 2.6 mmol)obtained in stage B in DMF (5 ml) was added dropwise DIPEA (of 0.08 ml, 0.5 mmol), was added dropwise 2M solution of dimate the amine-THF (1.8 ml, 3.6 mmol), HOBT (0.5 g, 3.6 mmol) and EDC (0.7 g, 3.6 mmol) in that order. After stirring the reaction mixture at ambient temperature for 12 h, the solution was concentrated in vacuum. The residue was diluted with EtOAc and washed with saturated aqueous NaHCO3, water and 1N. HCl. The organic solution was dried over MgSO4concentrated in vacuo and the residue was purified by chromatography on a column (eluent: EtOAc:Hex = 1/2)to give the target compound (1.1 g, 93%).

MS[M+H] = 490(M+1)

Stage D: (2S,4S)-1-BOC-4-[(4,4-diverticulosis)(3-methoxy-2,2-dimethylpropanoyl)amino]-2-[(dimethylethylamine)carbonyl]pyrrolidin

To a solution of (2S,4S)-1-BOC-4-[(4,4-diverticulosis)(3-hydroxy-2,2-dimethylpropanoyl)amino]-2-[(dimethylamino)carbonyl]pyrrolidine (1.1 g, 2.3 mmol), obtained in stage C, in THF at 0°C was added NaH (83 mg, of 3.45 mmol) and iodomethane (490 mg, of 3.45 mmol)and the solution was stirred at ambient temperature for 2 hours. After completion of the reaction the solution was concentrated in vacuo and was extracted with 1N. HCl and EtOAc. The organic layer was washed with saline, dried over MgSO4and concentrated in vacuum. The residue was purified by chromatography on columns (eluent: EtOAc/Hex = 1/2)to give the target compound (1,06 mg, 94,6%).

MS[M+H] = 504(M+1

Stage E: (4S)-4-[(4,4-diverticulosis)(3-methoxy-2,2-dimethylpropanoyl)amino]-N-ethyl-N-methyl-L-prolinamide

C left the compound was obtained according to the procedure described in stage E of example A1 using (2S,4S)-1-BOC-4-[(4,4-diverticulosis)(3-methoxy-2,2-dimethylpropanoyl)amino]-2-[(dimethylethylamine)carbonyl]pyrrolidine (100 mg, 0.20 mmol)obtained in stage D (79 mg, 98%).

MS[M+H] = 404(M+1)

Stage F: N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-[(4,4-diverticulosis)(3-methoxy-2,2-dimethylpropanoyl)amino]-N-ethyl-N-methyl-L-prolinamide TFA Salt

The target compound was obtained according to the procedure described in stage F of example A1, using (4S)-4-[(4,4-diverticulosis)(3-methoxy-2,2-dimethylpropanoyl)amino]-N-ethyl-N-methyl-L-prolinamide (79 mg, 0,19 mmol)obtained in stage E, and (3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-carboxylic acid obtained in example receiving the A9-2 (112 mg, 89%).

MS[M+H] = 667(M+1)

1H NMR (400 MHz, CDCl3) δ 7,38 (d, 2H), 7,31 (d, 2H), 4,65-4,59 (m, 1H), 4,22-was 4.02 (osirm, 1H), 4,00-3,93 (m, 1H), 3,86-3,74 (m, 2H), 3,71 is 3.57 (m, 2H), 3,56-3,19 (m, 9H), 2,96 (d, 3H), 2,86-2,63 (osirm, 1H), 2,33-of 2.21 (m, 1H), 2.21 are 2,10 m, 1H), 2,10 is 1.96 (m, 1H), 1,86-1,14 (m, 8H), 1,44 (c, 9H), 1,22 (m, 6H), is 1.11 (t, 3H).

Example C10: (4S)-4-[(3-amino-2,2-dimethylpropanoyl)(4,4-dimethylcyclohexyl)amino]-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-N,N-dimethyl-L-prolinamide Salt HCl

HCl

Stage A: 1-BOC-(2S,4S)-4-[(2-cyano-2-methylpropanoyl)(4,4-dimethylcyclohexyl)amino]-2-[(dimethylamino)carbonyl]pyrrolidin

The target issue for lighting the e compound was obtained according to the procedure described in stage B~D of example A1, using (2S,4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)amino]pyrrolidin-2-methylcarbazole (1,46 g, 4.14 mmol), obtained at the stage of example A1, and 2-cyano-2-methylpropanoate obtained in the example of a A4-3 as starting materials (1.07 g, 56%).

MS[M+H] = 463(M+1)

Stage B: 1-BOC-(2S,4S)-4-[(3-amino-2,2-dimethylpropanoyl)(4,4-dimethylcyclohexyl)amino]-2-[(dimethylamino)carbonyl]pyrrolidin

To a solution of 1-BOC-(2S,4S)-4-[(2-cyano-2-methylpropanoyl)(4,4-dimethylcyclohexyl)amino]-2-[(dimethylamino)carbonyl]pyrrolidine (1.07 g, 2,31 mmol)obtained in stage A, in methanol was added Pd/C (9 mg) and spent the hydrogen reaction at ambient temperature for 10 hours. After completion of the reaction, the reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuum and purified HPLC, obtaining the target compound (0.84 g, 78%).

MS[M+H] = 467(M+1)

Stage C: 1-BOC-(2S,4S)-4-[(3-{[(benzoyloxy)carbonyl]amino}-2,2-dimethylpropanoyl)(4,4-dimethylcyclohexyl)amino]-2-[(dimethylamino)carbonyl]pyrrolidin

The target compound was obtained according to the procedure described in stage E of example B7, using 1-BOC-(2S,4S)-4-[(3-amino-2,2-dimethylpropanoyl)(4,4-dimethylcyclohexyl)amino]-2-[(dimethylamino)carbonyl]pyrrolidine (200 mg, 0.43 mmol)obtained in stage (201 mg, 80%).

MS[M+H] = 601(M+1)

Stage D: (4S)-4-[(3-{[(benzoyloxy)carbonyl]amino}-2,2-dime ispropanol)(4,4-dimethylcyclohexyl)amino]-N,N-dimethyl-L-prolinamide

The target compound was obtained according to the procedure described in stage E of example A1 using 1-BOC-(2S,4S)-4-[(3-{[(benzoyloxy)carbonyl]amino}-2,2-dimethylpropanoyl)(4,4-dimethylcyclohexyl)amino]-2-[(dimethylamino)carbonyl]pyrrolidine (200 mg, 0.33 mmol)obtained in stage C (162 mg, 98%).

MS[M+H] = 501(M+1)

Stage E: (4S)-4-[(3-{[(benzoyloxy)carbonyl]amino}-2,2-dimethylpropanoyl)(4,4-dimethylcyclohexyl)amino]-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-N,N-dimethyl-L-prolinamide

The target compound was obtained according to the procedure described in stage F of example A1, using (4S)-4-[(3-{[(benzoyloxy)carbonyl]amino}-2,2-dimethylpropanoyl)(4,4-dimethylcyclohexyl)amino]-N,N-dimethyl-L-prolinamide (162 mg, 0.32 mmol), obtained in stage D (217 mg, 89%). The next stage reaction was conducted without further purification, and at the stage F for cleaning used HPLC.

MS[M+H] = 766(M+1)

Stage F: (4S)-4-[(3-amino-2,2-dimethylpropanoyl)(4,4-dimethylcyclohexyl)amino]-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-N,N-dimethyl-L-prolinamide Salt HCl

The target compound was obtained according to the procedure described in stage E of example obtaining A1-1, using (4S)-4-[(3-{[(benzoyloxy)carbonyl]amino}-2,2-dimethylpropanoyl)(4,4-dimethylcyclohexyl)amino]-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-N,N-dimethyl-L-prolinamide (217 mg, 0.28 and m is ol), obtained in stage E, and HPLC purification (160 mg, 91%).

MS[M+H] = 632(M+1)

1H NMR (400 MHz, CDCl3) δ 8,10-of 8.04 (m, 1H), 6,97-6,93 (m, 1H), 6,79-6,74 (m, 1H), 4,70 (t, 1H), 4,35-4,22 (m, 2H), 3.95 to 3,90 (m, 2H), 3,81 at 3.69 (m, 1H), 3,67-of 3.54 (m, 2H), 3,42 be 3.29 (m, 2H), 3,22-3,11 (m, 1H), 2,99 (c, 3H), 2.95 and (c, 3H), 2,92-2,70 (m, 3H), 2,19-of 1.97 (m, 1H), 1,61-of 1.39 (m, 4H), 1,49 (c, 9H), 1,31-of 1.15 (m, 4H), 1.27mm (c, 6H), 0,95 (c, 3H), 0,91 (c, 3H).

Example C11: (4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-{[3-(dimethylamino)-2,2-dimethylpropanoyl](4,4-dimethylcyclohexyl)amino}-N,N-dimethyl-L-prolinamide Salt HCl

HCl

Stage A: 1-BOC (2S,4S)-2-[(dimethylamino)carbonyl]-4-{[3-(dimethylamino)-2,2-dimethylpropanoyl](4,4-dimethylcyclohexyl)amino}pyrrolidin

The target compound was obtained according to the procedure described under example A1 using 1-BOC-(2S,4S)-4-[(3-amino-2,2-dimethylpropanoyl)(4,4-dimethylcyclohexyl)amino]-2-[(dimethylamino)carbonyl]pyrrolidine (142 mg, 0.3 mmol), obtained in stage B of example C10, and formaldehyde (105 mg, 71%).

MS[M+H] = 495(M+1)

Stage B: (4S)-4-{[3-(dimethylamino)-2,2-dimethylpropanoyl](4,4-dimethylcyclohexyl)amino}-N,N-dimethyl-L-prolinamide

The target compound was obtained according to the procedure described in stage E of example A1 using 1-BOC (2S,4S)-2-[(dimethylamino)carbonyl]-4-{[3-(dimethylamino)-2,2-dimethylpropanoyl](4,4-dimethylcyclohexyl)amino}pyrrolidin (105 mg, 0.21 mmol)obtained in stage (82 mg, 98%).

MS[M+H] = 395(M1)

Stage C: (4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-{[3-(dimethylamino)-2,2-dimethylpropanoyl](4,4-dimethylcyclohexyl)amino}-N,N-dimethyl-L-prolinamide Salt HCl

The target compound was obtained according to the procedure described in stage F, G of example A1, using (4S)-4-{[3-(dimethylamino)-2,2-dimethylpropanoyl](4,4-dimethylcyclohexyl)amino}-N,N-dimethyl-L-prolinamide (82 mg, 0.18 mmol)obtained in stage B and (3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-carboxylic acid obtained in example receiving the A9-2 (105 mg, 89%).

MS[M+H] = 658(M+1)

1H NMR (400 MHz, CDCl3) δ 7,50 (d, 2H), 7,32 (d, 2H), 4,70 (t, 1H), 4,35-4,22 (m, 2H), 3.95 to 3,90 (m, 2H), 3,81 at 3.69 (m, 1H), 3,67-of 3.54 (m, 2H), 3,42 be 3.29 (m, 2H), 3,22-3,11 (m, 1H), 2,99 (c, 3H), 2.95 and (c, 3H), 2,88 is 2.55 (m, 3H), 2,30 for 2.01 (m, 7H), 1,61-of 1.39 (m, 4H), 1,49 (c, 9H), 1,31-of 1.15 (m, 4H), 1.27mm (c, 6H), 0,95 (c, 3H), 0,91 (c, 3H).

Example C12: N-{(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-[(dimethylamino)carbonyl]pyrrolidin-3-yl}-N-(4,4-dimethylcyclohexyl)-2,2-diethylmalonate TFA Salt

TFA

Stage A: 1-BOC-(2S,4S)-4-[(2-cyano-2-methylpropanoyl)(4,4-dimethylcyclohexyl)amino]-2-[(dimethylamino)carbonyl]pyrrolidin

The target compound was obtained according to the procedure described in stage B~D of example A1, using (2S,4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)amino]pyrrolidin-2-methylcarbazole (1.77 g, 5 mmol), obtained at the stage of example A1, and 2-cyano-2-methylpropanoic the chloride, received in the sample receiving A4-3 as a source material (1.3 g, 56%).

MS[M+H] = 463(M+1)

Stage B: 1-BOC-(2S,4S)-4-[(3-amino-2,2-dimethyl-3-oxopropanoic)(4,4-dimethylcyclohexyl)amino]-2-[(dimethylamino)carbonyl]pyrrolidin

To a solution of 1-BOC-(2S,4S)-4-[(2-cyano-2-methylpropanoyl)(4,4-dimethylcyclohexyl)amino]-2-[(dimethylamino)carbonyl]pyrrolidine (1.06 g, 2.3 mmol)obtained in stage A, in methanol (10 ml) was added 10h. NaOH (5 ml) and stirred at 80°C for 2 hours. After completion of the reaction the solvent was concentrated in vacuum, diluted with water and was extracted with EtOAc. Extracted organic layer was dried over MgSO4concentrated in vacuo and purified by chromatography on columns (eluent: EtOAc/Hex = 3/1)to give the target compound (970 mg, 88%).

MS[M+H] = 481(M+1)

Stage C:N-{(3S,5S)-5-[(dimethylamino)carbonyl]pyrrolidin-3-yl}-N-(4,4-dimethylcyclohexyl)-2,2-diethylmalonate

The target compound was obtained according to the procedure described in stage E of example A1 using 1-BOC-(2S,4S)-4-[(3-amino-2,2-dimethyl-3-oxopropanoic)(4,4-dimethylcyclohexyl)amino]-2-[(dimethylamino)carbonyl]pyrrolidine (226 mg, 0.47 mmol)obtained in stage B (166 mg, 98%).

MS[M+H] = 381(M+1)

Stage D: N-{(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-[(dimethylamino)carbonyl]pyrrolidin-3-yl}-N-(4,4-dimethylcyclohexyl)-2,2-diethylmalonate TFA Salt

MS[M+H] = 644(M+1)

1H NMR (500 MHz, CDCl3) δ of 7.36 (d, 2H), 7,29 (d, 2H), 4,60 (t, 1H), to 4.38-4.25 in (m, 1H), 4,25-to 4.14 (m, 1H), 3,92-of 3.78 (m, 1H), 3.72 points-of 3.27 (m, 6H), 3,19-of 3.12 (m, 1H), 2,98 (d, 3H), equal to 2.94 (d, 3H), 2,85 of 2.68 (m, 1H), 2.13 and of 1.99 (m, 1H), 1,62-1,11 (m, 8H), 1,43 (c, 9H), 1.39 in (c, 3H), 1,33 (c, 3H), 0,90 (c, 3H), 0,87 (c, 3H).

Example C13: S-(3-{[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-5-{[ethyl(methyl)amino]carbonyl}pyrrolidin-3-yl](4,4-dimethylcyclohexyl)amino}-2,2-dimethyl-3-oxopropyl)attentioin Salt HCl

HCl

Stage A: 1-BOC-(2S,4S)-4-{[3-(acetylthio)-2,2-dimethylpropanoyl](4,4-dimethylcyclohexyl)amino}-2-{[ethyl(methyl)amino]carbonyl}pyrrolidin

The product of stage C of example A4, BOC-(2S,4S)-4-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]-2-{[ethyl(methyl)amino]carbonyl}pyrrolidine (1 g, 2.1 mmol), was introduced into the reaction according to the procedure described in stage C of example obtaining A1-1, obtaining 1-BOC-(2S,4S)-4-[(4,4-dimethylcyclohexyl){2,2-dimethyl-3-[(methylsulphonyl)oxy]propanoic}amino]-2-{[ethyl(methyl)amino]carbonyl}pyrrolidin (0,72 g, 61%). This compound (200 mg, 0.36 mmol) and thioacetic potassium (411 mg, 3.6 mmol)was dissolved in methanol (3.6 ml), and the solution was stirred for 8 hours. After completion of the reaction the solution was concentrated in vacuo and extracted with EtOAc. The organic extracts were washed with water, dried over MgSO4and concentrated in vacuum, obtaining the target compound (0.14 g, 76%).

MS[M+H] = 540(M+1)

Stage B: S-(3-{[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-5-{[ethyl(methyl)amino]carbonyl}pyrrolidin-3-yl](4,4-dimethylcyclohexyl)amino}-2,2-dimethyl-3-oxopropyl)attentioin Salt HCl

The target compound was obtained according to the procedure described in stage E~G of example A1, using 1-BOC-(2S,4S)-4-{[3-(acetylthio)-2,2-dimethylpropanoyl](4,4-dimethylcyclohexyl)amino}-2-{[ethyl(methyl)amino]carbonyl}pyrrolidine (100 mg, 0,19 mmol)obtained in stage (60 mg, 44%).

MS[M+H] = 705(M+1)

1H NMR (400 MHz, CDCl3) δ 8,10-8,03 (m, 1H), of 6.96-6,93 (m, 1H), 6,79-6,74 (m, 1H), 4,70 (t, 1H), 4,35-4,22 (m, 2H), 3,95 is 3.40 (m, 2H), 3,81 at 3.69 (m, 1H), 3,67-of 3.54 (m, 2H), 3,42 be 3.29 (m, 2H), 3,26-3,10 (m, 3H), 2,99 (c, 3H), 2.82 from 2.63 in (m, 3H), 2,19-of 1.97 (m, 1H), 1,61-of 1.39 (m, 4H), 1,49 (c, 9H), 1.32 to to 1.15 (m, 7H), 1.27mm (c, 6H), 0,95 (c, 3H), 0,91 (c, 3H).

Example C14: (4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(3-mercapto-2,2-dimethylpropanoyl)amino]-N-ethyl-N-methyl-L-prolinamide Salt HCl

HCl

To a solution of S-(3-{[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-5-{[ethyl(methyl)amino]carbonyl}pyrrolidin-3-yl]4,4-dimethylcyclohexyl)amino}-2,2-dimethyl-3-oxopropyl)ethanoate (32 mg, 0.045 mmol)obtained in example C13, in methanol/water (5:1, 1 ml) was added potassium carbonate (38 mg, 0.28 mmol)and the solution was stirred for 5 hours. The methanol in the reaction solution was concentrated in vacuo, was purified preparative-TLC without further process and processed according to the procedure described in stage G of example A1, obtaining the compound (7 mg, 23%).

MS[M+H] = 663(M+1)

1H NMR (400 MHz, CDCl3) δ 8,10-8,03 (m, 1H), of 6.96-6,93 (m, 1H), 6,79-6,74 (m, 1H), 4,70 (t, 1H), 4,35-4,22 (m, 2H), 3,95 is 3.40 (m, 2H), 3,81 at 3.69 (m, 1H), 3,67-of 3.54 (m, 2H), 3,42 be 3.29 (m, 2H), 3,26-of 3.07 (m, 5H), 2,99 (c, 3H), 2,82-2,30 (m, 4H), 2,19-of 1.97 (m, 1H), 1,61-of 1.39 (m, 4H), 1,49 (c, 9H), 1.32 to to 1.15 (m, 7H), 1.27mm (c, 6H), 0,95 (c, 3H), 0,91 (c, 3H).

Example C15~25

The following examples were obtained according to the procedure described in example C1~14 using intermediate compounds, which were obtained in a series of example And reactions between the appropriate compounds of example, obtain A1, A2, A4, A9 and the corresponding amines.

Table 8

Scheme D

The process of obtaining the intermediate compounds D1 and examples were synthesized in accordance with the procedure of scheme D are as follows.

Example D1: (4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(2,4-differenl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide TFA Salt

TFA

Stage A: (2S,4S)-1-Boc-4-azidopyridine-2-carboxylic acid

To a solution of (2S,4S)-1-Boc-4-azidopyridine-2-methylcarbamate (10 g, 37 mmol), obtained in stage D of example obtaining A1-1, in methanol (100 ml) and water (100 ml) was added LiOH (2.5 g, 111 mmol). The solution was stirred at ambient temperature for 3 hours, concentrated in vacuo, acidified 1H. HCl and was extracted with EtOAC. The organic extracts were washed with saline, dried over MgSO4and concentrated in vacuum, obtaining the target compound (9.5 g, 95%).

MS[M+H] = 257(M+1)

Stage B: (2S,4S)-1-Boc-4-azido[(dimethylamino)carbonyl]pyrrolidin

To a solution of (2S,4S)-1-Boc-4-azidopyridine-2-carboxylic acid (9.5 g, 35 mmol)obtained in stage A, in DMF (30 ml)was added dropwise DIPEA (1,15 ml, 6,70 mmol), was added dropwise a solution of 2M dimethylamine-THF (26,3 ml of 52.5 mmol, HOBT (7 g, is 52.5 mmol) and EDC (10.2 g, is 52.5 mmol) in that order. The reaction mixture was stirred at ambient temperature for 12 h and concentrated in vacuum. The residue was diluted with EtOAc and washed with saturated aqueous NaHCO3, water and 1N. HCl. The organic solution was dried over MgSO4concentrated in vacuo and the residue was purified by chromatography on a column (eluent: EtOAc:Hex = 1/2)to give the target compound (9.1 g, 93%)

MS[M+H] = 284(M+1)

Stage C: (2S,4S)-1-Boc-4-amino[(dimethylamino)CT is of IMT]pyrrolidin

To a solution of (2S,4S)-1-Boc-4-azido[(dimethylamino)carbonyl]pyrrolidine (9 g, 32 mmol), obtained in stage B in dioxane (30 ml) was added dropwise Pd/C (900 mg). The reaction mixture was stirred in the atmosphere of hydrogen for 24 hours, filtered through Celite and concentrated in vacuum, obtaining the target compound in the form of oil (8.1 g, 98.5 per cent).

MS[M+H] = 258(M+1)

Stage D: (2S,4S)-1-Boc-4-[(2,4-differenl)amino]-2[(dimethylamino)carbonyl]pyrrolidin

To a solution of (2S,4S)-1-Boc-4-amino[(dimethylamino)carbonyl]pyrrolidine (8 g, to 31.5 mmol)obtained in stage C, in toluene (100 ml) was added tert-piperonyl sodium (of 3.46 g, 36 mmol), 2-(di-tert-butylphosphino)diphenyl (800 mg, 2.68 mmol), Tris(dibenzylideneacetone)dipalladium (0) (1.6 g, to 1.79 mmol) and 1-bromo-2,4-differental (6,94 g, 36 mmol)and the solution was stirred at 110°C for 10 hours. After completion of the reaction the solution was filtered through Celite and was extracted with water and EtOAc. The organic layer was dried over MgSO4concentrated in vacuo and purified by chromatography on columns (eluent, EtOAc/Hex = 1/4)to give the target compound (1.5 g, 78%).

MS[M+H] = 370(M+1)

Stage E: (4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(2,4-differenl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide TFA Salt

The target compound was obtained according to the procedure described in stage B, E, F, G of example A1, using the receiving (2S,4S)-1-Boc-4-[(2,4-differenl)amino]-2[(dimethylamino)carbonyl]pyrrolidine (0.5 g, of 1.34 mmol)obtained in stage D, as the original material (0,46 g, 55%).

MS[M+H] = 617(M+1)

1H NMR (500 MHz, CDCl3) δ EUR 7.57 (d, 2H), 7,41 (d, 2H), 7,35-7,14 (m, 1H), 7,13-7,00 (m, 1H), 6,99-6,89 (m, 1H), 4,82-4,71 (m, 1H), br4.61-a 4.53 (m, 1H), 3,92-to 3.49 (m, 5H), 3,29-3,20 (m, 1H), 3,14-to 2.85 (m, 2H), 3.04 from (d, 3H), of 2.93 (d, 3H), 2,59-to 2.42 (m, 1H), 2.21 are of 2.10 (m, 1H), 1,40 (c, 9H), 0,97 (c, 9H).

Example D2~39

The following examples were obtained according to the procedure described in example D1 using intermediate compounds, which were received in series a, the reaction between suitable compounds from the sample receiving A1, A2, A4, A9 and the corresponding amines.

Table 9

Scheme E

Example E1-1: (4S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide

Stage 1-BOC-(3R,4S)-3-(4-chlorophenyl)-4-({(2S,4S)-2-[(dimethylamino)carbonyl]-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidin-1-yl}carbonyl)pyrrolidin

The target compound was obtained according to the procedure described in stage F of example A1, using (4S)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide (350 mg, 1.0 mmol)obtained in stage E of example A1, the (3S,4R)-1-(tert-butoxycarbonyl)-4-(4-chlorophenyl)pyrrolidin-3-carboxylic acid, received in the sample receiving the A9-9 (593 mg, 90%).

MS[M+H] = 659(M+1)

Stage B: (4S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide

1-BOC-(3R,4S)-3-(4-chlorophenyl)-4-({(2S,4S)-2-[(dimethylamino)carbonyl]-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidin-1-yl}carbonyl)pyrrolidine (100 mg, 0.15 mmol)obtained in stage A, was treated according to the procedure described in stage E of example A1, and were HPLC purified. This TFA salt compounds were podslushivaet 1H. NaOH and was extracted with EtOAc. The organic layer was dried over MgSO4and concentrated in vacuum, obtaining the target compound (75 mg, 90%).

MS[M+H] = 559(M+1)

1H NMR (500 MHz, CDCl3) δ 7,30 (d, 2H), 7,24 (d, 2H), 4,71 (t, 1H), 4,29-4,19 (m, 1H), 3,78-3,60 (osirm, 2H), 3,45-3,19 (m, 4H), 3,59-to 3.50 (m, 1H), 3,06 (c, 3H), 2,96 (c, 3H), 2,96-to 2.74 (m, 2H), 2,50-to 2.41 (m, 1H), 2,09-of 1.95 (m, 1H), 1,63 of-1.04 (m, 8H), 1,18 (c, 9H), 0,95 (c, 3H), 0,92 (c, 3H).

Example E1-2~58

The following examples were obtained according to the procedure described in example E1-1, using intermediate compounds, which were obtained in a series of example A, B, C, D, reactions between suitable compounds from the sample receiving A1, A2, A4, A9 and the corresponding amines.

Table 10

Example E2-1: (4S)-1-{[(3S,4R)-1-(aminocarbonyl)-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide

To a solution of (4S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide (84 mg, 0.15 mmol)obtained in example E1-1, in DMF was added dropwise KOCN (24 mg, 0.3 mmol) and catalytic amount of acetic acid. The reaction mixture was stirred at ambient temperature for 1 hour, extracted with EtOAc, washed with excess water and brine, and the organic solution was dried over MgSO4. The residue was purified HPLC, obtaining the target compound.

MS[M+H] = 602(M+1)

1H NMR (500 MHz, CDCl3) δ 7,30 (d, 2H), 7,24 (d, 2H), 4,71 (t, 1H), 4,29-4,19 (m, 1H), 4,05-of 3.77 (m, 4H), 3,76-of 3.60 (m, 2H), 3,59-to 3.50 (m, 1H), 3,06 (c, 3H), 2,96 (c, 3H), 2,99-a 2.71 (m, 2H), 2,50-to 2.40 (m, 1H), 2,09-of 1.95 (m, 1H), 1,63 of-1.04 (m, 8H), 1,18 (c, 9H), 0,95 (c, 3H), 0,94 (c, 3H).

Example E2-2~25

The following examples were obtained according to the procedure described in example E2-1, using intermediate compounds, which were obtained in a series of example A, B, C, D, reactions between suitable compounds from the sample receiving A1, A2, A4, A9 and the corresponding amines.

Table 11

the example E3-1: (4S)-1-({[(3S,4R)-4-(4-chlorophenyl)-1-(ethylamino)carbonyl]pyrrolidin-3-yl}carbonyl)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide

To a solution of (4S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide (84 mg, 0.15 mmol)obtained in example E1-1, and tea (0.04 ml, 0.3 mmol) in DCM was added dropwise utilizationa (16 mg, 0.22 mmol). The reaction mixture was stirred at ambient temperature for 1 hour, extracted with EtOAc, washed with excess water and brine, and the organic solution was dried over MgSO4. The residue was purified HPLC, obtaining the target compound.

MS[M+H] = 630(M+1)

1H NMR (500 MHz, CDCl3) δ 7,28 (d, 2H), 7.23 percent (d, 2H), 4,71 (t, 1H), 4.26 deaths is 4.13 (m, 1H), 4,08-3,98 (m, 1H), a 3.87-3,62 (osirm, 3H), to 3.58-3,37 (osirm, 3H), 3,37-is 3.21 (m, 3H), 3,10-2,96 (m, 1H), 3,05 (c, 3H), 2,94 (c, 3H), 2,74-2,60 (m, 1H), 2,09-to 1.98 (m, 1H), 1,63 of-1.04 (m, 8H), 1,18 (c, 9H), 1.14 in (t, 3H), 0,95 (c, 3H), 0,93 (c, 3H).

Example E3-2: N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-[(ethylamino)carbonothioyl]pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-diverticulosis)-3-hydroxy-2,2-dimethylpropanamide

To a solution of N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidin-3-yl)-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-dimethylpropanamide (93 mg, 0.15 mmol)obtained in example E1-57, and tea (0.04 ml, 0.3 mmol) in DCM was added dropwise utilizationa (19 mg, 0.22 mmol). The reaction mixture was stirred at ambient temperature for 1 hour, extracted with EtOAc, washed houses the com of the water and salt solution, and the organic solution was dried over MgSO4. The residue was purified HPLC, obtaining the target compound (74,4 mg, 84%).

MS[M+H] = 591(M+1)

1H NMR (500 MHz, CDCl3) 7,55-of 7.48 (m, 2H), was 7.36-7,28 (m, 2H), 3.95 to 3,20 m, N), 3,12-2,89 (m, 4H), 1,86 by 1.68 (m, 1H), 1,67-of 1.53 (m, 6H), 1,52-to 1.14 (m, 9H), 0,94 (c, 3H), 0,91 (c, 3H), from 0.88 (t, 3H).

Example E3-3~37

The following examples were obtained according to the procedure described in example E3-1,2, using intermediate compounds, which were obtained in a series of example A, B, C, D, reactions between suitable compounds from the sample receiving A1, A2, A4, A9 and the corresponding amines.

Table 12

Example E4-1: (4S)-1-({[(3S,4R)-1-acetyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide

The target compound was obtained according to the procedure described in stage F of example A1, using (4S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide (84 mg, 0.15 mmol)obtained in example E1-1, and AcOH reaction of amide combinations.

MS[M+H] = 601(M+1)

1H NMR (500 MHz, CDCl3) δ 7,30 (d, 2H), 7,24 (d, 2H), 4,71 (t, 1H), 4,29-4,19 (m, 1H), 4,16-4.09 to (m, 1H), 4,03-3,79 (osirm, 3H), 3,78-3,60 (osirm, 2H), 3,59-to 3.50(m, 1H), 3,37-3,29 (m, 1H), 3,06 (c, 3H), 2,96 (c, 3H), 2.91 in-2,69 (osirm, 2H), 2,14 (c, 3H), 2,09-of 1.95 (m, 1H), 1,63 of-1.04 (m, 8H), 1,18 (c, 9H), 0,95 (c, 3H), 0,94 (c, 3H).

Example E4-2~14

The following examples were obtained according to the procedure described in example E4-1, using intermediate compounds, which were obtained in a series of example A, B, C, D, reactions between suitable compounds from the sample receiving A1, A2, A4, A9 and the corresponding amines.

Table 13

Example E5-1: (4S)-1-({[(3S,4R)-4-(4-chlorophenyl)1-cyclopropylboronic-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide Salt HCl

HCl

To a solution of (4S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide (100 mg, 0.18 mmol)obtained in example E1-1 in DCE (5 ml) was added 1-amoxicillinprevpacclinical (47 mg, 0.27 mmol) and cyanoborohydride sodium (23 mg, 0.36 mmol), added a catalytic amount of acetic acid, and the solution was stirred at 80°C for 2 hours. After completion of the reaction the solvent was concentrated in vacuo and was extracted with saturated aqueous NaHCO3and EtOAc. The organic solution was dried over MgSO4concentrated in vacuo, and the residue was purified HPLC. This TFA salt compounds clicks sativali according to the procedure described in stage G of example A1, receiving the target connection.

MS[M+H] = 599(M+1)

1H NMR (400 MHz, CDCl3) δ EUR 7.57 (d, 2H), 7,32 (d, 2H), 4,70 (t, 1H), 4,35-4,22 (m, 2H), 3.95 to 3,90 (m, 2H), 3,81 at 3.69 (m, 1H), 3,67-of 3.54 (m, 2H), 3,42 be 3.29 (m, 2H), 3,22-3,11 (m, 1H), 2,99 (c, 3H), 2.95 and (c, 3H), 2,82 of 2.68 (m, 1H), 2,15-to 1.79 (m, 2H), 1,61-of 1.39 (m, 4H), 1,31-of 1.15 (m, 4H), 1,22 (c, 9H), 0,95 (c, 3H), 0,91 (c, 3H), 0,82 is 0.65 (m, 4H).

Example E5-2: (4S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-(tetrahydro-2H-Piran-4-yl)pyrrolidin-3-yl]carbonyl}-4-{(4,4-dimethylcyclohexyl) [(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-N-ethyl-N-methyl-L-prolinamide Salt HCl

HCl

(4S)-4-[(4,4-Dimethylcyclohexyl)(tetrahydrofuran-2-ylcarbonyl)amino]-N-ethyl-N-methyl-L-prolinamide (100 mg, 0.26 mmol)obtained in stage D of example A2, and (3S,4R)-1-(tert-butoxycarbonyl)-4-(4-chlorophenyl)pyrrolidin-3-carboxylic acid obtained in example receiving the A9-9, was introduced into the reaction according to the procedure described in stage F of example A1, and then according to the procedure described in stage E of example A1. This compound was introduced into the reaction with tetrahydro-4H-Piran-4-one by reductive amination as described under example A1, and were HPLC purified. This TFA salt of the compounds were processed according to the procedure described in stage G of example A1, obtaining the target compound (139 mg, 80%).

MS[M+H] = 671(M+1)

1H NMR (500 MHz, CDCl3) δ 7,66-7,52 (m, 2H), 7,37-7,27 (m, 2H), 4,73-to 4.62 (m, 1H), to 4.52-4,39 (m, 1H), 4,32-4,16 (m, 1H), 4,15-3,69 (osirm, 10th), 3,59-3,12 (SIRM, 10-e)3,00-is 2.88 (m, 3H), 2.23 to-2,80 (osirm, 8H), 1,65 of-1.04 (m, 11H), 0,98 is 0.86 (m, 6H).

Example E5-3~21

The following examples were obtained according to the procedure described in example E5-1,2, using intermediate compounds, which were obtained in a series of example A, B, C, D, reactions between suitable compounds from the sample receiving A1, A2, A4, A9 and the corresponding amines.

Table 14

Example E6: N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-(methylsulphonyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-2-methyl-N-(CIS-4-methylcyclohexyl)propanamide

To a solution of N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidin-3-yl]-N-(CIS-4-methylcyclohexyl)-2-methylpropanamide TFA salt (124 mg, 0.2 mmol)obtained in example E1-2, in DCM (3 ml) was added tea (50 mg, 0.5 mmol), and at 0°C was added methanesulfonamide (27.4 mg, 0.24 mmol), and stirred at ambient temperature within 30 minutes After completion of the reaction the solvent was concentrated in vacuo, the residue was extracted with water and EtOAc, and the organic layer was dried over MgSO4. The residue was purified HPLC, obtaining the target compound (82,8 mg, 77%).

MS[M+H] = 538(M+1)

1H NMR (400 MHz, CDCl3) 7,40-7,10 (m, 4H), a 3.87-to 3.50 (m, 6H), 3,47-is 3.21 (m, 3H), 2,84 (c, 3H), 2,80-2,69 (m, 2H), 2,60 is 2.33 (m, 2H), 1,78-of 1.57 (m, 8H), 1,50-to 1.21 (m, 9H), of 0.95 (d, 3H).

Example E7-1: (3R,4S)-3-(4-chlorophenyl)-4-({(3S)-3-[(CIS-4-methylcyclo exil)(2-methylpropanoyl)amino]pyrrolidin-1-yl} carbonyl)-N-(2,2,2-triptorelin)pyrrolidin-1-carboxamid

To a solution of phosgene (148 mg, 1.5 mmol) and tea (30 mg, 0.3 mmol) in DCM (5 ml) was slowly added dropwise N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidin-3-yl)-N-(CIS-4-methylcyclohexyl)-2-methylpropanamide TFA salt (90 mg, 0.15 mmol)obtained in example E1-2, and stirred at ambient temperature for 30 minutes, and concentrated in vacuum to remove the phosgene. To the residue was added DCM (5 ml) and tea (30 mg, 0.3 mmol), was added dropwise 2,2,2-triptorelin (20 mg, 0.2 mmol), and stirred at ambient temperature for 1 hour. After completion of the reaction the solvent was concentrated in vacuo, and the residue was extracted with EtOAc and water and dried over MgSO4. The residue was purified HPLC, obtaining the target compound with 53.4 mg, 67%).

MS[M+H] = 585(M+1)

1H NMR (500 MHz, CDCl3) 7,35-7,28 (m, 2H), 7,22-7,11 (m, 2H), 4,06-3,93 (m, 1H), 3,91-3,71 (m, 5H), 3,70-of 3.46 (m, 5H), 3,44-3,10 (m, 4H), 2,86-of 2.66 (m, 2H), 2,55 at 2.45 (m, 1H), 2,02-of 1.92 (m, 1H), 1,79-of 1.56 (m, 5H), 1,51-of 1.39 (m, 2H), 1,10-of 1.03 (d, 6H), 1,02-to 0.96 (m, 3H).

Example E7-2~3

The following examples were obtained according to the procedure described in example E7-1, using intermediate compounds, which were obtained in a series of example A, B, C, D, reactions between suitable compounds from the sample receiving A1, A2, A4, A9 and the corresponding amines.

Table 15

Example E8-1: (3,4S)-3-(4-chlorophenyl)-4-({(3S)-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]pyrrolidin-1-yl}carbonyl)pyrrolidin-1-methylcarbamoyl

To a solution of N-[(3S)-1-{[(3S,4R))-4-(4-chlorophenyl)pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-dimethylpropanamide (93 mg, 0.15 mmol)obtained in example E1-57, and tea (0.04 ml, 0.3 mmol) in DCM was added dropwise methylchloroform (20 mg, 0.22 mmol). The reaction mixture was stirred at ambient temperature for 1 hour, extracted with EtOAc, washed with excess water and brine, and the organic solution was dried over MgSO4. The residue was purified HPLC, obtaining the target compound (76 mg, 90%).

MS[M+H] = 562(M+1)

1H NMR (500 MHz, CDCl3) 7,30-to 7.15 (m, 4H), 4,00-to 3.33 (m, 13H), 3,32-up 3.22 (m, 1H), 3,21-3,11 (m, 1H), 2,78 of 2.68 (m, 0,6N), 2,61 is 2.51 (m, 0,6N), of 2.51-2.40 a (m, 0,4H), 1,98-1,89 (m, 0,4H), 1,86 by 1.68 (m, 1H), 1,67-of 1.35 (m, 7H), 1,32-1,14 (m, 8H), 0,93 (c, 6H).

Example E8-2~5

The following examples were obtained according to the procedure described in example E8-1, using intermediate compounds, which were obtained in a series of example A, B, C, D, reactions between suitable compounds from the sample receiving A1, A2, A4, A9 and the corresponding amines.

Table 16

Example E9: N-[(3S)-1-{[(3S,4R)-1-[amino(imino)methyl]-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-2-methyl-N-(CIS-4-methylcyclohexyl)propanamide TFA Salt

TFA

To a solution of N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrole the n-3-yl]-N-(CIS-4-methylcyclohexyl)-2-methylpropanamide (248 mg, 0.4 mmol)obtained in example E1-2, in THF (5 ml) was added N,N'-bis-Boc-1-guanidinate (186 mg, 0.6 mmol) and stirred at ambient temperature for 12 hours. After completion of the reaction the solvent was concentrated in vacuo, the residue was extracted with water and EtOAc, and the organic layer was dried over MgSO4added DCM (3 ml), was added TFA (1 ml) and stirred at 40°C for 10 hours. The solvent was concentrated in vacuo, and the residue was purified HPLC, obtaining the target compound (190 mg, 77%).

MS[M+H] = 502(M+1)

1H NMR (500 MHz, CDCl3) 7,34-7,28 (m, 2H), 7,25-of 7.23 (m, 1H), 7,15-7,11 (m, 1H), 4,06-3,93 (m, 1H), 3,91-3,71 (m, 5H), 3,69-of 3.12 (m, 7H), 2,86-of 2.66 (m, 2H), 2,55 at 2.45 (m, 1H), 2,02-of 1.92 (m, 1H), 1,79-of 1.56 (m, 5H), 1,51-of 1.39 (m, 2H), 1,10-of 1.03 (m, 6H), 1,02-to 0.96 (m, 3H).

Example E10: N-[(3S)-1-({(3S,4R)-4-(4-chlorophenyl)-1-[(ethylamino)(imino)methyl]pyrrolidin-3-yl}carbonyl)pyrrolidin-3-yl]-2-methyl-N-(CIS-4-methylcyclohexyl)propanamide TFA Salt

TFA

Stage A: N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-cyanopyrrolidine-3-yl]carbonyl}pyrrolidin-3-yl]-2-methyl-N-(CIS-4-methylcyclohexyl)propanamide

To a solution of N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidin-3-yl]-N-(CIS-4-methylcyclohexyl)-2-methylpropanamide (120 mg, 0.21 mmol)obtained in example E1-2, in ethanol (5 ml) was added brazian (33 mg, 0.31 mmol) and NaHCO3(88 mg, 1.05 mmol), and stirred at ambient temperature for 1 hour. The reaction Rast is the PR was concentrated in vacuum, was extracted with water and EtOAc, and the organic layer was dried over MgSO4. The organic solution was concentrated, obtaining the target compound, which was used in the next stage without further purification.

MS[M+H] = 485(M+1)

Stage B: N-[(3S)-1-({(3S,4R)-4-(4-chlorophenyl)-1-[(ethylamino)(imino)methyl]pyrrolidin-3-yl}carbonyl)pyrrolidin-3-yl]-2-methyl-N-(CIS-4-methylcyclohexyl)propanamide TFA Salt

To a solution of compound stage And in hexafluoroisopropanol (2 ml) was added tea (1 ml) and an excess of ethylamine hydrochloride and heated to 70°C. the Reaction solution was stirred for 5 hours, concentrated in vacuo and purified HPLC, obtaining the target compound (98,7 mg, 73%).

MS[M+H] = 530(M+1)

1H NMR (500 MHz, CDCl3) 7,35-7,28 (m, 2H), 7,25-7,22 (m, 1H), 7,15-7,11 (m, 1H), 4,06-3,93 (m, 1H), 3,91-3,71 (m, 5H), 3,70-of 3.46 (m, 3H), 3,44-3,10 (m, 6H), 2,86-of 2.66 (m, 2H), 2,55 at 2.45 (m, 1H), 2,02-of 1.92 (m, 1H), 1,79-of 1.56 (m, 5H), 1,51-of 1.39 (m, 2H), 1,35 is 1.23 (m, 3H), 1,10-of 1.03 (m, 6H), 1,02-to 0.96 (m, 3H).

Example E11: N-[(3S)-1-{[(3S,4R)-1-[(acetylamino)(imino)methyl]-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-2-methyl-N-(CIS-4-methylcyclohexyl)propanamide

To a solution of N-[(3S)-1-{[(3S,4R)-1-[amino(imino)methyl]-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-2-methyl-N-(CIS-4-methylcyclohexyl)propanamide TFA salt (185 mg, 0.3 mmol)obtained in example E9, in DCM (3 ml) was added acetic anhydride (46 mg, 0.45 mmol) and tea (71 the g 0.7 mmol), and stirred at ambient temperature for 6 hours. After completion of the reaction the solvent was concentrated in vacuo, extracted with water and EtOAc, and the organic layer was dried over MgSO4. The organic solution was concentrated in vacuum and purified HPLC, obtaining the target compound (139 mg, 85%).

MS[M+H] = 544(M+1)

1H NMR (500 MHz, CDCl3) 7,38-7,10 (m, 4H), 4,21-of 4.05 (m, 1H), 3,95 is 3.57 (m, 3H), 3,56-of 3.42 (m, 2H), 3.40 in totaling 3.04 (m, 3H), 2,75-2,62 (m, 1H), 2,54-to 2.40 (m, 1H), 2,36-of 2.21 (m, 2H), 2,01-1,89 (m, 1H), 1,80-is 1.51 (m, 6H), 1,48 is 1.34 (m, 3H), 1,33-1,22 (m, 1H), 1,13-of 0.90 (m, 11H.)

Example E12-1: N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-phenylpyrrolidine-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-propanamide

To a solution of N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-dimethylpropanamide (124 mg, 0.2 mmol)obtained in example E1-57 in toluene (5 ml) was added monobrominated (31 mg, 2 mmol) and followed the procedure described in stage D of example D1, obtaining the target compound (90 mg, 78%).

MS[M+H] = 580(M+1)

1H NMR (500 MHz, CDCl3) 7,55-7,47 (m, 2H), 7,41-to 7.32 (m, 2H), 7,28-7,11 (m, 3H), 3.95 to 3,20 m, N), 3,01-of 2.93 (m, 0,4H), 2,75 of 2.68 (m, 0,6N), 2,48-of 2.38 (m, 0,6N), 2,18-of 2.08 (m, 0,4H), 1,86 by 1.68 (m, 1H), 1,67-of 1.35 (m, 7H), 1,32-1,14 (m, 8H), 0,94 (c, 3H), 0,91 (c, 3H).

Example E12-2~6

The following examples were obtained according to the procedure described in example E12-1, using intermediate compounds, which have been well-received series of example A, B, C, D, reactions between suitable compounds from the sample receiving A1, A2, A4, A9 and the corresponding amines.

Table 17

Example E13-1: N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-(4,5-dihydro-1H-imidazol-2-yl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-dimethylpropanamide TFA Salt

TFA

To a solution of N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-dimethylpropanamide (124 mg, 0.2 mmol)obtained in example E1-57, in acetonitrile was added 1-(4,5-dihydro-1H-imidazol-2-yl) - for 3,5-dimethyl-1H-pyrazole bromohydrin (of 73.5 mg, 0.3 mmol) and tea (40 mg, 0.4 mmol) and stirred at 90°C for 5 hours. After completion of the reaction the solvent was concentrated in vacuo, extracted with water and EtOAc, and the organic solution was dried over MgSO4. The residue was purified HPLC, obtaining the target compound (114 mg, 83%).

MS[M+H] = 572(M+1)

1H NMR (500 MHz, CDCl3) 7,33-to 7.15 (m, 4H), 4,01-of 3.12 (m, N), 2,85-2,78 (m, 2H), 2,78-a 2.71 (m, 0,6N), 2,61 of $ 2.53 (m, 0,6N), 2,53 is 2.43 (m, 0,4H), 2.00 in at 1.91 (m, 0,4H), 1,74-of 1.65 (m, 3H), 1,58-of 1.32 (m, 7H), 1,32-1,14 (m, 8H), 0,94 (c, 6H).

Example E13-2: N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-(4,5-dihydro-1H-imidazol-2-yl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-dimethylpropanamide

The TFA salt

TFA

The target compound was obtained according to the procedure described in example E13-1, using N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidin-3-yl]-N-(CIS-4-methylcyclohexyl)-2-methylpropanamide obtained in example E1-2.

MS[M+H] = 528(M+1)

Functional test

Physiological activity of the compounds according to the present invention was evaluated by measuring agonistic activity and binding activity in relation to melanocortin receptors according to the following tests.

1. Luciferase test.

The cell line expressing the human receptor melanocortin 4 (MC4R), was separated from the cups with tissue culture medium, rinsing does not contain Ca++, Mg++DPBS, were treated with 1 time a solution of Trypsin/EDTA for 1 minute at 37°C and re-suspended with DMEM (GIBCO-BRL), supplemented with 10%FBS. Cells were counted and diluted in DMEM, supplemented with 10%FBS and 200 μg/ml Geneticin to 5×105cells/ml 90 ál of cell suspension was inoculated into each well of 96-well culture tablets with black wall and clear bottom (Costar). After incubation for 24 hours in an atmosphere of 6% CO2at 37°C to each well was added 10 μl of NDP-MSH and test compounds diluted in DMSO. The final concentration of DMSO was 1%. After 4 hours of incubation in an atmosphere of 6% O2at 37°C to each well was added 50 μl of Bright-Glo (Promega). Luciferase asset is ity was measured using a luminometer L-Max (Molecular Device). The amount of luciferase activity induced by the processing of NDP-MSH, was defined as 100%, to obtain the relative effectiveness of the test compounds. C0,5MSHwas defined as the concentration of test compounds, which leads to half-maximal activity of NDP-MSH. EC50was defined as the concentration of test compound, which leads to half of the maximum intrinsic activity.

2. Test the accumulation of camp.

The cell line expressing the human receptor melanocortin 4 (MC4R), were grown in culture cups F150 mm in DMEM (GIBCO-BRL), supplemented with 10%FBS, 200 μg/ml Geneticin (GIBCO-BRL) and antibiotics (penicillin and streptomycin)( GIBCO-BRL) in an atmosphere of 6% CO2at 37°C. When cells were fully grown, the cells were washed once with 10 ml containing Ca++, Mg++DPBS. Cells were incubated with 8 ml containing Ca++, Mg++DPBS for 15-30 minutes at 37°C until cells started not easily separated using a pipette. Cells were collected in 50 ml conical tubes and centrifuged at 1500 rpm for 5 minutes the Supernatant was discarded and the cells re-suspended in 8 ml and centrifuged at 1500 rpm for 5 minutes the Supernatant was discarded, and the sediment re-suspended in 3 ml of buffer for membrane preparations (10 mm Tris pH 7.4; 0,32M sucrose; 4 μg/ml leupeptin; 10 μm phospho the starch; 40 μg/ml bacitracin; 5 μg/ml Aprotinin). Sediment homogenized using a homogenizer Downs (Bellco glass pestle type “B”) using 20 strokes. The homogenate was centrifuged at 1300×g at 4°C for 10 min Supernatant were collected, and the precipitate is re-suspended in the buffer for membrane preparations and repeated homogenization and centrifugation. All supernatant collected and centrifuged at 40 000 rpm (Beckman Ultracentrifuge XL-100K, the Rotor 45 Ti, test tube centrifuge 50 ml) at 4°C for 15 minutes the Precipitate is re-suspended in the buffer for membrane preparations, and protein was determined using kit BCA test (PIERCE). Aliquots were placed in test tubes and kept at -80°C.

20 μl of NDP-MSH or test compounds diluted in DMSO, was added to each well of 96-well plate with V-shaped wells. 20 μl of the membrane fraction of 750 µg/ml in the buffer of Mr was added to each well. After carrying out the reaction at ambient temperature for 15 minutes of camp was measured using a set of test currents(3H) (Amersham, cat. No. TRK 432). The number of camp-induced processing of the test compound was compared with that produced in response to NDP-MSH, which was defined as 100%agonist. EC50was defined as the concentration of test compound, which leads to half the maximum net is aktivnosti.

As can be seen by the above results, the compounds according to the present invention showed agonistic activity against each MCR. In particular, the compounds according to the present invention showed excellent agonistic activity against MC4R, as shown in Table 18 below.

1. The compound of the following formula 1, its pharmaceutically acceptable salt or stereoisomer:

in which R1denotes hydrogen, amidino,1-C4-alkylamino,1-C4-alkanolamide, C1-C10-alkyl, C3-C7-cycloalkyl,6-C10-aryl, 6-membered heterocycle with one oxygen atom, 5-membered heterocycle with two nitrogen atoms, a 6-membered heteroaryl with one or two nitrogen atoms, 5-membered heteroaryl with two heteroatoms, one of which is a nitrogen atom, and the other is a sulfur atom, a C1-C6-alkylsulphonyl,3-C7-cycloalkylcarbonyl,1-C4-alkoxycarbonyl,6-C10-aryl-C1-C4-alkoxycarbonyl, -SO2-C1-C4-alkyl, -C(O)-N(R6)(R7or-C(S)-N(R6)(R7),
and R6and R7each independently represents hydrogen, C1-C6-alkyl or C3-C7-cycloalkyl, alkyl, cycloalkyl, heterocycle, aryl or heteroaryl unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, amino, C1-C4-alkyl, trifloromethyl, hydroxy, C1-C4-alkoxy and oxo,
R2stands With6-C10-aryl, which is unsubstituted or mono - or Disaese Deputy selected from the group consisting of halogen, hydroxy, C1-C4-alkyl, C1-C4-alkoxy, cyano, amino,
R3denotes hydrogen, cyano, C1-C6-alkyl, C3-C7-cycloalkyl,2-C6alkenyl monocyclic 5-membered heterocycle with one atom of nitrogen and oxygen, monocyclic 5-membered heteroaryl containing heteroatoms, one of which is a nitrogen atom and the other atom of oxygen or sulfur, -C(O)-R8or-C(S)-R8,
and R8denotes hydroxy, C1-C4-alkyl, C1-C4-alkyloxy or N(R9)(R10),
R9and R10each independently represent hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl,1-C4-alkyloxy, phenyl or 5-membered heteroaryl with two heteroatoms, one of which is a nitrogen atom and the other atom of sulfur, 6-membered heteroaryl with one nitrogen atom,
R9and R10together with at the IOM nitrogen, with which they are associated, to form the only 4-6-membered ring, which may optionally include an oxygen atom or sulfur,
moreover alkyl, cycloalkyl, heterocycle, phenyl or heteroaryl unsubstituted or substituted by a Deputy selected from the group consisting of methyl, trifloromethyl, hydroxy, hydroxyimino, amino, acetylamino, (C1-C4-alkyl)amino and (C1-C4-alkyl)(C1-C4-alkyl)amino,
R4means3-C8-cycloalkyl,6-C10-aryl, 5-membered heteroaryl containing two heteroatoms, one of which is a nitrogen atom and the other atom is sulfur, 6-membered heteroaryl with one nitrogen atom, or a 6-membered heterocycle with one oxygen atom,
With6-C10-aryl or heteroaryl unsubstituted or mono - or polyamidine Deputy selected from the group consisting of halogen, hydroxy, C1-C4-alkyl, trifloromethyl,1-C4-alkoxy, amino,
cycloalkyl or heterocycle unsubstituted or mono - or polyamidine Deputy selected from the group consisting of halogen, hydroxy, C1-C4-alkyl, trifloromethyl,1-C4-alkoxy and oxo,
R5denotes hydrogen, C1-C6-alkyl, -C(O)-R11C1-C6-alkylsulfonyl, C6-C10-arylsulfonyl, -(CH2)p- 6-C10-aryl, -(CH2)p-heteroaryl or -(CH2)p-C3-C8-cycloalkyl where heteroaryl represents a 5-membered heteroaryl with one heteroatom selected from nitrogen, oxygen, or sulfur, which can optionally contain a nitrogen atom as a second heteroatom, and R represents 1 or 2,
R11represents C1-C10-alkyl, C2-C6alkenyl,3-C8-cycloalkyl,3-C8-cycloalkenyl, amino, C1-C4-alkylamino, (C1-C4-alkyl)(C1-C4-alkyl)amino, C6-C10-aryl, 5-membered heteroaryl with one heteroatom selected from nitrogen, oxygen, or sulfur, which can optionally contain a nitrogen atom as a second heteroatom, or 6-membered heterocycle containing two heteroatoms, one of which is a nitrogen atom and the other is an oxygen atom, 5 - or 6-membered heterocycle with one oxygen atom,
moreover, the alkyl is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy, mercapto, C1-C4-alkoxy, C1-C3-alkylcarboxylic, amino, dimethylamino,1-C4-alkylcarboxylic, cyano, carbamoyl, dimethylcarbamoyl, hydroxyimino and oxo,
aryl or heteroaryl unsubstituted Il is mono - or tizamidine Deputy selected from the group consisting of halogen, hydroxy, C1-C4-alkyl, trifloromethyl,1-C4-alkoxy, amino,
cycloalkyl, cycloalkenyl or heterocycle unsubstituted or mono - or tizamidine Deputy selected from the group consisting of halogen, hydroxy, amino, C1-C4-alkyl, trifloromethyl,1-C4-alkoxy and oxo.

2. The compound according to claim 1, in which
R1denotes hydrogen, amidino,1-C4-alkylamino,1-C4-alkanolamide, C1-C6-alkyl, C3-C7-cycloalkyl, phenyl, 6-membered heterocycle with one oxygen atom, 5-membered heterocycle with two nitrogen atoms, a 6-membered heteroaryl with one or two nitrogen atoms, 5-membered heteroaryl with two heteroatoms, one of which is a nitrogen atom, the other is a sulfur atom, a C1-C6-alkylsulphonyl, TRIFLUOROACETYL,1-C4-alkoxycarbonyl,6-C10-aryl-C1-C4-alkoxycarbonyl, -SO2-C1-C4-alkyl, carbarnoyl, C1-C6-allylcarbamate, (C1-C6-alkyl)(C1-C6-alkyl)carbarnoyl, thiocarbamoyl,1-C6-alkylthiomethyl or (C1-C6-alkyl)(C1-C6-alkyl)thiocarbamoyl,
moreover, the alkyl is unsubstituted or substituted by trifluoromethyl, or pharmaceuticas is acceptable salt or stereoisomer.

3. The compound according to claim 2, in which
R1denotes hydrogen, amidino, methylamino, ethylamide, acetylamino, methyl, ethyl, triptorelin, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, imidazolyl, tetrahydropyranyl, thiazolyl, pyridinyl, acetyl, TRIFLUOROACETYL, propionyl, butyryl, isobutyryl, pivaloyl, methoxycarbonyl, etoxycarbonyl, benzyloxycarbonyl, methylsulphonyl, carbarnoyl, methylcarbamoyl, ethylcarbitol, triptoreline, propellerblades, isopropylcarbamate, butylcarbamoyl, tert-butylcarbamoyl, thiocarbamoyl, methylthiocarbamate, etildiocolmain or methylethylketon, or its pharmaceutically acceptable salt or stereoisomer.

4. The compound according to claim 1, in which
R2denotes phenyl, unsubstituted or mono - or disubstituted by a Deputy selected from the group consisting of F, C1 and methyl, or its pharmaceutically acceptable salt or stereoisomer.

5. The compound according to claim 4, in which
R2denotes phenyl, 4-forfinal, 4-chlorophenyl, 4-were or 2,4-differenl, or its pharmaceutically acceptable salt or stereoisomer.

6. The compound according to claim 1, in which
R3denotes hydrogen, cyano, C1-C4-alkyl, C2-C4alkenyl, CH2C(CH3)2CH2HE oxazolyl, thiazolyl, oxazoline is, carboxy, C1-C4alkylsulphonyl,1-C4-allyloxycarbonyl, carbarnoyl, thiocarbamoyl,1-C4-allylcarbamate, (C1-C4-alkyl)(C1-C4-alkyl)carbarnoyl, (C1-C4-alkyl)(C1-C4-alkyloxy)carbarnoyl,1-C4-alkylthiomethyl or (C1-C4-alkyl)(C1-C4-alkyl)thiocarbamoyl, phenylcarbamoyl, heteroarylboronic, azetidinone, pyrrolidinecarbonyl, piperidinylcarbonyl or morpholinylcarbonyl,
moreover, the alkyl unsubstituted or substituted by a Deputy selected from the group consisting of hydroxy, hydroxyimino, amino, amine(C1-C4-alkyl) and (C1-C4-alkyl)(C1-C4-alkyl)amino, or its pharmaceutically acceptable salt or stereoisomer.

7. The connection according to claim 6, in which
R3denotes hydrogen, cyano, methyl, ethyl, propyl, allyl, -CHNOH, hydroxymethyl, -CH(CH3HE, aminomethyl, dimethylaminomethyl, oxazolyl, thiazolyl, oxazolyl, carboxy, acetyl, propanol, methoxycarbonyl, etoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, carbarnoyl, thiocarbamoyl, ethylcarbitol, tert-butylcarbamoyl, dimethylcarbamoyl, methylethylketon, metrotextual, diethylthiocarbamoyl, phenylcarbamoyl, heteroarylboronic, -C(O)NH(CH2)2NH2azetidinone, pyrrole carbonyl, piperidinylcarbonyl or morpholinylcarbonyl, or its pharmaceutically acceptable salt or stereoisomer.

8. The compound according to claim 1, in which
R4stands With4-C7-cycloalkyl monocyclic or 6-membered heterocycle with one oxygen atom, unsubstituted or mono - or politeley Deputy selected from the group consisting of halogen, hydroxy, C1-C4-alkyl, trifloromethyl,1-C4-alkoxy and oxo;
or phenyl or monocyclic 5-membered heteroaryl containing two heteroatoms, one of which is a nitrogen atom and the other atom of sulfur, 6-membered heteroaryl with one nitrogen atom, unsubstituted or mono - or disubstituted by a Deputy selected from the group consisting of halogen, hydroxy, C1-C4-alkyl, trifloromethyl,1-C4-alkoxy and amino, or its pharmaceutically acceptable salt or stereoisomer.

9. The connection of claim 8, in which
R4denotes cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 4,4-dimethylcyclohexyl, 4,4-diverticulosis, 4-cryptometrics, 3,4-tetramethylcyclobutane, tetrahydropyranyl, pyridinyl, N-methylpyridine or phenyl, and phenyl unsubstituted or mono - or Disaese Deputy selected from the group consisting of F, C1, methyl and methoxy, or its pharmaceutically acceptable whom I salt or stereoisomer.

10. The compound according to claim 1, in which
R5denotes hydrogen, C1-C6-alkyl, -CO-R11C1-C6-alkylsulfonyl, -CH2-C6-C10-aryl, -CH2-heteroaryl or-CH2-C3-C8-cycloalkyl where heteroaryl represents a 5-membered heteroaryl with one heteroatom selected from nitrogen, oxygen, or sulfur, which can optionally contain a nitrogen atom as a heteroatom,
and R11represents C1-C6-alkyl, deformity, trifluoromethyl, C2-C6alkenyl,3-C8-cycloalkyl,3-C8-cycloalkenyl, amino, C1-C4-alkylamino or (C1-C4-alkyl)(C1-C4-alkyl)amino, phenyl, monocyclic 5-membered heteroaryl with one heteroatom selected from nitrogen, oxygen, or sulfur, which can optionally contain as a second heteroatom a nitrogen atom, or a monocyclic 6-membered heterocycle containing two heteroatoms, one of which is a nitrogen atom, and the second oxygen atom, 5 - or 6-membered heterocycle with one oxygen atom,
moreover, the alkyl is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy, mercapto, C1-C4-alkoxy, acetoxy, amino, acetylamino, cyano, carb is Oila, dimethylcarbamoyl, hydroxyimino and oxo,
phenyl or heteroaryl unsubstituted or mono - or tizamidine Deputy selected from the group consisting of F, hydroxy, methyl, trifloromethyl, methoxy and amino,
cycloalkyl, cycloalkenyl or heterocycle unsubstituted or mono - or tizamidine Deputy selected from the group consisting of C1-C4-alkyl, C1-C4-alkoxy and oxo, or its pharmaceutically acceptable salt or stereoisomer.

11. The connection of claim 10, in which
R5denotes hydrogen, C1-C5-alkyl, trifluoromethyl, C1-C6-alkylsulphonyl, TRIFLUOROACETYL, acryloyl, methacryloyl,3-C8-cycloalkylcarbonyl,3-C8-cycloalkylcarbonyl, carbarnoyl,1-C4-allylcarbamate, (C1-C4-alkyl)(C1-C4-alkyl)carbarnoyl, methanesulfonyl, econsultancy, propanesulfonyl, benzoyl, hydroxybenzoyl, aminobenzoyl, monocyclic heteroarylboronic, heterocyclicamines, benzoyl, -CH2-monocyclic heteroaryl or-CH2-C3-C8-cycloalkyl,
With1-C5-alkyl or C1-C6-alkylsulphonyl unsubstituted or mono - or di-substituted by the Deputy selected from the group consisting of F, hydroxy, mercapto, methoxy, ethoxy, acetoxy, amino, methylcobalamine, cyano, carbamoyl, hydroxy the Mino and oxo, or its pharmaceutically acceptable salt or stereoisomer.

12. Connection by claim 11, in which
R5denotes hydrogen, methyl, ethyl, propyl, isobutyl, hydroxyethyl, -CH2C(CH3)2CH2HE, -CH2C(CH3)2CH(CH3HE, -CH2CH2N(O)CH3aminoethyl, acetyl, TRIFLUOROACETYL, hydroxyacetic, methoxyacetyl, ethoxyacetic, propionyl, ethoxypropanol, isobutyryl, cyanocobalamin, hydroxyisobutyryl, carbamoylethyl, 3,3-dimethylbutanol, pivaloyl, Perevalov, giftacular, hydroxypivalic, mercaptoethanol, dihydroxybiphenyl, metaxopoulos, ethoxyethanol, aminodialkyl, dimethylaminoethanol, hydroxyaminobuteroyl, acetylserotonin, -C(O)C(CH3)2CH(CH3HE, -C(O)C(CH3)2C(CH3)2HE, acryloyl, methacryloyl, cyclopentanecarbonyl, cyclohexanecarbonyl, carbarnoyl, dimethylcarbamoyl, methysulfonylmethane, benzoyl, thiofentanyl, furoyl, oxazolidinyl, diazocarbonyl, imidazolidinyl, pyrazolinones, tetrahydrofuroyl, dihydrouracil, tetrahydropyranyl, morpholinylcarbonyl, methanesulfonyl, benzoyl, furanosyl, thiazolyl or imidazolyl,
or its pharmaceutically acceptable salt or stereoisomer.

13. The compound according to claim 1, in which
R1denotes hydrogen, amidino, methylamide is but arylamidine, acetylamino, methyl, ethyl, triptorelin, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, imidazolyl, tetrahydropyranyl, thiazolyl, pyridinyl, acetyl, TRIFLUOROACETYL, propionyl, butyryl, isobutyryl, pivaloyl, methoxycarbonyl, etoxycarbonyl, benzyloxycarbonyl, methylsulphonyl, carbarnoyl, methylcarbamoyl, ethylcarbitol, triptoreline, propellerblades, isopropylcarbamate, butylcarbamoyl, tert-butylcarbamoyl, thiocarbamoyl, methylthiocarbamate, etildiocolmain or methylethylketon,
R2denotes phenyl, 4-forfinal, 4-chlorophenyl, 4-were or 2,4-differenl,
R3denotes hydrogen, cyano, methyl, ethyl, propyl, allyl, -CHNOH, hydroxymethyl, -CH(CH3HE, aminomethyl, dimethylaminomethyl, oxazolyl, thiazolyl, oxazolyl, carboxy, acetyl, propanol, methoxycarbonyl, etoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, carbarnoyl, thiocarbamoyl, ethylcarbitol, tert-butylcarbamoyl, dimethylcarbamoyl, methylethylketon, metrotextual, diethylthiocarbamoyl, phenylcarbamoyl, heteroarylboronic, -C(O)NH(CH2)2NH2azetidinone, pyrrolidinecarbonyl, piperidinylcarbonyl or morpholinylcarbonyl,
R4denotes cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohex the forces, 4,4-dimethylcyclohexyl, 4,4-diverticulosis, 4-cryptometrics, 3,4-tetramethylcyclobutane, tetrahydropyranyl, pyridinyl, N-methylpyridine or phenyl,
and phenyl unsubstituted or mono - or Disaese Deputy selected from the group consisting of F, C1, methyl and methoxy,
R5denotes hydrogen, methyl, ethyl, propyl, isobutyl, hydroxyethyl, -CH2C(CH3)2CH2HE, -CH2C(CH3)2CH(CH3HE, -CH2CH2N(O)CH3aminoethyl, acetyl, TRIFLUOROACETYL, hydroxyacetic, methoxyacetyl, ethoxyacetic, propionyl, ethoxypropanol, isobutyryl, cyanocobalamin, hydroxyisobutyryl, carbamoylethyl, 3,3-dimethylbutanol, pivaloyl, Perevalov, giftacular, hydroxypivalic, mercaptoethanol, dihydroxybiphenyl, metaxopoulos, ethoxyethanol, aminodialkyl, dimethylaminoethanol, hydroxyaminobuteroyl, acetylserotonin, -C(O)C(CH3)2CH(CH3HE, -C(O)C(CH3)2C(CH3)2HE, acryloyl, methacryloyl, cyclopentanecarbonyl, cyclohexanecarbonyl, carbarnoyl, dimethylcarbamoyl, methysulfonylmethane, benzoyl, thiofentanyl, furoyl, oxazolidinyl, diazocarbonyl, imidazolidinyl, pyrazolinones, tetrahydrofuroyl, dihydrouracil, tetrahydropyranyl, morpholinylcarbonyl, methanesulfonyl, benzoyl, furane the sludge, thiazolyl or imidazolyl, or its pharmaceutically acceptable salt or stereoisomer.

14. The connection 13, selected from the following groups:
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-{(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-N,N-ethylmethyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-{(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-N-ethyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]-N-ethyl-N-methyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-diverticulosis)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-diverticulosis)(2.2-dimethylpropanoyl)amino]-N-ethyl-L-prolinamide
(4S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-methylpyrrolidine-3-yl]carbonyl}-4-[(2,2-dimethylpropanoyl)(CIS-4-methylcyclohexyl)amino]-L-prolinamide
N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-dimethylpropanamide
N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]rbony}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(methylsulphonyl)amino]-N,N-dimethyl-L-prolinamide
N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl](4,4-dimethylcyclohexyl)amino}-2,2-DIMETHYLPROPANE-1-ol
(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-N-isobutyl-N-(CIS-4-methylcyclohexyl)pyrrolidin-3-amine
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(CIS-4-methylcyclohexyl)(tetrahydro-2H-Piran-4-ylcarbonyl)amino]-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-diferenciales-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(3-thienylboronic)amino]-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(isobutyryl)amino]N,N-dimethyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(2,2-dimethylpropanoyl)(CIS-4-methylcyclohexyl)amino]-N,N-dimethyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N-ethyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N-N-methyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N-isopropyl-L-prolinamide
N-[(3S,5S)-5-(azetidin-1-ylcarbonyl)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(2,5-dihydrofuran-3-ylcarbonyl)(4,4-dimethylcyclohexyl)amino]-N,N-dimethyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino]-N,N-dimethyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-diverticulosis)(3-hydroxy-2,2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]-N-ethyl-N-methyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(3-furoyl)amino]-N,N-dimethyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(3-furoyl)amino]-N-ethyl-N-methyl-L-prolinamide
N-[(3S)-1-{[(3S,4R)-1-tre the-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-[(4,4-diverticulosis)(3-hydroxy-2,2-dimethylpropanoyl)amino]-N-ethyl-N-methyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino]-N-ethyl-N-methyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-diverticulosis)(2.2-dimethylpropanoyl)amino]-N-ethyl-N-methyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-N-ethyl-4-[(3-hydroxy-2,2-dimethylpropanoyl)(CIS-4-methylcyclohexylamine]-N-methyl-L-prolinamide
N-[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-{[ethyl(methyl)amino]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide
N-[(3S,5S-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-(pyrrolidin-1-ylcarbonyl)pyrrolidin-3-yl]-N-(4,4-diverticulosis)-2,2-dimethylpropanamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-]-N-ethyl-N-methyl-4-{Spiro[2,5]Oct-6-yl[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-L-prolinamide
N-[(3S,5S-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-(morpholine-4-ylcarbonyl)pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)ndimethylacetamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)[(2R)-tetrahydrofuran-2-ylcarbonyl]amino]-N-ethyl-N-methyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]-N-ethyl-L-Proline is foreign
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N-phenyl-L-prolinamide
(2S)-N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)tetrahydrofuran-2-carboxamide
N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-2-methyl-N-[CIS-4-(trifluoromethyl)cyclohexyl]propanamide
(2S)-N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)tetrahydrofuran-2-carboxamide
N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl} pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)tetrahydrofuran-3-carboxamid
N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-dimethylpropanamide
N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-cycloheptyl-3-hydroxy-2,2-dimethylpropanamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-{(4,4-dimethylcyclohexyl)[(methylsulphonyl)amino}-N-ethyl-N-methyl-L-prolinamide
(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-N-(4,4-dimethylcyclohexyl)-N-3-furylfuramide 3-amine
N-[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-(4,5-dihydro-1,3-oxazol-2-yl)pyrrolidin-3-yl]-N-(4,4-dimethylcyclohex who yl)-2,2-dimethylpropanamide
N-{(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-[(dimethylamino)carbonothioyl]pyrrolidin-3-yl}-N-(4,4-dimethylcyclohexyl)-2-methylpropanamide
N-[(3S,5R)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-5-(1,3-thiazol-2-yl)pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide
N-[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-(hydroxymethyl)pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide
N-[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-methylpyrrolidine-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide
N-{(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-5-[(E)-(hydroxyimino)methyl]pyrrolidin-3-yl}-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide
N-[(3S,5S)-5-(aminoethyl)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide
N-[(3S,5S)-5-[(acetylamino)methyl]-1-{[(3S,4R)-1-tert-butyl-4-(2,4-dichlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide
N-[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-dichlorophenyl)pyrrolidin-3-yl]carbonyl}-5-[(dimethylamino)methyl]pyrrolidin-3-yl}-]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide
N-[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-5-cyanopyrrolidine-3-yl]-2,2-dimethyl-N-(CIS-4-methylcyclohexyl)disappear to the amide
N-[(3S,5R)-5-acetyl-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide
N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-(1-hydroxymethyl)pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide
(4S)-4-[acetyl - (4,4-dimethylcyclohexyl)amino]-N-(2-amino-ethyl)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]methyl-L-prolinate have been obtained
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-L-Proline
N-[(3S,5R)-5-(aminocarbonyl-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide
N-{(3S,5R)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-5-[(dimethylamino)carbonothioyl]pyrrolidin-3-yl}-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide
N-[(3S,5R)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-5-propionylthiocholine-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide
N-[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-propionylthiocholine-3-yl]-N-(4,4-diverticulosis)-2,2-dimethylpropanamide
N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}is irreligion-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-diethylmalonate
N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-methoxy-2,2-dimethylpropanamide
(3E)-N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-(hydroxyimino)-2,2-dimethylpropanamide
N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-Dimethylbutane
N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethyl-3-oxobutanamide
N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2,3-trimethylbutane
N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-fluoro-2,2-dimethylpropanamide
N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3,3-debtor-2,2-dimethylpropanamide
N-[(3S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-[(4,4-diverticulosis)(3-methoxy-2,2-dimethylpropanoyl)amino]-N-ethyl-N-methyl-L-prolinamide
(4S)-4-[(3-amino-2,2-dimethylpropanoyl)(4,4-dimethylcyclohexyl)amino]-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-N,N-dimethyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]ka is bonyl}-4-{[3-(dimethylamino)-2,2-dimethylpropanoyl](4,4-dimethylcyclohexyl)amino}-N,N-dimethyl-L-prolinamide
N-{(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-[(dimethylamino)carbonyl]pyrrolidin-3-yl}-N-(4,4-dimethylcyclohexyl)-2,2-diethylmalonate
S-(3-{[(3S,5S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-5-{[ethyl(methyl)amino]carbonyl}pyrrolidin-3-yl](4,4-dimethylcyclohexyl)amino}-2,2-dimethyl-3-oxopropyl)attentioin
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(3-mercapto-2,2-dimethylpropanoyl)amino]-N-ethyl-N-methyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-diverticulosis)(3-methoxy-2,2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-diverticulosis)(3 ethoxy-2,2-dimethylpropanoyl)amino]-N-ethyl-N-methyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(2,4-differenl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(2,2-dimethylpropanoyl)(4-methoxyphenyl)amino]-N,N-dimethyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-{(2,2-dimethylpropanoyl)[4-(trifluoromethyl)phenyl]amino}-N,N-dimethyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(2,2-dimethylpropanoyl)(4-were)amino]-N,N-dimethyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-tre the-butyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-{(2,4-differenl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino]-N-N-dimethyl-L-prolinamide
(4S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide
(2S)-N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)tetrahydrofuran-2-carboxamide
N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(CIS-4-methylcyclohexyl)3-pyramid
N-(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(CIS-4-methylcyclohexyl)-2,5-dihydrofuran-3-carboxamid
(4S)-N-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(2,2-dimethylpropanoyl)(CIS-4-methylcyclohexyl)amino]-D-prolinamide
N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-5-(1-hydroxymethyl)pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide
(4S)-1-{[(3S,4R)-1-(aminocarbonyl)-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide
(3R,4S)-3-(4-chlorophenyl)-4-({(3S)-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]pyrrolidin-1-yl}carbonyl)pyrrolidin-1-carboxamid
(3R,4S)-3-(4-chlorophenyl)-4-({(3S)-3-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidin-1-yl}carbonyl)pyrrolidin-1-carboxamid
(4S)-1-({[(3S,4R)-4-(4-chlorophenyl)-1-(ethylamino)carbonyl]pyrrolidin-3-yl}carbonyl)-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide
N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-[(ethylamino)carbonothioyl]PI is Raiden-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-diverticulosis)-3-hydroxy-2,2-dimethylpropanamide (3R,4S)-3-(4-chlorophenyl)-4-({(3S)-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2.2-dimethylpropanoyl)amino]pyrrolidin-1-yl}carbonyl)-N-ethylpyrrolidin-1-carboxamid
(3R,4S)-3-(4-chlorophenyl)-4-({(3S)-3-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidin-1-yl}carbonyl)-N-ethylpyrrolidin-1-carboxamid
(3R,4S)-3-(4-chlorophenyl)-4-({(3S)-3-[(2,4-differenl)(2.2-dimethylpropanoyl)amino]pyrrolidin-1-yl}carbonyl)-N-ethylpyrrolidin-1-carboxamid
(3R,4S)-3-(4-chlorophenyl)-N-ethyl-4-({(3S)-3-[isobutyryl(CIS-4-methylcyclohexyl)amino]pyrrolidin-1-yl}carbonyl)-N-methylpyrrolidine-1-carboxamid
(4S)-1-({[(3S,4R)-1-acetyl-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide
N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-isobutylpyrazine-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide
(4S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-isobutylpyrazine-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-L-prolinamide
(4S)-1-({[(3S,4R)-4-(4-chlorophenyl)1-cyclopropylboronic-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide
(4S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-(tetrahydro-2H-Piran-4-yl)pyrrolidin-3-yl]carbonyl}-4-{(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-N-ethyl-N-methyl-L-prolinamide
N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-(2,2,2-triptorelin)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide
(4S)-1-{[(3S,4R)-4-(2,4-differenl)-1-isobutylpyrazine-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropyl is Noel)amino]-N,N-dimethyl-L-prolinamide
(4S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-cyclobutylmethyl-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide
(4S)-1-{[(3S,4R)-1-cyclopentyl-4-(2,4-differenl)pyrrolidin-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolinamide
N-{(3S,5S)-1-{[(3S,4R)-4-(2,4-differenl)-1-isobutylpyrazine-3-yl]carbonyl}-5-[(dimethylamino)carbonato]pyrrolidin-3-yl}-N-(4,4-dimethylcyclohexyl)-2,2-dimethylpropanamide
N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-(methylsulphonyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-2-methyl-N-(CIS-4-methylcyclohexyl)propanamide
(3R,4S)-3-(4-chlorophenyl)-4-({(3S)-3-[(CIS-4-methylcyclohexyl)(2-methylpropanoyl)amino]pyrrolidin-1-yl}carbonyl)-N-(2,2,2-triptorelin)pyrrolidin-1-carboxamid
(3R,4S)-3-(4-chlorophenyl)-4-({(3S)-3-[(4,4-dimethylcyclohexyl)(2.2-dimethylpropanoyl)amino]pyrrolidin-1-yl}carbonyl)-N-(2,2,2-trifluoromethyl)pyrrolidin-1-carboxamid
(3R,4S)-3-(4-chlorophenyl)-4-({(3S)-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]pyrrolidin-1-yl}carbonyl)pyrrolidin-1-methylcarbamoyl
N-[(3S)-1-{[(3S,4R)-1-[amino(imino)methyl]-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-2-methyl-N-(CIS-4-methylcyclohexyl)propanamide
N-[(3S)-1-({(3S,4R)-4-(4-chlorophenyl)-1-[(ethylamino)(imino)methyl]pyrrolidin-3-yl}carbonyl)pyrrolidin-3-yl]-2-methyl-N-(CIS-4-methylcyclohexyl)propanamide
N-[(3S)-1-{[(3S,4R)-1-[(acetylamino)(imino)mate the]-4-(4-chlorophenyl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-2-methyl-N-(CIS-4-methylcyclohexyl)propanamide
N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-phenylpyrrolidine-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-propanamide
N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-pyridin-2-iparralde-3-yl]carbonyl}pyrrolidin-3-yl]-2,2-dimethyl-N-(CIS-4-methylcyclohexyl)propanamide
N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-(4,5-dihydro-1H-imidazol-2-yl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-dimethylpropanamide
N-[(3S)-1-{[(3S,4R)-4-(4-chlorophenyl)-1-(4,5-dihydro-1H-imidazol-2-yl)pyrrolidin-3-yl]carbonyl}pyrrolidin-3-yl]-N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-dimethylpropanamide,
or their pharmaceutically acceptable salt or isomer.

15. The pharmaceutical composition exhibiting agonistic activity against receptor melanocortin containing the compound of formula 1, as defined in claim 1, its pharmaceutically acceptable salt or stereoisomer together with a pharmaceutically acceptable carrier.

16. The composition according to § 15 for the prevention and treatment of obesity.

17. The composition according to § 15 for the prevention and treatment of diabetes.

18. The composition according to § 15 for the prevention and treatment of inflammation.

19. The composition according to § 15 for the prevention and treatment of erectile dysfunction.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to novel derivatives of cis-2,4,5-triarylimidazoline of general formula I and pharmaceutically acceptable salts thereof, where X1 is selected from a group comprising lower alkoxy; X2 and X3 are independently selected from a group comprising hydrogen, halogen, cyano, lower alkyl, lower alkoxy, piperidinyl, -NX4X5, -SO2NX4X5, -C(O)NX4X5, -C(O)X6, -SOX6, -SO2X6, -NC(O)-lower alkoxy, -C≡C-X7, provided that both X2 and X3 do not denote hydrogen, lower alkyl or lower alkoxy, provided that when X2 or X3 denote hydrogen, the other does not denote lower alkyl, lower alkoxy or halogen, provided that when X2 denotes -HX4X5, X3 does not denote hydrogen, X2 and X3 together can form a ring selected from 5-7-member unsaturated rings which can contain three heteroatoms selected from S, N and O, X4 and X5 are independently selected from a group comprising hydrogen, lower alkyl, lower alkoxy, lower alkyl, substituted by a lower alkoxy, -SO2-lower alkyl, -C(O)piperazinyl-3-one; X6 is selected from a group comprising lower alkyl, morpholine, piperidine, pyrrolidine; X7 is selected from a group comprising hydrogen, lower alkyl, trifluoromethyl; Y1 and Y2 are independently selected from a group comprising halogen; R is selected from a group comprising lower alkoxy, piperidinyl substituted with a five-member heterocyclic ring which contains one nitrogen heteroatom, piperidinyl substituted with a hydroxy, -CH2OH or -C(O)NH2, piperazinyl substituted with one or two R1 [1,4]diazepanyl, substituted R1, R1 can denote one or two substitutes selected from a group comprising oxo, lower alkyl substituted with one R2, -C(O)R3, -SO2-lower alkyl, -SO2-five-memer heterocyclyl, which is selected from isoxazolyl, dimethylisoxazolyl, pyrrolidinyl, pyrrolyl, thiophenyl, imidazolyl, thiazolyl, thiazolidinyl, imidazolidinyl; R2 is selected from a group comprising -SO2-lower alkyl, hydroxy, lower alkoxy, -NH-SO2-lower alkyl, -cyano, -C(O)R4; R3 is selected from a group comprising a five-member heterocyclyl which is selected from isoxazolyl, dimethylisoxazolyl, pyrrolidinyl, pyrrolyl, thiophenyl, imidazolyl, thiazolyl, thiazolidinyl, imidazolidinyl, lower alkyl, lower alkenyl, lower alkyl substituted with a six-member heterocyclyl selected from piperidinyl, piperazinyl, 3-oxopiperazinyl, morpholinyl, C3-cycloalkyl; R4 is selected from a group comprising hydroxy, morpholine, piperidine, 4-acetylpiperazinyl, -NR5R6; R5 and R6 are independently selected from a group comprising hydrogen, lower alkyl, lower alkyl substituted with lower alkoxy or cyano, lower alkoxy and C3-cycloalkyl. The invention also relates to a pharmaceutical composition based on the formula I compound, use of the formula I compound in preparing a medicinal agent and a method for synthesis of the formula I compound.

EFFECT: novel derivatives of cis-2,4,5-triarylimidazoline of general formula I are obtained, which can be used to treat diseases, based on reaction of the MDM2 protein with p53-like protein, particularly as anticancer agent.

54 cl, 412 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I), where R1 denotes a 5- or 6-member ring of formulae

(II) or (III), respectively: R2 denotes H, C1-C7-alkyl, C3-C6-cycloalkyl or -(CH2)m,-Ra; R3 denotes aryl or heteroaryl, which can be substituted with CN, Cl, F, Br, CF3, CHF2, C3-C6-cycloalkyl or denotes heteroaryl which can be possibly substituted with C1-C7-alkyl; R4 denotes H, -OH, Cl, F, Br, CN, -CHF2, CF3, C1-C7-alkyl, C3-C6-cycloalkyl or -(CH2)m-Re; R5 denotes C1-C7-alkyl, -(CH2)n-O-Rf, or -(CH2)n-Re; Ra denotes -OH; Re denotes -OH; Rf denotes C1-C7-alkyl; m equals 1-4; n equals 2-6; and pharmaceutically acceptable salts thereof. The invention also relates to a medicinal agent containing said derivatives, use thereof in preparing medicinal agents suitable for treating diseases of the central nervous system.

EFFECT: novel compounds suitable for treating diseases of the central nervous system are obtained and described.

29 cl, 111 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel antibacterial compounds of formula (I). Compounds of formula (I) Q-NH-CO-R3, where Q stands for group of the following structure , R1 represents hydrogen, halogen, hydroxy, amino, mercapto, alkyl, heteroalkyl, alkeloxy, heteroalkyloxy, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, cycloalkyloxy, alkylcycloalkyloxy, heterocycloalkyloxy or heteroalkylcycloalkyloxy, X1, X2, X3, X4, X5 and X6 each independently on each other represent nitrogen atom or group of formula CR2, R2 represents hydrogen, halogen or hydroxy, amino, alkyl, alkenyl, alkinyl or heteroalkyl group, R3 is selected from the following groups R5 represents group of formula -B-Y, where B represents alkylene, alkenylene, alkinylene, -NH- or heteroalkylene, and Y represents aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl or heteroalkylcycloalkyl, or their pharmaceutically acceptable salt, solvate, hydrate or pharmaceutically acceptable composition, as well as to pharmaceutical composition, which possesses antibacterial activity, based on said compounds and to their application for preparation of medication, intended for treatment of bacterial infections.

EFFECT: obtained and described are compounds, which can be useful in medicine.

9 cl, 147 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of genera formula (1) (where A denotes an oxygen or sulphur atom, -CH2- or -NH- group; R1 denotes C1-6alkyl group, possibly substituted ; R1A denotes a hydrogen atom or a C1-6 alkyl group; or these two radicals together with a carbon atom to which they are bonded form a cyclic C3-6 alkyl group; R2 denotes a C1-6 alkyl group or a C3-6 cycloalkyl group; R3 denotes an aryl group or a heteroaryl group, which can be substituted; R4 denotes a hydrogen atom; R5 denotes C1-6 alkyl group, aryl or heteroaryl group, which can be substituted), a pharmaceutical composition containing said derivatives and intermediate compounds. Said compounds (1) can inhibit bonding between SIP and its receptor Edg-1 (SIP1).

EFFECT: possibility of use in medicine.

18 cl, 2 tbl, 28 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to new compounds of formula (1) or its pharmaceutically acceptable salts, with properties of antagonist CXCR2 of human neutrophils receptor. In formula (1) R1 represents a group selected from C1-8alkyl; where this group is possibly substituted with 1 substituent, independently selected from phenyl or 5-6-unit heteroaryl, containing 1-2 heteroatoms selected from N, S; where phenyl and heteroaryl are possibly substituted by 1, 2 or 3 substitutors, independently selected from halogeno, cyano, -OR4, -COOR7, -SO2R10, C1-6alkyl; X represents -CH2-, oxygen, sulfur; R2 represents C3-7carbocyclil, possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4; or R2 represents 5-unit ring, containing 2 heteroatoms, selected from O, -NR8, and where this ring is possibly substituted with 1 substituent, independently selected from C1-3alkyl; or R2 represents group, selected from C1-8alkyla, where this group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-C1-6alkylcarbamoyl, N,N-di(C1-6alkyl)carbamoyl, carboxy, -NR8COR9 and -CONR5R6; R3 represents group -NR5R6, or R3 represents phenyl, possibly condensed with 6-unit heterocyclil, containing nitrogen, naphthyl, 4-8-unit monocyclic heterocyclil, containing 1-3 heteroatoms, selected from N, O, S, possibly condensed with benzole ring or 3-unit nitrogen-containing ring, where heteroring may be non-saturated, partially or fully saturated, and one or more than one circular atom of carbon may form carbonyl group, and where each phenyl or heterocyclil group is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, phenyl, 5-6-unit heteroaryl, containing 1-2 atoms of nitrogen, -OR4, -NR5R6, -CONR5R6, -COR7, -COR20, -COOR7, -NR8COR9, -SO2R10, -SO2NR5R6 or C1-6alkyl [possibly additionally substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR20, -COOR20, -NR18R19, -CONR18R19, phenyl or 5-6-unit of monocyclic heteroaryl, containing 1-2 heteroatoms O, N, S, or 10-unit bicyclic heteroaryl, containing 1 heteroatom O, where heteroring may be partially or fully saturated, and where each phenyl or heteroaryl is group possibly substituted with 1 or 2 substituents, independently selected from halogeno, cyano, nitro, -OR20, -NR5R6, -COOR7, -NR8COR9, 6-unit heterocyclil, containing two heteroatoms, selected from O and N, 5-unit heteroaryl, containing 3 heteroatoms N, C1-6alkyl (possibly additionally substituted with 1 substituent, independently selected from halogeno, cyano, nitro, -OR20, -COOR20; or R3 represents group, selected from C3-7carbocyclil, C1-8alkyl, where this group is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6; R4 represents hydrogen; R5 and R6 independently represent hydrogen or group, selected from C1-6alkyl and monocyclic 6-unit saturated heterocyclil containing 1 heteroatom N; where C1-6alkyl is possibly substituted with 1 substituent, independently selected from -NR15R16; or R5 and R6 together with atom of nitrogen, to which they are linked, form 4-7-unit saturated heterocyclic circukar system, possibly containing additional heteroatom, selected from oxygen, -SO(n)- (where n equals 0, 1 or 2) and atoms of nitrogen; R10 represents hydrogen or group, selected from C1-6alkyl; and each of R7, R8, R9, R15, R16, R17 independently represents hydrogen, C1-6alkyl; R18, R19 and R20 represent hydrogen or group, selected from C1-6alkyl, where this group is possibly substituted with 1 substituent, independently selected from -NR8R9, -CONR8R9.

EFFECT: production of new compounds, which may find application in production of medicinal agent for use in treatment of diseases and disorders mediated with chemokines, such as asthma, allergic rhinitis, chronic obstructive pulmonary disease, inflammatory intestine disease, irritable colon syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis or psoriasis, and also for treatment of cancer.

12 cl, 155 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I: or its pharmaceutically acceptable salt or stereoisomer, where a is independently equal to 0 or 1; b is independently equal to 0 or 1; R1 is selected from aryl, heterocyclyl and NR10R11; said aryl or heterocyclyl group is optionally substituted with between one and five substitutes, each independently selected from R8; R5 is selected from C1-6alkyl, C2-6alkenyl, -C(=O)NR10R11, NHS(O)2NR10R11 and NR10R11, each alkyl, alkenyl or aryl is optionally substituted with between one and five substitutes, each independently selected from R8; R8 independently denotes (C=O)aObC1-C10alkyl, (C=O)aObaryl, (C=O)aObheterocyclyl, OH, Oa(C=O)bNR10R11 or (C=O)aCbC3-C8cycloalkyl, said alkyl, aryl, heterocyclyl are optionally substituted with one, two or three substitutes selected from R9; R9 is independently selected from (C=O)aCb(C1-C10)alkyl and N(Rb)2; R10 and R11 is independently selected from H, (C=O)Cb(C1-C10)alkyl, C1-C10alkyl, SO2Ra, said alkyl is optionally substituted with one, two or three substitutes selected from R8 or R10 and R11 can be taken together with nitrogen to which they are bonded with formation of a monocyclic heterocycle with 5 members in each ring and optionally contains one or two heteroatoms, in addition to the nitrogen, selected from N and S, said monocyclic heterocycle is optionally substituted with one, two or three substitutes selected from R9; Ra is independently selected from (C1-C6)alkyl, (C2-C6)alkenyl; and Rb is independently selected from H, (C1-C6)alkyd, as well as to a pharmaceutical composition for inhibiting receptor tyrosine kinase MET based on this compound, as well as a method of using said compound to produce a drug.

EFFECT: novel compounds which can be used to treat cell proliferative diseases, disorders associated with MET activity and for inhibiting receptor tyrosine kinase MET are obtained and described.

8 cl, 32 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds with common formulae I, II, IV and V: (I), (III), (IV), (V), values of radicals, such as provided in invention formula. Besides, proposed invention relates to pharmaceutical composition on the basis of above-described compounds, to their application, and also to method for treatment of repeated urination, incontinence and higher activity of urinary bladder, besides, to method to treat pain.

EFFECT: new compounds have been produced and described, which may be useful for treatment of diseases related to fatty-acid amide-hydrolase (FAAH), in particular to treat repeated urination and incontinence, higher activity of bladder and/or pain.

16 cl, 442 ex, 73 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds with common formulae I, II, IV and V: (I), (III), (IV), (V), values of radicals, such as provided in invention formula. Besides, proposed invention relates to pharmaceutical composition on the basis of above-described compounds, to their application, and also to method for treatment of repeated urination, incontinence and higher activity of urinary bladder, besides, to method to treat pain.

EFFECT: new compounds have been produced and described, which may be useful for treatment of diseases related to fatty-acid amide-hydrolase (FAAH), in particular to treat repeated urination and incontinence, higher activity of bladder and/or pain.

16 cl, 442 ex, 73 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrazine-2-carboxamide derivatives of general

formula , where R1 denote a 5- or 6-member ring, having a formula given in claim 1, R2 denotes H or C1-C7-alkyl; R3 denotes phenyl, pyridinyl or pyrimidinyl, possibly substituted with the following substitutes: Cl, F or Br; R4 denotes H, CI, F, Br, CF3 or C1-C7-alkyl; R5 denotes C1-C7-alkyl; as well as pharmaceutically acceptable salts thereof. Disclosed compounds are metabotropic glutamate receptor (mGLUR 5) antagonists. The invention also pertains to a medicinal agent based on disclosed compounds.

EFFECT: improved method.

17 cl, 23 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula I and to its pharmaceutically acceptable salts. In formula I , R1 means hydrogen or ; is specified from phenyl, and a 5-member heteroaromatic ring containing 1 to 2 heteroatoms specified inhe group consisting of sulphur and nitrogen; X is specified from lower alkylene, cyclisated lower alkylene containing 3 to 6 carbon atoms, and hydroxy(lower alkylene); R5 and R6 are independently specified in the group including hydrogen, lower alkyl, halogen and lower alkoxygroup; R3 is specified from hydrogen and -NH-R7; R4 is specified from hydrogen and -O(CH2CH2O)y-R10; R7 means lower alkyl; R10 means lower alkyl; n means an integer within 0 to 1; and y is equal to 0; provided when n is equal to 0, and R1 means hydrogen, then R3/R4 both cannot mean hydrogen. The invention also concerns a pharmaceutical composition containing a therapeutically effective amount of the compound under the invention.

EFFECT: preparation of the new compounds which show CDK1 kinase inhibiting activity and can be effective in cancer treatment, particularly breast cancer, lung cancer, colon cancer and prostate cancer treatment.

45 cl, 21 ex

Organic compounds // 2411239

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I, in which R1 denotes alkyl or cycloalkyl; R2 denotes phenyl-C1-C7-alkyl, di-(phenyl)- C1-C7-alkyl, naphthyl- C1-C7-alkyl, phenyl, naphthyl, pyridyl-C1-C7-alkyl, indolyl- C1-C7-alkyl, 1H-indazolyl- C1-C7-alkyl, quinolyl C1-C7-alkyl, isoquinolyl- C1-C7-alkyl, 1,2,3,4-tetrahydro-1,4-benzoxazinyl- C1-C7-alkyl, 2H-1,4-benzoxazin-3(4H)-onyl-C1-C7-alkyl, 9-xanthenyl-C1-C7-alkyl, 1-benzothiophenyl-C1-C7-alkyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 9-xanthenyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl, where each phenyl, naphthyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl are unsubstituted or contain one or up to 3 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy-C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkoxy-C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkanoyloxy- C1-C7-alkyl, amino- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkylamino- C1-C7-alkyl, C1-C7-alkanoylamino- C1-C7-alkyl, C1-C7-alkylsulphonylamino- C1-C7-alkyl, carboxy- C1-C7-alkyl, C1-C7-alkoxycarbonyl- C1-C7-alkyl, halogen, hydroxy group, C1-C7-alkoxy group, C1-C7-alkoxy- C1-C7-alkoxy group, amino- C1-C7-alkoxy group, N-C1-C7-alkanoylamino-C1-C7-alkoxy group, carbamoyl- C1-C7-alkoxy group, N-C1-C7-alkylcarbamoyl-C1-C7-alkoxy group, C1-C7-alkanoyl, C1-C7-alkoxy-C1-C7-alkanoyl, C1-C7-alkoxy- C1-C7-alkanoyl, carboxyl, carbamoyl and N-C1-C7-alkoxy-C1-C7-alkylcarbamoyl; W denotes a fragment selected from residues of formulae IA, IB and IC, where () indicates the position in which the fragment W is bonded to the carbon atom in position 4 of the piperidine ring in formula I, and where X1, X2, X3, X4 and X5 are independently selected from a group containing carbon and oxygen, where X4 in formula IB and X1 in formula IC can assume one of these values or can be additionally selected from a group comprising S and O, where carbon and nitrogen ring atoms can include a number of hydrogen atoms or substitutes R3 or R4 if contained, taking into account limitations given below, required to bring the number of bonds of the carbon ring atom to 4 and 3 for the nitrogen ring atom; provided that in formula IA at least 2, preferably at least 3 of the atoms X1-X5 denote carbon and in formulae IB and IC at least one of X1-X4 denotes carbon, preferably 2 of the atoms X1-X4 denote carbon; y equals 0 or 1; z equals 0 or 1; R3, which can be bonded with any of the atoms X1, X2, X3 and X4, denotes hydrogen or a C1-C7-alkyloxy-C1-C7-alkyloxy group, phenyloxy-C1-C7-alkyl, phenyl, pyridinyl, phenyl- C1-C7-alkoxy group, phenyloxy group, phenyloxy-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, tetrahydropyranyloxy group, 2H,3H-1,4-benzodioxynyl-C1-C7-alkoxy group, phenylaminocarbonyl or phenylcarbonylamino group, where each phenyl or pyridyl is unsubstituted or contains one or up to 3 substitutes, preferably 1 or 2 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy group, C1-C7-alkoxy group, phenyl-C1-C7-alkoxy group, where phenyl is unsubstituted or substituted with a C1-C7-alkoxy group and/or halogen; carboxy- C1-C7-alkyloxy group, N-mono- or N,N-di-(C1-C7-alkyl)aminocarbonyl-C1-C7-alkyloxy group, halogen, amino group, N-mono- or N,N-di-(C1-C7-alkyl)amino group, C1-C7-alkanoylamino group, morpholino-C1-C7-alkoxy group, thiomorpholino-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, pyrazolyl, 4- C1-C7-alkylpiperidin-1-yl, tetrazolyl, carboxyl, N-mono- or N,N-di-(C1-C7-alkylamino)carbonyl or cyano group; or denotes 2-oxo-3-phenyltetrahydropyrazolidin-1-yl, oxetidin-3-yl-C1-C7-alkyloxy group, 3-C1-C7-alkyloxetidin-3-yl- C1-C7-alkyloxy group or 2-oxotetrahydrofuran-4-yl- C1-C7-alkyloxy group; provided that if R3 denotes hydrogen, then y and z are equal to 0; R4, if contained, denotes a hydroxy group, halogen or C1-C7-alkoxy group; T denotes carbonyl; and R11 denotes hydrogen, or pharmaceutically acceptable salts thereof. The invention also relates to use of formula I compounds, a pharmaceutical composition, as well as a method of treating diseases.

EFFECT: obtaining novel biologically active compounds having activity towards rennin.

11 cl, 338 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of genera formula (1) (where A denotes an oxygen or sulphur atom, -CH2- or -NH- group; R1 denotes C1-6alkyl group, possibly substituted ; R1A denotes a hydrogen atom or a C1-6 alkyl group; or these two radicals together with a carbon atom to which they are bonded form a cyclic C3-6 alkyl group; R2 denotes a C1-6 alkyl group or a C3-6 cycloalkyl group; R3 denotes an aryl group or a heteroaryl group, which can be substituted; R4 denotes a hydrogen atom; R5 denotes C1-6 alkyl group, aryl or heteroaryl group, which can be substituted), a pharmaceutical composition containing said derivatives and intermediate compounds. Said compounds (1) can inhibit bonding between SIP and its receptor Edg-1 (SIP1).

EFFECT: possibility of use in medicine.

18 cl, 2 tbl, 28 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: tricyclic compounds of formula I: $ substituted with heterocycle are disclosed, or pharmaceutically acceptable salt or solvate of specified compound, isomer or racemic mixture, where stands for optional double link, dotted line stands for link or does not stand for link, which results in double or single link according to requirements of valency and where A, B, G, M, X, J, n, Het, R3, R10, R11, R32 and R33 and other substituents are such as indicated in formula of invention. Invention also relates to pharmaceutical compositions, which contain them, method of thrombin receptor or cannabinoid receptor inhibition, and to method for treatment of disease related to thrombosis, atherosclerosis, restenosis, hypertension, stenocardia, arrhythmia, cardiac failure and cancer by administration of specified compounds.

EFFECT: production of compounds having properties of antagonists of thrombin receptors.

33 cl, 6 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula I and its pharmaceutically acceptable salts. In formula (I) , R stands for 6-unit ring, containing one ore two heteroatoms of nitrogen, and substituted with group selected from the following groups: (lower)alkyl, -C(O)-R1, (lower)alkyl, substituted with group -SO2-(lower)alkyl, (lower)alkyl, substituted with group -C(O)-R1, -SO2-(lower)alkyl, or 5-unit saturated ring, containing one heteroatom of nitrogen, R1 is selected from group, including (lower)alkyl, -N((lower)alkyl)2, or R1 stands for 6-unit saturated ring, containing two heteroatoms, selected from N and O, X1 and X2 are independently selected from group, including hydrogen, (lower)alkoxy, each Y1 and Y2 are independently selected from group, including -Cl and -Br, and absolute stoichiometric configuration in position 4 and 5 imidazoline ring includes S and R configuration, accordingly. Invention also relates to pharmaceutical composition, having inhibiting activity regarding interaction of MDM2 - p-53, containing efficient amount of invention compound.

EFFECT: production of compounds, having inhibiting activity as regards interaction of MDM2-p-53.

12 cl, 17 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to new compounds of formula (1) or its pharmaceutically acceptable salts, with properties of antagonist CXCR2 of human neutrophils receptor. In formula (1) R1 represents a group selected from C1-8alkyl; where this group is possibly substituted with 1 substituent, independently selected from phenyl or 5-6-unit heteroaryl, containing 1-2 heteroatoms selected from N, S; where phenyl and heteroaryl are possibly substituted by 1, 2 or 3 substitutors, independently selected from halogeno, cyano, -OR4, -COOR7, -SO2R10, C1-6alkyl; X represents -CH2-, oxygen, sulfur; R2 represents C3-7carbocyclil, possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4; or R2 represents 5-unit ring, containing 2 heteroatoms, selected from O, -NR8, and where this ring is possibly substituted with 1 substituent, independently selected from C1-3alkyl; or R2 represents group, selected from C1-8alkyla, where this group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-C1-6alkylcarbamoyl, N,N-di(C1-6alkyl)carbamoyl, carboxy, -NR8COR9 and -CONR5R6; R3 represents group -NR5R6, or R3 represents phenyl, possibly condensed with 6-unit heterocyclil, containing nitrogen, naphthyl, 4-8-unit monocyclic heterocyclil, containing 1-3 heteroatoms, selected from N, O, S, possibly condensed with benzole ring or 3-unit nitrogen-containing ring, where heteroring may be non-saturated, partially or fully saturated, and one or more than one circular atom of carbon may form carbonyl group, and where each phenyl or heterocyclil group is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, phenyl, 5-6-unit heteroaryl, containing 1-2 atoms of nitrogen, -OR4, -NR5R6, -CONR5R6, -COR7, -COR20, -COOR7, -NR8COR9, -SO2R10, -SO2NR5R6 or C1-6alkyl [possibly additionally substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR20, -COOR20, -NR18R19, -CONR18R19, phenyl or 5-6-unit of monocyclic heteroaryl, containing 1-2 heteroatoms O, N, S, or 10-unit bicyclic heteroaryl, containing 1 heteroatom O, where heteroring may be partially or fully saturated, and where each phenyl or heteroaryl is group possibly substituted with 1 or 2 substituents, independently selected from halogeno, cyano, nitro, -OR20, -NR5R6, -COOR7, -NR8COR9, 6-unit heterocyclil, containing two heteroatoms, selected from O and N, 5-unit heteroaryl, containing 3 heteroatoms N, C1-6alkyl (possibly additionally substituted with 1 substituent, independently selected from halogeno, cyano, nitro, -OR20, -COOR20; or R3 represents group, selected from C3-7carbocyclil, C1-8alkyl, where this group is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6; R4 represents hydrogen; R5 and R6 independently represent hydrogen or group, selected from C1-6alkyl and monocyclic 6-unit saturated heterocyclil containing 1 heteroatom N; where C1-6alkyl is possibly substituted with 1 substituent, independently selected from -NR15R16; or R5 and R6 together with atom of nitrogen, to which they are linked, form 4-7-unit saturated heterocyclic circukar system, possibly containing additional heteroatom, selected from oxygen, -SO(n)- (where n equals 0, 1 or 2) and atoms of nitrogen; R10 represents hydrogen or group, selected from C1-6alkyl; and each of R7, R8, R9, R15, R16, R17 independently represents hydrogen, C1-6alkyl; R18, R19 and R20 represent hydrogen or group, selected from C1-6alkyl, where this group is possibly substituted with 1 substituent, independently selected from -NR8R9, -CONR8R9.

EFFECT: production of new compounds, which may find application in production of medicinal agent for use in treatment of diseases and disorders mediated with chemokines, such as asthma, allergic rhinitis, chronic obstructive pulmonary disease, inflammatory intestine disease, irritable colon syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis or psoriasis, and also for treatment of cancer.

12 cl, 155 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds with common formulae I, II, IV and V: (I), (III), (IV), (V), values of radicals, such as provided in invention formula. Besides, proposed invention relates to pharmaceutical composition on the basis of above-described compounds, to their application, and also to method for treatment of repeated urination, incontinence and higher activity of urinary bladder, besides, to method to treat pain.

EFFECT: new compounds have been produced and described, which may be useful for treatment of diseases related to fatty-acid amide-hydrolase (FAAH), in particular to treat repeated urination and incontinence, higher activity of bladder and/or pain.

16 cl, 442 ex, 73 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds with common formulae I, II, IV and V: (I), (III), (IV), (V), values of radicals, such as provided in invention formula. Besides, proposed invention relates to pharmaceutical composition on the basis of above-described compounds, to their application, and also to method for treatment of repeated urination, incontinence and higher activity of urinary bladder, besides, to method to treat pain.

EFFECT: new compounds have been produced and described, which may be useful for treatment of diseases related to fatty-acid amide-hydrolase (FAAH), in particular to treat repeated urination and incontinence, higher activity of bladder and/or pain.

16 cl, 442 ex, 73 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-cyclopropyl-1 -{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate of formula:

. The invention also relates to salts and solvates of the said compound, a method of producing said compound, a pharmaceutical agent having angiotensin II antagonist activity, based on said compound.

EFFECT: compound can be used in medicine to prevent and treat blood circulatory system diseases.

18 cl, 1 dwg, 8 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: in compounds of formula:

, A and B denote a pair of condensed saturated or unsaturated 5- or 6-member rings, where the said system of condensed rings A/B contains 0-2 nitrogen atoms, and said rings are further substituted with 0-4 substitutes independently selected from halogen, lower alkyl or oxo; and a and b are bonding positions for residues Y and D, respectively, and these positions a and b are in the peri-position relative each other on the said condensed ring system A/B; d and e are condensed positions between ring A and ring B in the said condensed ring system A/B; D is an aryl or heteroaryl cyclic system which denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S; which can be further substituted with 0-4 substitutes independently selected from lower alkyl and amine; Y is selected from -CH2 and -O-; M is selected from aryl, aryl substituted with a halogen or alkoxy; R1 is selected from aryl, aryl substituted with a halogen, heteroaryl, heteroaryl substituted with a halogen, where heteraryl denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S, and CF3; and if Y denotes -CH2- or -O-, then R1 further denotes a lower alkyl. The invention also pertains to use of compounds in claim 1, a pharmaceutical composition, a screening method on selective ligands of prostanoid receptors, as well as compounds of the formula.

EFFECT: obtaining novel biologically active compounds for inhibiting binding of prostanoid E2 with EP3 receptor.

25 cl, 46 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.

EFFECT: preparation of the new anti-HIV antiviral compounds.

4 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of genera formula (1) (where A denotes an oxygen or sulphur atom, -CH2- or -NH- group; R1 denotes C1-6alkyl group, possibly substituted ; R1A denotes a hydrogen atom or a C1-6 alkyl group; or these two radicals together with a carbon atom to which they are bonded form a cyclic C3-6 alkyl group; R2 denotes a C1-6 alkyl group or a C3-6 cycloalkyl group; R3 denotes an aryl group or a heteroaryl group, which can be substituted; R4 denotes a hydrogen atom; R5 denotes C1-6 alkyl group, aryl or heteroaryl group, which can be substituted), a pharmaceutical composition containing said derivatives and intermediate compounds. Said compounds (1) can inhibit bonding between SIP and its receptor Edg-1 (SIP1).

EFFECT: possibility of use in medicine.

18 cl, 2 tbl, 28 ex

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