UA73579C2 - 2-aminocarbonyl-9n-purine derivatives - Google Patents

Abstract

The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such compounds.

Description

Description of the invention

This invention relates to purine derivatives. More specifically, the present invention relates to derivatives of 2 2-aminocarbonyl-UN-purine and to methods of their preparation, to intermediate compounds used in their preparation, to compositions containing them and to the use of such derivatives.

Such derivatives are selective functional agonists of the Aga adenosine receptor in humans and can be used as anti-inflammatory agents in the treatment, in addition, of diseases of the respiratory tract.

Adenosine is a ubiquitous molecule that plays a central role in the intermediate metabolism of 70 mammals. Regardless, adenosine acts on many surface receptors, providing a large number of reactions in response. Adenosine receptor classification revealed the presence of at least four subtypes: A1, Aga,

A2b and AZ. It has been reported that stimulation of A2 adenphin receptors on the surface of human neutrophil leukocytes effectively inhibits a number of neutrophil functions. Activated neutrophils can damage lung tissue by releasing reactive oxygen species, such as superoxide anion radicals (O5), 19 and granular products, such as human neutrophil elastase (HME), along with other inflammatory mediators. In addition, activated neutrophils carry out both synthesis and release of arachidonate products, such as leukotriene VA (I TV). And TV. is an effective chemoattractant that attracts additional neutrophils to the center of inflammation, since the released O»5 and NME adversely affect the pulmonary intercellular matrix. A2 subtype of the receptor, which mediates many similar reactions in response (05 20 I. TV//NME release and cell adhesion) is established as Aga. The A2 subtype (Aha or A2B), which mediates other types of action, is still being established.

Selective A2 receptor agonist activity is considered to offer a significant therapeutic advantage over non-selective adenosine receptor agonists, as interactions with other subtypes are associated with adverse effects in the lung, as shown in animal models 29 and in human tissue studies. For example, in asthmatics, but not in non-asthmatics, narrowing of the bronchi is observed when adenosine is injected into the body for the production of antibodies in the form of inhalation. Such a reaction in response is at least partially associated with the activation of At! receptor subtype. Activation of AT receptors also promotes neutrophil chemotaxis and adhesion to endothelial cells, thus promoting lung injury. In addition, many patients with respiratory tract diseases are prescribed p o-agonists, and about 30 animal models have demonstrated a negative interaction between isoprenaline and adenosine receptors, which are negatively associated with adenylate cyclase. Degranulation of human mast cells is promoted by activation of A2p adenosine receptors, thus, selectivity in relation to A2B5 receptor is also favorable. at

The authors of this invention unexpectedly found that these purine derivatives inhibit the function of neutrophils and are selective agonists of the Aga adenosine receptor. They can also have antagonistic activity in relation to AZ adenosine receptor. These compounds can also be used to treat any disease that requires an Aga receptor agonist. they can be used to treat a disease that involves leukocyte (eg, neutrophil, eosinophil, basophil, lymphocyte, macrophage)-induced tissue damage. they can be used as anti-inflammatory agents in the treatment of diseases of the respiratory tract, such as respiratory failure syndrome in adults (AKO5), bronchitis, C 50 chronic bronchitis, chronic obstructive pulmonary disease, fibrocystic degeneration, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis These compounds can also be used in the treatment of septic

From" shock, male erectile dysfunction, male infertility factor, female infertility factor, hypertension (high blood pressure), stroke, epilepsy, cerebral ischemia, peripheral vascular disease, postischemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, 45 psoriasis , dermatitis, allergic dermatitis, eczema, ulcerative colitis, Crohn's disease, inflammatory bowel disease, gastritis caused by Neiyobasieg ruyogi, gastritis caused by non-Neiyobasieg co-ruyogi, damage to the gastrointestinal tract or psychotic disease caused by non-steroidal anti-inflammatory drugs, or for wound healing. Accordingly, in the first embodiment, this invention relates to a compound of the formula: - 50 vy () 3e) zvi: 55 y io "M ve shk o tu ko "-; oi 60 Ov or its pharmaceutically acceptable salt or solvate, where

B' represents H, C 4-Cb alkyl or fluorenyl, the specified C-C alkyl is optionally substituted with 1-2 substituents, each of which is independently selected from phenyl and naphthyl, the specified phenyl and naphthyl are optionally substituted C.4-Ce alkyl, C--Ce alkoxy, halogen or cyano;

(A) B? is H or C 4-Cb alkyl, BK" is H or C 4-Cb alkyl, and X is either (i) an unbranched Co-C3 alkylene, optionally substituted with C.4-Ce alkyl or C5- Ca cycloalkyl, or (ii) a group of the formula: "СНУ (СНа)р- where MU is C 5-C7, cycloalkylene, optionally substituted by C .-Ce alkyl, n equals 0 or 1, and p equals 0 or 1 , or (B) "C is H or C 1 -C 1 alkyl, and B 2 and X, taken together with the nitrogen atom to which they are attached, represent azetidin-C-yl, pyrrolidine-C-yl, piperidine-C- yl, piperidin-4-yl, homopiperidin-3-yl or 70 homopiperidin-4-yl, each of which is optionally substituted C.4-C6 alkyl, or (C) B? is H or C 4-Cb alkyl, and "Z and X, taken together with the nitrogen atom to which they are attached, represent azetidin-Z-yl, pyrrolidine-Z-yl, piperidin-Z-yl, piperidin-4- yl, homopiperidin-3-yl or homopiperidin-4-yl, each of which is optionally substituted C1-C6 alkyl; or B3 and B", taken together with the nitrogen atom to which they are attached, are azetidinyl, pyrrolidinyl, 72 piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl, each of which is optionally substituted on a ring nitrogen or carbon atom with C.4-Ce alkyl or C.3-C.cycloalkyl and optionally substituted on a ring carbon atom not adjacent to by a nitrogen atom, MEUV", or KZ represents H, C-C alkyl, C3-C cycloalkyl or benzyl, and KE" represents: (a) azetidin-3-yl, pyrrolidin-Z-yl, piperidin-Z- yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each of which is optionally substituted with C 4 -C 4 alkyl, C 3 -C 6 cycloalkyl, phenyl, benzyl or Ni, or (B) - (Co-Cv alkylene)-VKU, (c) -"C4-Cv alkyl n)-K C or сч (4) C4-Cv alkyl or Ca-Cv cycloalkyl;

IN? is CHNOH or COM "VU; o 25 V or each, independently, is H or C 4-Ce alkyl, or, taken together with the nitrogen atom to which they are attached, is azetidinyl, pyrrolidinyl or piperidinyl, the indicated azetidinyl, pyrrolidinyl or piperidinyl is optionally substituted by C.--Cv alkyl; Ge)

K is (i) azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homopiperazin-1-yl or tetrahydroisoquinolin- 1-yl, each of which is optionally substituted - on the ring carbon atom by C.-Cv alkyl, C3-Cv cycloalkyl, phenyl, C--Cv alkoxy-(C.4-Cv)-alkyl, Is) in M -(C1-Cv)-alkyl, fluoro-(C1-Cv)-alkyl, -SOMAUVU, "SOM? or Co-C alkanoyl, and optionally (hu substituted on the ring carbon atom not adjacent to the nitrogen atom, fluoro-(C.4-Cv)-alkoxy, halogen, -OVKU, cyano, -5(O)0B' 9, -MEUVU, 5ООМВОВ?, -МВОСОВБ'О or -МКЗ8028'О, and the specified piperazin-1-yl and -homopiperazin-1-yl are optionally substituted on the ring nitrogen atom not connected to C 5 -Cv alkylene group, C.4-Cv alkyl, phenyl, C4-Cv alkoxy-(Co-Cv)-alkyl, EUKUM-(Co-Cv)-alkyl, fluoro-(C.4-Cv)-alkyl,

C, -Cv alkanoyl, -СООВ У, C3-Cv cycloalkyl, -5028 9, -BO2MA UA? or -SOMAUV? or "(j) MV" va; - with B? represents H, C.4-Cv alkyl, C.3-Cv cycloalkyl or phenyl; "B"9 represents C.-Cv alkyl, C3-Cv cycloalkyl or phenyl;

B" represents H, C.4-Cv alkyl, C3-Cv cycloalkyl or benzyl;

В" is H, C 4-Cb alkyl, Ca-Cv cycloalkyl, phenyl, benzyl, fluoro-(C4-Cv)-alkyl, -SOMAEU, -SOOK U, -75 C, -Cv alkanoyl or -502MAVUV; o c" represents (a) phenyl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, each of which is optionally substituted C.4-Cv alkyl, C.--Cv alkoxy, - (C4-C3 alkylene)-(C--Cv alkoxy), halogen, cyano, -(C4-C33 os alkylene)-CM, СОН, -(C4-C3 alkylene)-СОоН, -СО5(C4-Cv alkyl) . "B"", or (B) azetidin-2-yl, azetidin-Z-yl, pyrrolidin-2-yl, pyrrolidin-Z-yl, piperidin-2-yl, piperidin-Z-yl, piperidin-4-yl .

B" represents H or C1-C8 alkyl optionally substituted by cyclopropyl; t is 0, 1 or 2; o U represents CO, C5, 505 or C-M(CM); and "Her" used in the definition of VK" and "Z, is a C-bonded, 4-6-membered ring, a heterocycle, where it has either 1-4 ring heteroatoms of nitrogen, or 1-2 ring heteroatoms of nitrogen and 1 ring heteroatom of oxygen or sulfur, optionally substituted with C o 4-Ce oalkyl, C5-Cv cycloalkyl, C.--Cv alkoxy, 60 C3-Cv cycloalkoxy, hydroxy, oxo or halogen.

In the second version of the embodiment, this invention relates to the compound of the formula:

Ov or a pharmaceutically acceptable salt or solvate thereof, where K' represents H, C 4-Cb alkyl or fluorenyl, the specified C-Cb alkyl is optionally substituted with 1-2 substituents, each of which is independently selected from phenyl and naphthyl, the indicated phenyl and naphthyl are optionally substituted by C.4-C6 alkyl, C--C6 alkoxy, halogen or cyano;

B2 is H or C 1 -Ce alkyl, or B3 and B, taken together with the nitrogen atom to which they are attached, are azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl, each of which is optionally substituted by ring nitrogen atom or carbon atom C.4-Ce alkyl or C3-Ce cycloalkyl and optionally substituted on the ring carbon atom not adjacent to the nitrogen atom, MAV group, or KZ is H, C.-Ce alkyl, C3- C 1 -cycloalkyl or benzyl, and KE" is: (a) azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each of which is optionally substituted C 4 -C 4 alkyl, C 3 -C 4 cycloalkyl, phenyl, Ha benzyl or Ni, or o (5) "(C 4 -C 4 alkylene)-CZ or (c) -"C 4 -C 4 alkylene )-K 73,

VE? is СНоОН or СОМ "В"Я; 25 Its B" or each, independently, represent H or C 1-C 1 alkyl, or, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl or piperidinyl, the specified azetidinyl, pyrrolidinyl h- or piperidinyl are necessarily substituted by C.-C. alkyl;

C represents () azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, o homopiperidin-1-yl, homopiperazin-1-yl or tetrahydroisoquinolin- 1-yl, each of which is optionally substituted He) on the ring carbon atom by C.-Cv alkyl, C3-Cv cycloalkyl, phenyl, C--Cv alkoxy-(C.4-Cv)-alkyl, chn vVOVOM -(C1-Cv)-alkylOm, fluoro-(C.4-Cv)-alkyl, -"SOMAUVU, -SOOB? or Co-C alkanoyl, and optionally substituted on the ring carbon atom not adjacent to the nitrogen atom, fluoro-(C.4-Cv)-alkoxy, halogen, -OKU, cyano, -5(O)pB'O, -MEOVU, -5802MeUVU, -MYASOV' or -MKO5028'O, and the indicated piperazin-1-yl: and "homopiperazin-1-yl" are optionally substituted on the ring nitrogen atom not bonded to C 5-Sv alkylene group, C4-Cv alkyl, phenyl, C4-Cv alkoxy-(Co-Cv)-alkyl, C"VUM-(Co-Cv)-alkyl, fluoro-(C4-Cv)-alkyl, t c C,- C alkanoyl, -SOOK "U, C3-C cycloalkyl, -8028 2, -BO2MA UR? or "SOMAUV?" or with" () mA" in;

VE? is H, C1-C8 alkyl, C3-C8 cycloalkyl or phenyl;

BO is C1-C8 alkyl, C1-C8 cycloalkyl or phenyl; -And B" represents H, C.4-Cv alkyl, C3-Cv cycloalkyl or benzyl; c B"? is H, C 4-Cb alkyl, Ca-Cv cycloalkyl, phenyl, benzyl, fluoro-(C4-Cv)-alkyl, -SOMAEU, -SOOK U,

C, -Sv alkanoyl or -502MAVUV;

Mn BZ is phenyl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, each of which is optionally -I 50 substituted C 1 -C 6 -alkyl, C 4 -C 6 alkoxy, halogen or cyano; c B" represents H or C-C alkyl, optionally substituted by cyclopropyl;

B "5 represents H or C-C-C alkyl; t is 0, 1 or 2;

X is an unbranched C 25-C3 alkylene, optionally substituted with C 4-C;e alkyl or C5-C8 cycloalkyl; (F; U represents CO, C5, 505 or C-M(CM); and ka "Her", used in the determination of KE", represents a C-bonded, 4-6-membered ring, heterocycle, which has either 1-4 ring heteroatoms of nitrogen, or 1-2 ring heteroatoms of nitrogen and 1 ring heteroatom of oxygen or sulfur, optionally substituted by C.-Ce alkyl, C.sub.3-C.sub.cycloalkyl, C.sub.3-Cv. , hydroxy, oxo or halogen.

In the above definitions, halogen means fluorine, chlorine, bromine or iodine, and alkyl, alkylene, alkanoyl and alkoxy groups containing the required number of carbon atoms, except as indicated, may be straight or branched. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutane, sec-butyl and tert-butyl. Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Examples of alkanoyl include acetyl and propanoyl. Examples of alkylene include methylene, 1,1-ethylene, 1,2-ethylene, 1,3-propylene and 1,2-propylene. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl (relevant examples also refer to cycloalkyl). Examples of cycloalkylene include cyclopentylene, cyclohexylene, and cycloheptylene. "Her" can be aromatic or partially or fully saturated, and "C-linked" means that it is attached to an adjacent group through a carbon atom. Examples of these include pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxydiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl.

Pharmaceutically acceptable salts of compounds of formula (I) include their additive salts of acids and bases. 70 Suitable acid addition salts are obtained from acids that form non-toxic salts, and examples are salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, hydrophosphate, acetate, maleate, malate, fumarate, lactate, tartrate, citrate , gluconate, succinate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate, adipate, and xinafoate (1-hydroxy-2-naphthoate).

Suitable base salts are obtained from bases which form non-toxic salts, and examples are sodium, potassium, aluminum, calcium, magnesium, zinc and diethanolamine salts.

For an overview of the corresponding salts, see Vegode ei a/., ).RNagt. zZsi., 66, 1-19, 1977.

Pharmaceutically acceptable solvates of the compounds of formula (I) and their salts include hydrates.

The volume of compounds of formula (I) and their salts also includes their polymorphs and derivatives labeled with a radioactive isotope.

The compound of formula (I) may contain one or more additional asymmetric carbon atoms and, therefore, exist in the form of two or more stereoisomeric forms. The present invention includes, along with their mixtures, individual stereoisomers of the compounds of formula (I) and, where appropriate, their individual tautomeric forms.

Separation of diastereoisomers can be carried out by conventional methods, for example, by means of fractional crystallization, chromatography or HPLC of a stereoisomeric mixture of a compound of formula (I) or its corresponding salt or derivative. The individual enantiomer of the compound of the formula (I) can also be obtained from the corresponding optically pure intermediate compound or by optical separation, for example, using HPLC of the corresponding racemate using a suitable chiral support or fractional crystallization of diastereoisomeric salts obtained i) by the interaction of the corresponding racemate with the corresponding optically active acid or base where appropriate.

Preferably, B is a C.1-C6 alkyl, optionally substituted with 1 or 2 phenyl substituents, the specified phenyl is optionally substituted by a C.--C6 alkyl or halogen. Gee!

Mostly, VE! represents C.1-C alkyl, optionally substituted with 1 or 2 phenyl substituents, the indicated phenyl is optionally substituted with methyl or chlorine. -

Mostly, KE! is C-C alkyl optionally substituted with 1 or 2 phenyl substituents. Yes)

Preferably, K' is a C 4-C alkyl substituted with 1 or 2 phenyl substituents, the indicated phenyl c is not necessarily substituted with methyl or chlorine.

Zo Mostly, KE! is C-C-C alkyl substituted with 1 or 2 phenyl substituents. -

Preferably, K' is a C 3-Cv alkyl substituted with 2 phenyl substituents, the specified phenyl is not necessarily substituted with methyl or chlorine.

Preferably, B" is a C 1-Cv alkyl substituted with 2 substituents, each of which is independently selected from "20 phenyl, 3-methylphenyl, and 3-chlorophenyl. Preferably, B is a C 1-Cv alkyl substituted 2 phenyl substituents. Preferably, EC is diphenylethyl, bis(3-methylphenyl)ethyl or bis(3-chlorophenyl)ethyl. Preferably, BE is diphenylethyl.

Preferably, B" is 2,2-diphenylethyl, 2,2-bis(3-methylphenyl)ethyl or 2,2-bis(3-chlorophenyl)ethyl.

Preferably, B" represents 2,2-diphenylethyl. and Preferably, B? represents H. (9) Preferably, B" represents H. sl Preferably, X represents 1,2-ethylene or 1,3-propylene.

Preferably, X is 1,2-ethylene. - and 20 Preferably, K represents H, K represents H, and X represents 1,2-ethylene, 1,3-propylene or a group of the formula: с "СНУ (ОНо2)р- where MU is Св-С7 cycloalkylene , n equals 0 or 1, and p equals 0 or 1.

Mostly, V? is H, B "" is H, and X is 1,2-ethylene, 1,3-propylene or a group of the formula: "SnadeM-(CHa)p- (F; where MU is C1-C7 cycloalkylene, n is 0, and p is 0. Preferably, B is H, B is H, and X is 1,2-ethylene, 1,3-propylene, or cyclohexylene. Preferably, K is H , BK "? represents H, and X represents 1,2-ethylene, 1,3-propylene or 1,4-cyclohexylene.

Mostly, B? represents H, B"? represents H, and X represents 1,2-ethylene, 1,3-propylene or trans-1,4-cyclohexylene.

Mostly, V? represents H, KK" represents H, and X represents 1,2-ethylene. because Preferably, "Z represents H, and K2 and X, taken together with the nitrogen atom to which they are bonded, represent

3-pyrrolidinyl or 3- or 4-piperidinyl, each of which is optionally substituted with C 1-6 alkyl.

Preferably, "C is H, and K2 and X, taken together with the nitrogen atom to which they are bonded, are

3-pyrrolidinyl or 4-piperidinyl, each of which is optionally substituted with C 1 -C 6 alkyl.

Preferably, "C is H, and K2 and X, taken together with the nitrogen atom to which they are bonded, are

C-pyrrolidinyl or 3- or 4-piperidinyl.

Preferably, B" is H, and BK 2 and X, taken together with the nitrogen atom to which they are bonded, are

C-pyrrolidinyl or 4-piperidinyl.

Preferably, C is H, and K2 and X, taken together with the nitrogen atom to which they are bonded, are 70. (ZBE)-pyrrolidinyl or 4-piperidinyl.

Preferably, 2 is H, and B"" and X, taken together with the nitrogen atom to which they are bonded, are

3-pyrrolidinyl or 3- or 4-piperidinyl, each of which is optionally substituted with C 1-6 alkyl.

Mostly, V? is H, and B "Z and X, taken together with the nitrogen atom to which they are bonded, are

3-pyrrolidinyl or 4-piperidinyl, each of which is optionally substituted with C 1 -C 6 alkyl. then Preferably, 2 represents H, and B"" and X, taken together with the nitrogen atom to which they are bound, represent

C-pyrrolidinyl or 3- or 4-piperidinyl.

Preferably, 2 is H, and B"" and X, taken together with the nitrogen atom to which they are bonded, are

C-pyrrolidinyl or 4-piperidinyl.

Preferably, 2 is H, and B"" and X, taken together with the nitrogen atom to which they are attached, are (ZK)-pyrrolidinyl, (35)-pyrrolidinyl or 4-piperidinyl.

Mostly, EZ is H.

Preferably, KB" is piperidin-3-yl or piperidin-4-yl, each of which is optionally substituted with benzyl or PE as defined above. c

Preferably, KE" represents piperidin-3-yl or piperidin-4-yl, each of which is optionally substituted by d) benzyl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, each of the specified pyridin-2-yl, pyridin-3-yl and pyridin-4-yl is optionally substituted with C 4-Ce alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, hydroxy, oxo or halogen.

Preferably, B" is piperidin-3-yl or piperidin-4-yl, each of which is substituted with benzyl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl.

Preferably, B" is piperidin-3-yl or piperidin-4-yl, each of which is substituted by benzyl.

Preferably, BE" is piperidin-3-yl or piperidin-4-yl, each of which is substituted with pyridin-2-yl.

Preferably, "BE" is piperidin-4-yl substituted with pyridin-2-yl. i)

Preferably, B" is 1-benzylpiperidin-4-yl. -

Preferably, B" is 1-(pyridin-2-yl)piperidin-4-yl.

Preferably, B" is -(Co-Cv alkylene)-K8.

Preferably, B" represents -SNoSNoVU. "

Preferably, КВ" represents -(C.4-Cv alkylene)-B 3. - then Preferably, K7 represents СНОВ З or -"СНоСНОВ 3. с Preferably, B" represents C3-Св cycloalkyl. Preferably, K is cyclohexyl.

Mostly, VE? is -СНоОН or -СОМН(C.4-Cv alkyl).

Mostly, VE? is -СНоОН or -СОМНСНоСН»а. - and mainly, KE? is "SOMNSN SN". c Preferably, LC is (i) azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homopiperazin-1-yl or tetrahydroisoquinolin-1-yl, each of which 1 is optionally substituted on the ring carbon atom with C 4-Ce alkyl, and the specified piperazin-1-yl and - 50 homopiperazin-1-yl are optionally substituted on the ring nitrogen atom , not connected to a C 5-C alkylene group, a C 1-C alkyl, or (ii) is ME" B, c Preferably, EZ is piperidin-1-yl or tetrahydroisoquinolin-1-yl, each of which is is necessarily substituted on the ring carbon atom by C.4-Cv alkyl.

Preferably, KZ is piperidin-1-yl, optionally substituted on the ring carbon atom with isopropyl.

GF) Preferably, BZ is piperidin-1-yl, 4-isopropylsheridin-1-yl or tetrahydroisoquinolin-1-yl. 7 Preferably, KZ is ME "B", where ME" is M(C 4-Cv alkyl)", M(C4-Cv alkylXia-Cv cycloalkyl) or M(C.4-Cv alkylbenzyl). , KZ represents ME 872, where ME"? is M,M-diisopropylamino, M,M-di-n-butylamino,

M-cyclopentyl-M-isopropylamino, M-cyclohexyl-M-isopropylamino or M-benzyl-M-isopropylamino.

Preferably, B"! is H or C-C6 alkyl.

Preferably, B"! is C4-C8 alkyl.

Preferably, KE"! represents isopropyl or n-butyl. b5 Preferably, K 2 represents H, C4-Cv alkyl, C3-Cv cycloalkyl or benzyl.

Preferably, B" is C4-Cv alkyl, Ca-Cv cycloalkyl or benzyl.

Mostly, V? is isopropyl, cyclopentane, cyclohexyl or benzyl.

Preferably, KZ is either phenyl, optionally substituted -(C 4-C3 alkylene)-ME "B"? or SON, or piperidin-2-yl, piperidin-3-yl, or piperidin-4-yl, each of which is optionally substituted with benzyl.

Preferably, KZ is phenyl, optionally substituted by -CH 0 oM(СНоСНа4» or СОН, or piperidin-4-yl, substituted by benzyl.

Preferably, B is phenyl, 4-(N,M-diethylamino)methylphenyl, 4-carboxyphenyl or 1-benzylpiperidin-4-yl. Preferably, K"" is H or C-Cb alkyl.

Preferably, K"" represents H or ethyl.

Preferably, U is CO.

Mostly, no. ze he represents

And oh oh ich-

IS)

Rg

J. "Conditions and their M y shi s z

Mr., -I (95) i-th -k

R: -I iChe) t

N ime) 60 re ro) , b5 lesson , rn ; roar

Y ur eotecyr n y y dit ry g . o t M F sny, y y n Fe | yes

S 5 ' - s rn z y ren (U ; - ! s - 50 s o 55 yuyu b5 y ha. av an

From eh a morgue oche and sch 7 i, oh that 30 .- is

And so she « and ke - I en NU z UT hu -I

GK) 5. - 50 s (F)

Po) because b5

I - m y aa ЧИ в na s (8) (22) " ich-

IS)

M. dv,

And so m.

In the above-mentioned preferred groups, "EGg" means ethyl, "Irg" means isopropyl, "y"Vy" means n-butyl, and "PA" means phenyl. Especially preferred variants of the compound of formula (I) are those which given below in the "Examples" section, "especially given in examples 8 and 34, together with their pharmaceutically acceptable salts and solvates.

Compounds of formula (I) may be prepared by conventional methods, such as using the following illustrative methods, in which EB", B2, KZ, 7, KE", "5, X and Y, unless otherwise indicated, are as defined above for the compound of formula (1). o The compound of the formula (I), where X represents CO, can be obtained by the interaction of the compound of the formula: 1 with ИИ и ней п -И те) b ! B ke -

Cr

60 () with a compound of the formula: in the usual form.

vZvamso 1 (PI) 1 . . K-4. . . where 7" represents a suitable leaving group such as chlorine or 1H-imidazol-1-yl.

In a typical method, the compounds are reacted together in a suitable solvent, such as toluene, isopropanol, or dichloromethane, or in any combination thereof, optionally under heating, for example, at the reflux temperature of the solvent.

Compounds of formula (II) can be prepared by conventional methods.

The compound of formula (II) can be obtained as shown in scheme 1. 70 Scheme of I and I with and ZU

An a g a

And And: | th " i

In N

"from VA

M et 7 i in ! « m n) s 25.

In not i) meaning

Tr - t g vod chen F i" is ih) t - ny " v sya (ze)

And "

Zo and h - - cm, b and ' «

Scheme 1 (continuation) - section GU and . "" "Ж dro-nn--ya nn "SHY ov - o s. - sv inii / s) (95) yaz 1 и - 50 iChe) y I o . tone z o

F) Mr

GF where B? is Co 4-C. alkyl, BK" is a suitable protecting group, such as tetrahydro-2H-pyran-2-yl, KZ is a suitable group that forms a complex ester, such as C1-Cb alkyl or bo benzyl, preferably C-C6 alkyl, and KB"? and C29 either each represent a suitable protecting group such as acetyl or benzoyl or, taken together, represent a suitable protecting group such as C 4 -C 10 alkylene optionally substituted with phenyl, for example 1,1-dimethylmethylene or phenylmethylene.

In a typical method, where B" is tetrahydro-2H-pyran-2-yl, the chloropurine of formula (IM) is M-protected by reaction with 3,4-dihydro-2n-pyran, which proceeds in the presence of an appropriate acid catalyst 65 , such as p-toluenesulfonic acid (PTSC), benzenesulfonic acid, camphorsulfonic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid or pyridinium p-toluenesulfonate, and in a suitable solvent such as ethyl acetate, toluene, dichloromethane, dimethylformamide (DMF), tert -butyl methyl ether, diisopropyl ether, tetrahydrofuran (THF) or acetonitrile, at a temperature from 02C to the boiling temperature of the solvent with a reflux condenser. Preferably, the reaction is carried out in ethyl acetate in the presence of PTSK during heating. Other suitable protective groups K"" are indicated in the specified in this description references to Sgeepe ei ai.

The obtained compound of the formula (M) can be converted into an amine of the formula (MI) by interaction with a compound of the formula: v'Mmn" (KHMI)

The compounds are reacted in the presence of a suitable acid acceptor such as triethylamine, 4-methylmorpholine or M-ethyldisopropylamine and in a suitable solvent such as methanol, ethanol or isopropanol at room temperature to the reflux temperature of the solvent. M-ethyldisopropylamine and isopropanol are preferably used under reflux conditions.

The amine of formula (MI) is then reacted with sodium or potassium thisalkoxide in an appropriate solvent such as dimethylsulfoxide (DMSO), DMF, or 1-methyl-2-pyrrolidinone at room temperature to the reflux temperature of the solvent. Preferably, sodium or potassium thiomethoxide in DMF at 100-260 is used as reaction conditions.

The resulting thioether of formula (MI) is then oxidized to the sulfone of formula (MI) using a suitable oxidizing agent such as Oxon (Ohope Trade Mark) (potassium peroxymonosulfate), dimethyldioxirane, m-chloroperbenzoic acid or peracetic acid, optionally in the presence of a suitable base , for example, sodium bicarbonate, and in a suitable solvent, such as aqueous acetone or dichloromethane, at temperatures from 8°C room temperature to 50°C. Oxon (Ohope - a trademark) and sodium bicarbonate in aqueous acetone at room temperature are preferably used.

A sulfone of formula (MI!) can be converted to a nitrile of formula (IX) by reaction with a suitable source of cyanide, such as potassium cyanide, zinc cyanide, sodium cyanide or copper cyanide, and in a suitable solvent such as DMSO, DMF, 1-methyl- 2-pyrrolidinone, THF or acetonitrile, at a temperature from room temperature F) to the boiling point of the solvent with a reflux condenser. Preferred conditions are potassium cyanide in DMF m at 12096.

Alternatively, a chloropurine of formula (MI) can be converted to a nitrile of formula (IX) using a suitable cyanide source, such as potassium cyanide, zinc cyanide, sodium cyanide or copper cyanide, in a suitable solvent, e.g. DMF, DMSO, 1 -methyl-2-pyrrolidinone, THF or acetonitrile, optionally in the presence of a suitable palladium catalyst, for example, tetrakis(triphenylphosphine)palladium(0) or y-palladium(P) acetate in combination with triphenylphosphine, tri-o-tolylphosphine, ( K)- or (5)- or racemic 2,2'-bis(diphenylphosphino)-1,1-binaphthyl or 1,1-bis(idiphenylphosphino)ferrocene, and optionally in the presence of a suitable base, for example triethylamine, 4 -methylmorpholine or M-ethyldiisopropylamine, at a temperature from room temperature to the boiling temperature of the solvent under reflux (optionally under pressure). Alternatively, the reaction can be carried out by reacting a chloropurine of formula (MT) with sodium or potassium cyanide in a suitable solvent, such as DMSO, 1-methyl-2-pyrrolidinone or DMF, at room temperature to the reflux temperature of the solvent. refrigerator Preferably, the interaction is carried out using zinc cyanide, triethylamine and tetrakis(triphenylphosphine)palladium(0) in DMF at 80-852C under elevated argon pressure. - In the nitrile of the formula (IX) under normal conditions, the protective group can be removed to obtain the nitrile of the formula (X). For example, when K"" represents tetrahydro-2H-pyran-2-yl, deprotection can be accomplished in the presence of an appropriate acid, such as hydrochloric acid, trifluoroacetic acid, sulfuric acid,

Mn trichloroacetic acid, phosphoric acid, p-toluenesulfonic acid, benzenesulfonic acid, -I 20 methanesulfonic acid or camphorsulfonic acid, and in a suitable solvent, such as C 4-C/ alkanol, which may optionally contain water, preferably at an elevated temperature , such as the reflux temperature of the solvent. In the treatment process, the pH can be adjusted to a value between pHB and pHN1i1 using an aqueous base, such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, to generate the free base of the compound of formula (X). Preferred conditions are the use of 2M 25 aqueous hydrochloric acid in ethanol at room temperature or the use of trifluoroacetic acid

HF) in aqueous isopropanol under reflux conditions, with subsequent adjustment of the pH in the process of processing to pHeO-10.5 with an aqueous solution of sodium hydroxide.

Nitrile of the formula (X) can be converted into a complex ester of the formula (XII) by interaction with C.-C,. sodium or potassium alkoxide in the appropriate C--C, alkanol as a solvent, optionally at elevated temperature, 60 including acid treatment during treatment of the reaction mixture. Preferably, the interaction is carried out using sodium methoxide in methanol at reflux temperature with treatment with aqueous hydrochloric acid in the process of processing the reaction mixture.

Alternatively, an ester of formula (XII) may be prepared by carbonylation of a compound of formula (MI) with a compound of formula: Von using carbon monoxide, optionally under pressure, together with a suitable palladium catalyst in the presence of a suitable base, for example a tertiary amine base, and optionally at an elevated temperature to obtain a compound of the formula: (MIA) "5

Goy (MA) and , , , , , , ,

Of course, a catalytic amount of palladium(II) acetate is used together with a suitable ligand such as 1,1"-bis(diphenylphosphino)ferrocene, triphenylphosphine, tri-o-tolylphosphine, or VIMAR ((K)- or (5)- or racemic 2 ,2'-bis(idiphenylphosphino)-1,1-binaphthyl), a suitable alcohol of the formula B'ZON, for example methanol, ethanol, 1-propanol, isopropanol or 1-butanol (which is also used as a solvent), and a base such as Triethylamine, Hanigs (Nipidv) base (ethyldiisopropylamine), 4-methylmorpholine, sodium carbonate, sodium bicarbonate, potassium carbonate or cesium carbonate, in the presence of carbon monoxide, optionally at a pressure of 1-3000

KPa in a hermetically sealed vessel at 20-2002С. A compound of formula (MIA) can be deprotected to give a compound of formula (XII) using appropriate deprotection conditions, such as those described for converting a compound of formula (IX) to a compound of formula (X). with

An ester of the formula (XIII) can be subjected to binding with a compound of the formula: о (их) ду : и - ов ю со b) i - where 7 represents a suitable leaving group, such as acetoxy, benzoyloxy, methoxy or halogen, for example , chlorine, and B" and 229 represent the corresponding protecting groups as defined above in the presence of an appropriate acid or Lewis acid, for example, trimethylsilyl trifluoromethanesulfonate, preferably using an excess thereof. The reaction can be carried out using a compound of formula (XI) in in the form of the 2K- or tc 25-diastereoisomer or in the form of their epimeric mixture. The reaction is usually carried out in a suitable solvent, for example, 1,2-dimethoxyethane, dichloromethane, acetonitrile, 1,1,1-trichloroethane or toluene, or in » their mixtures, preferably using pretreatment of the compound of formula (XIII) with a suitable silylating agent, for example, trimethylsilyl trifluoromethanesulfonate, M,O-bis(trimethylsilyl)acetamide, trimethylsilyl chloride or hexamethyldisilazane, optionally presence of a tertiary amine base, for example, M-methylmorpholine, before adding the compound of formula (XI). When interacting, you can use an elevated temperature. Preferred conditions include primary treatment of a compound of formula (XIII)

with M,O-bis(trimethylsilyl)acetamide in 1,1,1-trichloroethane, heating the reaction mixture at reflux, before treating with a solution of the compound of formula (XI) and trimethylsilyl-50 trifluoromethanesulfonate in toluene, and then heating for approx. at 1002. It is necessary to take into account that when the use of the compound of formula (XI) is envisaged, where is KE? is CHOOH, the hydroxyl group can be appropriately protected for this reaction (see below for the definition of KH), then the protecting group can be removed in a further transformation to give a compound of the formula (CM).

Deprotection of the compound of the formula can be carried out using conventional conditions, for example, when each of KU and K29 is acetyl or benzoyl, under basic conditions, such as, for example, using (F) sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate

He in a solvent such as methanol, ethanol, isopropanol, 1,2-dimethoxyethane, THF, DMF, acetone, 2-butanone or 4-methyl-2-pentanone, also optionally in the presence of water at a temperature of 0 to 802C. Alternatively, any tertiary amine base such as triethylamine, diisopropylethylamine, or 4-methylmorpholine may be used in an alcoholic solvent such as methanol, ethanol, isopropanol, or 1-propanol at 0 to 80°C, or C.- WITH; sodium or potassium alkoxide, for example, sodium methoxide or ethoxide in the corresponding C.--C. alcohols, for example, methanol or ethanol. Alternatively, an amine such as ammonia, methylamine, ethylamine, dimethylamine can be used in a suitable solvent such as methanol, ethanol, isopropanol, THF or dichloromethane at a temperature of 0 to 80C. It is preferable to use sodium carbonate in methanol at room temperature.

The complex ester of the formula (CHM) can be converted into the amide of the formula (II) by interaction with the compound of the formula: v'5mn-x-mchnA 2 (XM) optionally at elevated temperature optionally in an inert solvent such as 1,2- dimethoxyethane or 2-methoxyethyl ether and optionally under pressure. Preferably, the interaction is carried out in the absence of a solvent at a temperature of 100-1202C. A person skilled in the art should bear in mind that in order to achieve the required regioselectivity in this reaction, it is possible to use a suitable /o protecting group (for example, trifluoroacetyl) located on the selected M atom in the compound of formula (XU), and then carry out deprotection in the resulting protected intermediate compound.

The compound of the formula (II) can also be obtained by the aminocarbonylation reaction of the compound of the formula (ХМИЙ) with the compound of the formula: в'змн-х-мна 2 (ХУ)

By a method similar to that described below, to convert the compound of the formula (CHMI) into the compound of the formula (I). A person skilled in the art should bear in mind that in order to achieve the desired regioselectivity in this reaction, it is possible to use a suitable protecting group (for example, trifluoroacetyl) located on the selected M atom in the compound of the formula (XM) and then carry out deprotection in the resulting protected intermediate

UCI

Compounds of formula (XI) or (XM) can be prepared by conventional methods. 2. Compounds of the formula (I), where ХУ is CO, can be obtained by the aminocarbonylation reaction of the compound of the formula: с а ХМ их; KU) o) not "x "| F -4 cha che IS

With (ze) he | in. 20 where 73 represents a corresponding leaving group, such as bromine, iodine, -Zp(C 4-C10 alkyl)uz or СЕ350О20О-, preferably в-в iodine, with a compound of the formula: с:з» v'5Mn-X-mA 2-y-mA ZB (CHMII) in the presence of carbon monoxide and a suitable condensation catalyst (it will be clear that this route -I 75 can also be used for compounds of the formula where U differs from CO). Preferably, the catalyst is a palladium (I) catalyst, more preferably 1,1"-bis(idiphenylphosphino)ferrocenedichloropalladium(II) (4) (optionally in the form of a 1:11 complex with dichloromethane). Alternatively, palladium (I) acetate sl can be used in the presence of an appropriate ligand such as 1,1"-bis(idiphenylphosphino)ferrocene, triphenylphosphine, tri(o-tolyl)phosphine, or (K)-, (5)- or racemic 2,2'-bisbidiphenylphosphino)-1,1 '-binaphthyl. -And 50 In a typical method, the interaction is carried out in a hermetically sealed vessel in the presence of carbon monoxide at an elevated pressure, for example, about 345KPa (5O0ft/sq.in), at an elevated temperature, for example, at about 609C, and in a suitable solvent, for example, tetrahydrofurans, methanol or ethanol.

A suitable organic base may optionally be present, such as a tertiary amine, for example triethylamine, M-ethyldiisopropylamine or 4-methylmorpholine. whether and

Intermediates of the formula (CHMs) can be prepared as shown in Scheme 2.

GF) Scheme of the 2nd stage of hydrolysis of water

Olu 9 bla o where BA is as defined below, 73 is as defined above for the compound of formula (CHMII), and "Ac" 65 is acetyl (although it should be noted that alternative suitable protecting groups may be used in the transformation groups as illustrated in this description).

In a typical method, a compound of formula (XIX) reacts with an amine of the formula:

B'Mno (XM) in the presence of a suitable acid acceptor, for example, triethylamine, and in a suitable solvent, for example, acetonitrile, if necessary at an elevated temperature. In the resulting product (XX), the protective groups can be removed by hydrolysis to obtain a compound of the formula (CHMII) using a conventional method, for example, using a suitable inorganic base, for example, sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate, in a suitable solvent, for example, methanol, ethanol, isopropanol, 1,2-dimethoxyethane, tetrahydrofuran, dimethylformamide, acetone, 2-butanone or 4-methyl-2-pentanone, optionally in aqueous conditions, with temperature from 02C to the boiling point of the solvent under reflux, for example, at room temperature. Alternatively, deprotection can be accomplished using a suitable amine as a base, such as triethylamine, diisopropylethylamine, 4-methylmorpholine, ammonia, methylamine, ethylamine or dimethylamine, in a suitable solvent such as methanol, ethanol, n-propanol, isopropanol , tetrahydrofuran or dichloromethane, at a temperature from 02С to the boiling temperature of the solvent with reflux.

The intermediate compound of formula (XIX) can be prepared in a conventional manner.

The intermediate compound of the formula (CHMIIII) can be obtained by the interaction of the compound of the formula: v'5mn-x-mchnA 2 (XM) with the compound of the formula: vZvamso 1 (PI) under conditions similar to those described above for the conversion of compounds of the formulas (II) and ( II) into the compound of formula (1).

A skilled person should take into account that in order to achieve the desired regioselectivity in this reaction, it is not necessary to use a corresponding protecting group (for example, trifluoroacetyl) located on the selected nitrogen atom in the compound of formula (XU), with its subsequent removal in the resulting protected intermediate compound what

Z. The compound of the formula (I), where XM is CO, can be obtained by removing the protective groups in the compound of the formula: o

EE. (XXI) at 7 o'clock

AHA

; "- with yours! ;" yin and 004) (95) sl de V yy 2? or each individually represents a suitable protecting group such as acetyl or benzoyl, or taken together represents a suitable protecting group such as C 1 -C 1 alkylene optionally substituted with phenyl, and for example 1-dimethylmethylene or phenylmethylene, CA is CH OH, CHO or COM MV and 23

He is a suitable protecting group such as acetyl or benzoyl (noting that this route can also be used for compounds of formula (I) where U is different from CO).

Conventional deprotection conditions can be used and will depend on the nature of the protecting groups

In addition, it will be understood by one skilled in the art that the protecting groups K7", 2221823 can be removed all together, individually or in any combination to give a compound of formula (I). For example, when K o is a SNOM, or B and KE can be removed first with subsequent removal of the protective group B 3, or vice versa. In a typical method, where each of VK", K22 and KZ is acetyl, deprotection is carried out using a suitable inorganic base, for example, sodium carbonate, sodium hydroxide, potassium hydroxide 60, lithium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate , and in a suitable solvent, for example, methanol, ethanol, isopropanol, 1,2-dimethoxyethane, tetrahydrofuran, dimethylformamide, acetone, 2-butanone or 4-methyl-2-pentanone, optionally in aqueous conditions at a temperature from 09C to a temperature refluxing the solvent, for example at room temperature Alternatively, deprotection can be carried out using a suitable amine as a base, such as triethylamine, for isopropylethylamine, 4-methylmorpholine, ammonia, methylamine, ethylamine or dimethylamine, in a suitable solvent such as as methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran or dichloromethane, at temperatures from

02С to the boiling temperature of the solvent with reflux, or using С 4-С,. sodium or potassium alkoxide, for example, sodium methoxide or ethoxide, in the appropriate C4-C4 alkanol, for example, methanol or ethanol.

In a typical way, where B? and K22 taken together are 1,1-dimethylmethylene, in the compound of formula (XXI) the protecting groups can be removed by treatment with an appropriate acid, such as hydrochloric acid, trifluoroacetic acid, sulfuric acid, phosphoric acid, p-toluenesulfonate pyridinium, p- toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, acetic acid or formic acid, or a mixture thereof, or an acidic ion exchange resin, optionally in the presence of a suitable solvent, for example ethanol, and optionally in aqueous conditions. The reaction can be carried out at an elevated temperature, such as the boiling point of the solvent at reflux.

Deprotection of a compound of formula (XXI) to give a compound of formula (I) can also be performed as above with subsequent conversion of a compound of formula (XXI!) to a compound of formula (XXI) as described below. In this case, where each of K?, K22 and K3 is acetyl, the method of deprotection using an inorganic base is preferred, for example, the reaction mixture containing the compound of formula (XXI) is treated with an aqueous solution of sodium hydroxide in 1.2 -dimethoxyethane at a temperature of 5-2096.

The compound of the formula (XXI) can be obtained by condensation of the compound of the formula: and (XX) - 20 Pak

The third 4 bur ii Sha sm shchi 6)

OO) F 30. - with a compound of the formula:

IF) (XX) (ze)

C5 t: the same hezi "40 - c where 7" represents a suitable leaving group, such as acetoxy, benzoyloxy, methoxy or halogen, for example, and H and" chlorine, under conditions similar to those described above, for the conversion of the compound of the formula (XII ) in (HP).

The compound of formula (XXI) can be prepared using conventional methods as illustrated in Scheme 3. Such methods can be adapted from those described above in this specification.

Scheme Z - --- (95) schi its axis | "by NU) is optionally substituted 5 noya on Y -.70 4 in E 3e) bom ke / sho is i (F; і | r St ii ie t y ogo bo | . ov de В" represents a corresponding group, such as tetrahydro-2H-pyran-2-yl.The acid of the formula (XXMI) can be obtained using conventional methods, for example, by basic hydrolysis of a compound of the formula (IX), for example, using an aqueous solution of sodium hydroxide followed by acidification in processing process.

The compound of formula (XXIII) can be prepared by conventional methods.

A compound of formula (XXI) where ERA is SOME "B" can also be prepared as shown in Scheme 4.

Scheme 4 (xy) 70

She "And web wallpaper 0009

WITH

4 | that's about in chi (o)

Gkii ni you (OH) b ichyu (ze) ' im- y no " I, oh, s to "oda bot) ;" -I (95) 1 - 50 iChe) (F) ko bo b5

Scheme 4 (continuation) g) ; h-

SHI

10 tons. but

WITH -

U'ko Oyaz Federal District) 15 20 century

FI t goes c) Y s s o as y y, y a same « M) y (o)

Scheme 4 (continuation) M (ze) p; i - he o 2 - :z" ne SI i tsu - to osha (XX) -I (95) C) c In a typical method, the compound of the formula (XII) interacts with the compound of the formula (XXIII), where BU is a sn.ovZ under conditions similar to those described above to convert the compound of formula (XII) into (XII). 7 In the resulting compound of formula (XXX), the protecting groups can be removed under conventional conditions, for example, where (Che) each B21-23 is acetyl, using a suitable base such as sodium carbonate, potassium carbonate, sodium ethoxide, sodium methoxide or potassium tert-butoxide, in the presence of a suitable alcoholic solvent, for example ethanol, optionally in the presence of another solvent such as 1,2-dimethoxyethane, optionally in the presence of water and optionally at an elevated temperature for up to 24 hours, and also optionally with direct use of the crude reaction mixture from the previous stage.

The resulting compound of formula (XXXI) can be protected with a suitable protecting group or with suitable protecting groups. When B, taken together, is 1,1-dimethylmethylene, this can be accomplished by reaction with acetone or an acetone ketal, or a combination of both, in the presence of an acid such as hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid , sulfuric acid, phosphoric acid or trifluoroacetic acid, in a solvent such as acetone, toluene, dichloromethane or tetrahydrofuran, optionally at elevated temperature. Preferably, the interaction is carried out using acetone and 2,2-dimethoxypropane in the presence of sulfuric acid.

Alternatively, a compound of formula (XXX) can be directly converted into a compound of formula (XXXIII) by selective enzymatic hydrolysis, for example, using a lipase enzyme.

The resulting compound of formula (XXXIII) can be oxidized to a carboxylic acid of formula (XXXIII) either in one step by treatment with an appropriate oxidizing agent in an appropriate solvent, or in two steps by primary treatment to generate the appropriate aldehyde followed by further treatment by a suitable oxidizing agent in a suitable solvent. Typical conditions for a one-step process include treating the primary alcohol with an oxidizing agent such as chromic acid, sodium periodate, chromium trioxide, potassium permanganate, sodium chlorite, sodium hypochlorite, or oxygen in a suitable solvent such as acetonitrile, dichloromethane, toluene, or ethyl acetate , optionally in the presence of a suitable catalyst such as ruthenium trioxide, ruthenium chloride, 2,2,6,6-tetramethylpiperidinyl-1-oxy free radical or platinum, optionally in the presence of a catalyst such as sodium hypochlorite, sodium bromide or potassium bromide, 70 optionally in the presence of water, optionally in the presence of an interphase transfer catalyst such as tetrabutylammonium bromide, benzyltriethylammonium chloride or tetrabutylammonium chloride, optionally in the presence of an inorganic base such as sodium carbonate, sodium bicarbonate, potassium carbonate or sodium hydroxide, and optionally in the presence of additional auxiliary additives such as sodium chloride. Suitable conditions for the two-step process include pretreatment with an oxidizing agent such as Swern's reagent 7/5 (Zmegt), tetrapropylammonium perutenate, pyridinium dichromate, pyridinium chlorochromate, sulfur trioxide-pyridine complex, or /1,1,1-triacetoxy-1 ,1-dihydro-1,2-benziodoxol-3(1H)-one, in a suitable solvent and optionally in the presence of an additional oxidant such as M-methylmorpholine-M-oxide, followed by treatment of the intermediate aldehyde with another suitable agent which oxidizes such as chromic acid, sodium periodate, chromium trioxide, potassium permanganate, sodium chlorite, sodium hypochlorite or oxygen in a suitable solvent such as acetonitrile, dichloromethane, toluene or ethyl acetate, optionally in the presence of a suitable catalyst such as trioxide ruthenium, ruthenium chloride, 2,2,6,6-tetramethylpiperidinyl-1-oxy free radical or platinum, optionally in the presence of an additional catalyst such as sodium hypochlorite, sodium bromide or potassium bromide, optionally in the presence water, optionally in the presence of an interphase transfer catalyst such as tetrabutylammonium bromide, tributylammonium chloride or tetrabutylammonium chloride, optionally in the presence of an inorganic base such as sodium carbonate, sodium bicarbonate, potassium carbonate or sodium hydroxide, and optionally in the presence of i) additional auxiliary additives such as sodium chloride. Preferred conditions include treatment of the alcohol of formula (XXXI) with a catalytic amount of the free radical 2,2,6,6-tetramethylpiperidinyl-1-oxy in acetonitrile in the presence of water and sodium dihydrogen phosphate, followed by the addition of aqueous sodium hypochlorite (catalytic Ge!zo Amount) and aqueous chlorite of sodium at elevated temperature. Alternatively, the alcohol of formula (XXXIII) is treated with the free radical 2,2,6,6-tetramethylpiperidinyl-1-oxy (catalytic amount) and sodium hypochlorite in dichloromethane in the presence of water, sodium bicarbonate and a catalytic amount of tetrabutylammonium bromide.

The resulting carboxylic acid of the formula (XXXIII) can be converted into an amide of the formula (XXX/IM) under conventional condensation conditions, for example, by activating the acid using a suitable activating agent, optionally in the presence of a catalyst, and then treating with excess amine formula:

NM in the appropriate solvent. Typically, the reaction is carried out by treating the acid with an activating agent such as M',M'-carbonyldiimidazole, thionyl chloride, oxalyl chloride or phosphorus oxychloride in a solvent such as THF, DMF, ethyl acetate, acetonitrile, toluene, acetone or dichloromethane at a temperature from O to 1009C s for 1-20 hours, followed by the addition of an amine or its acid addition salt, optionally in the presence of a tertiary amine as an acid acceptor, such as triethylamine, ethyldisopropylamine or "M-methylmorpholine", at a temperature from O to 1002C. Alternatively, the acid is reacted with 1-"3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or M,M'-dicyclohexylcarbodiimide, then with 1-hydroxy-7-azabenzotriazole or 1-hydroxybenzotriazole hydrate, then with an amine in the presence of an excess of 4 -methylmorpholine, triethylamine, or ethyldisopropylamine in THF, DMF, ethyl acetate, acetonitrile, toluene, acetone, or dichloromethane at room temperature. The interaction can also be accomplished by reacting the acid with benzotriazole-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate 1 bromo-tris -pyrrolidinophosphonium or Mukayama's reagent (Mickaiwata) (2-chloro-1-methylpyridinium iodide) and amine -1 50 in the presence of 4-methylmorpholine, triethylamine or ethyldisopropylamine in THF, DMF, dichloromethane or ethyl acetate at room temperature. The interaction is preferably carried out by primary treatment acid (Che) with M,M'-carbonyldiimidazole in ethyl acetate followed by addition of the amine in THF.

The resulting compound of formula (XXIII) can be hydrolyzed to give a carboxylic acid of formula (XXXX) under conventional ester hydrolysis conditions, such as using an alkali metal base in a suitable solvent in the presence of water, optionally at elevated temperature, followed by acid treatment to obtain carboxylic acid. In a typical reaction, the interaction is carried out using lithium hydroxide, sodium hydroxide or potassium hydroxide in a solvent such as aqueous ethanol, methanol, isopropanol, butanol, industrial methyl alcohol, tetrahydrofuran, DMF, 1,2-dimethoxyethane at a temperature of 0 to 1002 Preferably, the interaction is carried out using sodium hydroxide in a mixture of 60 methanol and water at 20-6596.

The resulting acid of formula (XXXM) can be converted into an amide of formula (XXI) using conventional condensation conditions, such as by activating the acid with a suitable activating agent, optionally in the presence of a catalyst, and then treating with an excess of an amine of the formula: 65 v5Mmv-x -mA 2-in-mA Sv (HM)

in a suitable solvent. In a typical method, the acid is treated with an activating agent such as

M',M'-carbonyldiimidazole, thionyl chloride, oxalyl chloride or phosphorus oxychloride, in a solvent such as

THF, DMF, ethyl acetate, acetonitrile, toluene, acetone or dichloromethane, at a temperature of 0 to 1009, followed by the addition of an amine or its acid addition salt, optionally in the presence of a tertiary amine such as triethylamine, ethyldisopropylamine or M-methylmorpholine, at a temperature from 0 to 100 260.

Alternatively, the acid is reacted with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or

with M,M'-dicyclohexylcarbodiimide, then 1-hydroxy-7-azabenzotriazole or 1-hydroxybenzotriazole hydrate, followed by amine in the presence of excess 4-methylmorpholine, triethylamine, or ethyldiisopropylamine in THF, 70 DMF, ethyl acetate, acetonitrile, toluene, acetone, or dichloromethane at room temperature. The interaction can also be carried out by reacting the acid with benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate, bromo-tris-pyrrolidinophosphonium hexafluorophosphate or Mukayama's reagent (2-chloro-1-methylpyridinium iodide) and an amine in the presence of 4-methylmorpholine, of triethylamine or ethyldiisopropylamine in THF, DMF, dichloromethane, or ethyl acetate at room temp. 75 The reaction is preferably carried out by primary treatment of the acid with M,M'-carbonyldiimidazole in dichloromethane followed by addition of an amine, optionally in the form of a suitable acid addition salt such as the hydrochloride salt, and in the presence of an acid acceptor such as triethylamine at room temperature .

A compound of formula (XXXIII) can also be prepared as shown in Scheme 5.

Scheme 5 2 0004) s shchi 6) shko x x v u non F

OM M som yu (ze)

A thiol of formula (XXXI) can be selectively oxidized to give a diol of formula (XXXIII), usually with

Using a selective oxidizing agent such as sodium hypochlorite in the presence of a catalytic amount of 2,2,6,6-tetramethylpiperidinyl-1-oxy free radical and bromine ion (provided as sodium bromide, potassium bromide, or tetraalkylammonium bromide ), or using oxygen in the presence of a platinum catalyst, in a suitable solvent, such as water, acetonitrile, dichloromethane, toluene, or ethyl acetate, or in a mixture of an organic solvent and water together with an interphase transfer catalyst, such as C 70 such as tetrabutylammonium bromide, tetrabutylammonium chloride or benzyltriethylammonium chloride. c The diol of the formula (XXXMII) can be protected by an appropriate protecting group or groups. When the protecting group is 1,1-dimethylmethylene, this is achieved by interaction with acetone or ". . Kk "y . . . derivative of acetone in the presence of an acidic reagent. In a typical reaction, the diol reacts with acetone or an acetone ketal such as 2,2-dimethoxypropane, or a combination of both, in the presence of an acid such as hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, phosphoric acid or trifluoroacetic acid, and in a solvent such as acetone, toluene, dichloromethane or tetrahydrofuran, optionally at elevated temperature. B" can also be obtained, as shown in diagram 6. -i iChe) ime) 60 b5

Scheme b

So)

And in Z. yav "Zhk

SYA and "xx"E

Gen) no "on SOLI. y no, h - ; І "Z "E

Ha with in . 5) 00 b xxx) (o)

Scheme 6 (continued) | them-

ОХ) ИС) shk o i - uk x7 g - s no;» ШЧИ У -b o b- o 0) and I (95) with ЧИ -0.750 In a typical method in the compound of the formula (XXI), where VU represents CH OK, where K272Z represent the corresponding protecting groups, such as acetyl, remove the protective group under conventional conditions, such as treatment of i3e) with a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium ethoxide, sodium methoxide or potassium tert-butoxide, in a suitable alcoholic solvent, optionally in the presence of another solvent, such as 1,2-dimethoxyethane, optionally in the presence of water and optionally at elevated temperature.

GF) The resulting compound of formula (XXXIII) can be selectively protected under normal conditions. When K7 and 22 taken together are 1,1-dimethylmethylene, this is done by reacting the thiol with acetone or an acetone ketal such as 2,2-dimethoxypropane, or a combination of both, in the presence of an acid such as hydrochloric acid. p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, phosphoric acid or trifluoroacetic acid, and in a solvent such as acetone, toluene, dichloromethane or tetrahydrofuran, optionally at an elevated temperature.

Alternatively, a compound of formula (XXI) can be directly converted to a compound of formula (XXXIX) by selective enzymatic hydrolysis, for example, using a suitable lipase enzyme.

An alcohol of formula (XXXIX) can be oxidized to an acid of formula (XXXX) using conditions similar to those described above to convert a compound of formula (XXXIII) to (XXXI).

An acid of formula (XXXX) can be converted to an amide of formula (XXI) using conditions analogous to those described above for the conversion of a compound of formula (XXXIII) to (XXXIM). 4. The compound of the formula (I), where XU represents C5, can be obtained by the interaction of the compound of the formula: 756575 where each of 72 and 79 represents a corresponding leaving group, with the compound of the formula (Ii) followed by the interaction of the obtained intermediate compound of the formula:

Du (ХХМА) 55 ж 4 р т (и хо овд «а ОН и сн (ХХТУА) with an amine of the formula: с вЗвеМН о 751725, which can be the same or different, usually chosen from -5(С4-Св alkyl) or 1Н -imidazol-1-yl. 5. The compound of the formula (I), where X represents 505, can be obtained by the interaction of the compound of the formula: vzvamvoyat COM) o where 7 is a leaving group, with the compound of the formula (II), neob' necessarily in the presence of an acid acceptor.

The compound of the formula (XXMIII) can be obtained by the usual methods of activation from the compound of the formula: yuyu co vZvaM8ozNn (XXMIII) m. for example, using PCi"5, when 7" represents SI. The compound of the formula (XXMIII) can be obtained by the interaction of chlorosulfonic acid with amine of the formula: вСв'МН " 6. The compound of the formula (I), where U represents С-М(СМ) can be obtained by the interaction of the compound of the formula: С с 78с-МЩ(сМ 9 (XXIX)). "» - ! - ! ! . where each of 78 and 79 is a leaving group, with a compound of formula (II) with further interaction of the obtained intermediate compound of the formula: - с (ХХМВ) (95) и ; С щ -и сану (Che) "ОН и он о хм) име) with an amine of the formula: бо кЗв"МН 75 and 76 can be the same or different, for example, -5(C4-C8 alkyl), preferably -ССНи. In a typical method, a solution of a compound of the formula (I) in a suitable solvent, such as ethanol, is treated with dimethylcyanothioimidocarbamate, preferably at room temperature. When the reaction is actually complete, an amine of the formula KEZVUMN is added, and to obtain the desired product, the reaction mixture is heated, preferably under reflux .

7. Any compound of the formula (I) can be obtained by the interaction of a complex ester of the formula (KHIM) with an amine of the formula: an inert solvent such as 1,2-dimethoxyethane or 2-methoxyethyl ether, and optionally under pressure. Preferably, the interaction is carried out in the absence of a solvent at a temperature of 100-12090. 70 All of the above reactions and the preparation of new starting substances using the previous methods are conventional, and the appropriate reagents and reaction conditions for their implementation or preparation, as well as methods for the isolation of the target products, will be well known to those skilled in the art with reference to the literature precedents and examples given and receiving In particular, suitable methods of introducing and removing protective groups are well known in the art, for example, as described in S. Geep. "Rgoiesime Sgours ip Ogdapis 75 zZupipeviv", Tpiga Edyiop, dUopp U/ieu «« ope TSI.

A pharmaceutically acceptable salt of a compound of formula (I) can easily be prepared by mixing together solutions of a compound of formula (I) and the desired acid or base, if necessary. The salt may precipitate out of solution and be collected by filtration, or it may be isolated by evaporation of the solvent.

The anti-inflammatory properties of compounds of formula (I) are demonstrated by their ability to inhibit neutrophil function, indicating agonistic activity against the Aga receptor. This value is estimated by determining the profile of the compound in an assay that measures the production of superoxide from activated MI R neutrophils. Neutrophils were isolated from human peripheral blood using dextran sedimentation followed by centrifugation in RisoP-Nuradze solution. Any contaminating erythrocytes in the granulocyte pellet were removed by lysis using ice-cold distilled water. Superoxide production from SC neutrophils was induced by IMI P in the presence of a priming concentration of cytochalasin B. Adenosine deaminase was included in the assay to remove any endogenously produced adenosine that might inhibit (o)superoxide production. The effect of the compound on the MI R-induced response was monitored colorimetrically by the recovery of cytochrome C in the assay buffer. The efficacy of the compounds was evaluated by the concentration giving 5090-no inhibition (ISvo) Compared with the control reaction in response to MI R. Fu

The compounds of formula (I) may be administered by themselves, but will usually be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier, selected having regard to the route of administration contemplated and in accordance with standard pharmaceutical practice. yu

For example, the compounds of formula (I) can be administered orally, buccally or sublingually in the form of tablets, capsules, multigranules, gels, films, coated beads, elixirs, solutions or suspensions, which may contain flavorings or dyes, for immediate, delayed-release applications. , modified, sustained, M pulsed release, or controlled release. The compounds of formula (I) can also be administered in the form of fast-dissolving or rapidly dispersing dosage forms, or in a form with a high release energy or in the form of coated particles. Suitable compositions of the compounds of formula (I) can be, if desired, in the form of a coated or non-coated form. 20 Such solid pharmaceutical compositions, for example, tablets, may contain excipients such as -o microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (mainly corn, potato or cassava starch), disintegrating agents , such as sodium starch glycolate, croscarmellose sodium and some complex silicates, and granulating binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPROS), bacharose, gelatin and gum arabic. Additionally, lubricating agents such as magnesium stearate-1, sodium stearyl fumarate, sodium lauryl sulfate, stearic acid, glyceryl behenate and talc can be included in the composition.

General examples (95) The composition of a tablet can typically contain from 0.01 mg to 500 mg of active compound, while the weight of the filler in the tablet can vary from 50 mg to 1000 mg. An example of the composition for a 1Omg tablet is illustrated below: -I 20 Ingredient 96 wt/wt compound of formula (i) or salt 10.0007 sci lactose 64.125 starch 21.375 croscarmellose sodium 3.000 magnesium stearate 1.500 o "The amount is adjusted according to the activity of the medicinal product.

Tablets can be obtained by conventional methods, for example, direct compression or methods of wet or dry granulation. The core of the tablets can be covered with a suitable shell. 60 Solid compositions of this type can also be used as fillers in gelatin or HPMC capsules. Preferred excipients in this ratio include lactose, starch, cellulose, milk sugar or high molecular weight polyethylene glycol. For aqueous suspensions and/or elixirs, the compounds of formula (I) can be combined with various sweetening or flavoring agents, pigments or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol or glycerol and their connections

The compounds of formula (I) can also be administered parenterally, for example, intravenously, intraarterially, intraperitoneally, intrathecally (submucosally), intraventricularly (inside the ventricle), intrauterinely, intracranially, intramuscularly or subcutaneously, or they can

ADMINISTER THROUGH infusion or needleless methods of injection. For such parenteral administration, they are best used in the form of a sterile aqueous solution, which may contain other substances, for example, a co-solvent and/or a sufficient amount of salt or glucose to form a solution isotonic with blood. The aqueous solution, if necessary, should be buffered accordingly (preferably to a pH of 3 to 9).

The preparation of suitable parenteral formulations under sterile conditions is easily accomplished using 7/0 standard pharmaceutical methods well known to those skilled in the art.

For oral and parenteral administration to human patients, the daily dosage level of the compounds of formula (I) will usually be from 0.00001 to 10 Ωg/kg, preferably from 0.0001 to 10 Ωg/kg (as single or divided doses).

Thus, tablets or capsules of the compound of formula (I) can contain from 0.01 to 50 Ωg of the active compound 7/5 for a single administration or for two or more times depending on the situation. The attending physician will in any case determine the actual dosage that will be most appropriate for each individual patient and will vary according to the age, weight and response of the particular patient. The above dosage is illustrative for an average case. Of course, individual exceptions are possible when higher or lower dosage ranges are prescribed, and they are also within the scope of this invention.

The compounds of formula (I) may also be administered intranasally or by inhalation and are readily manufactured as a dry powder inhaler or as an aerosol spray delivery device from a pressurized container, pump, nebulizer, nebulizer (preferably an electrohydrodynamic fine mist nebulizer) or aerosol inhaler, with or without the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, s ov Hydrofluoroalkane, such as 1,1,1,2-tetrafluoroethane, (NEA 134A - trade mark) or 1,1,1, 2,3,3,3-heptafluoropropane (NEA 227EA - trade mark), carbon dioxide, additionally perforated and) a hydrocarbon such as perflubron (Repibrgop - trade mark) or other suitable gas. In the case of a pressurized aerosol, the unit dosage form may be defined by a metered dose valve. Pressurized container, pump, nebulizer, nebulizer or aerosol inhaler b z o May contain a solution or suspension of the active compound, for example, using a mixture with ethanol (optionally with aqueous ethanol) or a suitable dispersing, solubilizing or releasing agent - which is consumed , and propellant as a solvent, which may additionally contain a lubricant, for example, sorbitol trioleate. For use in an inhaler or an insufflation device, capsules, blisters (blisters) and ampoules (obtained, for example, from gelatin or HPMS), containing a powdered mixture of me) can be developed

From a compound of formula (I), a suitable powdered base such as lactose or starch, and a performance modifier such as 1-leucine, mannitol or magnesium stearate.

The appropriate composition of the solution for use in an electrohydrodynamic pulverizer for obtaining a fine mist may contain from 100 mg to 17 mg of the compound of formula (I) or its salt, and the effective volume may vary from 1 to 100 μl. A conventional composition may include a compound of formula (I) or a salt thereof, propylene glycol, sterile water, ethanol and sodium chloride. in c Aerosols or compositions of dry powders are preferably composed in such a way that each measured dose or . the "puffable cloud" contained from 1 to 400 µg of a compound of formula (I) for delivery to the patient. The total daily dose when using an aerosol, which can be administered during the day in the form of a single dose or, more commonly, in the form of divided doses, will range from 1 μg to 20 mg.

Alternatively, the compounds of formula (I) can be administered in the form of suppositories or pessaries, or they can be used for external application in the form of a lotion, solution, cream, ointment or dusting agent. The compounds of formula (I) can also be administered on the surface of the skin or transdermally, for example, when using a skin patch. They can also be administered by pulmonary, vaginal or rectal routes. c For external use on the skin, the compounds of formula (I) can be introduced into the composition of a suitable ointment containing the active compound suspended or dissolved, for example, in a mixture with one or more

Sh - selected from mineral oil, liquid petroleum jelly, white petroleum jelly, propylene glycol,

Ge) polyoxyethylene-polyoxypropylene compound, emulsifying wax and water. Alternatively, they may be incorporated into a suitable lotion or cream, suspended or dissolved, for example, in admixture with one or more of the following: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl ester waxes, cetearyl alcohol, 2- octyldodecanol, benzyl alcohol and water.

The compounds of formula (I) can also be used in combination with cyclodextrin. It is known that (F, cyclodextrins form inclusion and non-inclusion complexes with drug molecules. The formation of a drug-diclodextrin complex can modify such properties of the drug molecule as solubility, dissolution rate, bioavailability and/or stability. Drug complexes- dcyclodextrin is commonly used for most preparative dosage forms and routes of administration.

As an alternative to direct complexation with the drug, cyclodextrin can be used as an auxiliary additive, for example, as a carrier, diluent or solubilizer. Most often, alpha-, beta- and gamma-cyclodextrins are used, and relevant examples are described in UUO-A-91/11172,

UMO-A-94/02518 and UMO-A-98/55148. 65 It should be understood that all references to treatment in this description include curative, palliative and prophylactic treatment.

Thus, the invention relates to: (Y) a compound of formula (I) or its pharmaceutically acceptable salt or solvate; (ii) a method of obtaining a compound of formula (I) or its pharmaceutically acceptable salt or solvate; (ii) a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable excipient, diluent or carrier; (m) a compound of formula (I) or its pharmaceutically acceptable salt, solvate or composition for use as a medicinal product; (M) use of the compound of formula (I) or its pharmaceutically acceptable salt, solvate or composition for the preparation of a medicinal product having agonistic activity against the Aga receptor; (mi) use of a compound of formula (I) or its pharmaceutically acceptable salt, solvate or composition to obtain an anti-inflammatory agent; (my) use of a compound of formula (I) or its pharmaceutically acceptable salt, solvate or composition for the preparation of a medicinal product for the treatment of respiratory tract diseases; (mii) application is similar to (mii), where the disease is selected from the group consisting of respiratory failure syndrome in adults (AKOB5), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, fibrocystic degeneration, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis; (their) use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof for the preparation of a medicinal product for the treatment of septic shock, male erectile dysfunction, male infertility factor, female infertility factor, hypertension (high blood pressure) , stroke, epilepsy, cerebral ischemia, peripheral vascular disease, postischemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, dermatitis, allergic dermatitis, eczema, ulcerative colitis, Crohn's disease, inflammatory bowel disease, gastritis caused by Neiobasieg ruiogi, gastritis caused by non-Neiyiobrasieg p uiogi, gastrointestinal injury or psychotic illness caused by non-steroidal anti-inflammatory drugs, or for i) wound healing; (9) a method of treating a mammal, including a human, with an Aga receptor agonist, comprising treating said mammal with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or hesocomposition thereof; (xi) a method of treating a mammal, including a human, for the treatment inflammatory disease, which includes - treating the indicated mammal with an effective amount of the compound of formula (I) or its pharmaceutically acceptable salt, solvate or composition; (xi) a method of treating a mammal, including a human, for the treatment of a respiratory tract disease, which me) zv Includes the treatment of the indicated a mammal with an effective amount of a compound of formula (I) or its pharmaceutically acceptable salt, solvate or composition; (khii) the method is similar to (khii), where the disease is selected from the group consisting of respiratory failure syndrome in adults (AKO5), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, fibrocystic degeneration, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis; (chem) method of treating a mammal, including a human, for the treatment of septic shock, male erectile dysfunction, male factor infertility, female factor infertility, hypertension (high blood pressure), stroke, epilepsy, cerebral ischemia, peripheral vascular disease , and?" post-ischemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, dermatitis, allergic dermatitis, eczema, ulcerative colitis, Crohn's disease, inflammatory bowel disease, Neihorasieg ruiogi gastritis, non-Neiorasieg ruiogi gastritis, -I damage gastrointestinal or psychotic disease caused by non-steroidal anti-inflammatory drugs, or for wound healing, comprising treating said mammal with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof; and c (xu) of certain novel intermediates disclosed herein.

In the following examples and formulations, "THF" means tetrahydrofuran, "DMSO" means

Dimethylsulfoxide and "TLC" means thin layer chromatography.

Ge) The following examples illustrate the preparation of compounds of formula (1):

Example 1 6-(2,2-diphenylethyl)amino|-9-(2kK,3K,45,55)-5-Ketylamino)carbonyl|-3,4-dihydroxytetrahydro-2-furanyl)-M-(2-I412 -(1-piperidinyl)ethylamino)carbonyl)amino|dethyl)-9H-purine-2-carboxamide

And yo er "ai .

SD si 5 65 yin o

M-(2-aminoethyl)-6-(2,2-diphenylethyl)amino|-9-(2kK,3K,45,55)-5-Ketyl-amino)carbonyl/|-3,4-dihydroxytetrahydro-2 -furanyl)-9UN-purine-2-carboxamide (Preparation 10) (9Omg, 0.15mol) and

N -(2-β-1-piperidinyl)ethyl I|-1H-imidazole-1-carboxamide (Preparation 18) (Zbmg, 0.1 bmol) was dissolved in dichloromethane (Zml). Toluene (4 ml) and isopropanol (ml) were added and dichloromethane was removed by evaporation at atmospheric pressure. The remaining solution was heated at reflux for four hours.

TLC analysis showed that the reaction was not complete, so additional was added

IM-(2-(1-piperidinyl)ethyl|-1H-imidazole-1-carboxamide (25 mg, 0.11 mol) and heating was continued for four hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on 7/0 ultragel, eluting with dichloromethane:methanol:concentrated aqueous ammonia (90:10:1, by volume).The fractions containing the product were evaporated and the resulting solid was triturated with diethyl ether, filtered and dried to give the title compound as a white of powder (bOmg). "H-NMR (400MHz, SOSIV) 5: 8.20 (1H, s), 7.35-7.20 (1OH, m), 5.90 (1H, m), 4.90 -4.60 (4Н, m), 4.40 (2Н, m), 3.60-3.00 (8Н, m), 2.45-2.25 (6Н, m), 1.60-1 .40 (6H, m), 1.00 (ZH, t).

And AM5 (thermal spraying): t/2 (МН 729.

Example 2

M-2-(((2-(diisopropylamino)ethylamino)carbonyl)amino|ethyl)-6-|(2,2-diphenylethyl)amino|-9-(2K,3K,45,55)-5-Ketylamino) carbonyl|-3,4-dihydroxy-tetrahydro-2-furanyl)-9H-purine-2-carboxamide sn,

Ddrvyh o d no i, me 5) and t ton

M-(2-aminoethyl)-6-(2,2-diphenylethyl)amino|-9-(2kK,3K,45,55)-5-Ketyl-amino)carbonyl/|-3,4-dihydroxytetrahydro- 2-furanyl)-9UN-purine-2-carboxamide (Preparation 10) (9Omg, 0.1 bmol) and i-

I-(2-(diisopropylamino)ethyl I|-1H-imidazole-1-carboxamide (Preparation 19) (40 mg, 0.17 mol) was dissolved in dichloromethane (3 mL). Toluene (4 mL) and isopropanol (mL) were added, and the dichloromethane was removed by evaporation. at about atmospheric pressure. The remaining solution was then heated at reflux for one to four hours. TLC analysis showed that the reaction was incomplete, so additional

1-(2-(diisopropylamino)ethyl|-1H-imidazole-1-carboxamide (3 mg, 0.1 μmol) and heating was continued for an additional four hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane :methanol:concentrated aqueous ammonia (90:10:1, v/v) to give the title compound as a white solid (bomg). " "H-NMR (400MHz, COCl3-CO3O0) 5: 8.15 (1M, s), 7.30-7.10 (ION, m), 6.15 (IN, m), 4.70-4.50 (ЗН, m), З7З then 4.40-4.30 (ЗН, m), 3.60-3.10 (6Н, m), 3.05-2.85 (4Н, m), 2.45 (2Н, m), 1.00-0.85 (15Н , m). c I AM5 (thermal spraying): t/2 (МН 745. :з» Example C 9-(2К,ЗК,45,5К)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2- furanyl-6-(2,2-diphenylethyl)amino|-M-2-(((2-(1-piperidinyl)ethylamino)carbonyl)amino|ethyl)-9H-purine-2-carboxamide

In ve (95) o GU - 50 ich i s 2 kl g i ; "and nn

BUT (about On

GI M-(2-aminoethyl)-9-(2kK,ZKk,45.5K)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl|-6-K2,2-diphenylethyl)amino|) -9H-purine-2-carboxamide (Preparation 17) (9Omg, 0.17mol) and in IM-(2-"1-piperidinyl)ethylI|-1H-imidazole-1-carboxamide (Preparation 18) (40mg, 0, 18mol) was dissolved in a mixture of toluene (4ml) and isopropanol (1ml) and the solution was heated at reflux for four hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane:methanol:concentrated aqueous ammonia (85:15:1.5, by volume).

Fractions containing the product were evaporated and the resulting solid was triturated with diethyl ether, filtered and dried to give the title compound as a white powder (85mg).

TN-NMR (400MHz, СОСИ3-СО3O0) 5: 7.95 (1Н, p), 7.35-7.15 (1НО, m), 5.35 (1Н, m), 4.85 (1Н, m ), 4.40-4.20

(BN, m), 4.00 (1Н, m), 3.80 (1Н, m), 3.60 (1Н, m), 3.50-3.30 (ЗН, m), 3.10 ( 2Н, m), 2.35-2.15 (6Н, m), 1.50-1.30 (6Н, m).

And AM5 (thermal spraying): t/2 (МН 688.

Example 4 9-K(2K,ZK,45,5K)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl|-M-(2-IC(2-(isopropylamino)ethyl|amino) carbonyl)amino|ethyl)-6-((2,2-diphenylethyl)amino|-UN-purine-2-carboxamide sn. 0 -on shchi g on

M-(2-aminoethyl)-9-(2kK,ZKk,45.5K)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl|-6-K2,2-diphenylethyl)amino|)- 9UN-purine-2-carboxamide (Preparation 17) (9Omg, 0.17mol) and

I-(2-(diisopropylamino)ethyl|-1H-imidazole-1-carboxamide (Preparation 19) (5mg, 0.19mol) was dissolved in a mixture of toluene (4ml) and isopropanol (1ml) and the solution was heated at reflux for four hours.The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane:methanol:concentrated aqueous ammonia (85:15:1.5, by volume).

Fractions containing the product were evaporated and the resulting solid was triturated with diethyl ether, filtered and dried to give the title compound as a white powder (85mg). "NA-NMR (400 MHz, СОСИ3-СО5О0) 85: 8.00 (1M, s), 7.30-7.10 (ION, m), 5.85 (IN, m), 4.75 (1Н, m), i) 4.40-4.20 (4H, m), 4.15 (IN, m), 3.95 (IN, m), 3.80 (IN, m), 3.60-3 .30 (4Н, m), 3.05-2.85 (4Н, m), 2.45 (2Н, m), 0.90 (12Н, d).

And AM5 (thermal spraying): t/2 (МН 704. Ге)

Example 5 m 6-(2,2-diphenylethyl)amino|-9-(2kK,3K,45,55)-5-Ketylamino)carbonyl|-3,4-dihydroxytetrahydro-2-furanyl)-M-(2- I412-(4-isopropyl-1-piperidinyl)ethyl(amino)carbonyl)iamino|ethyl)-9H-purine-2-carboxamide

Fe o i - y: ; I say: "

IF carry | - с 5 "» Obtained from " M-(2-aminoethyl)-6-(2,2-diphenylethyl)amino|-9-(2кК,3К,45,55)-5-Ketylamino)carbonyl|-3,4 -dihydroxytetrahydro-2-furanyl)-9H-purine-2-carboxamide (Preparation 10) and

M-(2-(4-isopropyl-1-speridinyl)ethyl I|-1H-imidazole-1-carboxamide (Production 22) by a method similar to that described in example 1.

Ge) "NA-NMR (400MHz, SOZO0/SOSiO) 5; 8.10 (1M, s), 7.30-7.10 (ION, m), 5.95 (1H, d), 4.75 ( IN, width s), 4.50-4.20 (5H, m), 3.50-3.40 (2H, m), 3.20 (IN, m), 3.10 (2H, m) , 2.80 (2H, m), 2.25 (2H, m), 1.80 (2H, m),

Mn 1.55 (2Н, m), 1.30 (1Н, m), 1.10 (2Н, m), 0.95 (ЗН, т), 0.90 (1Н, m), 0.80 ( 6H, d). - and 20 I VM (thermal spraying): t/z2 (МН 772. с Example 6 -(2-4(2-(cyclopentyl(isopropyl)amino|ethyl)amino)carbonyl|amino)ethyl)-6-((2 ,2-diphenylethyl)amino|-9-(2K,

Zzk,45,35)-5-(ethylamino)carbonyl/|-3,4-dihydroxy-tetrahydro-2-furanyl)-9H-purine-2-carboxamide i o

F). to NK

ZU that. sn, 60 so Z im X re

To o o -»oy biy EYA o on . 65 Received from

M-(2-aminoethyl)-6-(2,2-diphenylethyl)amino|-9-(2kK,3K,45,55)-5-Ketylamino)carbonyl|-3,4-dihydroxytetrahydro-2

-furanyl)-9H-purine-2-carboxamide (Production 10) and

M-(2-(cyclopentyl(isopropyl)amino|ethyl)-1H-imidazole-1-carboxamide (Production 26) by a method similar to that described in example 1. (1M, s), 7.35-7.15 (TON, m), 6.10 (IN, m), 4.70 (2Н, m), 4.55 (IN, m), 4.40- 4.30 (ZN, m), 3.60-2.90 (1OH, m), 2.60-2.40 (2Н, m), 1.70-1.20 (8Н, m), 1, 00-0.90 (9Н, m).

Example 7

M-(2-1C42-Icyclohexyl(isopropyl)amino)ethyl)amino)carbonyl|amino)ethyl)-6-((2,2-diphenylethyl)amino|-9(2K,3

K,45,55)-5-Ketylamino)carbonyl)-3,4-dihydroxy-tetrahydro-2-furanyl)-9H-purine-2-carboxamide

AND

In GI and ry

Ah tu three

N ze dA still i on

Received from

M-(2-aminoethyl)-6-(2,2-diphenylethyl)amino|-9-(2kK,3K,45,55)-5-Ketylamino)carbonyl|-3,4-dihydroxytetrahydro-2-furanyl)- 9H-purine-2-carboxamide (Preparation 10) and

M-(2-(cyclohexyl(isopropyl)amino|)ethyl)-1H-imidazole-1-carboxamide (Production 29) by a method similar to that described in example 1.

TN-NMR (400MHz, CO3O0/SOCI3) 6: 8.10 (1H, p), 7.30-7.10 (1OH, m), 6.05 (1H, m), 4.70-4.55 (2H, m), 4.45 o (IN, m), 4.40-4.25 (ЗН, m), 3.60-2.90 (TON, m), 2.60-2.40 ( ЗН, m), 1.75-1.60 (4Н, m), 1.50 (1ИН, m), 1.20-1.05 (ЕН, m), 1.00-0.90 (9Н, m).

And AM5 (thermal spraying): t/2 (МН 786. (о)

Example 8 m 6-(2,2-diphenylethyl)amino|-9-(2kK,3K,45,55)-5-Ketylamino)carbonyl|-3,4-dihydroxytetrahydro-2-furanyl)-M-(2- I411-(2-pyridinyl)-4-piperidinylamino)carbonyl)amino|ethyl)-9H-purine-2-carboxamide IF) 58 o i -

Phew

There is also Kha produ « uzh i - shon Z s dn 7

I" M

Received from

M-(2-aminoethyl)-6-(2,2-diphenylethyl)amino|-9-(2kK,3K,45,55)-5-Ketylamino)carbonyl|-3,4-dihydroxytetrahydro-2-15-furanyl )-9H-purine-2-carboxamide (Preparation 10) and

1-(1-(2-pyridinyl)-4-piperidinyl|-1H-imidazole-1-carboxamide (Preparation 30) by a method similar to that described in (95) example 1. c "NA-NMR (400 MHz, CO3O0) 5; 8.40 (1M, m), 8.00 (IN, d), 8.05 (1IN, d), 7.45 (1H, m), 7.40-7.30 (4H, m), 725 -120 (4H, m), 7.10 (2H, m), 6.70 (1H, d), 6.55 (1IN, m), 6.10 (1H, m), 4.50-4, 35 (4H, m), 4.00 (2H, m),

W- 3.65 (1H, m), 3.50 (2H, m), 3.4 (2H, m), 3.30 (1H, m), 3.25 (1H, m), 2.85 (2Н, m), 1.80 (2Н, m), 1.30 (2Н, m), 1.00 (ЗН, m).

Ge) and AM5 (thermal spraying): t/2 (МН 778.

Examples 9-27

The compounds of the following examples given in the tables were obtained by a method similar to the method of example 1, using the corresponding amine and imidazoline as starting substances.

Table 1 shows the structures of the compounds, and Table 2 shows the analytical data for each compound. iF) The term "n-Vy" in Table 1 means n-butyl. ko The starting imidazolide for examples 13, 24 and 25 can be obtained by the method described by Mopaiva. Spet., 88, 35 (1957). The starting imidazolide for examples 14 and 26 can be prepared as described in 3). Spent wasps because Rezhip Tgapv. 1, 11, 1205 (1996).

The starting imidazolide for example 15 can be prepared as described in Division 1 of App. Spet., 648, 72 (1961).

Table 1 b5

SD no

She 70 Yad | "1. Ayu

SAD iv od lvo sad ts s she 0595 ; day Od o

Z for F! i- od (Z yu

Shl, with | m. g | « y Che Z s o oo 15 g (7 1 -.20 (Che) (F) ko 60 65

SH Y

17 8 , ad bedskh 8 G -yi5 sd- ! GO st is hell 19 a SHHI. academic

OO F zo ; Kk 20 SIYA a Y

YOU are 21; "she ofyuok and s pnia z" S | 22 - Щ Х Х г выш | x t

C, 50 -1 50 and ge fvo 3e) | , where is it?

F) ko vo b5 t axis

There is also A FI 25 and ve g i n chi

S h min 21

OO sya shchi c) yin

Table 2

Table 2 (is)

H-NMR (400 MHz) solvent TAM (electrospraying): m

Me puh (Sosiz/StoOi) 8: 8.10 (18, s), 7.30-7.10 yu (108, m), 6.00 (38, d), 4.80 (18, wid. s ), 4.60-4.25 (5Н, m), 3.50- me 1773 3.40 (2Н, m), 3.20 (IN, m), 3.10 mg s (2Н, m), 2.45 (2Н, m), 2.35 (2Н, m), 1.40-1.35 (4Н, m), 1.20 (4Н, m), 1.00 (ЗН, t), 0 .80 (6H, t). - (SoSiz/SozOb) 8: 8.35 (18, m), 7.90 (18, m), 7.30-7.10 (158, m), 5.95 (18, m), 5, 20 (18, m), 4.75 (18, m), 4.55- . 10 14.45 (2H, m), 4.40-4.20 (ZH, m), iimn')7t92 « 3.50-3.20 (108, m), 2.65 (1H, m), 2.50 (18, m), 2.00-1.80 (24, m), 1.70-1.55 (2H, m), 1.20 (IN, m), 1:05-0, 90 (ZK, m). о, с (СрС13/СзО0) ate: 8.10 (1Н, с), 7.30-7.10 с "158, m), 6.05 (18, m), 4.70-4.55 Й z» 11 |(8, m), 4.45 (18, m), 4.40-4.25 imn'1794 " (3, m), 3.55-3.15 (VN, m), 3 .00- 2.80 (3Н, m), 2.45 (18, m), 1.00- 0.90 (98, m). (срс137С0505) 8: 8.35 (18, width s), 8.10 -I (18, s), 7.30-7.10 (158, m), 6.05 (IN, m), 1.75 (18, width s), 4.65 , so 12 (IN, width c), 4.50 (18, m), 4.40- IMN'1806 4.20 (ZN, m), 3.60-3.10 (108, m), 3.00- 2.85 (28, m), 2.75 (?Н, m), s! 1.80 (28, m), 1.50 (28, m), 1.40- and 1.10 (38) . , c), 4.50 mn" 1708, c | (2E, width s), 4.45 (18, s), 4.35- ImMma"/730 4.20 (6H, m), 3.50-3.15 (68, m), 0.95 (СрС1з/СО500) 8: 8.40 (18, width s), 8.15 14 | PE, s), 7.30-7.00 (158, m), 6.10 imn ')t22, - (18, width, s), 4.65-4.50 (ZH, m), mmA"1744 4.35-4.20 (ZY, m), 3.60-3.15 ( 6Y,

GF! m), 2.60 (28, m), 0.95 (ZN, t). more

NAME" 700, yu (sosiz/Sryu) nya to, bo 65

5: 8.15 (18, s), 7.30-7.10 (1bn, m), 6.05 (18, m), 4.70-4.20 (6, m), 3.60- 3.20 (78, M), 1.70, (2H, m), 1.60-1.40 (ZH, m), 1.20 (an, m), 1.00-0.90 (BN , m). (СОС13/С8305) and 5: 8.05 (1Н, s), 7.30-7.00 (13Н, m), 6.90 (1Н, m), 6.00.(1Н, ! 16 |m ), 4.70-4.60 (28, m), 4.40-4.20 "Mn"1778 (48, mi, 3.70-3.60 (28, m), 3.55- 3, 10 (ВН, m), 2.90-2.60 (68, m), 0.90 (ЗН, m). (со505) Y b: 8.10 (18, с), 7.30-7, 05 , 17 (158, m), 6.00 (18, width s), 4.50 IMN'Y598, (2H, width s), 4.45 (MN, s), 4.35- mma" )620 4.20 (68, m), 3.50-3.15 (68, m), 0.95 (ZV, t). (соС13/С9300) 5: 8.60 (18, width s), 8.15 (18, s), 7.30-7.15 (108, m), 6.05 , (18, dl), 4.80 (1H, width c), 4.50- and 184.30 (H, m), Z,50-3,15 (bY, z), 011 ! 2.45-2.35 (bH, m), 1.70 (2H, m), Y 1.55 (48, m), 1.40 (28, m), 1.05

IZN, t).

TSbsiiz/C0z05) I b: 8.15 (18, s), 7.30-7.10 (108, m), 6.05 (1H, m), 4.70 (1H, ; 19 |m), 4.45 (28, m), 4.40-4.20 (Z, IMN'i760 and m), 3.50-3.10 (bH, m), 3.05-2.90 (AN, m ), 2.45 (2n, mi), 1.70 (2N,m), 1.00-0.90 (15N,m).

ISrsiz/sruv) 8: 8.50 (18, s), 7.95 (1H, s), 7.40-7.20 (105, m), 6.50 (1H, m), 4.80 ( 18, m), 4.60-4.35 (ZN, m), 20 14.30-4.20 (OH, m), 3.80 (18, m), imi'i784 3.60 (1Н, m), 3.40-3.20 (ZN, m), ! 2.60-2.40 (EN, m), 2.15-2.00 (4H, ! m), 1.65-1.20 (101, m), 1.20 (ZN, | se t) . (SoS13/SUOYU) | at 5: 8.30 (15, s), 7.85 (18, m), 7.30-7.10 (10H, m), 6.10 (1H, m), Y 4.60 (1H, m), 4.50 (1Sh, m), 4.35 21 (2H, m), 4.20 (28, m), 3.80 (1H, (mya"1800 m), 3.50-3, 20 (ZN, m), 3.10 (2, m), 2.90 (2H, m), 2.50 (28, m), 7.00 (an, m), 1.40-1.20 (4H, m), He) zo 1.05 (ZH, t), 1.00-0.90 (12, m). ysrzor) 786 in b: 8.40 (1, s), 7.30- 7.50 (108, m), 6.10 (1H, m), 4.80 (1H, IS m), 4.50-4.25 (58, m), 4.05 (1H, m), 3.90 (28, m), 3.40-2.90 (VN, so m), 2.60 (2H, m), 1.90 (2H, m), 1.50 (2H, m), 1.10-1.00 (15Н, m). (СО300) y and b: 8.40 (18, s), 7.30-7.10 (105, m); 6.10 (1Н, m) , 4.80 (1H, 23 |m), 4.50-4.25 (7H, m), 4.05 (18, (mn'1771 m); 3.70 (18, m), 3.60 -3.10 (ВН, m), 2.60 (28, m), 2.15 (18, m), 2.10 (18, m), 1.10-1.00 (15Н, m). « (sozO0) 5: 8.40 (1H, s), 7.20-7.10 (158, m), 6.70 (18, m), 6.10 (18, - 24 |m), 4 .60 (18, m), 4.45 (2H, m), (mn'1735 s | 4.50-4.30 (4H, m), 3.80 (1H, m), 3.60-3 .29 (7H, m), 2.30 (1M, m), .2.10 (18, m), 1.053, is). and TSrzOYU)

And b: 8.20 (18, s), 7.30-7.10 (1158, m), 5.95 (1H, m), 4.70-4.40 25 |(4H, mu, 4, 30-4.20 (4K, m), 3.80 im-n')746 (IN, m), 3.55 (18, m), 3.30-3.00 (YAN, m), 2, 00-1.80 (2H, m), 2.40 -i (2H, mi, 110438, t). 100300)

OO | b: 8.40 (1, c), 7.40-7.10 ov | 58, m), 6.10 (1H, m), 4.60-4.20 Im-v' 1746 (7H, m), 3.70 (18, m), 3.50-3.20 1 ( bH, m), 2.80 (2Я, mi, 2.25 (18, m), 2.00 (1Н, m), 1.00 (ЗН, t). (Соз00И -| b: 8.40 ( 1Н, с), 8.00 (18, m), 7.50 (18, m), 7.35-7.20 (ВН, m),

He) Y 7.10 (28, m), 6.90 (18, m), 6.60 27 |(1Н, m), 6.05 (1Н, m), 4.60-4.15 im- n')802 "VN, m), 3.80-3.65 (2Н, m), 3.50- 3.20 (4Н, m), 2.85 (28, m), 2.25 (IN , m), 2.00 (18, m), 1.85 (28, m), 1.45 (2H, m), 1.00 (3H, t).

Example 28

F) (2553554К,5К)-5-2-((3К)-3-(C(2-diisopropylaminoethylamino)carbonyl)amino|pyrrolidinyl)carbonyl)-6-((2,2 ka -diphenylethyl)amino|-9Н -purin-9-yl)-M-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide bo 65

And here I am

CHON at 5. he

Solution of 6-(2,2-diphenylethyl)amino|-9-(2kK,3K,45,55)-5-Ketylamino)carbonyl|-3,4-dihydroxytetrahydro-2-furanyl)-9H-purin-2- carboxylic acid (Preparation 39) (200mg, 0.37mol), 79. M-(2-(diisopropylamino)ethylI-M'-(ZE)-pyrrolidineylurea (Preparation 44) (10bmg, 0.41mol), hydrochloride 1-" 3-dimethylaminopropyl)-3-ethylcarbodiimide (79 mg, 0.41 mol) and 1-hydroxybenzotriazole (5 mg, 0.037 mol) in dichloromethane (5 mL) were stirred at room temperature for 14 h. Water (mL) was added and the organic layer was separated. The aqueous phase was further extracted with dichloromethane (2 x 1 ml) and the combined extracts were dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a gradient system of dichloromethane: methanol concentrated aqueous ammonia (90:10:1, by volume), replacing the mixture of dichloromethane: methanol with concentrated aqueous ammonia (80:20:1, by volume). After evaporation of the corresponding fractions, the residue was triturated with diethyl ether with fir, filtered and dried to give the target compound as a white solid, (0.1g, 3590). 1H-NMR (400MHz, CO300) 8: 8.25 (1H, p), 7.30-7.10 (TON, m), 5.95 (IN, m), 4.70 (IN, m), 4.45 (2H, m), c 29 4.30-4.10 (4H, m), 3.70-3.40 (4H, m), 3.30-3.00 (7H, m), 2.50 (2N, m), 2.20 (2N, m), 1.80 (1N, m), 1.10-0.90 (15N, m). Gee)

IEM: t/h2 (MN) 771.

Example 29 (25535,4K,5K)-5-2-((35)-3|(12-(diisopropylamino)ethyl|amino)carbonyl)amino|pyrrolidinyl)carbonyl)-6-((2,2 b zo - diphenylethyl)amino|-9H-purin-9-yl|-M-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide ve and sn, iv) and i - s, o, h "on « yn and o) s Received with "with 6-(2,2-diphenylethyl)amino|-9-(2kK,3K,45,55)-5-Ketyl-amino)carbonyl/|-3,4-dihydroxytetrahydro-2-furanyl)-9H- of purine-2-carboxylic acid (Production 39) and M-(2-(isopropylamino)ethyl-M'-(35)-pyrrolidinyl|urea (Production 45) using the same method as in example 28. Specified in the title compound was obtained as a white powder - TN-NMR (400 MHz, CO5O0) 5: 8.25 (1M, s), 7.30-7.10 (1OH, m), 5.95 (IN, m), 4.70 (1IN, m), 4.45 (2Н, m), (95) 4.30-4.10 (4Н, m), 3.80-3.60 (4Н, m), 3.10 -2.90 (7N, m), 2.55 (IN, m), 2.40 (1IN, m), 2.30 (2N, m), 1.85 (1N, s m), 1.60 (2Н, m), 1.10-0.90 (15Н, m).

IEM: t/z IM-H") 769. - and Example 30 with 6-12,2-bis(3-methylphenyl)ethylamino)-M-(2-(12-(diisopropylamino)ethylamino)carbonyl)amino |ethyl)-9-(2K,3

Kk,45,55)-5-(ethylamino)carbonyl)-3,4-dihydroxytetrahydro-2-furanyl)-9H-purine-2-carboxamide not | | o o ' her A AKA in | p

And GU shock about

Dn

Bbb solution (2, ZK, A5,55)-4-(benzoyloxy)-2-(6-Х2,2-bis(3-methylphenyl)ethyl|amino)-2-iodo-9H-purin-9-yl) -5-Ketylamino)carbonyl|tetrahydro-3-furanylbenzoate (Preparation 48) (200mg, 0.24mol),

M-(2-aminoethyl)-M'-(2-(diisopropylamino)ethyl|urea (Preparation 52) (27mg, 1.18mol) and tetrakis(triphenylphosphine)palladium(0) (27mg, 0.024mol) in THF ( bBml) were subjected to carbonylation at 609C and

C45Kpa in a carbon monoxide atmosphere for 14 hours. TLC analysis showed the presence of the target product alongside a substance that had partially lost its protective groups. In order to achieve complete removal of protective benzoate groups, the solvent was evaporated under reduced pressure, the residue was dissolved in methanol (1Oml), sodium carbonate (1Omg) was added, and the mixture was left to stir at room temperature for 24 hours.

The solvent was evaporated again under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a gradient system of dichloromethane:methanol (90:10, by volume), changing to a mixture of 7/0 dichloromethane:methanol:concentrated aqueous ammonia (90:10 :11, by volume). After evaporation of the corresponding fractions, the residue was triturated with diethyl ether, filtered and dried to give the target compound as a white solid (0.11m, 61965). 7"H-NMR (400 MHz, CO5O0) 5: 8.40 (1M, s), 7.20-7.10 (6H, m), 6.95 (2H, m), 6.10 (1H, m ), 4.45-4.35 (4H, m) g 3.55-3.00 (TON, m), 2.55 (2H, m), 2.30 (BN, s), 1.10- 0.90 (15N, m).

IEM: t/ MN" 773.

Example 31 6-12,2-bis(33-chlorophenyl)ethyl|amino)-M-2-(((2-(diisopropylamino)deethylamino)carbonyl)amino|ethyl)-9-(2K,3K 45.55) -5-Ketylamino)carbonyl/|-3,4-dihydroxytrahydro-2-furanyl)-9H-purine-2-carboxamide: 909 s a

She is "U sha s s ! kl sn, o nya OM " ve Ye pn F

(2K,3K,45,55)-4-(benzoyloxy)-2-(6-(2,2-bis(3-chlorophenyl)ethyl|amino)-2-iodo-9H-purine-9 -yl)-5-Ketylamino)carbon of yl|hetrahydro-3-furanylbenzoate (Preparation 49) and M-(2-aminoethyl)-M'-(2-(disopropylamino)ethyl|urea it) (Preparation 52) in a similar way described in example 30. The target compound was obtained as a white solid. "H-NMR (400MHz, СО5О0) 5: 8.40 (1M, s), 7.45-7.15 (6Н, m), 6.10 (1Н, m), 4.50-4.40 ( 4Н, m), 3.60-3.20 - (ЕН, m), 3.05 (2Н, m), 2.90 (2Н, m), 2.45 (2Н, m), 1.05 ( ЗН, т), 0.80 (12Н, d).

IEM: t/y (М-Н 815.

Example 32 "6-12,2-bis(3-chlorophenyl)ethyl|amino)-9-(2k,3K,45,55)-5-K(ethylamino)carbonyl)|-3,4-dihydroxytetrahydro-2- fu -o : : : y y y s ranyl)-m-(2-((12-(1-piperidinyl)ethylIamino)carbonyl)iamino)ethyl)-9H-purine-2-carboxamide;" - and b ZU o | E -K 1 your -0..50 n ud i o iChe)

Obtained from (2K,3K,45,55)-4-(benzoyloxy)-2-(6-12,2-bis(3-chlorophenyl)ethyl|amino)-2-iodo-9H-purin-9-yl) -5-Ketylamino)carbon 5B of yl|Itetetrahydro-3-furanylbenzoate (Production 49) and /M-(2-aminoethyl)-M'-(2-(1-piperidinyl)ethyl|urea (Production 53) by a method similar to that described in example 30. The target compound was obtained as a white (F) solid. co 1n-NMR (400 MHz, СО53О0) δ: 8.40 (1M, w.c), 7.45-7.10 (8H, m) , 6.10 (1IN, d), 4.50-4.35 (4Н, m), 3.55-3.20 (8Н, m), 2.80-2.60 (6Н, m), 1 .70-1.40 (6H, m), 1.00 (ZH, t). in IEM: t/h IM-H") 797.

Example 33 6-12,2-bis(3-methylphenyl)ethylamino)-9-(2K,3K,45,55)-5-Ketylamino)carbonyl|-3,4-dihydroxytetrahydro-2-furanyl)- M-12-I412-(1-piperidinyl)ethylamino)carbonyl)amino|ethyl)-9H-purine-2-carboxamide b5 ev what ; at 7 with o

AND

/ n loyu ne і і on

Obtained from (2K,3K,45,55)-4-(benzoyloxy)-2-(6-12,2-bis(3-methylphenyl)ethyl|amino)-2-iodo-9H-purin-9-yl) -5-Ketylamino)carbo 7/5 Nil|tetrahydro-3-furanylbenzoate (Preparation 48) and M-(2-aminoethyl)-M'-(2-(1-piperidinyl)ethyl)urea (Preparation 53) by a method similar to described in example 30. The target compound was obtained as a white solid.

TN-NMR (400MHz, SOZO0) 85: 8.40 (1Н, shr.s), 7.20-7.10 (6Н, m), 6.95 (2Н, m), 6.10 (1Н, d ), 4.45-4.30 (AN, m), 3.55-3.20 (8Н, m), 2.80-2.60 (6Н, m), 2.20 (6Н, s), 1.70-1.40 (6H, m), 1.00 (ZH, t).

IEM: t/h2 MN") 758.

Example 34 4A-ISH(2-(1(6-К(2,2-diphenylethyl)amino|-9-(2к,3Кк,45,55)-5-(ethylamino)carbonyl!/|-3,4- dihydroxytetrahydro-2-furanyl)-9H-purin-2-yl)carbonyl|amino)ethyl)amino)carbonyl)amino)methyl|benzoic acid dO o (8) t 2 I i (o)

Yi yu yu, chayn " - ro v

Benzyl solution o

A-IKSHK2-1(6-(2,2-diphenylethyl)amino|-9-(21k,3kK,45,55)-5-(ethylamino)carbonyl|/-3,4-dihydroxytetrahydro-2-fur anil)-9H-purin-2-yl)carbonyl|iamino)ethyl)amino|carbonyl)iamino)methyl|benzoate (Preparation 55) (15Omg, 0.18mol) in ethanol (1Oml) was hydrogenated at room temperature over 1095 wt/ mass, palladium-on-carbon (ZOmg) for 28 hours at 414 Kpa. The catalyst was removed by filtration through Arbocel (Agrose! - trade mark) and the solvent was evaporated under reduced pressure to give the title compound as a white powder (26bmgH). "H-NMR (400 MHz, CO3O0) 5: 8.40 (1M, s), 7.80 (2H, d), 7.40 (4H, m), 7.25 (6H, m), 7.15 (2Н, m), 610 s (IN, m), 4.80 (1Н, m), 4.50-4.30 (5Н, m), 3.60-3.40 (4Н, m), 3 .40-3.20 (2H, m), 1.05 (ZH, t). "» IEM: t/g2 (M-H7) 750. " Example 35 6-(2,2-diphenylethyl)amino 9-(2kK,3K,45,55)-5-Ketylamino)carbonyl11-3,4-dihydroxytetrahydro-2-furanyl)-M- (2-ISHTC1-(2-pyridyl)-4-piperidinylIamino)carbonyl)amino| Ethyl)-9H-purine-2-carboxamide -1 and in her "DK with VL MAH AKA 2 iChe) it ion 25 To the solution

HF) 9-(Zac,4k,65,base)-6-Ketylamino)carbonyl|-2,2-dimethyltetrahydrofuroyl3,4-4111,3|dioxol-4-yl)-6-K2,2-diphenylyl) amino|-M-12-I411-(2-pyridinyl)-4-piperidinylamino)carbonyl)amino)ethyl)-9H-purine-2-carboxamide. (Preparation 71) (20.9 g, 0.0255 mol) in absolute ethanol (200 ml) was added aqueous hydrochloric acid (76.5 ml of 1M solution, 0.0765 mol) and the resulting solution was heated at 60-652C for 24 hours. The reaction mixture 60 was allowed to cool to ambient temperature and a saturated aqueous solution of sodium bicarbonate (200 mL) was carefully added. The resulting mixture was then concentrated in vacuo and then the aqueous mixture was extracted with ethyl acetate (200ml) and then with dichloromethane (200ml). The extracts were dried over anhydrous magnesium sulfate, which precipitated the resin, which was redissolved by adding dichloromethane (100 mL) and methanol (20 mL). The resulting purple solution was then concentrated in vacuo to give the crude product as a purple foam (20.86 g), which was purified by flash chromatography on silica gel (bO0OgHg),

eluting using a gradient system starting at 695 rpm. methanol in dichloromethane, changing to 895 v/v. methanol in dichloromethane, changing to 1095 vol./vol. methanol in dichloromethane, changing to 1595 vol./vol. methanol in dichloromethane to give the title compound in several fractions of varying purity.

The main fraction (11.4g) was dissolved in dichloromethane (2b64ml) and filtered to remove undissolved matter. Diethyl ether (112 ml) was added to this solution and the resulting cloudy mixture was stirred at ambient temperature for 1 hour. The solids were then collected by filtration and dried under vacuum. This substance was then crushed using a pestle and mortar and dried additionally in a vacuum at 502C, obtaining the title compound (9.9g) in the form of finely ground colorless 7/0 powder.

I EM (positive chemical ionization at atmospheric pressure): t/2 (МН 7,778. "H-NMR (600 MHz, a--DMSO, 302С) 5: 8.80 (0.8Н, width t), 8, 67 (02H, width s), 8.53 (02H, width s), 8.48 (0.8H, s), 8.28 (IN, t), 8.10-8.02 (1, 8H, m), 7.84 (02H, width s), 7.50-7.30 (5H, m), 7.26 (4H, t), 7.14 (2H, t), 6.75 (1H, d), 6.56 (1H, dd), 6.11-5.82 (ZH, m), 5.65 (1IN, d), 5.57 (02H, width.s), 5, 53 (0.8N, d), 4.72 12 (02N, width.s), 4.68-4.50 (2.2N, m), 4.36-4.21 (2.8N, m) , 4.17 (08H, width c), 4.04 (2H, width d), 3.67-3.55 (IN, m), 3.40-3.10 (6H, m (partly unclear due to the water signal), 2.91 (04H, width c), 2.81 (1.6H, width t), 1.74 (2H, width d), 1.30-1.16 (2H .

The following Preparations describe the synthesis of some intermediate compounds used in the previous examples.

PREPARATION 1 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-UN-purine

Phi p

A, o 2,6-dichloro-UN-purine (20m, 0.1imole) and 4-toluenesulfonic acid monohydrate (0.2g) were dissolved in b ethyl acetate (300ml), the mixture was heated to 50920 and slowly added over 30 minutes a solution - of 3,4-dihydro-2H-pyran (12.bml, 0.14mol) in ethyl acetate (bOml). The reaction mixture was cooled to room temperature, water (10 Oml) was added, and the pH of the solution was adjusted to 7 by adding a saturated aqueous solution and sodium bicarbonate. The organic layer was separated, washed successively with water and saturated salt solution, dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue was azeotroped with pentane (x2) to give the title compound as a slightly He contaminated white solid (30.9G). "H-NMR (400MGu, SOSI") 8: 8.30 (1M, s), 5.75 (1H, dd), 4.25-4.15 (1H, m), 3.85-3.70 (1Н, m), 2.20-1.60 (ЕН, m).

PREPARATION 2 "2-chloro-N-(2,2-diphenylethyl)-9-(tetrahydro-2H-pyran-2-yl)-9UN-purin-6b-amine ssh cineovae;" we - 2. (95) ; "and 1 - 50

Ge) A solution of 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9UN-purine (Preparation 1) (30.9g, 0.11mol) in isopropyl alcohol (bbOml) was treated with M-ethyl- M-isopropyl-2-propanamine (47.5 mol, 0.27 mol) and 2,2-diphenylethylamine (24.8 g, 0.1 mol) and the resulting mixture was heated at reflux for 3 hours. dv The solvent was removed under reduced pressure and the residue was subjected to azeotropic distillation with ethyl acetate. The residue was purified by column chromatography on silica gel, eluting using a gradient system (F, ethyl acetate-hexane (40:60, by volume), changing gradually to a mixture of ethyl acetate:hexane (60:40, by volume), and obtaining the title compound in the form of a foam (49, 7g). 7"H-NMR (400MHz, SOSILia) 8: 7.95-7.75 (1M, width s), 7.35-7.15 (1OH, m), 5 ... 10 (IN, d), 3.70 (1Н,...t), 2.05-1.95 (2Н, m), 1.95-1.80 (1Н, m), 1.80-1, 55 (ZN, m).

RECEIPT OF

IM-(2,2-diphenylethyl)-2-(methylsulfanyl)-9-(tetrahydro-2H-pyran-2-yl)-UN-purin-6b-amine b5 ni chu s 7i zsv,

A solution of 2-chloro-N-(2,2-diphenylethyl)-9-(tetrahydro-2H-pyran-2-yl)-9UN-purine-b6-amine (Preparation 2) (49.7g, 79,011mol) in dry M,M-dimethylformamide (200ml) was treated with sodium thiomethoxide (10g, 0.14mol) and the resulting mixture was heated under a nitrogen atmosphere at 10092 for 90 minutes. The mixture was stirred at room temperature for 72 hours and then heated additionally at 1009 for 2 hours. The reaction mixture was cooled and diluted with water (1000 ml). The resulting suspension was extracted with diethyl ether (x2). The combined organic layers were washed successively with water and saturated salt solution, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was azeotroped with diethyl ether and then with pentane to give the title compound as a foam (48.9G).

TN-NMR (400 MHz, SOS) 85: 7.80 (1H, p), 7.20-7.10 (TON, m), 5.70-5.55 (2H, d), 4.40-4 ,20 (ЗН, m), сч 4.20-4.05 (1Н, m), 3.80-3.65 (1Н, m), 2.60 (ЗН, с), 2.15-1, 90 (ZN, m), 1.90-1.60 (ZN, m).

RECEIVING 4 o)

IM-(2,2-diphenylethyl)-2-(methylsulfonyl)-9-(tetrahydro-2H-pyran-2-yl)-UN-purin-6b-amine cheF F ich-s nn

IS)

IN

4 and - because

A solution of Oxon (Ohope - trade mark) (potassium peroxymonosulfate) (44g, 71.7mol) in water (200ml) was added dropwise over 2 hours to a solution of o) with IM-(2,2-diphenylethyl)-2-(methylsulfanyl) -9-(tetrahydro-2H-pyran-2-yl)-9UN-purine-b6-amine (Preparation 3) (25g, "» 56.2mol) and sodium bicarbonate (20g, 238mol) in acetone (10000ml) and water (250ml). The resulting mixture was stirred at room temperature for 24 hours, filtered and the residue washed with acetone.

Acetone was removed from the filtrate under reduced pressure and the resulting aqueous residue was extracted with ethyl acetate and then dichloromethane. The combined organic layers were washed with saturated salt solution, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was triturated with diethyl ether, filtered, washed with diethyl ether and pentane and then dried to give the title compound as a white solid (20.32 g). ini TN-NMR (400 MHz, SOSIi) 85: 8,000 (IN, s), 7.35-7.15 (1OH, m), 6.05-5.95 (1H, width s), 5.75 ( 1H, d), and 20 AAO-435 (IN, m), 4.35-4.20 (2H, width s), 4.15-4.05 (1IN, m), 3.75 (1IN , t), 3.30 (ZH, s), 2.18-2.05 (1Н, m), 2.05-1.98 (1Н, m), 1.98-1.80 (1Н, 20 m), 1.80-1.60 (ZN, m). PREPARATION 5 6-(2,2-diphenylethyl)amino19-(tetrahydro-2H-pyran-2-yl)-9H-purine-2-carbonitrile

F) name) 60 / Zh ry

M cm b5

A solution of M-(2,2-diphenylethyl)-2-(methylsulfonyl)-9-(tetrahydro-2H-pyran-2-yl)-9UN-purin-6-amine (Preparation 4) (20.1g, 42.mol ) in dry M,M-dimethylformamide (100 ml) was treated with potassium cyanide (5.5 g, 84.6 mol) and the mixture was heated at 12027 for 24 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, poured into water (1000 ml) and stirring was continued for an additional 1 hour. The resulting solid was filtered and washed several times with water. Then the solids were dissolved in dichloromethane and the solution was washed with water, dried with anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue was subjected to azeotropic distillation with diethyl ether (twice).

Obtaining the title compound as an oil (17g). 70 TNA-NMR (400MHz, SOSI) 85: 8.00 91M. C), 7.40-7.20 (TON, m), 6.00-5.75 (1H, width s), 5.70 (1H, d), 4.40-4.20 (ZH, m), 4.20-4.10 (1Н, m), 3.80-3.70 (1Н, m), 2.20-1.90 (ЗН, m), 1.90-1.60 ( ZN, m).

PREPARATION 6 6-(2,2-diphenylethyl)amino|-9UN-purine-2-carbonitrile sad and sy

A solution of 6-(2,2-diphenylethyl)amino|-9-(tetrahydro-2H-pyran-2-yl)-9UN-purine-2-carbonitrile (Preparation 5) (17g, 40.1mol) in ethanol (8500ml) was treated with 2N aqueous hydrochloric acid (5Oml) and the mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure, the remaining He) was dissolved in ethanol and the solvent was removed again under reduced pressure. The residue was triturated with diethyl ether, filtered, washed with diethyl ether and pentane, and dried to give the title compound as a solid (13.6 gHg). 7TH-NMR (400MHz, DMSO-dv) 5: 8.30 (1M, s), 8.20-8.05 (1H, upshr.s), 7.40-7.10 (10OH, m), 4 .60-4.40 (1.4Н, b m), 4.20-А.00 (1.6Н, m). m

And EM ((thermal spraying): t/2 (МН 7 341. ю

RECEIVING 7

Methyl 5-((2,2-diphenylethyl)amino|-UN-purine-2-carboxylate)

A solution of 6-((2,2-diphenylethyl)amino|)-UN-purine-2-carbonitrile (Preparation 6) (5.0g, 14.7mol) and sodium methoxide (4.0g, 74.1mol) in methanol (ZOO ml) was heated at reflux for 24 s hours. Sodium methoxide (2.0 g, 3/mol) and methanol (10 Oml) were additionally added, and heating was continued for an additional 24 hours. The reaction mixture was allowed to cool and the solvent was removed under reduced pressure. The residue was dissolved in tetrahydrofuran (THF) (375 ml), 2N aqueous hydrochloric acid -1 50 (125 ml) was added and the mixture was stirred at room temperature for 24 hours. THF was removed under reduced pressure and the suspension was basified to pH7 with a saturated aqueous solution of sodium bicarbonate. Ethyl acetate (100 ml) was added and

Me) a white solid, which is mainly the target product, was filtered off, washed with a small amount of water and ethyl acetate and dried. Purification by column chromatography on silica gel, with elution using a gradient system, starting from a mixture of dichloromethane:methanol (90:10, by volume) and gradually changing to a mixture of dichloromethane:methanol (75:25, by volume) gave the indicated in the title the compound y

Gee! in the form of a white solid, 1.25 g (25965). Evaporation of the ethyl acetate filtrate yielded 2.6 bg of the starting material. where "H-NMR (400 MHz, SOSIv) 5: 12.40 (1M, width s), 8.05 (IN, s), 7.55 (1H, s), 7.30-7.20 (1OH , m), 4.80 (2Н,

M), 4.75 (1Н, m), 3.80 (ЗН, с). 60 I AM5 (thermal spraying): t/2 (MN) 375.

RECEIVING 8

Methyl 9-(21k,3kK,4Kk,55)-3,4-bis(benzoyloxy)-5-Ketylamino)carbonyl|tetrahydro-2-furanyl)-6-((2,2-diphenylethyl)amino|- 9H- purine-2-carboxylate b5 ni ! | "

En wasp, yuyu. чно vo ї -7 o o o

A suspension of methyl 6-((2,2-diphenylethyl)amino|--H-purine-2-carboxylate (Preparation 7) (44mg, 1.18mol) in 1,1,1-trichloroethane (25ml) was treated with M,O- bis(trimethylsilyl)acetamide (1.7 mL, 6.95 mol). The mixture was heated at reflux for one hour. The solution was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was treated with a solution (25, 35, 4K, 5K )- and (25,35,4K,55)-5-(acetyloxy)-4-(benzoyloxy)-2-Ketylamino)carbonyl|hetrahydro-3-furanyl-benzoate (Preparation 14) (620mg, 1.4mol) in anhydrous toluene (25 mL) and then trimethylsilyltrifluoromethanesulfonate (0.26 bmL, 1.42 mol). The resulting solution was then heated at 1102C in a nitrogen atmosphere for 2.5 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (200 ml) and washed with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography, using gradient elution first with a mixture of dichloromethane:ethyl acetate (5:1, v/v), then dichloromethane:ethyl acetate (1:11, v/v) to give the title compound as a foam (54Omg, Ge") from 6095).

TN-NMR (400 MHz, SOSIz) 5: 8.10 (ZH, m), 7.80 (2H, d), 7.60 (1H, m), 7.50-7.40 (4H, m), 7.35-7.20 (16Н, - m), 6.40 (IN, m), 6.20 (2Н, m), 5.90 (IN, m), 4.90 (1Н, d), 4.40 (ZN, m), 4.00 (ZN, s), 3.55 (IN, m), 3.35 1 (IN, m), 1.15 (ZN, t). co

And M5 (thermal spraying): t/2 (MMa "| 777.

RECEIPT 9 -

Methyl 6-(2,2-diphenylethyl)amino|-9-(2kK,3kK,45,55)-5-Ketylamino)carbonyl|-3,4-dihydroxy)hetrahydro-2-furanyl)-9H-purin- 2-carboxylate "- with 2" and -I "I 7zn o - osn, 1 - "Chon

Ge) not I he

Solution methyl 25 9-(21k,3kK,4Kk,55)-3,4-bis(benzoyloxy)-5-Ketylamino)carbonyl|tetrahydro-2-furanyl)-6-((2,2-diphenylethyl)amino|-

HF) of 9H-purine-2-carboxylate (Preparation 8) (3.4g, 4.5mol) and sodium carbonate (50mg) in dry methanol (bOml) was stirred at room temperature for four hours.

The solvent was removed under reduced pressure and the residue was placed in a mixture of dichloromethane:methanol (95:5, by volume, bOml). Inorganic salts were filtered off and the filtrate was evaporated under reduced pressure. The residue was triturated with 60% diethyl ether, filtered and dried to give the title compound as a white solid (2.4g, 98965). "H-NMR (400 MHz, DMSO-iv) 5: 8.60 (1M, m), 8.15 (2H, lat.s), 7.40-7.15 (1OH, m), 6.00 ( 1H, width - m), 5.60 (IN, width.s), 5.50 (IN, width.s), 4.60-4.40 (ZN, m), 4.30 (IN, s) , 4.10-4.05 (2Н, m), 4.00-3.80 (ЗН, m), в5 3.20 (2Н, m), 1.00 (ЗН, t).

And AM5 (thermal spraying): t/2 (МН 547.

RECEIPT 10

M-(2-aminoethyl)-6-(2,2-diphenylethyl)amino1-9-(2k,3K,48,55)-5-Ketylamino)carbonyl|-3,4-dihydroxytetrahydro-2-furanyl)- 9M-purine-2-carboxamide and c) and "

In and Zhayu m, "chn on

A mixture of methyl 6-(2,2-diphenylethyl)amino|-9-(2kK,3K,45,55)-5-Ketylamino)carbonyl|-3,4-dihydroxytetrahydro-2-furanyl)-9H-purin-2 -carboxylate (Preparation 9) (1.1 g, 2 mol) and 1,2-ethylenediamine (1.1 g, 18.3 mol) were heated at 105 2C for 2.5 hours. The mixture was dissolved in a small amount of dichloromethane and purified by column chromatography on silica gel, eluting with a mixture of dichloromethane:methanol:concentrated aqueous ammonia (85:15:1.5, by volume).

After evaporation of the corresponding fractions, the residue was triturated with diethyl ether, filtered and dried to give the target compound as a white solid (0.99g, 86905). s 29 "H-NMR (400MHz, SOS15) 5: 8.75 (1M, width, s), 8.60 (1IN, width.s), 7.50 (IN, width.s), 7.40- 7.20 (10N, m), 9 6.90 (IN, d), 6.10 (IN, width.s), 5.05 (1TN, s), 4.55 (1N, s), 4, 45-4.20 (4H, m), 3.50-3.35 (4H, m), 2.95 (2H, t), 1.25 (ZH, t).

I AM5 (thermal spray): t/2 (MH) 575. o z OBTAINED 11 (Za5,45,6K,bac)-Mm-ethyl-6-methoxy-2,2-dimethyltetrahydrofuroi3,4-4111,3|dioxol- 4-carboxamide o dk o so "v i - l z, He o sn, "

To a stirring solution, (Zac,45,6K,ba)-6-methoxy-2,2-dimethyltetrahydrofuro3,4-4111,3|dioxol-4-carboxylic acid |). Ateg. Set. ts bos, 80, 5168-5173 (1958)) (23.30g, 107mol) in anhydrous dichloromethane (120ml) and M,M-dimethylformamide (2 drops) was added dropwise to oxalyl chloride (14.0ml, 1b0mol) and the mixture was stirred at room temperature for 3 hours until gas evolution stopped. TLC analysis showed that some starting material still remained in the reaction mixture, so additional M,M-dimethylformamide (2 drops) was added and stirring was continued for 1 hour. The solvent was removed under reduced pressure and the residue was azeotroped and distilled with anhydrous dichloromethane (x2). The residue was dissolved in anhydrous dichloromethane (200 ml) and the solution was treated dropwise with ethylamine (2 M solution in tetrahydrofuran, 140 ml, 280 mol). This solution was left for 48 hours at room temperature. Diethyl ether (2500 ml) was added and the mixture was stirred for 15 minutes. The mixture was filtered and the solvent was removed from the filtrate under reduced pressure. The residue was purified by -I 20 column chromatography on silica gel, eluting using a gradient system starting with dichloromethane and changing gradually to a mixture of dichloromethane ethyl acetate (44:66, by volume) to afford the title compound as a yellow solid (24, 70OGh). "H-NMR (400 MHz, SOSIv) 5: 6.53 (1M, w.m), 5.12 (1H, dd), 5.07 (1H, d), 4.60 (1H, d), 4 .54 (1Н, dd), 3.46 (ЗН, с), 3.32 (2Н, m), 1.51 (ЗН, с), 1.34 (ЗН, с), 1.15 (ЗН, t).

And AM5 (thermal spraying): t/2 (MH 246. (F) PREPARATION of 12 from (25,35,4K,5K)- and (25,35,4K,55)-M-ethyl-3,4-dihydroxy- 5-methoxytetrahydro-2-furancarboxamide a 60 "a Oh

NI I he b5

A solution of (Za5,45,6K,bac)-M-ethyl-b6-methoxy-2,2-dimethyltetrahydrofuroyl3,4-a)P1,3)dioxole-4-carboxamide (Preparation 11) (24.60g, 100mol) and Pyridinium p-toluenesulfonate (2.50g, 1Omol) in methanol (500ml) was heated at reflux for 18 hours. NMR analysis showed that some of the original Dichovy still remained in the reaction mixture and therefore the solvent was removed under reduced pressure. The residue was dissolved in methanol (500 ml) and heated at reflux for 8 hours. NMR analysis showed that some starting material still remained in the reaction mixture and therefore the solvent was removed under reduced pressure, the residue was dissolved in methanol (500ml) and heating at reflux was continued for 24 hours. The solvent was removed under reduced pressure and the residue was azeotropically distilled with dichloromethane (x3) to give the title compound as an oil and a mixture of A and B anomers (20.50 g).

TNA-NMR (400 MHz, SOSIv) 5: 6.58 (1N, shir.m), 4.99 (0.25N, d), 4.94 (0.75N, d), 4.46 (0.25N , d), 4.37 (1.5N, m), 4.24 (0.25N, dd), 4.05 (1N, m), 3.52 (0.75N, s), 3.47 ( 2.25Н, с), 3.30 (2Н, m), 1.16 (ЗН, m).

PREPARATION 13 (25,35,4K,5K)- and (25535,4K,55)-4-(benzoyloxy)-2-Ketylamino)carbonyl|-5-methoxytetrahydro-3-furanylbenzoate

A solution of benzoyl chloride (30.00 ml, 259 mol) in dichloromethane (100 ml) was slowly added to a solution of (25535,4K,5K)- and (25,535,4K,55)-M-ethyl-3,4-dihydroxy-5-methoxytetrahydro- of 2-furancarboxamide (Preparation 12) (20.50g, 100mol) and pyridine (33.00ml, 409mol) in dichloromethane (4000ml) and the resulting mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue was partitioned between diethyl ether and aqueous hydrochloric acid (1M, 300ml). The layers were separated and the aqueous layer was re-extracted with diethyl ether. The organic layers were combined, washed successively with water and saturated salt solution, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting using a gradient system of dichloromethane:diethyl ether (955, by volume), gradually changing to a mixture of m dichloromethane:diethyl ether (80:20, by volume), obtaining the title compound in the form of oil and in the form of a mixture of anomers (37,OGh).

TNA-NMR (400 MHz, SOSIL) 85: 8.16 (0О5БН, d), 7.95 (1.5Н, d), 7.88 (1.5Н, d), 7.81 (05Н, d), 7.25-7.66 (6Н, m), 6.65 (IN, width, m), 5.88 (1Н, m), 5.60 (0.75Н, dd), 5.46 (025Н, d), 5.23 (0.75N, d), 5.17 (0.25N, « t), 4.80 (1N, m), 3.59 (2.25N, s), 3.49 ( 0.75Н, с), 3.39 (2Н, m), 1.23 (ЗН, t). 2 s RECEIVING 14 (25,35,4K,5K)- and ; (25,35,4K,55)5-(acetyloxy)-4-(benzoyloxy)-2-K(ethylamino)carbonyltetrahydro-3-furanylbenzoate Che) Y » 5B Solution of (25,35,4K,5K)- and (25,35,4K,55)-4-(benzoyloxy)-2-(ethylamino)carbonyl|-5-methoxytetrahydro-3-furanylbenzoate (Preparation 13) o (37.0g, 89.bmol) in a mixture of acetic acid (30ml, 5.7/mol) and acetic anhydride (w/ml, 7O09mol) was cooled to -102C, then treated dropwise with aqueous hydrochloric acid ( 12n, 7.0ml, 132mmol).

The mixture was stirred for 18 hours, allowing it to warm to room temperature during this time. 60 After cooling the mixture to 02С, water (1000ml) was slowly added to it and then extracted with ethyl acetate (3x500ml). The organic layers were combined, washed successively with water, a saturated aqueous solution of sodium bicarbonate and a saturated salt solution, then dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting using a gradient system, starting from a mixture of diethyl ether:pentane (66:44, by volume), and changing gradually to diethyl ether. The residue was further purified by column chromatography on silica gel, eluting using a gradient system, starting with a mixture of dichloromethane:diethyl ether (95:5, by volume) and changing gradually to a mixture of dichloromethane:diethyl ether (90:10, by volume) , obtaining the title compound in the form of a mixture of A and B anomers (15.40 g).

TNA-NMR (400 MHz, SOSIL) 85: 8.12 (08M, d), 7.97 (12H, d), 7.92 (1.2H, d), 7.79 (08H, d), 7, 24-7.65 (bH, m), 6.73 (04H, d), 6.62 (04H, width, m), 6.46 (0.6H, width, m), 6.42 (0, 6Н, d), 6.07 (0.4Н, dd), 5.95 (0.6Н, t), 5.72 (06Н, d), 5.44 (04Н, t), 4.94 (04Н , d), 4.86 (0О6Н, d), 3.36 (2Н, m), 2.17 (1.8Н, с), 2.10 (1.2Н, с), 1.20 (ЗН, m).

PRODUCTION 15 9-(21k,3kK,4kK,5K)-3,4-bis(acetyloxy)-5-(acetyloxy)methyl|hetrahydro-2-furanyl)-6-((2,2-diphenylethyl)amino) 70 -9H-purine-2-carboxylate

Suspension of methyl 6-((2,2-diphenylethyl)amino|--H-purine-2-carboxylate (Preparation 7) (1.5g, 4.02mol) in ( 8) 1,1,1-trichloroethane (40 mL) was treated with M,O-bis(trimethylsilyl)acetamide (4.vmL, 19.bmol). The mixture was heated at reflux for two hours. The solution was allowed to cool to room temperature and The solvent was removed under reduced pressure. .98 ml, 5.433 mol). The resulting solution was heated at reflux in a nitrogen atmosphere for 3 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (20 ml) and washed with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was separated and dried over anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure.

335 Column chromatography on silica gel using gradient elution, starting with a mixture of ethyl acetate:pentane (70:30, by volume), then ethyl acetate:pentane (80:20, by volume), then ethyl acetate, obtaining the indicated in title compound in the form of foam (2.05 g).

TN-NMR (400MHz, SOSIi) 85: 8.00 (1M, lat.s), 7.35-7.20 (11Н, m), 6.25 (IN, m), 5.85-5.70 (ЗН, m), 4.50-4.30 (5Н, m), 4.00 (ЗН, с), 2.15 (ЗН, с), 2.10 (ЗН, с), 2.05 ( ZN, c). "

And EM (thermal spraying): t/2 |MMa | 655. - with PREPARATION 16 i Methyl ,» 9-(2K,ZK,45,5K)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl-6-(2,2-diphenylethyl)amino| -UN-purine-2-carboxylate with 58 (95) 1 - 70 ! ; "hE te) r | A osn,

IN

"on (F, i on o Solution methyl 9-(2k,3kK,4Kk,5K)-3,4-bis(acetyloxy)-5-Kacetyloxy)methyl/tetrahydro-2-furanyl)-6-(2,2 -diphenylethyl)amino|-9H- 60 purine-2-carboxylate (Preparation 15) (2.0g, 3.17mol), sodium carbonate (35mg) and dry methanol (40ml) were stirred at room temperature for 3.5 hours. Solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using gradient elution starting with dichloromethane:methanol (94:6, v/v), then dichloromethane:methanol (92:68, v/v) to give the indicated in the title, the compound in the form of a white powder (1.5 Hg). for "H-NMR (400 MHz, SOSIia) 5: 7.80 (1M, width c), 7.35-1.20 (1OH, i), 5 .95 (IN, width s), 5.75 (2H, m), 5.10

(IN, m), 4.90 (1H, ushr.s), 4.40 (ZH, m). 4.30 (1H, s), 4.15 (1H, m), 3.90 (1H, m), 3.80-3.70 (4H, m), 3.15 (1H, s).

And M5 (thermal spraying): t/2 (MMa "| 528.

ACQUISITION 17

M-(2-aminoethyl)-9-К2К,ЗК,45,5К)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl|-6-(2,2-diphenylethyl)amino|-9Н -purine-2-carboxamide | that chh "1 - Z ih

KM, "vol

BUT. t-

EZ on

A mixture of methyl 9-(2K,ZK,45,5K)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl|-6-((2,2-diphenylethyl)amino|-9H-purine-2 -k carboxylate (Preparation 16) (0.52 g, 1.0 mol) and 1,2-ethylenediamine (0.bg, 1 mol) were heated at 10592 for

From hours The mixture was dissolved in a small amount of dichloromethane and purified by column chromatography on silica gel, eluting with a mixture of dichloromethane:methanol:concentrated aqueous ammonia (85:15:1.5, by volume). After He evaporation of the corresponding fractions, the residue was triturated with diethyl ether, filtered and dried, obtaining the target compound as a white solid (0.43 g, 78905). "H-NMR (400 MHz, SOSIa) 5: 8.00 (1M, s), 7.30-7.15 (12H, m), 5.85 (1H, d), 4.70 (1H, t) , 4.40-4.30 (2H, m), 4.30-4.10 (ZH, m), 3.95-3.85 (1H, m), 3.80-3.70 (1H, m), 3.50-3.40 (2H, m), 2.80 (2H, m).

I VM (thermal spraying): t/z2 МН") 534. b"

RECEIVING 18

IM-(2-"1-piperidinyl)ethyl|-1H-imidazole-1-carboxamide

IC) o i - 2-(1-piperidinyl)ethylamine (1.28 g, 1 mol) was added to a stirred solution of M,M'-carbonyldiimidazole (1.627, 1 mol) in THF (25 mL) at room temperature. The reaction mixture was stirred overnight and the solvent was removed by evaporation under reduced pressure. The residue was partitioned between ethyl acetate (100 ml) and water (50 ml), the ethyl acetate layer was separated, washed with a saturated salt solution (30 ml) and dried (Ma»zOd). - c Evaporation of the solvent under reduced pressure gave the title compound in the form of a white solid "from substance (1.8G). " NA-NMR (400MHz, SOCIv) 8: 8.10 (1M, s), 7.35 ( IN, s), 7.10 (IN, s), 6.80 (IN, width.s), 3.45 (2H, m), 2.55 (2H, m), 2.50-2.30 (4Н, m), 1.60-1.40 (6Н, m).

PREPARATION 19 - I-(2-(diisopropylamino)ethyl|-1H-imidazole-1-carboxamide (95) nou - 50 sn, sr M,M'-diisopropyl-1,2-ethanediamine (ig, b 3mol) was added to stirring solution

of M,M'-carbonyldiimidazole (1.12g, 6.94mol) in dichloromethane (50ml) at room temperature. The reaction mixture was stirred for one hour and diluted with dichloromethane (5Oml), washed with water (bOml), dried (anhydrous magnesium sulfate) and the solvent was removed under reduced pressure. This gave the indicated in the title

F! compound in the form of a white solid (bOOmg). X-ray TN-NMR (400 MHz, SOSIv) 5: 8.05 (1H, s), 7.25 (1H, p), 7.05 (1H, s), 6.65 (1H, lat.s), 3 .40-3.35 (2H, m), 3.10-3.00 (2H, m), 2.75-2.70 (2H, m), 1.05-1.00 (6H, m) .

PREPARATION 20 60 2-(2-(4-isopropyl-1-piperidinyl)ethyl/|-1H-isoindole-1,3 (2H)-dione o

Jan, b5 o'clock,

A solution of 4-isopropylpiperidine (3.3 g, 20.2 mol), M-(2-bromomethyl)phthalimide (5.4 g, 21.3 mol), potassium carbonate (5.9 g, 45.4 mol), and acetonitrile (100 mL) was heated at refluxed for 2.5 hours, then stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with an additional amount of ethyl acetate (100 ml). The combined organic extracts were dried (Ma»b5O),) and the solvent was removed by evaporation under reduced pressure. The resulting oil was purified by column chromatography on silica gel, eluting using a gradient system starting with dichloromethane, switching to dichloromethane:diethyl ether (50:50, by volume), switching to diethyl ether, to give the title compound (3 , ZG).

TN-NMR (400 MHz, SOSIi) 5: 7.80 (2M, m), 7.70 (2H, m), 3.80 (2H, t), 3.00 (2H, m), 2.60 ( 2Н, t), 1.95 (2Н, m), 1.60 (2Н, m), 1.40 (1Н, m), 1.20 (2Н, sq.d), 0.95 (1Н, m ), 0.80 (6H, d).

And EM (thermal spraying): t/z2 МН") 301

PREPARATION 21 2-(4-isopropyl-1-piperidinyl)ethylamine sn,

A solution of 2-(2-(4-isopropyl-1-piperidinyl)ethyl|-1H-isoindole-1,3(2H)-dione (Preparation 20) (3.2g, 10.bmol) in 339% w/w , a solution of methylamine in ethanol (bOml) was heated at reflux for three hours. The solvent was removed under reduced pressure, additional ethanol (bOml) was added and the solvent was removed again under reduced pressure. The residue was suspended in dichloromethane (100ml) and the solid was filtered off. It was washed with dichloromethane (10 Oml).The filtrate was evaporated under reduced pressure and the resulting oil was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane:methanol:0.88 MNH aqueous solution (90:10:11, by volume) to give a colorless oil o

Flask-to-flask distillation (150-1602C, 4KPa) afforded the title compound (1.0g, 55905).

TN-NMR (400 MHz, SOSIL) 8: 2.90 (2M, m), 2.80 (2H, t), 2.40 (2H, t), 1.95 (2H, m), 1.65 ( 2H, m), 1.40 (IN, m), 1.30-1.20 (4H, m), 1.00 (1H, m), 0.85 (BN, d). (22)

And EM (thermal spraying): t/2 (МН 171. ич-

ACQUISITION 22

IM-(2-(4-isopropyl-1-piperidinyl)ethyl I|-1H-imidazole-1-carboxamide that) . co

X sleep, -

A, a

It was obtained from 2-(4-isopropyl-1-piperidinyl)ethylamine (Preparation 21) and M,M'-carbonyldiimidazole by a method similar to the method of Preparation 19. 1H, s), 7.35 (1IN, s), 7.10 (IN, s), 6.80 (IN, width s), 3.45 (2H, m), " 2.55 (2H, m), 2.50-2.30 (4Н, m), 1.60-1.40 (6Н, m).

ACQUISITION 23

M-isopropylcyclopentanamine

Fa io ni sn, 1 - 50

Me) Perlman's catalyst (Reagitap) (2095 wt/wt, palladium hydroxide on carbon) (1.5g) was added to a solution of cyclopentylamine (15ml, 0.21mol) in acetone (200ml). The reaction mixture was stirred in an atmosphere of hydrogen gas at 414 KPa (bOlbs/sq.in). After stirring for 16 hours, the reaction mixture was filtered

Through Arbocel (Agbrose! - trade mark) and the solvent was removed under reduced pressure, obtaining the indicated in

GF! the title compound (15 ml) in the form of a low-viscosity oil. with 7TH-NMR (400 MHz, SOSIv) 5: 3.20-3.10 (1H, w, 2.90-2.80 (1H, m), 1.95-1.85 (2H, m), 1 .75-1.45 (4Н, m), 1.35-1.20 (2Н, m), 1.10-1.00 (6Н, m).

PRODUCTION 24 60 ICyclopentyl(isopropyl)amino|acetonitrile b5 weight sn,

Hydroxyacetonitrile (8.2 ml of a 7095 wt/wt solution in water, 0 O, mol) was added to the solution

M-isopropylcyclopentanamine (11.43g, 0.09mol) (Preparation 23) in ethanol (bOml). The reaction mixture was heated at 70°C under reflux for 3 hours, allowed to cool and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel, eluting with a mixture of dichloromethane:methanol (98:2, by volume), to give the title compound (14.1 g) as a clear oil. "H-NMR (400 MHz, SOSIa) 8: 3.60-3.50 (2H, s), 3.30-3.20 (2M, m), 2.00-1.85 (2H, m), 1.80-1.55 (4H, m), 1.45-1.30 (2H, m), 1.15-1.05 (6H, m).

ACQUISITION 25

M'-cyclopentyl-M-isopropyl-1,2-ethanediamine kn, o

Lithium aluminum hydride (bbml of a 1-molar solution in tetrahydrofuran, O0.0b6bmol) was added to a stirred solution of (cyclopentyl(isopropyl)amino|acetonitrile (10g, 0.bbmol) (Preparation 24) in tetrahydrofuran (100ml) at 02С. the mixture was stirred at 02C for 20 minutes and then heated at reflux for 2 hours. The reaction mixture was allowed to cool to room temperature and left overnight. The reaction mixture was cooled in an ice bath and treated dropwise with 4.8 mL of 7.590 wt/wt, aqueous sodium hydroxide solution, followed by 7.4 mL of water. The solvent was removed under reduced pressure and the residue was suspended in diethyl ether (200 mL) for 30 minutes and then filtered. The filtrate was evaporated under reduced pressure to give the title compound in the form of a colorless oil (10.30 g). H-NMR (400 MHz, SOSIv) 85: 3.10-2.95 (2M, m), 2.70-2.60 (2H, m), 2.50-2.40 (2H, m), 1.80-1.45 (1OH, m), 1.05-0.95 (6H, m). so

And M5 (thermal spraying): t/2 (МН) 171. cha

ACQUISITION 26

M-(2-(cyclopentyl(isopropyl)amino|ethyl)-1H-imidazole-1-carboxamide that « ve Ifshi s o 2 o

It was obtained from M'-cyclopentyl-M'-isopropyl-1,2-ethanediamine (Preparation 25) and M,M'-carbonyldiimidazole by a method similar to that described in Preparation 19. - and 7H-NMR (400 MHz, SOSIZv) 5: 8, 10 (1M, s), 7.35 (1H, s), 7.10 (1H, s), 6.80 (1H., width-s), 3.45 (2H, m), 2.55 ( 2H, syu m), 2.50-2.30 (4H, m), 1.60-1.40 (6H, m).

PREPARATION 27 1 Icyclohexyl(isopropyl)amino|acetonitrile - 50 iChe) spring and o Obtained from M-isopropylcyclohexylamine and hydroxyacetonitrile by a method similar to that described in the name) Preparation 24. "H-NMR (400MHZ, SOCIv) 5: 3.55 (2M, s), 3.20 (IN, m), 2.65 (IN, m), 1.85-1.70 (4Н, m), 1.30-1.20 (4Н, 60 m) ,1.10(8Н, m).

ACQUISITION 28

M'-cyclohexyl-M-isopropyl-1,2-ethanediamine b5

Cane

It was obtained from isocyclohexyl(isopropyl)amino|acetonitrile (Preparation 27) by a method similar to that described in Preparation 25. 70 TN-NMR (400 MHz, SOSILa) 8: 3.00 (1M, m), 2.60 (2H, m), 2.50 (2Н, m), 2.40 (1Н, m), 1.75-1.65 (4Н, m), 1.25-1.10 (4Н, m), 1.05-0, 90 (8H, m).

ACQUISITION 29

M-(2-(cyclohexyl(isopropyl)amino|)ethyl)-1H-imidazole-1-carboxamide g in Yam

Obtained from M'-cyclohexyl-M'-isopropyl-1,2-ethanediamine (Preparation 28) and M,M'-carbonyldiimidazole by a method similar to that described in Preparation 19.

TNA-NMR (400 MHz, SOSIZ) 5: 8.05 (1M, s), 7.30 (IN, s), 7.10 (IN, s), 6.65 (IN, lat.s), 3, 40 (2H, m), 3.10 (2H, m), 2.75 (2H, m), 2.45 (1H, m), 1.80-1.60 (4H, m), 1.30 -1.20 (4Н, m), 1.10-1.00 (8Н, m). high school

ACQUISITION 30

IM-(1-(2-pyridinyl)-4-piperidinyl|-1H-imidazole-1-carboxamide (o) st y ' cha a:

IS)

It was obtained from 1-(2-pyridinyl)-4-aminopiperidine (UMO 99/65895) and M,M'-carbonyldiimidazole by a method similar to Preparation 19. chn 7H-NMR (400 MHz, SOCIv) 8: 8.15 (1H, w, 8.05 MN, s), 7.45 (IN, m), 7.20 (1H, s), 7.00 (1H, s), 6.65 (1H, m), 6.55 ( 1H, m), 5.90 (1H, d), 4.25 (2H, d), 4.05 (1H, m), 2.95 (2H, t), 2.10 (2H, d) , 1.55 (2H, t).

RECEIVING 31 «

M-(3-aminopropyl)-6-(2,2-diphenylethyl)amino)|-9-(2k,3k,45,55)-5-Ketyl-amino)carbonyl|-3,4-dihydroxytetra 420 hydro- 2-furanyl)-9H-purine-2-carboxamide 8 i s Kh 2» -i s. about yati

And a 1 - | 50 MT - 3e) he.

A mixture of methyl 6-(2,2-diphenylethyl)amino|-9-(2kK,3k,45,55)-5-K(ethylamino)carbonyl|-3,4-dihydroxytetrahydro-2-furanyl)-9UN-purine- 2-carboxylate (Preparation 9) (0.35g, 0.b4mol) and o1,3-diaminopropane (0.45g, b.1mol) were heated at 10092 for 3 hours. The mixture was dissolved in a small amount of dichloromethane and purified by column chromatography on silica gel, eluting with a gradient system of dichloromethane:methanol:concentrated aqueous ammonia (80:20:12, by volume), changing to a mixture of dichloromethane:methanolconcentrated aqueous ammonia (88:12: 2, by volume). After evaporation of the appropriate fractions, the residue was triturated with diethyl ether, filtered and dried to give the target compound as a white solid, (0.22g, 5890).

TN-NMR (400 MHz, SOSIi) 5: 8.40 (IN, width s), 7.35-7.15 (1OH, m), 6.30 (IN, m), 4.70-4.50 (ЗН, m), 4.40-4.20 (ЗН, m), 3.50 (2Н, m), 3.30 (2Н, m), 2.85 (2Н, m), 1.80 ( 2Н, m), 1.10 (ЗН, t).

IEM: t/h2 МН") 590. because RECEIPT 32

Trans-M-(4-aminocyclohexyl)-6-(2,2-diphenylethyl)amino|-9-(2kK,3k,45,55)-5-Ketylamino)carbonyl-3,4-dihydroxytetrahydro-2-furanyl )-9H-purine-2-carboxamide

A mixture of methyl 6-(2,2-diphenylethyl)amino|-942k,3Kk,45,55)-5-Ketylamino)carbonyl/|-3,4-dihydroxytetrahydro-2-furanyl)-9H-puri n-2-carboxylate (Preparation 9) (0.35g, 0.b4mol) and trans-1,4-diaminocyclohexane (0.6bg, 6.14mol) were heated at 1059 for 3 hours. The mixture was dissolved in a small amount of dichloromethane and purified by column chromatography on silica gel, eluting with a gradient system of dichloromethane:methanol:concentrated aqueous ammonia (80:20:1.2, by volume), changing to a mixture of dichloromethane:methanol:concentrated aqueous ammonia (88 :12:2, by volume). After evaporation of the corresponding fractions, the residue was triturated with diethyl ether, filtered and dried to give the target compound as a white solid (0.32g, 79905). s "H-NMR (400MHz, SOSIZ) 5: 8.80 (IN, width s), 8.10 (IN, m), 7.60 (1H, m), 7.40-7.20 (1OH , m), 7.00 (1Н, о m), 6.15 (1Н, m), 5.15 (IN, m), 4.50 (IN, m), 4.40-4.20 (ЗН , m), 3.80 (IN, m), 3.40 (2Н, m), 2.75 (1Н, m), 2.10 (2Н, m), 1.95 (2Н, m), 1 ,40-1,20 (7Н, m).

IEM: t/MH" 630.

RECEIVING 33 F

M-(1-benzyl-4-piperidinyl)-6-(2,2-diphenylethyl)amino|-9-(2K,3K,45,55)-5-Ketylamino)carbonylic|-3,4-dihydro h- oxytetrahydro-2-furanyl)-UN-purine-2-carboxamido oyu s g o i - "In "KD y 98 y s or ОН. ;" pby b on

A mixture of methyl - 6-(2,2-diphenylethyl)amino|-9-(2kK,3K,45,55)-5-Ketylamino)carbonyl|-3,4-dihydroxytetrahydro-2-furanyl)-9H-purine -2-carboxylate (Preparation 9) (1.0g, 1.83mol) and 1-benzyl-4-piperidinylamine (2.4ml, 11mol) were heated at 1059C7 for 4 hours. The mixture was dissolved in a small amount of dichloromethane and purified by column chromatography on silica gel, eluting with a gradient system of dichloromethane:methanol (98:2, by volume), changing -I 20 to a mixture of dichloromethane:methanol (95:5, by volume) . After evaporation of the corresponding fractions, the residue was triturated with diethyl ether, filtered and dried to give the target compound as a white solid (1.0 g, 80965). "H-NMR (400 MHz, DMSO-av) 5: 8.45 (1M, width, s), 8.30 (2H, m), 8.20 (IN, m), 7.40-7.10 ( 15N, m), 5.95 (IN, m), 5.60 (1IN, m), 5.50 (IN, m), 4.60-4.50 (2N, m), 4.25 (1N , c), 4.20-4.10 (ZH, m), 3.80 (1IN, m), 3.40 59 (2H, m), 3.20 (2H, m), 2.70 (2H , m), 2.05 (2Н, m), 1.80 (2Н, m), 1.60 (2Н, m), 0.90 (ЗН, m).

GF) IEM: t/h (М-Н"1 703.

GF RECEIPT 34

М-КХЗК)-1-benzylpyrrolidinyl)|-6-К2,2-diphenylethyl)amino|-9-(2К,3К,45,55)-5-(ethylamino)carbonyl/|-3,4-dihydroxytetrahydro -2-furanyl)-9UN-purine-2-carboxamide b5

She is from br "Oh bring 5 on

C methyl 6-(2,2-diphenylethyl)amino|-9-(2kK,3K,45,55)-5-Ketylamino)carbonyl|-3,4-dihydroxytetrahydro-2-furanyl)-9H-purine was obtained 2-carboxylate (Preparation 9) and (3K)-1-benzylpyrrolidinylamine by a method similar to that described in

Obtained 33. The target compound was obtained as a white solid. "H-NMR (400 MHz, СО500) 5: 8.40 (1M, width.s). 7.40-7.10 (15Н, m), 6.10 (IN, m), 4.60-4, 30 (7Н, m), 3.60 (2Н, m), 3.30 (2Н, m), 2.90-2.60 (ЗН, m), 2.50-2.30 (2Н, m) , 1.80 (1Н, m), 1.05 (ЗН, t).

IEM: t/h2 (M-H7) 689.

PREPARATION 35 -(35)-1-benzylpyrrolidinyl|-6-(2,2-diphenylethyl)amino|-9-(2кК,3К,45,55)-5-Ketylamino)carbonyl-3,4-dihydroxytetrahydro-2 -furanyl)-9UN-purine-2-carboxamide s y DK 7 i (22) pi M / " tech y y so

Ch | the bottom of the 5th on

C methyl was obtained. 20 6-(2,2-diphenylethyl)amino|-9-(2kK,3K,45,55)-5-Ketylamino)carbonyl|-3,4-dihydroxytetrahydro-2-furanyl)-9H-pur -v s in -2-carboxylate (Preparation 9) and (35)-1-benzylpyrrolidinylamine by a method similar to that described in

Obtained 33. The target compound was obtained as a white solid. with TN-NMR (400 MHz, СО3О0) 5: 8.35 (1IN, sshyr.s), 7.40-7.10 (15Н, m), 6.05 (1Н, 5 m), 4.80 (1Н , m), 4.60-4.30 (6Н, m), 3.60 (2Н, m), 3.30-3.20 (2Н, m), 2.85 (IN, m), 2, 75 (IN, m), 2.65 (IN, m), 2.50-2.30 (2Н, m), 1.80 45. МН, m), 0.95 (ЗН, t). -I IEM: t/g2 (M-H7) 689. s PREPARATION 36 6-(2,2-diphenylethyl)amino|-9-(2кК,3К,45,55)-5-Ketylamino)carbonyl|-3, 4-dihydroxytetrahydro-2-furanyl)-M-s (4-piperidinyl)-UN-purine-2-carboxamide m s di iChe) .

M - o V t ia yan 60 t sa ne 2 . 5 Ge

Solution 65 /M-(1-benzyl-4-piperidinyl)-6-K(2,2-diphenylethyl)amino|-9-(2kK,3K,45,55)-5-Ketylamino)carbonyl/|-3, 4-dihydroxytetrahydro-2-furanyl)-9H-purine-2-carboxamide (Preparation 33) (1.03g, 1.47mol), palladium hydroxide (I!) (0.9g) -B50-

and ammonium formate (0.46 mg, 7.mol) in ethanol (1 Oml) was heated under reflux for 3 hours. The catalyst was removed by filtration through Arbocel (Agrose! - a trademark), the solvent was removed by evaporation under reduced pressure, and the residue was purified by column chromatography on silica gel, eluting with a gradient system of dichloromethane: methanol, concentrated aqueous ammonia (90:10:11, by volume), changing to dichloromethane:methanol:concentrated aqueous ammonia (80:20:2, by volume). After evaporation of the corresponding fractions, the target compound was obtained as a white solid, (0.6 bg, 6790). "H-NMR (400 MHz, as--DMSO) 5: 8.45 (IN, width.s), 8.30 (2Н, m), 8.20 (1Н, m), 7.40-7, 10 (15N, m), 5.95 (IN, m), 5.70-5.50 (2N, m), 4.70-4.50 (2N, m), 4.25 (1IN, s) , 4.20-4.10 (ZH, m), 3.80 (IN, m), 3.20 (2H, m), 70..2.95 (2H, m), 2.55 (2H, m), 1.80 (2Н, m), 1.40 (2Н, m), 0.90 (ЗН, m).

IEM: t/h2 МН") 615.

PREPARATION 37 6-(2,2-diphenylethyl)amino|-9-(2k,3Kk,45,55)-5-Ketylamino)carbonyl/|-3,4-dihydroxytetrahydro-2-furanyl)-M-Y (ZK )|Ipyrrolidinyl-UN-purine-2-carboxamide nn.

M

"ro le" ON p

I'm a dream, a dream

Received from

M-KZK)-1-benzylpyrrolidinyl)|-6-K2,2-diphenylethyl)amino|-9-(2kK,3K,45,55)-5-Ketylamino)carbonyl/|-3,4-dihydroxy (o) tetrahydro-2-furanyl)-9UN-purine-2-carboxamide (Preparation 34) by a method similar to that described in Preparation 36. The target compound was obtained as a white solid. "H-NMR (400MHz, SOZO0) 5: 8.40 (1M, lat.s), 7.35-7.10 (1OH, m), 6.10 (1H, m), 4.60-4, 30 (6Н, m), 340 (2Н, m), 3.30-3.20 (2Н, m), 2.35 (1Н, m), 2.10 (1Н, m), 1.25 (2Н , m), 1.00 (ZN, t). p

IEM: t/h2 (M-H) 599.

PRODUCTION 38 - 6-(2,2-diphenylethyl)amino|-9-(2kK,3K,45,55)-5-Ketylamino)carbonyl|-3,4-dihydroxytetrahydro-2-furanyl)-M-

K35)-pyrrolidinyl--H-purine-2-carboxamide and 5 | I - p. ;" in M. - ! C d) -on. oh, mm bn - 50

Received from

Me, -(35)-1-benzylpyrrolidinyl|-6-(2,2-diphenylethyl)amino|-9-(2кК,3К,45,55)-5-Ketylamino)carbonyl|-3,4-dihydrox itetrahydro- 2-furanyl)-UN-purine-2-carboxamide (Preparation 35) by a method similar to that described in Preparation 36. The target compound was obtained as a white solid. 52 "NA-NMR (400MHz, СО53О0) 5: 8.40 (1M, width s), 7.35-7.10 (TON, m), 6.10 (IN, m), 4.55-4 .25 (6H, m),

HF) 3.30-3.20 (2N, m), 3.00 (2N, m), 2.30 (1N, m), 1.90 (1N, m), 1.25 (2N, m) , 1.00 (ZN, t). t IEM: t/ MN" 601.

PREPARATION 39 6-(2,2-diphenylethyl)amino1-9-(2K,3K,45,55)-5-(ethylamino)carbonyl)-3,4-dihydroxytetrahydro-2-furanyl)-ZN bo -purine-2 - carboxylic acid b5 not "x vi r on ch "On

Nina on

Solution methyl 6-(2,2-diphenylethyl)amino|-9-(2kK,3K,45,55)-5-Ketylamino)carbonyl|-3,4-dihydroxytetrahydro-2-furanyl)-9H-purine-2 -carboxylate (Preparation 9) (0.7g, 1.28mol) and 1095 wt/wt of an aqueous solution of sodium hydroxide (1.3ml, 3.2mol) in methanol (2.3ml) were stirred at room temperature for 14 hours. The solution was adjusted to pH 4 by adding 2N aqueous hydrochloric acid, and the precipitated white solid was collected by filtration. The solid was washed with water and dried under reduced pressure to give the target compound as a white powder (0.21g, 30905). "H-NMR (400 MHz, as-DMSO) 5: 8.65-8.45 (IN, m), 8.35 (IN, lat.s), 8.05 (IN, lat.s), 7, 40-7.10 (1ОН, m), 6.05-5.95 (1Н, m), 5.70 (1Н, width s), 4.60-4.40 (2Н, m), 4, 30-4.10 (ZH, m), 3.20 (2H, m), 0.90 (ZH, t).

IEM: t/g2 МН") 615. p

PRODUCTION 40 (5) (2553554K,5K)-5-I6-K(2,2-diphenylethyl)amino|-2-34-(trifluoroacetyl)amino|-1-piperidinyl)carbonyl)-UN-purin-9-yl |-M-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamidla z ich-nn iv) -. . st. "7th St

He has 4

He « - s Solution 6-(2,2-diphenylethyl)amino|-9-(2kK,3K,45,55)-5--ethylamino)carbonyl/|-3,4-dihydroxytetrahydro-2-furanyl)-9H -pure :z» of n-2-carboxylic acid (Preparation 39) (0.2g, 0.33mol), 2,2,2-trifluoro-M-(4-piperidinyl)acetamide (83mg, 0.42mol) and hydrochloride 1-(3-dimethylaminopropyl)-33-ethylcarbodiimide (81 mg, 0.42 mol) in dichloromethane (5 mL) was stirred at room temperature for 48 hours and then heated at reflux for an additional 96 hours. The solution was allowed to cool to room temperature and then the solvent was removed by evaporation under reduced pressure. The residue was purified by column chromatography on (95) silica gel, eluting with a gradient system dichloromethane:methanol:concentrated aqueous ammonia (95:5:1, by volume), changing to dichloromethane:methanol concentrated aqueous ammonia (80:20:1, by volume). After evaporation of the corresponding fractions, the target compound was obtained as a white solid (4Zmg, 18905). - 7"H-NMR (400MHz, CO3O0) 5: 8.20 (1H, p). 7.30-7.10 (TON, m), 5.95 (IN, m), 4.70-4, 60 (2H, m), 4.50-4.40

He) (2H, m), 4.30-4.20 (ZN, m), 4.00 (IN, m), 3.65 (IN, m), 3.20 (2H, m), 2, 95 (IN, m), 2.00 (1Н, m), 1.90 (1Н, m), 1.60 (2Н, m), 1.05 (ЗН, т).

IEM: ti/g2 (M-H7) 709.

PREPARATION 41 o (25535,4K,51-5-(2-K4-amino-1-piperidinyl)carbonyl|-6-(2,2-diphenylethyl)amino|-9H-purin-9-yl)-M-ethyl -3,4-d hydroxytetrahydro-2-furancarboxamide ime) 60 b5 in I "o y

And oh me oh he

Solution t (2553554K,5K)-5-16-K2,2-diphenylethyl)amino|-2-(4-Ctrifluoroacetyl)amino)-1-piperidinyl)carbonyl)-9H-purin-9-yl 1-M-ethyl -3,4-dihydroxy-tetrahydro-2-furancarboxamide (Preparation 40) (40 mg, 0.05 bmol) in methanol (ml) and a concentrated aqueous ammonia solution (0.5 ml) were stirred at room temperature for 48 hours.

The solvent was removed by evaporation under reduced pressure to give the target compound as a white solid, (35mgHg).

TNA-NMR (400 MHz, CO5O0) 8: 8.25 (1M, s), 7.30-7.10 (TON, m), 6.00 (IN, m), 4.70-4.60, ( 2Н, m), 4.50-4.40 (2Н, m), 4.30-4.10 (ЗН, m), 3.70 (IN, m), 3.40 (IN, m), 3 ,20 (2Н, m), 2.95 (1Н, m), 2.10 (1Н, m), 1.95 (1Н, m), 1.60 (2Н, m), 1.05 (ЗН, t).

IEM: t/g2 МН") 615. p

ACQUISITION 42

M-KHZK)-1-benzylpyrrolidinyl|)-M'-(2-(diisopropylamino)dethyl|urea o

Me and Fr

She them-

Pho; (3K)-1-Benzyltrolidinylamine (0.5g, 2.84mmol) was added to a stirred solution (ze) of I-(2-(diisopropylamino)ethyl|-1H-imidazole-1-carboxamide (Preparation 19) (0.68g, 2.84mol) in 1,1,1-trichloroethane M (2.5ml) and isopropanol (2.5ml) and the reaction mixture was heated at reflux for four hours.The solution was allowed to cool to room temperature and the solvent was removed by evaporation under reduced pressure. (90:10:2, by volume).After evaporation of the corresponding fractions -v with s, the target compound was obtained as a white solid (0.98G).

TN-NMR (400 MHz, СО5О0) 5: 7.30-7.20 (BN, m), 4.15 (IN, m), 3.60-3.50 (2Н, m), 3.30-3 ,20 (2H, m), ;z» 3.10-3.00 (4H, m), 2.80-2.65 (2H, m), 2.55-2.30 (4H, m), 2.20 (1N, m), 1.55 (1N, m), 1.00 (12N, d).

IEM: t/ MN" 348.

PREPARATION 43 -I -((35)-1-benzylpyrrolidinyl/|-M'-(2-(diisopropylamino)ethyl|urea » ей и сн, с Я, ,

Obtained from (35)-1-benzylpyrrolidinylamine and M-I(2-(isopropylamino)ethyl|-1H-imidazole-1-carboxamide (Preparation 19) in the same manner as in Preparation 42. The target compound was obtained as a white solid substances

F) TN-NMR (400 MHz, СО5О0) 5: 7.30-7.20 (5M, m), 4.15 (IN, m), 3.60-3.50 (2Н, m), 3.30 -3.20 (2Н, m), ko 3.10-3.00 (4Н, m), 2.80-2.65 (2Н, m), 2.55-2.30 (4Н, m), 2.20 (1N, m), 1.55 (1N, m), 1.00 (12N, d).

IEM: t/ MN" 348. because ACQUISITION 44

IM-(2-(diisopropylamino)ethyl/|-M'-KZK)-pyrrolidinyl|urea b5 in

D sn, shi r Ve

A solution of /M-(ZK)-1-benzylpyrrolidinyl|-M'-(2-(diisopropylaminoethyl)urea (Preparation 42) (1.10Hg, 7/03.1bmol), palladium hydroxide (I) (1.0g) Ammonium formate (1.0 g, 1 mol) in ethanol (1 mL) was heated at reflux for 2 h. The catalyst was removed by filtration through Arbocel (Agrose! - a trademark) and the solvent was evaporated under reduced pressure to give the target compound as of a white solid (0.6bg, 67905). "H-NMR (400 MHz, СО8О0) 5: 4.15 (1Н, m. 3.20-2.90 (7Н, m), 2.70-2.55 (ЗН, m), 2.10 (1Н, m), 1.65 (1Н, 75...М), 1.10 (12Н, d).

BMI: ti/g MN") 258.

ACQUISITION 45

IM-(2-(diisopropylamino)ethyl/|-M'-KZ5)-pyrrolidinyl|urea 1 VE

It was obtained from M-((35)-1-benzylpyrrolidinyl|-M'-(2-(disoprotlamino)dethyl)urea (Preparation 43) in the same way as in Preparation 44. The target compound was obtained as a white solid. 1nH- NMR (400MHz, СО3О0) 5: 4.15 (1Н, ), 3.20-2.90 (7Н, m), 2.70-2.55 (ЗН, m), 2.10 (1Н, m) , 1.65 (1H,

M), 1.10 (12Н, d). Ge")

I vm: t/" (MN"1 258. i-

PREPARATION 46 (2k,3Kk,45,55)-2-(2-amino-6-chloro-9H-purin-9-yl)-4-(benzoyloxy)-5-Ketylamino)carbonyl|tetrahydro-3-furanyl benzoate so m. h

AK

- kn, "

N oche - 7 AAU o ;" -AND

Ha A suspension of 2-amino-b6-chloropurine (4.60 g, 27.1 μmol) in 1,1,1-trichloroethane (23 Oml) was treated

with M,O-bis(trimethylsilyl)acetamide (20 ml, 81.4 mol). The mixture was heated at reflux for b hours. The solution was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was treated with a solution of (25,35,4K,5K)- and (25,35,4K,55)-5-(acetyloxy)-4-(benzoyloxy)-2-Ketylamino)carbonyl|tetrahydro-3-furanylbenzoate (obtained from 14) (14.39g, 32.bmol) in anhydrous toluene (230ml) and trimethylsilyl trifluoromethanesulfonate (20ml, 108.5mol). The resulting solution was then heated at 902 under a nitrogen atmosphere for 90 minutes. The mixture was cooled to room temperature, diluted with ethyl acetate (250 ml) and washed with a saturated aqueous solution of sodium bicarbonate (350 ml), then with a saturated salt solution (350 ml). The organic layer was separated,

HF) was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane:methanol (98:22 by volume), obtaining the title compound as a foam (8.1 g). in "H-NMR (400 MHz, SOSIA) 5: 8.10-7.95 (ZM, m), 7.80 (2Н, m), 7.50-7.30 (6Н, m), 6.90 (1H, m), 6.40-6.20 (ZH, m), 5.20 (2H, width.s), 4.90 (1H, m), 3.45 (1H, m), 3, 30 (1H, m), 1.15 (ZH, t).

IEM: t/h2 (MN) 552.

PREPARATION 47 (2kK,3K,45,55)-4-(benzoyloxy)-2-(6-chloro-2-iodo-9H-purin-9-yl)-5-(ethylamino)carbonyl)|tetrahydro-3- furanilbe be NZOVtT -B4-

(oh - |!

WITH

-uschUyu and n-butyl nitrite (4.65 mL, 39.7 mmol) was added to a suspension of (2k, 3Kk, 45.55)-2-(2-amino-6-chloro-9H-purin-9-yl)-4-(benzoyloxy) -5-Ketylamino)carbonyl|tetrahydro-3-furanylbenz 75 sat (Production 46) (8.10g, 14.7mol), iodine (3.73g, 14.7mol), copper iodide (1) (6.16g, 32 , zmol) and diiodomethane (12.55 mL, 155.8 mol) in THF (100 mL) and the mixture was heated at reflux for 2.5 hours. The solution was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was distributed between an aqueous solution of sodium metabisulfite (5956 wt/vol, 10 Oml) and dichloromethane (100 ml). The organic layer was separated, filtered through Arbocel (Agrose! - trademark), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a mixture of dichloromethane:methanol (99:11, by volume) to give the title compound as a yellow foam (7.55 g, 78905). "H-NMR (400 MHz, SOSIv) 8: 8.55 (1Н, p). 8.05 (2Н, m), 7.80 42Н, m), 7.65-7.30 (6Н, m), 6.75 (IN, m), 6.50 (IN, m), 6.10-6.00 (2Н, m), 4.90 (1Н, m), 3.60-3.40 (2Н, m), 1.25 (ZN, t). p

I VM: t/» ММа") 684. o

PRODUCTION 48 (2kK,3K,45,55)-4-(benzoyloxy)-2-(6-12,2-bis(3-methylphenyl)ethylamino)-2-iodo-9H-purin-9-yl)-5 -Ketylamino)ka rbonyl|hetrahydro-3-furanylbenzoate

IS) so chh g Y m. r ' "tsi " "KU v - s o ;"

Solution - and (2kK,3K,45,55)-4-(benzoyloxy)-2-(6-chloro-2-iodo-9H-purin-9-yl)-5-K(ethylamino)carbonyl)tetrahydro-3 -furanylbenzoate (Preparation 47) (0.6g, 0.91mol) and 2,2-bis(3-methylphenyl)ethylamine (0.3g, 1.3bmol) in isopropanol (20ml) (95) were stirred at room temperature for 48 hours. The solvent was removed under reduced pressure and the residue 1 was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane:methanol (99:1, by volume), -1 50 to give the title compound as a beige foam (0.67g, 87905).

TNA-NMR (400 MHz, SOSIZ) 5: 8.00 (2M, m), 7.75 (ZN, m), 7.60-7.40 (BN, m), 7.25 (IN, m), 7.15 (1Н, m), s 7.10-7.00 (7Н, m), 6.20-6.00 (ЗН, m), 4.85 (IN, m), 4.25-4 ,10 (ZN, m), 3.65 (IN, m), 3.50 (1IN, m), 2.30 (6Н, s), 1.20 (ZN, t).

I KM: t/ MN i) 852. 29 RECEIVING 49

HF) (2kK,3K,45,55)-4-(benzoyloxy)-2-(6-(12,2-bis(3-chlorophenyl)ethyl|amino)-2-iodo-9H-purin-9-yl )-5-Ketylamino)ka yuyu rbonyl|hetrahydro-4-furanylbenzoate 60 b5 a re! with DC fi eh chi n 5 U-(3) o o o

Obtained from (2kK,3K,45,55)-4-(benzoyloxy)-2-(6-chloro-2-iodo-9H-purin-9-yl)-5-K(ethylamino)carbonyl)tetrahydro-3- furanylbenzoate (Preparation 47) and 2,2-bis(3-chlorophenyl)ethylamine in the same manner as in Preparation 48. The title compound was obtained as a yellow foam. "H-NMR (400 MHz, SOSI) 5: 8.00 (2M, m), 7.80 (ZH, m), 7.60 (1H, m), 7.55-7.40 (4H, m) , 7.30-7.10 (9Н, m), 6.25 (IN, m), 6.15-6.05 (2Н, m), 5.90 (IN, m), 4.90 (IN , m), 4.35 (IN, m), 4.25-4.15 (2Н, m), 3.65 (1Н,

M), 3.50 (1H, m), 1.25 (ZH, t).

RECEIVING 50 s

Benzyl 2-(((2-(diisopropylamino)ethylamino)carbonyl)amino)ethylcarbamate Ge)

Ok GO

A AL, 1 sha a vve F o sn, m

A solution of benzyl 2-aminoethyl carbamate hydrochloride (4.33 g, 18 vmol),

I-(2-(diisopropylamino)ethyl I|-1H-imidazole-1-carboxamide (Preparation 19) (3.73g, 15.64mol) and triethylamine (2.62ml, 18.vmol) in dichloromethane (100ml) were heated at boiling under reflux for 14 hours

The solution was allowed to cool to room temperature and then washed with water (20 Oml).

The aqueous layer was separated and additionally extracted with dichloromethane (20 ml). The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (6.25 g). "H-NMR (400 MHz, SOSIa) 85: 7.40-7.30 (5M, m), 5.50 (IN, width s), 5.10 (1H, s), 4.90 (1H, width s), 3.30 " (AN, m), 3.10 (2H, m), 3.00 (2H, m), 2.55 (2H, m), 1.00 (12H, d) .

IEM: t/g2 MH") 365. in s PREPARATION 51 "from Benzyl 2-I(2-(1-piperidinyl)ethylIamino)carbonyl)iamino)ethylcarbamate p

C kA - t (95) It was obtained from benzyl 2-aminoethylcarbamate hydrochloride and 1M-(2-1-piperidinyl)ethyl I|-1H-imidazole-1-carboxamide (Preparation 18) by a method similar to the method

Preparation of 50. The title compound was obtained as a yellow oil. - "H-NMR (400 MHz, SOSIa) 8: 7.30-7.20 (BM, m), 6.00 (IN, width s), 5.50 (1IN, m), 5.10-5 ,00 (ZN, width s),

He 3.30-3.10 (6Н, m), 2.40 (6Н, m), 1.55 (4Н, m), 1.40 (2Н, m).

IEM: t/h2 МН") 349.

ACQUISITION 52

M-(2-aminoethyl)-M'-(2-(diisopropylamino)ethyl|urea o cosn, 60

A solution of benzyl 2-(((diisopropylamino)ethylamino)carbonyl)aminodetyl carbamate (Preparation 50) (6.25 g, 14.45 mol) in ethanol (10 Oml) was hydrogenated at room temperature over palladium (II) hydroxide (2500 mg) for 4 hours at 414 KPa . The catalyst was removed by filtration through Arbocel (Agrose! - trade mark) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient system of dichloromethane:methanol:concentrated aqueous ammonia (90:10:11, by volume), -58v-

substituting with dichloromethane:methanol:concentrated aqueous ammonia (90:10:2, by volume) to give the title compound as a yellow oil (Z,bg). "H-NMR (400 MHZ, SOSIZ) 8: 5.30 (1M, width.s), 5.15 (IN, m), 3.20 (4H, m), 3.05 (2H, m), 2 .80 (2Н, m), 52.60 (2Н, m), 1.05 (12Н, d).

IEM: t/h2 (MN) 231.

ACQUISITION 53

M-(2-aminoethyl)-M'-(2-(1-piperidinyl)ethyl|urea and it AXA

Obtained from benzyl 2-(C(2-(1-piperidinyl)ethylamino)carbonyl)aminoethylcarbamate (Preparation 51) by a method similar to the method of Preparation 52. The title compound was obtained as a yellow oil. "H-NMR (400 MHz, SOSIa) 8: 5.65 (1M, lat.s), 5.15 (1IN, m), 3.20 (4H, m), 2.80 (2H, m), 2 .40 (6Н, m), 1.55 (4Н, m), 1.40 (2Н, m).

IEM: t/h2 (MN) 215.

ACQUISITION 54

Benzyl 4-1(1H-imidazol-1-ylcarbonyl//(amino|methyl)benzoate g o c o

Benzyl 4-(aminomethyl)benzoate hydrochloride (1.0 g, Zbmol) was dissolved in 1095 wt./wt. aqueous sodium hydroxide solution (20 ml) and the solution was extracted with dichloromethane (30 ml). The organic phase was separated, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure, obtaining the free amine base in the form of a thick oil. The oil was dissolved in dichloromethane (200 ml) and the solution was added dropwise to the solution

of M,M'-carbonyldiimidazole (1.62g, TOmol) in dichloromethane (20ml). After stirring for one hour at room temperature, the reaction mixture was diluted with diethyl ether (100ml) and washed with water (3x40ml) and saturated salt solution (40ml). The solution was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give the target compound as a white solid (0.97g, 8190). and. "H-NMR (400 MHz, SOSI") 5: 8.20 (1M, s), 8.00 (2H, d), 7.50-7.30 (OH, m), 6.95 (1H, s ), 5.40 (2H, s), 4.60 (2H, m). -

IEM: t/h2 МН") 336.

ACQUISITION 55

Benzyl « 4-I42-1(6-(2,2-diphenylethyl)amino|-9-(2kK,3K,45,55)-5-Ketylamino)carbonyl|-3,4-dihydroxytetrahydro-2-fur anil- 9UN-purin)-2-yl)/carbonylamino)zetyl)amino|)carbonyl)iamino)methyl|benzoate t 958;» / Her - er so ; Y deon yo 1 J on -I 250 Received from

M-(2-aminoethyl)-6-(2,2-diphenylethyl)amino|-9-(2kK,3K,45,55)-5-Ketylamino)carbonyl|-3,4-dihydroxytetrahydro-2c-furanyl) -9H-purine-2-carboxamide (Production 10) and benzyl 4-(H-imidazol-1-ylcarbonyl)amino|methyl)benzoate (Production 54) by a method similar to that described in example 1. The target compound was obtained as a white solid . 59 TN-NMR (400MHz, COzO0) 8: 8.35 (1Н, p), 7.70 (2Н, d), 7.40-7.10 (17Н, m), 6.05 (IN, m) , 5.20 (2H, m), (F) 4.70 (1H, m), 4.45-4.20 (BN, m), 3.55-3.40 (4H, m), 3, 20-3.30 (2H, m), 1.00 (ZH, t). co IEM: ti/g2 (M-H7) 841.

PREPARATION 56 vo -(2-(dibutylamino)ethyl/|-1H-imidazole-1-carboxamide ay and aa b5

Obtained from M',M'-dibutyl-1,2-ethanediamine and M,M'-carbonyldiimidazole by a method similar to the method

Preparation 19. The target compound was obtained as a white solid.

TN-NMR (400 MHz, SOSIz) 8: 8.05 (1H, p), 7.25 (1H, s), 7.05 (1H, s), 6.75 (1H, lat.s), 3, 40 (2Н, m), 2.60 (2Н, m), 2.50-2.30 (4Н, m), 1.40-1.20 (8Н, m), 0.85 (6Н, t) .

BMI: ti/ag (M-H7) 267.

ACQUISITION 57

M-(2-(benzyl(isopropyl)amino|ethyl)-1H-imidazole-1-carboxamide me 8 ste

Obtained from M-benzyl-M-isopropyl-1,2-ethanediamine and M,M'-carbonyldiimidazole by a method similar to 75 method of Preparation 19. The target compound was obtained as a white solid. "NA-NMR (400MHz, SOS) 5: 7.85 (1M, s), 7.30-7.15 (BN, m), 7.10 (IN, s), 7.05 (IN, s) , 6.00 (1H, width s), 3.50 (2H, s), 3.25 (2H, m), 3.00 (1H, m), 2.65 (2H, m), 1, 10 (EN, d).

ACQUISITION 58

M-(1-benzyl-4-piperidinyl)-1H-imidazole-1-carboxamide

Obtained from 1-benzyl-4-piperidinylamine and M,M'-carbonyldiimidazole by a method similar to

Preparation 19. The target compound was obtained as a white solid. o 7TH-NMR (400MHz, SOSIv) 8: 8.10 (1M, s), 7.40-7.20 (6H, m), 7.10 (IN, s), 5.85 (1IN, m) , 3.85 (1H, m), 3.50 (2H, m), 2.90-2.80 (2H, m), 2.25-2.00 (4H, m), 1.60 (2H , m).

OBTAINING 59 Ge")

1-((1-benzyl-4-piperidinyl)methyl/|-1H-imidazole-1-carboxamide with a frequency of 30) was obtained from (1-benzyl-4-piperidinyl)umethylamine and M,M'-carbonyldiimidazole by the method similar to the Preparation method 19. The target compound was obtained as a white solid. "NA-NMR (400 MHz, SOSIZ) 5: 8.10 (1M, s), 7.30-7.20 (6H, m), 7, 10 (IN, s), 5.90 (IN, m), 3.50 (2Н, b), 3.35 (2Н, m), 2.90 (2Н, m), 2.00 (2Н, m ), 1.75-1.60 (ZH, m), 1.40-1.30 (2H, m). "

PREPARATION 60 - c is -(4-(diethylamino)methyl|benzyl)-1H-imidazole-1-carboxamide :» D styas ve zv, this. It was obtained from M-(4-(aminomethyl)benzyl|-M,M-diethylamine and M,M'-carbonyldiimidazole by a method similar to d) method of Preparation 19. The target compound was obtained as a white solid. sl "H-NMR (400 MHz, SOSI»v) 5: 8.15 (1M, s), 7.35-7.05 (BN, m), 4.60 (2H, s), 3.50 (2H , c), 2.50 (4H, sq), 1.05 (6H, t).

IEM: t/g2 (MH) 287. and RECEIPT 61

Ge) IM-(2-(3,4-dihydro-2(1H)-isoquinolinyl)ethyl I|-1H-imidazole-1-carboxamide and AD compound

F)

GI was obtained from /2-(34-dihydro-2(1H)-isoquinolinylethylamine and M,M'-carbonyldiimidazole by a method similar to the method of Preparation 19. The target compound was obtained as a white solid. 60 "H-NMR (400 MHz, SOSIa) 85: 8.05 (1M, s), 7.25 (1H, s), 7.15-6.95 (BN, m), 6.65 (IN, width s), 3.70 (2H, c), 3.60 (2Н, m), 2.90 (2Н, m), 2.75 (4Н, m).

ACQUISITION 62

Ethyl 6-(2,2-diphenylethyl)amino)|-9-(tetrahydro-2H-pyran-2-yl)-9UN-purine-2-carboxylate b5

And we are "ms o br

79.1,1-bis(diphenylphosphino)ferrocene (7.00g, 0.012bmol) was added to a suspension of palladium acetate (I) (1.50g, 0.006b68mol) in absolute ethanol (1000ml) and the resulting suspension was stirred under a nitrogen atmosphere for 18 hours for obtaining a catalytic mixture. To a mixture of 2-chloro-M-(2,2-diphenylethyl)-9-(tetrahydro-2H-pyran-2-yl)-9UN-purine-b-amine. (M/O/0023457) (Preparation 2) (7O0Hg, 1.61 mol) and absolute ethanol (4500 ml) in an autoclave were added anhydrous sodium carbonate (94 g, 0.887 mol) and the catalytic mixture obtained above. The autoclave was purged twice with gaseous carbon monoxide, then the pressure was brought up to 2000Kpa with the help of gaseous carbon monoxide. The mixture was then heated at 103-1072C7 with stirring for 10 hours, and then the autoclave was vented through a valve, purged with carbon monoxide, and then re-pressurized to 2000KPa with carbon monoxide. Heating at 103-1072С7 with stirring was continued for an additional 14 hours. The mixture was cooled to 602C and then filtered through a layer of warm Celite (See trademark). The obtained filtrate was left with 29 to cool down to ambient temperature, while crystallization took place and, after stirring at this temperature for 7 hours, the obtained suspension was filtered. The filter precipitate was washed with cold absolute ethanol (500 mL) and the solid dried in vacuo for 24 h at 5523 to give the title compound as a cream-colored solid (575 g), m.p. (22) from 138-14026.

And EM (chemical ionization at positive atmospheric pressure: t/2 MH"); 472. - 1 NA-NMR (ZO0MHC, SOSIv) 85: 8.05 (1M, s), 7.45-7.15 (1OH, m), 5.95-5.80 (2H, m), 4.60-4.30 (5H, m), 4.15 lU (1H. width d), 3.80 (1H, width t ), 2.20-1.60 (6H, m), 1.50 (ZH, t).

ACQUISITION 63 o

Ethyl 6-(2,2-diphenylethyl)amino|-UN-purine-2-carboxylate ich- u nn shi s -

I» 7 in I oi -I

To a suspension of ethyl 6-(2,2-diphenylethyl)amino|-9-(tetrahydro-2H-pyran-2-yl)-9UN-purine-2-carboxylate and (Preparation 62) (250g, 0.530mol) in absolute ethanol (125O0ml) trifluoroacetic acid (73.5g, 0.645mol) was added under a nitrogen atmosphere and the resulting mixture was heated at 502C for 20 hours. The mixture was cooled and the solid 5p was collected by filtration. The precipitate on the filter was washed with absolute ethanol (35 ml) and then dried in a vacuum at 502C, obtaining the title compound (206.5 g) in the form of a finely divided powder

Ge) cream-colored, t.pl. 220090.

And EM (chemical ionization under positive atmospheric pressure): t/2 МН" 388. "H-NMR (300 MHz, α6-DMSO) 5: 8.36 (IN, width c), 8.00 (IN, width Tt), 7.48-7.127 (1OH, m), 4.80-4.00 (5E, width, m), 1.48-1.22 (ZN, width, m).

F! ACQUISITION 64

Ethyl de 9-(21k,3kK,4Kk,5K)-3,4-bis(acetyloxy)-5-(acetyloxy)methyl|hetrahydro-2-furanyl)-6-(2,2-diphenylethyl)amino|-9H - purine-2-carboxylate 60 b5 s u nn i

H ak u o Ge! not

To a suspension of ethyl 6-(2,2-diphenylethyl)amino|--H-purine-2-carboxylate (Preparation 63) (40.0 g, 0.10 mol) in anhydrous 1,2-dimethoxyethane (24 Oml) under a nitrogen atmosphere was added 4-methylmorpholine (11.5g, 12.5ml, 0.114mol) and the resulting mixture was heated to 459 with stirring. Trimethylsilyl trifluoromethanesulfonate (27.5g, 22.4ml, 0.124mol) was then added to this mixture over 10 minutes. The obtained orange solution was then heated to 559 and a solution of 1,2,3,5-tetra-O-acetyl-B-SO-ribofuranose (36.1 g, 0.11 μmol) in 1,2-dimethoxyethane (10 Oml plus 20 ml for rinsing). Then the reaction mixture was stirred at 57-6092С7 for 2 hours, after which the mixture was cooled to ambient temperature.

The reaction mixture was then carefully added to a mixture of a saturated aqueous solution of sodium bicarbonate (400ml) and ethyl acetate (400ml) with vigorous stirring. The layers were separated and the aqueous phase was extracted with ethyl acetate (400 ml). The combined organic phases were dried over anhydrous magnesium sulfate and then concentrated in vacuo to afford the crude product as an orange foam (74.9g), which could be used as such in the next step. The crude product can be purified using flash chromatography on silica gel, eluting with a gradient system consisting of 1095 v/v. of diethyl ether in dichloromethane, changing to 2590 vol./vol. diethyl ether in dichloromethane to give the title compound as a colorless foam.

I KM (chemical ionization at positive atmospheric pressure): pt/2 MNU 646. Me) 1H-NMR (300MHz, SOS) 6: 7.98 (1M, width s), 7.40-7.17 (TON, m), 6.27 (1IN, d), 6.00-5.78 (ZH, m) kyu 4.60-4.30 (8H, m), 2.16 (ZH, s), 2.08 (6H, s), 1.45 (ZH, t).

ACQUISITION 65 o

Ethyl so 9-K(2k,ZK,45,55)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl|-6-K(2,2-diphenylethyl)amino|-UN-purine- 2-k carboxylate - 98 " in . From the village

And" well, I'll do it - and no

Sho

(95) but he «sl To a solution of crude ethyl - 50 9-(еН,ЗА 4,5)-3,4-bis(acetyloxy)-5-(acetyloxy)methyltetrahydro-2-furanyl)-6-(2, 2-diphenylethyl)amino 9H-purine-2-carboxylate (Preparation 64) (74.9g, taken as 0.10mol) in warm absolute ethanol (330ml) (Che) was added portionwise over 23 hours to sodium ethoxide (1.2g, 0.018 mole). The resulting mixture was further stirred for 3 hours and then glacial acetic acid (1.5 ml) was added. The mixture was concentrated in vacuo to give the crude product as a light brown foam (63.7g), which was used as such in the next step. The crude product can be purified by flash chromatography on silica gel, eluting with a gradient system consisting of 595 v/v. of isopropanol in dichloromethane, changing to 7.595 vol./vol. iF) isopropanol in dichloromethane, changing to 1095 vol./vol. isopropanol in dichloromethane, followed by crystallization from tert-butylmethyl ether to give the title compound as colorless crystals, m.p. 118-12026, 60 I 2M5 (chemical ionization at positive atmospheric pressure): t/2 (МН 520. "H-NMR (Z00MHZts, 46-DMSO) 58.61 (0.25N, width.s), 8.47 (0.75H, width s), 8.17 (IN, width t), 7.45-7.10 (TON, m), 5.92 (1H, width d), 5.41 (IN , width d), 5.10 (IN, width d), 5.00 (1H, t), 4.80-4.45 (ZH, m), 4.44-4.10 (2H, m ), 4.09-4.03 (2H, m), 4.00-3.90 (1H, m), 3.78-3.61 (1H, m), 3.60-3.50 (1H , m), 1.48-1.11 (ZN, m).

PREPARATION 66 b5 Ethyl 9-(zac,4k,vk,bac)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro!|3,4-41(11,3)dioxol-4-yl|-6-K( 2,2-diphenylethyl)amino|-9H-purine-2-carboxylate in o 70 no o r

To a solution of crude ethyl 75 9-(2K,ZK,45,5K)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl|-6-(2,2-diphenylethyl)amino|-9UN-purine -2-arboxylate (Preparation 65) (62.7g, taken as 0.10Zmol) in dry acetone (314ml) in a nitrogen atmosphere, concentrated sulfuric acid (5.3ml, 0.10Zmol) was added and the resulting mixture was stirred at ambient temperature within 2.5 hours. Then 2,2-dimethoxypropane (21.5g, 25.4ml, 0.207mol) was added and stirring was continued for 2.5 hours. Then the reaction mixture was added to a saturated aqueous solution of sodium bicarbonate (30 Oml) and the resulting mixture was stirred at ambient temperature for 0.2 hours. The mixture was concentrated in vacuum and the aqueous residue was extracted with ethyl acetate (400 ml, then 200 ml). The organic phases were combined and washed with saturated salt solution (300 ml), dried over anhydrous magnesium sulfate and concentrated in vacuo to give a yellow foam (58.2 g). A solution of this foam in tert-butyl methyl ether (250 ml) was stirred at ambient temperature. su 25 atmosphere of nitrogen, obtaining a suspension, which was then cooled on ice for 1 hour, after which the solid was collected by filtration. The precipitate on the filter was washed with cold tert-butyl methyl ether (TBM) and the product was dried in vacuo to give the title compound as a colorless solid (12.7 g). The mother liquors were purified by flash chromatography on silica gel (400 g), eluting with 75,905 v/v. ethyl acetate in heptane to give a slightly impure product (32.9 g) as a foam, which was crystallized from (o) 30 tert-butyl methyl ether (150 mL) to give an additional amount of the title compound (8.3 g). The mother liquor was again concentrated in vacuo to obtain a foam (23.27), which was purified by flash chromatography, eluting using a gradient system consisting of 5095 v/v. 10) of ethyl acetate in toluene, changing to 9095 vol./vol. ethyl acetate in toluene, yielding 2 fractions (9.7g and 11.8Hg), which were crystallized separately from tert-butyl methyl ether (10OmL and 12OmL, respectively), yielding 35% additional amount of the title compound (b,bg and 8, 8g, respectively). The total yield of the title compound thus amounted to 36.4 g, and it was isolated as a colorless crystalline solid, m.p. 126-12896.

I KMZ (chemical ionization at positive atmospheric pressure): t/2 МН 560. « 7TN-NMR (Z00MHC, as-DMSO) 5: 8.60 (0.25N, width.s), 8.45 (0.75N , c), 8.19 (IN, width t), 7.42-7.11 (1OH, Z m), 6.19 (IN, width s), 5.40-5.25 (1Н, m), 5.12-4.90 (2H, m), 4.78-4.82 (1H, m), 4.80-445 (1H, width s), c 4.44-4.02 (4Н, m), 3.65-3.50 (2Н, m), 1.57 (ЗН, с), 1.50-1.10 (6Н, m). PREPARATION OF 67 (Za5,45,6K,bac)-6-I6-K2,2-diphenylethyl)amino|-2-(ethoxycarbonyl)-UN-purin-9-ylI|-2,2-dimethyltetrahydrofuroi 3,4 -4111,3)dioxol-4-carboxylic acid with 58 (95) 1 nn - 50 / s s | pu i vo no o 59 TU a ime)

To the solution of ethyl in 9-KZak,4k,bK,bak)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuroyl3,4-a11,3)dioxol-4-yl|-6-K2,2-diphenylethyl) 2,2,6,6-tetramethylpiperidinyl-1-oxy, free radical (0.30 g , 0.0019mol) and an aqueous solution of sodium dihydrogen phosphate (120 ml of a 0.67M solution). The resulting mixture was heated to 459C with stirring. A solution of sodium chlorite (6.5 g, O0.072 mol) in water 65 (7 Bml) and a solution of sodium hypochlorite (0.32 ml of a commercially available solution having 1295 wt/vol, available chlorine, 0.000551mol) in water (Zvml). The resulting mixture was then stirred at 45-509С7 for 10 hours and for 18 hours at ambient temperature. The reaction mixture was then added with stirring to a solution of sodium sulfite (18g, 0.14Zmol) in water (ZOOml). After stirring for 5 minutes, the pH was adjusted to 3.7 by adding 2M aqueous hydrochloric acid and the mixture was extracted with ethyl acetate (200 ml, then 100 ml). The organic phases were combined, dried over anhydrous magnesium sulfate, and then concentrated in vacuo to give the title compound (15.1 g) as a colorless foam, which was used as such in the next step. If necessary, this crude product can be purified by conventional methods, for example, flash chromatography on silica gel.

And EM (chemical ionization at positive atmospheric pressure: t/2 (MH 7 574: "NA-NMR (Z00MHC, as-DMSO) 5: 12.80 (IN, width s), 8.52 (0.25Н, width s), 8.38 (0.75H, s), 813 (1H, width t), 7.45-7.12 (1OH, m), 6.40 (1H, s), 5.81 (1Н, d), 5.48 (1Н, d), 4.80-4.00 (ЕН, m), 1.52 (ЗН, с), 1.45-1.13 (6Н, m),

PREPARATION 68 (Za5,45,6K,bac)-6-I6-K2,2-diphenylethyl)amino|-2-(ethoxycarbonyl)-9UN-purin-9-yl|-2,2-dimethyltetrahydrofuroia 3,4-4111 ,3)dioxol-4-carboxylic acid

And alsya oh, eat. o cm 25 r:4 o

To a solution of 9-(ZK,4K,bK,bak)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro!|3,4-41(1,3)dioxol-4-yl|-6-(2,2 2,2,6,6-tetramethylpiperidinyl-1-oxy, free radical (0.020g, 0.000128mol), tetrabutylammonium bromide (0.22g, i- 0.000682mol) and a saturated aqueous solution of sodium bicarbonate (2bml). An aqueous solution of sodium hypochlorite (3 mL of 0.531 M solution, 0.0175 mol) was then added to this mixture with rapid stirring for about minutes at ambient temperature, and stirring was continued for an additional 1.5 hours. An aqueous solution of sodium sulfite (5 Oml of 1095 wt/vol solution) was added to the resulting mixture, and stirring was continued for 10 minutes. Then the slightly cloudy organic phase was separated and then - concentrated to dryness in a vacuum, obtaining a yellow foam. The foam was partitioned between ethyl acetate (50 ml) and aqueous hydrochloric acid (25 ml of a 2 M solution). The organic phase was then washed with water and then concentrated in vacuo. The residue was redissolved in ethyl acetate (50ml) and concentrated again in vacuo to give the title compound (5.23g) as a pale yellow foam, which was used as such in the next step. If necessary, this crude product can be purified by conventional methods, for example, with flash chromatography on silica gel. with I KMZ (chemical ionization at positive atmospheric pressure: t/2 (MH 574. "NA-NMR (Z00MHC, as-DMSO) 5: 12.80 (IN, width.s), 8.52 (0.25Н, width s), 8.38 (0.75H, s), 813 (1H, width t), 7.45-7.12 (1OH, m), 6.40 (1H, s), 5.81 (1Н, d), 5.48 (1Н, d), 4.80-4.00 (ЕН, m), 1.52 (ЗН, с), 1.45-1.13 (6Н, m). - ACQUISITION 69

Ethyl o 9-(Zac,4k,65,base)-6-Ketylamino)carbonyl|-2,2-dimethyltetrahydrofuroi3,4-4111,3|dioxol-4-yl)-6-K2,2-diphenyl sl tyl) amino|-9UN-purine-2-carboxylate - 50 3e) nn and - o.

F) o - their) ik o. lo bo

To a solution of (Za5,45,6K,bac)-6-I6-K2,2-diphenylethyl)amino|-2-(ethoxycarbonyl)-9UN-purin-9-yl|-2,2-dimethyltetrahydrofuroi3,4-

1,1-Carbonyldiimidazole (6.80g, 0.0418mol) was added to 111.3)dioxol-4-carboxylic acid (Preparations 67 and 68) (20.0g, 0.0349mol) in anhydrous tetrahydrofuran 65 (0Oml) under a nitrogen atmosphere. and the resulting mixture was stirred at ambient temperature for 1.5 hours. A solution of ethylamine in tetrahydrofuran (24.4 ml of a 2M solution, 0.0488 mol) was then added to this solution while cooling to 1592C, and the resulting mixture was then stirred at ambient temperature for 2 hours. An additional amount of a solution of ethylamine in tetrahydrofuran (3.5 ml of a 2M solution, 0.0007 mol) was added to the mixture, and stirring was continued for an additional 2 hours, after which deionized water (100 ml) was added. The resulting mixture was concentrated in vacuo and then the residue was partitioned between ethyl acetate (200ml) and aqueous citric acid (200ml of a 0.5M solution). The layers were separated and the aqueous phase was extracted with ethyl acetate (50 ml). The organic phases were combined and washed sequentially with deionized water (200 mL), saturated aqueous sodium bicarbonate solution (200 mL), and saturated salt solution (200 mL) and then dried over anhydrous magnesium sulfate and 7/0 concentrated in vacuo to give the crude product as a foam. cream color (20.22Gg).

The crude product was purified by flash chromatography on silica gel (700 g), eluting with a gradient system consisting of 6595 v/v. of ethyl acetate in heptane, changing to 8095 vol./vol. ethyl acetate in heptane, changing to ethyl acetate, affording the title compound (16.55 g) as a colorless foam.

And 2M5 (chemical ionization at positive atmospheric pressure): t/2 (МН 601. "H-NMR (300 MHz, a--DMSO) 5: 8.53 (025Н, width с), 8.38 (0.75Н , c), 8.15 (IN, width t), 7.42-7.12 (11H, m), 6.40 (IN, width s), 5.59 (1H, width d), 5.40 (1H, width d), 4.80-4.00 (6H, m), 2.83-2.60 (2H, m) 1.55 (ZH, s), 1.45-1 .25 (6H, m), 0.52 (ZH, width t).

PREPARATION 70 9-(Zac,4k,65,baz)-6-Ketylamino)carbonyl|-2,2-dimethyltetrahydrofuroi3,4-4111,3)dioxol-4-ylII-6-K2,2-diphenylethyl)amino| )-UN-purine-2 carboxylic acid c ' ne o o 2 on o. I am 7 and

Ku - - t) Ka; I am

Egyl c 9-(Zac,4k,65,base)-6-Ketylamino)carbonyl|-2,2-dimethyltetrahydrofuroyl 3,4-4111,3|dioxol-4-yl)-6-K2,2-diphenylethyl is added to the solution )amino|-UN-purine-2-carboxylate (Preparation 69) (16.47g, 0.0274mol) was added to methanol (164ml) with an aqueous solution of sodium hydroxide (30.2ml of a 1M solution, 0.0302mol) and the resulting mixture was stirred at ambient temperature in a nitrogen atmosphere for 1.5 hours. The reaction mixture was then concentrated in vacuo and dichloromethane (1 bOml) and deionized water (1 bOml) were added to the residue. The pH of this mixture was adjusted to pHA by adding aqueous 2M hydrochloric acid while stirring. The organic phase was separated and the aqueous layer C t0 was extracted with dichloromethane (75 ml). The organic phases were then combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (15.5 g) as a cream-colored foam, which was used as such in the next step. If necessary, this product can be purified by conventional methods, such as flash chromatography on silica gel. 15 I 2M5 (chemical ionization under positive atmospheric pressure): t/2 (MH 573. - "NA-NMR (300MHZ, az-DMSO) 5: 12.71 (IN , width s), 8.52 (0.25N, width s), 8.36 (0.75N, s), 8.08 (1N, width t), 7.50 (1N, width t ), 7.40-7.12 (ION, m), 6.40 (IN, width c), 5.55 (IN, width d), 5.38 (IN, width d), o 4 .75-4.40 (2.5N, m), 4.25-4.03 (1.5N, m), 2.88-2.63 (2N, m), 1.55 (ЗН, s) . -41(1,3)dioxol-4-yl)-6-(2,2-diphen-ylethyl)amino|-M-12-I411-(2-pyridyl)-4-piperidinylamino)carbonyl)amino|ethyl) -UN-purine-2-carboxamide? s o s AI - where; about Ali

Kt at 60 CET r:

To a solution of 9-(Zac,4k,65,base)-6-Ketylamino)carbonyl|-2,2-dimethyltetrahydrofuroi3,4-4111,3|dioxol-4-ylI)-6-K2,2-diphenyl 65 tyl) 1,1-carbonyldiimidazole (4.7g, 0.029mol) was added to amino|--UN-purine-2-carboxylic acid (Preparation 70) (14.98g, 0.0262mol) in dichloromethane (/bml) under a nitrogen atmosphere and the resulting the mixture was stirred at ambient temperature for 1.5 hours, obtaining a solution of the acylimidazolide derivative. To a solution of urea dihydrochloride M-(2-aminomethyl)-M'-(1-(2-pyridinyl)-4-piperidinyl) (Preparation 73) (10.1g,

0.0301 mol) in dichloromethane (75 ml) under a nitrogen atmosphere, triethylamine (5.6 g, 7.7 ml, 0.055 mol) was added, and the resulting suspension was cooled to 1520. The acylimidazolide solution obtained earlier was then added to this suspension, and the resulting mixture was stirred at ambient temperature environment for 2 hours, after which deionized water (5 ml) was added. The mixture was washed with an aqueous solution of citric acid (150 ml of a 0.5 M solution), which was saturated with sodium chloride. The layers were separated and the aqueous phase was extracted with dichloromethane (15 ml).

The organic phases were combined and washed with a saturated aqueous solution of sodium bicarbonate. After separation of the 7/0 phases, the aqueous layer was extracted with dichloromethane (75 mL) and then the organic phases were combined, dried over anhydrous magnesium sulfate, and then concentrated in vacuo to give the title compound (21.28 g) as a light blue foam, which used as such at the next stage. This crude material can be purified by conventional methods, such as flash chromatography on silica gel, eluting with a system consisting of a mixture of 95:5:0.5, by volume, dichloromethane:methanol:concentrated aqueous ammonia, to give the indicated in 7 /5 header pure compound.

And EM (chemical ionization under positive atmospheric pressure: t/z2 (MH 7) 818. 7TN-NMR (Z000MHC, a6-DMSO) 5: 8.51 (IN, width c), 8.33 (IN, width s), 8.09 (IN, m), 8.01 (1H, width t), 7.58 (IN, width t), 7.48 (1H, t), 7.42-7.10 (ION, m), 6.78 (1H, d), 6.58 (1IN, dd), 6.42 (1H, s), 6.01 (1H, width s), 5.95 (IN, width d), 5.60 (IN, width d), 5.39 (IN, width d), 4.72-4.55 (2.5H, m), 4.33-4.00 ( 3.5N, m), 3.75-3.55 (1N, m), 3.44-3.20 (4N, m (partially unclear due to the water peak)), 2.88 (2N, width ), 2.80-2.62 (2Н, m), 1.87-1.70 (2Н, m), 1.53 (ЗН, с), 1.37 (ЗН, с), 1.36- 1.20 (2Н, m), 0.47 (ЗН, t).

ACQUISITION 72

Tert-butyl. 2-K1-(2-pyridinyl)-4-piperidinylamino)carbonyl)amino|ethylcarbamate

And s i and o se zr | at

To an ice-cooled solution of 1-(2-pyridinyl)-4-piperidinylamine dihydrochloride (ER-A-0021973) chn (20.82g, 0.0832mol) and 1,1-carbonyldiimidazole (14.85g, 0.915mol) M,M-diisopropylethylamine (22.0g, 29.7ml, 0.17Omol) was added to acetonitrile (1400ml) under a nitrogen atmosphere for 20 minutes. The resulting light-brown (I) solution was stirred at ambient temperature for 20 minutes and tert-butyl solution was added for 50 minutes. M-(2-aminoethyl)carbamate (14.0g, 0.0874mol) in acetonitrile (MOml plus 5ml for

From rinsing). The resulting mixture was then heated at reflux for 2.5 hours. in.

After cooling to ambient temperature, the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (15 Oml). This solution was washed sequentially with a saturated aqueous solution of sodium bicarbonate (70 ml) and deionized water (20 ml). The aqueous phases were extracted with ethyl acetate (2x100 ml) and the combined organic phases were washed with water. The organic phase was dried over anhydrous magnesium sulfate and the solution was concentrated under vacuum to a volume of approximately 200 ml. The obtained solution was then distilled at c) s atmospheric pressure to a volume of approximately 7 Bbml. The solution was left to cool down to ambient temperature, and crystallization took place during this time. The resulting thick suspension was diluted with ethyl acetate (bOml) and cooled on ice. The solid was collected by filtration and the precipitate on the filter was washed with cold ethyl acetate (2x330ml). The resulting solid was dried in vacuo at 509 for 20 hours to give the crude product (24.0g), which was recrystallized from ethyl acetate (270ml) to give this. the title compound (20.7g) as a colorless solid. (4) I 2M5 (chemical ionization at positive atmospheric pressure): t/2 (MH 364. sl TNA-NMR (400 MHz, SOSIi) 5: 8.20-8.10 (1M, m), 7.45 (IN , t), 6.65 (IN, d), 6.58 (1H, dd), 542 (1H, width t), 5.25 (IN, width s), 5.04 (1H, d) , 4.15 (2H, d), 3.90-3.68 (IN, m), 3.47-3.10 (4H, m), 3.00 (2H, - width t), 2, 00 (2H, width d), 1.55-1.28 (11H, m). s OBTAINING 73

M-(2-aminoethyl)-M'-/1-(2-pyridinyl)-4-piperidinyl|urea dihydrochloride

A saturated solution was added to a suspension of tert-butyl 2-(((1-(2-pyridinyl)-4-piperidinylamino)carbonyl)aminodetylcarbamate (Prepared in 72) (20.6g, 0.0567mol) in ethyl acetate (115ml) under a nitrogen atmosphere of hydrogen chloride in ethyl acetate (115 mL) and the resulting thick suspension was stirred at ambient temperature for 2 h. The solid was collected by filtration and the filter cake was washed with ethyl acetate (2 x 5 O mL), then dried in vacuo at 509C to give the title compound (21, 0g) in the form of a hygroscopic colorless solid, mp 112-12096, because I EM (chemical ionization at positive atmospheric pressure: t/2 (МН 7 264.

TNA-NMR (ZO00MHz, 020) 5: 7.92 (1M, t), 7.78 (1H, d), 7.23 (1H, d), 6.86 (IN, t), 4.00 ( 2H, width), 3.85-3.70 (1H, m), 3.47-3.24 (AN, m), 3.18-2.95 (2H, m), 2.10-1, 92 (2H, m), 1.53 (2H, square width).

ACQUISITION 74

M-(2-aminoethyl)-M'-(1-(2-pyridinyl)-4-piperidinyl|urea 0 sweat

1,1"-carbonyldiimidazole (0.713g, 0, . -carbonyldiimidazole (0.145g, 0.0009mol). The reaction mixture was stirred for an additional 2 hours and then added to a solution of 1,2-diaminoethane (24g, 2.ml, 0.04mol) in ethyl acetate (3ml) over 15 minutes along with additional amount of ethyl acetate (1/ml) used to rinse the instrument. The resulting mixture was stirred at ambient temperature for 18 hours and washed with saturated aqueous sodium bicarbonate solution. The layers were then separated and the aqueous phase was extracted with ethyl acetate (2x20ml). The organic layers were then combined , with was washed over anhydrous magnesium sulfate and then concentrated in vacuo to give the crude product (0.83g). Study of this crude product by high-performance liquid chromatography-mass spectroscopy and "H-NMR by comparison with a real sample of the compound indicated in the title (in the form of a free base, obtained from the solution of M-(2-aminoethyl)-M'-(1- (2-Pyridinyl)-4-piperidinyl|urea (Preparation 73), showed that the title compound was present as a major component along with minor impurities.

I EM (chemical ionization at positive atmospheric pressure): t/2 МН 264. "H-NMR (400MHz, SOSIia) 5: 8.15 (1M, d), 7.44 (1Н, t), 6.64 ( 1H, d), 6.59 (1IN, dd), 5.42-5.30 (2H, m), 4.15 (2H, width d), 3.90-3.70 (IN, m) , 3.28-3.08 (2H, m), 3.05-2.88 (2H, m), 2.79 (2H, t), 2.07-14.85 (2H, m), FI 1.52-1.28 (2H, m).

PHARMACOLOGICAL DATA -

The biological activity of the compounds of Examples 1-35 was tested by the method described above, and all of them were found to have ICs less than 1000 nm. with

Claims (79)

35 The formula of the invention 1. The formula compound: uka f shchi « sh- 40 Nm - s M - KE BKIa EZ :» Sy t M shk UM. va 45 -i o pon o (95) Z on FO - 50 or its pharmaceutically acceptable salt or solvate, where K' represents H, C 4-Cv alkyl or fluorenyl, 3e) specified C.4-Cv alkyl is optional is substituted with 1 or 2 substituents, each of which is independently selected from phenyl and naphthyl, and the specified phenyl and naphthyl are optionally substituted with C.4-Ce alkyl, C.-C.sub.alkoxy, halogen or cyano; (A) B? is H or C 4-Cb alkyl, BK" is H or C 4-Cb alkyl, and X is either (i) o unbranched Co-C3 alkylene, optionally substituted by C.4-Ce alkyl or C5 -Ca cycloalkyl, or (iii) a group of the formula: o "CH M (CH) p-, where MU is C 5-C7, cycloalkylene, optionally substituted with C .-Ce alkyl, n is 0 or 1, and p 60 is 0 or 1, or (B) "Z is H or C 1 -C 1 alkyl, and B 2 and X, taken together with the nitrogen atom to which they are attached, are azetidin-Z-yl, pyrrolidine-3Z- yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each of which is optionally substituted C.4-C6 alkyl, or (C) B2 is H or C 1-Cv alkyl, and B" and X, taken together with the nitrogen atom to which they are attached, because they are azetidin-Z-yl, pyrrolidine-Z-yl, piperidin-Z-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each of which is optionally substituted C1-C6 alkyl; B3 and B taken together with the nitrogen atom to which they are attached are a zetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperidinyl, or homopiperazinyl, each of which is optionally substituted on a ring nitrogen or carbon atom with C.4-C.sub.4 alkyl or C.3-C.sub.a cycloalkyl and optionally substituted on a ring carbon atom that is not adjacent with a nitrogen atom, MEUV" or KZ is H, C-Cb alkyl, C-Cb cycloalkyl or benzyl, and B" is: (ha) azetidin-3Z-yl, pyrrolidin-3-yl, piperidin-Z -yl, piperidin-4-yl, homopiperidin-3-yl, or homopiperidin-4-yl, each of which is optionally substituted C 4 -C 4 alkyl, C 3 -C 6 cycloalkyl, phenyl, 70 benzyl, or Ni, or (5 ) "(Co-Cv alkylene)-KU, (c) -"C4-Cv alkylene)-BE U, or (4) C4-Cv alkyl or Ca-Cv cycloalkyl; 18 V? is CHNOH or COM "VU; 25 Her VC" or each, independently, is H or C /-Cv alkyl, or, taken together with the nitrogen atom to which they are attached, is azetidinyl, pyrrolidinyl or piperidinyl, the specified azetidinyl , pyrrolidinyl or piperidinyl are optionally substituted by C.4-Cv alkyl; BZ is () azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homopiperazin-1-yl or tetrahydroisoquinolin-1 -yl, each of which is optionally substituted on the ring carbon atom by C.-Cv alkyl, C3-Cv cycloalkyl, phenyl, C--Cv alkoxy-(C.4-Cv)-alkyl, vve M-(C. 4-C)-alkyl, fluoro-(C4-C)-alkyl, -SOMAUVEU, -SOOKO or Co-C5 alkanoyl, and optionally substituted on the ring carbon atom not adjacent to the nitrogen atom, fluoro-(C.4 -Ci)-Alkoxy, Halogen, -OKU, Cyano, -5(O)pVO, -MEUV9, -502MVUV9U, -MV9SOV'O or -MEKO85028'O, and the specified piperazin-1-yl and SM homopiperazin-1-yl are optionally substituted on the ring nitrogen atom not connected to C 5-Cv alkylene d) group, C.4-Cv alkyl, phenyl, C4-Cv alkoxy-(Co-Cv)-alkyl, EUKUM-(Co -Cv)-alkyl, fluoro-(C,4-Cv)-alkyl, C,-Cv alkanoyl, -SOOK "U, C3-Cv cycloalkyl, -5028 9, -BO2MA UA? or -SOMAUVU, or (i) MVV, b B? represents H, C.4-Cv alkyl, Xa-Cv cycloalkyl or phenyl; represents C-Cv alkyl, C-Cv cycloalkyl or phenyl; "he B" represents H, C.4-Cv alkyl, C.sub.3-Cv cycloalkyl or benzyl; Is) B"? is H, C 4-Cv alkyl, C3-Cv cycloalkyl, phenyl, benzyl, fluoro-(C4-Cv)-alkyl, -"SOMARVU,-COOV, (in C. -Sv alkanoyl or -ZO2MAV; and - BZ represents (a) phenyl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, each of which is optionally substituted C.4-Cv alkyl, C.--Cv alkoxy, -(C4-C3 alkylene)-(C--Cv alkoxy), halogen, cyano, -(C4-C33 alkylene)-CM, СОН, -(C4-C3 alkylene)-СО2OH, -СО5(C4-C3 alkyl) . '", or (B) azetidin-2-yl, azetidin-3-yl, « pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-2-yl, sv) with homopiperidin-3-yl or homopiperidin-4-yl, each of which is optionally substituted with C 4-Cv alkyl, C3-Cv cycloalkyl, phenyl, benzyl or Ni; ;" B" represents H or C1-C8 alkyl, optionally substituted by cyclopropyl; t is 0, 1 or 2; U represents CO, C5, 505 or C-M(CM); and -i "It is used in the definition of B" and KZ, is a C-bonded, 4-6-membered ring, a heterocycle, which has either 1-4 ring heteroatoms of nitrogen, or 1-2 ring heteroatoms of nitrogen and 1 ring heteroatom of oxygen or sulfur , optionally substituted by C 4-Ce alkyl, C 3-C 6 cycloalkyl, C 1-C 6 alkoxy, C 5-C 1 cycloalkyl, hydroxy, oxo or halogen. - 20 2. The compound according to claim 1, where B is C-C6 alkyl, optionally substituted with 1 or 2 phenyl substituents, the indicated phenyl is optionally substituted by C-C6 alkyl or halogen. Wed 3. The compound according to claim 2, where KE" represents diphenylethyl, bis(3-methylphenyl)ethyl or bis(3-chlorophenyl)ethyl. 4. Compound according to claim 3, where KE! is 2,2-diphenylethyl, 2,2-bis(3-methylphenyl)ethyl or 2,2-bis(3-chlorophenyl)ethyl. 5. Compound according to claim 4, where B! is 2,2-diphenylethyl. (F; 6. The compound according to any of the previous clauses, where 22 is N. ka 7. A compound according to any of the previous clauses, where VZ is H. 8. The compound according to any of the previous items, where X represents 1,2-ethylene or 1,3-propylene. in 9. The compound according to claim 8, where X represents 1,2-ethylene. 10. The compound according to any of claims 1-5, where is the VK? represents H, VK "? represents H, and X represents 1,2-ethylene, 1,3-propylene or a group of the formula: "Snaya UM (СНа)р-, where MU is Св-С7 cycloalkylene, n equals 0 or 1, and p is equal to 0 or 1. 65 11. The compound according to claim 10, where B is H, B is H, and X is 1,2-ethylene, 1,3-propylene or a group formulas: "Snaya UM (СНа)р-, where MU is Св-С7 cycloalkylene, n equals 0, and p equals 0. 12. Compound according to claim 11, where B? represents H, K "? represents H, and X represents 1,2-ethylene, 1,3-propylene or 1,4-cyclohexylene. 13. The compound according to claim 12, where 2 represents H, B": represents H, and X represents 1,2-ethylene. 14. The compound according to any of claims 1-5, where K 15 is H, and B 2 and X, taken together with the nitrogen atom to which they are bonded, are 3-pyrrolidinyl or 3- or 4- piperidinyl, each of which is optionally substituted with C1-C8 alkyl. 15. The compound according to claim 14, where "C is H, and B 2 and X, taken together with the nitrogen atom to which they are attached, are 3-pyrrolidinyl or 4-piperidinyl. 16. A compound according to any one of claims 1-5, where 22 represents H, and B"? and X, taken together with the nitrogen atom to which they are bonded, represent 3-pyrrolidinyl or 3- or 4- piperidinyl, each of which is optionally substituted by C1-C8 alkyl 17. The compound according to claim 16, where 2 represents H, and B "Z and X, taken together with the nitrogen atom to which they are connected, represent 3-pyrrolidinyl or 4-piperidinyl. 18. A compound according to any of the previous clauses, where VZ is H. 19. A compound according to any of the preceding clauses, where B is piperidin-3-yl or piperidin-4-yl, each R is optionally substituted with benzyl, pyridin-2-yl, pyridin-3Z-yl or pyridine -4-yl, each of the specified pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl is optionally substituted with C.sub.6 alkyl, C.sub.3-C.sub.cycloalkyl, C.sub.4-C.sub.alkoxy, C.sub.1-C.sub.cycloalkyl, hydroxy, oxo or halogen. 20. The compound according to claim 19, where B" is piperidin-3-yl or piperidin-4-yl, each of which is substituted with benzyl, pyridin-2-yl, pyridin-Z-yl or pyridin-4-yl. Ha 21. The compound according to claim 20, where VE" represents piperidin-4-yl substituted with pyridin-2-yl. o 22. The compound according to claim 21, where K7 is 1-(pyridin-2-yl)piperidin-4-yl. 23. The compound according to any of claims 1-18, where KE" is -(Co-Cv alkylene)-K8. 24. Compound according to claim 23, where K7 represents -"SNSNOVA. zo 25. The compound according to any of claims 1-18, where КЕ" is -(С4-Св alkylene)-К 13. Ф 26. The compound according to claim 25, where В" represents -SNOV Z or -"SNoSNOV Z. v. 27. The compound according to any one of claims 1-18, where B is C3-Cv cycloalkyl. yu 28. The compound according to claim 27, where VE" represents cyclohexyl. 29. A compound according to any of the previous items, where KE? is -СНоОН or -СОМН(C.--Cv alkyl). at 30. Compound according to claim 29, where E? is -SOMNSN SNU. uh- 31. The compound according to claim 23 or 24, where KZ is () azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl , homopiperazin-1-yl or tetrahydroisoquinolin-1-yl, each of which is optionally substituted on the ring carbon atom with C 4-Cv alkyl, and said piperazin-1-yl and " homopiperazin-1-yl are optionally substituted on the ring nitrogen atom not connected to the C 5-C alkylene 70 group, C.-Ce alkyl or (ii) is ME'B 2, 8 s 32. The compound according to item 31, where KZ is piperidin-1-yl or tetrahydroisoquinolin-1-yl, each of which "z" is optionally substituted on the ring carbon atom by C-C alkyl. 33. The compound according to claim 32, where BE is piperidin-1-yl, 4-isopropylpiperidin-1-yl or tetrahydroisoquinolin-1-yl. - 34. The compound according to claim 31, where KZ is ME "B", where ME" is M(C 4-Cv alkyl)". M(C.-C., alkyl) and C.-Cv cycloalkyl) or M(C4-Ce alkyl(benzyl). o 35. The compound according to claim 34, where ME" is M,M-diisopropylamino, M,M-di-n-butylamino, 1M-cyclopentyl-M-isopropylamino, M-cyclohexyl-M-isopropylamino or M-benzyl- M-isopropylamino. -0.750 36. The compound according to claim 31, where K"" represents H or C 4-Ce alkyl, and BK" represents H, C 4-Cv alkyl, C3-Cv cycloalkyl or benzyl. 37. The compound according to claim 36, where BK"! represents C 4-Cb alkyl, and BK? represents C 4-Cv alkyl, Ca-Cv cycloalkyl. or benzyl. 38. The compound according to claim 37, where B"! represents isopropyl or n-butyl, and B 72 represents isopropyl, n-butyl, cyclopentyl, cyclohexyl or benzyl. HF) 39. The compound according to claim 25 or 26, where KZ is either phenyl, optionally substituted with -(C.-C3 alkylene)-MV'YAB" or SON, or piperidin-2-yl, piperidin-Z-yl or piperidin-4-yl, each of which is optionally substituted with benzyl 40. The compound according to claim 39, where B'Z is phenyl, 4-(M,M-diethylamino)methylphenyl, 4-carboxyphenyl or 1-benzylpiperidin-4-yl. 41. The compound according to any of the previous clauses, where U is CO. 42. Compound according to claim 1, where b5 in: E? EZ o is Shchi z kneoMNnoY 7 o Ir N su M Shko zktekdeomio o 1; , From o to ! - | (22) M Even with KNsOoMN yu o so yi- i, ! y Z KnsOoME « o - s ma ! and 7 MNsOoMneno - about (95) 1; , and K. M -0. 2 y Z kNNeomnoY 7 y, Me, o 1Rg , D 1 o t et kNeomno 7 IF y o 60 vv n M M More ZOZ MNSOoMNO Vi 65 (8) n M Sche - U KNSOMNSN,RE o 1Igg ' M ra Re y Shchy Neo MN -p o N , M MNSOMNo te 75 y na Mo sr, o n t (77 Tknooknstusnrv o n M Ge 25 That belt (5) not o son n F 30 Shchi belt m k- Z -E (BO). yu so a a ' 35 E Xya shi - o « "v so i s MM z y yur eomshno Z o 45 syu Shcho mnsomn- sl o - 70 n ' Ge) shaf 1; her o ZMNSOMNA Ser, 55 o n SCHI z TE IF: MO Ru o t N o 65 n , (9) mNSOMN Ir , : M Zh 7 TUR y t (9) (9) MnesOoMNnenNoR. Z (9) НН proe Ж M o sm n ! 5) proe o F , m M AD yu grow: (o) m- Ir ra -iRE « MnosOMN Z o cho, :z» y r GO them or (95) TI . and M - 7 МНсОоМНно С7ТИРЕ Shk) Z M G (9) F) 43. The compound according to claim 1, which is de 6-(2,2-diphenylethyl)amino|-9-(2кК,3К,45,55)-5-Ketylamino)carbonyl|-3,4-dihydroxytetrahydro-2- furanyl)-M-12-Y ((1-(2-pyridinyl)-4-piperidinylamino)carbonyl)amino|)ethyl)-9H-purine-2-carboxamide or its pharmaceutically acceptable salt or solvate. A. The compound according to claim 1, which is 4-I42-1(6-(2,2-diphenylethyl)amino|-9-(2кК,3К,45,55)-5-Ketylamino)carbonyl|-3,4 -dihydroxytetrahydro-2-furanyl)-9H-purin-2-yl)carbonylamino)ethyl)amino|carbonylamino)dimethyl|benzoic acid or its pharmaceutically acceptable salt or solvate. 65 45. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-44 together with a pharmaceutically acceptable excipient, diluent or carrier. 46. The compound of formula (I) or its pharmaceutically acceptable salt, solvate or composition according to any of claims 1-44 and claim 45, respectively, is suitable as a medicinal product. 47. The compound of formula (I) or its pharmaceutically acceptable salt, solvate or composition according to any of claims 1-44 and claim 45, respectively, is suitable as an Aga receptor agonist. 48. The compound of formula (I) or its pharmaceutically acceptable salt, solvate or composition according to any of claims 1-44 and claim 45, respectively, is suitable as an anti-inflammatory agent. 49. The compound of formula (I) or its pharmaceutically acceptable salt, solvate or composition according to any of claims 1-44 and claim 45, respectively, is suitable for the treatment of respiratory diseases. 70 50. The compound according to claim 49, where the disease is selected from the group consisting of respiratory failure syndrome in adults (AKO5), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, fibrocystic degeneration, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis . 51. The compound of formula (I) or its pharmaceutically acceptable salt, solvate or composition according to any of claims 1-44 and claim 45, respectively, is useful in the treatment of septic shock, male erectile dysfunction, 7/5 male factor infertility, female factor infertility, hypertension (high blood pressure), stroke, epilepsy, cerebral ischemia, peripheral vascular diseases, postischemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, dermatitis, allergic dermatitis, eczema, ulcerative colitis, Crohn's disease, inflammatory intestinal disease, gastritis caused by Neuobasieg ruiogi, gastritis caused by non-Neioobrasieg ruiogi, gastrointestinal tract injury, or 2o psychotic disease caused by nonsteroidal anti-inflammatory drugs, or for wound healing. 52. A method of treating a mammal, including a human, with an Aga receptor agonist, comprising treating said mammal with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, according to any of claims 1-44 and claim 45, respectively. high school 53. A method of treating a mammal, including a human, for the treatment of an inflammatory disease, comprising treating said mammal with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, i) solvate or composition, according to any of claims 1-44 and claim 45 , respectively. 54. A method of treating a mammal, including a human, for the treatment of a respiratory tract disease, comprising treating said mammal with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, Ge! from a solvate or composition according to any of claims 1-44 and claim 45, respectively. 55. The method according to claim 54, where the disease is selected from the group consisting of respiratory failure syndrome in adults (AKO5), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, fibrocystic degeneration, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis. 56. A method of treating a mammal, including a human, for the treatment of septic shock, male erectile dysfunction, male factor infertility, female factor infertility, hypertension (high blood pressure), stroke, epilepsy, cerebral ischemia, peripheral vascular diseases, post-ischemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, dermatitis, allergic dermatitis, eczema, ulcerative colitis, Crohn's disease, inflammatory bowel disease, gastritis caused by Neuiobasieg ruiogi, gastritis not caused by Neuiobasieg ruiogi, intestinal tract or psychotic illness caused by nonsteroidal anti-inflammatory drugs, or for wound healing involving the treatment of said mammal. an effective amount of the compound of formula (I) or its pharmaceutically acceptable salt, solvate or composition, according to any of claims 1-44 and claim 45, respectively. 57. The method of obtaining the compound of the formula (I) according to claim 1, where M represents CO, and B, B, KZ, VK, Z, KZ and such are as defined in claim 1, which includes the interaction of the compound of the formula: In vk o KI: v "0 --52 M hu iChe) o zap ON o t o Z son FO GI with a compound of the formula: vVZe7McO7 (PV, where 7" represents a leaving group; with optional further transformation compound of formula (I) into its pharmaceutically acceptable salt. 58. The method of obtaining the compound of the formula (I) according to claim 1, which includes the aminocarbonylation reaction of the compound of the formula: b5 Whew! ' sh- nya M 2 s | M m M M UZ (o; pon 70 and con SSIU) where 7 is a leaving group with a compound of the formula: v'MNn-X-Me2-u-Me Z (KhMI, where B", B, 3, vl, c, C X and Y are as defined in claim 1, in the presence of carbon monoxide and a condensation catalyst, with optional further conversion of the compound of formula (I) into its pharmaceutically acceptable salt. 59. The method of obtaining the compound of the formula (I), which includes the removal of protective groups in the compound of the formula: EI! , sh-- WE M em K!: ki Z 2 1 sch -3i M dy ne kn. o OT osv o y Fu z o vl Or ve ie- or each of B! and BE? represents a protecting group, or, taken together, they represent a protecting group Io), KA represents СНоОН, СН2ОВ2Z or СОМ "В", 23 represents a protecting group, and В", 2, ВЗ, вл, вя, с В ", X and Y are as defined in claim 1, the protecting group(s) are removed together, individually or in any combination; i- with optional further transformation of the compound of formula (I) into its pharmaceutically acceptable salt. 60. The method of preparation for obtaining the compound of formula (I), where U is C5, and B is 7, 2, 3, c, c, c? and X are as defined in claim 1, which includes the interaction of the compound of the formula: A) with where 72/75 is a leaving group with an amine of the formula: v'v'Mn with optional further conversion of the compound of formula (I) into its pharmaceutically acceptable salt. 61. The method of obtaining a compound of the formula (I), where U represents 505, and B", 2, 3, 27, VU, "5 and X are as defined in claim 1, by the interaction of a compound of the formula: iF) VZ" m505727 (XXII) co where 7" is a leaving group with a compound of formula (II) as defined in part (a); with optional further transformation of the compound of formula (I) into its pharmaceutically acceptable salt. bo 62. The method of obtaining the compound of the formula (I), where ХУ represents С-М(СМ), and B 7, 2, 3, в, вк тах are as defined in claim 1, which includes the interaction of the compound of the formula: b5 Whew! , - NM M em EV in 2 shk M 7 M MU, FEMALES UV/yaya b uon 9 70 ; 5 t, оон SOPUV) where 78/77 represents a leaving group with an amine of the formula: вСв"МН; with optional further conversion of the compound of formula (I) into its pharmaceutically acceptable salt. 63. The method of obtaining the compound of the formula (I), which includes the interaction of the compound of the formula: B! shnya MEx s X OKI1Z mother-in-law (o; (o; se en OHn o von CO) (22) where KZ is a group that forms a complex ether with an amine of the formula: v'MH-X-Me 2-u -Me ЗВ (ХМ), ге de B", Kk, Z, Bl, B", B", X and M are as defined in claim 1, with optional subsequent transformation of the compound of formula (I) into a pharmaceutically acceptable salt thereof. co 64. The compound of the formula: 1 , - ry NM 15 a Mia EE i ny h M put - s (o; I» neon o t5 scha V on FO s where B", V, E?, VE?" and X are as follows , as defined in claim 1. 65. Compound formula: 1 EI! , -14.50 nn s M te and I OKI1Z mother-in-law (F. o echa"OH o 5 t yu 009 H SOU) where B? represents COM "VU, "8 represents a group that forms a complex ester, and B" and KE" are as defined in claim 1. 66. Formula compound: b5 IS! , - NI 15 2 from M Kr VI VE ni r -i Msh prut ra OT osv o ; VA Or OO where or each of B! and BE? is a protecting group, or taken together they are a 75 protecting group, KA is СНоОН, СН»ОВ2З or СОМ В/М, 23 is a protecting group, and В", 2, ВЗ, вы, ВМ, В 5, X and Y are as defined in claim 1. 67. The compound of the formula: ВЕ , - ny Mem VE OB2 VZ SK Жrya -t N sk Kut o s SOS) o where B", B, 23, VU, B", X and U are as defined in the claim 1. 68. The compound of the formula: ВЕ , sht (o) zony sh MM ВИ5 ВЗ ВЗ 6 Oryu schy pd one, MM Ty vya s y z5 Kk o og i - where В?" represents a protective group, and В", 2, VU, VU, B "U, X and U are as defined in claim 1. 69. The compound of the formula: ry ' ih NM ne s M zm KIZ I PO damage d-t mass zd - E o OS (95) where KE?" is a protective group, and B", B, VE "5 and X are as defined in claim 1. p. 70. The compound of the formula: (F. no (o) o; se - 22 lo 9 ObOop) because where V" represents a group that forms a complex ether, and either each of VE?! and 22 represents a protective group, or, taken together, they is a protecting group and B is as defined in claim 1. 71. Compound of the formula: b5 IS! , - ny M t her i "1 oviv ke si po (9) 70 14 ! гг Е и т сув22 во ок СсоОсго де В" is an ester-forming group, and either each of ВЕ?! and 22 is a protecting group, or taken together they are a protecting group, and K" and K"" are as defined in claim 1. 72. The compound of the formula: VZ ' sh- nya g IL on GOV - ee si v (9) 7 ; Where either each of K7' and K?? represents a protecting group or, taken together, they represent a protecting group, iv and K"" are as defined in claim 1. 73. The compound of the formula: (o) VI , - - ny IS) M 5 y a ovi o x y- 8) НО (8) yo Onch yu no OsOOSUt Z s de K "Z is a group that forms a complex ether , and B is as defined in claim 1. "» 74. The compound of the formula: p -E ' NM CHI sia MM. u o shi hosu wa sl (o) -0. 2 but (o) with E2o Oky ov where or each of BC? and KE? represents a protecting group, or, taken together, they represent a protecting group, 1K, p, VZ, rya, 5, X and U are as defined in claim 1. ГФ! 75. The compound of the formula: ime) 60 b5 ry: ny y M em KIZ E2 EZ i 1 o KA A rather MM UM. what? НО (о; 10 dya 2 Y 22 E2O OB ovo where either each of Ki K?? represents a protecting group, or, taken together, they represent a protecting group, IC, p2, VZ, c, B, X and U are as defined in claim 1. 15 76. The compound of the formula: ВЕ , 7 НМ Мем Е!Й 2 20 s | - M Ii tya binds SBiRiie (8) zap SN o ch 25 t o - Yu on SOU A) where 72/75 is a leaving group, and KE", B2, VU, B" and X are such that as defined in claim 1. 77. Compound of the formula: (22) В , в. IS) M em EV in C | this is so -o M back if- syak HO to-m(singing b uon 9 and " EZ? en - s ots "from where 78/79 represents a departing group, and KE", B2, VU, B" and X are as defined in claim 1." 78. The compound of formula (I), as defined in claim 1, is selected from ethyl 6-(2,2-diphenylethyl)amino|-9UN-purine-2-carboxylate; ethyl and 9-(21k,3kK,4kK,5K)-3,4-bis(acetoxy)-5-Kacetyloxy)methyl/hetrahydro-2-furanyl)-6-(2,2-diphenylethyl)amino|-9H- Pus rin-2-carboxylate; ethyl o 9-(2K,ZK,45,5K)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl|-6-((2,2-diphenylethyl)amino|-9H-purine-2 -k - 50 carboxylate; ethyl Me; 9-KZak,4k,bK,bak)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuroi|3,4-4111,3|dioxol-4-yl|-6-( 2,2-diphenylethyl)amino|-UN-purine-2-carboxylate; (Za5,45,6K,bac)-6-I6-K2,2-diphenylethylamino|-2-(ethoxycarbonyl)-9H-purin-9-yl|-2,2-dimethyltetrahydrofuroiZ 4-41(1,3)dioxol -4-carboxylic acid; o ethyl 9-(Zac,4k,65,base)-6-Ketylamino)carbonyl|-2,2-dimethyltetrahydrofuroi3,4-4111,3|dioxol-4-yl)-6-K2,2-diphenyl o ethyl) amino|-9UN-purine-2-carboxylate; 9-(Zac,4k,65,baz)-6-Ketylamino)carbonyl|-2,2-dimethyltetrahydrofuroi3,4-4111,3)dioxol-4-ylII-6-K2,2-dife 60 nylethyl)amino|- 9H-purine-2-carboxylic acid; 9-(Zac,4k,65,baz)-6-Ketylamino)carbonyl|-2,2-dimethyltetrahydrofuroyl3,4-4111,3)dioxol-4-ylII-6-K2,2-diphenylethyl)amino)|- M-(2-(41-(2-pyridyl)-4-piperidinylamino)carbonyl)amino)ethyl)-9H-purine-2-carboxamide; tert-butyl 2-(C(1-(2-pyridinyl)-4-piperidinylamino)carbonyl)amino|)ethylcarbamate; of M-(2-aminoethyl)-M'1-(2-pyridinyl)-4-piperidinyl)urea dihydrochloride or 65 M-(2-aminoethyl)-M'|(1-(2-pyridinyl)-4-piperidinyl) urea 79. The compound of the formula: in MemKO VK2 Z I -t- M sny ot ono from 7, Z it or its pharmaceutically acceptable salt or solvate, where K' represents H, C 4-Cv alkyl or fluorenyl, 75 specified C.- Ce alkyl is optionally substituted with 1-2 substituents, each of which is independently selected from phenyl and naphthyl, and said phenyl and naphthyl are optionally substituted with C 4-Ce alkyl, C-4-Cv alkoxy, halogen or cyano; IN? represents H or C1-C1 alkyl, B3 and B, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl, each of which is optionally substituted on a ring atom nitrogen or carbon atom C.4-Ce alkyl or C.-C.cycloalkyl and optionally substituted on the ring carbon atom not adjacent to the nitrogen atom, MAV group, or KZ is H, C.-C.alkyl, C.-C.cycloalkyl or benzyl, and KE" is: (a) azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or c homopiperidin-4-yl, each of which is optionally substituted C 4-Cv alkyl, C3-Cv cycloalkyl, phenyl, Ge) benzyl or Ni, or (5) "(Co-Cv alkylene)-KZ or (c) -"C4-Cv alkylene) -K 73, b" V? represents SNOON or SOM "VU; 25 Her VK" or each, independently, represents H or C /-Cv alkyl, or, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl or piperidinyl, the specified azetidinyl, pyrrolidinyl or piperidinyl are optional are necessarily substituted by C 1-C alkyl; C is () azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, o homopiperidin-1- yl, homopiperazin-1-yl or tetrahydroisoquinolin-1-yl, each of which is optionally substituted on the ring carbon atom by C-C alkyl, C3-C cycloalkyl, phenyl, C-C alkoxy-(C. 4-Cv)-alkyl, vVVVUM-(C1-Cv) alkyl, fluoro-(C1-Cv)-alkyl, -SOMAUVU, -SOOBU or Co-C alkanoyl, and optionally substituted on a ring carbon atom not adjacent to a nitrogen atom, fluoro-(C.4-Cv)-alkoxy, halogen, -OVKU, "yu cyano, -5(O)pA 9, -MVOV?, -502-MVUVU, -MVOSOV'Y or -MKO5028'O , and the indicated piperazin-1-yl and C homopiperazin-1-yl are optionally substituted on the ring nitrogen atom not bonded to C 5-Cv alkylene ova with a group, C.-Cv alkyl, phenyl, C.4-Cv alkoxy-(Co-Cv)-alkyl, KUEUM-(Co-Cv)-alkyl, fluoro-(C4-Cv)-alkyl, with C, -Cv alkanoyl, -SOOK M, C3-Cv cycloalkyl, -502K 2, -VOMA UA? or -"SOVUVU, or (y)-MA vag; IN? represents H, C.4-Cv alkyl, C.sub.1-Cv cycloalkyl or phenyl; - B "9 represents C.-Cv alkyl, C3-Cv cycloalkyl or phenyl; o B" represents H, C.4-Cv alkyl, C3-Cv cycloalkyl or benzyl; sl B" is H, C 4-Cb alkyl, Ca-Cv cycloalkyl, phenyl, benzyl, fluoro-(C4-Cv)-alkyl, -SOMAEU, -SOOK U, 50. Co-C alkanoyl or -802MAUv; and BZ is phenyl, pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl, each of which is optionally (Che) substituted C 1-4 alkyl, C 41-6 alkoxy, halogen, or cyano ; B" is H or C.-Cv alkyl, optionally substituted by cyclopropyl; B" is H or C.4-Cv alkyl; t is equal to 0, 1 or 2; o X is an unbranched C25-C3 alkylene, optionally substituted with C4-C6 alkyl or C5-C8 cycloalkyl; ko U represents СО, С5, 505 or С-М(СМ); and "Her" used in the definition of B" is a C-bonded, 4-6-membered ring, heterocycle having either 1-4 ring nitrogen heteroatoms or 1-2 ring nitrogen heteroatoms and 1 ring heteroatom of oxygen or sulfur, optionally substituted with C 4 -Ce alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, hydroxy, oxo or halogen. Official Bulletin "Industrial Property". Book 1 "Inventions, Useful models, topography of integrated circuit boards", 2005, M 8, 15.08.2005. State Department of Intellectual Property of the Ministry of Education and