UA82074C2 - Pyrimidinone derivatives as therapeutic agents against acute and chronic inflammatory, ischaemic and remodelling processes - Google Patents

Abstract

The invention relates to novel heterocyclic derivatives, processes for their preparation, and their use in medicaments, especially for the treatment of chronic obstructive pulmonary diseases.

Description

Description of the invention

The presented invention relates to new heterocyclic derivatives, methods of their preparation and their use 2 in medicines, especially for the treatment of chronic obstructive pulmonary diseases, acute coronary syndrome, acute myocardial infarction and progressive heart failure.

The fibrillar protein elastin, which constitutes a significant percentage of all proteins contained in tissues such as arteries, some connective tissues, lungs, and heart, can be hydrolyzed or otherwise degraded by certain groups of enzymes belonging to the class of elastases. Human leukocyte elastase (HNE, EC 70 3.4.21.37), also known as human neutrophil elastase (HME), is a glycosylated strongly basic serine protease and is found in the azurophilic granules of human polymorphonuclear leukocytes (PMLs).

NME is released from activated PMMs and is involved in the pathogenesis of acute and chronic inflammatory diseases. NME is capable of degrading a wide range of matrix proteins including elastin and collagen, and in addition to this action on connective tissue, NME has a wide range of inflammatory effects including upregulation of II-8 gene expression, 12 edema formation, mucous gland hyperplasia, and mucus hypersecretion. It also acts as a mediator of tissue damage due to the hydrolysis of the collagen structure, for example, in the heart after an acute myocardial infarction or during progressive heart failure, thus damaging endothelial cells, promoting extravasation of neutrophil adhesion to the endothelium, and influencing the adhesion process.

Pulmonary diseases where NME has been suggested to play a role include pulmonary fibrosis, pneumonia, acute respiratory distress syndrome (ARDS5), pulmonary emphysema including smoking-induced emphysema, chronic obstructive pulmonary disease (COPD) and cystic fibrosis. In cardiovascular diseases,

NME is involved in the increased generation of ischemic tissue damage due to myocardial dysfunction after acute myocardial infarction and in the remodeling processes occurring during progressive heart failure. NME also causes rheumatoid arthritis, atherosclerosis, brain injury, cancer, and related conditions involving neutrophils. heh)

Thus, inhibitors of NHE activity can be potentially useful in the treatment of a number of inflammatory diseases, especially chronic obstructive pulmonary diseases (|K.A. Bioskiiu, Metshigorpiiv apa rgoiease/apiirgoiease itraiapse, At. U. Kevzrig. Sty. Sage 160, 549-552 (1999)). Inhibitors of NO E activity can be potentially useful in the treatment of acute myocardial syndrome, unstable angina, acute myocardial infarction and coronary artery bypass grafting (CABG) |S.R. TieHepraspeg ei ai., Ippibyop oi eiYiavziaze m. itrgomez tuosagaia! Tipsiop apyeg gerefime izspaetia apa tuosagaia! ipbagsyop ip (She gayi Ppeapy, EEig. 3.

Rpuzioi 433, 5563-5570 (1997); Oipegptap ei ai., Ipsgeavzed peshigorniY eiaviaze geiease ip tsipviarie apdipa o resiogiv apa askie tuosagaia! ipbagsyop, U. At. soybeans Sagayu!. 15, 1559-1563 (1990)), progressive heart failure |5.U. (Pre ei a). Ipsgeasei oehrgezvsiop oirgotaiygih teyai Porgoieipase-9 apa peshhorpii 32 eiaviave ip sapipe saiasea sagaiotuoraipu, Sagaiom. Caves. 34, 5377-5383 (1997) and atherosclerosis.

The synthesis of 5-ethoxycarbonyl-1-phenyl-b-methyl-4-(3-nitrophenyl)-3,4-dihydropyrimidin-2(1H)-one is described in M.

Negegosusiis Spem. 38, 1051 (2001)). The pharmacological activity of this compound was not mentioned. "

The presented invention relates to compounds of the general formula (I) - p. and? so ko o - ch

F) ko 60 b5

In" in: y

And | Ah, 7 more and d! gays with 7 3 o (I), "I de "a

A represents aryl or heteroaryl, 27, 82 and BZ independently of each other represent hydrogen, halogen, nitro, cyano, C 4-Cv-alkyl, hydroxy and- or C.i-Cv-alkoxy, where C.i-Cv- alkyl and C.-C-Alkoxy can be further substituted by one or three identical or different radicals selected from the group containing halogen, hydroxy and C.-C-Alkoxy, co represents trifluoromethylcarbonyl, IF; 1-C1-alkylcarbonyl, C1-C1-alkylcarbonyl,

C.-C -alkenoxycarbonyl, hydroxycarbonyl, aminocarbonyl, mono- or /di-C.-C.,-alkylaminocarbonyl,

Ce-Ce-arylaminocarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl, heterocyclyl or cyano, where Ce-Ce-alkyl carbonyl, C.4-C.-alkylcarbonyl, mono- and di-C.4-C,.-alkylaminocarbonyl can be in " further substituted by one or three identical or different radicals selected from the group containing - C3-C8-cycloalkyl, hydroxy, C.-C. di-Ci-C.-alkylaminocarbonyl, C.-C.-alkylcarbonylamino, (C.4-C.-alkylcarbonyl)-C.-C.-alkylamino, cyano, amino, with mono- and di-C.i -C,-alkylamino, heteroaryl, heterocyclyl and tri-(Ci-Cv-alkyl)silyl, and where heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl and heterocyclyl may be further substituted with C.4-C.-alkyl, vo represents C.-C ,-alkyl, which can be substituted by one to three identical or different radicals,

Go! selected from the group containing halogen, hydroxy, C 4-Cv-alkoxy, C-Cv-alkenoxy, C.i-Cv-alkylthio, amino,

Mmono- and di-C4-C6-alkylamino, arylamino, hydroxycarbonyl, C.1-C6-alkoxycarbonyl and the radical -0-C4-C,-alkyl-O-C.-C,-alkyl, where O-C.- Su O-c.-c, or o b -1 50 vo represents amino, po represents hydrogen, C 4-C-alkyl, formyl, aminocarbonyl, mono- or di-C.-C,-alkylaminocarbonyl, c» C. -Cu-cycloalkylcarbonyl, C.4-Cv-alkylcarbonyl, C.4-Cv-alkoxycarbonyl, M-(C4-C/-alkylsulfonyl)aminocarbonyl,

M-(C4-C.-alkylsulfonyl)-IMm-(C 4-C.-alkyl)uaminocarbonyl, heteroaryl, heterocyclyl, heteroarylcarbonyl or heterocyclylcarbonyl, where C.-Cv-alkyl, Mmono- and 0 di-Ci-Cv- alkylaminocarbonyl, C.-Ce-alkylcarbonyl, 5o C.-Cv-aluoxycarbonyl, heteroaryl and heterocyclyl can be substituted by one or three identical or o different radicals selected from the group containing aryl, heteroaryl, hydroxy, C 4-Cv- Alkoxy, hydroxycarbonyl, C.--Cv-Alkoxycarbonyl, amino-carbonyl, mono- and di-Ci-C,.-alylaminocarbonyl, amino, mono- and co di-C.-C.,-alkylamino, C.-C ,-alkylcarbonylamino, tri-(C4-Cv-alkyl)silyl, cyano, M-(mono- and di-Ci-Cv-alkylamino-C4-C.,-alkyl)aminocarbonyl, M-(C.4-C, -Alkoxy-C-C,-alkyl)aminocarbonyl and halogen, 6o or

VE? represents the substitute of the formula b5

(Sn, from 70 de

BX is selected from the group consisting of hydrogen and C-Ce-alkyl, and n represents an integer of 1 or 2,

K represents halogen, nitro, cyano, C.4-Cv-alkyl, hydroxy or C.--Cv-alkyl, where C.-Cv-alkyl and C.--Cv-alkyl may be further substituted by one or three identical or different radicals selected from 7/5 of the Group containing halogen, hydroxy, and C.-C.-alkoxy, and

U, mg, 3, y, and U5 independently represent CH or M, where the ring contains either 0.1 or 2 nitrogen atoms.

The compounds of this invention may also exist in the form of salts, hydrates and/or solvates thereof.

Physiologically acceptable salts are preferred in the context of the present invention.

Physiologically acceptable salts according to the invention are non-toxic salts, which are usually obtained by the reaction of compounds (I) with an inorganic or organic base or acid, which are usually used for these purposes. Non-limiting examples of pharmaceutically acceptable salts of compounds (I) are alkali metal salts, for example, lithium, potassium and sodium salts, alkaline earth metal salts, such as magnesium and calcium salts, and Quaternary ammonium salts, such as, for example, triethylammonium salts, acetates, benzenesulfonates ) . -

Hydrates of compounds of the invention or their salts are stoichiometric compositions of compounds with water, such as, for example, hemi-, mono- or dihydrates.

Solvates of the compounds of the invention or their salts are stoichiometric compositions of the compounds with solvents. with

The present invention includes both individual enantiomers and diastereomers and the corresponding racemates or diastereomeric mixtures of the compounds according to the invention and their corresponding salts. In addition, include all possible tautomeric forms of the compounds described above according to the present invention. Diastereomeric mixtures can be separated into separate isomers using chromatographic techniques. Racemates can be separated into their respective enantiomers either by chiral phase chromatographic techniques or by resolution. "

In the context of the present invention, the substituents, unless otherwise indicated, usually have the following meanings: - c Alkyl usually represents an unbranched or branched hydrocarbon radical having from 1 to 6, and preferably from 1 to 4 carbon atoms. Non-limiting examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, "" isobutyl, t-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl. The same applies to radicals such as alkoxy, alkylamino, alkoxycarbonyl and alkoxycarbonylamino.

Alkoxy illustratively and preferably represents methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy,

Go! n-pentoxy and n-hexoxy.

Alkylcarbonyl usually represents an unbranched or branched hydrocarbon radical having from 1 to 6, preferably from 1 to 4 carbon atoms, which has a carbonyl function at the point of attachment. Non-limiting examples are formyl, acetyl, n-propionyl, n-butyryl, isobutyryl, pivaloyl, n-hexanoyl.

Alkoxycarbonyl is illustrative and preferably represents methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

T» Alkylamino represents an alkylamino radical having one or two (independently selected) alkyl substituents, illustratively and preferably represents methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, M,M-dimethylamino, M,M-diethylamino, M-ethyl-M-methylamino, M-methyl-M-n-propylamino, M-isopropyl-M-n-propylamino, M-tert-butyl-M-methylamino, M-ethyl-M- n-pentylamino and

M-n-hexyl-M-methylamino. (F. Alkylaminocarbonyl represents an alkylaminocarbonyl radical having one or two (independently selected) co-alkyl substituents, illustratively and preferably represents methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, or n-hexylaminocarbonyl, M, M-dimethyl-aminocarbonyl, M,M-diethylaminocarbonyl, M-ethyl-M-methylaminocarbonyl,

M-methyl-M-n-propylaminocarbonyl, / M-isopropyl-M-n-propylaminocarbonyl, M-tert-butyl-M-methylaminocarbonyl,

M-ethyl-M-n-pentylamino-carbonyl and M-n-hexyl-M-methyl-aminocarbonyl.

Alkylsulfonyl usually represents an unbranched or branched hydrocarbon radical having from 1 to 6, preferably from 1 to 4 carbon atoms, which has a sulfonyl group at the point of attachment. Non-limiting 65 examples are methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, tert-butylsulfonyl.

Cycloalkyl usually represents a cyclic saturated hydrocarbon radical having from 3 to 8, preferably from 3 to 6 carbon atoms. Non-limiting examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Aryl reg ze i in arylcarbonyl represents a mono- - tricyclic aromatic carbocyclic radical, which usually has from 6 to 14 carbon atoms, illustratively and preferably represents phenyl, naphthyl and phenanthrenyl.

Arylcarbonyl is illustratively and preferably benzoyl and naphthoyl.

Heteroaryl in heteroarylcarbonyl represents an aromatic mono- or bicyclic radical, usually having from 5 to 10 and preferably 5 or b ring atoms and up to 5 and preferably up to 4 heteroatoms selected from the group consisting of 5, O and M , illustratively and preferably represents thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, quinolinyl, isoquinolinyl.

Heteroarylcarbonyl is illustratively and preferably thienylcarbonyl, urylcarbonyl, pyrrolylcarbonyl, thiazolylcarbonyl, oxazolylcarbonyl, imidazolylcarbonyl, pyridylcarbonyl, pyrimidylcarbonyl, /5 pyridazinylcarbonyl, indolylcarbonyl, indazolylcarbonyl, benzofuranylcarbonyl, benzothiophenylcarbonyl, quinolinylcarbonyl, iz.

Heterocyclyl reg ze i in heterocyclylcarbonyl represents a mono- or polycyclic, preferably mono- or bicyclic, non-aromatic heterocyclic radical, which usually has from 4 to 10 and preferably from 5 to 8 ring atoms and up to 3 and preferably up to 2 heteroatoms and/or heterogroups, which are selected from the group containing M, 9,3, ZO and 5O". Heterocyclic radicals can be saturated or partially saturated. Preference is given to 5- to 8-ene monocyclic saturated heterocyclyl radicals having up to two heteroatoms selected from the group containing O, M and Z, such as, illustratively and preferably, tetrahydrofuran-2-yl, pyrrolidin-1- yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, piperidinyl, morpholinyl, perhydroazepinyl. with

Heterocyclylcarbonyl is illustrative and preferably represents tetrahydrofuran-2-carbonyl, pyrrolidine-1-carbonyl, pyrrolidine-2-carbonyl, pyrrolidine-3-carbonyl, pyrrolinecarbonyl, piperidinecarbonyl, (8) morpholinecarbonyl, perhydroazepinecarbonyl.

Halogen represents fluorine, chlorine, bromine and iodine.

When it is indicated that U". U?. UZ. u? and 8 represent CH or M, OH should also become a ring /-"f carbon atom, which is replaced by the substituent KZ or VK". The 7th symbol after the bond means the point of attachment to the molecule. t

In another embodiment, the presented invention relates to compounds of the general formula (I), where

A represents aryl or heteroaryl, 27, 82 and BZ independently of each other represent hydrogen, halogen, nitro, cyano, C 4-Cv-alkyl, hydroxy cm or C.i-Cv-alkyloxy, where C.i-Cv-alkyl and C .-C-C-Alkoxy can be further substituted by one to three 9 identical or different radicals selected from the group containing halogen, hydroxy and C-C-C-Alkoxy,

B" represents C 4 -C 1 -alkylcarbonyl, C 1 -C 1 -alkylcarbonyl, C 4 -C 1 -alkenoxy carbonyl, hydroxycarbonyl, aminocarbonyl, mono- or di-C 1 -C 1 -alkylaminocarbonyl, C 1 -C 1 - arylaminocarbonyl, heteroarylcarbonyl, "heterocyclylcarbonyl, heteroaryl, heterocyclyl or cyano, where C.i.-C.sub.-alkylcarbonyl, C.i.-C.sub.-alkylcarbonyl, mono- and di-C.-C.-alkylaminocarbonyl may be further substituted by one or three identical or - with different radicals selected from the group containing C 2 -C 2 -cycloalkyl, hydroxy, C. C.i-C.-alkylaminocarbonyl, C.-C,-alkylcarbonyl amino, amino, mono- and di-C.--C,-alkylamino, heteroaryl, heterocyclyl and tri-(C.4-C-alkyl) silyl, vo represents C.-C.-alkyl, which can be substituted by one or three identical or different radicals selected from the group containing halogen, hydroxy, C.4-C.-alkoxy, C.-C.-alkenoxy, C. i-Sev-alkylthio, amino, co-mono- and di-Ci-Cv-alkylamino, arylamino, hydroxy carbonyl, C.-Cv-alkoxycarbonyl and the radical ka -0-C04-C,-alkyl-O-C.4-C,-alkyl, or - vo represents amino, -I 50 po represents hydrogen, C 4-Cv- alkyl, formyl, aminocarbonyl, mono- or di-C.-C,-alkylaminocarbonyl, C.-C.sub.-cycloalkylcarbonyl, C.-C.sub.-alkylcarbonyl, C.-C.-alkylcarbonyl, M-(C.sub.1-C,-allylsulfonyl )aminocarbonyl,

M-(C4-C.-alkylsulfonyl)-IMm-(C 4-C.-alkyl)uaminocarbonyl, heteroaryl, heterocyclyl, heteroarylcarbonyl or heterocyclylcarbonyl, where C.-Cv-alkyl, Mmono- and 0 di-Ci-Cv- alkylaminocarbonyl, C.-Ce-alkylcarbonyl,

C1-C1-Alkoxycarbonyl, heteroaryl and heterocyclyl may be substituted with one to three identical or different radicals selected from the group consisting of aryl, heteroaryl, hydroxy, C1-C1-Alkoxy,

ГФ) hydroxycarbonyl, C.4-C-alkoxycarbonyl, amino-carbonyl, mono- and di-C--C.-alkylaminocarbonyl, amino, mono- and

Ф di-C.-C.,-alkylamino, C.-C,-alkylcarbonylamino, tri-(C4-Sev-alkyl)silyl, cyano, M-(mono- and di-Ci-C.-alkylamino-C4- C.,-alkyl)aminocarbonyl, M-(C.4-C,-alkoxy-C-C,-alkyl)aminocarbonyl and halogen, 60 or

VE? represents the substitute of the formula b5

"Ж "ХХ "Х ; aso (sn) mA o z'p 1 de

BH is selected from the group containing hydrogen and C-Ce-alkyl, and n represents an integer of 1 or 2, c' represents halogen, nitro, cyano, C-Ce-alkyl, hydroxy or C-Ce-alkoxy, where C 1 -C 6 -alkyl and C 1 -C 6 -alkyl may be further substituted with one or three identical or different radicals selected from the group 12 containing halogen, pdroxy, and C 1 -C 1 - alkoxy,

U, mg, M, y, and U5 independently represent CH or M, where the ring contains 0.1 or 2 nitrogen atoms.

In another embodiment, the presented invention relates to compounds of the general formula (I), where

A represents phenyl, naphthyl or pyridyl,

B", the 82nd VZ independently of each other represent hydrogen, fluorine, chlorine, bromine, nitro, cyano, methyl, ethyl, trifluoromethyl or trifluoromethoxy,

Ge represents C 4-C-alkyl carbonyl, C-C-alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, c g Mono-C-C,-alkylaminocarbonyl or cyano, where C-Ce-alkylcarbonyl, C-C-C- Alkoxycarbonyl and o-mono-C.-C.-alkylaminocarbonyl can be substituted by one to three identical or different radicals selected from the group containing C 3-C-cycloalkyl, hydroxy, C. and 4-C; - alkoxy, C. --C,-Alkoxycarbonyl, amino, mono- or di-C,-C,-alkylamino, heteroaryl and heterocyclyl,

IS? represents methyl or ethyl, chi po represents hydrogen, C 4-C-alkyl, mono- or di-C.--C,-alkylaminocarbonyl, C.-C-alkylcarbonyl,

C-S-Alkoxycarbonyl or heterocyclylcarbonyl, where C-C-C-Alkyl and C-C-C-Alkoxycarbonyl may be substituted by one or three identical or different radicals selected from the group consisting of heteroaryl, "2 hydroxy, C-C ,-Alkoxy, Hydroxycarbonyl, C.-Cv-Alkoxycarbonyl, Aminocarbonyl, MOono- and di-Si-C.,-Alkylaminocarbonyl, Cyano, Amino, Mono- and Di-C.4-C.-Alkylamino,

Zo or (ge)

VE? represents the formula substitute

The same "" not that av tk with s; azo vA (SN.)a p t 1 de o bA y y s, .

CA is selected from the group containing hydrogen and C.-C.-alkyl, and n represents an integer of 1 or 2, where B" represents halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, methyl or ethyl, o Um, 3, ma and U5 each represent CH.

In another embodiment, the presented invention relates to compounds of the general formula (I), - where

T" A represents phenyl or pyridyl,

In the VZ, each represents hydrogen,

IN? represents fluorine, chlorine, bromine, nitro or cyano, 52 B" represents cyano, C4-C4-alkylcarbonyl or C4-C4-alkylcarbonyl, where C4-C4-alkylcarbonyl can be substituted by a radical selected from the group, which contains hydroxy, C-4-C-alkoxy, C-C-alkoxycarbonyl, mono- and di-C4-C-alkylamino, heteroaryl and heterocyclyl, where VE? represents methyl,

VU represents hydrogen, C 4-C 4 -alkyl, mono- or di-C 1 -C 4 -alkylaminocarbonyl, C 4 -C 4 -alkylcarbonyl or 17A 17A tA

C1-C1-Alkoxycarbonyl, where C1-C1-Alkyl and C4-C1-Alkoxycarbonyl may be substituted with a radical selected from the group consisting of heteroaryl, shydroxy, C1-C1-Alkoxy, hydroxycarbonyl, aminocarbonyl, mono- and di-Ci-C-alkylaminocarbonyl, amino, mono- and di-Ci-C,-alkylamino,

Or 65 25 represents a substitute for the formula

"Ж "Ж 7 70 С schu with de

BA is selected from the group consisting of hydrogen and methyl,

B" represents trifluoromethyl or nitro, and

Um, 3, ma and U5 each represent CH.

In another embodiment, the present invention relates to compounds according to the general formula (I), where

And there is phenyl or pyridyl.

In another embodiment, the present invention relates to compounds according to the general formula (I), where B' is hydrogen.

In another embodiment, the present invention relates to compounds according to the general formula (I), where B? is cyano, especially where A is phenyl or pyridyl and 22 is cyano in the para-position to the central dihydropyrimidinone ring. high school

In another embodiment, the present invention relates to compounds according to general formula (I) where hydrogen is present. at

In another embodiment, the present invention relates to compounds according to the general formula (I), where

C1-C1-Alkoxycarbonyl, optionally substituted hydroxy, and especially 2-hydroxyethoxycarbonyl, or where B" is

C.-C.-alkyl carbonyl, especially methyl carbonyl. chi

In another embodiment, the present invention relates to compounds according to the general formula (I), where VE? is methyl. Cha

In another embodiment, the present invention relates to compounds according to the general formula (I) where 9 is hydrogen. at

In another embodiment, the present invention relates to compounds according to the general formula (I), devB' is c trifluoromethyl or nitro, especially where B/ is trifluoromethyl located in the meta-position relative to c of the central dihydropyrimidinone ring.

In another embodiment, the presented invention relates to compounds of the general formula (IA) (A) « and M 2 c . » n She 7 1 7

And so shcha ko o v. to still - M l | A, with ko) di

And this

ЧА), b5 where 7 represents CH or M, and

B", 83, 27 and 25 have the values indicated above.

Compounds of the presented invention, where P? there is hydrogen, they can enolize into the corresponding hydroxyamidines: in v and z and a | ' 4 in --- 20 . | A, 5 re - IY ie; "Mshe i ee i i ke 7 i vo v" "I

Compounds of general formula (I) can be synthesized by condensing compounds of general formula (II) - (ав) (1

V' y s v" i - s " ee 18 (I), o io) o de

Ah, V! 82 have the values indicated above, and with the compounds of the general formula (PI) and" (1) and (Ф) it is in (11), where

Its 25 have the values indicated above, because the compounds of the general formula (IM)

(M 70 "a and d! r v

PU), where

ВЗ, Ві У - УЗ have the values specified above, in the presence of an acid or in a three-component/one-stage reaction, or sequentially obtaining compounds of the general formula (IV) with 2 (В) o "I in! "a o s do so te" A, p e "M she

In Oud

I'm sorry

Ii ko 3 o ey still (IV), ch de

А, В'-в5, В/м - У5 have the values indicated above, but not necessarily, with the following reaction of the compounds of the general formula (IV) with the compounds of the general formula (М) ke poh (U) because where ш ох has the value B , as indicated above, but does not represent hydrogen, and

X represents a leaving group such as halogen, tosylate, mesylate or sulfate in the presence of a base.

Compounds of the general formula (I), where KE? represents cyano, BC? represents amino and KU represents hydrogen, because it is possible, alternatively, to obtain by condensation of compounds of the general formula (II) with compounds of the general formula (IM) and a compound of the formula (MI)

Mo-СНо-СМ (М) and not mm - and in the presence of acid or in a three-component/one-stage reaction, or sequentially.

Suitable solvents for the process (1)4(KMI)NIM) -»(IV) are usually ordinary organic solvents that do not change under the reaction conditions. Solvents are ethers such as diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, ethyl acetate, acetone, acetonitrile, dimethylsulfoxide, 70 dimethylformamide or alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or t-butanol, or hydrocarbons such as pentane, hexane, cyclohexane, benzene, toluene or xylene or halogenated hydrocarbons such as dichloromethane, dichloroethane, trichloromethane or chlorobenzene. It is also possible to use mixtures of the solvents mentioned above. Tetrahydrofuran is preferred for the process.

Suitable acids for process (1)(P3AMI)(IM) -»(IV) are usually inorganic or organic acids.

The acids are preferably carboxylic acids, such as, for example, acetic acid or trifluoroacetic acid, sulfonic acids, such as, for example, methanesulfonic acid or p-toluenesulfonic acid, hydrochloric acid, or phosphoric acids, such as polyphosphoric acids. Prolyphosphoric acid ethyl ester is preferred. The acid is used in an amount from approximately 0.25 mol to 1000 mol, relative to Tmol of the compound of the general formula (PP).

The process is usually carried out at a temperature in the range from 4202C to 1502C, preferably from 1609C to -10026C.

The process is usually carried out at normal pressure. However, it is also possible to conduct it at increased pressure or at reduced pressure (for example, in the range from 0.5 to 5 bar).

Suitable solvents for the process (IV)(M)-»(I) are usually ordinary organic solvents that do not c 285 Change under the influence of reaction conditions. Solvents are ethers such as diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, ethyl acetate, acetone, acetonitrile, dimethylsulfoxide, o dimethylformamide or hydrocarbons such as pentane, hexane, cyclohexane, benzene, toluene or xylene or halogenated hydrocarbons. , such as dichloromethane, dichloroethane, trichloromethane or chlorobenzene. It is also possible to use mixtures of the solvents mentioned above. Tetrahydrofuran is preferred for the process. hE

Suitable bases for the process (IV)H(M)-(I) are ordinary inorganic or organic bases. The bases are preferably cyclic amines, such as, for example, piperidine or 4-M,M-dimethylaminopyridine or Se(C,4-C,)-trialkylamine, such as, for example, triethylamine or diisopropylethylamine, or hydrides, such as sodium hydride . Sodium hydride is preferred. The base is used in an amount from approximately 0.mol to 1Omol, preferably from Tmol to Zmol, relative to Tmol of the compound of the general formula (IM). with

The process is usually carried out at a temperature in the range from 09C to 1502C, preferably from -202C to 809C, especially at room temperature.

The process is usually carried out at normal pressure. However, it is also possible to carry out at increased pressure or at reduced pressure (for example, in the range from 0.5 to 5 bar).

Compounds of the general formulas (I), (PI), (M), (M) and (MI) are known by convention, or they can be obtained using conventional methods. The above-mentioned method can be illustrated with the help of the following diagram:

AND

Go d) E: ko tsa o.

A vch o o X - o Sha; (F) Compounds according to the invention exhibit an unpredictable spectrum of useful pharmacological and pharmacokinetic activity. Therefore, they are suitable as medicines for the treatment and/or prevention of disorders in humans and animals. Unexpectedly, the compounds of the present invention inhibit the activity of human neutrophil elastase (NME) and are therefore suitable for the preparation of medicaments for the treatment of diseases associated with the activity of NME. They can provide effective treatment of acute and chronic inflammatory processes, such as rheumatoid arthritis, atherosclerosis, and especially acute and chronic lung diseases, such as pulmonary fibrosis, cystic fibrosis, pneumonia, acute respiratory distress syndrome (AKO5), in particular, pulmonary emphysema, 65 Including smoking-induced emphysema, and chronic obstructive pulmonary disease (COPD), chronic bronchitis, and bronchiectasis. The compounds of the present invention can also provide effective treatment of cardiovascular ischemic diseases, such as acute coronary syndrome, acute myocardial infarction, unstable and stable angina pectoris, coronary artery bypass grafting (CABG) and progressive heart failure, atherosclerosis, moral heart disease, atrial septal defects, with transcutaneous transluminal coronary angioplasty (PTCA), inflammation after open heart surgery and pulmonary hypertension. They may also be useful in the effective treatment of rheumatoid arthritis, acute inflammatory arthritis, cancer, acute pancreatitis, ulcerative colitis, periodontal disease, Chury-Strauss syndrome, acute and chronic atopic dermatitis, psoriasis, systemic lupus erythematosus, bullous pemphigus, sepsis, alcoholic hepatitis , liver fibrosis, Behcet's disease, allergic 7/0 fungal sinusitis, allergic sinusitis, Crohn's disease, Kawasaki disease, glomerulonephritis, acute pyelonephritis, colorectal diseases, chronic purulent otitis, chronic venous leg ulcers, inflammatory bowel disease, bacterial and viral infections, injuries brain, stroke and other conditions in which neutrophils are involved.

The present invention also provides medicaments containing at least one compound according to the invention, preferably together with one or more pharmacologically safe excipients or carrier substances, as well as their use for the purposes mentioned above.

The active component can act systemically and/or locally. For this purpose, it can be used in an acceptable manner, for example, orally, parenterally, pulmonaryly, nasally, sublingually, lingually, buccally, rectally, transdermally, conjunctivally, topically or as an implant.

For these routes of administration, the active ingredient can be administered in the form of forms suitable for use.

Useful for oral administration are forms that release the active ingredient rapidly and/or in a modified form, such as, for example, tablets (uncoated tablets or coated tablets, e.g. enteric-coated), capsules, sugar-coated tablets, granules, dragees, powders , emulsions, suspensions, solutions with ov 1 aerosols.

Parenteral administration can be performed avoiding the absorption stage (intravenous, (8) intraarterial, intracardiac, intraspinal, or intraperitoneal) or including absorption (intramuscular, subcutaneous, intradermal, transdermal, or intraperitoneal). The useful forms for parenteral use are injection formulations and formulations for infusion in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.

Forms suitable for other routes of application are, for example, pharmaceutical forms for inhalation - (including powders for inhalers, nebulizers), nasal drops/solutions, sprays; tablets or capsules for lingual, sublingual or buccal administration, suppositories, ear and eye formulations, vaginal capsules, aqueous suspensions (lotions, mixed mixtures), lipophilic suspensions, ointments, creams, milk, pastes, dusting powders or implants. co

Active components can be transformed into the mentioned preparative forms by methods known in the art. This is done using inert non-toxic pharmaceutical excipients. Such excipients are carriers (for example, microcrystalline cellulose), solvents (for example, liquid polyethylene glycols), emulsifiers (for example, sodium dodecyl sulfate), dispersing agents (for example, polyvinylpyrrolidone), synthetic and natural biopolymers (for example, albumin), stabilizers (for example , antioxidants such as c ascorbic acid), colorants (eg, inorganic pigments such as iron oxides) or flavor and/or odor modifiers. For human use, in the case of oral administration, the recommended doses are in the range from 0.001 to 5Omg/kg, preferably 0.01mg/kg to 2O0mg/kg. In the case of parenteral

Application, such as, for example, intravenous or nasal, buccal or by inhalation through the mucous membrane, the recommended dose is from 0.001mg/kg to 0.5mg/kg.

However, it may be necessary in some cases to waive the mentioned amounts, namely taking into account body weight, the route of administration used, the individual response to the active ingredient, the method of administration and the time or interval at which the application takes place. For example, in some cases, it may be sufficient to use less than the minimum amount mentioned above, while in other cases, the mentioned upper limit will be exceeded. In the case of using large quantities, it may be desirable to divide the dose into several separate doses for use throughout the day.

The percentages in the tests and examples below are, unless otherwise indicated, by weight; fractions are also weighted. The ratios of solvents, diluents and concentrations given for liquid/liquid solutions are in volumes.

A. Assessment of physiological activity

GF) The activity of the compounds of the invention to inhibit the activity of neutrophil elastase can be demonstrated, for example, using the following studies:

Y. Ip conducted a study of human neutrophil elastase enzyme (NME) in study components study buffer: O0.1M HERE5-Maon buffer pH?7.4, 0.5M Masi, 0.195 (v/o) bovine serum albumin; suitable concentration (see below) NME (18O/mg lyophil

Neideirego, Septapu) in the research buffer; suitable concentration (see below) of the substrate in the research buffer; 65 suitable concentration of the compound under test, diluted with the research buffer with 10 mM of the ready solution in dm.

Example A

IP migo inhibition of HME using a fluorogenic peptide substrate (continuous readout of the signal, 384

MTR research format):

In this protocol, the elastase substrate MeObZys-AIa-AIa-Rho-Ma-AMS (85324740,

SaiIriospet-Momariospet Sogrogayop, Metgsk KOSaA, Yuagptviadi, Septapu). The test solution is obtained by mixing 1 µl of the diluted test compound, 200 µl of NME of the diluted enzyme (final concentration of 8 - 0.4 µO/ml, usually 2.1 µO/ml) and 20 µl of the diluted substrate (final concentration of IMM - 1 µM, usually 20 µM), respectively. The solution is incubated for 0-2 hours at 37 C (usually one hour). Measure 7/0 fluorescence, which is released by AMC due to the enzymatic reaction at 37 °C (TESAM plate reader, Zresiga Pshog riv). The rate of increase in fluorescence (ex. C95nm, em. 4bOnm) is proportional to the activity of elastase. The value of IC 50 is determined using the KRO-to-|) graph. The values of K and Kt(arr) are determined using Lineweaver-Burke graphs and converted into K values using Dixon graphs.

The preparative examples in this study had an IC value of 5o in the range of ZNM - 5μM. Sample data 75 are given in Table 1: p (8) "I cha o s so - s ;" so ko o - ch

F) ko 60 b5

Example Me | 1So (NMI

And we s 1 « o s

And 5 row and 5 Z - |in " 73 pis so 74 kosh 3 work - and I 5

Ф) where Example B in Ip of inhibition of NME using a fluorogenic insoluble substrate of elastin (continuous reading of the signal, 96 MTP research format):

In this protocol, the substrate of elastase was used - elastin-fluorescein (2100620, ISM Vioteadis!Y5

OtrnN, Ezspzhede, Sepgtapu). The test solution is prepared by mixing 3 µl of the diluted compound to be tested, 7/µl of NME of the diluted enzyme (final concentration 0.22O/ml - 2.2mO/ml, usually 21.7µO/ml) and vOl of the substrate suspension (final concentration 2mg/ ml). The suspension is incubated for 0-16 hours at 372 (usually four hours) with gentle agitation. To stop the enzyme reaction, 100 μl of 0.1M acetic acid (final concentration 500 mM) is added to the solution being tested. Polymeric elastin-fluorescein is precipitated by centrifugation (centrifuge Errepdogi 5804, 3000 rpm, 10 rpm).

The supernatant is transferred to a new MTP and the fluorescence of the fluorescein released by the peptide due to the enzymatic reaction is measured (WMO Rishioviag tablet reader). The fluorescence coefficient (ex. 49 Ohm, em. 52 Ohm) is proportional to the activity of elastase. The value of IC5o is determined by KEO-do-(|) graphs.

I. Migo type of research on human neutrophils

Example A

The purpose of the study of PMM elastolysis: 70 This study is used to determine the elastolytic activity of human polymorphonuclear cells (PMM) and to estimate the part of degradation due to neutrophil elastase, see 7. MU. ZNe ei aI.,, At. 9. Kezrig. Seiya

My. Vio!. 9, 386-392 (1993).

Tritiated elastin, in suspension, is applied to a 96-well tablet in the amount of 1 Ωkg per well. The test compound and the control compound (20O-0892 (y). Med. Spem. 40, 7/5 1876-1885, 3173-3181 (1997), MO 95/21855) and an AT inhibitor are added to the wells in acceptable concentrations. proteases (ATRI). Human PMMs are isolated from the peripheral venous blood of healthy donors and resuspended in a culture medium. Neutrophils are added to the filled wells in concentrations from 1x1059 to 1x102 cells per well. Pig pancreatic elastase (1.3 μM) is used as a positive control for the study, and ATRI (1.2 μM) is used as a positive inhibitor of neutrophil elastase. The cell control is PMM without compound at each acceptable cell density. Cells plus compounds are incubated in a humid incubator at 372C for 4 hours. Tablets are centrifuged, settling only the supernatant liquid. The supernatant liquid is transferred to 75 μl of the corresponding wells of a 96-well Iitaria (tm) (solid scintillation-containing tablets). The tablets are dried until there is no liquid in the wells and read in a beta counter for 3 minutes per well.

Elastolysis leads to an increase in the amount of ZN-elastin in the supernatant. Inhibition of this c elastolysis is manifested in the reduction of tritium in the supernatant, compared to the cellular control. ARI gives Ge) 83.46-43.9795 (value "-s.k.p.) inhibition at 1.2 μM (p-Z3 different donors at 3.6 x10? cells per well). The IS value was obtained based on the control compound 20-0892 45.50 -7.75 NM (value s.cop.) (p-2. different donors at 3.bh105 cells per well).

Based on the fact that 7270-0892 is a selective inhibitor of PMM elastase, together with the ARI inhibition data, these results indicate that the main degradation of PMM elastin is due to the release of neutrophil elastase rather than another elastolytic enzyme such as matrix metalloproteinase (MMP ). The compounds of the present invention were evaluated for their inhibitory activity in this NME-dependent model of neutrophil elastolysis. at 19 September

Example B. ! . | co

Inhibition of membrane-bound elastase:

Measurement of inhibition of neutrophil membrane-bound elastase was performed using studies on human neutrophils. Neutrophils stimulate I RZ at 372C for 35X minutes. and then precipitated at 16 bO0rpm. After that, membrane-bound elastase is fixed on neutrophils using 390 « 20 paraformaldehyde and 0.2595 glutaraldehyde during Zhv. at 49C. Neutrophils are then precipitated and C7Zc solvent and test compound are added, followed by the addition of the substrate MeOsis-AIIa-AIa-Pho-Mai-AMS (5324740,

SaiIriospet-Momariospet Sogrogayop, Megsk KSaA, Vagtvzvgiadi, Segtapu) in the amount of 200 µM. After 25 min. inking: with" at 372С, the reaction is stopped by adding PMSE (phenylethanesulfonyl fluoride), and fluorescence is determined at ex: 40 Ohm and em: 505 nm. Determine the value of IC5o by interpolation on the graphs of relative fluorescence to

Inhibition concentrations. because I. You are not a model

Example A co Ip mimo model of acute lung injury in the rat: o Injection of human neutrophil elastase (HME) into the lungs of rats causes lung injury. The extent of this 5p damage can be assessed by measuring pulmonary hemorrhage. - and Rats were anesthetized with Hypnorm/Hypnovel/'water and injected into the lungs with NME or saline using

See micro sprayer. Test compounds are administered by intravenous injection, oral administration, or by inhalation immediately prior to administration of NME. Sixty minutes after the administration of elastase to the animals, they were euthanized by administering an excessive dose of anesthetic (pentobarabiton sodium), and the lungs were washed with 2 ml of heparinized phosphate-buffered saline (PB5). The volume of bronchoalveolar fluids (BAL) is measured and the samples are stored on ice. Each sample of VAI is centrifuged at 9OOb/min. (F) for 10 minutes at 4-1020. The supernatant is discarded and the rest of the cells are resuspended in PB5 and the sample is centrifuged again. The supernatant is discarded again and the rest of the cells are resuspended in ml of 0.190 cetyltrimethylammonium bromide (STAB) URV5Z for cell treatment. Samples are frozen until analysis of blood content. because Before analyzing the hemorrhage, the samples are thawed and mixed. 100 μl of each sample is placed in a separate well of a 96-well flat-bottomed tablet. All samples are tested twice. 100 μl of 0.190 STAV/RV5 is included as a control. Measure the absorbance of the contents of the wells at 415 nm using a spectrophotometer. The standard curve is built by measuring the OO at 415 nm at different blood concentrations of 0.195 STAV/RV5. The value of the content in the blood is calculated by comparison with the standard curve (included in each tablet) and normalized to 65 for the VAG volume of the extracted liquid.

The compounds of the present invention are evaluated for their inhibitory activity in this model of NME-induced hemorrhage in rats when administered intravenously, orally, or by inhalation.

Example B

IP mimo model of acute myocardial infarction in rats:

Elastase inhibitors are being tested in rat models of heart attack. Male Wistar rats (weight »300g) receive 1Omg/kg of aspirin per ZOhv. before surgery. they are anesthetized with isoflurane and ventilated (120-13 breaths/min, stroke volume 200-25O0μl; MipiMmepi Toure 845, Nydo Zasyz EIectopic, Segptapu) throughout the operation. After a left thoracotomy in the fourth intercostal space, the pericardium is opened and the heart is quickly removed. The thread is passed around the left coronary artery (I AC) without tightening the artery. The thread is brought to the surface of the skin up to 7/0 of the animal's neck. The chest is closed and the animal is left to recover for 4 days. On the fifth day, rats are anesthetized with ether during Zkhv. and the thread is tightened and the GAYU is closed under the control of the ESO. Test compounds are administered before and after closure of the I AO reg o5, intraperitoneally or intravenously (bolus or continuous infusion). After 1 h of occlusion, the thread is released and reperfusion is allowed. Hearts are excised and infarct sizes are determined 48 hours after reoccluded hearts are stained with Evans blue, followed by /5 incubation with TTS (triphenyltetrazolium chloride) of 2 mm pieces of heart. Normoxic (non-occluded tissue) areas are colored blue, ischemic (occluded but living tissue) areas are colored red and necrotic (occluded dead tissue) areas remain white. Each piece of tissue was scanned and the size of the infarction was determined using computer planimetry.

B. Examples

Abbreviations: water. water conc. concentrated

DMF M, M-dimethylformamide si

DMSO dimethylsulfoxide

IS! electron impact ionization (for MS) o

ESI electro-spray ionization (for MS)

HPLC high-performance liquid chromatography

LC-MS liquid chromatography with mass spectroscopy

Tpl. melting point

Mo mass spectroscopy -

NMR nuclear magnetic resonance about from theo. Theoretical (output)

Chu retention time (for HPLC) with tgF tetrahydrofuran c

General techniques:

All reactions are carried out in an argon atmosphere, unless otherwise specified. The solvent is used as it was purchased in Aiaghisn, without additional purification. "Siligagel" refers to silica gel 60 (0.040mm-0.06Zmm) «

From the company Megsk KSaA. Melting points were taken on a Vysna 512 or similar melting point measuring device and were not corrected. and Compounds purified by preparative HPLC were purified on a KR18 column using acetonitrile and "" water as an eluent, and using a gradient of 1:9 - 9:1.

LC-MS/HPLC methods:

RH-MO method 1 o Device: MisgomMasa Otsaigo I! C7, HP1100; column: Oriizrpege NOO, 5O0mmx2.0mm, Zmkm; eluent A: water 00590 formic acid, eluent B: acetonitrile 0.05956 formic acid; gradient: O, Ohv. 10095 A. »0.2 min. at 10090 A. »2.9 min. 3090 A. »3.1 min. 10905 A. »4.5 min. 10905 A; oven: 559C; flow: O, vml/min.; UV detection: 208-40Ohm. av | LC-MS method 2

Apparatus: UUai (eg ATCShapse 2790 IS; column: Zutteyu C18, 50mmx2.1mm, Z.5μm; eluent A: water 0.190

With formic acid, eluent B: acetonitrile 0.195 formic acid; gradient: O, Ohv. 590 V-»5.0 min. 1090

I" B-"6, Okhv. 10905 V; temperature: 502C; flow: 1.Oml/min.; UV detection: 210Ohm.

LC-MS method Z

Device: MisgoMasa Rianogt I C2, HP1100; column: Adzavyi S-18, 5 ohmx2, Ohm, Z μm; eluent A: water 0.0590 formic acid, eluent B: acetonitrile and 0.0595 formic acid; gradient: O, Ohv. 100956 A-»0.2 min. 10090

GF) A 52.9 min. 3090 A. »3.1 min. 10905 A. »4.5 min. 10905 A; oven: 559; flow: O, vml/min.; UV detection: 208-40Ohm.

HPLC method 4 and Device: HP 1100 with UAYUO detection; column: Kgotavi! KR-18, bOhm x2mm, Z,bmcm; eluent: A-OmMl in HClO,/l No, B- acetonitrile; gradient: cover 2950 V, O, bhv. 2956 B, 4, bkhv. 9095 B, b, bhv. 9095 V; flow:

O.75 ml/min.; temperature: 302; UV detection: 21Ohm.

LC-MS method 5

Device: MisgomMasa TOB-MYH-Ipietase 4-fold parallel injection, with HPLC UUaiege 600; column:

Oriizrpege NOO, 5 Ohmx2, Ohm, 3.0 μm; eluent A: 1 ml of water and 50906 ml of formic acid, eluent B: 65 ml of acetonitrile and 5095 ml of formic acid; gradient: O, Ohv. 10095 A-»0.2 min. 10095 A. »2.9 min. 3095 A. »3.1 min. 1095 A. 54.5 min. 1095 A »54, bhv. 10095 A »b, bhv. 10095 A; oven: room temperature; flow: 0O.8ml/min.;

UV detection: 21Ohm.

LC-MS method 6

Device: MisgomMasa Riabogt I C7 with VERH Adiyepi bZegie 1100; speaker: Sgot-51Y 120 005-4 NO, 5О0mmх2, Ohm, Zmkm; eluent A: 1 liter of water and 5095 ml of formic acid, eluent B: 1 l of acetonitrile - 5095 ml of formic acid; gradient: O, Ohv. 100905 A. »0.2 min. 10095 A. »2.9 min. ZO9o A »3.1 min. 1090 A »4.5 bkhv. 1090 A; furnace: 5592; flow:

Oh, vml/min.; UV detection: 208-400nm.

LC-MS method 7

Device: MisgoMasa Otsaigo /C72 with HPLC Adiyepi Zegie 1100; column: Oriizrpege NOO, 50mmx2.0mm, Zmkm; 70 eluent A: 1 ml of water - 5095 ml of formic acid, eluent B: 1 ml of acetonitrile and 5095 ml of formic acid; gradient: O, Ohv. 10095 A »0.2 min. 10095 A »2, Okhv. 3090 A »3.1 min. 10956 A »4.5 min. 1095 A; furnace: 5592; flow:

Oh, vml/min.; UV detection: 208-400nm.

Starting materials:

Example LA 2-Bromo-5-(1,3-dioxalan-2-yl)pyridine

G

6-Bromo-3-pyridinecarbaldehyde (500mg, 2.7mmol) and 1,2-ethanediol (200mg, 3.2mmol) are dissolved in toluene (5BOml) together with Atbrepuzi 15 (100mg ) in a round-bottomed flask equipped with a reflux condenser and a nozzle o

Dean Stark. The solution is stirred at reflux overnight, then cooled to room temperature, filtered and concentrated in vacuo. The crude product was chromatographed on 32 silica gel using cyclohexane and ethyl acetate as eluent to give the title compound as a colorless oil.

Yield: 0.489g (79905 from theory)

TOP (method 4): 3.46 min. "

MO (EsSipoz): t/2-231 (MAN)7 70 "H-NMR (300 MHz, SOSI»v): 5-8.46 (d, 1H), 7.64 (m, 1H), 7.49 (m, 1H), 4.15-4.00 (m, 4H) m.p. c) c Example 2A, c» 5-(1,3-Dioxalan-2-yl)-2-pyridinecarbonitrile

M so h - - h

F) co

Example TA (2.8g, 12.5mmol), zinc cyanide (1.6bg, 13.8mmol) and tetrakis(triphenylphosphine)palladium (0) (1.4g, 60 1.3mmol) are dissolved in dimethylformamide (10Oml) and mixed during the night (18 h) at 80 "С. Tetrakis-(triphenylphosphine)palladium (0) (0.1 g) is added and the reaction is again stirred overnight (18 g) at 802C, then left to stand at room temperature for 2 days (48 hours). The solvent is removed in vacuo, water (100 ml) is added to the residue and the product is extracted with ethyl acetate (1 l). The organic phase is washed with a saturated aqueous solution of sodium chloride (200 ml), dried with magnesium sulfate monohydrate, filtered and concentrated under vacuum. The crude product was chromatographed on silica gel using cyclohexane and ethyl acetate as eluent to give the title compound as a white amorphous solid.

Output: 0.94g (4295 from theory)

TOP (method 4): 3.21 min.

MO (EsSipoz): t/2-177 (MAN)7 "H-NMR (400 MHz, DMSO-av): 5-8.81 (s, 1H), 8.09 (s, 2H), 5.95 ( s, 1H), 4.13-3.94 (m, 4H) m.h.

Example ZA 5-Formyl-2-pyridinecarbonitrile

M heh: shchi

N o

Method a):

Obtained by analogy with the method of Yuoda, O. ei a. Yu. Ogd. Spem. 1992, 57, 7226-7234) To a stirred solution of 5-(1,3-dioxalan-2-yl)-2-pyridinecarbonitrile (Example 2A; 85 Ωg, 4.8 mmol) in acetone/water 85:15 (59 , bml) add p-toluenesulfonic acid (102mg, 0.59mmol). The reaction is stirred at reflux overnight (18g), then p-toluenesulfonic acid (50mgH) and water (ml) are added.

The reaction is stirred at reflux for another 48 hours. The solution is cooled to about room temperature and quenched with saturated sodium bicarbonate solution. The product is extracted with ethyl acetate (3x10 Oml), dried with magnesium sulfate monohydrate, filtered and concentrated in a vacuum. The crude product is purified by preparative HPLC to give a pale yellow solid. "AND

Output: 0.6 bg (9395 from theory) M

Tpl.: 80-82

TOP (method 4): 2.13 min. (av)

MO (EsSipoz): t/2-133 (MAN)" sc "H-NMR (400 MHz, DMSO-av): 5-10.18 (s, 1H), 9.21 (m, 1H), 8.49 (m, 1H), 8.27 (m, 1H) m.h.

Method b): dissolve 1.04 g (8.2 mmol) of oxalyl chloride in 3 ml of dichloromethane. At -7892C, 1.28g (16b,4mmol) of dimethylsulfoxide is added dropwise. The solution is stirred at -782C for 20 minutes, then 1 g (7.4 mmol) of the compound of Example 5A, dissolved in 7 ml of dichloromethane, is added and stirred at -782C for the next 20 2 hours. Then 3.4 g (33.mmol) of triethylamine is added dropwise and after heating to room temperature, the mixture is purified by column chromatography (silica gel, eluent cyclohexane to c cyclohexane/ethyl acetate 2:1). :z» Yield: 0.76g (7790 from theory)

Analytics: See above.

Example 4A and y 5-Methyl-2-pyridinecarbonitrile so y M o - g" and y: -

F) and CH, 60 Zbg (209 mmol) of 2-bromo-5-methylpyridine and 37.5 g (418 mmol) of copper cyanide are refluxed for two hours in 500 ml of dimethylformamide. After cooling to 50 oC, add 1095 aqueous ammonia solution (500 ml) while stirring. The product is extracted with dichloromethane, the organic phase is dried over magnesium sulfate and the solvent is removed under vacuum. The product is purified using column chromatography (silica gel, eluent cyclohexane/ethyl acetate 9:1). because Output: 18g (7395 from theory)

7H-NMR (300 MHz, SOSI»v): 5-2.4 (s, 3H), 7.6 (m, 2H), 8.6 (s, 1H) m.p.h.

Example 5A 5-(Hydroxymethyl)-2-pyridinecarbonitrile

And M and i:

The compound of Example 4A (13 g, 110 mmol) is dissolved in 400 ml of tetrachloromethane and 29.4 g (165 mmol) is added

M-bromosuccinimide and 0.4 g (1.6 mmol) of dibenzoyl peroxide. The reaction mixture is refluxed for three hours, cooled to room temperature and filtered. The solution is washed with aqueous sodium thiosulfate, dried over magnesium sulfate, and the solvent is removed in vacuo. The residue is dissolved in 200 ml of dioxane and 200 ml of water, calcium carbonate (44 g, 440 mmol) is added and the mixture is stirred at reflux for 2 hours. After cooling to room temperature, the mixture is filtered and dichloromethane is added. After phase separation, the organic phase is dried over magnesium sulfate and the solvent is removed under vacuum. The product is purified by chromatography (silica gel, eluent He) cyclohexane/ethyl acetate 2:1).

Yield: 5.2 g (3595 from theory) 7H-NMR (300 MGu, DMSO-av): 5-4.7 (d, 2H), 5.6 (t, 1H), 8.0 (m, 2H) , 8.7 (s, 1H) m.h. « from Obtaining Examples:

Example 1 -

Ethyl 4-(4-cyanophenyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl/d-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

Master of Science in Sociology;» p r y

What With | From Mon to Sen, from Mon to Mon,

HF) 7.0 g (34.29 mmol) of M-III-trifluoromethyl)phenylurea, 8.99 g (68.58 mmol) of 4-cyanobenzaldehyde, 8.92 g (68.58 mmol) of ethyl 3-oxobutanoate and 20 g of ethyl ester of polyphosphoric acid is suspended in 250 ml of THF.

The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by silica gel column chromatography using cyclohexane/ethyl acetate as eluent.

Yield: 13.4 g (9190) "H-NMR (200 MHz, DMSO-iv): 5-1.1 (t, ЗН); 2.0 (s, ЗН); 4.0 (k, 2); 5 .4 (d, 1H); 7.6 (m, ЗН); 7.7 (m,

ZN); 7.9 (m, 2H); 8.4 (d, 1H) m.h. 65 Example 2 4-05-Acetyl-6-methyl-2-oxo-1-3-trifluoromethyl)phenylide-1,2,3,4-tetrahydro-4-pyrimidinyl)benzonitrile and ra | and

OM sleep, and

CE, t (8) 265 mg (1.3 mmol) of M-III-trifluoromethyl)phent|urea, 131 mg (1.0 mmol) of 4-cyanobenzaldehyde and 100 mg (1.0 mmol) of 2,4-pentanedione are suspended in 2 ml of THF and added catalytic amount of concentrated hydrochloric acid. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica gel using cyclohexane/ethyl acetate as eluent. what

Yield: 29 mg (790) o "H-NMR (200 MHz, DMSO-iv): 5-2.0 (s, ЗН); 2.2 (s, ЗН); 5.5 (d, 1Н); 7, 5 (m, 71Н); 7.6 (m, ЗН); 7.7 (m, 1Н); 7.8 (m, 1Н); 7.9 (m, 2Н); 8.5 (d, 1Н ) m.ch. s

Example From co

Ethyl 4-(4-bromophenyl)-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl|-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate and "- c ;" i e so o ne oon, t AZ g» o m sn,

F) and CE 60 C 204 mg (100 mmol) of M-III-trifluoromethyl)phent|urea, 142 mg (0.77 mmol) of 4-bromobenzaldehyde and 100 mg (0.77 mmol) of ethyl 3-oxobutanoate are suspended in 2 ml of THF and a catalytic amount of concentrated hydrochloric acid. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue was purified by 65 column chromatography on silica gel using cyclohexane/ethyl acetate as eluent.

Yield: 2Zmg (6905) "H-NMR (200MHz, DMSO-yv): 5-1.1 (t, ZN); 2.0 (s, ZN); 4.0 (k, 2); 5.3 (d, 1H); 7.4 (m, 2H); 7.6 (m,

ZN); 7.7 (m, ZN); 8.3 (d, 1H) m.h.

Example 4

Ethyl 4-(4-cyanophenyl)-6-methyl-2-oxo-1-I(4-fluorophenyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate and HO sn» osmos en, c : ( o) "I

M o 154 mg (1.0 mmol) of M-I(I4-fluorophenyl|urea, 101 mg (0.77 mmol) of 4-cyano-benzaldehyde and 100 mg (0.77 mmol) of ethyl 33-oxobutanoate are suspended in 2 ml of THF and a catalytic amount of concentrated hydrogen chloride

From acid. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate as eluent.

Yield: 40 mg (1496) « 7TN-NMR (200 MHz, DMSO-iv): 5-1.1 (t, ZN); 2.0 (c, ZN); 4.0 (k, 2H); 5.3 (d, 1H); 7.3 (m, 4H); 7.5 (m, 790 2nu; 7.9 (m, 2H); 8.3 (d, 1H) m.ch. With s Example 5 "» Ethyl 4-(4-cyanophenyl)-6-methyl-2 -oxo-1-3-chlorophenyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

F) ko 60 b5

b

And And | With om sen, | ; 17 mg (1.0 mmol) of M-III-chlorphent|urea, 10 mg (0.77 mmol) of 4-cyano-benzaldehyde and 100 mg (0.77 mmol) of ethyl

Z-oxobutanoate is suspended in 2 ml of THF and a catalytic amount of concentrated hydrochloric acid is added.

The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica gel using cyclohexane/ethyl acetate as eluent. Cha

Yield: 1Zmg (490) "H-NMR (200MHz, DMSO-yv): 5-1.1 (t, ZN); 2.1 (s, ZN); 4.0 (k, 2); 5.3 (d, 1H); 7.2 (m, 1H); 7.4 (m, o

ZN); 7.5 (m, 2H); 7.9 (m, 2H); 8.3 (d, 1H) m.h. everything

Example 6

Zo (15)-2-Methoxy-1-methyl-2-oxoethyl co 4-(4-cyanophenyl)-6-methyl-2-oxo-1-3-trifluoro-methyl)phenyl|c-1,2, 3,4-tetrahydro-5-pyrimidine carboxylate - with 5 sn. с со - With what; ,

Fo no o | MN

V. 8. Ah, l nas Mo

F) and CE 60 Z 200 mg (0.98 mmol) M-IZ-"trifluoromethyl)phenyl|urea, 129 mg (0.98 mmol) 4-cyanobenzaldehyde, 92 mg (049 mmol) (15)-2-methoxy-1-methyl-2 -oxoethyl 3-oxobutanoate and 295 mg of polyphosphoric acid ethyl ester are suspended in 3 ml of THF. The mixture is stirred under reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica gel using cyclohexane/oethyl acetate as eluent.

A mixture of diastereomers is obtained.

Yield: 9Ubmg (4096) "H-NMR (200MGhCts, DMSO-ydv): 5-1.3 (d, ZN); 1.4 (d, ZN); 2.0 (s, ZNYAAZN); 3.6 (c, ZN); 3.6 (c, ZN); 5.0 (m, 1NaATN); 5.4 (m, TNYATN); 7.6-7.9 (m, 8Н8Н); 8.4 ( m, 1Н-Н1ТН) m.p. 4-(6-Methyl-5-(4-morpholinylcarbonyl)-2-oxo-1-3-trifluoromethyl)phenyl 4-pyrimidinyl)benz nitrile and Phyre

Nm o s (8) ; "I yu CE, M 15O0mg (0.7Zmmol) M-IZ-"trifluoromethyl)phenyl|urea, 9U9bmg (0.7Zmmol) 4-cyanobenzaldehyde, bZmg "z (0.37mmol) 4-(4-morpholinyl)-4 -oxo-2-butanone and 220 mg of polyphosphoric acid ethyl ester are suspended in

Zml THF. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica gel using dichloromethane/methanol as eluent.

Yield: 28 mg (1690). (w s, 1H); 7.6 (m, 2H); 7.7 (m, « 1H); 7.8 (m, 2H); 7.9 (m, 2H); 8.0 (w s , 1H) m.ch.

Example 8 - c 4-(4-Cyanophenyl)-N,M-diethyl-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-5- pyrimidinecarboxamide;" so ko o - ch

F) ko 60 b5

Ck! 15. o 200 mg (0.98 mmol) M-III-trifluoromethyl)phent|urea, 128 mg (0.98 mmol) 4-cyanobenzaldehyde, 77 mg (0.49 mmol) 4-(4-diethylamino)-4-oxo-2-butanone and 295 mg of polyphosphoric acid ethyl ester are suspended in

Zml THF. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica gel using dichloromethane/methanol as eluent.

Yield: 106 mg (4796) t "H-NMR (SO0MHCz, DMSO-ydv): 5-0.9 (m, 6H); 31 (m, 4H); 5.2 (w s, 1H); 7.6 (m, 2); 7.7 (m, 1); 7.8 (m, F 2H); 7.9 (m, 2H); 8.0 (sh s, 1H) mch. s

Example 9

Zo 6-Amino-4-(4-cyanophenyl)-2-oxo-1-3-"-trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-5-pyrimidinecarbonitrile so 40. - s ;" yu sm t NM o - g» om nn,

F) and ;

SE, 60. 400 mg (1.97 mmol) of M-III-trifluoromethyl)phenylurea, 199 mg (1.5 mmol) of 4-cyanobenzaldehyde and 100 mg (1.51 mmol) of malononitrile are suspended in 2 ml of THF and a catalytic amount of concentrated hydrochloric acid is added. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica gel using dichloromethane/methanol as eluent.

Yield: 4mg(190) 7"H-NMR (400MHz, DMSO-iv): 5-5.2 (d, 71H); 6.0 (s, 2H); 7.6 (m, 3H); 7 .7 (m, 2H); 7.8 (m, 1H); 7.9 (m, 2H); 8.4 (d, 1H) m.ch.

Example 10

Ethyl 4-(4-cyanophenyl)-3-formyl-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

Her m i m 07 cm Sen, ts o : "I

CE, these 100mg (0.23mmol) of Example 1 are dissolved in 1ml of dimethylformamide and 35.7mg (0.23mmol) ("c") of phosphoryl chloride are added. The reaction mixture is stirred at 709 for two hours. After cooling to room temperature, the product is isolated by preparative HPLC.

Yield: 4Zmg (4196) (se) "H-NMR (300MHz, DMSO-iv): 5-1.1 (t, ЗН); 2.1 (s, ЗН); 4.1 (Kk, 2Н); 6.4 (s, 1H); 7.6 (m, 2H); 7.7 (m, 1H); 7.8 (m, 1H); 7.9 (m, 4H); 9.2 (s , 1H) m.ch.

Example 11 "du 4-(4-Cyanophenyl)-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl/|-1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid - si" M ; so ko o (. z l y ni ON

AND MORE o o M sn, ko 60

CE, because Zg (ummol) of Example 1 is dissolved in a mixture of 5 bbml of water and 100 0 ml of 595 KOH in ethanol. The reaction mixture was stirred at room temperature for 18 hours. The solvent is removed in vacuo and the residue is purified by silica gel column chromatography using dichloromethane/methanol as eluent.

Yield: 1.27 g (4590). (m, 2); 7.7 (m, 1H); 7.8 (m, 1H); 7.9 (m, ЗН); 8.3 (d, 1H); 12.5 (s, 1H) m.h.

Example 12 4-(4-Cyanophenyl)-6-methyl-2-oxo-N-propyl-1-3-(trifluoromethyl)phenyl/|-1,2,3,4-tetrahydro-5-pyrimidinecarboxamide

M million SN

NM and Z om" son ii z o "I

M

CE, about 4 mg (0.1 mmol) of Example 11 is dissolved in 2 ml of dimethylformamide, 7 mg (0.11 mmol) of n-propylamine, 5 mg (011 mmol) of 1-hydroxy-IN-benzotriazole hydrate and 12 mg (0.1 mmol) of 4-dimethylaminopyridine are added. . The reaction mixture is stirred at 09, then 21 mg (0.11 mmol) of 1-"3-dimethylaminopropyl)-33-ethylcarbodiimide hydrochloride is added. The reaction mixture is stirred at room temperature for 18 hours, then water and ethyl acetate are added. The organic phase is washed with saturated aqueous NaOH ,, water and "a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness under vacuum. If necessary, the product is further purified using column chromatography or preparative HPLC. shsh s Yield: 29 mg (6696) h" "H-NMR (Z00MHz, DMSO-yv): 5-0.7 (t, ZN); 1.3 (sex, 2H); 1.7 (c, ZN); 3.0 (k, 2H); 54 (d, 1 M); 7.6 " (m, ZN); 7.7 (m, 2H); 7.8 (m, 2H); 7.9 (m, 1H); 8.1 (d, 1H) m.h.

Example 13 4-(4-Cyanophenyl)-N-(2-methoxyethyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2,3,4-tetrahydro-5-pyrimidine so carboxamide ko o - ch

F) ko 60 b5

Nm M sn, and A N

WITH

;

SE school

From (o) 48 mg (0.12 mmol) of Example 11 is dissolved in 2 ml of dimethylformamide, 1 mg (0.1 mmol) of 2-methoxyethylamine, 18 mg (0.1 mmol) of 1-hydroxy-YAN-benzotriazole hydrate and 15 mg (0.12 mmol) of 4 -dimethylaminopyridine. The reaction mixture is stirred at 02C, then 25 mg (0.1 mmol) of 20 1-(3-dimethylaminopropyl)-33-ethylcarbodiimide hydrochloride is added. The reaction mixture is stirred at room temperature for 18 hours, then water and ethyl acetate are added. The organic phase is washed with saturated aqueous KNHZO,), water and/or saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated to dryness in vacuo. If necessary, the product is further purified by column chromatography or preparative HPLC.

Yield: 22 mg (4096) He "H-NMR (300 MHz, DMSO-iv): 5-1.7 (s, ЗН); 3.2 (s, ЗН); 3.3 (m, 4Н); 54 ( d, 1H); 7.6 (m, ZN); 7.7 (m, so

ZN); 7.9 (m, 2H); 8.1 (m, 1N) m.h.

Example 14

Ethyl 4-(4-cyanophenyl)-3,6-dimethyl-2-oxo-1-3-"(trifluoromethyl)phenylide-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate "- c ;" co z b o c. masses to" ten with" Z | Kk zom ton, o and ko 60

CE, 8mg (0.21mmol) of Example 1 is added to a suspension of 12.4mg (0.31mmol) 6095 sodium hydride (in mineral oil) in 2ml of THF. The mixture is stirred at room temperature for two hours. Then add 26 mg

(0.21 mmol) of dimethyl sulfate and the mixture is stirred at room temperature for another 2 hours. Then water and ethyl acetate are added and the organic phase is washed with water and a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness under vacuum. If necessary, the product is further purified by

Using column chromatography or preparative HPLC.

Output: 85mg (9396)

TN-NMR (200 MHz, DMSO-iv): 5-1.1 (t, ZN); 2.0 (c, ZN); 2.8 (c, ZN); 4.0 (k, 2H); 5.5 (c, 1H); 7.6 (m,

ZN); 7.7 (m, 1H); 7.8 (m, 2H); 7.9 (m, 2H) m.h.

Example 15

Ethyl

3-acetyl-4-(4-cyanophenyl)-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

With | from school

M what o o sn, "I cha o

Se sch

100 mg (0.23 mmol) of Example 1 was added to a suspension of 12 mg (0.28 mmol) of 609% sodium hydride (in mineral oil) in 2 ml of THF. The mixture is stirred at room temperature for two hours. Then 91 mg (1.1 mmol) of acetyl chloride is added and the mixture is stirred at room temperature for another 2 hours. Then water and ethyl acetate are added and the organic phase is washed with water and a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness under vacuum. If necessary, the product is further purified by column chromatography or preparative HPLC.

Output: 9Zmg (8590) ;" 7TH-NMR (200MHz, DMSO-iv): 5-1.2 (t, ZN); 2.1 (c, ZN); 2.5 (c, ZN); 4.2 (m, 2H); 6.7 (c, 1H); 74 (m, 1H); 7.5 (m, 2H); 7.6 (m, 1H); 7.7 (m, 1H); 7.8 (m, 1H); 7.9 (m, 2H) m.h.

Example 16 diethyl 6-(4-cyanophenyl)-4-methyl-2-oxo-3-3-3-trifluoromethyl)phenyl)-3,6-dihydro-1,5 (2H)-pyrimidine dicarboxylate

F) ko 60 b5 eto m | oh dream, and Zh

From c. 5 SE. (8) 100 mg (0.23 mmol) of Example 1 is added to a suspension of 12 mg (0.28 mmol) of 609% sodium hydride (in mineral oil) in 2 ml of THF. The mixture is stirred at room temperature for two hours. Then 126 mg (1.16 mmol) of ethyl chloride carbonate is added and the mixture is stirred at room temperature for another 2 hours. Then water and ethyl acetate are added and the organic phase is washed with water and a saturated aqueous solution of sodium chloride, the mixture is dried over sodium sulfate and evaporated to dryness under vacuum. If necessary, the product is further purified by column chromatography or preparative HPLC. -

Yield: 92 mg (7996) o 7"H-NMR (200 MHz, DMSO-iv): 5-1.2 (t, ЗН; t, ЗН); 2.1 (s, ЗН); 4.2 (m, 2H); 4.3 (k, 2H); 6.4 (s, 1); 74 ch (m, 1H); 7.5 (m, ЗН); 7.7 (m, 1H); 7.8 (m, 1H); 7.9 (m, 2H) m.h.

Example 17 ge)

Ethyl 4-(4-cyanophenyl)-6-methyl-1-(3-methylphenyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate - c;» at. so ko o rya z NI o son - | shko

Y o) and m sn

WITH

GF) - ko 6o ; t sn, 1500 mg (1.0 mmol) of M-13-methylphenyl|urea, 101 mg (0.77 mmol) of 4-cyano-benzaldehyde and 100 mg (0.77 mmol) of ethyl 33-oxobutanoate are suspended in 2 ml of THF and a catalytic amount of concentrated hydrogen chloride b5 is added acid The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica gel using cyclohexane/ethyl acetate as eluent.

Yield: mg (396) "H-NMR (200 MHz, DMSO-iv): 5-1.1 (t, ZN); 2.0 (s, ZN); 2.3 (s, ZN); 4.0 (Kk, 2); 5.3 (d, 1H); 7.0 (m, 2H); 7.2 (m, 1H); 7.3 (m, 1H); 7.6 (m, 2H) 7.9 (m, 2H); 8.2 (d, 1H) m.h.

Example 18

Ethyl 4-(4-chlorophenyl)-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

I fi p. oh cm sen, mch

And oh "AND

From CE. 204 mg (1.0 mmol) of M-3-trifluoromethyl)phent urea, 108 mg (0.77 mmol) of 4-chlorobenzaldehyde and 1000 mg (0.77 mmol) of ethyl 3-oxobutanoate are suspended in 2 ml of THF and a catalytic amount of concentrated hydrochloric acid. The mixture is stirred at reflux for 18 hours. After c cooling to room temperature, the solvent is removed in vacuo and the residue is purified by c column chromatography on silica gel using cyclohexane/ethyl acetate as eluent.

Yield: 29 mg (995) "H-NMR (200 MHz, DMSO-iv): 5-1.1 (t, ZN); 2.0 (s, ZN); 4.0 (k, 2); 5.3 (d, 1H); 7.5 (m, 5H); 7.6 (m, « 1H); 7.7 (m, 2H); 8.3 (d, 1H) m.h.

Example 19 - c Ethyl "z 6-(bromomethyl)-4-(4-cyanophenyl)-2-oxo-1-I(3--trifluoromethyl)phenyl/d-1,2,3,4-tetrahydro-5- pyrimidine carboxylate p so ko o - ch

F) ko 60 b5 in | From they

Phi p

SE, (about)

3 g (/ummol) of Example 1 is dissolved in 100 ml of chloroform. At 02C, 558 mg (3.48 mmol) of bromine is added dropwise. The mixture is stirred at room temperature for two hours, then the solvent is removed in vacuo. The residue is purified by column chromatography on silica gel using CH cyclohexane/ethyl acetate as eluent. Cha

Yield: 3.2 g (9090) "H-NMR (200 MHz, DMSO-iv): 5-1.1 (t, ЗН); 4.0 (k, 2Н, d, 1Н); 4.6 (w d , 1H); 54 (d, 1H); 7.6 (m, ЗН); Ф 7.7 (m, 2H); 7.8 (m, 1H); 7.9 (m, 2H); 8, 6 (d, 1H) m.ch. p

Example 20

Ethyl co 4-(4-cyanophenyl)-6-(diethylamino)methyl)-2-oxo-1-3-(trifluoromethyl)phenyl-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

M « - s ;» So and Yu

NM

From her oon, "from" . om -sn,

M o - son, ko 60

CE, 20 mg (0.04 mmol) of Example 19 is dissolved in 2 ml of acetone and 8 mg (0.1 mmol) of diethylamine is added. The mixture is stirred at room temperature for 18 hours, then the solvent is removed in vacuo. The residue 65 is purified by preparative HPLC.

Yield: 15mg (75965)

7TH-NMR (30 MHz, DMSO-iv): 5-0.6 (t, 6H); 1.1 (t, ZN); 2.0 (m, 2H); 2.2 (m, 2H); 31 (w d, 1H); 3.9 (w, d, 1H); 41 (k, 2H); 5.4 (d, 1H); 7.5 (m, 1H); 7.6 (m, 4H); 7.7 (m, 1H); 7.9 (m, 2H) m.h.

Example 21

Ethyl 6b-(anilinomethyl)-4-(4-cyanophenyl)-2-oxo-1-3-(trifluoromethyl)phenyl-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate and base (o) and CE" " 5 mg (0.1 mmol) of Example 19 is dissolved in 2 ml of acetone and 18 mg (0.20 mmol) of aniline is added. He ate the mixture. stirred at room temperature for 18 hours, then the solvent was removed in vacuo. The residue is purified using preparative HPLC.

Yield: 28mg (5595) s 7TH-NMR (SO0MCHc, DMSO-iv): 5-1.1 (t, ЗН); 3.6 (d/d, 1H); 4.1 (Kk, 2H); 4.4 (d/d, 1H); 54 (m, 23); 62 "0 (m, 2H); 6.5 (m, 1H); 6.9 (m, 2H); 7.6 (m, 6H); 7.9 (m, 2H); 8.4 (d, 1H) m.h.

Example 22 ()-Ethyl "4-(4-cyanophenyl)-6-methyl-2-oxo-1-3-"(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-5-pyridinecarboxylate - c M ;" so ko o - y t y vi osn, with Oo7lZ sen,

F) o and 60 se,

The enantiomers of Example 1 are separated using preparative HPLC on the chiral phase: 100 mg of compound bo dissolved in 1.5 ml of ethyl acetate, KVO 8361 column (chiral silica gel selector based on monomer

M-methacryloyl-I-leucine-1-mentylamide, (see EP-A-379 9171), 250mmx2Omm, eluent ethyl acetate, flow 25ml/min., temperature 232C, injection volume 2500μl, detection 254nm. "H-NMR (300 MHz, DMSO-yv): 5-1.1 (t, ЗН); 2.0 (s, ЗН); 4.0 (k, 2); 5.4 (d, 1Н); 7.6 (m, 3H); 7.7 (m, 2H); 7.8 (m, 1H); 7.9 (m, 2H); 8.4 (d, 1H) m.h.

IA12O---3.32 (3-589nm, dichloromethane, c-535.0mg/100ml)

Example 23 (-)-Ethyl 4-(4-cyanophenyl)-3,6-dimethyl-2-oxo-1-3-"(trifluoromethyl)phenylide-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

I f c)

N S di A lu oto sen, o M SN, (5) "I cha and E -

10 mg (0.2 mmol) of Example 22 was added to a suspension of 14 mg (0.35 mmol) of 6095 sodium hydride (in mineral oil) in 2 ml of THF. The mixture is stirred at room temperature for two hours. Then 29 mg of O9 (0.233 mmol) of dimethyl sulfate was added and the mixture was stirred at room temperature for another 2 hours. Then water and ethyl acetate are added, the organic phase is washed with water and a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness under vacuum. The product is purified by silica gel column chromatography using cyclohexane/ethyl acetate as eluent.

Yield: 7bmg (7495) - with TN-NMR (200MHz, DMSO-iv): 5-1.1 (t, ZN); 2.0 (c, ZN); 2.8 (c, ZN); 4.0 (k, 2H); 5.5 (c, 1H); 7.6 (m, "from ZN); 7.7 (m, 1H); 7.8 (m, 2H); 7.9 (m, 2H) m.h.

IA129--18.12 (3-589nm, dichloromethane, c-530, Ω/100ml)

Example 24 o Ethyl 4-(6-cyano-3-pyridinyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate - ch

F) ko 60 b5

Y " | A. nm o i : h- p

SE, Fr

To a stirred solution of Example ZA (7 mg, 0.58 mmol) in tetrahydrofuran (bml) is added ethyl

Z-oxobutanoate (75 mg, 0.58 mmol), M-I(Z-trifluoromethyl)phenylurea (118 mg, 0.58 mmol) and ethyl ester of polyphosphoric acid (200 mg; freshly prepared according to the method (Sama et al., ). Ogu. Spem. 1969, 34, 26651). hE The reaction mixture is refluxed for two days (48 hours), after which the solution is diluted with DMSO (2 ml) and purified by preparative HPLC. Fractions with the product are concentrated in a vacuum and again chromatographed on silica gel using cyclohexane and ethyl acetate as an eluent. at

Output: 92 mg (3595 from theor.)

MO (EsSipoz): t/2-431 (MAN)7

TOP (method 4)-4 63 min. so "H-NMR (SO0MHCz, DMSO-ydv): 5-8.76 (s, 1H), 8.36 (d, 1H), 8.16-8.00 (m, 2H), 7.83- 7-74 (m, 2H), 7.75-7.58 (m, 2H), 5.47 (d, 1H), 4.03 (quartet, 2H), 2.06 (s, ЗН), 1 ,08 (t, ZN) m.h.

Example 25 "4-5-(1H-Imidazol-1-ylcarbonyl)-6-methyl-2-oxo-1-3-"trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-4-pyrimidinyl ) benzonitrile - - M ;» so ko o I - l : -i

M A o NE Mo ko 60

C Z bo To a solution of 501 mg (125 mmol) of the compound of Example 11 in bml of dry dimethylformamide, add 567 mg

(3.5 mmol) of M,M-carbonyldiimidazole. After that, the reaction mixture is left to stand overnight, and the solvent is evaporated under vacuum. The residue is transferred to ethyl acetate and washed with water and a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, the solvent is evaporated under vacuum.

Output: 50Ω (88,690 from theory)

MS (EI): t/2-452 (МН)" 7H-NMR (200MGu, DMSO-av): 5-1.40 (d, ЗН), 5.5 (d, 1H), 7.0 (s , 1H), 7.55-8.0 (m, 9H), 8.4 (s, 1H), 8.45 (d, 1H) m.h.

Example 26 2-Hydroxyethyl 70. 4-(4-cyanophenyl)-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl)|-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate and ( 8) o Me "I cha as: shchi from p

45.1 mg (0.1 mmol) of the compound of Example 25 is added to 0.5 ml of ethylene glycol. The reaction mixture is stirred 89 at about 1002 for 1 hour. After cooling, the reaction mixture is purified using preparative HPLC (column: Addiepi 7ogra Ehiep C18 20mmx5Omm, 5μm; solvent A: acetonitrile, solvent

A: water 0.195 conc. ammonia; gradient: cover 10905 A, 2 min. 1095 A, bhv. 9095 A, 7 min. 90905 A, 7.1 min. 1095 A, min. 1090 "

AND; wavelength: 22 Ohm; injection volume: approximately B50Omcl; number of injections: 1). Fractions containing the product are combined and concentrated in a vacuum. t s Yield: 22 mg (49490 from theor.) "from MSs(EI): t/2-446(MZhN)" "H-NMR (ZO0MHCts, DMSO-ydv): 5-2.05 (d, ZN), 3.5 (quartet, 2H), 3.95-4.15 (m, 2H), 4.75 (t, 1H), 5.45 (d, 15 1H), 7.55-7.75 (m . cyanophenyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate o 50 - h

F) ko 60 b5

M 8 o sn, e in net МН 3 nim o

AND

SE. high school

About 45.1 mg (01 mmol) of the compound of Example 25 is added to O0.B ml of 2-(dimethylamino)dethanol. The reaction mixture is stirred at about 1002 for 1 hour. After cooling, the reaction mixture is purified using preparative HPLC (column: Adyepi 7ogra Ekhiepa C18 20mmx5OmMmm, bmcm; solvent A: acetonitrile, solvent B: water 0.195 conc. ammonia; gradient: Ohv. 1095 A, 2 min. 10905 A, bhv. 9090 А, 7 min 9090 А, - 7.1 min 1095 А, Input 1095 А; wavelength: 22Ohm; injection volume: approximately; 5O0Omcl; number of injections: chn 1). Fractions containing the product are combined and concentrated in a vacuum.

Yield: 24 mg (50.895 from theory) ("in

MS (EI): t/2-473 (MAN)" s "H-NMR (SO0MHCz, DMSO-ydv): 5-2.05 (d, ZN), 2.1 (s, 6H), 2.4 (m, 2), 4.1 (m, 2H), 5.35 (d, 1H), 7.55 (d, 79 1n), 7.6 (d, 2H), 7.7 (m, 2H ), 7.8 (d, 1H), 7.85 (d, 2H), 8.35 (d, 1H) m.p. co

Example 28 2-(4-Pyridinyl)ethyl 4-(4-cyanophenyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate "

M. s

I" so l o

Heh in about MN and A and Koshe

F) why

CE, 45.1 mg (01 mmol) of the compound of Example 25 is added to 0.5 ml of 2-(4-pyridinyl)ethanol. The reaction mixture is stirred at about 1002 for 1 hour. After cooling, the reaction mixture is purified using preparative HPLC (column: Adyepi 7ogra Ekhiepa C18 20mmx5OmMmm, bmkm; solvent A:

acetonitrile, solvent B: water 0.195 conc. ammonia; gradient: cover 1095 A, 2 min. 10905 A, building 9090 A, 7 min. 9090 A, 7.1 min. 1095 A, min. 1095 A; wavelength: 22 Ohm; injection volume: approximately 5O0Omcl; number of injections: 1). Fractions containing the product are combined and concentrated in a vacuum.

Yield: 17 mg (33,590 from theory)

MS (EI): t/2-507 (MZHN)" 7"H-NMR (300 MHz, DMSO-iv): 5-2.0 (d, ZN), 2.9 (t, 2M), 4.3 (t, 2M), 5.25 (d, 1H), 7.15 (d, 2H), 7.45 (d, 2H), 7.5 (d, 1H), 7.65 (t, 2H) , 7.8 (m, ZN), 8.35 (d, 1H), 8.4 (d, 2H) m.h.

Example 29 70 2-(2-Pyridinyl)ethyl 4-(4-cyanophenyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-5- pyrimidine carboxylate

I S Her o chn s o him o "I

M

("in")

CE with -

From 45.1 mg (0.1 mmol) of the compound of Example 25 is added to 0.0 bml of 2-(2-pyridinyl) ethanol. The reaction mixture 9 is stirred at about 1002 for 1 hour. After cooling, the reaction mixture is purified using preparative HPLC (column: Adyepi 7ogra Ekhiepia C18 20mmx5OmMmm, bmcm; solvent A: acetonitrile, solvent B: water 0.195 conc. ammonia; gradient: Ohv. 1095 A, 2 min. 10905 A, bh. 9090 A, 7 min. 9090 A, « 7.1 min. 1095 A, min. 1095 A; wavelength: 22Ohm; injection volume: approximately 5O0Omcl; number of injections: 1). Fractions containing the product are combined and concentrated in a vacuum. t s Yield: 22 mg (43.490 from theory) "from MS (EI): t/2-507 (MAN) 7TN-NMR (300 MHz, DMSO-yv): 5-2.0 (d, ZN), 3, 0 (t, 2H), 4.4 (t, 2H), 5.25 (d, 1H), 7.15-7.25 (m, 2H), 74 15 (d, 2H), 7.5 ( d, 1H), 7.6-7.75 (m, ЗН), 7.8 (m, ЗН), 8.3 (d, 1Н), 8.45 (d, 1Н) m.h.so Example 30 2-(2-Oxo-1-pyrrolidinyl)ethyl ke 4-(4-cyanophenyl)-6-methyl-2-oxo-1-3-trifluoromethyl)-phenylde-1,2,3,4-tetrahydro -5-pyrimidine carboxylate ("in") 50 - ch

F) ko 60 b5

10 St. on mo

And and with

SE. (8) 45.1 mg (0.01 mmol) of the compound of Example 25 is added to 0.5 ml of 1-(2-hydroxyethyl)-2-pyrrolidinone. The reaction mixture is stirred at about 1002 for 1 hour. After cooling, the reaction mixture is purified by preparative HPLC. (column: Adiepi 2ogra Ekhiepa C18 20mmx5Omm, 5μm; solvent A: acetonitrile, solvent B: water 0.195 conc. ammonia; gradient: Ohv. 1095 A, 2 min. 10965 A, bhv. 9095 A, 7 min. 9096 A, Zh 7, 1 min 1095 A, input 1095 A, wavelength: 22 Ohm, injection volume: approximately 5000 μl, number of injections: M 1). Fractions containing the product are combined and concentrated in a vacuum.

Output: 25 mg (48.895 from theory) ("v

MS (EI): t/2-513 (MAN) s "NA-NMR (300 MHz, DMSO-iv): 5-1.8 (quintet, 2H), 2.0 (d, ЗН), 2.1 ( t, 2M), 3.2 (t, 2M), 34 (t, 2H), 40-42 (m, 2H), 5.35 (d, 1H), 7.55 (d, 1H), 7, 6 (d, 2H), 7.7 (t, 2H), 7.8 (d, 1H), 7.9 (d, 2H), 8.4 (d, 1H) mch.

Similar to the methods for Examples 14-16, the following compounds are obtained: "- с ;" so ko o - ch

F) ko 60 b5

Her shi | and Goeavavu | names

Ez rt and viki Her I ke rnrensya I and GU f: sope st vesm ss ssvk і droz vytsya sa peaynjvyyin E slnihstisny dk her not I and E - banni 7 x y ' KE Bern y "| I Y U 7 i oi a | ши ши ш ; : tb ШИ i i i 4. r : || i Y. : KE what

In Ts 1 and I In g Sh I Y Her | : ! ah! I and I. E | i and her o s 5 shi EK Y Ж t g BE M ryy s och svv se HIM I pay in under them zhdy RNA NN o, | and I CAN ro ocycloiropane in 9 14090 I | ssch: still in Ya seti ey ss: HE zinc she» pan sko ko yi her KU y ! This one; ! | AND! Io: Ky U ZY: x i «KE and 7th. and her and in 4. Ya Kab niya ' Ko her NI 1 Yi wai: SHY! GO I

B y i Sv Ya KU Pii Sh shcha i Ya t EE Ts. Ts Io CHA ! : y St g IE EI f 1: o zh g Yav. I ии и и и и сч

But g s: NN and | , || ; From r

Ж ЦЯ write what else Z t Zhiriklo Claude ee SK Ey Ky і- o

I'll call it what it is in tA I IE them EY! eat - | | ос и у веб и лиш: и и: |!

IS . : - ZY. and m KE; And VI E with Zi E « 0 Ж and Her I Ж ж | і ях To - m va і і Ні Мі SINGULAR MN She M - | re peetuya ti le NE y khie t ny -- a PTM ih, BE SO zdiikya sosok VE zok no By t " KI E ey 4. V z E z. :

Hey y y y T y I.

Ж Somewhere and i t I EE 1! ; ! with. I and | . Well, ! in -.: KE : PN CE z Y Z Z Z so I I Bu 7 shchi tsu Y Si nas go Z - Z E ke E " pav, i PI a i zu -z "E ST oi Y - | Sk | What is it? What is it? n 3 Y I

Her. It should be done as | so vani tt Z. her 7 ; -1 50 what else do they eat? b5

7-0 Щ щ ni tt sik I Ni rt KI no che po iv) Y DM n more

And y y y a From Example 1. Z E roko o VK ;f she shk sho SHY dimethyle | And! how cash inve pocha Y and I! I'm talking about I! Y E" | nene Pk esstnaki B TI: PEZEVNN TE M i ssh :

What E! What is it. I am blue "EN! and I KE 4. I and Z Z Z son V and, and | : ii with | Same Sat what; | ; g e : Z I T t Z H - i | and and and in | 1 Her "! NOT what: | Yaovnovyh ryaa ranakh yav. i" и Y I I and | g i | A. and more | KO u

N y H o y ! t J. 60 b5 -A1-

KI to" doctor "rashesya ss ""IIKAYA otit s vsvshtya zhk and aso sY set nos I As shchi echo in r ste laki chik at Yake vaye and from penya and matetala NIZH Z still NED | 1 masya 1

Zrlei i e TK TO MZHK to oven tov St. Zhkvaivnsye same. fo titi Zh

What is it? ; and

Forces KO apAA-- t I o pt i. che Tita --- - 117 MI - Ш-- -Щ- яНч"ttshi o t h t i dna ZD syu nis - y ren Z

In : sha ' | s E SCHE t V sche n KE. IS

K oh sy y ah s Va y kety Z Y SHY p Z Y Kk SHY "U. 3

E and entrance to secondary school. From khparidokarben tavylokarbone Tu and: ! : E і r U V Shveya ey va vnodistnk) apiary vne Ж P V y

K 5 V K " i K EE 19 1 ; Ed M I i I i i i ko, i E i i

I and Ii r and KI and dl and she I I More! I and Dn SCHA Z carbonate and. ,; PM Z , y y V y Something iv Kz y y I J Rhyme y z | І Ге дк " І Sho U Кк і І І ОВ ре T even ж ше ІІ І ! ri o і TO І ЕІ і і ' і EE: VA і І 5

Z. So and Y and V

I L; E I и че и «ех Я : . Co

SI shsh- No

I'm still here. З: и И Б , и 4 у и ни г E Examples; From KZ Ha! y ss NE s NE sHE STILL sv EI | y y KE sky dy they OD se esyunvsmiyuntskoyuyussyayuy zush M zorom zey v. | I vro OVO, Tdetylcarbamnovo 9 BAy5(|I BU M so . B. in щ Y p cilvo Aa z y y ne OH; Z zybla NT chloride Tita te and I I i: : Mezha Y v. y PI vys PESEN KMIN y г З г г г роде: ZV y ; I VZ ! i i ; | s s. She : y o t І і І Ше і : bo zhi ; Г. я ее. шщ ; В і І і І і

SM. and i and pe :» | F | ! ! ! WHAT and WHO I am: ko a vi and v

S Shi: SHY She She she sho

And: so Sha Ya She rani - y! more: yes, on petanque OK PI CHI Y -o HER and dov ve. Bosch aa | sky ryu I sulfonidn | ak rAnBfII century; : keV ZE: is the PI of Zharbamino G: y o I IK CHE s MI between s Y I I zo | WHAT. About Zzhislotikhlorid | : and - and 1 these others. I I Ku es sovy SHHI i , I i l | or, | ; E НЕЙ и и - M. dizoadn, pronanaankh NN A svyishoi ezhrntshnia Dido ko bo b5 -d2-

TKryklad! birukra | Bymdnimatvvny | vyma | Chuikhvi | mass; : NO oi : ii : ; and and! - See! ! | And go; r 7" y I y yo ; o bromoacetamide; ha Yad: : di : 8) y y y y Iy i a s ; : E I ; ha liu Y I ' :

E «re 7 What m ! AND I !

And there's THERE lodging house; schi | 8 I go sia ii Y s: ME M o Vbekviv MAN | and so and With I -? In : I " ! ; ! Not A y . y | Sha She tu . ; y; «g zo 1 r ШЙ sh y.

Y Pn y tata put nity Ist esvani voda runa y ze nya atinvnvnnnia Ki o i y che : shchi Nryklad; ! | sha» shk shi she A M nn oo o i shi ESE: more on p ' x Tv about I 2b'ekviv. Man: and what

I and K I i 1 G. E Ts ; z che E pkt koki Y g If: (ee) y -k Z t jin no: I E V y y zhihorsnanv nivy menya cha v, so ts skova nok still what hundred: Я , Я i: о яв рату ще Mavtypvydynu | in a swarm; In! same 1 ke. and I, Io

F) io) bo b5 -A3-

"| zhi rve Geovaeii VN: dvovtstonvn shi: pov and certain ki dream ZVsKsA sake I NO sna sttVsii sya as t and for iii V ZR en ona! and the forest director; yo nebyuche shi em v o: "y i Z I E v Ai LYa b I

EK And her nZ НВ I JH JH

KE. K and I | her V pvh y and Z V y y y y Sho | sh In syo B i mouth, he. I d bbroveme Z zon t I . p ZI . | i tu iv i sn, i metilitsetvnid; SU LAK in the thing

And Their I -.zy "Dn. Y ' MECH NYANY S Ei z

Her I her seg Y t - 1 и и, | | her: ! the whole G. still : r To z Shi shchy p M s | But co

ХК зд, : sіy b і inіy і - бю НВ ковеачсня і "і К nave bu і; ra Kr li B ov yan

Y vala and she M "' z": foamy hay; b ini poori Shust zi -ofyvtvntk si kii t pasi potresiv svy. It is woven - VK It is sho pd that - ny shi sy Her EE Ef sny ny ny y MORE how how KU how; and Ok s-g E | sei | and

Another 50 / yar" in bu y ! | ! | I

F) them) 60 b5 -YES-

And ' | M / own kN

Z. Z | and and! Reinai and-y What is I E?

PI VIM THEY NN. poppy PACHINNNN IN

With S. Y E I and IZ

Z i, E; zn hl E i ! then B and I (Vromemetinue | | I I

With Her, give me, oh, I say SHYMY as 1 deenyutkh sleep and p SO and kidrobromi where and! ) where E p niniin WIFE Her i ; 1 Ko E ! ' and g -k Bide her her her about | IZ ai che. ! IS ! Oh and eat

They and Brno ant skl st 4 | Y. y y

I And everything I Sich i r Zala Z vestoy in: pevtyakh Valya svi ny Z ns: I. disappeared 1 year

I and I ik zach Yes! sya Zh and zh et before what; І Shchi s y 1 І ch o oxadiazeya. about what and what! and і this and і і і і

And! : kny C 1 th E I CHE z Her and I ! and : B, и и : ; : : 1 : : ee I, : r SHI") ; y IV I : x ; (i about acetamides | : | pt

And I KV shk Be Bas I | ts | her she : o, b y : y : ee y y y | She; in I; with" and 5 sk dk and dk ery Mr. VYN nya and wiki o go, sen ; Beh. --e and: -k ; ss E MN Z still ve and zkoineva M

Similar to the methods for Examples 6-8, the following compounds are obtained:

her t Her m BaYA Z I - , Ben r y

I am her. I B Di NI 1 Z ий збжже I; M Z erifiore ; and and! E ikh i tia au SVO PL SE t r E i

E HER | i po o t i i B 170 MORE; In I and EE and r | svis s zak Ah I vas fe svisi ini A T ch-ea0 bkumaznevny Z clear

VE av I Y I TSI dv vch as nzhryven zey Y Vo SV Fo in WHAT I said: Z YUK

She and Be. tai r i TT ЖЖ lu nt U i : E her Z g. i; и хи я и и |. And and and and

With with. З Гх У - Ш ВЩХ y Х t. E t shii I Y y

I I r E- B U -, Y t

U i zako Yaryi E v i : N E I : V ! : shk and | ; iy

I and dream ve ZD Y gechaltvii vna g 1 I KHE

And ryze E for s ot NKI and urea; o E MK " p more: shi shi a p LY "| va izhree| vv I. and I BE vo. hey -h : ; WE WILL GET CHUCK. Compartment 4: Huh!

In: a and ЗB outside the end of R S and Pd. . F: 5 lo St i iz o ; Ch. SCHE Y KI Y schy and "Mr. And to her K where soda g I E |; As

TSI "in Ts | i IS

I Their 9) in ZHE, S tu i ai Ve i i Sean: In HM : . ! I

To I VK! . what an eye naslinyan-isvsyai h "E KE E Yaru E IK : 4. IZ! 5 SCHO tov Z Bolyu shk, idaskaiyu CHI iE and M

IV in KE y "and scha Y Bosh not with given Z y ; | I Z I o z I. Still iya t same hell rr Greek I .. EE oz

GE. 1, DY sya: metiniraniy" In Ya 4 in v: y in m ya Ya yah Y chen y MmeEtylidaniyi" eV n ! y ts schi p Shk sha Х u | IK Z her x I: i povveletvnavn the nerve of the nryakhi "Z with Sche

B "M va pa che LYN pyah rr dyak E i s

Not in " y And her y y With Ya. vay and yaiOeezhenyunh ittosi vek vogsetlntya r pftnn, I and e that In KI, I van More

And | read 0 Ge NVNOVENZNLONYA pi! ! y N B ban vyni Z y Ins svna KV kre giis sna zhi and Go to YAE, M M No y KI y z ;: Ese, I ey t T. y P More

And: ' with E EN two vshvyzhnkya: Ж Я ге и

I AM ! I am ; I: U. | « i Bi i SO sliding and in i in 1 I same Z zhd - ery: | и и з - и и и осив зве. : he stumps Her. : I E 3 s t. 5 77 ve i i Ya Kk E

B. zvvnnia a shvah si ionni, it pnnlnnneya 7 silence ha r son ny sia z sha sia pnstinnesn uschk ino iv ni-ni iations nits vit a I I k z rapalrditt Ei t i yi u ve Her | With ih s r Z Y 7 y r Y M Y y Z and her Y; I ven de zbi ZI g: Z IV tskh E (se) "KE . zya Me: ee ShK: y y svitu n | y I y V ' e nn y Be Z Men he E U her TV) y ih CYA EY I ' r iYA hYA y V pln ma TCS ve y V r

Ko IY E t Y S VUZh i ii ii ii ii M. i;

Yes; TO and mele okoVetiliV" Z and T.: tya I r as s Ped ex ns Vo ivntii Y І І ІІ 7" - bo b5 -dv-

tk | Fo roar! NOT:

В E sh Z і jastipipheniyi: Z Sh t ! ; with in Hey I I (I I and that and And and I still: still

I In 1 fe dinnobenzaldeinich In a same. ! : i o Zhdimetytak i Z I ; i i: Eh ; 4. I Kk : r I I ns ket nuyati STILL IN . . pl y Y o t HU Ya. y

Ki V pi i V KI ZMEN SHIN PECHE PIV PKT OM

Example 59

Ethyl 4-(4-cyanophenyl)-6-methyl-3-(2-(4-morpholinyl)-2-oxoethyl)-2-oxo-1-3-(trifluoromethyl)phenyl)-1,2,3 ,4-tetrahydro-5-pyrimidine carboxylate

M.Sc. "I

With cha o

M min sh » m osn, so o sm" ssn, « - s;»

8 mg (0.1 mmol) of Example 44 is dissolved in 2 ml of dimethylformamide, 1 mg (0.18 mmol) of morpholine is added, io) 24 mg (0.18 mmol) of 1-hydroxy-1H-benzotriazole hydrate and 20 mg (0.1 mmol) of 4- dimethylaminopyridine. The reaction mixture is stirred at 09, then 35 mg (0.18 mmol) of 5-pro/1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is added. The reaction mixture was stirred at room temperature for 18 hours, then water and ethyl acetate were added. The organic phase is dried over sodium sulfate and evaporated to dryness under vacuum. If necessary, the product is further purified using column chromatography or preparative ch

TOP.

Yield: 78 mg (8590). , 4H); 3.7 (d, 1H); 41 (m, 2H); 4.5 (d, 1H); 5.5 (s, 1H); 7.6 (m, 5H); 7.8 (m, 1H); 7.9 (m, 2H) ppm (F, Analogously to the methods for Example 59, the following compounds are obtained: ko 60 b5

Be pe Z TOZ OT Te a TOZ ZK I 4.

I sadno B 4: - I sdeas X 5 ee ND y

Я и Я A: Ше г Я жк КТ ШЭ 2 Я " This and І ; іх Z ! г 7 m 1 і 7 |! velasya pstennspivinny PY nann t.

І и дк І и І и І ЛК : І svv M) ! and Ki

E y ot K VI I E y Y N VY

Y. write" - dreams Z and: Z Z B Examples. ke Zh u y le s h Y. KE are znvni blue M BV I E I Z Kh tya iy under: Psy v sya i. ai s a ect. NE A ve y re p ay la: Zissnnv y y; : y, shi She: In piperazine and and 4: and KE in ! ! ; ; and Yae Gi : and : ! Z CHI : V, y V i Y : Kk y HER y y Х " y . HER : na Na : r : ZE

I Z Z B "Z m SHA soda ; K; sche y Psy Ne ozh I she ; щ I. re y Ey y, TE y eh is se: pe A : vn y: y I react Z

EI in Ж (Ж -х-вййй slya E kremi; - с и и их и К шча И о Ж ОН, , ny и и У "I. з с

Ch. and the same | changes from Z to ; me and (about)

M. with Cl is 1 N. D U in K

Y i t Y : 18 | y y chy y E me y Zhov y y ; ME

Her J wok with ; ; I: r. KI I I Z I and Z I:

Ge ee o S Dn De r A U YN NY SHA NI i a i NI t eh ZY

Who is she, alas, "OV S syayu LO MODA METYSTtYA i la. TK OM lyny ter r ti y? I Y ШЧА pi tt i Shchi CHE zo Th VI . y: z z 4. x I And more

I am a member of Zk p. Y r. - I and r! i i i Y Z T

J. Y. Yuk, 7th Example and; With me. And a

Kob I'm still OO UNO and divetylanini 83 aa bib.

Zo Ya shchi E ko V Ya vi ya she oman: ia: ih ni yi so sia y cha i emu Ko V Vi

Y Y Z I V sh t 3 he than sho PV r i i i 4 ; 17

IV! like her iy in B | ; Y vh V B: etc. E i ! wait! I: I in I "ch

M Shchi I ShK with Tch x I ih v | WITH

Z and I 1 And, Chi with and and -

Similarly to the methods for Examples 5-8, the following compounds are obtained: y Kir lety nen: su NV nan stuk sonna NI TOV te TU Kuna MAK su t SHLE I tia NN PDG Z rusyn a Z sf SALA J : A: dati: I YN B EKS DYA t SCHE preezhleekke Y Y Naik enne E I es Осв ДН Енс селеня сыснеювсы Reskyest s I ZM dog, ШY ЗМИВ ts Вык still your Ж и sн Ж sdohloetiyu. M tbdy well Z with BZ in G bbvoavi her me

KE Kk and; E Z Z: Znek Sh Shk eko kiyai I nev SHE so y i WDE Da sh n ZA a i ME i ANI Vlas chi m vh IN NYA M I rear i her t i i Z cho I i TOO E g a chto tr va EE viy an vi pe. y t, E7 te Z her y ta va y. y i ay tv E ko x ; 8 Shchi g: de n nn insa shchi schu 23 she Fe na v I ! ; и о и г Фе І метилифенийх (5. і 4. і траіі: Volya pazh :і ше Іі: - Ж жов І і і 1 ! u Z PN re CHIY soaYke і do de і Eh EY TE in !

Lol! I'm a Ukrainian." t u y z Z N y : sho y Z i y . 7 th

I. ; ШЭ ek Ш Y ШЩ и о Ш sa. KE t I 1 same ; "och pe : "benzaldehyde;; I also went to coffee with her. And, and. and; 4 about her Y Y . : for now, for now

I U p Y circle: y z nnazonnoe: y y As in 7

Her: se SNYDNY | te KE 4: Z nie g ze and is RE

D) K I sho i vro l i X F t Z

And | ; and S. uyae shchi: and Her | EE Z

That than ns him her r y tv on sun mon day some ki vky inn dk, B and sy Kosyk ne kin inno SUK sho Z-D dao sinistiine blue he di tenisni y KE bo b5 -AV-

. sya yeyaoo V Z I I schi ANTI I some 7. z, IDLUUITUYUT I

With Me Ei and | Ж Zv 4 yuyu Ж vva Ж

In U Ya and E Rv Se . rskinenvinnnnai DYA " ET sh y

She is ! 1 ! Tv shiya pyt ot doba tihvni and-y pyt vptn what "OLYA V sh sh ry m E E it vals of evil hys slani pok ET pu ru plan Srvar r v rit

A 1 THE SAME TM (tshifto va java y. y AND WE JH POPY KIM Y Z Z Z Y

I | vs t vyaetipifeniyn | She

Her and ok y dasvts miracle r yk y |! ; nen! EZ sovno sey 'n Bo | и : и ЧИ; and" or Me: more : 1 ! ; ! And let me go, bezotivzome | ; I eat

I: Well, that's a sign of E! y oy ro bivtsv K. and Koh g Be Z: iz a (thrice por | Mecha Z ik a zh eV. iya y goi Y sa I. Я | 1 ts. і і і і і pot | y U y E і Ch What am I

I am from Kv: : V Shch g. I'm me

I y y nn: r K other tn y | Z Y g! и З І 4. з пи и и ; Ж ц Ш I pe zh eh Z iya E iya i ovo i noshsche i |; : Shu

I am shk I Aa trifluore | With IY - ! LV 1 And And ! same F is M. and: know Z about what E E I still

And KI She and barley; And ! Ks y Ka Ye Chk Z E poh y ! ; ; hey : ; on. |! | Mr

In V M u a. ze. and E: Che! II C: 1 Aametokra is | : in "

I N I Y shk Y g y

In and out; still with t y I J s y : pa t- | : и E I I i) dreadlocks vv kosh sh- as s ia p Y, sk g d sne; and in the directory | AKA: Doo. KZ

E, Y Z I M | IN | : -

Go! y in y ! jawbone; With and so on

I NYA Vt i i shchen" i I C. E ko E 7 i h chu V i ik i On I i

With and -k I "de KI for pk y y i І ("in: иK х g M М Я | "ie g ; E

Б 7-7 схоДх В Ne eh TIN M Y y g Ki "7 4 Oy styn 1 eeruritinya" | и и и и и Я х7 и ОЖ КУ t З и ГЕ ". bo b5 -To-

Hibicladi brUmuva 1 VIMdnimennany | View 1 CHUV | Ma «r t I I How | oil Vany - mim myshi zvy he i / G fo mMetInyreniya: | | i yu | et and evchbvina; her and IE: and t heat in Y Ku le church on pyt and ! І и т что ре Ton I и : и оку: Й K. И и ; With ! na dishe ov in S U in NNYA KIMN ek LY SHY SHY WHOSE kt honor that va U prifdorya 8 1 ZI YAVA, ho Her Z shk ! ; Y I I z.

Oh, that's crazy ; y Y sce pav i eh i 3 | yo koki E | : and Y i

DC! Pe ay, 1 benvanvdeni Her ; then! and | My chriftor | | | и и Н И и и и и и и и и и и и и И и Ше: se; xx Y Z reno feno ke same Y |. i pe p I ON i NN A AN AN : : ; - by: g

Example 70 4-(4-Cyanophenyl)-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl/|-1,2,3,4-tetrahydro-5-pyrimidinecarboxamide (ав) with 3о M (he ) - s g. f i . "» and o t A, o not M o

WITH

- ch

And | SE

Ge) With io) 200 mg (0.bmmol) of Example 11 is dissolved in bml of tetrahydrofuran and bmg (0.05mmol) of 4-M,M-dimethylaminopyridine, 77mg (O0.bmmol) of M,M-diisopropylethylamine and 115mg (0.bmmol) are added ) of hexafluorophosphate 60 benzotriazol-1-yloxy-tris(pyrrolidino)phosphonium. The reaction mixture is stirred at room temperature for 15 minutes, then bml (2.5 mmol) of ammonia (as a 0.5 M solution in dioxane) is added. The reaction mixture was stirred at room temperature for 1 hour, then water and ethyl acetate were added. The organic phase is dried over sodium sulfate and evaporated to dryness under vacuum. The product is further purified by preparative HPLC. bo Yield: 55 mg (2895 from theory) -BO0-

7TH-NMR (200 MHz, DMSO-iv): 5-1.8 (s, ZN); 54 (d, 1H); 7.2 (w s, 1H); 7.4 (w s, 1H); 7.6 (m, 5H); 7.7 (m, 1); 7.9 (m, 2H); 8.1 (d, 1H) m.h.

Example 71 (143-4-(4-Cyanophenyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl/d-1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid 15. . y Zh om sen, s o "I x SE, vol

The enantiomers of Example 11 are separated using preparative HPLC on a chiral phase (KVO column 8361 (chiral silica gel selector based on the monomer M-methacryloyl-|-leucine-1-mentylamide, (see

ER-A-379 9171), 250mmx2Omm, eluent: ethyl acetate -» methanol -» ethyl acetate, flow rate 25 ml/min., temperature 232C, s detection 254 nmi. with

TN-NMR (30 MHz, DMSO-iv): 5-2.0 (s, ZN); 54 (d, 1H); 7.6 (m, 1H); 7.6 (m, 2H); 7.7 (m, 1H); 7.8 (m, 1H); 7.9 (m, ZN); 8.3 (d, 1H); 12.5 (s, 1H) m.h.

IA12o--2.5o (3-589nm, methanol, c-505mg/100ml). "

Example 72 10 (3-2-Hydroxyethyl o)c 4-(4-cyanophenyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-5 -pyrimidine carboxylate 2» M so ko o i -I . about him at 60 and 65 CE

WITH

Under argon, 156 µg (3.89 mmol) of the compound of Example 71 is added to 19.bml of DMF. After adding 1.095 mL (7.8 mmol) of triethylamine and 1.11 mL (15.7 mmol) of 2-bromoethanol, the reaction mixture was stirred at approximately 7022 for 8 hours. After cooling, the reaction mixture is concentrated in vacuo. The residue is transferred to ethyl acetate and washed with water. After drying over magnesium sulfate, the organic phase is evaporated under vacuum.

The residue is transferred to ml of methanol and purified using preparative HPLC (column: Misieovii 100-5 C 18 Mashiiv5, 20x5O0mm, 5μm; solvent A: acetonitrile, solvent B: water 0.395 formic acid; gradient:

Ohv. 1095 A, 2 min. 1095 A, bhv. 9095 A, 7 min. 9095 A, 7.1 min. 1095 A, min. 1095 A; wavelength: 22 Ohm; injection volume: approximately 50 Ωcl; number of injections: 18). Fractions containing the product are combined and lyophilized.

Output: 129Omg (74,590 from theory)

MS (EI): t/2-446(MZHN)" "H-NMR (Z00MHCc, DMSO-Idv): 5-2.05 (d, ZN); 3.5 (quartet, 2H); 3.95-4.15 (m, 2H); 4.75 (t, 1H); 5.45 (d, 1H); 7.55-7.75 (m, 5H); 7.75 (d, 1H); 7.85 (d, 2H); 8.35 (d, 1H) m.h.

IA179---14.39 (3-589nm, methanol, c-455mg/100ml).

Example 73 5-5-Acetyl-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-4-pyrimidinyl)-2-pyridinecarbonitrile

SHI

-- cm (8) no (Hn ch

A t zoM ke! Fo s so ' «

SE. To a stirred solution of Example 3 (75 mg, 0.57 mmol) in tetrahydrofuran (ml) is added: 2,4-pentanedione (57 mg, 0.57 mmol), M-III-trifluoromethyl)phenyl|urea ( 11bmg, 0.57mmol) and ethyl ester of polyphosphoric acid (200mg) Freshly obtained according to the method of Sama ei ai!., U. Ogud. Spam 34, 2665 (1969).

The reaction mixture is refluxed for 24 hours, after which the solution is diluted with DMSO (2 ml) and purified by preparative HPLC.

Yield: 101 mg (4490 from theory) co "H-NMR (200MHz, DMSO-iv): 5-2.02 (s, ЗН); 2.24 (s, ЗН); 5.54 (d, 1Н) 7.52-7.90 (m, 4H); 8.08 (d, 2H); o 8.50 (d, 1H); 8.81 (s, 1H) m.h.

Example 74 (13-5-15-Acetyl-b-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-4-pyrimidinyl)-2- pyridinecarbon l ytril

F) ko 60 b5 b 70 -E vni re nt Mo i | SE, Fr

The enantiomers of Example 73 are separated using preparative HPLC on a chiral phase (KVO 8361 column (chiral silica gel selector based on M-methacryloyl-|-leucine-1-mentylamide monomer, (see "g zo ER-A-379 9171), 250mmx20mm, eluent: ethyl acetate -» methanol -» ethyl acetate, flow rate 25 ml/min, temperature 232C, detection 254 nmi.

TN-NMR (300 MHz, SOSIz): 5-2.06 (s, ZN); 2.35 (c, ZN); 5.69 (d, 71H); 6.02 (d, 1H); 7.29-7.50 (m, 28); "is 7.57-7.75 (m, ZN); 7.83 (dd, 1H); 8.74 (d, 1H) m.h. high school

MO (EsSipoz): t/2-401 (MAN)7

IA12o---25.12 (5-589nm, methanol, c-505mg/100ml). (se) 2-(2-Pyridinyl)methyl 4-(4-cyanophenyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-5- pyrimidine carboxylate

M « - s. ;" so ko is about MN with nm about

F) because SE

Me:

To a solution of 40.1 mg (0.1 mmol) of the compound of Example 11 in 0.4 ml of dry dimethylformamide, 48.0 mg (0.3 mmol) of M,M-carbonyldiimidazole is added. After standing the reaction mixture for an hour, the reaction mixture is diluted with water and extracted with dichloromethane. After drying over magnesium sulfate, the solvent is evaporated under vacuum. 0.5 ml of (2-pyridinyl)methanol is added to the residue. The reaction mixture is stirred at about 1002C for 1 hour. After cooling, the reaction mixture is purified using preparative HPLC (column:

Mysieovii 100-5 C 18 Matsshiiv 20mmx 50mm, 5μm; solvent A: acetonitrile, solvent B: water and 0.195 formic acid; gradient: cover 1095 A, 2 min. 10905 A, building 9090 A, 7 min. 9090 A, 7.1 min. 10905 A, entry 1095 A; flow rate 25ml/min; wavelength: 22 Ohm; injection volume: approximately 55O0μl; number of injections: 1). Fractions containing the product are combined and concentrated in a vacuum.

Yield: 17 mg (34,590 from theory)

MS (EI): t/2-493 (MN)" "H-NMR (30 MHz, DMSO-av): 8-21 (d, ZN); 5.15 (dd, 2H); 5.45 (d, 1H); 7.05 (d, 1H); 7.3 (dd, 1H); 70..7.5-7.85 (m, 9H); 8.35 (d, 1H); 8.5 (d, 2H) m.h.

Example 76 2-(3-Pyridinyl)ethyl 4-(4-cyanophenyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

Mai

M zha | s t i

So MN o and sm o - cha o s - so

WITH

72.9 mg (0.15 mmol) of M,M-carbonyldiimidazole is added to a solution of 60.2 mg (0.15 mmol) of the compound of Example 11 in 0.57 ml of dry dimethylformamide. After standing the reaction mixture for an hour, the reaction mixture is diluted with water and extracted with ethyl acetate. After drying over magnesium sulfate, the solvent is evaporated under vacuum. 185 mg (1.5 mmol) of 2-(3-pyridyl)ethanol and 20 μl (0.27 mmol) of triethylamine are added to the residue. "» The reaction mixture is stirred for an hour at 1002. Then the reaction mixture is diluted with 04 ml of methanol, "filtered and purified using a preparative . HPLC (column: Mysieovii 100-5 C 18 Mashiv 20mmx5Omm, 5μm; solvent A: acetonitrile, solvent B: water 0.195 formic acid; gradient: Ohv. 10905 A, 2 min. 1090 A, 35 min. 90906 A, min. 9095 A , 7, min. 1095 A, min. 1095 A; flow rate 25 ml/min.; wavelength: 22 Ohm; so injection volume: approximately 550 μl; number of injections: 1). Fractions containing the product are combined and concentrated under vacuum.

Yield: 44 mg (57.990 from theor.) at 50 RH-MS (EI, Method 5): t/2-507 (MAN), hChu-z, 19 min. -I Example 77 4-(4-Cyanophenyl)-3,6-dimethyl-2-oxo-1-3-"-trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid

F) ko 60 b5 -B4-

. and | And net

CE, about 4.1 g (9925 mmol) of Example 14 is dissolved in 100 ml of ethanol. To this solution, add 6.2 ml (27.bmol) of a solution of potassium hydroxide in water (25 g.95). The reaction mixture is left to stand at room temperature for 18 hours. Then add another 12.4 ml (55.2 mmol) of a solution of potassium hydroxide in water (25 g.9 o) and the reaction mixture is stirred for 2 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate.

The aqueous phase is acidified with 1M hydrochloric acid and extracted with ethyl acetate. This last extract is dried over magnesium sulfate and evaporated under vacuum. The residue is purified by column chromatography on silica gel using cyclohexane/ethyl acetate as eluent.

Yield: 1.5 g (3995 from theory) p

MS(EI):t/2-416 (MAN)" s "H-NMR (Z300MHz, DMSO-av): 5-2.0 (s, ZN); 2.8 (c, ZN); 5.5 (d, 1H); 7.6-7.8 (m, 6H); 7.9 (d, 2H); 12.6 (s, 1H) m.h.

Similarly to the methodology for Example 76, the following compounds are obtained:

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Fe Z-pyridinylmethanol is combined with Fe, M, and

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ЕК и : | и Ш - a In the above research, the use of tyre, ethylene, and hydrogen chloride in the presence of DMOA Example 102 av Ethyl 4-(4-cyanophenyl)-1-(3,5-dichlorophenyl)-b-methyl-2- oxo-1,2,3,4-tetrahydro-5-pyrimidine carboxylate -I ch ko 60 b5 и ий ? 7 | And 7 mo

And sh

S SI si o

Under argon, 30.8 mg (0.15 mmol) of M-(3,5-dichlorophent)urea is mixed with 39.8 mg (0.3 mmol) of 4-formylbenzonitrile, 30 mg (0.03 mmol) of ethyl 3-oxo-butanoate and 9 mg of trimethylsilyl polyphosphate in 0.bml of dioxane at 802 for 4 hours. After adding a small amount of DMSO, the reaction mixture is filtered and purified using preparative HPLC (column: Addiepi 7ogra Ekhiepa C18 20mmx5Omm, bmcm; solvent "Ж

A: acetonitrile, solvent B: water 0.195 conc. water ammonia; gradient: cover 1095 A, 2 min. 1095 A, bhv. 9095 A, 7 min. cha ob A, 7, ikhv. 1095 A, min. 1095 A; flow rate 25 ml/min.; wavelength: 22 Ohm; injection volume: approximately 500 μl; number of injections: 1). Fractions containing the product are combined and concentrated in a vacuum. (av)

Output: 38.1 mg (5990 from theor.)

RH-MS (EI, Method 7): t/2-431 (MAN), Chu-4.14 min.

From Example 103 p

Ethyl β-methyl-4-(3-nitrophenyl)-2-oxo-1-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

N i 2 sho s Z 2» ' m o) "MN » i - ne sm to ch o 7OTSE ko) Z

30 mg (0.15 mmol) of M-3-trifluoromethyl)urea is shaken together with 453 mg (0.15 mmol) of 60 mg and 1 mg of urea.

3-nitrobenzaldehyde, 30 mg (0.3 mmol) of ethyl 3-oxobutanoate and 9 mg of polyphosphoric acid ethyl ester

Freshly obtained according to the Sama ei ai technique.,). Oh Spam 34, 2665 (1969)). in 0.5 ml of dioxane and 00 ml of DMF at 802 for 18 hours. After adding 200 μl of DMF, the reaction mixture is filtered and purified using preparative HPLC (column: Mysieovi 100-5 C 18 Mashiiv 20mmx5Omm, μm; solvent A: v5 acetonitrile, solvent B: water and 0.195 formic acid; gradient: Ohv. 1095 A, 2min 1090A, 90905A, 7min 9095A, 7.1min 1095A, 1095A inflow, flow rate 25ml/min, wavelength: 22Ohm, injection volume: approx.

800 μl; number of injections: 1). Fractions containing the product are combined and concentrated in a vacuum.

Output: Zamg (50,490 from theory)

RH-MO (EI, Method 6): t/2-450 (MEN), Chu -3.94 min.

Similarly to the methodology for Example 102, the following compounds are obtained:

Example Structure Source materials Output | Chu (hvi | Mass

In re) | (way) | (MANI 70 104 M (Z-nitrophenyl)- 70.5 I 3.65(6)| 417 i- urea; h ХХ 4-xporbenzaldehyde; ! Ho M ! MH ethyl З-oxobutanoate ne no mo, 2» o, M-(Z-nitrophenyl)- 36146) 427 urea; with 29 o? mn z-nitrobenzaldehyde; (5) vch ethyl 3-oxobutanoate neo o shh s cha

MO, ("in")

E M-(Z-nitrophenyl)- 3.63 (6) s.c

And her urea; so 4-fluorobenzaldehyde; MH ethyl 3-oxobutanoate «

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Example 108 4-(4-Cyanophenyl)-6-methyl-2-oxo-1-3-(trifluoromethyl)phenylide-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid 2-cyanoethyl ester

10 Ii 15 Ii | AND,

WITH

20

SE, ch 25 9.87g (48.3mmol) M-IZ-"trifluoromethyl)phenyl|urea, 12.68g (96.68mmol) 4-cyanobenzaldehyde, 15g (8) (96.6mmol) (2-cyanoethyl) 3 -oxobutanoate and 37.5 g of polyphosphoric acid ethyl ester are suspended in 250 ml of THF. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified using "g

From column chromatography on silica gel using cyclohexane/ethyl acetate as eluent.

Yield: 25g (10095 from theory) - 7TN-NMR (200MHz, DMSO-ydv): 5-2.1 (s, ZN); 2.8 (m, 2H); 4.2 (m, 2H); 54 (d, 1H); 7.6 (m, 4H); 7.7 (m, about 2H); 7.9 (m, 2H); 8.5 (d, 1H) m.h.

Example 109 s 35 4-(4-Cyanophenyl)-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile s 40 vn - s y ;" 45 so yu Mo

MN g» ns M o

F) her Me: 60 z

0.bOOg (1.52mmol) of Example 70 is dissolved in bOml THF and 1.24g (12.93mmol) of (methoxycarbonylsulfamoHl)utriethylammonium-M-betaine is added. The reaction mixture was stirred at room temperature for 1 hour, the solvent was removed in vacuo and the residue was purified by column chromatography on silica gel using dichloromethane/methanol as eluent.

Output: 249 mg (4390 from theory)

7H-NMR (Z00MGu, DMSO-α): 5-1.8 (s, ZN); 5.4 (d, 1H); 7.7 (m, 4H); 7.8 (m, 2H); 8.0 (m, 2H), 8.4 (d, 1H) m.h.

Example 110

Ethyl b-methyl-4-(4-nitrophenyl)-2-oxo-1-3-trifluoromethyl)phenyl|d-1,2,3,4-tetrahydropyrimidine-5-carboxylate 2

I fi (. 7 rya nego | Mn » ny mo s o

S Z

7.84 g (38.4 mmol) of M-III-trifluoromethyl)phenylurea, 5.81 g (38.4 mmol) of 4-nitrobenzaldehyde, 5.0 g (38.4 mmol) of ethyl 3-oxobutanoate and 15 g of ethyl ester of polyphosphoric acid suspend in 10 bml of THF. p

The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica gel using toluene/ethyl acetate as eluent. urine

Yield: 8.75 g (51 95 from theory) "H-NMR (200 MHz, DMSO-iv): 5-1.1 (t, ZN); 2.1 (s, ZN); 4.0 (m, 2H); 54 (d, 1H); 7.5-7.8 (m, 6H); 8.3 so (m, 2H); 8.5 (d, 1H) m.h.

Example 111 5-Acetyl-b-methyl-4-(4-nitrophenyl)-2-oxo-1-3-"'trifluoromethyl)phenyl/|-1,2,3,4-tetrahydropyrimidine "- still MO, and? so ko o -i | , i» not | MN; A. net

F) ko 60

With 0.407g (2.Ommol) M-III-trifluoromethyl)phenylurea, 0.302g (2.00mmol) 4-nitrobenzaldehyde, 0.2g

(2.0 mmol) of 2,4-pentanedione and 04 g of polyphosphoric acid ethyl ester are suspended in 20 ml of THF. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica gel using cyclohexane/ethyl acetate as eluent.

Yield: 0.302 g (36905 from theory) 7H-NMR (200 MGu, DMSO-α): 5-2.0 (s, ZN); 2.2 (c, ZN); 5.5 (d, 1H); 7.5-7.8 (m, 6H); 8.3 (m, 2H); 8.5 (d, 1N) mch.

B. Operational examples regarding pharmaceutical compositions

The compounds according to the invention can be transformed into pharmaceutical formulations as follows:

Tablet

Composition of 100 mg of the compound of Example 1, 5 mg of lactose (monohydrate), 5 mg of corn starch (natural), 1 mg of polyvinylpyrrolidone (PVP 25) (from VABE, Izpatep, Segtapu) and 2 mg of magnesium stearate.

Tablet weight 212 mg, diameter mm, bending radius 12 mm.

Obtaining

The mixture of the active component, lactose and starch is granulated with a 595 solution (m/m) of PVP in water. After drying, the granules are mixed with magnesium stearate for 5 minutes. This mixture is pressed using a conventional tablet press (tablet format, see above). The applied pressing force is typically 15KN.

Suspension for oral use

The composition of 100mg of the compound of Example 1, 7100mg of ethanol (9695), 400mg of Rodigel (xanthan gum from EMC,

Reppzuimapia, OA) and 99g of water.

A single dose of 10 mg of the compound according to the invention is contained in 1 ml of oral suspension. everything

Obtaining

Rodigel is suspended in ethanol and the active component is added to the suspension. When mixing, add i9) water. Stirring is continued for approximately 1 hour until the Rodigel is completely swollen.

Claims (1)

The formula of the invention a cha 1. Pyrimidinone derivatives of the general formula (I) o 2 ;() s va « 70 v mo Z sh А "» z che zhk / z so te ko) pe A represents aryl or heteroaryl, o 27, 82 ii VZ regardless of one one is represented by hydrogen, halogen, nitro, cyano, C 4-Cv-alkyl, hydroxy-I 20 or cCi-Cv-alkoxy, where C.i-Cv-alkyl and C.-Cv-alkyl can be further replaced by one - by three identical or different radicals selected from the group containing halogen, hydroxy, and C.-C.-alkoxy, where trifluoromethylcarbonyl, IF; C.-C -alkenoxycarbonyl, hydroxycarbonyl, aminocarbonyl, Mmono- or di-Ci-C.-alkylaminocarbonyl, Ce-Ci-arylaminocarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl, heterocyclyl or cyano, where C.-Ci-alkylcarbonyl, Si -C6-Alkoxycarbonyl, mono- and di-Ci-C,-alkylaminocarbonyl can be in HF) further substituted by one or three identical or different radicals selected from the group containing C3-C6-cycloalkyl, hydroxy, C.- C,-Alkoxy, C,-C,-Alkoxycarbonyl, Hydroxycarbonyl, Aminocarbonyl, Mono- and Di-C--C,-Alkylaminocarbonyl, C,-C,-Alkylcarbonylamino, (C,-C,-Alkylcarbonyl)-C. -C,-C alkylamino, cyano, amino, mono- and di-C,-C alkylamino, heteroaryl, heterocyclyl and tri-(Ci-Ci-alkyl)silyl, and where heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl and heterocyclyl can be further substituted by C.4-C.-alkyl, B? represents C.-Ci-alkyl, which can be substituted by one or three identical or different radicals selected from the group containing halogen, hydroxy, C 4-Ci-alkoxy, Ci-Ci-alkenoxy, C.i-Ci- alkylthio, amino, Mmono- and di-Ci--Cv-alkylamino, arylamino, hydroxycarbonyl, C-C-C-Alkoxycarbonyl and the radical 65 -0-C04-C,-alkyl-O-C.4-C,-alkyl, or ω represents amino, ω represents hydrogen, C 4 -C 1 -alkyl, formyl, aminocarbonyl, mono- or di-C 1 -C 1 -alkylaminocarbonyl, C.-Ci-cycloalkylcarbonyl, C.4-Ci-alkylcarbonyl, C.4-Ci-alkoxycarbonyl, M-(C4-C/-alkylsulfonyl)aminocarbonyl, MA(C.-C,-alkylsulfonyl)-M-(C 1-C.-alkyl)aminocarbonyl, heteroaryl, heterocyclyl, heteroarylcarbonyl or heterocyclylcarbonyl, where C.-C.sub.-alkyl, M.mono- and di-C.sub.-C.-alkylaminocarbonyl, C.-C.sub.-alkylcarbonyl, C.-C-Alkoxycarbonyl, heteroaryl and heterocyclyl can be substituted by one or three identical or different radicals selected from the group consisting of aryl, heteroaryl, hydroxy, C.-C., hydroxy, hydroxycarbonyl, C.-C -Alkoxycarbonyl, aminocarbonyl, mono- and di-C.i.C.-alkylaminocarbonyl, amino, mono- and 10. di-Ci-C,-alkylamino, C.-C,-alkylcarbonylamino, tri-(C4-Ci-alkyl)silyl, cyano, mMono- and di-C4-C.-alkylamino-C 4-C.- Alkylaminocarbonyl, C.-C.-Alkoxy-C.4-C.-Alkylaminocarbonyl and halogen, or BE? represents the substitute of the formula (8) , (8) or (8) , b and I m? C, also that C where BX is selected from the group containing hydrogen and C-Ce-alkyl, and n represents an integer of 1 or 2, B" represents halogen, nitro, cyano, C4-Cv-alkyl, hydroxy or C. and C-C-Alkoxy, where C-C-Alkyl and C-C-C-Alkoxy can be further substituted by one or three identical or different radicals selected from the Group containing halogen, hydroxy and C-C-Alkoxy, and (8) U, U2, X3, m, and U5 independently of each other represent CH or M, where the ring contains 0, 1, or 2 nitrogen atoms, and their salts, hydrates, and/or solvates and their tautomeric forms. 2. Pyrimidinone derivatives of the general formula (I) according to point 1, where A represents aryl or heteroaryl, and B", 2 and C independently of each other represent hydrogen, halogen, nitro, cyano, C-C-alkyl, hydroxy c3 or C.-Cv-Alkoxy, where C.--Cv-Alkyl and C.-Cv-Alkoxy can be further substituted by one to three identical or different radicals selected from the group containing halogen, hydroxy and C.- C,-Alkoxy, Zo in represents C --C-C-alkylcarbonyl, C-C-C-Alkoxycarbonyl, C-C-C-alkenoxycarbonyl, hydroxycarbonyl, (he) aminocarbonyl, mono- or di-C,-C,-alkylaminocarbonyl , Ce-Cio-arylaminocarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl, heterocyclyl, or cyano, where Ci-Ci-alkylcarbonyl, C.4-Ci-alkylcarbonyl, mono- and di-Ci-Ci-alkylaminocarbonyl may be further substituted by one - by three identical or "different radicals selected from the group containing C 2 -C 1 -cycloalkyl, hydroxy, C 1 -C 1 -alkyl, C.-C.-Alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, Mmono- and di-C.-C.-alkylaminocarbonyl, - with C,-C,-alkylcarbonylamino, amino, mono- and di-C--C,-alkylamino, heteroaryl, heterocyclyl and tri-(C4-C6-alkyl)silyl, Iz» B? represents C.-Ci-alkyl, which can be substituted by one or three identical or different radicals selected from the group containing halogen, hydroxy, C 4-Ci-alkoxy, Ci-Ci-alkenoxy, C.i-Ci- alkylthio, amino, Mmono- and di-Ci--Cv-alkylamino, arylamino, hydroxycarbonyl, C.-C.O.-Alkoxycarbonyl and the radical -0-C04-C,-alkyl-O-C.4-C,-alkyl, co or Kz vo represents amino, o vo represents hydrogen, (F 1-Ce-alkyl, formyl, aminocarbonyl, mono- or di-C4-Ca-alkylaminocarbonyl, C.-Ci-cycloalkylcarbonyl, C.4-Ci-alkylcarbonyl, C.4-Ci-alkoxycarbonyl, M-(C4-Ci-alkylsulfonyl)aminocarbonyl, -I M-(C4-Ci-alkylsulfonyl)-IMm- (C 4 -C 1 -alkyl)aminocarbonyl, heteroaryl, heterocyclyl, heteroarylcarbonyl or l heterocyclylcarbonyl, where C 1 -C 1 -alkyl, Mmono- and di-C 1 -C 1 -alkylaminocarbonyl, C 1 -C 2 -alkylcarbonyl, C.-C-Alkoxycarbonyl, heteroaryl and heterocyclyl can be substituted by one or three identical or different radicals selected from the group consisting of aryl, heteroaryl, hydroxy, C.-C., hydroxy, hydroxycarbonyl, C.-C -Alkoxycarbonyl, aminocarbonyl, mono- and di-C.i-C.-alkylaminocarbonyl, amino, mono- and di-C4-C.-alkylamino, C.-C,-alkylcarbonylamino, tri-(C4-C-alkyl) silyl, cyano, mMono- and HF) di-C4-C.-alkylamino-C 4-C.-alkylaminocarbonyl, C.-C.-Alkoxy-C.4-C.-alkylaminocarbonyl and halogen, t or VE? represents the substitute of formula 60 8) ; 8) or p , A more A more A I Mlyn" sh: Si b5 de BA is selected from the group consisting of hydrogen and C.-Ci-alkyl, and n is an integer of 1 or 2, Ge is halogen, nitro, cyano, C.4-Ci-alkyl, hydroxy, or C.-Ci-alkyl, where Si - C 1 -alkyl and C 1 -C 1 -alkoxy can be further substituted by one or three identical or different radicals selected from the group containing halogen, hydroxy and C 1 -C 1 -alkoxy, M, m, y 5 independently of each other represent CH or M, where the ring contains 0, 1 or 2 nitrogen atoms. 3. Pyrimidinone derivatives of the general formula (I) according to item 1 or 2, where A represents phenyl, naphthyl or pyridyl, B", 2 and BZ independently of each other represent hydrogen, fluorine, chlorine, bromine, nitro, cyano, methyl, ethyl, trifluoromethyl or trifluoromethoxy, 7 represents C 4 -C 4 -alkylcarbonyl, C 4 -C 6 -C 6 -alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, mono-C 1 -C 1 -alkylaminocarbonyl or cyano, where C 1 -C 6 -alkylcarbonyl, cC 1 -C-C-Alkoxycarbonyl and mono-C.-C.-Alkylaminocarbonyl can be substituted by one or three identical or different radicals selected from the group containing C 3-C-cycloalkyl, hydroxy, C-C 4-Alkoxy , C.--C.-alkoxycarbonyl, amino, mono- or di-Ci-C.-alkylamino, heteroaryl and heterocyclyl, B? represents methyl or ethyl, VU represents hydrogen, C.4-C-alkyl, mono- or di-C.-C/-alkylaminocarbonyl, C.-C.-alkylcarbonyl, C.-Ci,-Alkoxycarbonyl or heterocyclylcarbonyl, where C.I-Ci-Alkyl and C.I-Ci-Alkoxycarbonyl can be substituted by one or three identical or different radicals selected from the group containing heteroaryl, hydroxy, C.i -C,-Alkoxy, hydroxycarbonyl, C,-C-Alkoxycarbonyl, aminocarbonyl, mono- and di-Ci-C,-alkylaminocarbonyl, cyano, amino, mono- and di-Ci-C,-alkylamino, or o represents a substituent of the formula Ha! 8; o or (8) , (5) not yet A also ki t o "I where "a BX is chosen from the group containing hydrogen and C.4-C.-alkyl, and n represents an integer 1 or 2, and- B" represents halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, methyl or ethyl, He and other U, mg, 3, y | U5 each represents CH. co 4. Pyrimidinone derivatives of the general formula (I) according to item 1, 2 or 3, where A represents phenyl or pyridyl, B and BZ each represent hydrogen, "B2 represents fluorine, chlorine, bromine, nitro or cyano, ssh c B" represents cyano, C 4-C 1-alkylcarbonyl or C 4-C 6-alkylcarbonyl, where C 4-C 6-alkylcarbonyl may be partially substituted by a radical selected from the group containing hydroxy, C 4-C 6- oxy, C-C-Alkoxycarbonyl, mono-" and di-C--C-Alkylamino, heteroaryl and heterocyclyl, B? represents methyl, po represents hydrogen, C 4 -C.-alkyl, mono- or di-C.-C,-alkylaminocarbonyl, C.-C.-alkylcarbonyl or co-C.-C.-alkylcarbonyl, where C.i- C-Alkyl and C4-C-Alkoxycarbonyl can be substituted by a radical selected from the group consisting of heteroaryl, shydroxy, C-C,-Alkoxy, hydroxycarbonyl, aminocarbonyl, mono- and di-Ci-C-Alkylaminocarbonyl, amino, mono- and di-c.-C.,-alkylamino, o or -| 7 o VE? represents a substituent of the formula l Ho) or (8) , not yet A also le o (F; where KkZz vo is selected from the group containing hydrogen and methyl, K7 represents trifluoromethyl or nitro, because and U, mg, m, m | U5 each represents a SN. 5. Pyrimidinone derivatives of the general formula (I) according to any of items 1-4, where A is phenyl or pyridyl. 6. Pyrimidinone derivatives of the general formula (I) according to any of clauses 1-5, where B! is hydrogen. in 7. Pyrimidinone derivatives of the general formula (I) according to any of items 1-6, where B is cyano. 8. Pyrimidinone derivatives of the general formula (I) according to any of items 1-7, where VZ is hydrogen. 9. Pyrimidinone derivatives of the general formula (I) according to any of items 1-8, where B 7 is C,-C,-Alkoxycarbonyl, optionally substituted by hydroxy, or where B is C,-C,-Alkylcarbonyl. 10. Pyrimidinone derivatives of the general formula (I) according to any of items 1-9, where B? is methyl. 2 11. Pyrimidinone derivatives of the general formula (I) according to any of items 1-10, where KZ is hydrogen. 12. Pyrimidinone derivatives of the general formula (I) according to any of items 1-11, where KE" is trifluoromethyl or nitro. 13. Derivatives of pyrimidinone of the general formula (I) according to any of items 1-12, where the radical 0 РЕ means the group СМ , Э в! - About the village where 7 represents CH or M, and Ge represents the values specified in 1, BZ, B" and 297 have the values specified in 1, VE? represents methyl, U71-m4 each represents a CH group, and B" represents trifluoromethyl in position C of the phenyl radical. 14. A pharmaceutical composition having the properties of a human neutrophil elastase inhibitor, containing at least one compound of the general formula (I) according to any of items 1-13 and a pharmaceutically acceptable urine thinner. (8) Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2008, M 05, 11.03.2008. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. hE cha o s Zo so - with . and? so ko o - ch F) ko 60 b5