UA81271C2 - 2-pyridone derivatives as inhibitors of neutrophile elastase, process for the preparation thereof and pharmaceutical composition based thereon - Google Patents

Abstract

There are provided novel compounds of formula (I) wherein R1, R4, R5, G1, G2, X, L, Y1, Y2 and n are as defined in the Specification and optical isomers, racemates and tautomers thereof, and pharmaceutically acceptable salts thereof; together with processes for their preparation, compositions containing them and their use in therapy. The compounds are inhibitors of neutrophil elastase.

Description

Description of the invention

This invention relates to new 2-pyridone derivatives, methods of their preparation, pharmaceutical compositions containing them, and their use in therapy.

Elastases are perhaps the most destructive enzymes in the body that have the ability to decompose almost all components of connective tissue. Unregulated proteolytic degradation by elastases is involved in a number of pathological conditions. Human neutrophil elastase (NEP), a member of the chymotrypsin superfamily of serine proteases, is an enzyme with a size of ZZkDa, stored in the azurophilic granules of neutrophils. In 70 neutrophils, the concentration does not exceed 5 mM, and its total cell count is estimated as Zpg. Upon activation, NE is quickly released from the granules into the extracellular space with some portion remaining bound to the neutrophil plasma membrane | See Kaularai and a). 2002, Eisg. 9. RIagtasoi. 451, 1-10). The main intracellular physiological function is NOT the decomposition of foreign organic molecules phagocytosed by neutrophils, since the main target for extracellular elastase is elastin (Yuapoii et al., 1965, .). 12 Ex. Honey. 128, 1137-1155). It is NOT unique compared to other proteases (for example, proteinase 3) in that it has the ability to decompose almost all extracellular matrix proteins and key plasma proteins. U. Rpaptasoi. 451,1-10). It decomposes a large number of extracellular matrix proteins, such as elastin. Type C and type 4 collagens, laminin, fibronectin, cytokines, etc. (Oprauzny, M., 2002, Ekhregp Orip.

Ipmevid. Yugidv, 11, 965-980). NE is the main common mediator of many pathological changes observed in chronic lung diseases involving epithelial damage |Ziosideu, K.A. 1994, At. .).

Caesar Stia Sage Mea. 150, 109-113).

The destructive role was NOT established almost 40 years ago, when Ashgay and Egikezop discovered the association of chronic airflow obstruction and emphysema with serum A-antitrypsin deficiency | Ashgai! apa

Egiisvvop, 1963, Zsapa. 9. Siip. Ipmevi 15, 132-140). Then it was determined that A.-antitrypsin is the most important 29 endogenous inhibitor of human HE. An imbalance between human HE and endogenous antiprotease, it can be considered, Ge) causes an excess of human HE in lung tissues, which is considered the main pathogenic growth factor in chronic obstructive pulmonary disease (COPD). pulmonary structure, and then an irreversible increase in the respiratory air lumen, observed mainly in emphysema. There is an increase in the influx of neutrophils into the lungs, which is associated with an increased load on the lungs by elastase and emphysema in mice deficient in proteinase inhibitor A. Samata, 1996, art. Ipmevi 75, 273-280). Individuals with higher levels of the HE-inhibitor agprotease complex in the bronchoalveolar lavage fluid show a significantly accelerated decline in lung function compared to individuals with lower levels of IVeiziuaka ei a). "-- 2000, Kezgzrigayop, 67, 261-267). Infusion of human HE through the trachea in rats causes hemorrhagia of the lungs, accumulation of neutrophils during the acute phase and emphysematous changes during the chronic phase (Kagaki ei ai., so 2002, At. 9. Kezr. Stii. Sage Mea., 166, 496-500). Studies have shown that the acute phase of pulmonary emphysema and pulmonary hemorrhagia, caused by HE in hamsters, can be inhibited by preliminary treatment with HE inhibitors (Etsie ei aiI., 1999, IPYAatt. Kez. 48, 160-167. "

Neutrophil-dominant airway inflammation and mucosal airway obstruction are the main pathological features of OSA, involving cystic fibrosis and chronic bronchitis. It does NOT weaken the production of mucin, leading to mucous obstruction of the respiratory tract. NE, as disclosed, increases expression

From" the main gene of respiratory mucin, MOS5AS (Rizspeg, V.M. 5 Moupomu, 2002, At. U). Kezrig; Sow! Vioi!., 26, 447-452). Application of HE aerosol to guinea pigs causes extensive epithelial damage within 20 minutes of contact (Zygiki ei aiI.,, 1996, At. U. Kezr. Stii. Sage Med., 153, 1405-1411). In addition, NE reduces the ciliary frequency of the human respiratory epithelium (Ztaitap et al., 1984, Tpogah, 39, 663-667), which is compatible with the reduced mucociliary clearance observed in patients with SORO |Sitye et al., 1984 , - Tpogah, 42, 126-130). Infusion of NE into the respiratory tract causes hyperplasia of mucous glands in hamsters (Hiseu ei ai!.,, 1985, At. Kevzr. Stii. Sage Meyd., 132, 362-366). NE is also involved in hypersecretion of mucus in asthma. In a model of acute asthma in allergen-sensitized guinea pigs, the inhibitor does NOT prevent goblet cell degranulation and mucus hypersecretion. IMaadei ei ai!., 1999, EEig. Kegr. .)., 13, 190-196). NE has also been shown to play a role in the pathogenesis of pulmonary fibrosis. Complex NE:inhibitor A /-protenase is "7 increased in the serum of patients with pulmonary fibrosis, which correlates with clinical parameters in these patients (Matapoistpi ei ai., 1998, Eig. Kegzr. y. 11, 120-125). In mice in models of human pulmonary fibrosis, the inhibitor of NE reduces bleomycin-induced pulmonary fibrosis | TasokKa ei ai., 1997, At. resistant to

HF) of bleomycin-induced pulmonary fibrosis | Ophthalmology, 2001, Spevi, 120, 355-365). Plasma NE levels were found to be elevated in patients with advanced AKO5, implicating the importance of NE in the early pathogenesis of AKO5 disease. |OoppeiPu ei aiYi., 1995, At. U. Caves. Saint Sage Mei. 151, 428-1433). Antiproteases and NE in a complex with antiprotease are increased in the area of lung cancer. Kegzr. .). 2, 60 623-629). Modern studies have shown that polymorphism in the promoter region of the gene is NOT associated with the development of lung cancer (Tapidisnpi ei a!., 2002, Siip. Rak Kez., 8, 1115-1120).

Acute lung injuries caused by endotoxin in experimental animals are associated with increased levels of NO GIKamzhmabaiia, ei aiI., 1999, At. 9). Caesar Stia Sage, 161, 2013-2018). Acute inflammation of the lungs caused by intratracheal injections of lipopolysaccharide in mice has been shown to increase the activity of NO in the bronchoalveolar lavage fluid and is significantly inhibited by a NO inhibitor (Etsie et al., 1999, Eig. U.

Rpagtasoi., 374, 117-125; Mavyi, ei aiYi.,, 1995, Etsg. Kevzr. 9., 8, 1293-1299). NE also plays an important role in the neutrophil-induced increase in permeability of pulmonary microvasculature observed in a model of acute lung injury induced by tumor necrosis factor A (TMEA) and phorbol myristate acetate (PMA) in isolated perfused rabbit lungs |Miuazaki ei a! ., 1998, At. 9. Kezrig.

Stia Sage Med., 157, 89-94).

The role of NE has also been suggested in monocrotoline-induced thickening of the walls of pulmonary vessels and cardiac hypertrophy. RNagtasoi. 38, 2411-2419). A serine elastase inhibitor reverses monocrotaline-induced pulmonary hypertension and remodeling in rat pulmonary arteries 70 ISomzhap ei ai, 2000, Mayshge Meaisipe, b, 698-702). Modern studies have shown that serine elastase, which is NOT or vascular elastase, is important in cigarette smoke-induced muscularization of small pulmonary arteries in guinea pigs. IN). Kegrig. Stia Sage Mead., 166, 954-960).

NE plays a key role in experimental cerebral ischemic damage | Zpitakiga ei ai., 2000,

Vgaiip Kezeagsi, 858, 55-60), ischemic-reperfusion damage of the lungs |Kizpita ei AI., 1998, App. Tnogas /5 Zygu. 65, 913-918) and myocardial ischemia in the heart of a rat (Tiegepraspeg ei aI.,, 1997, Eig. U.. Rnuzioi!., 433, 563-570). Levels of human NE in plasma are significantly increased above normal in inflammatory bowel diseases, for example, Crohn's disease and ulcerative colitis. In addition, NE has also been suggested to be involved in the pathogenesis of rheumatoid arthritis |Adeueti ei ai., 1986, Kpeitatsy!|. Ipi., 6, 57|. The development of collagen-induced arthritis in mice is inhibited by an inhibitor of NE ICakKitoyo ei ai., 1995,

SeiIshag Ittipoi. 165, 26-32.

Therefore, human NE is known as one of the most destructive serine proteases and is involved in various inflammatory diseases. An important endogenous inhibitor of human HE is A. antitrypsin. An imbalance between human HE and antiprotease can be assumed to lead to an increase in the excess of human HE, leading to unregulated tissue destruction. The protease/antiprotease balance can be disrupted by reduced availability of γ-antitrypsin due to inactivation by oxidants, such as cigarette smoke, or as a result of a genetic inability to obtain adequate serum levels. Human NO is implicated in the stimulation or exacerbation of a number of i) diseases, such as pulmonary emphysema, pulmonary fibrosis, adult respiratory distress syndrome (ADS5), ischemic reperfusion injury, rheumatoid arthritis, and pulmonary hypertension.

MO 02/0535431| discloses pyridone derivatives having affinity for the cannabinoid receptor type 2. The present invention relates to novel 2-pyridone derivatives that are inhibitors of human neutrophil elastase and homologous serine proteases, such as protease C or pancreatic elastase, and are therefore useful in - therapy. with

The presented invention relates to the compound of formula (I) "- !

That d) in the neck; uk: "We are 7 - ! . "» ' V v n (ee) - . ime) - 50 - , (B)

F) with () 60 where

X represents O or 5;

U represents M or SK, and when KE! represents OH, U" can also represent MA in its tautomeric form; and Ug? represents SEZ, and when U" represents SK, U? can also represent M; in! represents M or C 4.alkyl; said alkyl is optionally substituted with one or more substituents,

independently selected from the group: halogen, CM, CHO, OK", MAE? (CO) 9 and ZOM Be, and when U! represents M, B can also represent OH;

Ge represents H, C 46 alkyl or phenyl; the specified phenyl is, optionally, additionally substituted with a substituent selected from the group: halogen, C. valkyl and C. .valkoxy; 2 represents H, halogen or C. alkyl; Ge represents M or E;

WITH! represents phenyl or a five- or six-membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, C and M; or b represents a five- or six-membered saturated partially 70 unsaturated cycloalkyl ring; or C' represents a five- or six-membered saturated or partially unsaturated heterocyclic ring containing one heteroatom selected from 0, 5 and MA", where BZ represents M or C. alkyl;

IN? represents H, halogen, C 4 alkyl, SM, C valuoxyl, MO», MA""B"?, C. valkyl substituted by one or more E atoms or C. valuoxyl substituted by one or more E atoms;

B" and B"? independently represent M or C ..valkyl; the specified alkyl, as an option, is additionally substituted by one or more E atoms; n equals the whole number 1, 2 or 3, and when n represents 2 or 3, each group E? selected independently; 27 and VU independently represent M or C 4 alkyl; the specified alkyl, as an option, is additionally substituted with a substituent selected from the group: OH or C. valoxyl; or B" and | are joined together so that the group -MA7I. represents a 5-7-membered azacyclic ring, optionally containing one more heteroatom selected from 0, 5 and Me 75;

It represents a connection, O, MK 293 or S. valkil; said alkyl optionally contains a heteroatom selected from

О, 5 and ME"; and, as an option, the indicated alkyl is additionally substituted with a substituent selected from the group: OH or ОМе; сч с? represents a monocyclic ring system selected from the group: i) phenyl or phenoxyl, and 9) и) 5 or b--len heteroaromatic ring containing one to three heteroatoms, independently selected from 0, 5 there, iii) C3 saturated or partially unsaturated cycloalkyl, or im) C saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms , che independently selected from О, 5(О)р and МВ" and, as an option, additionally contains a carbonyl group; or m 2 represents a dicyclic ring system, in which each of the two rings is independently selected from the group: i) phenyl, c i) 5 or b--a heteroaromatic ring containing one to three heteroatoms, independently selected from 0, 5 there, "- ii) Sz. saturated or partially unsaturated cycloalkyl, or a saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms, O0 independently selected from O, C(O)»p and MW» and, optionally, additionally containing a carbonyl group; and the two rings are fused together, or joined together directly, or separated by a linking group selected from 0, 5(O)4 or CH", " a monocyclic or dicyclic ring system is optionally indicated, additionally substituted by one to three 70 substituents independently selected from the group: SM, OH, S. valkyl, Si valcoxyl, halogen, ME"8879, MO", O50»K 38, no) with Sov? с(еМНИМНо, С(ОМ? в, с(в)МAZв?Я, 5С(-МНИМНо, MAZ'СЕ(-МНИМНо, 5(0)5829, 5О2МЕ29827, :з» C. zaloxyl substituted by one or more atoms E, and C. alkyl substituted 502839 or by one or more E atoms; or (ee) when GI. does not represent a bond, 2 may also represent H; with t, p, a, z and Uy independently equal to the whole number 0 ,1 or 2;

E8 and VE? independently represent H, C..alkyl, formyl or Co alkanoyl; the specified alkyl, as an option, is additionally substituted with phenyl, as an option, with a substituted substituent selected from the group: halogen, C ..alkyl, Si. valkoxil -40.20. or 50589; or the MEZVU group together represents a 5-7-membered azacyclic ring containing, as an option, one more - - heteroatom selected from O, 5 and MA28;

BZ and k'"Z independently represent H, C 4 alkyl, formyl, Sovalkanoyl, (0832 or 502 ME ZB; the indicated alkyl is, as an option, additionally substituted with a substituent selected from the group: halogen, CM, C 4 lalkoxyl or 25 somMv" ve ;

F) 225 represents H, C-alkyl or C-cycloalkyl; the indicated alkyl, as an option, is additionally substituted by one or more substituents independently selected from the group: OH, SIM, SOMAZ?v36, СО5837, OSOK, Савcycloalkyl,

C, a saturated heterocyclic ring containing one or two heteroatoms independently selected from OO, 5(O)p and 60 Me and a phenyl or 5-6b--len heteroaromatic ring containing one to three heteroatoms independently selected from О, Z and M; the specified aromatic ring is optionally additionally substituted with one or more substituents independently selected from the group: halogen, CM, Si.dalalkyl, Si.dalyl, OH, COM, CO, (OA and MNSOSN"; be 225 and EC" independently represent H, S. valkyl, formyl or Co valcanoyl;

VZ? represents H, C, alkyl or C3 cycloalkyl;

dz represents H, C 4alkyl or phenyl; specified phenyl, as an option, is additionally substituted with a substituent selected from the group: halogen, C..valkyl or C.valoxyl;

Vo, 2, g, ey B, ey 27, 22, ey c, 8, to dz B, 3 t, 5, dz 3, dz, ey E7, c,

BZ c, 5, p and KE" independently represent M or C. alkyl; and their pharmaceutically acceptable salts, provided that the following compounds are omitted:

M-benzyl-5,6-dimethyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide;

M-(2-phenethyl)-5,6-dimethyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide;

M-(2-hydroxyethyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide; -(2--(dimethylamino)ethyl/c-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide; 4-(2-C1,2-dihydro-1-( 4-methylcyclohexyl)-2-oxo-3-pyridinyl)carbonylamino|ethyl|-benzoic acid; and 4-(2-IK1-cyclohexyl-1,2-dihydro-2-oxo-3-pyridinylcarbonylamino|)ethyl|-benzoic acid acid.

Compounds of formula (I) can exist in the form of enantiomers. It should be understood that all enantiomers, diastereomers, racemates or mixtures thereof are included within the scope of the invention.

Compounds of formula (I) can exist in the form of various tautomers. For example, compounds of formula (I), where B! represents OH, and U" represents M, are tautomers of compounds of the formula (Ia), where Z represents H.

All possible tautomers and mixtures thereof are included within the scope of the invention. Compounds of formula (Ia), where 29 represents M 5 or is substituted, as an option, by Su. valkyl, thus included in the scope of the invention. (ee) Unless otherwise defined, the term "C. alkyl" as used herein means linear or branched alkyl having from 1 to b carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and sec-butyl. The terms "S..zalkil" and "S. lalkil" should be interpreted similarly. Examples of "C 1-4 alkyl substituted with one or more E atoms" include fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and 3,3,3-trifluoropropyl.

Unless otherwise defined, the term "C-Alkoxy" as used herein means an oxygen substituent that - M is attached to a linear or branched alkyl having from 1 to b carbon atoms. Examples of such groups include methoxy, ethoxy, n-propoxyl, i-propoxyl, n-butoxyl, i-butoxyl and sec-butoxyl. The terms "Si zaloxyl" and "S. daloxyl" should be interpreted similarly.

Examples of "C.sub.-alkoxyls substituted with one or more atoms in" include fluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, and 3,3,3-trifluoropropoxy.

F. Unless otherwise defined, the term "co valcanoyl" as used herein means a linear or branched co alkyl having from 1 to 5 carbon atoms attached to the molecule through a carbonyl. Examples of such groups include acetyl, propionyl and pivaloyl. Unless otherwise defined, the term "halogen" as used herein means fluorine, chlorine, bromine, and iodine.

Examples of a five- or six-membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, C, and M include furan, thiophene, pyrrole, oxazole, oxadiazole, isoxazole, imidazole, thiazole, triazole, thiadiazole , pyridine, pyrimidine and pyrazine.

Unless otherwise defined, the term "C3-saturated or partially unsaturated cycloalkyl" as used herein means a 3-6-membered non-aromatic carbocyclic ring optionally having one or more double bonds.

Examples include cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl. The term "five- or six-membered saturated or partially unsaturated cycloalkyl ring" should be interpreted similarly.

Unless otherwise defined, the term "C, a saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms independently selected from O, C(O)p, and ME" and, optionally, additionally containing a carbonyl"

Represented herein is a 4-7-membered non-aromatic heterocyclic ring that optionally has one or more double bonds and optionally contains a carbonyl. Examples include tetrahydrofuran, thiolane 1,1-dioxide, tetrahydropyran, 4-oxo-4H-pyran, pyrrolidine, pyrroline, imidazolidine, 1,3-dioxolane, piperidine, piperazine, morpholine, perhydroazepine, pyrrolidone, and piperidone. The term "five- or six-membered saturated or partially unsaturated heterocyclic ring containing one heteroatom selected from O, C and MA"3 should be interpreted similarly.

Examples of a "5-7-ene azacyclic ring optionally containing another heteroatom selected from 0, 5 and ME"!9" include pyrrolidine, piperidine, morpholine, thiomorpholine and piperazine.

In definition I, "C. alkyl; said alkyl optionally contains a heteroatom selected from 0, 5 and Mb" includes a straight or branched chain of 1-6 carbon atoms in which any two carbon atoms are optionally , separated by ОО, 5 or MA759, The definition therefore covers, for example, methylene, ethylene, propylene, hexamethylene, ethylethylene, -"СНоСНоО-СН»о-, -"СНАСНоО-СНо-СНоСНоСН»З5- and -"СНОСНоМВ 5-,

Examples of dicyclic ring systems in which two rings are fused together or joined together directly or separated by a linking group selected from O, 5(0)- or CH 5 include diphenyl, thienylphenyl, pyrazolylphenyl, phenoxyphenyl, naphthyl, indanyl , quinolyl, tetrahydroquinolyl, benzofuranyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, isoquinolyl, chromanyl, indenyl, quinazolyl, quinoxalyl, chromanyl, isochromanyl, 3H-indolyl, 1H-indazolyl, quinuclidyl, tetrahydroquinolyl , dihydrobenzofuranyl, morpholin-4-ylphenyl, 1,3-benzodioxolyl, 1,1-dioxido-2,3-dihydro-1-benzothienyl, 2,3-dihydro-1,4-benzodioxynyl, and 3,4-dihydroisochromenyl.

Examples of dicyclic ring systems in which the two rings are separated by a linking group (0) F include 4-(piperazin-1-ylsulfonyl)phenyl, 4-(morpholin-4-ylsulfonyl)phenyl, (3 4-(piperidine-1 -ylsulfonyl)phenyl,4-(pyrrolidin-1-ylsulfonyl)phenyl, 4-(4-pyridinylsulfonyl)phenyl, 4-(phenylsulfonyl)phenyl, 4-(thiazolylsulfonyl)phenyl, 4-(pyrimidin-2-ylsulfonyl)phenyl, 4-(imidazolylsulfonyl)phenyl, 4-(triazolylsulfonyl)phenyl and 4-(oxazolylsulfonyl)phenyl. -

In one embodiment, o represents H, halogen, C..alkyl, CM, C.alkyl, C.alkyl substituted by one or more E atoms, or C.alkoxyl substituted by one or more E atoms. In yet another embodiment, - represents halogen , C ..alkyl, SM, C alkyl or C. alkyl substituted by one or more P atoms. In yet another embodiment, o represents halogen, CHn, CM, OSN" or CE.

In one embodiment, n is an integer of 1 or 2. In yet another embodiment, n is an integer of 1. --

In one embodiment, E? represents halogen, CM or CE; n is equal to the whole number 1; and S! represents phenyl. (uh)

According to one aspect, the present invention relates to a compound of formula (I) where X represents 0; In 1 represents St.; IN? represents St. represents, as a variant, substituted S..valkyl; c"! represents phenyl or a five- or six-membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, 5 and "

M; B" represents H; I represents C 4 alkyl; and C? represents, as an option, a substituted monocyclic ring system selected from the group: C c i) phenyl, » i) 5 or b-membered heteroaromatic ring containing one - three heteroatoms, independently selected from 0, 5 there, ii) C3 saturated or partially unsaturated cycloalkyl, or im) Si saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms, co independently selected from O, 5(O) p and ME", and optionally, additionally contains a carbonyl. - In another aspect, the presented invention relates to compounds of formula (I), where X represents O, Y! represents Yuyu Seg; in? represents the SCU; B" represents C. alkyl; B? and KZ each represent H; C! represents phenyl or a five- or six-membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, 5 and

Sh- M; IN? represents H; I. represents C /.valkil; and 52 represents, alternatively, a substituted monocyclic ring

Kk system selected from the group: i) phenyl, i) 5 or b--lens heteroaromatic ring containing one to three heteroatoms, independently selected from 0, 5 there, iii) Cz. saturated or partially unsaturated cycloalkyl, or them) Si saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms,

Ф, independently selected from О, З(О)»р and МВ, and optionally additionally contains carbonyl. име) In another aspect, the presented invention relates to a compound of formula (I), where X represents 0; In! represents M or ME, and B" represents OH or its tautomer; Y? represents SVU; Z! represents phenyl or a 60 five- or six-membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, 5 and M; 7 represents H; | represents C 4-6 alkyl; and 52 represents, as an option, a substituted monocyclic ring system selected from the group: i) phenyl, i) a 5 or b-membered heteroaromatic ring containing one to three heteroatoms, independently selected with 0, 5 b5 there, iii) C3 saturated or partially unsaturated cycloalkyl, or im) C saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms independently selected from О, З(О)»р and МВ, and alternatively, additionally contains a carbonyl.

In another aspect, the present invention relates to a compound of formula (I), where X represents 0; M! represents SK 2; M? represents SV Z; IN! represents C. valkil; BC? and VZ, each, represent H; WITH! represents phenyl or pyridyl; 7 represents H; And represents C 4 alkyl; and c2 represents, as an option, substituted phenyl.

In another aspect, the present invention relates to a compound of formula (I), where X represents 0; In! represents SV 2; IN? represents CE Z; KK! represents S. valkil; BC? and VZ, each, represent H; WITH! represents phenyl or pyridyl; 7 represents H; | represents methylene; and o 2 represents, as an option, substituted phenyl.

In one embodiment, X in formula (I) represents 0.

In one embodiment, the invention discloses compounds of formula (I) in which U! represents CE 2; IN? represents

SZZ, In yet another embodiment, the invention discloses compounds of formula (I) in which U! represents CE 2, U? represents SEZ, and EC? and KZ, each, represent N.

In yet another embodiment, 2 and 23 each represent M. In yet another embodiment, v" represents OH in tautomeric form and U! represents MA.

In one embodiment, v is optionally substituted C 4-6 alkyl. In yet another embodiment,

B represents S. alkyl, especially methyl.

In one embodiment, C" represents phenyl or a five- or six-membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, 5, and M. In yet another embodiment, C" in formula (I) represents phenyl or pyridyl. In yet another embodiment, C in formula (I) represents phenyl. In yet another embodiment, C in formula (1) represents phenyl, and (Y) represents CE in the 3-position.

In one embodiment, N. o

In one embodiment, Y represents C 4 alkyl. In yet another incarnation, She is represented by -СН 5-. In yet another incarnation, AND represents ME??? and E?? represented by M.

In one embodiment, 52 represents, as an option, a substituted monocyclic ring system selected from the group: - i) phenyl, i) 5 or b) a heteroaromatic ring containing one to three heteroatoms independently selected from 0, 5 there, iii) Sz. saturated or partially unsaturated cycloalkyl, or with them) Si saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms "- independently selected from O, C(O)"p and ME" and optionally additionally containing carbonyl .

Zo In yet another embodiment, 52 is optionally substituted phenyl. In another embodiment, C 2 represents co-phenyl substituted by O505838, (0358295, 50229827, MA "ZV"Z (where at least one of KZ and KE)? and represents 5(0X82 or 502323) or C. alkyl substituted by 502839,

In another aspect, the invention specifically relates to one or more of the compounds described herein in the examples, in their non-salt form or pharmaceutically acceptable salts thereof. -at

Specific compounds include: c N-(4-chlorobenzyl)-1-(4-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide; c» b-methyl-M-I(4-(methylsulfonyl)benzyl|)|-2-oxo-1-3--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide b-methyl-M- (4-morpholin-4-ylbenzyl)-2-oxo-1-3-"-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide b-methyl-M-I(4-(methylsulfonyl)phenyl) |-2-oxo-1-IZ--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide o I-(4-(dimethylamino)benzyl)|-b-methyl-2-oxo-1-IZ -"-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide -(4-(aminosulfonyl)benzyl)|-b-methyl-2-oxo-1-3-"-trifluoromethyl)phenyl)-1 ,2-dihydropyridine-3-carboxamide - M-(4-methoxybenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide with M-benzyl-b -methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide

M-(4-chlorobenzyl)-1-(2-fluoro-5-methylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide - M-(3-chlorobenzyl)-1-(2 -fluoro-5-methylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide also 1--2-fluoro-5-methylphenyl)-M-(4-methoxybenzyl)-6-methyl- 2-oxo-1,2-dihydropyridine-3-carboxamide

M-(4-methoxybenzyl)-1-(3-methoxyphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

M-(3-chlorobenzyl)-1-(3-methoxyphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

M-(4-chlorobenzyl)-1-(3-methoxyphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

I-(4-(aminosulfonyl)benzyl|/|-1-(3-chlorophenyl)-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (F) M-(4-chlorobenzyl)-1 -(3-chloro-4-methylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

GI 1-(3-chloro-4-methylphenyl)-M-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

M-(4-chlorobenzyl)-1-(-2,3-dimethylphenyl)-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide in M-(4-chlorobenzyl)-1-(3- chloro-4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3-chloro-4-fluorophenyl)-M-(4-methoxybenzyl)-6-methyl-2- oxo-1,2-dihydropyridine-3-carboxamide

M-(4-chlorobenzyl)-1-(3-ethylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3-bromophenyl)-M-(4-chlorobenzyl)-6 -methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3--bromophenyl)-M-(4-methoxybenzyl)-6-Thiethyl-2-oxo-1,2-dihydropyridine-3-carboxamide 65 IM-22,3-dihydro-1-benzofuran-5-ylmethyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridin-3-car boxamide;

b-methyl-2-oxo-M-I(3-(2-oxopyrrolidin-1-yl)propyl|-1-(3-"-trifluoromethyl)phenyl/)-1,2-dihydropyridine-3-carboxa copper.

M-(4-bromobenzyp)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

M-(4-Chlorophenyl)-6-methyl-2-oxo-1-IZ-"(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide b-methyl-2-oxo-1-IZ-"- trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

M-(4-methoxybenzyl)-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

M-(4-chlorobenzyl)-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

M-(4-chlorobenzyl)-1-(3,5-dimethylphenyl)-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 70 I-(4-(aminosulfonyl)benzyl/|-1- (3,5-dimethylphenyl)-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3,5-dimethylphenyl)-M-(4-methoxybenzyl)-6b-methyl-2-oxo -1,2-dihydropyridine-3-carboxamide

M-benzyl-1-(3,5-dimethylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxypiacetate

M-(4-chlorobenzyl)-6-methyl-1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

M-(4-methoxybenzyl)-6-methyl-1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

M-(3-Chlorobenzyl)-6-methyl-1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

M-(4-chlorobenzyl)-1-(3-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

M-(3-chlorobenzyl)-1-(3-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3-chlorophenyl)-M-(4-methoxybenzyl)-6b -methyl-2-oxo-1,2-dihydropyridine-3-carboxamide methyl 4-((11-(3-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-ylcarbonyl)amino)- methyl|benzoate 4-I411-(3-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-ylcarbonylamino)methyl|-benzoic acid 1-(3-cyanophenyl)-M-cyclohexylmethyl)-6b -methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl)-M-(2-furylmethyl)-6-methyl-2-ox-1,2-dihydropyridine-3-carboxamide 1 -(3-cyanophenyl)-6-methyl-2-oxo-N-(pyridin-3-ylmethyl)-1,2-dihydropyridin-3-carboxamide

M-benzyl-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide сч 1-(3-cyanophenyl)-M-2,3-dihydro-1H-inden- 1-yl-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl)-M-(2-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine -3-carboxamide i) 1-(3-cyanophenyl)-6-methyl-2-oxo-M-(3,4,5-trimethoxybenzyl)-1,2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl) -M-(2,5-dimethoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl)-M-(3,4-dimethoxybenzyl)-6-methyl- 2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl)-N-(1-ethylpyrrolidin-2-yl)methyl/|-6-methyl-2-oxo-1,2 -dihydropyridine-3-carboxamide

M-(4-chlorobenzyl)-1-(3-cyanophenyl)-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide - 1-(3-cyanophenyl)-M-(4-methoxybenzyl)- 6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide c

M-(3-chlorobenzyl)-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl)-6-methyl-2-oxo-M -(thien-2-ylmethyl)-1,2-dihydropyridin-3-carboxamide -- 1-(3-cyanophenyl)-M-(cyclopropylmethyl)-6-methyl-2-oxo-1,2-dihydropyridin-3- carboxamide so 1-(3-cyanophenyl)-M-(3-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl)-6-methyl-2-oxo -M-(pyridin-4-ylmethyl)-1,2-dihydropyridin-3-carboxamide 1-(3-cyanophenyl)-M-(2-(3,4-dimethoxyphenyl)ethyl|-b-methyl-2-oxo -1,2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl)-b-methyl-M-(2-(1-methylpyrrolidin-2-yl)ethyl|-2-oxo-1,2-dihydropyridine-3 -carboxamide

IM-(2-(3-chlorophenyl)ethyl|-1-(3-cyanophenyl)-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide with 1-(3-cyanophenyl)-6- methyl-2-oxo-N-(2-pyridin-2-ylethyl)-1,2-dihydropyridine-3-carboxamide -methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1-3-cyanophenyl)-N-(2-(2-methoxyphenyl)ethyl)-6-methyl-2-oxo-1, 2-dihydropyridine-3-carboxamide

IM-(2-(2-chlorophenyl)ethyl|-1-(3-cyanophenyl)-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl)-M-(2 -(3-methoxyphenyl)ethyl/|-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide,

Go! 1-(3-cyanophenyl)-M-(2-(4-fluorophenyl)ethyl|-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl)-M-(2 -(2,4-dichlorophenyl)ethyl|-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide - 1-(3-cyanophenyl)-M-I(2-(3-fluorophenyl)ethyl| -b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide co 1-(3-cyanophenyl)-M-(2-(2-fluorophenyl)ethyl|-b-methyl-2-oxo-1, 2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl)-M-(2-cyclohex-1-en-1-ylethyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

SH-IM-(2-(4-bromophenyl)ethyl)-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide as M-(3-bromobenzyl)- 1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

M-(4-bromobenzyl)-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

M-(2-bromobenzyl)-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl)-M-(3,4-dihydro- 2H-pyran-2-tmethyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl)-6-methyl-M-(4-methylbenzyl)-2-oxo- 1,2-dihydropyridine-3-carboxamide,

F) 1-(3-cyanophenyl)-6-methyl-N-(1-naphthylmethyl)-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl)-N-(2-ethoxybenzyl) )-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl)-6-methyl-N-(4-"methylsulfonyl)benzyl|)|-2-oxo-1, 2-dihydropyridine-3-carboxamide in 1-(3-cyanophenyl)-6-methyl-N-(3-methylbenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl)- M-(4-fluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

IM-(1,3-benzodioxol-5-ylmethyl)-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3-Cyanophenyl)-M-( 2,4-dichlorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl)-6-methyl-H-(2-methylbenzyl)-2-oxo-1, 2-dihydropyridine-3-carboxamide 65 1-(3-cyanophenyl)-M-3,4-difluorobenzyl)-6b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl)- M-3,4-dichlorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

1-(3-cyanophenyl)-β6-methyl-N-((5-methyl-2-furyl)methyl|)|-2-oxo-1,2-dihydro-3-carboxamide 1-(3-cyanophenyl)- 6-methyl-2-oxo-M-1,2,3,4-tetrahydronaphthalen-1-yl-1,2-dihydropyridin-3-carboxamide 1-(3-cyanophenyl)-M-(2,3-dimethoxybenzyl) -bmethyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl)-M-(3,5-dimethoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3- carboxamide 1-(3-cyanophenyl)-M-(1-(4-fluorophenyl)ethyl|-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

IM-(1-(4-chlorophenyl)ethyl|-1-(3-cyanophenyl)-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl)-M-(2 ,5-difluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-carboxamide 1-(3-cyanophenyl)-M-(2,3-dihydro-1-benzofuran-5-ylmethyl)-6 -methyl-2-oxo-1,2-dihydropyridin-3-carboxamide 70 methyl 4-(11-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-ylcarbonyl)-amino) methyl|benzoate 1-(3-cyanophenyl)-6-methyl-2-oxo-M-(4-phenoxybenzyl)-1,2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl)-M-(15)- 2,3-dihydro-1H-inden-1-yl|-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl)-6-methyl-2-oxo-M- (thien-3-ylmethyl)-1,2-dihydropyridin-3-carboxamide. 1-(3-cyanophenyl)-β6-methyl-N-((5-methylisoxazol-3-yl)methyl|/|-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl)- M-(2,5-dimethyl-3-furyl)methyl/|-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl)-M-(3-furylmethyl)- 6-methyl-2-oxo-1,2-dihydropyridin-3-carboxamide 1-(3-cyanophenyl)-6-methyl-2-oxo-M-I4-(1H-pyrazol-1-yl)/benzyl/| -1,2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl)-6-methyl-2-oxo-N-(4-thien-2-ylbenzyl)-1,2-dihydropyridine-3-carboxamide

I-(4-(aminosulfonyl)benzyl)-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

IM-(2-(1,3-benzodioxol-5-yl)ethyl|-1-(3-cyanophenyl)-b-methyl-2-oxo-1,2-dihydropyridin-3-carboxamide 1-(3-cyanophenyl) )-6-methyl-2-oxo-N-(2-thien-2-ylethyl)-1,2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl)-N-(2-(2,4-dimethylphenyl) )ethyl/|-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(3-cyanophenyl)-b6-methyl-M-(2-(4-methylphenyl)ethyl/|-2- oxo-1,2-dihydropyridine-3-carboxamide

M-(2-(4--aminosulfonyl)phenyl|ethyl)-1-(3-cyanophenyl)-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide сч 1-(3-cyanophenyl)- 6-methyl-2-oxo-N-(15)-1-phenylethyl|-1,2-dihydropyridine-3-carboxamide

M-(cyclohexylmethyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide i)

M-(2-furylmethyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide b-methyl-2-oxo-M-(pyridine-3- ylmethyl)-1-IZ-"-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide -2,3-dihydro-1H-inden-1-yl-b6-methyl-2-oxo-1-IZ- "-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide"-zo M-(2-methoxybenzyl)-6-methyl-2-oxo-1-3-"trifluoromethyl)phenyl"-1,2- dihydropyridine-3-carboxamide b-methyl-2-oxo-N-(tetrahydrofuran-2-ylmethyl)-1-IZ-«(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide - b-methyl-2- oxo-1-III-"-trifluoromethyl)phenyl|-N-(3,4,5-trimethoxybenzyl)-1,2-dihydropyridine-3-carboxamide c

M-(3-fluorobenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide

IM-(2,5-dimethoxybenzyl)-b-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide --

I-I 1-Ethylpyrrolidin-2-yl)umethyl|-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide so

M-(2-chlorobenzyl)-6-methyl-2-oxo-1-3-"-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

M-(4-Chlorobenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

M-(3-chlorobenzyl)-6-methyl-2-oxo-1-(3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide b-methyl-2-oxo-M-(thien-2 -ylmethyl)-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

M-(cyclopropylmethyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide with M-(3-methoxybenzyl)-6-methyl-2- oxo-1-3-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide b-methyl-2-oxo-N-(pyridin-4-ylmethyl)-1-3-trifluoromethyl)phenyl -1,2-dihydropyridine-3-carboxamide and? IM-(2-(3,4-dimethoxyphenyl)ethyl/|-6-methyl-2-oxo-1-3--trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide

I-(2-(4-Methoxyphenyl)ethyl|-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide b-methyl-2-oxo-M -(2-phenylethyl)-1-(3--trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide

Go! b-methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl|-2-oxo-1-I(3--trifluoromethyl)phenyl/|-1,2-dihydropyridin-3-carboxam

ID

- IM-(2-(3-chlorophenyl)ethyl|-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide and b-methyl-2-oxo- M-(2-pyridin-2-ylethyl)-1-I(3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide

I-(2-(2-Methoxyphenyl)ethyl|-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

N-N-(2-(2-chlorophenyl)ethyl|-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide as I-(2-(Z -methoxyphenyl)ethyl|-6-methyl-2-oxo-1-3-"(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

1M-(2-4-fluorophenyl)ethyl/|-6-methyl-2-oxo-1-1(3--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide

IM-(2-(2,4-dichlorophenyl)ethyl/|-6-methyl-2-oxo-1-3--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide

IM-(2-(3-fluorophenyl)ethyl/|-6-methyl-2-oxo-1-(3--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide

IM-(2-(2-fluorophenyl)ethyl/|-6-methyl-2-oxo-1-I(3--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide

F) 14-(2-cyclohex-1-en-1-ylethyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide 2-(4-bromophenyl)ethyl)|-b-methyl-2-oxo-1-3-"-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide b-methyl-2-oxo-M- (15)-1-phenylethyl|-1-III-"-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide in M-(3-bromobenzyl)-6b-methyl-2-oxo-1-III- "-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide,

M-(4-bromobenzyl)-6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

M-(2-bromobenzyl)-6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

IM-(3,4-dihydro-2-pyran-2-ylmethyl|-b-methyl-2-oxo-1-3-"-trifluoromethyl)phenyl|-1,2-dihydropyridin-3-carboxam

ID

65 b-methyl-M-(4-methylbenzyl)-2-oxo-1-3-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide b-methyl-M-(1-naphthylmethyl)-2 -oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide

M-(2-ethoxybenzyl)-6-methyl-2-oxo-1-3-"-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide b-methyl-M-(3-methylbenzyl)-2 -oxo-1-3-"-trifluoroethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide

M-(4-Fluorobenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide

IM-(1,3-benzodioxol-b-ylmethyl-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

1M-(2,4-dichlorobenzyl)-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide b-methyl-M-(2-methylbenzyl)- 2-oxo-1-3-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

IM-(3,4-difluorobenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

M-(2-fluorobenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide 70 M-(2-chloro-4-fluorobenzyl)-6 -methyl-2-oxo-1-III--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide

1M-(3,4-dichlorobenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide b-methyl-M-((5-methyl- 2-furyl)methyl|)|-2-oxo-1-3--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide b-methyl-2-oxo-M-1,2,3,4- Tetrahydronaphthalen-1-yl-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

IM-(2,3-dimethoxybenzyl)-b-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

IM-(1-(4-chlorophenyl)ethyl|-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

IM-(2,5-difluorobenzyl)-6-methyl-2-oxo-1-III--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide methyl 4-X1(b-methyl-2-oxo -1-III--trifluoromethyl)phenyl|-1,2-dihydropyridin-3-yl)/carbonyl)amino|methyl)benzoate b-methyl-2-oxo-N-(4-phenoxybenzyl)-1-III-- trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

M-K2,2-dimethyl-1,3-dioxolan-4-yl)umethyl|-b-methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-k arboxamide b-methyl-M-((5-methylisoxazol-3-yl)methyl|/|-2-oxo-1-3-"-"trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxa copper -K2, 5-dimethyl-3-furyl)methyl|i|-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxami

HA

M-(3-furylmethyl)-6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide and) b-methyl-2-oxo-M-(4- 71H-pyrazol-1-yl)benzyl/|-1-I(3--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide b-methyl-2-oxo-H-(4-thien-2 -ylbenzyl)-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

IM-(2-(1,3-benzodioxol-5-yl)ethyl|-6-methyl-2-oxo-1-(3-"-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxam"-

ID that b-methyl-2-oxo-N-(2-thien-2-ylethyl)-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide -

IM-(2-(4-tert-butylphenyl)ethyl|-6-methyl-2-oxo-1-III--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide with b-methol-M-12 -(4-methylphenyl)ethyl/|-2-oxo-1-3--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide

M-(2-(4-aminosulfonyl)phenyl|ethyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carbox -- samide co b-methyl -2-oxo-M-((1K)-1-phenylethyl-1-3-"-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide 3-14-(2-methocyphenyl)piperazine-1- ylcarbonyl)-6-methyl-1-13-trifluoromethyl)phenyl|pyridin-2(1H)-one

M-K4-cyanocyclohexyl)methyl)|-b-methyl-2-oxo-1-3-"-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide 3-(4-(4-fluorophenyl)piperazine -1-yl|Icarbonyl)-6-methyl-1-3-"trifluoromethyl)phenyl|pyridin-2(1H)-one"

IM-(2-(4-fluoro-1,1"-diphenyl-4-yl)ethyl|-6-methyl-2-oxo-1-13-"-trifluoromethyl)phenyl|-1,2-dihydropyridin-3 -carb with oxamide. M-(2-hydroxy-1-phenylethyl)-6-methyl-2-oxo-1-3-"(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide" b-methyl-2-oxo-N-((2K)-2phenylcyclopropyl/|-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

I-(1-(4-chlorobenzylpiperidin-4-yl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

Go! that β-methyl-N-(2-morpholin-4-ylethyl)-2-oxo-1-3-[(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

1M-(2-"4-chlorophenyl)ethyl|-6-methyl-2-oxo-1-3-"trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide - M-(2-hydroxy-2- phenylethyl)-6-methyl-2-oxo-1-IZ-"(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide co M-cyclopentyl-b-methyl-2-oxo-1-IZ-"- trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

1N-(2-(1H-imidazol-4-yl)ethyl|-b-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

N-1M-(3,5-dimethoxybenzyl)-b-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide as M-(4-hydroxycyclohexyl)-b -methyl-2-oxo-1-3-"-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide b-methyl-2-oxo-N-(2-pyridin-2-ylethyl)-1-I (3-trifluoromethyl)phenyl (1,2-dihydropyridine-3-carboxamide b-methyl-2-oxo-M-1H-1,2,4-triazol-3-yl-1-trifluoromethyl) phenyl|-1,2-dihydropyridine-3-carboxamide

M-P1-(hydroxymethyl)-2-methylpropyl-b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

F) 3-113-(3,4-dichlorophenoxy)pyrrolidin-1-ylcarbonyl|-6-methyl-1-3-trifluoromethyl)phenyl|pyridin-2(1H)-one ka b-methyl-2-oxo -N-(pyridin-3-ylmethyl)-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridin-3-carboxamide

M-(2-methoxyethyl)-b-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide in M-(2-hydroxypropyl)-6-methyl-2- oxo-1-IZ-"trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide ethyl 4-I(6-methyl-2-oxo-1-IZ--trifluoromethyl)phenyl/|-1,2-dihydropyridine -3-yl)/carbonyl)amino|piperidine-1-carboxylate

1-3-(1H-imidazol-1-yl)propyl|-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

M-(4-chlorobenzyl)-1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide 65 M-(4-chlorobenzyl)-6'-methyl-2-oxo-2H-1 ,2-dipyridine-3-carboxamide

M-(4-niethoxybenzyl)-1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide methyl 4-((11-(3-methylphenyl)-2-oxo-1,2-dihydropyridine- 3-ylcarbonyl)amino|methyl)-benzoate 4-I411-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-ylcarbonylamino)methyl|benzoic acid

M-(4-chlorobenzyl)-1-(2-fluoro-5-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide 1--2-fluoro-5-methylphenyl)-M-(4- methoxybenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

I-(4-(dimethylamino)benzyl|)-1-(2-fluoro-5-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

I-(4-(aminosulfonyl)benzyl|)|-1-(2-fluoro-5-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

M-(4-chlorobenzyl)-4-methyl-2-oxo-2H-1,2'-dipyridine-3-carboxamide

M-(4-chlorobenzyl)-1-(2,5-dimethylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide 70 1-2,5-dimethylphenyl)-M-14-methoxybenzyl)-2- oxo-1,2-dihydropyridine-3-carboxamide -(4-(dimethylamino)benzyl)-1-(2,5-dimethylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

M-(4-chlorobenzyl)-1-(2-methyl-5-«-«trifluoromethyl)phenyl)|-2-oxo-1,2-dihydropyridine-3-carboxamide

M-(4-methoxybenzyl)-1-(2-methyl-5-trifluoromethyl)phenyl/|-2-oxo-1,2-dihydropyride carboxamide

I-(4-(dimethylamino)benzyl|)-1-(2-methyl-5-"trifluoromethyl)phenyl|-2-oxo-1,2-dihydropyridine-3-carboxamide

M-benzyl-5-methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide

M-(2-chlorobenzyl)-5-methyl-2-oxo-1-(3--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide 5-methyl-2-oxo-M-(2-phenylethyl) )-1-(3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide

M-(4-chlorophenyl)-5-methyl-2-oxo-1-3-"(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide b-ethyl-M-14-(methylsulfonyl)benzyl|- 2-oxo-1-3-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

I-(4-("methylsulfonyl)benzyl|-2-oxo-6-propyl-1-3--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide b-butyl-M-(4-(methylsulfonyl) )benzyl|-2-oxo-1-III-"trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide 6-(methoxymethyl)-M-I4--"methylsulfonyl)benzylide|-2-oxo-1- 13--trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide 6b-(hydroxymethyl)-M-I4--"methylsulfonyl)benzylide|-2-oxo-1-13--trifluoromethyl)phenyl/| -1,2-dihydropyridine-3-carboxamide

I-(4-(aminosulfonyl)benzyl/-2,4-dioxo-3-3-"-trifluoromethyl)phenyl)|-1,2,3,4-tetrahydropyrimidine-5-carboxam i)

ID

-(4-(dimethylamino)benzyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl/|-1,2,3,4-tetrahydropyrimidine-5-carboxamide

M-(4-chlorobenzyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl/d-1,2,3,4-tetrahydropyrimidine-5-carboxamide 1-benzofuran-5-ylmethyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl/|-1,2,3,4-tetrahydropyrimidine-5-carboxamide -

I-(4-("methylsulfonyl)benzyl-2,4-dioxo-3-IZ-""trifluoromethyl)phenylide|-1,2,3,4-tetrahydropyrimidine-5-carboxa with copper

M-(4-bromobenzyl)-2,4-dioxo-3-3-"-trifluoromethyl)phenyl/|-1,2,3,4-tetrahydropyrimidine-5-carboxamide --

M-(4-Methoxybenzyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl/c-1,2,3,4-tetrahydropyrimidine-5-carboxamide

IM-(1,3-benzodioxol-5-methyl)-2,4-doxo-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide

M-(3-chlorobenzyl)-2 4-dioxo-3-(3--trifluoromethyl)phenyl|/-1,2,3,4-tetrahydropyrimidine-5-carboxamide 1-butyl-M-I(4--methylsulfonyl (benzyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-k arboxamide with 1-(2-methoxyethyl)-M-I4 --methylsulfonyl)benzyl/d-2,4-dioxo-3-3-trifluoromethyl)phenyl/d-1,2,3,4-tetrahydropyr. imidine-5-carboxamide and? 1-methyl-M-1(4-methylsulfonyl)benzyl/|-2,4-dioxo-3-3-trifluoromethyl)phenyl/d-1,2,3,4-tetrahydropyrimidine-5-k arboxamide 1- ethyl-M-(4-(methylsulfonyl)benzyl)-2,4-dioxo-3"3-"trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide

M-(4-chlorobenzyl)-1-(2-methocaethyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carb - oxamide co 5 -iodo-6-methyl-M-I(I4-(methylsulfonyl)benzyl|d|-2-oxo-1-3-"-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

Sh-M-(4-chlorobenzyl)-1-(2-methoxyethyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide

M-(4-Methoxybenzyl)-1-(2-methoxyethyl)-2,4-dioxo-3--3--trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide 1-( 2-methoxyethyl)-2,4-dioxo-N-(pyridin-4-ylmethyl)-3-III--trifluoromethyl)phenyl)|-1,2,3,4-tetrahydropyrimidine-5-carboxamide

F) IM-(2-(3,4-dimethoxyphenyl)ethyl|-1-(2-methocaethyl)-2,4-dioxo-3-13-"-trifluoromethyl)phenyl)-1,2,3,4 -tetrahydropyrimidine-5-carboxamide 1-(2-methoxyethyl)-M-2-(3-methoxyphenyl)ethyl|-2,4-dioxo-3-I(3--'trifluoromethyl)phenyl|-1,2 ,3,4-tetrahydropyrimi 60 dyne-5-carboxamide 1-(-2-methoxyethyl)-N-(4-methylbenzyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl/|-1,2, 3,4-tetrahydropyrimidine-5-carboxamide 1-(-2-methoxyethyl)-M-(4-(methylsulfonyl)benzyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl)|-1, 2,3,4-tetrahydropyr imidine-5-carboxamide 65 M-(4-fluorobenzyl)-1-(2-methoxyethyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl/d-1,2, 3,4-tetrahydropyrimidine-5-carboxamide

1M-(1,3-benzodioxol-5-ylmethyl)-1-(2-methoxyethyl)-2,4-dioxo-3-13-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine -5-carboxamide

M-(2-chloro-4-fluorobenzyl)-1-(2-methoxyethyl)-2,4-dioxo-3-3-3-trifluoromethyl)phenyl-1,2,3,4-tetrahydropyrimidin-5-carboxamide

IM-(3,4-dichlorobenzyl)-1-(2-methoxyethyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl/d-1,2,3,4-tetrahydropyrimidine-5-carboxamide methyl 4 -4(41-(2-methoxyethyl)-2,4-dioxo-3-I(3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)carbonyl)amino) 7/ 0 methyl)benzoate 1--2-methocaethyl)-M-(5-methylisoxazol-3-yl)methyl/d-2,4-dioxo-3-I(3--trifluoromethyl)phenyl|d-1,2, 3,4-tetrahydro pyrimidine-5-carboxamide 1-(2-methoxyethyl)-2,4-dioxo-N-(4-(1H-pyrazol-1-yl)benzyl|/|-3-III-"-trifluoromethyl )phenyl/d-1,2,3,4-tetrahydropyrimidine-5-carboxamide

M-(4-chlorobenzyl)-3-(3Z-chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide 3-(3Z-chlorophenyl) -M-(4-methoxybenzyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide 3-(33-chlorophenyl)-1-(2-methoxyethyl) )-2,4-dioxo-M-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide 3-(3-chlorophenyl)-M-I(2-(3,4- dimethoxyphenyl)ethyl|-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide 3-(3-chlorophenyl)-1-(2-methoxyethyl)-M- (2-(33-methoxyphenyl)ethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carb oxamide

M-(3-bromobenzyl)-3-(3-chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide 3-3-chlorophenyl)- 1-(2-methoxyethyl)-N-(4-methylbenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide 3-(33-chlorophenyl)-1-(2-methoxyethyl) -M-I(4-(methylsulfonyl)benzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-ca rboxamide 3-(33-chlorophenyl)-M-(4-fluorobenzyl) -1-(2-imethoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide i)

IM-(1,3-benzodioxol-5-methyl)-3-(33-chlorophenyl)-1-(2-methocaethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide 3-(33-chlorophenyl)-M-(3,4-difluorobenzyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxam "-

ID that M-(2-chloro-4-fluorobenzyl)-3-(3-chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxy - samide c 3-(33-chlorophenyl)-M-(3,4-dichlorobenzyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide methyl -- 4-I(3-(3-chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-ylcarbonyl)amino)methyl|benzoate so 3- (3-chlorophenyl)-1-(2-methoxyethyl)-N-(5-methylisoxazol-3-yl)methyl/d-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide 3- (33-Chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-N-14-(1H-pyrazol-1-yl)benzyl/c-1,2,3,4-tetrahydropyrimidine-5-k arboxamide « 1-butyl-N-(4-chlorobenzyl)-3-yl3-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide with c 1-butyl-3-(Z -methoxyphenyl)-M-(2-(33-methoxyphenyl)ethyl)|-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. M-(3-bromobenzyl)-1-butyl-3-(33-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and? 1-butyl-N-(4-fluorobenzyl)-3-(3-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyridine-5-carboxamide

IM-(1,3-benzodioxol-5-ylmethyl)-1-butyl-3-(3-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

Go! 1-Butyl-N-(2,4-dichlorobenzyl)-3-(3-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1-butyl-M-(3,4-difluorobenzyl)-3-(3-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide - 1-butyl-M-(2 -chloro-4-fluorobenzyl)-3-3-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide co 1-butyl-M-(2,3-dihydro-1- benzofuran-5-ylmethyl)-3-(3-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

N-1-butyl-N-(4-chlorobenzyl)-3-(3Z-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide as 1-butyl-3-(Z -chlorophenyl)-M-(4-methoxybenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide 1-butyl-3-(3-chlorophenyl)-2,4-dioxo-M -(pyridin-4-ylmethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide 1-butyl-3-(3-chlorophenyl)-M-(2-(3,4-dimethoxyphenyl)ethyl/c- 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide 1-butyl-3-(3-chlorophenyl)-M-I2-(3-methoxyphenyl)ethyl)-2,4-dioxo- 1,2,3,4-tetrahydropyrimidine-5-carboxamide

M-(3-bromobenzyl)-1-butyl-3-(33-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

F) M-(4-bromobenzyl)-1-butyl-3-(3Z-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide ka 1-butyl-3-(Z -chlorophenyl)-M-(4-methylbenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide 1-butyl-3-(3-chlorophenyl)-M-(4-(methylsulfonyl) )benzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in 1-butyl-3-(3-chlorophenyl)-N-(4-fluorobenzyl)-2,4-dioxo -1,2,3,4-tetrahydropyrimidine-5-carboxamide

IM-(1,3-benzodioxol-5-ylmethyl)-1-butyl-3-(3-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide 1-butyl-3 -(3-chlorophenyl)-M-(2,4-dichlorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide 1-butyl-3-(3-chlorophenyl)-M- (3,4-difluorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide 1-butyl-M-(2-chloro-4-fluorobenzyl)-3-(3-chlorophenyl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide 65 1-butyl-3-(3-chlorophenyl)-M-(3,4-dichlorobenzyl)-2,4-dioxo-1 ,2,3,4-tetrahydropyrimidin-5-carboxamide 1-butyl-3-(3-chlorophenyl)-M-(2,3-dihydro-1-benzofuran-5-ylmethyl)-2,4-dioxo-1, 2,3,4-tetrahydropyrimidine-5-carboxamide 1-butyl-3-(3-chlorophenyl)-M-(4-cyanocyclohexyl)methyl|)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine 1-butyl-3-(3-chlorophenyl)-N-(5-methylisoxazol-3-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide -5-carboxamide copper and 1-butyl-3-(3-chlorophenyl)-2,4-dioxo-M-I4-(1H-pyrazol-1-yl)benzyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide 1- butyl-3-(3-chlorophenyl)-2,4-dioxo-M-I3-(2-oxo Pyrrolidin-1-yl)propyl|-1,2,3,4-tetrahydropyrimidine-5-carboxamide 1-butyl-N-(4-chlorobenzyl)-3-(3-cyanophenyl)-2,4-dioxo-1 ,2,3,4-tetrahydropyrimidine-5-carboxamide 70 1-butyl-3-(3-cyanophenyl)-M-(4-methoxybenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5 -carboxamide 1-butyl-3-(3-cyanophenyl)-2,4-dioxo-M-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide 1-butyl-3-( 3-cyanophenyl)-M-(2-(3,4-dimethoxyphenyl)ethyl/d-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide 1-butyl-3-(3-cyanophenyl) )-M-2-(33-methoxyphenyl)ethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide:

M-(3-bromobenzyl)-1-butyl-3-(3-cyanophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

M-(4-bromobenzyl)-1-butyl-3-73-cyanophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide 1-butyl-3-(3-cyanophenyl)- M-(4-methylbenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide 1-butyl-3-(3-cyanophenyl)-M-4-"methylsulfonyl)benzyl/) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide 1-butyl-3-(3-cyanophenyl)-M-(4-fluorobenzyl)-2,4-dioxo-1,2, 3,4-tetrahydropyrimidine-5-carboxamide

IM-(1,3-benzodioxol-5-ylmethyl)-1-butyl-3-(3-cyanophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide 1-butyl-3 -(3-cyanophenyl)-M-(2,4-dichlorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide 1-butyl-3-(3-cyanophenyl)-M- (3,4-difluorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide 1-butyl-3-M-(2-chloro-4-fluorobenzyl)-3-(3- cyanophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide 1-butyl-3-(3-cyanophenyl)-M-(3,4-dichlorobenzyl)-2,4-dioxo- 1,2,3,4-tetrahydropyrimidine-5-carboxamide 1-butyl-3-M-(4-cyanocyclohexyl)methyl|)-3-(3-cyanophenyl)-2,4-dioxo-1,2,3, 4-tetrahydropyrimidine-5-carboxa sch

Copper 1-butyl-3-(3-cyanophenyl)-N-(5-methylisoxazol-3-yl)methyl/d-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbox i) amide 1-butyl-3-(3-cyanophenyl)-2,4-dioxo-M-I4-(1H-pyrazol-1-yl)benzyl/i-1,2,3,4-tetrahydropyrimidine-5-carboxamide 1- butyl-3-(3-cyanophenyl)-2,4-dioxo-N-(3-(2-oxopyrrolidin-1-yl)propyl|-1,2,3,4-tetrahydropyrimidine-5-carboxamide 1-butyl-M-4-chlorobenzyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl/|-1,2,3,4-tetrahydropyrimidine-5-carboxamide - 1-butyl-M-(4 -methoxybenzyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxami with d 1-butyl-2,4-dioxo-M-(pyridine-4 -ylmethyl)-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxase -- with Mid so 1-butyl-N-(2-(3,4-dimethoxyphenyl)ethyl )-2,4-dioxo-3-3-trifluoromethyl)phenyl )-1,2,3,4-tetrahydropyrimidine-5-carboxamide 1-butyl-N-(2-(3-methoxyphenyl)ethyl) -2,4-dioxo-3-3-trifluoromethyl)phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide "

M-(3-bromobenzyl-1-butyl-2,4-dioxo-3-I(3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide with M-(4- bromobenzyl)-1-butyl-2,4-dioxo-3-3-trifluoromethyl)phenyl/|-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1-butyl-N-(4-methylbenzyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide and? 1-butyl-M-I(4-methylsulfonyl)benzyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl)|-1,2,3,4-tetrahydropyrimidine-5-k arboxamide 1- butyl-N-(4-fluorobenzyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide

Go! IM-(1,3-benzodioxol-5-ylmethyl)-1-butyl-2,4-dioxo-3-3-trifluoromethyl)phenyl/|-1,2,3,4-tetrahydropyrimidine-5-carboxamide - 1 -butyl-N-(2,4-dichlorobenzyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxam

ID and 50 1-butyl-N-(3,4-difluorobenzyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide as 1-butyl -M-(2-chloro-4-fluorobenzyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl|d-1,2,3,4-tetrahydropyrimidine-5-carb oxamide 1-butyl-M- (3,4-Dichlorobenzyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxam

ID

59 1-Butyl-N-(2,3-dihydro-1-benzofuran-5-ylmethyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyr ( F) imidine-5-carboxamide 1-butyl-N-(4-cyanocyclohexyl)methyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine- 5-carboxamide in 1-butyl-N-(5-methylisoxazol-3-yl)methyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine - 5-carboxamide 1-butyl-2,4-dioxo-M-I4-(1H-pyrazol-1-yl)/benzyl|-3-I(3-"-trifluoromethyl)phenyl/)-1,2,3, 4-tetrahydropyrimidine-5-carboxamide 1-butyl-2,4-dioxo-M-|3-(2-oxopyrrolidin-1-yl)propyl|-3-III-"trifluoromethyl)phenyl-1,2,3,4 -tetrahydropyrimide 65 in-5-carboxamide b-(chloromethyl)-M-(4-(methylsulfonyl)benzyl-2-oxo-1-3--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide - (4-"("methylsulfonyl)benzyl|-6-(methylthio)methyl|)|-2-oxo-1-3-""trifluoromethyl)phenyl|-1,2-dihydropyridine-3-k arboxamide -(4- ((methylsulfonyl)benzyl-6-(4-(methylsulfonyl)benzylamino)methyl)-2-oxo-1-3-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carb oxamide -(4-("methylsulfonyl)benzyl-6-(morpholin-4-ylmethyl)-2-oxo-1-3-trifluoromethyl)phenyl|)|-1,2-dihydropyridin-

Z-carboxamide 6-(cyanomethyl)-M-(4-(methylsulfonyl)benzyl|/|-2-oxo-1-3-trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carbox 70 samide b- isopropyl-M-(4-(methylsulfonyl)benzyl/|-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxam

ID

-(4-ethylsulfonyl)benzyl|/|-6b-methyl-2-oxo-1-3--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide

M-I (3-chloro4-(methylsulfonyl)benzyl|-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide b-methyl-2-oxo-1- (3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-33-carboxylic acid 4-cyclopropanesulfonyl-benzylamide

IM-I (13-methoxy-4-(methylsulfonyl)benzyl|-b-methyl-2-oxo-1-13-trifluoromethyl)phenyl-1,2-dihydropyridine-3-car boxamide

IM-13-bromo-4-(methylsulfonyl)benzyl|/|-6-methyl-2-oxo-1-13--trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide

1-3-Cyano-4-(methylsulfonyl)benzyl|-b-methyl-2-oxo-1-3-"-trifluoromethyl)-phenyl/|-1,2-dihydropyridine-3-carb oxamide b-methyl-M -13-methyl-4-(methylsulfonyl)benzyl|d|-2-oxo-1-13-"-trifluoromethyl)-phenyl|-1,2-dihydropyridine-3-carboxamide b-methyl-M-I4 -(methylthio)benzyl|-2-oxo-1-3--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide and) b-methyl-M-I(4-(methylsulfonyl)benzyl|)|- 2-oxo-1-3-(trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide

I-(4-(benzylsulfonyl)benzyl|-6-methyl-2-oxo-1-III--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide b-methyl-2-oxo-M-I4- (propylsulfonyl)benzyl|-1-(3--trifluoromethyl)phenyl/|-1/"2-dihydropyridine-3-carboxamide"-zo I-(4-(butylsulfonyl)benzyl)|-b-methyl-2-oxo -1-3-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

I-(4-(isobutylsulfonyl)benzyl|-b-methyl-2-oxo-1-III--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxami - d

I-(4-(tert-butylsulfonyl)benzyl|/|-6-methyl-2-oxo-1-3--trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide --

I-(4-(isopropylsulfonyl)benzyl|-6-methyl-2-oxo-1-13-"-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxam co

ID b-methyl-M-4-(3-methylbutyl)sulfonyl|benzyl)-2-oxo-1-1-3-"-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carb oxamide

M-4-((cyclopropylmethyl)sulfonylbenzyl)-6-methyl-2-oxo-1-III-"(trifluoromethyl)phenyl|-1,2-dihydropyridine-3"-carboxamide in c b-methyl-2-oxo- M-14-((tetrahydrofuran-2-ylmethyl)sulfonyl|-benzyl)-1-3-"-trifluoromethyl)phenyl|-1,2-dihydro.pyridine-3-carboxamide and?" M-4-(2-Hydroxyethyl)sulfonyl|benzyl)-6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-car boxamide

M-4-(cyanomethyl)sulfonyl|benzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

M-4-((2-amino-2-oxoethyl)sulfonyl|benzyl)-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl|-1,2-dihydropyridine--3-carboxamide co M -4-(4-cyanobenzyl)sulfonyl|benzyl/b-methyl-2-oxo-1-III--trifluoromethyl)phenyl-1,2-dihydropyridine-3-carb oxamide

Ш- M-4-(2-cyanoethyl)sulfonyl|benzyl)-b-methyl-2-oxo-1-3--trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide

M-4-((3-hydroxypropyl)sulfonyl|benzyl)-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-k arboxamide

M-4-42-(dimethylamino)-2-oxoethyl|sulfonyl|benzyl)-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl-1,2-dihydro pyridine-3-carboxamide o ethyl. 3-(4-C(b-methyl-2-oxo-1-3-trifluoromethyl)phenyl-1,2-dihydropyridin-3-yl)cocarbonyl)amino|methyl)phenyl)sulfonyl|propanoate 2- K4-Z(6β-methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridin-3-yl)/carbonyl)amino|methyl)phenyl)sulfonyl|ethyl acetate

M-4-((3-cyanobenzyl)sulfonyl|benzyl)-6-methyl-2-oxo-1-3-"(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-car boxamide methyl 3-(4- C((6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridin-3-yl)ucarbonyl)amino|methyl)phenyl)sulfone 65 yl|propanoate b-methyl-M -(4-S(2-methyl-1,3-thiazol-4-yl)umethyl|sulfonyl)benzyl)-2-oxo-1-3-"-trifluoromethyl)phenyl!/|-1,2-didropyridin -3-carboxamide b-methyl-2-oxo-M-14-(pyridin-4-ylmethyl)sulfonyl|benzyl)-1-3-"(trifluoromethyl)phenyl|-1,2-dihydropyridin-3-carboxamide

M-(4-((33-cyanopropyl)sulfonyl|benzyl)-6-methyl-2-oxo-1-3-"(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carb oxamide

M-(4--(3,5-Dimethylisoketsol-4-yl)umethyl|sulfonyl)benzyl)-6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridin- 3-carboxamide

M-(4-4-acetylamino)benzyl|sulfonyl)benzyl)-6-methyl-2-oxo-1-3-(trifluoromethyl)phenylic|-1,2-dihydropyride 70 yn-3-carboxamide b-methyl- M-I4-(2-K5-methyl-1,3,4-thiadiazol-2-yl)iamino|-2-oxoethylsulfonyl)benzylide|-2-oxo-1-3--trifluoromethyl)phenyl/)|- 1,2-dihydropyridine-3-carboxamide b-methyl-M-I(4-"methylsulfonyl)phenoxy|-2-oxo-1-3-"-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxami d b -methyl-2-oxo-1-(3--rifluoromethylphenyl)-1,2-dihydropyridine-3-carboxylic acid (4-bromo-phenoxy)-amide b-methyl-2-oxo-M-phenoxy-1-IZ -"-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

M-(4-aminobenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydroproline-3-carboxamide b-methyl-M-4-(methylsulfonyl)amino|benzyl )-2-oxo-1-III-"-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

M-(4-(bis(methylsulfonyl)amino|benzyl)-6-methyl-2-oxo-1-I(3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-car boxamide

M-Do4-((dimethylamino)sulfonyl|amino|phenyl|methyl|d|-1,2-dihydro-b6-methyl-2-oxo-1-IZ--trifluoromethyl)phenyl!/|-3-pyridinecarboxamide b- methyl-M-4-(methyl(methylsulfonyl)amino|benzyl)-2-oxo-1-3--trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-c carboxamide -((4-(butyl(methylsulfonyl )amino|phenyl|methyl)-1,2-dihydro-b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-3-pi and) ridincarboxamide 1,2-dihydro-6-methyl- M-((4-((1-methylethyl)(methylsulfonyl)-amino|phenyl|methyl|-2-oxo-1-(III--trifluoromethyl)phenyl|-3-pyridinecarboxamide "-zo M-(4- (2-methoxyethylmethylsulfonyl)amino|benzyl)-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide -

M-4-(2-cyanoethyl)x(methylsulfonyl)amino|benzyl)-b-methyl-2-oxo-1-3-"-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

M-4-(ethyl(methylsulfonyl)amino|benzyl)-b-methyl-2-oxo-1-III-"-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-k -- arboxamide co 1,2 -dihydro-6-methyl-M-(4-(methylsulfonyl)propylamino|-phenyl|methyl/)|-2-oxo-1-43--trifluoromethyl)phenyl|-3-pyridinecarboxamide

M-Do4-(3-amino-3-oxopropyl/umethylsulfonyl)amino|phenyl|-methyl|)|-1,2-dihydro-b6-methyl-2-oxo-1-IZ--trifluoro methyl)phenyl|- 3-pyridinecarboxamide « 1,2-dihydro-6-methyl-N-(4-(methylsulfonyl)oxy|phenyl|methyl|/|-2-oxo-1-(3-"trifluoromethyl)phenyl|-3-pyridine with c arboxamide, 2-propanesulfonic acid i?» 4-C(1,2-dihydro-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl|-3-pyridinylcarbonylamino|methyl|phenyl-ester

IM-(O1,1-dioxido-2,3-dihydro-1-benzothien-5-yl)umethyl/|-6-methyl-2-oxo-1-I(IZ--trifluoromethyliphenyl|-1,2-dihydro pyridine-3-carboxamide

Go! IM-(O1,1-dioxido-2,3-dihydro-1-benzothien-5-yl)umethyl|-5-iodo-6-methyl-2-oxo-1-IZ--trifluoromethyl)phenyl|d-1 ... coridine-3-carboxamide 1,2-dihydro-6-methyl-N-(4-(methylsulfonyl)methyl|phenyl|-methyl|/|-2-oxo-1-3--trifluoromethyl)phenyl|-Z- pyrides - ncarboxamide as b-chloro-5-methyl-4-(3-methylphenyl-N-(4-(methylsulfonyl)benzyl|-3-oxo-3,4-dihydropyrazine-2-carboxamide 5-bromo-6-( -difluoromethyl)-M-(4-(methylsulfonyl)benzylidene|-2-oxo-1-3--trifluoromethyl)phenyl/|-1,2-dihydropyridin-3-carboxamide 6-(difluoromethyl)-M-(4 -(methylsulfonyl)benzyl|-2-oxo-1-3--(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

F) IM-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-kacarboxamide b-methyl-M-III-"methylsulfonyl)benzyl|)|-2-oxo-1-III--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide in b-methyl-M'-I( 4--("methylsulfonyl)phenyl|-2-oxo-1-3-"-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carbohydrazide

M'(4-bromophenyl)-6-methyl-2-oxo-1-1-(3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carbohydrazide

M-K5-methoxy-4-oxo-4H-pyran-2-yl)umethyl|-b-methyl-2-oxo-1-3-trifluoromethyl)phenyl]-1,2-dihydropyridine-3-k arboxamide 65 M-(4-cyanobenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

M-3-(4-methoxyphenyl)isoxazol-5-yl|methyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridin-3

-carboxamide

M'-(4-cyanophenyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carbohydrazide b-methyl-2-oxo-M-((1 -phenyl-1H-pyrazol-4-yl)umethyl-1-(3-"-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

IM-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-6-methyl-2-oxo-1-3-trifluoromethylphenyl)-1,2-dihydropyridin-3-carboxamide b-methyl-M -C1-(3-methylphenyl)-1H-pyrazol-4-yl|methyl)-2-oxo-1-3--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide 70 M'-(4- chlorophenyl)-6-methyl-2-oxo-1-III--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carbohydrazide b-methyl-2-oxo-M-(2-(tetrahydro-2H-hydropyridine- 3-carboxamide

I-I 1-ethyl-1H-pyrazol-4-yl)methyl/|-6-methyl-2-oxo-1-3--trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide.

M-(4-benzylmorpholin-2-yl)methyl)|-b-methyl-2-oxo-1-3--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxam

ID

9 b-methyl-M-I(3-(2-methylpiperidin-1-yl)propyl|-2-oxo-1-3--trifluoromethyl)phenyl/|-1,2-dihydropyridin-3-carboxamide methyl 2 -((6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridin-3-yl)/carbonyl)amino|methyl)-3-furoate b-methyl-M-( 1-methyl-1H-pyrazol-4-yl)methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

M-(3-azepan-1-ylpropyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridin-3-carboxamide b-methyl-M-(3-morpholine- 4-ylpropyl)-2-oxo-1-3-trifluoromethyl)phenyl (1,2-dihydropyridine-3-carboxamide b-methyl-2-oxo-N-(3-piperidin-1-ylpropyl)-1 -III-"trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide sc

IM-(3,5-dimethyl-1Hpyrazol-1-yl)propyl|-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridin-3-carboxamide ( 8)

IM-IZ-(2-ethylpiperidin-1-yl)ipropyl)|-b-methyl-2-oxo-1-IZ-"-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide b-methyl -M-12-(1-methyl-1H-imidazol-5-yl)ethyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridin-3-carbox"-iso amide

IM-((1-ethyl-3-methyl-1H-pyrazol-4-yl)methyl|-b-methyl-2-oxo-1-13--trifluoromethyl)phenyl/|-1,2-dihydropyridin-3- k - arboxamide p

M-4-(acetylamino)benzyl|/|-6-methyl-2-oxo-1-III--trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide b-methyl-2-oxo-M- I(3-(1H-pyrazol-1-yl)propyl I|-1-III--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide -- b-methyl-2-oxo-M-(pyridine- 2-ylmethyl)-1-III-"-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide so b-methyl-M-C1-(4-methylphenyl)-1H-pyrazol-4-yl|methyl) -2-oxo-1-III--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide b-methyl-M'-(4-methylphenyl)-2-oxo-1-III--trifluoromethyl)phenyl| -1,2-dihydropyridine-3-carbohydrazide b-methyl-N-1(3-(4-methylpiperidin-1-yl)propyl|-2-oxo-1-3--trifluoromethyl)phenyl/|-1, 2-dihydropyridine-3-carboxamide with c-methyl-2-oxo-N-(3-(5-oxo-4,5-dihydro-1H-pyrazol-4-yl)propyl|-1-(Z -"trifluoromethyl)phenyl|-1,2-dihydropyrs

Y din-3-carboxamide a ethyl 5-methyl-4-((((6b-methyl-2-oxo-1-3-"trifluoromethyl)phenyl|-1,2-dihydropyridin-3-yl)/carbonyl)amino |methyl)-2-furoate

Go! that M-Kb-fluoro-4H-1,3-benzodioxin-8-yl)umethyl|-6-methyl-2-oxo-1-13-"(trifluoromethyl)phenyl|-1,2-dihydropyridine-

3-carboxamide - b-methyl-2-oxo-N-(2-pyridin-3-ylethyl)-1-I(3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide co IM-( (1,3-dimethyl-1H-pyrazol-4-yl)methyl/|-6-methyl-2-oxo-1-I(3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carb oxamide

β-methyl-2-oxo-N-(2-pyridin-4-ylethyl)-1-I(3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide. as M'-(4-fluorophenyl)-6-methyl-2-oxo-1-13-'-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carbohydrazide b-methyl-M-(1-methyl-1H -pyrrol-2-yl)methyl/|-2-oxo-1-3--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxami d b-methyl-2-oxo-N'-phenyl-1 -III--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carbohydrazide

IM-((1-ethyl-5-methyl-1H-pyrazol-4-yl)methyl|-b-methyl-2-oxo-1-I3--trifluoromethyl)phenyl|-1,2-dihydropyridin-3-k (F) arboxamide. ka b-methyl-N-(2-(1-methyl-1H-imidazol-4-yl)ethyl|-2-oxo-1-3-trifluoromethyl)phenyl)|-1,2-dihydropyridin-3-carbox samide in IM-(2-(1,3-dioxolan-2-yl)ethyl|-6-methyl-2-oxo-1-3-"trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

IM-(1-benzothien-3-ylmethyl)-6-methyl-2-oxo-1-I(3-trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide

1M-(1,5-dimethyl-1H-pyrazol-4-yl)methyl/|-6-methyl-2-oxo-1-I(13--trifluoromethyl)phenyl/|-1,2-dihydropyridin-3- carb oxamide

IM-(2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl|-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|)|-1,2-dihydropyridin-3 -car 65 boxamide

1M-(2-(3,5-dimethylisoxazol-4-yl)ethyl|-6-methyl-2-oxo-1-3-"-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

IM-(3,4-dihydro-1H-isochromen-1-ylmethyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridin-3-carb oxamide

M-((2K)-1-ethylpyrrolidin-2-yl|methyl)-b-methyl-2-oxo-1-3-"-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide b- methyl-2-oxo-M-(2K)-tetrahydrofuran-2-trimethyl-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide 5-chloro-M-4-( (dimethylamino)sulfonyl|benzyl)-6-methyl-2-oxo-1-3--trifluoromethyl)phenyl/|-1,2-dihydropyrides 70 n-3-carboxamide

M-4-((dimethylamino)sulfonyl|benzyl)-b-methyl-2-oxo-1-III--trifluoromethyl)-phenyl|-1,2-dihydropyridine-3-car boxamide 5-chloro-6-methyl- 2-oxo-N-(4-(piperazin-1-ylsulfonyl)benzyl-1-3-"-trifluoromethyl)phenyl)-1,2-dihydropyridin-

3-carboxamide b-methyl-2-oxo-M-I4-(piperazin-1-ylsulfonyl)benzyl-1-(3-"-trifluoromethyl)-phenyl|-1,2-dihydropyridin-3-carb oxamide b-methyl -M-I4-(morpholin-4-ylsulfonyl)benzyl|-2-oxo-1-I(3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide b-methyl-2-oxo-M -I4-(piperidin-1-ylsulfonyl)benzyl-1-(3--trifluoromethyl)-phenyl|-1,2-dihydropyridine-3-carb oxamide b-methyl-M-4-(methylamino)sulfonyl|benzyl)- 2-oxo-1-3-"-trifluoromethyl)-phenyl/|-1,2-dihydropyridine-3-carboxamide b-methyl-2-oxo-M-I4-(pyrrolidin-1-ylsulfonyl)benzyl|-1 -III-"trifluoromethyl)phenyl|-1,2-dihydropyridin-3-carboxamide 5-chloro-6-methyl-2-oxo-M-I(4-(pyrrolidin-1-ylsulfonyl)benzyl)-1- IZ-"trifluoromethyl)phenyl|-1,2-dihydropyridine-

Z-carboxamide (8) 5-chloro-6-methyl-M-I(4--("methylsulfonyl)benzyl|)|-2-oxo-1-3--trifluoromethyl)-phenyl|-1,2-dihydropyridine -3-carb oxamide

M-4-Kacetylamino)sulfonyl|benzyl)-b-methyl-2-oxo-1-III--trifluoromethyl)-phenyl|-1,2-dihydropyridine-3-carb"-zo oxamide

I-(4-(isolrotyl(ulfonyl)benzyl|-5-iodo-6-methyl-2-oxo-1-3-(trifluoromethyl)-phenyl|-1,2-dihydropyridin-3-car-boxamide c

IM-(4-(cyclopropylsulfonyl)benzyl/|-5-iodo-b-methyl-2-oxo-1-3-"trifluoromethyl)phenyl|-1,2-dildropyridin-3-k arboxamide -- 1,2 -dihydro-6-methyl-N-(4-(methylsulfonyl)oxy|phenyl|methyl|/|-2-oxo-1--3-"trifluoromethyl)phenyl|-3-pyridinco arboxamide

IM-I4-(1,1-dioxydoisothiazolidin-2-yl)benzyl/|-6-methyl-2-oxo-1-IZ--trifluoromethyl)phenyl|-1-2-dihydropyridine-

3-carboxamide b-methyl-2-oxo-N-((4-(4-pyridinylsulfonyl)phenyl|methyl|-1-(3-"'trifluoromethyl)phenyl/|-1,2-dihydropyridin-3-ka" b-methyl-2-oxo-M-I4-"(phenylsulfonyl)benzyl|)-1-(3--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide. b-methyl-2 -oxo-M-I(4-(1,3-thiazol-2-ylsulfonyl)benzyl/|-1-(3--trifluoromethyl)phenyl/|-1,2-dihydropyridin-3-carb and oxamide b- methyl-2-oxo-M-I4-(pyrimidin-2-ylsulfonyl)benzyl|-1-3--trifluoromethyl)phenyl|-1,2-dihydropyridin-3-carboxamide

Go! IM-I(I4-(1H-imidazol-2-ylsulfonyl)benzyl|-b6-methyl-2-oxo-1-IZ-"-trifluoromethyl)phenyl-1,2-dihydropyridin-3-car boxamide - b-methyl -M-14-(1-methyl-1H-1,2,4-triazol-5-yl)usulfonyl|benzyl)-2-oxo-1-I(3--trifluoromethyl)phenyl|d|-1,2 -dihydropyridine-3-carboxamide b-methyl-N-4-(5-methyl-1,3-oxazol-4-yl)usulfonyl|benzyl)-2-oxo-1-13-"-trifluoromethyl)phenyl -1,2-dihydropyr - idine-3-carboxamide as b-methyl-N-16-(methylsulfonyl)pyridin-3-yl)-2-oxo-1-3--trifluoromethyl)phenyl/|-1,2- dihydropyridine-3-carboxamide 5-fluoro-6-methyl-M-I(4--"methylsulfonyl)benzyl|d|-2-oxo-1-3--trifluoromethyl)phenyl/|-1,2-dihydropyridine- 3-car 5B boxamide

1-(4-(methylsulfonyl)benzylidene-2-oxo-6-(2-oxoethyl)-1-3-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carbox (F) samide B5- ethyl-β6-methyl-M-I(4--"methylsulfonyl)benzyl|)|-2-oxo-1-3--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide and their pharmaceutically acceptable salt

The present invention covers compounds of formula (I) in the form of salts, in particular acid addition salts.

Suitable salts include those formed from organic and inorganic acids. Such acid addition salts should usually be pharmaceutically acceptable, although salts of pharmaceutically unacceptable acids may be used to obtain and purify the compounds of the invention. Therefore, the best salts are formed from chloride, bromide, sulfate, phosphate, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, methanesulfonic, and benzenesulfonic acids.

According to the following aspect, the present invention relates to a method of obtaining the compound of formula (1), which contains the reaction of the compound of formula (III) .

Sun 4 o) with B. ;" co (1 - co de B", 02 and | defined in formula (I), - 50 and, where required or necessary, conversion of the formed compound of formula (I), or its other salt, into its pharmaceutically acceptable salt; or conversion of one compound of formula (I) into another compound of formula (I) and, where necessary, conversion of the compound of formula (T) into its optical isomer.

The method is carried out at a suitable temperature, generally between 02С and the boiling point of the solvent, in a suitable solvent, such as dichloromethane or M-methylpyrrolidinone. The method, as an option, is carried out in the presence of a base and/or coupling reagent, such as NATU, NOAT, NOVT or OEEA. Suitable leaving groups I include OH and halogen, especially OH.

Compounds of formula (H), where U" represents SV 2; U? represents SV 3, 17 represents OH, and 22 and B? o represent hydrogen, can be obtained by condensing the compound of formula (IM) 60 b5

(M di de B" is defined in formula (I), with the compound of formula (M)

AND

(

КА, счо (У - where 0", КР? and п are defined in formula (I) in the presence of a suitable base, such as sodium methoxide, in a suitable solvent, such as ethanol, and then by hydrolysis using of a suitable base, such as sodium hydroxide.

In general, compounds of formulas (IM) and (M) are known or can be obtained by methods known to those skilled in the art. d)

For example, compounds of the formula (IM) can be obtained by the methods |Z.M. ., Temganeagop, 1994, 50, 10331-103381I. "

Compounds of formula (I), where U" represents SK2; U? represents SKU, I! represents OH, and K" represents hydrogen o) c can be obtained by the reaction of compounds of formula (MI);» "I), -th so ro ts YAZ We,

PF) ( n - 50 , - (

F) where 0", B? and n are defined in formula (I), with the compound of formula (MI!) 60 b5

(M) ; about and

Y. nnnnnnyy

And ah shchi and where is V? or EZ as defined in formula (I), at a suitable temperature, such as 1602C, followed by base-stimulated cyclization and acid hydrolysis. Compounds of the formula (MI!) can be obtained according to O5 3,838,155).

Compounds of formula (I), where U" represents SV 2; y? represents SVU, |" represents OH, VC represents methyl, and 2? and EZ represent hydrogen, can be obtained by condensing the compound of the formula (MI) с (М) Ге) а: СМ рай - «- " (Й и и . с «-

I c where 0", KE? and n are defined in formula (I), with 4-methoxy-3-buten-2-one in the presence of a suitable base, such as o) c 1,4-diazadicyclo|2,2, 2) octane, at a suitable temperature in a suitable solvent, such as diethylene glycol "» monomethyl ether, and then by acid hydrolysis. "Compounds of formula (II), where KE! represents OH, U" represents nitrogen. 15 and U? represents SEZ, can be obtained by condensation of compounds of formula (IX)

So (yu - name) 1 - is i a Kk Tso ( i Iv

Ф) ю (ИХ) because 1 5 ! ! where 0", K" and n are defined in formula (I), with the compound of formula (X) b5

00

And whether

(x) in the presence of a suitable base, such as sodium ethoxide, at a suitable temperature in a suitable solvent, such as ethanol.

The compound of formula (IX) can be obtained from the corresponding isocyanate derivative by treatment with ammonia in acetonitrile.

Salts of compounds of formula (I) can be obtained by the reaction of the free base or salt, enantiomer, tautomer or its protected derivative with one or more equivalents of a suitable acid. The reaction can be carried out in a He) solvent or medium in which the salt is insoluble, or in a solvent in which the salt is soluble, and then the solvent is removed under vacuum or sublimation. Suitable solvents include, for example, water, dioxane, ethanol, 2-propanol, tetrahydrofuran or diethyl ether, or mixtures thereof. The reaction can be carried out by an exchange method or on an ion exchange resin. -

The compounds of formula (I) and their intermediates can be obtained as such or in a protected form. Protection and removal of rch-protection of functional groups, for example, (described in "Rgoiesiime Sgotsrz ip Ogdapis Spetivigu, ediey ru 9. MU.

E. MsOtiev, Riepyt Rgezz (1973), and "Rgoyesiime Ogotsirz ip Ogdapis Zupipeviv, Zga edyiop, T. MU. Ogeepe 85 R. 0. M. p.

UMiiv, UMieu-Ipiegzsiepse (1999). "-

Compounds of the invention and intermediates can be isolated from their reaction mixture and, if necessary, additionally purified using standard methods. co

The compounds of formula (I) may exist in enantiomeric or diastereoisomeric forms or as mixtures thereof, all of which are included within the scope of the invention. Different optical isomers can be isolated by separating a racemic mixture of compounds using conventional methods, for example, fractional recrystallization or HPLC. Alternatively, individual enantiomers can be produced by reacting a suitable optically active starting material under reaction conditions that will not cause racemization. c Intermediates can also exist in enantiomeric form and can be used as purified c» enantiomers, diastereomers, racemates or mixtures thereof.

According to the following aspect of the invention, we offer a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.

The compounds of formula (I), and their pharmaceutically acceptable salts, are useful because they have pharmacological activity in animals. The compounds of formula (I) have activity as pharmaceuticals, particularly as modulators of human neutrophil elastase and homologous serine proteases such as proteinase C and pancreatic elastase, and as such would be expected to be useful in therapy. The compounds of formula (I) are particularly useful as inhibitors of human neutrophil elastase. they can thus be used in the treatment or prevention of inflammatory - and 250 diseases and conditions. that Examples of these conditions are: adult respiratory distress syndrome (AKO5), cystic fibrosis, pulmonary emphysema, chronic obstructive pulmonary disease (COPD)), ischemia-reperfusion injury. The compounds of the present invention may also be useful in modulating endogenous and/or exogenous biological stimuli that cause and/or increase atherosclerosis, diabetes, myocardial infarction; liver disorders, including but not limited to cirrhosis, systemic lupus erythematosus, inflammatory disease of lymphoid origin, including but not limited to

HF) limitation of T-lymphocytes, B-lymphocytes, thymocytes; autoimmune diseases, bone marrow; inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout); inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis, pancreatitis and gastritis); skin inflammation (especially psoriasis, eczema, dermatitis); in tumor metastasis or invasion; in the treatment associated with unregulated decomposition 60 of the extracellular matrix, such as osteoarthritis; with a disease with bone resorption (such as osteoporosis and disease

Paget); diseases associated with abnormal angiogenesis; increased collagen reconstruction associated with diabetes, dental disease (such as gingivitis), corneal ulceration, skin ulceration, conditions after surgery (such as colonic anastamosis), healing of dermal wounds; demyelinating diseases of the central and peripheral nervous system (such as multiple sclerosis); age-related diseases, such as dementia, 62 inflammatory diseases of cardiovascular origin; granulomatous diseases; kidney disease, including but not limited to nephritis and polyarteritis; cancer; pulmonary hypertension, the effect of poison, skin contact, insect bites, stings; asthma; rhinitis; progression of NTM disease; to minimize the effects of organ rejection during their transplantation, involving, but not limited to, human organs; and replacement therapy with proteinase inhibitors.

Therefore, another aspect of the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of diseases or conditions in which inhibition of neutrophil elastase activity is useful; and a method of treating, or reducing the risk of, diseases or conditions in which inhibition of neutrophil elastase activity is beneficial, which comprises administering to a person suffering from or at risk of said disease or condition a therapeutically effective amount of 7/0 bpol of formula (1) or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the production of a medicament for the treatment or prevention of inflammatory diseases or conditions; and a method of treating, or reducing the risk of, inflammatory diseases or conditions, which comprises administering to a person suffering from or at risk of said disease or condition, a therapeutically effective amount of compound 7/5 of formula (I) or a pharmaceutically acceptable salt thereof.

In particular, the compounds of the present invention can be used in the treatment of adult respiratory distress syndrome (ARDS), cystic fibrosis, pulmonary emphysema, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, asthma, rhinitis, ischemia-reperfusion injury, rheumatoid arthritis, osteoarthritis, cancer , atherosclerosis and injury to the gastric mucosa.

Prophylaxis is expected to be particularly important in the treatment of individuals who have experienced previous cases or are otherwise believed to be at increased risk for the disease or condition in question. Individuals at risk for developing a particular disease or condition generally include those with a family history of the disease or condition, or those identified by genetic testing or screening as particularly susceptible to developing the disease or condition. with

For the above therapeutic indications, the dose of compound to be administered will depend on the compound being administered, the disease being treated, the regimen, age, weight and gender of the patient. Such factors can be determined i) by a doctor. However, generally satisfactory results are obtained when the compounds are administered to humans at weekly dosages of 0.1mg/kg - 100mg/kg (measured as the active ingredient).

The compounds of formula (I) can be used as such or in the form of suitable pharmaceutical compositions containing the compound of the invention in combination with a pharmaceutically acceptable diluent, adjuvant or carrier.

Compositions that do not contain material capable of causing harmful reactions, for example - allergic reactions, are especially preferable. Conventional methods of selecting and obtaining suitable pharmaceutical compositions are described in, p.

For example, "RpagtaseciisaIv - Te Zsiepse oi Oozade Bogt YuOevidpe", M. E. Aishiop, Spigspi I imipdviope, 19881.

According to the invention, a pharmaceutical composition containing preferably less than UBmas.vol, and 87 more preferably less than 5Omas.9o of the compound of formula (I) in a mixture with a pharmaceutically acceptable diluent or carrier is proposed.

We also provide a method of preparing such pharmaceutical compositions comprising mixing the ingredients.

The compounds can be administered topically, for example to the lungs and/or respiratory tract, in the form of solutions, "suspensions, NEA aerosols or dry powder compositions, for example, compositions in an inhaler known as with Tigripaiege; or systemically, for example, by oral administration in the form of tablets, pills, capsules, syrups, powders or granules; or parenteral use, for example, in the form of sterile parenteral;" solutions or suspensions; or rectal application, for example, in the form of suppositories.

Dry compositions of powder and NEA-aerosol under pressure of the compounds of the invention can be used orally or

By nasal inhalation. For inhalation, it is desirable to finely grind the compound. Finely ground compounds are preferred

Go! has an average diameter of less than 10 μm and can be suspended in the propellant mixture with a dispersant such as a s-Cofatty acid or its salt (eg, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or another pharmaceutically acceptable dispersant.

GI Compounds of the invention can also be used with a dry powder inhaler. The inhaler can be a single- or multiple-dose inhaler, and can be actuated by inhalation. - One possibility is to mix the finely divided compound with a carrier substance, for example mono-, di- or

Kk polysaccharide, sweet alcohol, or other polyol. Suitable carriers are sugars such as lactose, glucose, raffinose, melecitose, lactitol, mannitol, trehalose, sucrose, maltitol and starch. Alternatively, the finely ground compound may be coated with another substance. The powder mixture can also be dispersed in hard gelatin capsules, each of which contains the required dose of the active compound.

Another possibility is a method of finely grinding the powder into spheres that are sprayed during inhalation. This (F, spheronized powder) can be packed into the drug reservoir of a multi-dose inhaler, known as a Tigryaienkyae, in which a metering element measures the required dose, which is then inhaled by the patient. From this system, the active compound, with or without a carrier substance , is delivered to the patient. 60 For oral administration, the active compound may be mixed with an adjuvant or carrier such as lactose, sucrose, sorbitol, mannitol, a starch such as potato starch, corn starch, or amylopectin, a cellulose derivative, a binder , e.g., gelatin or polyvinylpyrrolidone; and/or a lubricant, e.g., magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, etc., and then compressed into tablets. If coated tablets are desired, the cores obtained as described above may be coated a concentrated solution of 65 CHUUKRU, which may contain, for example, gum arabic, gelatin, talc, titanium dioxide, etc. Alternatively, the tablets may be coated with a suitable polymer rum dissolved in a volatile organic solvent.

To obtain soft gelatin capsules, the compound can be mixed, for example, with vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the compound using the above-mentioned tablet excipients. Also, liquid or semi-solid drug compositions can be packaged in hard gelatin capsules.

Liquid preparations for oral administration may be in the form of syrups or suspensions, for example, solutions containing a compound balanced with sugar and a mixture of ethanol, water, glycerin and propylene glycol, alternatively, such liquid preparations may contain dyes, flavors, saccharin and/or carboxymethylcellulose as a thickening agent, or other excipients known to specialists. 70 The compounds of the invention can also be used together with other compounds used to treat the above conditions.

The following examples are intended to illustrate, but not limit, the scope of the invention.

General methods

TN NMR and C NMR are recorded on a Magiap Ipoma 400MHz device or a Magpap Megsigu-UH 300MHz device. The central 75 peaks of chloroform-y (bn 7.27 ppm, dimethylsulfoxide-yv (bn 2.50 ppm), acetonitrile-dz (bn 1-95 ppm "). or methanol au (bn 3.31 mln"") are used as internal standards. Low-resolution mass spectra are obtained on an Adiiepi 100 RH-MS system equipped with a HIAT (chemical ionization at atmospheric pressure) ionization chamber.

Column chromatography is performed using silica gel (0.040-0.06Zmm, MegskK).

Unless otherwise specified, source materials are commercially available. All solvents and commercial reagents are laboratory grade and used as received. Unless otherwise specified, organic solutions are dried using anhydrous sodium sulfate.

Unless otherwise specified, the following methods are used for HPLC and LC-MS analysis:

RH-MO-Method A

Device - Adiiepi 1100; Column - M/aFegz Zutteiigu 2.1x3O0mm; Mavgv HIAT; flow rate - 0.7 ml/minute; s wavelength is 254 nm; Solvent A: VodazhO, 195 TFOC; In: Acetonitrile 0.1956 TFOC; Gradient 15-9595/8 8 minutes, ge) 95905 V 1 minute.

RH-Method V

Device - Adiiepi 1100; Column - KE '0-5218 150хх4, b6mm; flow rate - 1.0 ml/minute; wavelength 220 nm; Solvent A: Water, 196 TFOK; In: AcetonitrileO0.196 TFOK; Gradient 20-10096/8 8 minutes, 10095 V 2 - 3o minutes. -

The following abbreviations are used:

GBTU O(Benzotriazol-1-yl)-M,M,M',M'-tetramethyluronium hexafluorophosphate cm

GATU O-(7-Azabenzotriazol-1-yl)-M,M,M',M'-tetramethyluronium hexafluorophosphate --

HOBT 1-Hydroxybenzotriazole

GOAT 1-Hydroxy-7-azabenzotriazole co

DIPE M,M-Diisopropylethylamine

M-MP 1-M-Methyl-2-pyrrolidinone

THF Tetrahydrofuran «

TFOK Trifluoroacetic acid -o 70 Example 1 M-(4-Chlorobenzyl)-(4-chlorophenyl)-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide c a) Ethyl 3-K4-chlorophenyl)amino |-33-oxopropanoate :z» The title compound is obtained essentially as described |. M. Okhaipeizv ei ai., Teigapedgop, 1994, 50, 10331-103381.

B) Ethyl 1-(4-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate

A mixture of ethyl 3-(4-chlorophenyl)amino|-3-oxopropanoate (1g, 4mmol), 4-methoxy-3-buten-2-one (0.42g, so 395 4.2mmol) and sodium methoxide (0.22g) , 4.1 mmol) in ethanol (1 Oml) is heated to the boiling point under reflux for 5 hours. After cooling, the solvent is evaporated. The residue was chromatographed on silica using heptane/ethyl acetate (1:1-1:5) as eluent to give the title compound (297 mg, m.p. 2590).

TN NMR (SOSI»v): 5 8.17 (1Н, 4); 7.49 (2H, a); 7.13 (2H, a); 6.21 (1H, 4); 4.34 (2H, 4); 2.03 (ZH, 5); 1.35 (ZH, 0. and c) 1-4-Chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid shkkch Ethyl 1-( 4-chlorophenyl)-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (297 mg, 1.0 mmol) was dissolved in a mixture of 1 M sodium hydroxide solution (bml) and THF (ml). The reaction mixture is stirred for 2.5 hours at room temperature, then acidified to pH2 using 5M hydrochloric acid, and then extracted with dichloromethane. The combined organic phases were washed with water, dried, filtered and evaporated to give the title compound in (268mg, 10090). (F. NMR (SOSI"): 6 8.51 (1H, a); 7.59 (2H, a); 7.18 (2H, 4); 6.53 (1H, 49); 2.15 ( ЗН, 5). ka a) M-(4-Chlorobenzyl)-1-(4-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

A mixture of 1-(4-chlorophenyl)-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (100mg, 0.33mmol), GBTU vo (BOmg, 0.42mmol), HOBT (ba4mg, 0 .42 mmol) and DIPE (195 μl, 1.14 mmol) in M-MP (1 mL) were added to 4-chlorobenzylamine (108 mg, 0.7 mmol) in M-MP (0. bmL). The reaction mixture was stirred for 18 hours.

The solvent was evaporated and the residue was purified by preparative HPLC to give the title compound (bOmg, 4195). "YAN yaYMR (SOSIV): 5 9.91 (1H, Bgv); 8.54 (IN, a); 7.53 (2H, a); 7.24 (4H, 8); 7.13 (2H, 4); 6.42 (1H, 4); 65 4.53 (2H, 4); 2.07 (ZH, c).

Applying the general method described in example 1, the compounds of examples 1.1-1.27 are obtained:

Example 1,1 6-Methyl-M-I4-methylsulfonate)benzyl|-2oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide

TN NMR (SOSIv): 5 9.96 (IN, 9; 8.57 (IN, a); 7.85 (2H, a); 7.80 (IN, a); 7.73 (IN, 9; 7.50 (ZN, Bho); 5742 (1H, a); 6.46 (1H, a); 4.65 (2H, a); 3.00 (ZN, 5); 2.07 (ZN, 5 ).

Example 1,2 6-Methyl-N-(4-morpholin-4-ylbenzyl)-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

TN NMR (DMSO-iv): 5 9.69 (IN, Brid; 8.38 (1H, a); 7.89-7.87 (2H, t); 7.79 (IN, 0; 7.70 (1H, a); 7.15 (2H, 4); 6.87 (2H, 4); 6.62 (1H, 49); 4.36 (2H, a); 3.72-3.69 ( 4H, t) 3.05-3.03; (4H, t); 2.00 (ZH, 5).;

HIAT-MS ti/: 472|MN.

Example 1,3 6-Methyl-M-I4-methylsulfonyl)phenyl|-2-oxo-1-III-"-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide" NMR (SOSIV): 5 12.00 (IN, in); 8.66 (IN, a); 7.92-7.85 (B5H, t); 7.79 (IN, 9; 7.56 (1H, c); 7.49 (1H, a); 6.55 (1H, 4); 3.04 (ЗН, 5); 2.13 (ЗН, c) and HIAT-MS ti/g: 451|MN.

Example 1.4

I-(4-(Dimethylamino)benzyl|-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

TN NMR (SOSIv): 5 9.67 (1Н, ге); 8.57 (1H, a); 7.78 (IN, 4); 7.71 (IN, 0; 7.49 (1H, 8); 7.41 (1H, 9); 20721 (2H, bga); 6.72 (2H, Bgv); 6.43 (1H, a) 4.50 (2H, a), 2.91 (BN, 5), 2.05 (ZH, c).

Example 1,5 -(4-(aminosulfonyl)benzyl)|-b-methyl-2-oxo-1-3-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

TN NMR (DMSO-yv): 5 9.89 (IN, Bgv); 8.37 (IN, a); 7.91 (IN, 8); 7.59 (IN, a); 7.80 (IN, a); 7.75 (2H, a); 7.72 (1H, 4); 7.45 (2H, a); 7.27 (2H, 5); 6.62 (1H, 4); 4.54 (2H, 5); 2.02 (ZN, c). with

Example 1.6

M-(4-Methoxybenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide o

TN NMR (SOSIv): 5 9.72 (1H, Bbgv); 8.59 (IN, a); 7.79 (IN, a); 7.72 (IN, 9; 7.49 (IN, 5); 7.42 (1H, 4); 7.24 (2H, a); 6.82 (2H, a); 6.44 (1H, a); 4.52 (2H, a); 3.76 (ZH, 58); 2.05 (ZH, c).

Example 1,7 M-Benzyl-β6-methyl-2-oxo-1-3--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide --

TN NMR (SOSIv): 5 9.85 (IN, Bbgv); 8.62 (IN, a); 7.81 (IN, a); 7.74 (IN, 9; 7.52 (IN, 5); 7.44 (1H, 4); che 7.36-7.21 (5H, t); 6.47 (1H, a); 4 .61 (2H, 4); 2.08 (ZH, c).

Example 1.8 M-(4-Chlorobenzyl)-1-(2-fluoro-5-methylphenyl)-6-methyl-2-oxo-1,2-dihydro)pyridine-3-carboxamide with "YAN NMR (CO3O0) : 5 8.48 (1H, a); 7.40-7.36 (IN, t); 7.30 (4H, 85); 7.25 (IN, 9; 7.19 (1H, ad); 6.62 (IN, "- zvo 9); 4.56 (2H, 9); 2.39 (ZN, c); 2.13 (ZN, c). so

Example 1,9 M-(3-chlorobenzyl)-1-(2-fluoro-5-methylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide "YAN NMR (CO500): 5 8 .48 (1H, 4); 7.40-7.36 (1H, t); 7.33-7.32 (IN, t); 7.29-7.22 (DN, t); 7.20 (1H, ad); 6.62 (1H, 4); 4.57 (2H, a); 2.39 (ZH, 5); 2.13 (ZH, 5).

Example 1.10 « 40. 1-(2-Fluoro-5-methylphenyl)-M-(4-methoxybenzyl)-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide shsh c "YAN NMR ( C0O50O0): 5 8.48 (1H, a); 7.40-7.36 (IN, t); 7.27-7.21 (ZH, t); 7.02 (IN, a); 6, 86 (2H, a); 6.62 a (TN, 9); 4.50 (2H. a); 3.75 (ZN, 5); 2.39 (ZN, 8); 2.12 (ZN, 5).

Example 1.11 M-(4-Methoxybenzyl)-1-3-methoxyphenyl)-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide" NMR (SOSIV): 5 9.86 (1H, Bgv); 8.54 (IN, 4); 7.45 (IN, 0; 7.23 (2H, a); 7.04-7.01 (IN, t); 6.80 (2H, bo a ); 6.78-6.75 (1H, t); 6.70 (1H, 9; 6.39 (1H, 4); 4.51 (2H, 49); 3.82 (ZH, 5); 3.76 (ZN, 5); 2.09 (ZN. 5). -th HIAT-MS pi/: 379 (MN. ky Example 1.12 M-(33-Chlorobenzyl)-1-(3-methoxyphenyl) -6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide" NMR (SOSIS): 5 10.00 (1H, Bgv); 8.55 (1H, a); 7.47 (IN, 0; 7.30 (IN, Bgv); 7.19 (ZN, Bgv); 7.05-7.01 - (IN, t); 6.80-6.75 (1H, t); 6.72 (1H, 9; 6.41 (1H, 4); 4.55 (2H, a); 3.83 (ЗН, 5); 2.11 (ЗН, c). Щк Example 1.13 M-(4 -Chlorobenzyl)-1-(3-methoxyphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

TN NMR (SOSIv): 5 10.00 (1H, Bgv); 8.56 (1H, 4); 7.48 (1H, 0; 7.28 (4H, 8); 7.07-7.03 (IN, t); 6.81-6.77 (IN, t); 6.73 (1TN, 9 6.41 (1H, 49), 4.56 (2H, a), 3.85 (ZH, 5), 2.12 (ZH, c).

Example 1,14 M-I4-(aminosulfonyl)benzyl|-1-(3-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

TN NMR (SOSIv): 5 9.99 (IN, 0; 8.55 (IN, a); 7.84 (2H, a); 7.53-7.49 (2H, t); 7.46 ( 1IN, a); 7.25-7.24 o (IN, t); 7.14-7.10 (1H, t); 6.44 (1H, a); 4.72 (2H, Bgv); 4.64 (2H, 49); 2.10 (ZH, c). eat) Example 1.15 M-I4-Chlorobenzyl)-1-(3-chloro-4-methylphenyl)-6-methyl-2-oxo -1,2-dihydropyridine-3-carboxamide N NMR (SOSIV): δ 9.93 (1H, Bgv); 8.56 (IN, 4); 7.44 (1H, 4); 7.28 (4H , 8); 7.24 (1H, a); 7.03 (1H, ad); 60,643 (1H, 49); 4.56 (2H, 49); 2.46 (ZH, c); 2, 12 (ZN, c).

Example 1,16 1-(3-Chloro-4-methylphenyl)-M-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide "YAN NMR (SOSIV): 5 9 .80 (1H, Bgv); 8.54 (IN, 4); 7.40 (IN, a; 7.23 (2H, a); 7.20 (IN, a); 7.00 (1H, ad ); 6.81 (2H, a); 6.39 (1H, a); 4.51 (2H, 49); 3.76 (ZH, 5); 2.43 (ZH, 5); 2.09 (ZN, c).

Example 1.17 M-(4-Chlorobenzyl)-1-(2,3-dimethylphenyl)-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide b5 TN NMR (SOCIv): 85 10.04 (1H, Bbg8); 8.58 (IN, a); 7.31-7.24 (BN, t); 6.96-6.94 (IN, t); 6.45 (1H, 4);

4.63-4.50 (2H, t); 2.38 (ZN, 5); 2.03 (ZN, 5); 1.95 (ZN, c).

Example 1.18 M-(4-Chlorobenzyl)-1-(3-chloro-4-fluorophenyl)-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide. "YAN YMR (SOSIv): 5 9.83 (IN, biv); 8.57 (IN, a); 7.38-7.32 (2H, t); 7.27 (4H, 8); 7, 15-7.11 (IN, t); 6.45 (1H, a); 4.57 (2H, a); 2.12 (ZH, c).

HIAT-MS ti/: 405,1,407 (MN.

Example 1,19 1-(3-Chloro-4-fluorophenyl)-M-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

TN NMR (SOSIs): 5 9.72 (1H, biv); 8.58 (1H, a); 7.39-7.31 (2H, t); 7.26 (2H, a); 7.14-7.10 (1H, t); 6.84 (2H, 4); 6.43 (1H, a); 4.54 /2H, a); 3.79 (ZN, 5); 2.11 (ZN, c).

Example 1.20 M-(4-Chlorobenzyl)-1-(3-ethylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

TN NMR (SOSI): 5 10.03 (1H, Bgv); 8.56 (1H, 4); 7.49 (1H, 0; 7.36 (1H, a); 7.28 (4H, 5); 7.02 (2H, to); 6.42 (1H, a); 4.61450 (2H, t); 2.75 (2H, a); 2.09 (ZH, 5); 1.29 (ZH, U.

Example 1,21 1-I3-Bromophenyl)-M-(4-chlorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

TN NMR (SOSIv): 5 9.86 (IN, bgv); 8.55 (1H, a); 7.67-7.64 (1H, t); 7.45 (1H, 9; 7.39 (1H, 0; 7.25 (4H, then 8); 7.17-7.15 (IN, t); 6.42 (1H, a); 4, 54 (2H, 4); 2.09 (ZH, c).

HIAT-MS ti/: 431.1, 433 MN).

Example 1.22 1-(3-Bromophenyl)-M-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide" NMR NMR (SOSIV): 5 9.74 (1Н , Bgv); 8.55 (IN, a); 7.65-7.63 (IN, t); 7.44 (IN, 0; 7.38 (IN, 0; 7.23 (2Н, а) 7.16-7.14 (1H, t); 6.81 (2H, a); 6.40 (1H, 4); 4.52 (2H, a); 3.76 (ZH, c); 2, 07 (ZN, 5).

Example 1.23

IM-(2,3-dihydro-1-benzofuran-5-ylmethyl)-6-methyl-2-oxo-1-3-"-trifluoromethyl)phenyl)-1,2-dihydropyridin-3-carboxamide "YAN NMR (SOSIv): δ 9.70 (1H, Ogv); 8.59 (IN, a); 7.79 (IN, a); 7.73 (1H, 0; 7.50 (1H, 5); 7.43 (IN, a); cm 25717 (1H, 5); 7.05 (IN, 4); 6.69 (1H, a ); 6.44 (1H. a); 4.56-4.50 (4H, t); 3.16 (2H, 9; 2.06 (ZH, c). (5)

HIAT-MS p/z: 429 (MN.

Example 1,24 b-methyl-2-oxo-M-I(3-(2-oxopyrrolidin-1-yl)propyl|-1-(3-"-trifluoromethyl)phenyl)-1,2-dihydropyridin-3- carboxamide

TN NMR (SOSIv): 5 9.55 (1H, Bgv); 8.55 (1H, a); 7.82 (1H, a); 7.75 (1H, 0; 7.52 (1H, 8); 7.45 (IN, fu; 6.45 (1H, a); 3.44-3.33 (6H, t); 2.38 (2H, 9; 2.05-1.98 (2H, t); 2.08 (ZH, 5); 1.86-1.79 (2H, t). rch-

HIAT-MS pi/l: 422 (M.Sc

Example 1.25

M-(4-Bromobenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide -

TN NMR (SOSIv): 5 9.84 (1Н, ге); 8.58 (IN, a); 7.81 (IN, 4); 7.73 (1H, 0; 7.51 (1H, 58); 7.43 (1H, d); so 7.A1 (2H, a); 7.20 (2H, a); 6.46 (1H , 4); 4.59449 (2H, t); 2.08 (ZH, 5).

HIAT-MS t/: 465,1,467 MN.

Example 1.26 M-(4-Chlorophenyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 407 (MN.

Example 1,27 6-Methyl-2-oxo-1-3-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide - with HIAT-MS pi/: 297 (M. m Example 2 M-(4 -Methoxybenzyl)-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide and a) 6-Methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carbonitrile

A mixture of cyanoacetanilide (0.80 g, mmol), 4-methoxy-3-buten-2-one (1.10 mmol) and 1,4-diazadicyclopordioctane (0.55 g, mmol) in diethylene glycol monomethyl ether was heated to 1259 for 5 hours. The reaction mixture is partitioned between dichloromethane (100 ml) and 2M hydrochloric acid (100 ml). The organic layer is separated, washed with water, dried, filtered and evaporated. The residue was chromatographed on silica using heptane/ethyl acetate (1:1) as eluent to give the title compound (6bOmg, 63965). where TN NMR (SOSI»v): 5 7.78 (1Н, 4); 7.52 (ZN, t); 7.17 (2H, ad); 6.22 (1H, 4); 2.06 (ZN, 5). -I 20 r) 6-Methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid ah 6-Methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carbonitrile ( 300 mg, 1.4 mmol) is dissolved in 2.5 M sulfuric acid (LOml). The mixture is heated to 100927 for 16 hours. After cooling, the solution is poured into water and made basic with a 5 M sodium hydroxide solution. The aqueous phase is washed with dichloromethane, then acidified to pH 2g- 3 using 2M hydrochloric acid. The acidified aqueous phase was extracted with dichloromethane, dried, filtered and evaporated to give the title compound: (300mg, 92965). in); 8.50 (1H, a); 7.59 /ZN, t); 7.23 (2H, aa); 6.53 (1H, a); 2.13 (ZN, 5).

GI c). M-(4-Methoxybenzyl)-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

The title compound is obtained from b-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid and 4-methoxybenzylamine by a method similar to that described in example 1, step (4). "YAN NMR (SOSIv): 5 9.87 (1H, Bgv); 8.56 (1H, Bga); 7.52 (ZH, t); 7.23 (2H, 4); 7.18 (2H, a); 6.79 (2H, ad); 6.40 (1H, a); 4.51 (2H, a); 3.75 (ZH, 5); 2.04 (ZH, c).

Compounds of examples 2,1-2,174 are obtained by a method similar to that described in example 1 or 2.

Example 2.1 M-(4-Chlorobenzyl)-bmethyl-2-oxo-1-phenyl-1,2-di|dropyridin.-3-carboxamide 65 TN NMR (SOCIv): 5 9.96 (1H, 5) ; 8.54 (IN, 4); 7.54 (ZN, t); 7.23 (4H, 8); 7.18 (2H, 4); 641 (1H, o); 4.54 (2H, a); 2.06 (ZN, 5).

Example 2.2 M-(4-Chlorobenzyl)-1-(3,5-dimethylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide" NMR (SOSIV): 5 10.01 (1H, Bgv); 8.52 (IN, a); 7.23 (4H, 5); 7.11 (1IN, c); 6.78 (2H, c); 6.38 (1H, 4) 4.53 (2H, a), 2.36 (6H, 5), 2.07 (ZH, c).

Example 2,3

M-(4-aminosulfonyl)benzyl/-13,5-dimethylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide NMR (SOSIV): 5 10.14 (1H, biv ); 8.51 (1H, 4); 7.82 (2H, a); 7.45 (2H, 4); 7.12 (1H, c); 6.79 (2H, c); 6.41 (1H, a); 4.72 (2H, 5); 4.62 (2H, 4); 2.36 (BN, 5); 2.09 (ZH, c).

Example 2,4 1-(3,5-Dimethylphenyl)-M-(4-methoxybenzyl)-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide.

TN NMR (SOSIv): 5 9.90 (IN, Bge); 8.54 (IN, 4); 7.24 (2H, 8); 7.11 (IN, 5); 6.81 (2H, 4); 6.79 (2H, with); 6.38 (1H, a); 4.52 (2H, a); 3.77 (ZN, 5); 2.37 (BN. 8); 2.07 (ZN, c).

Example 2.5 M-Benzyl-1-(3,5-dimethylphenyl)-6-metal-2-oxo-1,2-dihydropyridine-3-carboxamide

TN NMR (SOCI3): 59.98 (1H, Bgv); 8.57 (1H, a); 7.36-7.19 (BN, t); 7.13 (IN, c); 6.82 (2H, c); 6.41 (1H, a); 4.61 (2H, 4); 2.39 (6H, 5); 2.10 (ZN, c). t Example 2.6 M-(4-Chlorobenzyl)-6-methyl-1-(33-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide "' NMR (CO500): 5 8.46 ( IN, a); 7.47 (IN, 0; 7.36 (IN, 4); 7.30 (4H, 8); 7.10 (IN, 8); 7.06 (1H, a); 6 .60 (1H, a); 4.56 (2H, 5); 2.42 (ZH, 5); 2.09 (ZH, c).

HIAT-MS ti/2:367 (МН.

Example 2.7 M-(4-Methoxybenzyl)-6-methyl-1-3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

TN NMR (С0О500): δ 8.45 (IN, a); 7.44 (IN, 0; 7.33 (IN, 4); 7.22 (2H, a); 7.07 (IN, 8); 7.03 (1H, 4); 6.54 (2H, 4) 6.58 (1H, a), 4.49 (2H, c), 3.74 (ZH, 8), 2.41 (ZH, 58), 2.07 (ZH, c).

HIAT-MS pi/: 363 (MN.

Example 2.8 M-(3-Chlorobenzyl)-6-methyl-1-(3-methylphenyl)-2-oxo-1,2-dipdropyridin-3-carboxamide c

IN NMR (СО0500): δ 8.46 (1Н, а); 7.46 (1H, 0; 7.35 (1H, 4); 7.32-7.21 (4H, t); 7.10 (IN, c): 7.06 (1H, o a); 6 .60 (1H, 4); 4.56 (2H, 5); 2.42 (ZH, 5); 2.09 (ZH, c).

Example 2.9 M-(4-Chlorobenzyl)-3-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide "YAN NMR (DMSO-α): δ 9.86 (IN, 9; 8.35 (IN, 4); 7.59-7.58 (ZH, t); 7.39-7.29 (B5H, t); 6.60 (1H, a); 4.46 - (2H, 9); 2.04 (ZH, 5).

AND

HIAT-MS t/ 387,1,389 MN. in.

Example 2.10 M-(33-Chlorobenzyl)-1-(3-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide with "YAN NMR (DMSO-αiv): 5 9, 88 (IN, 9; 8.36 (IN, 4); 7.59-7.58 (ZH, t); 7.39-7.32 (4H, t); 7.25 (IN, a); 6.60 (IN, 49); 4.48 (2H, a); 2.04 (ZH, 5). --

HIAT-MS ti/: 387,1,389 (MN. (ee)

Example 2.11 1-(3-Chlorophenyl)-M-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide "H NMR (DMSO-iv): 5 9.73 (IN, 0; 8.34 (1H, 4); 7.56 (2H, a); 7.34-7.31 (1IN, t); 7.19 (2H, a); 6.85 (2H , a); 6.58 (1H, 4); 6.60 (1H, a); 4.38 (2H, a); 3.69 (ZH, 5); 2.01 (ZH, c), "

HIAT-MS pi/: 383 (MN.

Example 2.712 Methyl C c 4-4 1-(3-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-ylcarbonyl))amino)methyl|benzoate "from" NMR NMR (DMSO-iv) : 5 9.92 (IN, 0; 8.36 (IN, 4); 7.91 (2H, a); 7.60-7.58 (ZH, t); 7.41 (2H, a); 7.38-7.35 (IN, t); 6.60 (1H, a); 4.56 (2H, a); 3.83 (ZH, 5); 2.04 (ZH, c). 415 HIAT-MS pi/l: 411 (Mn. o Example 2,13 4-((Х(1-(2-Chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-ylcarbonylamino)methyl| b Senzoic acid - TN NMR (DMSO-v): 5 12.82 (IN, Bbgv); 9.91 (IN, 0; 8.36 (IN, a); 7.88 (2H, a); 7.59 -7.58 (ZH, t); 7.39 ko (2H, 4); 7.38-7.35 (1H, t); 6.60 (1H, a); 4.55 (2H, 4) 2.04 (ZN, 5).

HIAT-MS pi/: 397 (MH. Example 2.14 1-(3-Cyanophenyl)-M-(cyclohexylmethyl)-6b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide -from HIAT- MS ti/: 350 (MN.

Example 2.15 1-(3-Cyanophenyl)-M-(2-furylmethyl)-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/: 334 (MW. 99 Example 2,16 1-(3-Cyanophenyl)-6-methyl-2-oxo-N-(pyridin-3-ylmethyl)-1,2-dihydropyridin-3-carboxamide

F! HIAT-MS pi/: 345 (MN.

Example 2.17 M-Benzyl-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide. from HIAT-MS p/z: 344 (MN).

Example 2,18 1-(3-Cyanophenyl)-M-2,3-dihydro-1H-inden-1-yl-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 60 HIAT-MS pi /: 370 (MN.

Example 2,19 1-(3-Cyanophenyl)-M-(2-methoxybenzyl)-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS ti/g: 374 MN.

Example 2.20 1-(3-Cyanophenyl)-6-methyl-2-oxo-M-(3,4,5-trimethoxybenzyl)-1,2-dihydropyridine-3-carboxamide v5 HIAT-MS pi/l: 434 (MN.

Example 2.21 1-(3-Cyanophenyl)-M-(2,5-dimethoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS p/z: 404 (MN.

Example 2.22 1-(3-Cyanophenyl)-M-(3,4-dimethoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS t/2:404 (MN.

Example 2.23 1-(3-Cyanophenyl)-M-(1-ethylpyrrolidin-2-yl)umethyl|-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS ti/: 365 (MN.

Example 2.24 M-(4-Chlorobenzyl)-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/: 378 (MN.

Example 2.25 1-(3-Cyanophenyl)-M-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydrotyridine-3-carboxamide

HIAT-MS pi/: 374 (MN.

Example 2.26 M-(3-Chlorobenzyl)-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS p/z: 378 (MN.

Example 2.27 1-(3-Cyanophenyl)-6-methyl-2-oxo-N-(thien-2-ylmethyl)-1,2-dihydropyridin-3-carboxamide HIAT-MS pi/l: 350 (MH .

Example 2.28 1-(3-Cyanophenyl)-M-(cyclopropylmethyl)-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 308 (Mn.

Example 2.29 1-(3-Cyanophenyl)-M-(3-methoxybenzyl)-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/: 374 (MN.

Example 2.30 1-(3-Cyanophenyl)-6-methyl-2-oxo-N-(pyridin-4-ylmethyl)-1,2-dihydropyridine-3-carboxamide

HIAT-MS ti/g: 345 IMN.

Example 2.31 1-(3-Cyanophenyl)-M-(2-(3,4-dimethoxyphenyl)ethyl|-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide c

HIAT-MS p/z: 417 (M.O. o

Example 2.32 1-33-Cyanophenyl)-6-methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl|-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/: 365 (MN.

Example 2.33 M-(2-(3-Chlorophenyl)ethyl I|-1-(2-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide --

HIAT-MS ti/: 392 (Mn. ich-

Example 2.34 1-I3-Cyanophenyl)-6-methyl-2-oxo-M-|(2-pyridin-2-ylethyl)-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 359 (Mn. p

Example 2.35 M-(2-(4-Chlorophenyl)ethyl|-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide --

HIAT-MS p/z: 392 (Mn. co

Example 2.36 1-(3-Cyanophenyl)-M-(2-(2-methoxyphenyl)ethyl/|-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/: 388 (MN.

Example 2.37 M-(2-(2-Chlorophenyl)ethyl/I|-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/: 392 (MN. "

Example 2.38 1-(3-Cyanophenyl)-M-(2-(3-methoxyphenyl)ethyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide - with HIAT-MS ti/: 388. MS pi/: 376 (MN.

Example 2.40 1-(3-Cyanophenyl)-M-(2-(2,4-dichlorophenyl)ethyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/: 426 (Mn. so Example 2.41 1-(3-Cyanophenyl)-M-(2-(3-fluorophenyl)ethyl)/|-6-methyl-2-oxo-1,2-dihydropyridine -3-carboxamide - HIAT-MS pti/g: 376 (MN.

Example 2.42 1-(3-Cyanophenyl)-M-(2-(2-fluorophenyl)ethyl)|-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide t HIAT-MS pi/: 376 (МН. -| 50 Example 2.43 also 1-(3-Cyanophenyl)-M-(2-cispoheco-1-en-1-ylethyl)-6-methyl-2-oxo-1,2-dihydropyridine- 3-carboxamide

HIAT-MS pi/h: 362 (MN.

Example 2.44 M-I(2-(4-Bromophenyl)ethyl)|-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 5B HIAT-MS pi/ l: 438 (MN.

Example 2.45 M-(3-Bromobenzyl)-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide o HIAT-MS pi/l: 424 (Mn. ko Example 2.46 M-I(4-Bromobenzyl|i-(3-cyanophenyl)-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS p/z: 424 (M.N. 60 Example 2.47 "I-Bromobenzyl"NH-cyanoscrenyl"methyl-g-oxo-1.g-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 424 (MN.

Example 2.48 1-(3-Cyanophenyl)-M-(3,4-dihydro-2H-pyran-2-ylmethyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS ti/: 350 (Mn. bo Example 2.49 1-3-Cyanophenyl)-6-methyl-N-(4-methylbenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS ti/g: 358 (MN.

Example 2.50 1-3-Cyanophenyl)-6-methyl-N-(1-naphthylmethyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/: 394 (MN.

Example 2.51 1-(3-Cyanophenyl)-M-(2-ethoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/: 388 (MN.

Example 2.52 1-3-Cyanophenyl)-b-methyl-"4-(methylsulfonyl)benzyl/|-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS p/z: 422 (MN.

Example 2.53 1-3-Cyanophenyl)-6-methyl-N-(3-methylbenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS those": 358 (MN.

Example 2.54 1-(3-Cyanophenyl)-M-(4-fluorobenzyl)-6b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/h: 362 (MN.

Example 2.55

IM-(1,3-Benzodioxol-5-ylmethyl)-1-(2-cyanophenyl)-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, HIAT-MS pi/: 388 (Mn.

Example 2.56 1-(3-Cyanophenyl)-M-(2,4-dichlorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 412 (Mn.

Example 2.57 1-(3-Cyanophenyl)-b-methyl-N-(2-methylbenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide.

HIAT-MS pi/: 358 (MN.

Example 2.58 1-(3-Cyanophenyl)-M-(3,4-difluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/: 380 (MN.

Example 2.59 1-(3-Cyanophenyl)-M-(3,4-dichlorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS p/z: 412 (Mn. p

Example 2.60 1-(3-Cyanophenyl)-β6-methyl-N-(5-methyl-2-furyl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide o

HIAT-MS pi/: 348 (MN.

Example 2.61 1-(3-Cyanophenyl)-6-methyl-2-oxo-M-1,2,3,4-tetrahydronaphthalen-1-yl-1,2-dihydropyridine-3-carboxamide

HIAT-MS pti/: 384 (MN. --

Example 2.62 1-(3-Cyanophenyl)-M-(2,3-dimethoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide rch-

HIAT-MS pi/l: 404 (Mn.

Example 2.63 1-(3-Cyanophenyl)-M-(3,5-dimethoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide cm

HIAT-MS pi/l: 404 (M. --

Example 2.64 1-(3-Cyanophenyl)-M-(1-(4-fluorophenyl)ethyl)|-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide so

HIAT-MS pti/h: 376 (MN.

Example 2.65 M-(1--4-Chlorophenyl)ethyl/I|-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/: 392 (MN. "

Example 2.66 1-I(3-Cyanophenyl)-M-(2,5-difluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/: 380 (Mn. - s Example 2.67 1 a -(3-Dianophenyl)-M-(2,3-dihydro-1-benzofuran-5-ylmethyl)-6-methyl-2-oxo -1,2-dihydropyridine-3-carboxamide HIAT-MS pi/: 386 (Mn.

Example 2.68 Methyl

A-ICI1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbonyl)amino)methyl|benzoate so HIAT-MS p/z: 402 (M.N. - Example 2.69 1-(3-Cyanophenyl)-6-methyl-2-oxo-M-(4-phenoxybenzyl)-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 436 (Mn. de Example 2,70 -I 20 1-(3-Cyanophenyl)-M-K15)-2,3-dihydro-1H-inden-1-yl)-6-methyl -2-oxo-1,2-dihydropyridine-3-carboxamide chk HIAT-MS pti/g: 370 (MN.

Example 2.71 1-3-Cyanophenyl)-6-methyl-2-oxo-N-(thien-3-ylmethyl)-1,2-dihydropyridin-3-carboxamide

HIAT-MS pi/l: 350 (Mn.

Example 2.72 1-I3-Cyanophenyl)-6-methyl-M-|(5-methylisoxazol-3-yl)umethyl|-2-oxo-1,2-dihydropyridine-3-carboxamide (F, HIAT-MS pti /g: 349 (MH. ka Example 2.73 1-(3-Cyanophenyl)-M-(2,5-dimethyl-3-furyl)ethyl/|-6-methyl-2-oxo-1,2-dihydropyridine -3-carboxamide in HIAT-MS p/: 362 (Mn.

Example 2.74 1-(3-Cyanophenyl)-M-(3-furylmethyl)-6-methyl-2-ox-1,2-dihydropyridine-3-carboxamide

HIAT-MS p/z: 334 (MN.

Example 2.75 1-(3-Cyanophenyl)-b-methyl-2-oxo-M-(4-(1H-pyrazol-1-yl)benzyl/|-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 410 (M.N. 65 Example 2.76 1-(3-Cyanophenyl)-b6-methyl-2-oxo-N-(4-thien-2-ylbenzyl)-1,2-dihydropyridin- 3-carboxamide

HIAT-MS pi/: 426 (MN.

Example 2.77

M-(4--Aminosulfonyl)benzyl|-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 423 (Mn.

Example 2.78

IM-(2-(1,3-Benzodioxol-5-yl)ethyl)-1-(3-cyanophenyl)-b-methyl-2-oxo-1,2-dihydropyridin-3-carboxamide

HIAT-MS p/z: 402 (MN.

Example 2.79 1-(3-Cyanophenyl)-6-methyl-2-oxo-N-(2-thien-2-ylethyl)-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 364 (Mn.

Example 2.80 1-(3-Dianophenyl)-M-(2-(2,4-dimethylphenyl)ethyl)|-b-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide.

HIAT-MS ti/: 386 (MN.

Example 2.81 1-(3-Cyanophenyl)-6-methyl-H-(2-(4-methylphenylethyl-2-oxo-1,2-dihydropyridine-3-carboxamide)

HIAT-MS pi/: 372 (Mn. 19 Example 2.82 IM-(2-(4-(Aminosulfonyl)phenyl|ethyl)-1-(3-cyanophenyl)-6-methyl-2-oxo-1,2 -dihydrop iridine-3-carboxamide

HIAT-MS p/z: 437 (MN.

Example 2.83 1-(3-Cyanophenyl)-β6-methyl-2-oxo-N-((15)-1-phenylethyl)-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/: 358 (MN.

Example 2.84

M-(Cyclohexylmethyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

HIAT-MS ti/: 393 (MN.

Example 2.85 sc

M-(2-Furylmethyl)-6-methyl-2-oxo-1-3-[(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/: 377 (Mn. and)

Example 2.86 6-Methyl-2-oxo-N-(pyridin-3-ylmethyl)-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide

HIAT-MS ti/: 388 (MN. "-

Example 2.87 -2,3-dihydro-1H-inden-1-yl-6-methyl-2-oxo-1-3-"-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 413 (Mn. p

Example 2.88 "-

M-(2-Methoxybenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide 3o HIAT-MS pi/l: 417 (Mn. so

Example 2.89 6-Methyl-2-oxo-N-(tetrahydrofuran-2-ylmethyl)-1-3-(trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide

HIAT-MS pti/: 381 (MN. "

Example 2.90 70 6-Methyl-2-oxo-1-3-trifluoromethyl)phenyl|-M-(3,4,5-trimethoxybenzyl)-1,2-dihydropyridine-3-carboxamide 8 s HIAT-MS pi /l: 477 (Mn. :z» Example 2.91

M-(3-Fluorobenzyl)-6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide 415 HIAT-MS pi/l: 405 (M.O. Example 2 ,92

M-(2,5-Dimethoxybenzyl|)|-6b-methyl-2-oxo-1-I(3--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide - HIAT-MS pi/l: 447 (MN. ko Example 2.93

I-I 1-Ethylpyrrolidin-2-yl)umethyl|-b-methyl-2-oxo-1-3-"trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide and HIAT-MS pi/l: 408 (MN. - Example 2-94

M-(2-Chlorobenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

HIAT-MS p/z: 421 (MN.

Example 2.95 M-(4-Chlorobenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide o HIAT-MS pi/l: 421 ( MN.

Example 2.96 M-(3-Chlorobenzyl)-6-methyl-2-oxo-1-3-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide o HIAT-MS pi/l: 421 ( MN.

Example 2.97 60 v-Methyl-2-oxo-N-(thien-2-ylmethyl)-1-(3Z--trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/: 393 (MN.

Example 2.98

M-(Cyclopropylmethyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

HIAT-MS ti/g: 351 (Mn. for Example 2.99

M-B-Methoxybenzyl)-6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 417 (MN.

Example 2,100 8-Methyl-2-oxo-N-(pyridin-4-ylmethyl)-1-I-(3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

HIAT-MS ti/: 388 (MN.

Example 2.101

IM-(2-(3,4-dimethoxyphenyl)ethyl/|-6-methyl-2-oxo-1-3--trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 461 (MN.

Example 2.102

IM-(2--4-Methoxyphenyl)ethyl/|-6-methyl-2-oxo-1-3--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide

HIAT-MS p/z: 431 (MN.

Example 2,103 6-Methyl-2-oxo-N-(2-phenylethyl)-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 401 (MN.

Example 2.104 6-Methyl-M-(2-(1-methylpyrrolidin-2-yl)ethyl|-2-oxo-1-3-3-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

HIAT-MS p/z: 408 (MN.

Example 2.105

IM-(2-(3-chlorophenyl)ethyl|-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide 2 HIAT-MS pi/l: 435 ( MN.

Example 2,106 6-Methyl-2-oxo-N-(2-pyridin-2-ylethyl)-1-(3-"-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 402 (Mn. p

Example 2.107

IM-(2--2-Methoxyphenyl)ethyl/|-6-methyl-2-oxo-1-3--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide i)

HIAT-MS pi/l: 431 (MN.

Example 2.108

IM-(2-(2-chlorophenyl)ethyl|-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 435 (Mn.

Example 2.109 -

IM-(2-(3-Methoxyphenyl)ethyl/|-6-methyl-2-oxo-1-3--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide Ge

HIAT-MS p/z: 431 (Mn. "-

Example 2.110

M-(2-(4-fluorophenyl)ethyl)|-b-methyl-2-oxo-1-3--trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide c

HIAT-MS pi/l: 419 (MN.

Example 2.111

M-(2-(2,4-Dichlorophenyl)ethyl)|-b-methyl-2-oxo-1-3--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide «

HIAT-MS pi/l: 469 (Mn. Z

Example 2.112 s IM-(2-(3-fluorophenyl)ethyl/|-6-methyl-2-oxo-1-(3--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide :z» HIAT -MS t/2:419 (MN.

Example 2.113

IM-(2-(2-fluorophenyl)ethyl/|-6-methyl-2-oxo-1-I(3--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide o 75 HIAT-MS pi /l: 418 (MN.

Example 2,114 - M-(2-Cyclohex-1-en-1-ylethyl)-6-methyl-2-oxo-1-3-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

GI HIAT-MS p/z: 405 (MN.

Example 2-115

SH-IM-(2-(4-bromophenyl)ethyl)|-b-methyl-2-oxo-1-III-"-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide - HIAT-MS pi /: 388 (MN.

Example 2,116 6-Methyl-2-oxo-N-(15)-1-phenylethyl (3-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 401 (MN.

Example 2.117 o M-(3-Bromobenzyl)-6b-methyl-2-oxo-1-3-"trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide by HIAT-MS pi/l: 467 (MH.

Example 2.118 60 M-A(4-Bromobutyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 467 (MN.

Example 2.119

M-(2-Bromobenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

HIAT-MS p/z: 467 (Mn. bo Example 2,120

IM-(3,4-dihydro-2H-pyran-2-ylmethyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridin-3-carboxamide

HIAT-MS pi/: 393 (MN.

Example 2,121 8-Methyl-M-(4-methylbenzyl)-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

HIAT-MS p/z: 401 (MN.

Example 2.122 6-Methyl-N-(1-naphthylmethyl)-2-oxo-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 437 (MN.

Example 2.123

M-(2-Ethoxybenzyl)-6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

HIAT-MS p/z: 431 (MN.

Example 2.124 6-Methyl-M-(3-methylbenzyl)-2-oxo-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide,

HIAT-MS those": 401 (MN.

Example 2.125

M-(4-Fluorobenzyl)-6-methyl-2-oxo-1-3-"-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 405 (Mn.

Example 2.126

IM-(1,3-Benzodioxol-5-ylmethyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridin-3-carboxamide

HIAT-MS p/z: 431 (MN.

Example 2.127

IM-(2,4-Dichlorobenzyl)-6-methyl-2-oxo-1-IZ-"(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/: 456 (MN.

Example 2,128 (8) 6-Methyl-M-(2-methylbenzyl)-2-oxo-1-3-trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide

HIAT-MS p/z: 401 (MN.

Example 2.129 "--

M-III,.4-Difluorobenzyl)-6-methyl-2-oxo-1-III--trifluoromethyl)phenyl!/|-1,2-dihydropyridine-3-carboxamide m

HIAT-MS pi/l: 423 (Mn.

Example 2.130 Ge

M-(2-Fluorobenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide -

HIAT-MS pi/l: 405 (Mn.

Example 2.131 (ge)

M-(2-Chloro-4-fluorobenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

HIAT-MS p/z: 439 (MN.

Example 2.132 "

IM-(3,4-Dichlorobenzyl)-6-methyl-2-oxo-1-IZ-(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide 70 HIAT-MS t/g: 456 (МН. 8 s Example 2.133: 6-Methyl-Mm-|((5-methyl-2-furyl)methyl)-2-oxo-1-1(3-trifluoromethyl)phenyl)|-1,2-dihydropyridine -3-carboxamide

HIAT-MS p/z: 391 (MN.

Example 2,134 bo 15 6-Methyl-2-oxo-M-1,2,3,4-tetrahydronaphthalen-1-yl-1-3-"trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 427 (Mn. -th Example 2.135 with M-(2,3-Dimethoxybenzyl)-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl|-1,2-dihydropyridine -3-carboxamide

HIAT-MS pi/l: 447 (Mn. - Example 2.136 as IM-(1--4-Chlorophenyl)ethyl)-6-methyl-2-oxo-1-3--trifluoromethyl)phenyl/|-1,2 -dihydropyridine-3-carboxamide

HIAT-MS p/z: 434 (MN.

Example 2.137

M-(2,5-Difluorobenzyl)-6-methyl-2-oxo-1-(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 423 (Mn.

IF) Example 2.138 Methyl ime) 4-((6β-methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridin-3-ylcarbonyl)amino|methyl)benzoate

HIAT-MS p/z: 445 (MN). Example 2.139 6-Methyl-2-oxo-N-(4-phenoxybenzyl)-1-3-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 479 (MN.

Example 2-140 -K2,2-Dimethyl-1,3-dioxolan-4-yl)umethyl/|-6-methyl-2-oxo-1-3--trifluoromethyl)phenyl/|-1,2-dihydropyridine- 3-carb oxamide

HIAT-MS p/z: 411 (MN.

Example 2,141 6-Methyl-Mm-|((5-methylisoxazol-3-yl)methyl|-2-oxo-1-I(13--trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/: 392 (MN.

Example 2.142

M-K2,5-Dimethyl-3-furyl)methyl|-b-methyl-2-oxo-1-3--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 405 (Mn.

Example 2.143 70... mch-(3-Furylmethyl)-b-methyl-2-oxo-1-3-trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/: 377 (MN.

Example 2.144 6-Methyl-2-oxo-M-I4-(1H-pyrazol-1-yl)benzylI-1-(3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 453 (MN.

Example 2.145 6-Methyl-2-oxo-M-|4-thien-2-ylbenzyl)-1-3--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

HIAT-MS p/z: 469 (MN.

Example 2.146

IM-(2-(1,3-Benzodioxol-5-yl)ethyl|-6-methyl-2-oxo-1-3-"(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide 2 HIAT- MS pi/l: 445 (MN.

Example 2.147 6-Methyl-2-oxo-N-(2-thien-2-ylethyl)-1-3-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 407 (Mn. p

Example 2.148

IM-(2-(4-tert-butylphenyl)ethyl/|-6-methyl-2-oxo-1-3--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide i)

HIAT-MS pi/ 457 (MN.

Example 2.149 6-Methyl-N-(2-(4-methylphenyl)ethyl)-2-oxo-1-3-"-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide --

HIAT-MS pi/l: 415 (Mn.

Example 2.150 -

M-(2-(I4--Aminosulfonyl)phenyl|ethyl)-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxam Ge id -

HIAT-MS pi/l: 480 (Mn.

Example 2.151 (ge) 6-Methyl-2-oxo-N-((1K)-1-phenylethyl|-1-3-3-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

HIAT-MS p/z: 401 (MN.

Example 2.152 "

34-(2-Methoxyphenyl)piperazin-1-yl)carbonyl)-6-methyl-1-3-trifluoromethyl)phenyl|pyridin-2-yl)-one 70 HIAT-MS ti/»: 472 (Mn. 8 c Example 2,153: z»M-K4-Cyanocyclohexyl)methyl|-b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

HIAT-MS p/z: 418 (MN.

Example 2,154 bo 15 3-C4-(4-Difluorophenyl)piperazin-1-ylylcarbonyl)-6-methyl-1-(3-"-trifluoromethyl)phenyl|pyridin-2(1H)-one

HIAT-MS pi/l: 460 (Mn. Example 2.155 with IM-(2-(2-Fluoro-1,1"-diphenyl-4-yl)ethyl)-6-methyl-2-oxo-1- IZ-""trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxa in Mid sh- HIAT-MS ti/: 495 MN". shk Example 2,156 -(2-Hydroxy-1-phenylethyl)-6-methyl- 2-oxo-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

HIAT-MS p/z: 417 (MN.

Example 2.157 6-Methyl-2-oxo-M-((2K)-2-phenylcyclopropyl)-1-3-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide o HIAT-MS pi/l: 413 (plural name) Example 2.158

IM-(/1-«-4-Chlorobenzyl)piperidin-4-yl|-6-methyl-2-oxo-1-3--trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide 60 HIAT- MS pi/l: 504 (M.N. 73 Example 2.159 6-Methyl-IM-(2-morpholin-4-ylethyl)-2-oxo-1 -|3- (trifluoromethyl)phenyl|-1,2-dihydropyridine-3 -carboxamide

HIAT-MSt/2:410 МН.

Example 2.160 bo M-(2-(4-Chlorophenyl)ethyl)-6-methyl-2-oxo-1-3-3-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

HIAT-MS pti/z: 435 (MN.

Example 2.161

M-(2-Hydroxy-2-phenylethyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 417 (MN.

Example 2.162 M-Cyclopentyl-b-methyl-2-oxo-1-3-trifluoromethyl)-phenyl|-1,2-dihydropyridine-3-carboxamide

HIAT-MS ti/: 365 (MN.

Example 2.163

1N-(2-(1-Imidazol-4-yl)ethyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 391 (MN.

Example 2.164

1M-(3,5-Dimethoxybenzyl)-6-methyl-2-oxo-1-3-[(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

HIAT-MS p/z: 447 (MN).

Example 2.165 19 M-(4-Hydroxycyclohexyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/: 395 (MN.

Example 2.166 6-Methyl-2-oxo-N-(2-pyridin-2-ylethyl)-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 402 (MN.

Example 2,167 6-Methyl-2-oxo-M-1IN-1,2,4-triazol-3-yl-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

HIAT-MS pti/: 364 (MN.

Example 2.168 ch

M-P1-(hydroxymethyl)-2-methylpropyl)|-b-methyl-2-oxo-13--trifluoromethyl)phenyl|-1,2-dihydropyrudin-3-carboxami o d

HIAT-MS pi/: 383 (MN.

Example 2.169 3-13-(3,4-Dichlorophenoxy)pyrrolidin-1-ylcarbonyl)-6-methyl-1-3-trifluoromethyl)phenyl|pyridin-2(1H)-one

HIAT-MS pi/l: 512 (Mn.

Example 2,170 - 6-Metal-2-oxo-N-(pyridin-3-ylmethyl)-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide Ge

HIAT-MS ti/: 388 (MN. "-

Example 2.171

M-(2-Methoxyethyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide c

HIAT-MS pi/l: 355 (Mn.

Example 2.172

M-(2-hydroxypropyl)-6-methyl-2-oxo-1-3-"-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 355 (Mn. Z

Example 27173 Ethyl c 4-I(6-methyl-2-oxo-1-3--trifluoromethylphenyl|-1,2-dihydropyridin-3-yl)/carbonyl)amino|Ipiperidine-1-carboxylate: with» HIAT-MS t/y: 452 IIMN.

Example 2.174

1-3-(1H-imidazol-1-yl)propyl|-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide o 75 HIAT-MS pi /l: 405 (MN.

Example C M-(4-chlorobenzyl)-1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide - a) Diethyl 1|3-ethoxyprop-2-enylidene|malonate from Diethyl malonate ( 16b0Og, 1.0mol) is added dropwise while stirring and refluxing to a solution of 1,1,3,3-tetraethoxypropane (ZZOg, 1.5mol), acetic anhydride (30bg, 2.00mol) and - zinc chloride (10g, 0.07Zmol) for 30 minutes. The mixture is heated for 1 hour, and then the Dean-Stark apparatus is connected and the low-boiling components are driven off. Additionally, add acetic anhydride (15 Oml) and continue boiling under reflux for 1 hour. The reaction mixture was distilled to give the title compound as a yellow oil (182g, 75905), b.p. 139-1432С at O.8mm Na. "YAN NMR (SOSI): 5 7.38 (1H, a, 9-12.1Hz); 7.04 (1H, a, 9-12.2Hz); 6.19 (IN, 6 9-12.1Hz ); 4.27 (2H, a); 4.21 (2H, a); 3.96 (2H, a); 1.36-1.24 (9ZH, t). o B) Diethyl 43-(Z -methmphenyl)amino|prop-2-enylidene)malonate co Diethyl (|3-ethoxyprop-2-enylidene|malonate (9.7g, 400mmol) and m-toluidine (4.3g, 40mmol) were dissolved in ethanol (1500ml) and stirred at room temperature for 3 days. Solvents evaporated. 60 Chromatography on a silica column using heptane/ethyl acetate (4:1) as eluent gave the title compound as an oil which solidified over 2 days (10g, 83905).

TN NMR (SOSIv): 5 7.65 (1H, a, 9-12.4Hz); 7.39 (2H, ha, 9-7.7Hz); 7.19 (IN, 6 9-7.7 Hz); 6.85 (1H, a, 9-7.7Hz); 6.75 (1H, 8); 6.73 (1H, a, 9-6.5Hz); 6.46 (IN, t, 9-12.4, 6.5Hz); 4.32 (2H, a); 425 (2H, a); 2.35 (ZN, 5); 1.36 (ZN, O 1.33 (ZN, 0. bo HIAT-MS p/z: 304 (Mn. s) 1-(3-Methylphenyl)-2-oxo-1,2-dihydropyridine-3-carbon acid

Diethyl 43-(3-methylphenyl)amino|prop-2-enylidenemalonate (10g, 33mmol) was mixed with 2M sodium hydroxide solution (100ml) and stirred at room temperature for 30 minutes. The reaction mixture is extracted with ethyl acetate and the aqueous phase is acidified with hydrochloric acid to pH 3-4. The orange precipitate was filtered off, washed with water and dried to give the title compound (7.3g, 9790).

TN NMR (SOSB): δ 14.08 (1Н, 5); 8.64 (1H, ad, 1-12,2,2Hz); 7.72 (1H, aa, 1-6,1,2,2Hz); 7.47 (IN, 9-7.7 Hz); 7.37 (1H, a, 9-7.7Hz); 7.23 (1H, 5); 7.21 (1H, ha); 6.67 (1H, 6 9-7,2,6,7 Hz); 2.47 (ZN 5).

HIAT-MS p/z: 230 (МН. а). M-(4-Chlorobenzyl)-1-(3-methylphenyl)-2-OxO-1,2-dihydropyridine-3-carboxamide

In a mixture of 1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (115 mg, 0.5 mmol), GATU (209 mg,

0.5bMmol), GOAT (75mg, 0.55mmol) and DIPE (275µl, 1.bmmol) in dichloromethane (2.5ml) add 4-chlorobenzylamine (71mg, 0.bmmol) in dichloromethane (ml). The reaction mixture is stirred for 1 hour at room temperature. Dichloromethane is also added and the crude product is washed twice with aqueous sodium hydrogen carbonate, 0.5M aqueous citric acid and water. The solvent was removed in vacuo and the residue 75 was purified by silica column chromatography using dichloromethane/ethyl acetate (4:1) as eluent to give the title compound in near quantitative yield.

TN NMR (SOSIL): δ 10.10 (1H, b; 8.68 (1H, ad); 7.58 (1H, ad); 743 (1H, 0; 7.33-7.25 (BN, t ); 7.20-7.14 (2H, t); 6.53 (1H, 9; 4.59 (2H, 49); 2.45 (ZH, 5).

HIAT-MS pi/l: 353 (M.N. 20 Example 4 M-(4-Chlorobenzyl)-6'-methyl-2-oxo-2H-1,2-dipyridine-3-caryoxamide a) Diethyl (3-(b -methylpyridin-2-yl)amino|prop-2-enylidene)malonate

Diethyl |3-ethoxyprop-2-enylidene|malonate (1.7g, 7mmol) and 2-amino-β6-methylpyridine (1.08g, TOmmol) were heated (without solvent) at 1402 for b hours. The reaction mixture is processed as described in example C (b), obtaining the title compound, ЧІАТ-MS pi/: 305 (МН. о в) 6'-Methyl-2-oxo-2H-1,2'i-dipyridine-3 -carbonic acid

The title compound is obtained from diethyl 13-(b-methylpyridin-2-yl)iamino|prop-2-enylidene)umalonate by the method described in example C (c). "- from TN NMR (SOSIV): 5 14.02 (1H, Bgv); 8.65 (1IN. ad); 8.20 (IN, a; 7.84 (IN, 9; 7.68 (IN, a); 7.33 (1H, a); 6.72 (1H, 9; 2.64 (ZH, 5) -

HIAT-MS pi/l: 231 (Mn. Ge! s). M-(4-Chlorobenzyl)-6'-methyl-2-oxo-2H-1,2'-dipyridine-3-carboxamide

The title compound is obtained from 6'-methyl-2-oxo-2H-1,2'-dipyridine-3-carboxylic acid and 35 4-chlorobenzylamine by the method described in example C (a). at

TN NMR (SOSIv): δ 10.04 (IN, t; 8.68 (1H, ad); 7.95 (1H, as); 7.79 (1H, 9; 7.55 (2H, a); 7.29 (BN, ha); 6.58 (1H, 9; 4.61 (211, a); 2.62 (ZH, 5).

HIAT-MS ti/g: 354 (MN). "

The compounds of examples 4.1-4.18 are obtained by a method similar to that described in example 4. 40 Example 4.1 M-(4-Methoxybenzyl)-1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3 -carboxamide Z c TN o NMR (SOSI): 85 9.98 (IN, B; 8.68 (IN, aFf; 7.56 (IN, a; 7.42 (IN, 0; 7.32-7, 25 (ZH, t); "from 7.18-7.13 (2H, t); 6.84 (2H, 4); 6.52 (1H, 9; 4.56 (2H, a); 3, 79 (ZN, 5); 2.43 (ZN, 5).

HIAT-MS pi/: 349 (MN.

Example 4.2 Methyl 4-((11-(3-methylphenyl)-2-oxo-1,2-dihydropyridin-3-ylcarbonyl)iamino)methyl|benzoate. so TN NMR (SOSIv): 5 10.17 (1H, B; 8.69 (1H, ad); 7.98 (2H. a); 7.59 (1H, aa); 7.46-7.40 (ZH, t); 7.32 (IN, a); 7.20-7.16 (2H, t); 6.54 (1H, 9; 4.69 (2H, 4); 3.92 (ZH , c); 2.45 (ZH, c) - HIAT-MS p/z: 377 (Mn. co Example 4.3 4-(111-(3-Methylphenyl)-2-oxo-1,2-dihydropyridine- 3-ylcarbonyl)amino)methyl benzoic acid

A suspension of methyl o /4-K(1-(3-methylphenyl)-2-oxo-1,2-dihydropyridin-3-ylcarbonylamino)methyl| / of benzoate and (120 mg, O0.32 mmol) and a 2M solution of sodium hydroxide (0.5 ml) in methanol (2 Oml) and water (1 Oml) are stirred at - and 402С overnight. Methanol is evaporated and the aqueous solution is acidified with 1M hydrochloric acid (ml).

The resulting beige precipitate was filtered off, washed twice with water and dried to give the title compound (110mg, 9595). "YAN NMR (DMSO-yv): 5 12.84 (IN, 8); 10.05 (IN, 0; 8.45 (IN, aa); 7.99 (1Н, ach); 7.88 (2Н , 4); 22 7, AZ-7.38 (ZH, t); 7.30 (1H, a); 7.27 (1H, c): 7.24 (1H, 9); 6.61 (1H , 9, 4.57 (2H, a) 2.35 (ZH, c).

HF) HIAT-MS pi/: 363 (MN

TN nMR (SOSIv): 5 9.97 (1H, BO; 8.69 (1H, a); 7.51 (IN, aa); 7.31-7.26 (5H, t); 7.21- 7.15 (2H, U); in 6.56 (1H. 9; 4.59 (2H, bBgv); 2.40 (ZH, c).

HIAT-MS p/z: 371 (MN.

Example 4.5 1-(2-Fluoro-5-methylphenyl)-M-(4-methoxybenzyl)-2-oxy-1,2-dihydropyridine-3-carboxamide

TN NMR (SOSIv): 5 9.86 (1H, BO; 8.69 (IN, aa; 7.49 (IN, aa); 7.30-7.25 (ZN, t); 7.20-7 .14 (2H, t); 6.84 (2H, a); 6.54 (1H, 9; 4.56 (2H, ha); 3.79 (ZH, c); 2.39 (ZH, c ). 65 HIAT-MS pi/: 367 (MN.

Example 4.6 M-I(4-(Dimethylamino)benzyl-1-(2-fluoro-5-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

TN NMR (SOSI): 5 9.78 (1H, p; 8.69 (IN, ad); 7.47 (1H, a); 7.27 (1H, aa); 7.22 (2H, a) ; 7.19-7.13 (2H, t); 6.68 (2H, a); 6.53 (1H, 9; 4.53 (2H, ha); 2.92 (6H, 5); 2 ,39 (ZN, c).

HIAT-MS p/e: 380 MN.

Example 4.7 M-I4-(Aminosulfonate)benzyl|-1-(2-fluoro-5-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

TN NMR (SOSIV): 5 10.11 (IN, B; 8.69 (IN, aa; 7.86 (2H, a); 7.54 (1H, ach); 7.48 (2H, a); 7.30 (IN, ach); 7.20 (2H, a); 7.17 (2H, bha): 6.58 (1H, 9; 4.68 (2H, ha); 2.41 (ZH, in).

HIAT-MS pi/l: 416 (MN.

Example 4.8 M-(4-Chlorobenzyl)-4'-methyl-2-oxo-2H-1,2'-dipyridine-3-carboxamide. then TN NMR (SOSI): 5 10.02 (IN, B; 8.68 (IN, a; 8.48 (IN, a); 7.94 (1H, aa); 7.58 (IN, c) e 7.30-7.28 (AN, t); 7.23 (1H, a); 6.58 (1H, 9; 4.61 (2H, a); 2.48 (ZH, c),

HIAT-MS pi/: 354 (MN.

Example 4.9 M-(4-Chlorobenzyl)-1-(2,5-dimethylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

TN NMR (SOSIv): 5 10.11 (1H, B; 8.69 (1H, aa); 7.47 (1H, aa); 7.29-7-20 (6H, t); 7.02 ( 1H, c); 6.54 (IN, 9; 4.59 (2H, t); 2.38 (ZH, 5); 2.09 (ZH, c).

HIAT-MS pi/: 367 (MN.

Example 4,10 1-(2,5-Dimethylphenyl)-M-(4-methoxybenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

TN NMR (SOSIv): 5 9.97 (IN, BgO; 8.67 (1H, ad); 7.43 (1H, aa); 7.27-7.16 (4H, t); 6.99 ( 1H, zv); 6.81 (2H, a); 6.50 (IN, 9; 4.53 (2H, t); 3.77 (ZH, c); 2.35 (ZH, 5); 2 ,07 (ZN, c).

HIAT-MS ti/: 363 (MN.

Example 4.11 M-(4-(Dimethylamino)benzyl)-1-(2,5-dimethylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide" NMR (SOCIv): 5 9.91 ( IN, BO; 5.69 (1H, a); 7.43 (1H, ach); 7.26-7.19 (4H, t); 7.01 (1H, c); 6.68 (2H, rya a); 6.52 (1H, 9; 4.52 (2H, t); 2.92 (6H, 5); 2.37 (ZH, 5); 2.08 (ZH, 5).

HIAT-MS pi/: 376 (MN. o

Example 4.12 M-(4-Chlorobenzyl)-1-(2-methyl-5-"-"trifluoromethyl)phenyl|-2-oxo-1,2-dihydropyridine-3-carboxamide

TN NMR (SOSIv): 5 9.94 (IN, BO; 8.72 (IN, a; 7.69 (IN, ad); 7.53 (IN, a); 7.50 (1Н, 5); 7.46 (1H, ach); 7.28 (4H, 5); 6.60 (1H, 9; 4.59 (2H, t); 2.23 (ZH, c). "--

HIAT-MS pi/l: 421 (Mn. m

Example 4.13

M-(4-Methoxybenzyl)-1-(2-methyl-5-trifluoromethyl)phenyl|-2-oxo-1,2-dihydropyridine-3-carboxamide c

TN NMR (SOSIv): 5 9.80 (IN, B; 8.71 (1H, ad); 7.65 (1H, ad); 7.50 (IN, a); 7.47 (1H,. 8 ); 7.42 (1H, "-ad); 7.27-7.24 (AN, t); 6.82 (2H, 4); 6.56 (1H, 9; 4.54 (2H, t ); 3.76 (ZN, 5); 2.19 (ZN, c). 3o HIAT-MS ti/g: 417 MN. so

Example 4.14

I-(4-"Dimethylamino)benzyl)-1-(2-methyl-5-"-"trifluoromethyl)phenyl|-2-oxo-1,2-dihydropyridine-3-carboxamide

TN NMR (SOSIv): 85 9.75 (IN, BO; 8.73 (IN, a; 7.67 (1H, ad); 7.52 (IN, 4); 7.49 (1H, 5); 7.42 (1H, « du ad); 7.23 (2H, 4); 6.69 (2H, a); 6.57 (1H, 9; 4.53 (2H, t); 2.92 ( 6H, 8); 2.21 (ZH, 5). -

HIAT-MS pi/l: 430 (Mn. s Example 4.15 M-Benzyl-5-methyl-2-oxo-1-3-trifluoromethyl)-phenyl|-1,2-dihydropyridine-3-carboxamide; » HIAT-MS pti/h: 387 (MN.

Example 4.16 45. M-(2-Chlorobenzyl)-5-methyl-2-oxo-1-3-(trifluoromethyl)-phenyl)-1,2-dihydropyridine-3-carboxamide (os HIAT-MS pi/l : 421 (Mn. from Example 4,17 5-Methyl-2-oxo-N-(2-phenylethyl)-1-3-trifluoromethyl)-phenyl)|-1,2-dihydropyridine-3-carboxamide

HIAT-MS n/z: 401 (MN. name) Example 4.18 M-(4-Chlorophenyl)-5-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine- 3-carboxamide -I 20 HIAT-MS pi/l: 407 (MN.

Example 5 - 6-Ethyl-M-I4-(methylsulfonyl)benzyl)-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide a) 6-Ethyl-2 -ox-1-3-"(trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxylic acid

The title compound is obtained from ethyl 3-oxo-3-|3-trifluoromethyl)phenyl|amino)supropanoate -( and 1-methoxypent-Ten-3-one by the method described in example 1, stages (a), and (B) .

HF) "YAN yaNMR (SOSIV): 5 13.75 (IN, bgv); 8.59 (IN, 4); 7.87 (IN, 4); 7.79 (IN, 9; 7.55 (1IN , 5); 7.49 (1H, a); 6.61 (1H, a); 237 (2H, 4); 1.20 (ZH, 9.

HIAT-MS pi/l: 312 (Mn. in B) 6-Ethyl-M-I4-("methylsulfonyl)benzyl)-2-oxo-1-3--trifluoromethyl)phenyl/|-1,2-dihydropyridine- 3-carboxamide

The title compound is obtained from β-ethyl-2-oxo-1-3-trifluoromethyl)phenyl β-1,2-dihydropyridine-3-carboxylic acid and 4-(methylsulfonyl)benzylamine hydrochloride by the method described in example C (4 ). "YAN yaYMR (SOSIVZ): 5 10.00 (IN, BO; 8.64 (IN, 4); 7.88 (2H, 4); 7.82 (IN, a); 7.75 (IN, 9 ; 7.53 (2H, 4); 7.52 (1H, 5); 7.45 (1H, 4); 6.51 (1H, 4); 4.68 (2H, t); 3.02 ( ЗН, c); 2.31 (2Н, а); 1.17 (ЗН, 9. 65 HIAT-MS pi/l: 479 (МН.

The compounds of examples 5.1 and 5.2 are obtained by a method similar to that described in example 5.

Example 5/1

M-(4-I-Methylsulfonyl)benzyl)-2-oxo-6-propyl-1-III--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide "YAN nNMR (SOSIVZ): 5 10.00 (IN , B; 8.62 (IN, 4); 7.88 (2H, 4); 7.83 (IN, a); 7.75 (IN, 0; 7.53 (2H, a); 507.52 (1H, 5); 7.45 (1H, 4); 6.49 (1H, 4); 4.68 (2H, t); 3.02 (ZH, c); 2.26 (2H, 9; 1, 55 (2H. entrance); 0.87 (ZH, 9.

HIAT-MS pi/l: 493 (MN.

Example 5,2 b6-Butyl-M-(4-(methylsulfonyl)benzyl|-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

TN NMR (SOCI): 5 10.00 (IN, g; 8.62 (IN, 4); 7.88 (2H, a); 7.83 (1H, a); 7.75 (IN, 9; 7.54 (2H, db); 707.52 (1H, 5); 7.45 (1H, 4); 6.49 (1H, 4); 4.68 (2H, t); 3.03 (ЗН , 5); 2.29 (2H, 09; 1.49 (2H, am); 1.24 (2H, in); 0.80 (ZH, 0.

HIAT-MS ti/g: 507 (MN.

Example 6 6-(Methoxymethyl)-M-(4-(methylsulfonyl)benzyl)-2-ox-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide 15 a) 6-"Bromomethyl )-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxylic acid

The title compound is obtained by refluxing b-methyl-2-oxo-1-(3-"-trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-i"arbolic acid (297 mg, mmol),

of M-bromosuccinimide (24Omg, 1.3mmol) and 2,2-azobis-2-methylpropionitrile (AIVM) (15mg) in a mixture of carbon tetrachloride/chloroform (2:11, 5ml) overnight. The solvent is evaporated to give the title compound. 20 HIAT-MS tu» 376/378 МН". c) 6-"Methoxymethyl)-2-oxo-1-3--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxylic acid

The title compound is obtained by distillation of crude 6-(bromomethyl)-2-oxo-1-3-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxylic acid from excess sodium methoxide in methanol at 402 for 15 minutes. Organic solvents are removed, water is added, and the reaction mixture is washed with ethyl acetate. Aqueous phases are acidified with hydrochloric acid to pH 4. A yellowish precipitate formed (o), which was filtered off, washed (water and water/methanol, 1:11) and dried to give the title compound. "YAN yaYMR (SOSIV): 5 13.66 (IN, bge); 8.63 (1H, 4); 7.87 (IN, a); 7.77 (IN, 9; 7.58 (IN, 5 ); 7.50 (1H, a); "- zo 5.84 (1H, a); 3.96 (2H, a); 3.27 (ZH, 5).

HIAT-MS p/z: 328 (Mn. - s) s 6-(Methoxymethyl)-M-I4-(methylsulfonyl)benzyl)-2-oxo-1-13-"-trifluoromethyl)phenyl)-1-2 -dihydropyridine-3-carboxamide -- 35 The title compound is obtained from the combination of 6-(methoxymethyl)-2-oxo-1-I3--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxylic acid and 4-(methylsulfonyl ) of benzylamine hydrochloride by the method described in example C (a). (1H, 49); 7.73 (HO; 7.53 (ZH, t); 7.47 (1H, a); « 6.72 (1H, a); 4.67 (2H, t); 3 .92 (2H, 4); 3.23 (ZH, 5); 3.01 (ZH, c). 40 HIAT-MS ti/: 495IMN. With c Example 7 "» 6-(Hydroxymethyl)-M-( 4--("Methylsulfonyl)benzyl)-2-oxo-1-III--trifluoromethyl)phenyl-1,2-dihydropyridine-3-carbo" xamide a) 6-"Hydroxymethyl)-2-oxo-1-III- -trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxylic acid 45 The title compound is obtained by heating with 6-(bromomethyl)-2-oxo-1-3--trifluoromethyl)phenyl|-1-2-dihydropyridine-Z -carboxylic acid and diluted sodium hydroxide in methanol for several minutes ilin The reaction mixture is washed with ethyl acetate. Aqueous phases are acidified with hydrochloric acid. The formation of a precipitate is observed, which is recrystallized several times from a mixture of ethyl acetate/methanol, obtaining the title compound. -and 250 TN NMR (DMSO-iv): δ 13.99 (1H, Bg8); 8.53 (1H, 4); 8.00 (IN, 5); 7.94 (1H, 4); 7.83 (IN, 9; 7.81 (1H, ha a); 6.94 (1H, 4); 5.85 (1H, 9; 3.99 (2H, a).

HIAT-MS t/2:314 (MN), 99

B) 6-(Hydroxymethyl)-M-I(4-(methylsulfonyl)benzyl|)|-2-oxo-1-I(3--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide ( F) The title compound is obtained by Kk!

Ge 6b-(hydroxymethyl)-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxylic acid and 4-(methylsulfonyl)benzylamine hydrochloride by the method described in example C (a). in "YAN NMR (DMSO-yv): 5 9.92 (IN, B; 8.49 (IN, a); 7.92-7.81 (4H, t); 7.78 (IN, 9; 7 .71 (IN, a); 7.53 (2H, 4); 6.78 (1H, a); 5.71 (1H, 9; 4.57 (2H, Bha); 3.95 (2H, ha ); 3.16 (ZN, 5)

HIAT-MS pi/h: 481 |MITI.

Example 8

IM-(4-Aminosulfonate)benzyl)-2,4-deoxo-3-3-trifluoromethyl)phenyl/d-1,2,3,4-tetrahydropyrimidine-5-carboxamide 65 a) 2, 4-Dioxo-3-3-trifluoromethyl)phenylide-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

C-"Trifluoromethyl)phenyl isocyanate (3.52g, 22mmol) was added rapidly with vigorous stirring to an ice-cooled solution of aqueous ammonia (TOml, 3395) in acetonitrile (400ml). The mixture is heated at 40°C for 10 minutes, and then the solvent is evaporated, the formed urea is redissolved in dry ethanol (15 ml) and diethyl ethoxymethylene malonate (b5 ml, 24.7 mmol) is added, and at the end a solution of sodium ethoxide (bOmmol in ethanol), and the mixture boils Refrigerate for 2 hours. Water (1 Oml) is added and the mixture is allowed to cool, then washed with ethyl acetate, acidified to pH-3 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic extracts are dried and evaporated to give a solid material.

Recrystallization from a mixture of heptane/ethyl acetate gives the title compound (O.5g, 7905).

IN NMR (SOSIV): 5 12.41 (1H, ha, U-64Hz); 8.15 (1H, a, 9U-64Hz); 7.46 (1H, a, 9-7.6 Hz); 7.40 (1H, 5 70. e7.6Hz); 7.30 (Bgv, 1H); 7.22 (1H, a, 9-7.6Hz).

HIAT-MS ti/: 300 (MN.

B)

IM-(4--(Aminosulfonyl)benzyl)/)-2,4-dioxo-3-3-trifluoromethyl)phenyl/|-1,2,3,4-tetrahydropyrimidine-5-carboxamide

The title compound is obtained by Kk! 15..2,4-dioxo-3--3--'trifluoromethyl)phenyl|)-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and

I-(4-(aminosulfonyl)-benzylamine hydrochloride by the method described in example 1 (4).

TN NMR (DMSO-yv): 5 12.21 (IN, ha); 911 (IN, 9; 8.29 (IN, 8); 7.81 (2Н, а); 7.77-7.70 (ЗН, т); 7.65 (IN, а); 7.44 ( 1H, a); 7.28 (2H, 5); 4.46 (2H, a).

The compounds of examples 8.1-8.8 are obtained using the general method described in example 8,

Example 8/1

I-(4-(Dimethylamino)benzyl/-2,4-dioxo-3-3-trifluoromethyl)phenyl/c-1,2,3,4-tetrahydropyrimidine-5-carboxamide trifluoroacetate

TN NMR (СО5СМ): 5 9.73 (IN, ha); 8.96 (IN, B; 8.35 (IN, 4); 7.79 (IN, a); 7.72 (1H, 9; 7.63 (1H, 8); 7.55 (1H, a ); 736 (2H, a); 1.23 (2H, a); 4.49 (2H, 4); 3.04 (6H, 5). s

Example 8.2 o

IM-(4-Chlorobenzyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl/d-1,2,3,4-tetrahydropyrimidine-5-carboxamide

TN NMR (СО5СМ): δ 9.65 (1IN, Bha); 8.96 (IN, B; 8.39 (IN, 4); 7.80 (IN, a); 7.72 (1H, 9; 7.63 (1H, 8); 7.56 (1H, a ); 7.33 (2H, 4); 7.25 (2H, 4); 4.49 (2H, a). "- from Example 8.3

M-(2,3-dihydro-1-benzofuran-5-ylmethyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-3-carboxamide c "YAN yaYMR (SOSIV): 5 8.53 (1H, a); 7.76 (IN, t); 7.67 (IN, t); 7.53 (IN, t); 7.44 (IN, t), 7.13 (IN, t); 7.04 (1H, t); 6.68 (1H, a); 5.28 (2H, a); 4.57 (2H, 9; 3.19 (2H, 9. -

HIAT-MS p/z: 432 (Mn. p

Example 8.4

I-(4-"Methylsulfonyl)benzyl)-2,4-dioxo-3-3-"-trifluoromethyl)phenyl/d-1,2,3,4-tetrahydropyrimidine-3-carboxamide

TN NMR (SOSIs): 5 9.05 (IN, t); 8.52 (IN, 4); 8.40 (IN, t); 7.88 (2H, a); 7.75 (IN, a); 7.66 (1H, 9; « 7.53 (IN, t); 7.49 (2H, a); 7.44 (1H, 4); 4.65 (2H, a); 3.01 (ЗН , c). t0 HIAT-MS ti/: 468 (MN. 8 s Example 8.5 ; c" M-(4-Bromobenzyl)-2,4-dioxo-3-3-trifluoromethyl)phenylide-1,2 . , 4); 7.65 (IN, t); -7.52 (1IN, t); 7.42 (ЗН, t); 7.16 (2Н, а); 4.50 (2Н, а). o HIAT-MS p/z: 467 (MN.

Example 8.6 - M-(4-Methoxybenzyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide "YAN NMR (SOCIv) : 5 8.86 (IN, t); 8.62-8.53 (2H, t); 7.77 (1H, t); 7.69 (IN, t); 7.55 (1H, t) , 7.47 (1H, - 50 t), 7.24 (2H, t), 6.86 (1H, t), 4.52 (2H, a), 3.80 (ZH, c).

HIAT-MS pi/l: 420 (Mn. -. and Example 8.7

IM-(1,3-Benzodiokeal-5-ylmethyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl/|-1,2,3,4-tetrahydropyrimidine-5-carboxamide

TN NMR (SOSIs): 5 8.93 (IN, t); 8.71 (IN, t); 8.54 (IN, 0; 7.76 (IN, a); 7.68 (IN, 0; 7.54 (1H, t); 29 7Ab(1H, a); 7.27 (1H, 5) 6.85 (1H, 49); 6.76 (1H, 49); 5.95 (2H, a); 4.56 (1H, 49); 4.48 (1H, 4)

GF) HIAT-MS p/z: 434 (MN.

Example 8.8 o M-(3-Chlorobenzyl)-2,4-dioxo)-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide

TN NMR (SOSIV): 5 10.07 (IN, a); 9.11 (IN, 0; 8.54 (IN, a); 7.78 (IN, a); 7.69 (IN, 0; 7.55 (IN, t); 60 7.А7 (1Н, 4); 7.29 (1H, t); 7.26 (2H, t); 7.19 (1H, t); 4.58 (2H, a).

HIAT-MS pi/l: 424 (MN.

Example 9 1-butyl-M-I(4-(methylsulfonyl)benzyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl)1,2,3,4-tetrahydropyrimidine-5-carbo 65 xamide a) M-Butyl-M'-III-trifluoromethyl)phenyl|urea:

1-Isocyanato-3-trifluoromethyl)benzene (0.74 mL, 5.34 mmol) was added to an ice-cooled solution of n-butylamine (1.0 b mL, 10.68 mmol) in acetonitrile (10 mL). The mixture was stirred for 10 minutes and then the solvent was evaporated to give the title compound as a white solid (1.37g, 9990).

HIAT-MS pi/l: 261 (MN.

B) Ethyl 1-butyh2,4-dioxo-3-3-trifluoromethyl)phenyl|d-1,2,3,4-tetrahydropyrimidine-5-carboxylate

Into a solution of M-butyl-M'-(3--trifluoromethyl)phenyl|urea (1.37 g, 5.2 mmol) and diethyl (ethoxymethylene)malonate (2.133 ml, 10.68 mmol) in M-MP (bml) at 1009 add potassium tert-butoxide (0.10 g,

0.9 mmol) and the mixture is stirred for 1 hour. Ethyl acetate was added and the mixture was washed with 1 M hydrochloric acid 70, brine and water. The solvent was evaporated and the resulting oil was purified by HPLC to give the title compound (667mg, 3390).

TN NMR (SOSIs): δ 8.33 (1H, 8); 7.70 (IN, 4); 7.62 (IN, 0; 7.51 (IN, 8); 7.41 (IN, 4); 4.35 (2H, 4); 3.89 (2H, 9; 1.81-1.74 (2H, t); 1.45-1.33 (5H, t); 0.99 (ZH, 90.

HIAT-MS pi/: 385 (Mn. s) 1-butyl-2,4-dioxo-3-3-trifluoromethyl)phenyl/|-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

A solution of ethyl 1-butyl-2,4-dioxo-3-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate (101 mg, 0.2 mmol) and 0.5 M sodium hydroxide solution (700 μl, O0.ZBmmol) in THF is stirred for 2 hours.

Water is added and the mixture is washed with ethyl acetate. Acidification of the aqueous phase, extraction with ethyl acetate and removal of the solvent gave the title compound (b5mg, 7090).

TN nMR (SOCIs): δ 8.57 (1H, 8); 7.79 (IN, a); 7.70 (IN, 0; 7.55 (1H, 8); 7.46 (1H, a); 3.96 (2H, 0; 1.85-1.75 (2H, t); 1.50 -1.37 (2H, t); 1.00 (ZH, 9.

HIAT-MS ti/g: 357 (Mn. a) ch 1-butyl-M-I(4-methylsulfonate)benzyl)-2,4-dioxo)-3-IZ--trifluoromethyl)phenyl)-1, 2,3,4-tetrahydropyrimidine-5-carb oxamide o

A solution of 4-methylsulfonylbenzylamine hydrochloride (30mg, 0.14mmol) and DIPE (24µl, 0.14mmol) in dichloromethane (1ml) was added with stirring to a mixture of 1-butyl-2,4-dioxo-3-3-trifluoromethyl)phenyl| )-1,2,3,4-tetrahydrothyrimidine-5-carboxylic acid (44 mg, "-

0.12 mmol), GATU (52 mg, 0.14 mmol), GOAT (19 mg, 0.14 mmol) and DIPE (bZmCl, 0.37 mmol) in dichloromethane (ml).

The resulting mixture is stirred for 2 hours. The solvent was evaporated and the product was purified by HPLC and flash chromatography to give the title compound (22mg, 35905). high school

TN nMR (SOCIv): δ 9.14 (1H, 0; 8.55 (1H, 8); 7.89 (2H, a); 7.75 (1H, 4); 7.67 (IN, 0; 7.53 (1H, zv); 7.50 (2H, a); 7.44 (1H, a); 4.66 (2H, a); 3.93 (2H, 9; 3.03 (ZH, 5); 1.83-1.75 (2H, t); 1.47-1.38 (2H, t); 0.99 (ZH, 9. -

HIAT-MS p/z: 524 (Mn. ee)

The compounds of examples 9.1-9.4 are obtained using the general method described in example 9:

Example 91 1--2-Methoxyethyl)-N-(4-methylsulfonyl)benzyl|-2,4-dioxo-3-III-"trifluoromethyl)phenyl)|-1,2,3,4-tetrahydropyrimides" n-5 -carboxamide

TN nMR (SOSIv): 5,913 (1H, 0; 8.61 (1H, 8); 7.90 (2H, a); 7.75 (1H, 4); 7.67 (IN, 0; 7, 54 (1H, zv); - c 7.51 (2H, a); 7.45 (1H, a); 4.66 (2H, 4); 4.12 (2H, 9; 3.68 (2H, 9; 3.40 (ZH, 5); 3.03 (ZH, c). )benzyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carb oxamide

Me IN nMR (SOSIv): 5,910 (1H, 0; 8.57 (1H, 8); 7.90 (2H, a); 7.76 (IN, 4); 7.67 (IN, 0; 7 .52 (1H, zv); - 7.50 (2H, a); 7.43 (IN, a); 4.66 (2H, a); 3.61 (ZH, 5); 3.03 (ZH , 5). t HIAT-MS pi/l: 482 (MN.

Example 9,3- and 1-ethyl-N-(4-(methylsulfonyl)benzyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl/-1,2-3,4-tetrahydropyrimidine-5- carbo still xamide

TN nMR (SOSIv): 85,913 (IN, 0; 8.58 (IN, 5); 7.90 (2H, a); 7.75 (IN, a); 7.67 (IN, 0; 7, 53 (1H, zv); 7.50 (2H, 4); 7.44 (1H, 49); 4.66 (2H, 4); 4.01 (2H, a); 3.03 (ZH, c ); 1.45 (ZN, U.

HIAT-MS pi/l: 496 (MN.

Example 94 o M-(4-Chlorobenzyl)-1-(2-methoxyethyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl|d-1,2,3,4-tetrahydropyrimidine-5-carbox co amide

TN nMR (SOSIs): 5 8.99 (IN, 9; 8.60 (IN, 3); 7.74 (IN, 4); 7.66 (IN, 9; 7.53 (IN, 8); 7.44 (1H, a); for /7.30-7.22 (AN, t); 4.54 (2H, 4); 4.11 (2H, 9; 3.67 (2H, 9; 3 ,40 (ZN, 5).

HIAT-MS pi/l: 482 (MN.

Example 10 5-Iodo-6-methyl-N-(4-(methylsulfonyl)benzyl)-2-oxo-1-3-(trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide M-Iodosuccinimide ( 9.7 mg, 0.043 mmol) is added with stirring to a solution of b-methyl-M-I(4-"methylsulfonyl)benzyl|)|-2-oxo-1-3--trifluoromethyl)phenyl|-1,2-dihydropyridine -3-carboxamide

(20mg, 0.043mmol) in trifluoromethanesulfonic acid (0.5ml). The mixture is stirred for 10 minutes.

Dichloromethane (1 mL) was added and the organic phase was washed with aqueous sodium hydrogen carbonate, aqueous sodium thiosulfate, and water.

The extracts were dried and evaporated to give the title compound (10090). "YAN NMR (SOSIv): 5 9.81 (IN, g; 8.86 (1H, 8); 7.88 (2H, a); 7.82-7.69 (ZH, t); 7.48 (2H, a); 7.40 (1H, a); 4.65 (2H. t); 3.01 (ZH, 5); 2.28 (ZH, c).

The following Intermediates are obtained using the method described in example 9(c): 1-(2-Methoxyethyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5 -carbonic acid

HIAT-MS pt/ 359 (Mn. 3-(3-Chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

HIAT-MS pi/: 325 (Mn. 1-butyl-3-(3-methoxyphenyl)-2,4-dioxo-1,2,3-4-tetrahydropyrimidine-5-carboxylic acid

TN NMR (DMSO-iv): δ 12.09 (IN, Bg in); 8.79 (IN, 5); 7.39 (IN, 9; 7.01 (IN, aa); 9.91 (1H, 9; 685(1H, 12 4); 3.89 (2H, 9; 3.74 (ZH, 5); 1.61 (2H, pentet); 1.30 (2H, hexeth); 0.89 (3H, 9.1-butyl-3-3-trifluoromethyl)phenyl)-2,4-dioxo-1,2 ,3,4-tetrahydropyrimidine-5-carboxylic acid

TN NMR (DMSO-iv): δ 12.55 (IN, Bg 8); 8.76 (1IN, c); 7.84-7.60 (4H, t); 3.89 (2H, 9; 1.63 (2H, pentet); 1.30 (2H, hexeth); 0.89 (ZH, B. 1-butyl-3-(3-chlorophenyl)-2,4- dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

HIAT-MS pu 323 MN. 1-butyl-3-(3-cyanophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

TN NMR (DMSO-yv): 5 12.30 (IN, Bg 8); 8.74 (IN, 8); 7.94-7.85 (2H, t); 7.75-7.69 (2H, t); 3.89 (2H, 9; 1.63 (2H, pentet); 1.30 (2H, hexet); 0.89 (ZH, 0. Ge!

Example 11 Fr

M-(4-Chlorobenzyl)-1-(2-methoxyethyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl|d-1,2,3,4-tetrahydropyrimidine-5-carboxamide 1-- 2-Methoxyethyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl|-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (0.01 mmol, 0.2 M in M-MP) was added to resins POS-Carbodiimide (bOmg), HOBT (0.032mmol, 0.3M in M-MP), and M-MP h (200μl). The mixture was stirred for 15 minutes and 4-chlorobenzylamine (0.019 mmol, O.ZM in M-MP) was added.

After shaking overnight, the excess HOBT is removed using PS-Trisamine resin (45 mgH), - stirred for 2 hours, and then the resin is filtered. The title compound is obtained after purification by preparative HPLC. -

HIAT-MS pi/l: 482.4 MN.

Examples 11.1-11.13 are obtained from 1-(2-methoxyethyl)-2,4-dioxo-3-I;3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carbon acid /- and a suitable amine using the general method described in example 11:

Example 11.1 "

M-(4-Methoxybenzyl)-1-(2-methoxyethyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-3-car boxamide - with HIAT - MS pi/l: 478.5 MN. "» Example 11,2 " 1-(2-Methoxyethyl)-2,4-dioxo-N-(pyridin-4-ylmethyl)-3-(3--'trifluoromethyl)phenyl)|-1,2,3 ... ,4-dioxo-3-3--'trifluoromethyl)phenyl|)|-1,2,3,4-tetrahydropyrimidine-5-carboxamide t HIAT-MS pi/g: 522.5 (MH) -| 50 Example 11,4 also 1--2-Methoxyethyl)-M-(2-(3-methoxyphenyl)ethyl/)|-2,4-dioxo-3-3--trifluoromethyl)phenyl/|-1,2, 3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS pi/l: 492.5 MN.

Example 11.5 1--2-Methoxyethyl)-N-(4-methylbenzyl)-2,4-dioxo-3-3-3-trifluoromethyl)phenyl/d-1,2,3,4-tetrahydropyrimidine-5- karbok (F; samid ka HIAT-MS p/z: 462.5 MN.

Example 11.6 in 1-(2-Methoxyethyl)-N-(4-methylsulfonyl)benzyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine -5-carboxamide

HIAT-MS p/z: 526.5 MN.

Example 11.7

M-(4-Fluorobenzyl)-1-(2-methoxyethyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl/d-1,2,3,4-tetrahydropyrimidine-5-carbox 65 samide

HIAT-MS pi/: 466.4 MN.

Example 11.8

M-2,3-Benzodioxol-5-ylmethyl)-1-(2-methoxyethyl)-2,4-dioxo-3-I(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine -5-carboxamide

HIAT-MS pi/l: 492.5 MN.

Example 11.9 1Ch4-(2-Chloro-4-fluorobenzyl)-1-(2-methoethyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl)|-1,2,3,4-tetrahydropyrimidine - 5-carboxamide

HIAT-MS pi/l: 500.4 MN. 70 Example 11,10

IM-(3,4-DichlorobenzylNa2-methoxyethyl)-2,4-dioxo-3-3-(trifluoromethyl)phenyl/d-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS ti/: 516.4, 518.4 MN.

Example 11,11 Methyl 15... A-CID1-(2-methoxyethyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl) carbonyl) amino methyl) benzoate

HIAT-MS pi/l: 506.5 MN.

Example 11,12 1--2-Methoxyethyl)-N-(5-methylisoxazol-3-yl)methyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl|-1,2,3,4- tetrahydropyrimidine-3-carboxamide

HIAT-MS pti/g: 453.4 MN.

Example 11,13 1--2-Methoxyethyl)-2,4-dioxo-M-I(4-(1H-pyrazol-1-yl)benzyl)/|-3-III-"trifluoromethyl)phenyl/d-1 ...

Examples 11,14-11,29 get Kk! 3-(33-chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-bo-carboxylic acid and a suitable amine using the general method described in example 11:

Example 11,14 - 3o IM-(4-Chlorobenzyl)-3-(3-chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide -

HIAT-MS t/: 448.4, 450.4 MN. high school

Example 11,15 3-(3-Chlorophenyl)-M-(4-methoxybenzyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide "--

HIAT-MS ti/»: 444.4 (MN). co

Example 11,16 3-(3-Chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-N-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS ti/: 415.4 MN. "

Example 11,17 40. 3-(3-Chlorophenyl)-M-(2-(3,4-dimethoxyphenip)ethyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4 -tetrahydropyrimidine-5-carb - s oxamide and HIAT-MS ti/: 488.5 MN. ,» Example 11,18 3-(3-Chlorophenyl)-1-(2-methoxyethyl)-M-(2-(2-methoxyphenyl)ethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5-carboxy copper salt HIAT-MS m/z: 458.5 MN). - Example 11,19

M-(3-Bromobenzyl)-3-(3-chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide by HIAT-MS: 492.4.4943 MN). - 2 Example 11,20 3-(3-Chlorophenyl)-1-(2-methoxyethyl)-M-(4-methylbenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide" with HIAT-MS ti/: 425.4 MN.

Example 11,21 3-(3-Chlorophenyl)-1-(2-methoxyethyl)-N-(4-(methylsulfonyl)benzyl|)-2,4-dioxo-1,2,3,4-tetrahydropyripridin-5- carbo 29 xamide

HF) HIAT-MS t/": 492.4 MN). 7 Example 11,22 3-(3-Chlorophenyl)-M-(4-fluorobenzyl)-1-|12-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in HIAT -MS ti/: 432.4 MN.

Example 11.23

IM-(1,3-Benzodioxol-5-ylmethyl)-3-(33-chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-carb oxamide

HIAT-MS ti/: 458.4 MN. 65 Example 11,24 3-(3-Chlorophenyl)-M-(3,4-difluorobenzyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-3-carboxamide

HIAT-MS ti/g: 450.3 (Mn.

Example 11.25

M-(2-Chloro-4-fluorobenzyl)-3-(3-chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxami

DF DdD

HIAT-MS ti/: 466.4,468.4 (MN.

Example 11.26 3-I(III-Chlorophenyl)-M-(3,4-dichlorobenzyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS ti/: 482.3, 484.3 (Mn.

Example 11.27 Methyl 4-I(I3-(3-chlorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-ylcarbonyl))amino)methyl) benzoate

HIAT-MS t/z: 472.4 MN).

Example 11.28 3-(3-Chlorophenyl)-1-(2-methoxyethyl)-M-((3-methylisoxazol-3-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine -3-ka 19 rboxamide

HIAT-MS t/z: 419.4 MN).

Example 11.29 3-(3-Chlorophenyl)-1-|(2-methoxyethyl)-2,4-dioxo-M-I4-(1H-pyrazol-1-yl)benzyl-1,2,3,4- tetrahydropyrimidine-5-carbo xamide

HIAT-MS those": 4805 MN".

Examples 11.30-11.38 get Kk! 1-butyl-3-(3-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-b-carboxylic acid and the corresponding amine using the general method described in example 11:

Example 11.30 s 1-butyl-N-(4-chlorobenzyl)-3-(33-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide o

HIAT-MS t/: 442.4 MN).

Example 11,31 1-butyl-3-(3-methoxyphenyl)-N-(2-(3-methoxyphenyl)ethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide "- from HIAT-MS ti/: 452.3 MN.

Example 11.32 -

M-(3-Bromobenzyl)-1-butyl-3-(33-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide c

HIAT-MS ti/: 486.4, 488.4 (Mn.

Example 11.33 - 1-butyl-M-(4-fluorobenzyl)-3-I(3-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide c

HIAT-MS ti/: 426.3 MN.

Example 11.34

M-2,3-Benzodioxol-5-ylmethyl)-1-butyl-3-(3-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide "

HIAT-MS ti/: 413.3 (Mn.

Example 11.35 - with 1-butyl-M-(2,4-dichlorobenzyl)-3-(3-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide "» HIAT - MS t/: 476.4, 473.4 (MH. " Example 11.36 1-butyl-N-(3,4-difluorobenzyl)-3-(3-methoxyphenyl)-2,4-dioxo-1, 2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS t/: 444.3 (Mn. bo Example 11.37 - 1-butyl-N-(2-chloro-4-fluorobenzyl)-3-(3-methoxyphenyl)-2,4-dioxo-1, 2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS ti/: 460.3 MN. name)

Example 11,38 and 50 1-butyl-M-(2,3-dihydro-1-benzofuran-5-ylmethyl)-3-(3-methoxyphenyl)-2,4-dioxo-1,2,3,4 -tetrahydropyrimidine-3-carb boxamide

HIAT-MS t/z: 450.5 MN).

Examples 11.39-11.58 received Kk! 1-butyl-3-(3-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-3-carboxylic acid and an acceptable amine using the general method described in Example 11: (F; Example 11 ,39

GI 1-butyl-N-(4-chlorobenzyl)-3-(33-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS ti/: 446.4, 448.4 MN. in Example 11,40 1-butyl-3-(3-chlorophenyl)-M-(4-methoxybenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS t/: 442.4 MN).

Example 11,41 1-butyl-3-(3-chlorophenyl-2,4-dioxo-N-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide 65 HIAT-MS ti/ : 452.4 MN.

Example 11.42

1-butyl-3-(3-chlorophenyl)-M-(2-(3,4-dimethoxyphenyl)ethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS ti/: 486.4 MN.

Example 11.43 1-Butyl-3-(3-chlorophenyl)-M-(2-(3-methoxyphenyl|ethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-3-carboxamide

HIAT-MS p/z: 456.4 (MN).

Example 11.44

M-(3-Bromobenzyl)-1-butyl-3-(33-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS ti/: 490.3, 492.3 MN.

Example 11.45

M-(4-Bromobenzyl)-1-butyl-3-(33-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS ti/: 490.3,492.3 |MH 7).

Example 11.46 1-Butyl-3-3-chlorophenyl)-M-(4-methylbenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS ti": 426.4 (MN.

Example 11.47 1-Butyl-3-3-chlorophenyl)-N-(4-(methylsulfonyl)benzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS pi/l: 490.4 MN.

Example 11.48 1-Butyl-3-(3-chlorophenyl)-M-I(4-fluorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-3-carboxamide

HIAT-MS p/z: 430.4 (Mn.

Example 11.49

IM-(1,3-Benzodioxol-5-ylmethyl)-1-butyl-3-(33-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS pi/l: 456.4 MN.

Example 11.50 (8) 1-butyl-3-(3-chlorophenyl)-M-(2,4-dichlorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS ti/: 480.3,482.3 |MH 7).

Example 11.51 "-- 1-butyl-3-(3-chlorophenyl)-M-(3,4-difluorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide m

HIAT-MS pi/l: 448.4 MN.

Example 11.52 He 1-butyl-M-(2-chloro-4-fluorobenzyl)-3-(3-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide -

HIAT-MS ti/: 464.4, 466.4 MN.

Example 11.53 (ge) 1-butyl-3-(3-chlorophenyl)-M-(3,4-dichlorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS t/: 480.3, 482.4 MN.

Example 11.54 "1-butyl-3-3-chlorophenyl)-M-(2,3-dihydro-1-benzofuran-5-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine- 5-carboxamide o) with HIAT-MS pi/l: 452.4 MN. from» Example 11.55 1-butyl-3-(3-chlorophenyl)-N-(4-cyanocyclohexyl)methyl|)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS pi/l: 443.3 (Mn. bo 75 Example 11.56 1-butyl-3-(3-chlorophenyl)-M-(5-methylisoxazol-3-yl)methyl)-2,4-dioxo -1,2,3,4-tetrahydropyrimidine-3-carboxamide - HIAT-MS p/z: 417.3 (Mn. from Example 11.57 1-butyl-3-(3-chlorophenyl)-2,4-dioxo -M-I4-(1H-pyrazol-1-yl)benzyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide s- HIAT-MS pi/l: 478.4 MN shk Example 11.58 1- butyl-3-(3-chlorophenyl)-2,4-dioxo-N-I3-(2-oxopyrrolidin-1-yl)propyl|-1,2,3,4-tetrahydropyrimidine-3-carboxamide

HIAT-MS p/z: 447.3 (MN.

Examples 11.59-11.77 get Kk! 1-butyl-3-(3-cyanophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and a suitable amine using the general method described in example 11: co Example 11, 59 1-butyl-N-(4-chlorobenzyl)-3-(3-cyanophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyridine-5-carboxamide

HIAT-MS p/z: 437.4 (M.N. 60 Example 11.60 1-butyl-3-(3-cyanophenyl)-M-(4-methoxybenzyl)-2,4-dioxo-1,2,3, 4-tetrahydropyrimidine-5-carboxamide

HIAT-MS pi/l: 433.5 MN.

Example 11,61 1-butyl-3-(3-cyanophenyl)-2,4-dioxo-M-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide b5 HIAT-MS ti /: 404.3 MN.

Example 11.62 1-Butyl-3-3-cyanophenyl)-N-(2-(3,4-dimethoxyphenyl)ethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS t/: 477.4 MN.

Example 11.63 1-Butyl-3-(3-cyanophenyl)-N-(2-(3-methoxyphenyl)ethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS t/z: 447.3 MN.

Example 11.64

M-(3-Bromobenzyl)-1-butyl-3-(3-cyanophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS ti/: 481.4, 483.4 (Mn.

Example 11.65

IM-(4-Bromobenzyl)-1-butyl-3-3-cyanophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS ti/: 481.4, 483.4 (Mn.

Example 11.66 79. 1-butyl-3-(3-cyanophenyl)-M-(4-methylbenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS t/z: 417.4 (MN).

Example 11.67 1-Butyl-3-(3-cyanophenyl)-M-(4-(methylsulfonyl)benzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS ti/: 481.4 MN.

Example 11.68 1-Butyl-3-(3-cyanophenyl)-M-(4-fluorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS t/z: 421.3 MN,

Example 11.69 sch

IM-(1,3-Benzodioxol-5-ylmethyl)-1-butyl-3-(3-cyanophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS ti/: 447.4 MN. and)

Example 11.70 1-Butyl-3-(3-cyanophenyl)-M-(2,4-dichlorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS ti/": 471.4, 473.4 (Mn. "-

Example 11.71 1-Butyl-3-(3-cyanophenyl)-M-(3,4-difluorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-3-carboxamide -

HIAT-MS t/z: 439.4 MN). with

Example 11.72 1-Butyl-N-(2-chloro-4-fluorobenzyl)-3-(3-cyanophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-3-carboxamide. --

HIAT-MS pi/l: 455.4 MN. with

Example 11.73 1-Butyl-3-(3-cyanophenyl)-M-(3,4-dichlorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS t/l: 471.4,473.5 |MH 7). "

Example 11.74 49 1-Butyl-M-(4-cyanocyclohexyl)methyl)-3-(3-cyanophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide C with HIAT- MS pi/l: 434.5 MN. from» Example 11.75 1-Butyl-3-(3-cyanophenyl)-N-(5-methylisoxazole-Zyl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS pi/l: 408.4 MN. bo 75 Example 11,76 1-butyl-3-3-cyanophenyl)-2,4-dioxo-M-(4-(1H-pyrazol-1-yl)benzyl)-1,2,3,4-tetrahydropyrimidine- 5-carboxamide - HIAT-MS p/z: 469.5 MN). from Example 11.77 1-butyl-3-3-cyanophenyl)-2,4-dioxo-M-I3-(2-oxopyrrolidin-1-yl)propyl/|-1,2,3,4-tetrahydropyrimidine-5 -carboxamide sh- HIAT-MS pi/l: 438.4 MN. shk Examples 11.78-11.97 get Kk! 1-butyl-3-(3-"-trifluoromethyl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and a suitable amine using the general method described in example 11:

Example 11.78 1-butyl-N-((4-chlorobenzyl)-2,4-dioxo-3-(33-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide o HIAT- MS ti/v: 480.4, 482.4 MN. Name) Example 11.79 1-butyl-N-(4-methoxybenzyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl/d-1 ,2,3,4-tetrahydropyrimidine-5-carboxamide 60 HIAT-MS pi/: 476.5 MN.

Example 11.80 1-Butyl-2,4-dioxo-N-pyridin-4-ylmethyl)-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS t/z: 447 4 МН).

Example 11.81 bo /1-butyl-N-(2-(2,4-dimethoxyphenyl)ethyl)-2,4-dioxo-3-3-"trifluoromethyl)phenyl-1,2,3,4-tetrahydropyrimidine- 5-car boxamide

HIAT-MS t/: 520.4 MN.

Example 11.82 1-Butyl-N-(2-(33-methoxyphenyl)-ethyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine- 5-carboxamide

HIAT-MS t/z: 490.4 MN).

Example 11.83

M-(3-Bromobenzyl)-1-butyl-2,4-dioxo-3-3-trifluoromethyl)phenyl/d-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS ti/»: 524 4, 526.5 MN.

Example 11.84

M-(4-Bromobenzyl)-1-butyl-2,4-dioxo-3-I(3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS ti/»: 524 4, 526.5 MN.

Example 11.85 19. 1-butyl-M-(4-methylbenzyl)-2,4-dioxo-3-3-3-trifluoromethyl)phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS t/z: 460.4 MN).

Example 11.86 1-Butyl-M-I(4-methylsulfonyl)benzyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carb oxamide 720 HIAT-MS fluff: 524.5 (Mn.

Example 11.87 1-Butyl-M-I(4-(fluorobenzyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide

HIAT-MS ti/: 464.4 MN. with

Example 11.88

M-2,3-Benzodioxol-5-ylmethyl)-1-butyl-2,4-dioxo-3-3-trifluoromethyl)-phenyl-1,2,3,4-tetrahydropyrimidine-5-car(o)boxamide

HIAT-MS t/z: 490.5 MN).

Example 11.89 "- 1-butyl-N-(2,4-dihydrobenzyl)-2,4-dioxo-ZNIZ-"trifluoromethyl)phenyl|-1,2,3,4-tetrahydropyrimidine-3-carboxamide

HIAT-MS ti/l: 514.4, 516.4 (M.N. -

Example 11.90 Ge 1-Butyl-M-3,4-difluorobenzyl)-2,4-Dioxo-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxami - d

HIAT-MS ti/: 482.5 MN. (se)

Example 11.91 1-Butyl-N-(2-chloro-4-fluorobenzyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl/d-1,2,3,4-tetrahydropyrimidine-5-carbox copper

HIAT-MS ti/: 498.4, 500.4 MN.

Example 11.92 t s 1-butyl-N-(3,4-dichlorobenzyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide" » HIAT-MS t/: 514.4, 516.4 MN. " Example 11.93 1-butyl-N-(2,3-dihydro-1-benzofuran-5-ylmethyl)-2,4-dioxo-3 -III--trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimide in-B-carboxamide

Me HIAT-MS p/z: 486.5 MN. - Example 11.94 1-butyl-N-(4-cyanocyclohexyl)methyl)-2,4-dioxo-3-3-trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carb where oxamide -20 0 HIAT-MS fluff: 477.5 (Mn. also Example 11.95 1-butyl-N-(5-methylisoxazol-3-yl)methyl)-2,4-dioxo-3-IZ- -trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-k arboxamide

HIAT-MS pi/l: 451.3 (Mn.

Example 11.96 (F) 1-butyl-2,4-dioxo-M-I(4-1H-pyrazol-1-yl/benzyl)-3-3-trifluoromethyl)phenyl)-1,2,3 ,4-tetrahydropyrimidine-3-carbo

GI xamide

HIAT-MS pi/l: 512.5 MN. in Example 11.97 1-butyl-2,4-dioxo-H-|3-(2-oxopyrrolidin-1-yl)propyl|-3-3-trifluoromethyl)phenyl/d-1,2,3,4 -tetrahydropyrimidine-3-carboxamide

HIAT-MS p/z: 481.4 (MN).

Example 685 12,6-(Chloromethyl)-M-I4-(methylsulfonyl)benzyl)-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

The title compound is obtained by heating 6b-(hydroxymethyl)-M-I4-(methylsulfonyl)benzyl| 48mg, 0.1mmol) and excess thionyl chloride (1ml) in NaOH (100ml) for 1 hour. Removal of the solvents gave a white solid (50mg, 10095) after trituration with diethyl ether.

TN-NMR (DMSO-iv): 5,993 (IN, B); 8.67 (IN, a); 7.88 (2H, a); 7.86 (1H, a); 7.76 (IN, 0; 7.61 (IN, 8); 734 (1H, a); 7.52 (2H, 4); 6.75 (1H, 4); 4.68 (2H, t) 4.12 (2H, 5); 3.02 (ZH, 5).

HIAT-MS pti/: 499 (MN).

Example 13 70... M-(4-(Methylsulfonyl)benzyl-b|(methylthio)methyl|/|-2-oxo-1-I(3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3- karbok samid

The title compound is obtained by mixing β-(chloromethyl)-M-4-(methylsulfonyl)benzyl|)|-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide (40 mg, O .08mmol) with an excess of sodium methylthiolate (28mg, 0.4mmol) in M-MP (1Oml) at room temperature 75 overnight. Water was added and the reaction mixture was extracted with E(FAs). The crude product was purified by silica column chromatography using E(As/heptane (4:1) as eluent) to give 15 mg (3790) of the title compound.

TN-NMR (SOS): δ 9.97 (IN, g; 8.63 (IN, a); 7.88 (2Н, 4); 7.81 (1Н, 4); 7.73 (1Н, 0 ; 7.62 (1H, 5); 7.53 (ZH, t); 6.51 (1H, a); 4.67 (2H, t); 3.26 (2H. a); 3.02 ( ZN, 5); 2.03 (ZN, c).

HIAT-MS those": 511 (MN.

Example 14 -(4-"Methylsulfonyl)benzyl|1-6-(114-(methylsulfonyl)benzyl)amino|methyl)-2-oxo-1-3-""trifluoromethyl)phenyl-1, 2-dihydropyridine-3- carboxamide

The title compound is obtained by mixing with 29 b-(chloromethyl)-M-I(4-(methylsulfonyl)benzyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxami He) du with excess 4-(methylsularonyl)benzylamine hydrochloride and OEEA in M-MP at room temperature overnight. The crude product is purified by preparative HPLC.

HIAT-MS pi/: 648 (Mn. - zo Example 15 -(4-"Methylsulfonyl)benzyl)-6-(morpholin-4-ylmethyl)-2-oxo-1-3-trifluoromethyl)phenyl)|-1 ,2-dihydropyridine-3-k - arboxamide s.c

The title compound is obtained by mixing b-(chloromethyl)-M-I(4-(methylsulfonyl)benzyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide with an excess of morpholine in THF at 502C overnight. The crude product is purified by preparative HPLC. co

HIAT-MS pi/l: 550 (Mn.

Example 16 6-(Cyanomethyl)-M-4-("methylsulfonyl)benzyl)-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxam"

ID

The title compound is obtained by mixing 2 with b-(chloromethyl)-M-I(4-(methylsulfonyl)benzyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxami

I do with an excess of sodium cyanide in THF at 502C overnight. The crude product is purified by preparative HPLC. ,» HIAT-MS pti/: 490 (MN.

Example 17 8-Isopropyl-M-(4-(methylsulfonyl)benzyl)-2-oxo-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide (ee) a) 6-isopropyl- 2-oxo-1-3-trifluoromethyl)phenyl/1,2-dihydropyridine-3-carboxylic acid with a mixture of ethyl 3-oxo-3-trifluoromethyl)phenylamino)propanoate (5.5 g, 2 mmol ), 1-methoxy-4-methylpent-1-en-3-one was obtained by method |5.M. That's where it is, Zupiy. Sottyp., 23(4), 487-494 ko (1993)) (2.77, 21mmol) and sodium methoxide (2g, 40mmol) in ethanol (5Oml) were heated to boiling point under reflux for 5 hours and then cooled. Water (5 mL) and 2 M sodium hydroxide solution were added and the mixture was stirred at room temperature overnight. Organic solvents are removed and the reaction mixture is extracted with EtOAc. The aqueous phases were acidified with 0.5 M citric acid to pH 3-4, the precipitate formed was filtered off, washed with water and dried to give 0.4 g (690) of the title compound as a brownish powder. "H-NMR (SOSIV): 5 13.74 (1H, 8); 8.59 (IN, a); 7.87 (IN, a); 7.78 (IN, 9; 7.54 (1H, Running); 7.48 (1H, a);

Gee! 6.64 (1H, a); 2.54 (1H, t); 1.20 (6H, 9.

HIAT-MS pi/: 326 (Mn. 6-Isopropyl-M--4--(methylsulfonyl)benzyl|-2-oxo-1-3-(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide 6o In a mixture of b-isopyropropyl-2-oxo-1-3-(trifluoromethyl)phenyl)-2,2-dihydropyridine-3-carboxylic acid (98 mg,

O.Zmmol), GATU (12bmg, 0.3Zmmol), GOAT (45mg, O.3Zmmol) and OEEA (16b2µl, 0.95mmol) in M-MP (Zml) add 4-(methylsulfonyl)benzylamine hydrochloride (b9mg, 0 ,3'mmol), the pH is adjusted to approximately rnav-9

OEE

The mixture is stirred for 71 hours at room temperature. E(OAc) is added and the organic phase is washed twice with aqueous sodium hydrogen carbonate, 0.5 M citric acid and water. The solvent is removed under vacuum and the residue is purified by column chromatography on silica, using СНоСИО/ЕХАС (4:11) as an eluent, obtaining the title compound with a quantitative yield. "H-NMR (SOSIV): 5 .9.99 (IN, g; 8.65 (IN, 4); 7.87 (2H, 4); 7.82 (IN, a); 7.74 (IN, 0; 7.51 (ZH, t); 5744 (1H, a); 6.54 (1H, a); 4.67 (2H, t); 3.01 (ZH, 5) ; 2.49 (1H, t); 1.17 (6H, 9.

HIAT-MS pi/l: 493 (MN.

Example 18

M-(4-«-Ethylsulfonyl)benzyl|-6-methyl-2-oeso-1-3--trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide a) tert-Butyl (4-(methylsulfonyl)benzyl Carbamate

To a solution of (4-(methylsulfonyl)benzylamine (b0Omg, 2.7mmol) in THF (Od9ml), di-tert-butyldicarbonate (590mg, 2.7mmol) and DIPE (92bml, 5.4mmol) were added and the mixture was stirred overnight. After removal of the solvent, the crude product was purified by flash chromatography to give the sub-title compound (65mg, 84905). 00 (1H, c); 4.42 (2H, a); 3.05 (ZH, c); 1.48 (OH, 5).

HIAT-MSti/»: 169.1, 186.1 (MN).

B) tert-Butyl (4-(ethylsulfonyl)benzyl|carbamate

To a solution of tert-butyl (4-(methylsulfonyl)benzylcarbamate (40Omg, 1.4mmol) in THF (5ml) at -722C, n-butyllithium (175Ocl, 2.8mmol) was added dropwise, keeping the temperature at -702C. After the addition the temperature is allowed to rise to -402C and methyl iodide (1O05 µl, 1.7 mmol) is added. The mixture is stirred for 1 hour, an aqueous solution of ammonium chloride is added, and then the mixture is extracted with E(Ac.

The organic layer is washed with ammonium chloride solution and evaporated. The crude product was purified by preparative HPLC to give the sub-title compound (148mg, 35905). "H-NMR (SOCIv): δ 7.88 (2H, a); 7.49 (2H, a); 4.98 (1H, c); 4.43 (2H, bv); 3.11 ( 2H, a); 1.48 (9H, 8); 1.28 (ZH, 0.

HIAT-MS ti/: 183.2, 200.2 MN. c c) (4-(Ethylsulfonyl)benzyl)amine trifluoroacetate o

Tert-butyl 4-(ethylsulfonyl)benzylcarbamate (148mg, 0.5mmol) was stirred in 1095% TFOK in SiO2 for 3 hours. The solvent was evaporated, leaving the title compound (191 mgHg).

HIAT-MS pi/l: 200.1 (MH. a) Mch-(4-"Ethylsulfonyl)benzyl/|-b-methyl-2-oxo-1-3--trifluoromethyl)phenyl/|-1,2- dihydropyridine-Z-carboxamide w

The title compound is obtained from 4-(ethylsulfonyl)benzylamine trifluoroacetate and 1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid using a method similar to that described in example 17. c "H-NMR ( SOCIa): 85 9.98 (IN, 9; 8.59 (1H, a); 7.84-7.81 (ZH, t); 7.74 (IN, 0; 7.52-7.50 ( ЗН, т); 7.45 "-- (IN, 4); 6.48 (1Н, 4); 4.74-4.63 (2Н, т); 3.08 (2Н, а); 2, 09 (ZN, 9; 1.26 (ZN, 9. 101 HIAT-MS t/: 479.3 (MN. so

Example 19

IM-III-Chloro-4-(methylsulfonyl)benzyl|/|-6-methyl-2-oxo-1-III--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxa copper « a) 3- Chloro-4-(methylthio)benzaldehyde C t0 2-chlorothioanisole (1.25ml, 9.5mmol) in СНоСИБ at -52С, titanium(U) chloride (207bml, 18.9mmol) are added dropwise to the solution with stirring over 10 minutes. , keeping the temperature below 02C. After addition, the mixture was stirred for 10 minutes, and then А,А-dichloromethyl-methyl ether (0.94 ml, 10 4 mmol) was added dropwise, keeping the temperature below 02С. After adding the mixture, let it reach the external temperature and pour it into a saturated aqueous solution of sodium hydrogen carbonate (7 Oml). The mixture is filtered through a layer of brick, and washed with СНоСі. phases are separated and the aqueous phase is extracted with СНоСі". The combined organic phases are washed with brine and the solvent is removed under vacuum. The crude product was purified by flash chromatography to give the subtitle product (535mg, 3090). d) "H-NMR (SOCIv): δ 9.91 (1H, c); 7.84 (1H, a); 7.75 (1H, aa); 7.27 (1H, a); 2.56 (ZN, c)

HIAT-MS p/z: 187.1 (Mn. 7 V) 3-chloro-4-(methylthio)phenyl|methanol - M In a solution of 3-chloro-4-(methylthio)benzaldehyde (332mg, 1.ammol) in THF (bml) and water (0.bml), add Mavn. (269 mg, 7.1 mmol). The mixture is stirred for 2 hours. The reaction is quenched with 1M aqueous hydrochloric acid solution and E(OAc) is added. After phase separation, the organic layer is washed with water, dried and evaporated to give the Subtitle compound (35Omg, 9190). a); 7.26 (1H, ad); 7.17 (1H, 49); 4.66 (2H, c); 2.49 (ZH, c)

HIAT-MS p/z: 170.9 (MN). o c) (3-Chloro-4-(methylsulfonyl)phenyl|methanol.

3-Chloro-4-(methylthio)phenyl|methanol (350 mg, 1.9 mmol) is dissolved in aqueous sodium hydroxide (0.5 M, 4.44 ml) 60 and stirred for 20 minutes, sodium hydrogen carbonate (1.23 g) is added, and acetone (1.5 mL), and then oxone (1.85 g, 3, mol) in EDTA (b.5 mL, 0.4 mM) was added. After stirring for 2 hours, the reaction is quenched by adding sodium bisulfite (0.9g) in water, EFOAc is added, and the solution is acidified with a 2M aqueous solution of hydrochloric acid. Sodium chloride is added to the aqueous solution, then EAs is extracted. The organic layers are combined and washed with water, brine and dried. for Evaporation gave the sub-title compound as a white solid (35Omg, 8890).

7"H-NMR (SOCIv): δ 8.12 (1H, 4); 7.60 (1H, a); 7.44 (1H, aa); 4.81 (2H, c); 3.27 ( ЗН, c) a) 4-(bromomethyl)-2-chloro-1-methylsulfonyl)benzene

13-Chloro-4-(methylsulfonyl)phenyl|methanol (23U9mg, 1 immol) was added to dioxane. The slurry is mixed and heated to 402C before adding RBgz (71 μl, 0.vmmol). The reaction mixture is heated to 1002C for 1 hour and then allowed to cool. Water is added and the mixture is extracted with EIAs. The organic layer is washed with water and then with brine and dried. Evaporation gave the sub-title compound (31Omg, 100905).

T'NAMR (SOCI): 85 814 (IN, aFf; 7.61 (IN, a 749 (IN, ad); 446 (2H, 5); 3.28 (ZN, c). e)Y3-Chlor- 4-(Methylsulfonyl)benzylamine 4-(Bromomethyl)-2-chloro-1-(methylsulfonyl)benzene (16Omg, 0.5bmmol) is dissolved in methanol (3ml) and added to an equal mixture of ammonia (2895) and methanol (1Oml ). The reaction mixture is stirred at 402C for 1 hour and evaporated. The crude product is dissolved in EtOAc and aqueous 6M sulfuric acid. The aqueous phase is separated, adjusted to pH 14 using sodium hydroxide and extracted with CHCl." The dichloromethane phase is dried and evaporated , obtaining the title compound (b5mg, 5390). 79. HIAT-MS pil: 219.9 (Mn. 9

IM-III-Chloro-4-(methylsulfonyl)benzyl|/|-6-methyl-2-oxo-1-III--trifluoromethyl)-phenyl)-1,2-dihydropyridine-3-carboxamide

The title compound was prepared as described in Example 17. 720 TN-NMR (SOCI): δ 10.03 (1H, 0; 8.58 (1H, 4); 8.07 (IN, 9); 7.82 (1H, a); 7.75 (IN, 0; 7.52 (2H, d); 7.45 (IN, a); 7.41 (1H, a); 6.49 (1H, 49); 4.69-4 .57 (2H, t); 3.23 (ZH, 5); 2.10 (ZH, c).

HIAT-MS p/z: 499.0 (MN.

Example 20 6-Methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid su 4-cyclopropanesulfonyl-benzylamide a) 4-Cyclopropanesulfonyl-benzylamine and) 1-Dicyclopropanesulfonyl -4-methyl-benzene obtained by the MU method. E. Tgise, ei ai, U. Ogda. Spet., 1961, 26, 1463-1467, (190 mg, 0.969 mmol), M-bromosuccinimide (190 mg, 1.07 mmol) and benzoyl peroxide (12 mg) in carbon tetrachloride (4 ml) are heated at reflux temperature for 24 hours, "- zo is cooled, filtered and concentrated. The residue in methanol (ml) is added in portions over 10 minutes to a solution of ammonium hydroxide (28905, 2ml) in methanol (2ml). After 2 hours, the solution is distributed between EtOAc (1Oml) and sulfuric acid (0.4M, 1Oml), the pH of the aqueous layer is adjusted to 14 using 2M aqueous KOH, and then extracted three times with dichloromethane. The organic phase is dried and concentrated to give the sub-title compound (vZmg). -- "IN NMR (SOSIV): 5 7.78 (2H, Ba); 7.35 (2H, Ba); 2.46 (ZH, c); 2.46 (1H, t); 1.34 ( 2H, t); 1.02 (2H, t). p

HIAT-MS pi/l: 212 (MN.

The corresponding dibenzylamine (1295) is also presented.

B) 6-Methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid « 4-cyclopropanesulfonyl-benzylamide

The title compound is obtained from 4-cyclopropanesulfonyl-benzylamine and -c 1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid by a method similar to that described in example 17.

B TN-NMR (SOSI): 5 9.93 (IN, Bi0; 8.38 (IN, 9); 7.89 (2H, Ba); 7.84-7.80 (ZN, t); 7, 73 (1H, Ba); 7.53 (2H, 4); 6.26 (1H, a); 4.58 (2H, a); 2.80 (1H, t); 2.02 (ZH, 8 ); 1.08 (2H, t); 1.01 (2H, t).

HIAT-MS ti: 491.1 MH". Example 21 - IM-3-Methoxy-4-(methylsulfonyl)benzyl)-6-methyl-2-oxo-1-3--trifluoromethyl)phenyl-1,2- dihydropyridine-3-carboxyamide o a) (3-Methoxy-4-(methylsulfonyl)phenyl|methanol -I 20 IZ-Methoxy-4-(methylthio)phenyl|methanol, obtained as described (Sagsia ei ai. Zirgatoiesshag Spetizigu, 1992 , x 1, 31-45, (75 mg, 0.04 mmol) is dissolved in aqueous sodium hydroxide (0.5 M, 1.22 ml) and stirred for 30 7" minutes. Further, the reaction as in example 19 (c) gives, after trituration with toluene , the sub-title compound as white crystals (47mg, 54965) "H-NMR (SOCIA): 85 7.97 (a, 9 8Hz, yin); 7.15 (b, 1); 7.08 (a, 8Hz, yin); 4.81 (4, U 54 Hz, 2H); 4.04 (z, ZN); 3.32 (v, ZN). (F. HIAT-MS pi/l: 217 (Mn. ka v) 4-(Bromomethyl)-2-methoxy-1-methylsulfonyl)benzene

To a slurry of 13-methoxy-4-methylsulfonyl)phenylmethanol (bO9mg, 0.32mmol) and toluene at 409C is added boRViz (30mCl, 0.32mMmol). The reaction mixture is heated to 1002 for 1 hour, cooled and water is added .

The reaction mixture was diluted with E(OAc), washed with water and brine and dried. Evaporation gave the sub-title compound as a pale yellow oil (62 mg, 69965).

TNA-NMR (SOSIv): 5 7.97 (a, 9 8.0 Hz, 1); 7,14 (aa, 9 8,0,14Hz, 71); 7.10 (9, 9 1.2Hz, 1H); 4.50 (from, 2H); 4.05 (in, ZN) 3.24 (in, ZN) because HIAT-MS pti/g: 280 (Mn. s) 3-Methoxy-4-(methylsulfonyl)benzylamine

4-(Bromomethyl)-2-methoxy-1-(methylsulfonyl)benzene (62 mg, 0.22 mmol) in methanol was slowly added to an equal mixture of ammonia (2895) and methanol. The reaction mixture was stirred at room temperature for 2 hours and evaporated. The reaction mixture is partitioned between EOAc and aqueous 6M sulfuric acid. The aqueous phase is alkalized with sodium hydroxide and extracted with СНоСиИ»; The dichloromethane phase was dried and evaporated to give the title compound (Zbmg, 76905).

HIAT-MS p/z: 216 (МН. а)

I-(III-Methoxy-4-(methylsulfonyl)benzyl|-6-methyl-2-oxo-1-III--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carbo 70 xamide

The title compound is obtained from 3-methoxy-4-(methylsulfonyl)benzylamine and 1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid by a method similar to that described in example 17. "H-NMR (SOSIa): 5 10.03 (v, 1H); 8.60 (a, 9 7.5Hz, 1H); 7.91 (4, U 8yHz, yin); 7.83 (a, U 8.3Hz , MH); 75 7.16 (5 9 7.8Hz, 1); 7.54 (a, 9 4.7Hz, 71); 7.46 (a, 9 7.2Hz, 1Hn); 6.50 ( a, 9 7.2Hz, 1); 7.05 (4, in 7.9, 5.3Hz, 2H); 4.64 (I, In 6.3Hz, 2H); 3.98 (in, ЗН) ; 3.19 (in, ZN); 2.11 (in, ZN).

HIAT-MS ti/g: 495 (MN).

Example 22

M-III-Bromo-4-(methylsulfonyl)benzyl/|-6-methyl-2-oxo-1-3-"(trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxa copper a) 3-Bromo -4-(methylthio)benzaldehyde

Potassium carbonate (0.68 g, 4.92 mmol) and sodium metamethiolate (0.26 g, 3.69 mmol) are added to a solution of 3-bromo-4-fluorobenzaldehyde (0.5 g, 2.5 mmol) in M-MP (1 Oml). The mixture is heated to 702C for 7 hours, cooled, and partitioned between BEFOAs and water. The organic phase was dried, filtered, evaporated and purified by column chromatography on silica using heptane/E(OAc (4:1) as eluent to give He) the title compound (0.25g, 4490). "H-NMR (SOCI"): 5 9.89 (1H, c); 8.00 (1H, 49); 7.79 (1H, aa); 7.23 (1H, a); 2.54 ( ZN, 5). HIAT-MS t/": 465.3 МН 7.

B) 3-Bromo-4-(methylthio)phenyl|methanol

Sodium borohydride (0.2g, 5.4mmol) is added to a solution of 3-bromo-4-(methylthio)benzaldehyde (0.25g, 1.0v8mmol) in methanol (15ml). The solution is stirred at room temperature for 4 hours, water is added, and the mixture is extracted with СНоСИ".

The organic layer was dried, filtered and evaporated to give 0.24g (9595) of the title compound. cm "H-NMR (SOSIV): 5 7.55 (1H, a); 7.29 (1H, aa); 7.12 (1H, a); 4.64 (2H, 5); 2.48 ( ЗН, c). «- c) I(3-Bromo-4-(methylsulfonyl)phenyl)methanol c

A suspension of sodium hydroxide (2.5 ml, 1.25 mmol) and |3-Bromo-4-(methylthio)phenyl|methanol (0.24 g, 1.03 mmol) is stirred at external temperature for 20 minutes, then sodium hydrogen carbonate (0, 69Hg, 8.2mmol) and acetone (ml), and then after 10 minutes Oxon solution (1.6bg in bml 04MM EDTA) is added. The suspension is stirred overnight at room temperature. EtOAc is added and the solution is acidified with 5 M NOI. The organic phase was washed several times with water and then dried, filtered and evaporated to give the title compound Ж with 0.19g (7096). . HIAT-MS ti/»: 249.1, 251 MN). "" a) 2-Bromo-4-(bromomethyl)-1-(methylsulfonyl)benzene

3-Bromo-4-(methylsulfonyl)phenyl|methanol (0.19g, 0.72mmol) was mixed with toluene (bmL) and phosphorus tribromide (30mCl, 0.32mmol) at 402C and the mixture was stirred at 1002 for 20 minutes. EtOAc (100 mL) (ee) was added to the cooled solution and then washed with water. The organic phase was dried, filtered and evaporated to yield 0.23 g (97905) of the title compound. "H-NMR (DMSO-α): δ 8.06 (1H, 49); 8.02 (1H, 49); 7.73 (1H, 49); 4.76 (2H, c); 3.38 (ZH, 5). ko e) I3-Bromo-4-(methylsulfonyl)benzylamine -1 50 Solution of 2-Bromo-4-(bromomethyl)-1-(methylsulfonyl)benzene (23Omg, 0.7Omol) in methanol ( 3ml) and THF (ml) are added to MNAOH (7ml, 2895) over 30 minutes. - After 4 hours, the solution is acidified with 0.5M aqueous hydrochloric acid solution, washed twice with СНоСи» and then basified to pH14 with 5M sodium hydroxide. The aqueous phase is extracted with СНоСи », and the organic layer was dried, filtered and evaporated to give 80 mg (4395) of the title compound.

NMR (DMSO-α): δ 7.99 (1H, a); 7.89 (1H, a); 7.58 (1H, aa); 3.79 (2H, c); 3.31 (ZN, c)

HF) HIAT-MS ti/: 264, 266 (M.N. 9 o M-(3-Bromo-4-(methylsulfonyl)benzyl|-b-methyl-2-oxo-1-III--trifluoromethyl)phenyl|-1 ,2-dihydropyridine-3-carboxa copper 60 The title compound is obtained from 3-Bromo-4-(methylsulfonyl)benzylamine and 1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid by the method , similar to that described in example 17. 7TH-NMR (DMSO-ide): 5 9.94 (IN, 9; 8.37 (IN, 4); 8.02 (1H, 4); 7.93-7.68 (5H, t); 7.54 (1H, 4); 6.61 OH, a); 4.55 (2H, 4); 3.33 (ZH, 5). 55 HIAT-MS t/: 543, 2,545.2 (ML. -BO0-

Example 23

I-III-Cyano-4-methylsulfonyl)benzyl)-6-methyl-2-oxo-1-(trifluoromethyl)-phenyl|-1,2-dihydropyridine-3-carboxami d a) 5-formyl-2-(methylthio ) benzonitrile

The sub-title compound is obtained similarly to example 22a, but at room temperature for 1 hour instead of heating the reaction mixture. 7"H-NMR (400MHz, SOSIv): 5 9.94 (1H, 8); 8.07 (IN, a, 9 1.7Hz); 8.01 (IN, aa, U 8,3,1, 8Hz); 7.40 (1H, a, - 8.3Hz); 2.64 (ZH, 5).

GC-MS t/2:177 (M. 5) 5-(Hydroxymethyl)-2-(methylthio)benzonitrile The sub-title compound is obtained similarly to example 225. 7H-NMR (400 MHz, SOSI"): 5 7.62 (1H, in ); 7.53 (1H, a, U 8.3Hz); 7.32 (1H, a, U 8.3 Hz); 4.70 (2H, 85); 2.57 (ZH, 8). c) 5-(Hydroxymethyl)-2-(methylsulfonyl)benzonitrile

The subtitle compound is obtained similarly to example 22.

NMR (400 MGu, SOSI"): 5 8.17 (1H, a, U 8.1Hz); 7.93 (1H, c); 7.79 (1H, a, U 8.2 Hz); 4.88 (2H, 5); 3.27 (ZN, c). a) 5-(Bromomethyl)-2-(methylsulfonyl)benzonitrile

The subtitle compound is obtained similarly to example 224. "H-NMR (400 MHz, SOCIv): δ 8.18 (IN, 4, U 8 GHz); 7.93 (1H, a, at 1.7 GHz); 7.82 (1H, ad, 9 8.2, 1.6Gu); 4.51 (2H, 5); 3.29 (ZH, c). e) 5-(aminomethyl)-2-(methylsulfonyl)benzonitrile

The subtitle compound is obtained similarly to example 22e. 7H-NMR (400 MHz, CO300): δ 8.14 (1H, 4, U 8.2Gu); 8.04 (1H, c); 7.88 (1H, a, U 8.1Hz); 3.97 (2H, c); 3.29 (ZN, c)

HIAT-MS pu: (MN). with

In o

1-3-Cyano-4-(methylsulfonyl)benzyl|-b-methyl-2-oxo-1-3-"-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

The title compound is obtained similarly to example 17. 7H-NMR (400MHz, SOSI»v): δ 10.19 (1H, i, U 5.7Hz); 8.56 (1H, a; ZAG); 8.11 (1H, a, in 81); 7.85-7.71 (4H, -- t); 7.53 (1H, 8); 7.46 (IN, a, at 8.0Hz); 6.51 (IN, a, 9 7.5Hz); 4.71 (1H, aa, 9 15.9, 6.2Hz); 4.65 (1H, aa, M 15.9, 6.0Hz); 3.23 (ZN, 5); 2.11 (ZN, 5).

HIAT-MS pi/l: 490 (Mn. p

Example 24 "- 6-Methyl-Mm-III-methyl-4-(methylsulfonyl)benzyl|)|-2-oxo-1-I(3-trifluoromethyl-p-phenyl)-1,2-dihydropyridine-3-carbox

Zo samide co a) 3-Methyl-4-(methylthio)benzaldehyde

The subtitle compound is obtained similarly to example 22a.

GC-MS ti/: 166 (M. « c) (3-Methyl-4-(methylthio)phenyl|methanol 50 The sub-title compound is obtained similarly to example 226. From c "H-NMR (300MHC, SOSIZv): 5 7.18 -7.09 (ZH, t); 4.57 (2H, c); 2.44 (ZH, 5); 2.32 (ZH, 5). :z» c) (3-Methyl-4-( methylsulfonyl)phenyl|methanol

The subtitle compound is obtained similarly to example 22. 7H-NMR (300 MHz, SOS): δ 7.92 (1H, d, U 18.7Hz); 7.35-7.29 (2H, t); 4.73 (2H, c); 3.05 (ZN, 8); 2.66 (ZN, c). o a) 4-(bromomethyl)-2-methyl-1-(methylsulfonyl) gasoline

The sub-title compound is obtained similarly to example 224. - 7H-NMR (300 MHz, SOS"): δ 8.00 (1H, 4, U 8.1 Hz); 7.42-7.28 (2H, t); 4.46 (2H, 5); 3.07 (ZN, c); 2.70 (ZN, 5). ko e) |(3-Methyl-4-(methylsulfonyl)benzylamine: -I 50 The subtitle compound is obtained similarly to example 22e. 7H-NMR (400 MHz, SOS"): 5 7.98 (1H, 4, U 8.2Hz) ; 7.35-7.29 (2H, t); 3.93 (2H, c); 3.06 (ZH, c); 2.70 (ZH, 5). "With HIAT-MS pi/l: 200 (MN. 9 6-Methyl-M-3-methyl-4--"methylsulfonyl)benzyl|)|-2-oxo-1-3--trifluoromethyl)-phenyl|-1,2-dihydropyridine-3- Carbox 22 amide

HF) The title compound is obtained similarly to example 17. 1H-NMR (300 MHz, SOS): 6 9.91 (IN, B at 57 Hz); 8.58 (IN, a, 9 7.5 Hz); 7.95 ( IN, a, U 8y1Gu); 7.83-7.27 (6H, t); 6.47 (1H, aa, 9 7.5, 0.5Hz); 4.68 - 4.53 (2H, t ); 3.03 (ZN, 5); 2.66 (ZN, 5); 2.08 (ZN, 5). in HIAT-MS pi/l: 479 (MN.

Example 25 6-Methyl-M-I(4-(methylthio)benzyl)-2-oxo-1-3-"(trifluoromethyl)phenyl)1,2-dihydropyridine-3-carboxamide 6-Methyl-2-oxo-1 -3-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxylic acid (1.29 g, 4.35 mmol) and 4-(methylthio)benzylamine (0.66 g, 4.35 mmol) are dissolved in M -MP (18ml). GBTU (1.81g, v5 4.79mmol) and DIPE (1.8bml, 10.9mmol) were added at about room temperature and the mixture was stirred overnight. The reaction mixture is poured into EtOAc. The organic phase is washed with 2.595 aqueous sodium carbonate,

then three times with water and dried. Purification by flash chromatography (E(Ac:cyclohexane 9:1) gave the title compound (1,ZHg, bean).

TN-NMR (400MHz, DMSO-iv) δ 9.78 (IN, 6 9 5.8Hz); 8.38 (1H, a, 9 7.4 Hz); 7.91-7.69 (4H, t,; 7.22 (4H, t); 6.62 (1H, a, U 1.6 Hz); 4.42 (2H, a, U 5.9 Hz); 2.43 (ZN, 5), 2.01 (ZN, c).

HIAT-MS ti/: 433.1 MN.

Example 26 6-Methyl-M-I4-"(methylsulfinyl)benzyl|-2-oxo-1-3-"trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide 6-Methyl-M-I(4- (methylthio)benzyl|/|-2-oxo-1-3--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide (1.26g, 70.2.93mmol) was dissolved in СНоСИ» (12ml). The solution is cooled to -1592C. While stirring, 3-chloroperoxybenzoic acid (672 mg, 2.93 mmol) is added in portions to the solution. The reaction mixture is stirred for 1 hour.

The cooling bath is removed and the reaction mixture is allowed to reach room temperature. After 2 hours, add СНоСиИ» and a diluted solution of sodium thiosulfate. The mixture is shaken and the aqueous phase is separated.

The organic layer is washed twice with a saturated aqueous solution of sodium hydrogen carbonate, once with brine and dried at 75°C. Purification by flash chromatography (EuAc:Meon 9:1) gave the title compound (1.1g, 80905). 7"H-NMR (400MHz, DMSO-dv) 5 9.88 (IN, 6 at 5.9Hz); 8.38 (IN, a, 9 7.5Hz); 7.93-7.69 (4H, t,); 7.62 (2H, a, 9 8.2Hz); 7.47 (2H, a, U 8.2Hz); 6.62 (1H, a, 9 7.7Hz); 4.54 ( 2H, a, 7 6.0 Hz); 2.70 (ZH, c,); 2.02 (ZH, c).

HIAT-MS t/: 449.1 MN).

Example 27

I-(4-(benzylsulfonyl)benzyl|-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide. and). M-(4-Mercaptobenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide 6-Methyl-M-I4-(methylsulfinyl)benzyl -2-oxo-1-3-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide (0.30g, 0.6b7mmol) is dissolved in dry acetonitrile (3ml) and 2,6b-lutidine ( 0.24 ml, 2.0 in 8 mmol). The solution is cooled to -202C and trifluoroacetic anhydride (0.28 ml, 2.00 mmol) is added. The reaction mixture is kept between -10905 and 02 for 1 hour and then allowed to reach room temperature. All volatile materials evaporate (o) at 302C. The raw residue is cooled to 02C. A degassed dry 1:11 mixture of triethylamine (1.1 ml) and methanol (1.1 ml), cooled to 02C, was added. The reaction mixture was stirred at room temperature for 30 minutes and then evaporated. The residue is dissolved in a 1:1 mixture of methanol and 6M hydrochloric acid and stirred at 502C for 20 minutes. The main part of the solvent is evaporated. Add ethyl acetate and water. The aqueous phase is separated and washed again with ethyl acetate. The combined organic phase is washed with brine, dried, evaporated and used as a crude product in the next step. Ha

PH-MS; method B Ch3: 8.19 minutes,

HIAT-MS t/l: 419.3 MN, --

B) (ge)

M-(4-(Benzylsulfonyl)benzyl|-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

Dissolve in a flask filled with argon

M-(4-mercaptobenzyl)-b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) in dried degassed ethanol (0. 1ml) and cooled to 02С. A solution of potassium tert-butoxide (7.8 mg, 0.7 mmol) in ethanol (0.2 ml) was added. The reaction mixture was stirred for 45 minutes. - c (Bromomethyl)benzene (12 μl, 0.105 mmol) in ethanol (0.1 ml) is added. The ice bath is removed and the reaction mixture is stirred overnight. A mixture of ethyl acetate and 1M aqueous solution of ammonium chloride is added. The organic layer is separated, dried and evaporated. The residue is dissolved in CH 2Si" (24O0μl) and cooled with stirring to -152С. 3-Chloroperoxybenzoic acid (35mg, 0.154mmol) in СНоSiO (200μl) is added, the cooling bath is removed and the reaction mixture is stirred overnight, E(UAs) and 595% aqueous sodium thiosulfate are added. The organic layer is separated, washed with 595% aqueous sodium carbonate, brine and - dried Purification by preparative HPLC gave the title compound (11 mg, 30905).

TN-NMR (400 MHz, DMSO-ydv) 5 9.91 (IN, 6 9 bhz); 8.38 (IN, a, 9 7.5 Hz); 7.81 (4H, t); 7.66 (2H, ad, at about 8.4 Hz); 7.46 (2H, a, at 8.2Hz); 7.31-7.11 (5H, t,); 6.63 (1H, a, U 1.6Hz); 4.62 (2H, c,); 4.57 (2H, ad, U 6.1Hz); 2.03 (ZN, c). -0.70 HIAT-MS ti/»: 541.4 MN. Next, the compounds of examples 28-33 are obtained by the general method of example 27 (B):

Example 28 6-Methyl-2-oxo-M-I4-"(propylsulfonyl)benzyl)-1-III--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide

From N-(4-mercaptobenzyl)-6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl[1,2-dihydropyridine-3-carboxamide (29 mg, 59 0.07 mmol) and 1-bromopropane ( 1 µl, 0.105 mmol). Output: 12mg (3590). (F) "H-NMR (400 MHz, DMSO-iv) 5 9.93 (IN, 6 U b 1Hz); 8.38 (1H, a, 97.5Hz); 7.94-7.70 (6H, t); 7.53 (2Н,

GI a, 9U 8.2Hz); 6.63 (IN, a, 9 7.6Hz); 4.58 (2H, a, 9 61Hz); 3.22 (2H, t); 2.02 (ZN, 8); 1.52 (2H, a, 5 7.6bHz); 0.89 (ZN, i, U 7.4Hz). in HIAT-MS ti/z 493.3 MN 7.

Example 29 -(4-(Butylsulfonyl)benzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide

From N-(4-mercaptobenzyl)-6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and 1-bromobutane (11 μl, O0.105 mmol). Yield: 14mg, 0.028mmol (3996). 65 TN-NMR (400MHz, DMSO-4dv) 5 9.93 (1M, 6 V biHz); 8.38 (IN, a, at 7.4Hz); 7.93-7.70 (6H, t); 7.53 (2H, a, U 8.3Hz); 6.63 (IN, a, 9 7.7Hz); 4.59 (2H, a, 9U 61Hz); 3.24 (2H, t); 2.02 (ZN, a); 148 (2H, t); 1.31

(2H, t); 0.81 (ZN, i, U 7.3 Hz).

HIAT-MS ti/: 507.3 (MH)

Example 30

M-I4-(isobutylsulfonyl)benzyl)-b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

With M-(4-mercaptobenzyl)-6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide (29mg,

0.07 mmol) and 1-Bromo-2-methylpropane (11 μl, 0.105 mmol). Yield: 10mg, O.02O0mmol (28965).

TN-NMR (400MHz, DMSO-ydv) δ 9.93 (IN, 6, 9 6.0Hz); 8.38 (1H, a, 9 7.5Hz); 7.94-7.69 (6H, t,); 7.53 (2H, a, in 8.3Gsh); 663 (IN, a, 9 7.7 Ггу); 4.58 (2H, a, 9 62G); 316 (2H, a, at 6.5Hz); 2.02 (ZN, 5); 1.96 (1H, 70 quintet, in) 6.6Hz); 0.95 (6H, a, 9 6.7Hz).

HIAT-MS ti/: 507.3 MN.

Example 31 -(4-tert-butylsulfonyl)benzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide

From N-(4-mercaptobenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl[1,2-dihydropyridine-3-carboxamide 75 (29 mg, 0.07 mmol) and 2-bromobutane ( 11 μl, 0.105 mmol). Yield: 12mg, 0.024mmol (35965).

TN-NMR (400MHz, DMSO-4dv) δ 9.94 (IN, 6 9 6.0Hz); 8.38 (IN, a, at 7.5Hz); 7.93-7.69 (6H, t); 7.53 (2H, a, U 82Hz); 663 (IN, a, 9 7.8Hz); 4.59 (2H, a, 9 6 1Hz); 3.17 (IN, yes, 7134, 6.7Hz); 2.02 (ZN, 5); 1.77 (IN, t); 1.29 (1H, t); 1.11 (ZN, a, U 6.9Hz); 0.89 (ZN, E, U 7.5 Hz).

HIAT-MS ti/: 507.4 (MH)

Example 32

IM-(4-(isoprolylsulsronyl)benzyl|/|-6-methyl-2-oxo-1-III--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide

From N-(4-mercaptobenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide (29mg, 0.07mmol) and 2-bromopropane (1µl, 0.105 mmol). Yield: 11mg, 0.022mmol (33965). high school

TN-NMR (400 MHz, DMSOYAv) 5 9.94 (IN, 6 9 bhz); 8.38 (1H, a, U 7.4Hz); 7.94-7.69 (6H, t,); 7.54 (2H, 4, U 8.3Hz); 6.63 (1H, a, U 7.7Gu); 4.60 (2H, a, U 6.1Hz); 3.36 (1H, septet, / 62Hz); 2.03 (ZN, c); 1.13 (6H, a, U 6.8Hz). at

HIAT-MS ti/: 493.3 MN.

Example 33 6-Methyl-Mm-(4-((3-methylbutyl)sulfonyl)benzyl)-2-oxo-1-3-(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

From M-(4-mercaptobenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)erenyl-1,2-dihydropyridine-3-carboxamide in (29 mg, 0.07 mmol) and 1-Bromo- 3-methylbutane (1 µL, 0.105 mmol). Yield 11 mg, 0.021 mmol (3196). c 7"H-NMR (400 MHz, DMSO-iv) δ 9.93 (IN, 6 at bi1 GHz); 8.38 (IN, a, 9 7.4Hz); 7.94-7.69 (6H, t,); 7.53 (2H, a, in 8z3Hz); 6.63 (1H, a, 9 7.5Hz); 4.59 (2H, a, U 61Hz); 3.23 (2H, t); 2.02 (ZN, 5); 1.57 (1H, septet, ./ -- 6.8Hz); 1.39 (2H, t); 0.80 (6H, a, U 6.6Hz). (uh)

HIAT-MS t/z: 521.4 MN).

Next, by the general method of example 27, the compounds of examples 34-52 are obtained:

Example 34 "

M-(4-(Cyclopropylmethyl)sulfonyl|benzyl)-b-methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide ts With M-(4- mercaptobenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide (29mg "» 0.07mmol) and (bromomethyl)cyclopropane (1µl, 0.105mmol) . Yield: 1Zmg, 0.027mmol (38960). " TN-NMR (400MHz, DMSO-ydv) 5 9.93 (IN, 6 9 6.2Hz); 8.38 (1H, a, 9 7.5Hz); 7.93-7.70 (6H, t,); 7.53 (2H, a, U 8zGu); 663 (IN, a, 9 7.6Hz); 4.59 (2Н, а, 9У 61Гг3); 3.21 (2H, a, 9U 72Hz); 2.02 (ZN, in,); 0.80 (1H, tu, 043 (2H, t); 0.09 (2H, t). so HIAT-MS t/: 505.3 MN. - Example 35 t b-methyl-2-oxo-M- 14-(tetrahydrofuran-2-ylmethyl)sulfonyl|-benzyl)-1-III-"trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide - and 20 C M-(4-mercaptobenzyl)-6b- methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide (29mg, 0.07mmol more) and 2-(bromomethyl)tetrahydrofuran (12μl, 0.105mmol). Yield: 8mg , 0.015 mmol (2296). 7"H-NMR (400 MHz, DMSO-dv) δ 9.93 (IN, 6 at 6.0 Hz); 8.38 (IN, a, 9 7.5Hz); 7.93-7.70 (6H, t,); 7.51 (2H, a, U 82Hz); 6.63 (IN, a, 9 7.6Hz); 4.58 (2H, a, 9 6, 1Hz); 4.05 (1H, quintet, . 6.5Hz); 3.59 (1H, a, 9 in TaHcssh); 8.50 (ZN, t); 2.02 (ZN, in,); 1.94 (1H, t); 1.75 (2H, t); 1.54 (1H, t).

HIAT-MS ti/: 535.4 MN. (F, Example 36 with 4-K2-Hydroxyethyl)sulfonyl|benzyl)-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide in C M- (4-Mercaptobenzene)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and 2-bromoethanol (7 μl, 0.105 mmol) ). Yield: 12 mg, 0.025 mmol (3696).

TN-NMR (400 MHz, DMSO-ydv) 5 9.93 (IN, 6 9 bhz); 8.38 (IN, a, 9 7.4 Hz); 7.93-7.70 (6H, t,); 7.52 (2H, a, 9 8.3Hz); 6.63 (1H, a, 9 7.6Hz); 4.58 (2H, a, U 6.1 Hz); 3.65 (2H, i, U 6.4Hz); 3.40 (2H, i, U 6.5Hz); 2.02 (ZN, 5).

HIAT-MS ti/: 495.3 (MH) 65 Example 37 -(4-(Cyanomethyl)sulfonyl|benzyl/|-b-methyl-2-oxo-1-III--trifluoromethyl)phenyl/|-1,2 -dihydropyridine-3-carboxy copper

With N-(4-mercaptobenzyl)-6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide (29mg, 0O.07mmol) and chloroacetonitrile (7μl, O, 105 mmol). Yield: mg, 0.017mmol (24965).

TN-NMR (400 MHz, DMSO-ydv) 5 9.96 (IN, 6 9 bhz); 8.37 (IN, a, 9 7.5Hz); 7.95-7.69 (6H, t,); 7.62 (2H, a, U 8.3Hz); 6.63 (1H, a, U 7.6Hz); 5.20 (2H, 5); 4.61 (2H, a, U 6.2Hz); 2.03 (ZN, c).

HIAT-MS t/2:490.3 МН 7.

Example C8

M-14-(2-Amino-2-oxoethyl)sulfonyl|benzyl)-6-methyl-2-oxo-1-III-"-trifluoromethyl)phenyl!/|-1,2-dihydropyridin-3-ka 70 rboxamide

From N-(4-mercaptobenzyl)-6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and 2-bromoacetamide (14 mg, O0.105 mmol). Yield: 15mg, 0.029mmol (4196). "H-NMR (400 MHz, DMSO-v6) 5 9.94 (IN, 6 9 bhz); 8.38 (IN, 4, at 7.4 Hz); 7.95-7.46 (1OH, t,; 6.62 (IN, a, at 7.6 Hz), 4.58 (2H, a, at 6.0 Hz), 4.18 (2H, 5), 2.02 (ZN, 5).

HIAT-MS ti/: 508.3 MN".

Example 39

M-(4-(4-Cyanobenzyl)(sulfonyl)benzyl)-b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

From N-(4-mercaptobenzyl)-6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide (29mg, 0.07mmol) and 4-(bromomethyl) benzonpril (21 mg, 0.105 mmol). Yield: Zmg, O0.004mmol (6905). PH-MS; method B Ch3: 7.80 minutes,

HIAT-MS ti/: 566.4 MN.

Example 40 in M-4-(2-Cyanoethyl)sulfonyl)benzyl)-b-methyl-2-oxo-1-3-"-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxa, copper

With N-(4-mercaptobenzyl)-6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide (29mg, 00.07mmol) and 3-chloropropanenitrile (8μl, 0.105 mmol). Yield: 1mg, O0.002mmol (395).

PH-MS; method B Ch3: 7.16 minutes, HIAT-MS t/: 504.3 MN. "- from Example 41

M-4-((3-Hydroxypropyl)sulfonyl|benzyl)-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl-1,2-dihydropyridine-3-carb o oxamide

From M-(4-mercaptobenzyl)-6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and 3-bromopropane-1- ol (OMCL, 0.105 mmol). Yield: bmg, 0.012 mmol (1896). "-

PH-MS; method B Ch3: 6.40 minutes, so

HIAT-MS t/z: 509.3 MN.

Example 42

IM-I4-42-(Dimethylamino)-2-oxoethyl|sulfonyl)benzyl)-6-methyl-2-oxo-1-III--trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide "

With N-(4-mercaptobenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide (29 mM, 0.07 mmol) and 2-chloro -M,M-dimethylacetamide (11 μl, 0.105 mmol). Yield: 1Omg, 0.019mmol (2795). . PH-MS; method B Ch3: 6.61 minutes, "» HIAT-MS t/: 536.4 MN.

Example 43 Ethyl 3-K4-((6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|)|-1,2-dihydropyridin-3-yl)

Carbonyl)amino|methyl)phenyl)sulfonyl|propanoate (oo) C N-(4-mercaptobenzyl)-6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide (29 mg, -3z 0.07 mmol) and ethyl 3-bromopropanoate (1 µl, O0.105 mmol). Yield: 5mg, O0.009mmol (13965).

PH-MS; method B Ch3: 7.64 minutes, name) HIAT-MS t/z: 551.4 MN). -1 50 Example 44 2-K4-1(6-Methyl-2-oxo-1-3-trifluoromethyl)phenyl-1,2-dihydropyridin-3-yl)/carbonyl)amino|methyluphenyl)sulfone yl|ethyl acetate

With N-(4-mercaptobenzyl)-6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide (29mg, 0.07mmol) and 2-bromomethylacetate (12μl, 0.105 mmol). Yield: 7 mg, 0.014 mmol (2096).

PH-MS; method B Ch3: 7.19 minutes,

Gee! HIAT-MS t/: 537.3 MN.

Example 45 M-(4-((3-Cyanobenzyl)(sulfonali|benzyl)-b-methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide 60 From M-(4-mercaptobenzyl)-6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and 3-(bromomethyl)benzonitrile (21 mg, O, 105 mmol). Yield: 2mg, O0.004mmol (690).

PH-MS; method B Ch3: 7.77 minutes,

HIAT-MS t/z 566.3 (MN.

Example 46 bo Methyl-I(4-Csb-methyl-2-oxo-1-3-"-trifluoromethyl)phenylI-1,2-dihydropyridin-3-yl)carbonyl)amino|methyl)phenyl)sul -B4-

(fonyl)propanoate

With N-(4-mercaptobenzyl)-6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide (29mg, 0.07mmol) and methyl 3-bromopropanoate (11μl , 0.105 mmol). Yield: 2mg, O0.005mmol (7905).

PH-MS; method B Ch3: 7.28 minutes,

HIAT-MS ti/g: 537.3 (Mn.

Example 47 6-Methyl-m-(4-1(2-methyl-1,3-thiazol-4-ylylmethyl|sulfonal)benzyl)-2-oxo-1-3-trifluoromethyl)phenyl/-1,2- dihydropyridine-3-carboxamide trifluoroacetate 70 C of M-(4-mercaptobenzyl)-6-methyl-2-OxO-1-3-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide (29mg, 0.07mmol) and 4-(chloromethyl)-2-methyl-1,3-thiazole hydrochloride (19 mg, 0.105 mmol). Yield: 11 mg, 0.017 mmol (24965).

PH-MS; method B Ch3: 7.21 minutes,

HIAT-MS pi/g: 562.3 MN.

Example 48 6-Methyl-2-oxo-N-(4-((pyridin-4-ylmethyl)sulfonyl)benzyl)-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridin-3-carboxamide trifluoroacetate

From N-(4-mercaptobenzyl)-6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide (29 mg, 0.007 mmol) and 4-(chloromethyl)pyridine hydrochloride (17 mg, 0.105 mmol). Yield: 5 mg, 0.008 mmol (1196).

PH-MS; method B Ch3: 5.79 minutes,

HIAT-MS pi/: 542.3 MN.

Example 49

IM-I4-KZ-Cyanopropyl)sulfonyl)benzyl)-6-methyl-2-oxo-1-IZ--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide with

From M-(4-mercaptobenzyl)-6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and 4-bromobutanitrile (1 , O0.105 mmol). Yield: 11 mg, 0.022 mmol (3190).

PH-MS; method B Ch3: 7.19 minutes,

HIAT-MS pi/l: 518.3 (M.N.

Example 50 - 39 m-(4-4(3,5-Dimethylisoxazol-4-yl)methyl|sulfonyl)benzyl)-6-methyl-2-oxo-1-III-"trifluoromethyl)phenyl-1,2-dihyde M ropyridine-3-carboxamide trifluoroacetate

With M-(4-mercaptobenzyl)-6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide (29mg, s

0.007 mmol) and 4-(chloromethyl)-3,5-dimethylisoxazole (1 µl, 0.105 mmol). Output: Umg, O.01Zmmol (1995). - 116 RH-MS; method B Ch3: 7.50 minutes,

From HIAT-MS t/: 560.4 (Mn. so

Example 51

M-(4-((4--(Acetylamino)benzyl|sulfonyl)benzyl)-b-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-

Z-carboxamide «

From M-(4-mercaptobenzyl)-6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide (29 mg, - 70 00,007 mmol) and IM-I ( 4-(chloromethyl)phenyl|-acetamide (19mg, 0.105mmol). Yield: 7mg, 0.01Zmmol (18965). c LC-MS; method B Ch3: 6.98 minutes, HIAT-MS t/2: 598 Example 52 6-Methyl-m-I4-(2-(5-methyl-1,3,4-thiadiazol-2-yl)amino|-2-oxoethyl)sulfonyl)benzyl)- 2-oxo-1-III-I(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide b 15 Z M-(4-mercaptobenzyl)-6b-methyl-2-oxo-1-III--trifluoromethyl) phenyl|-1,2-dihydropyridine-3-carboxamide (29mg,

0.07 mmol) and 2-Bromo-N-(5-methyl-1,3,4-thiadiazol-2-yl)acetamide (25 mg, 0.105 mmol). Yield: 4mg, 0.00bmmol - (996). yuyu RH-MS; method B Ch3: 6.62 minutes,

HIAT-MS ti/: 606.2 MN. - and Example 53 also 6-Methyl-M-I(4--methylsulfonyl)phenoxy|-2-oxo-1-3-"trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

Into a mixture of /b-methyl-2-oxo-1-3--trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxylic acid (6b7mgH, 0.22mmol), GATU (93.7mg, 0.25mmol) , GOAT (Zamg, 0.25 mmol), DIPE (15 Ωcl, v87 mmol) and M-MP (2 ml) are added

O-I4-(methylsulfonyl)phenylhydroxylamine obtained by the method described in |U. Honey. Spet., 1967, 5121, (41 mg, 0.22 mmol). After stirring at room temperature for 3 hours, the mixture was partitioned between E(OAc) and (F) water. The organic extract was washed with brine, dried, filtered and evaporated to dryness. Crude

The GI product was further purified by preparative HPLC to give the title compound as a white solid (41mg, 40905). in NMR (SOSIV): δ 12.19 (1H, c); 8.58 (IN, a, 9 7.4Hz); 7.92-7.86 (ZN, t); 7.80 (IN, 6 9 7.9 Hz); 7.57 (1H, 8); 7.50 (1H, a, U 7.9Hz); 7.30-7.26 (5H, t); 6.56 (1H, a, 9 7.5 Hz); 3.03 (ZN, 5); 2.16 (ZN, 5).

HIAT-MS pi/: 567 (MN.

Example 54 6-Methyl-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic acid (4-Bromo-phenoxy)amide 65 Solution of b-methyl-2-oxo-1- -3- trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic acid (0.060 g, 0.200 mmol) in SNHCl" (Bml) and OCI" (Bml) was stirred for 3 hours at room temperature and then concentrated to give crude intermediate chloride as a solid product. The solid product is dissolved in 1,4-dioxane and O-(4-Bromo-phenyl)-hydroxylamine obtained by the method described in MM is added. Honey. Spet., 1967, 5121, (010g, O0.5Zmmol) and the mixture is stirred at room temperature for 10 minutes. Volatiles were removed and the residue was purified by preparative HPLC to afford 0.055g (5890) of the title compound as an off-white solid.

TN-NMR (SOCI"): δ 12.08 (1H, 8); 8.57 (IN, 4, 9 7.42Hz); 7.84 (IN, a, 9 8.01Hz); 7.77 (IN, 5, U 8.01Gu); 7.55 (1H, c); 7.47 (1H, a, U 8.01Gu); 7.38 (2H, a, U 8.87Hz); 7.00 (2H, 8.90Hz); 6.52 (1H, a, U 7.48Hz); 2.13 (ZN, c)

HIAT-MS ti/ 467.1 and 469.0 (Mn.

Example 55 6-Methyl-2-oxo-M-phenoxy-1-133--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide

The title compound is prepared as described in Example 53, starting with O-phenylhydroxylamine. 7"H-NMR (SOSIV): 85 12.04 (1H, 8); 8.58 (1IN, 4); 7.85-7.74 (2H, t); 7.55 (1IN, Bgv); 7.48 (1H, a); 7.32-7.26 (2H, t); 7.12 (2H, a); 7.02 (1H, 9; 6.51 (1H, 9); 2, 12 (ZN, c).

HIAT-MS pi/: 389 (MN.

Example 56 M-14-Aminobenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl-1,2-dihydroproline-3-carboxamide

In a mixture of 1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (212mg, 0.7mmol), GATU (272mgH, 0.7mmol), GOAT (97mg, 0.7mmol) and DIPE (275mg, 2.13mmol) in M-MP (3ml) add (4-aminobenzyl)amine (87mg, 0.7mmol) in M-MP (ml). The reaction mixture was stirred for 12 hours at room temperature. The reaction mixture is diluted with water (1.0 ml) and purified on a HiegtaefRger MS C8 column (19 x 500 mm) using a gradient of the SNUSM/water mixture at a flow rate of 20 ml/minute. Sublimation of the mixture gave the title compound (14Omg, 4996). 7TH-NMR (400 MHz, SOSIz), 5 9.74 (1H, i, at 5.А4Hz), 8.56 (IN, 4, 9 7.5Hz), 7.78 (1H, t), 7.50 (1H, c), 7.43 (IN, a, 9 7.8Hz), 7.27 (IN, 8), 7.15 (2H, a, 7 81Gu), 6.81 (2H, a, in 8, 2Hz), 6.43 (IN, a, at 7.4Hz), 4.49 sch (2H, t), 2.06 (ZN, in, at 9y1Hz)

HIAT-MS t/z 402.2 (Mn. o

Example 57 6-Methyl-Mm-4-((methylsulfonyl)amino|benzyl)-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxa copper

To a mixture of M-(4-aminobenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydroproline-3-carboxamide (in 80 mg, 0.2 mmol) in CHCl" is added methanesulfonyl chloride (2Zmg, O0.2mmol) and DIPE (2bmg, O.2mmol). The reaction mixture is stirred for 0.5 hours at room temperature. "СНССи" is evaporated and the remaining solvent of the CHССМ/water mixture is purified on a HiegasfRger MS C8 column (19Х5О0mm) using a gradient of the mixture

СНзсСМ/water at a flow rate of 20 ml/minute. Sublimation of the mixture gave the title compound (67mg, 70905). -

TN-NMR (400MHz, SOSIi) 5 9.83 (1H, 8), 8.59 (IN, a, 7 7.4Hz), 7.80 (IN, a, at 7.9Hz), 7.73 (IN, In jus 7.8Hz, 7.51 (IN, 8), 7.43 (IN, a, 9 7.9Hz, 7.931 (2H, a, 9 8.4Hz, 7.14 (2H, a, in 84Hz ), 646 (IN, a,» 7,AGu), 6.38 (1H, c), 4.57 (t, 1H), 2.97 (ZH, c, U 3.9Hz), 2.08 ( ЗН, в, В 4.3Hz).

HIAT-MS ti/: 480.1 MN. "

Example 58 40. M-A-Bis(methylsulfonyl)amino)benzyl)-b-methyl-2-oxo-1-III--trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carbox o) c samide " » The title compound is isolated as a by-product by the method described in example 57. " "H-NMR (400 MHz, SOSIS): 5 9.94 (5 at 5.6 Hz, tn), 8.59 (a, at 74 GHz, 1) , 7.82 (9, 9 7.9Hz, 1), 7.75 (i,

In 7.8Hz, 2H), 7.53 (in, 1), 7.45 (5 9 56Hz, ЗН), 7.29 (a, 9 9.7Hz, 2H), -6.47 (a, 9 7.5Hz, 1H), 4.64 (i, 9 5BLAGTS, 2H), 3.39 (z, 6H), 2.09 (z, ZN). so HIAT-MS t/z: 558.4 MN). td Example 59 with M-(o4-(dimethylamino)sulfonyl|amino|phenyl)methyl)-1,2-dihydro-b6-methyl-2-oxo-1-I(3-"'trifluoromethyl)phenyl|-3- pyridinecarboxamide - and The title compound is obtained by adding M-(4-aminobenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydroproline-3-carboxamide and dimethylsulfamoyl chloride (2 mg , 1090) by the method from example 57.

TN-NMR (400MHz, СО300) 5 8.48 (IN, a, 9 7.5Hz); 7.86 (IN, a, 9 7.4 Hz); 7.79 (2H, 6 9 7.9Hz); 7.73 vv H, 8); 7.59 (IN, a, 9 8.5 Hz); 7.25 (2H, a, 9 8.6 Hz); 717 (2H, a, 9 85Hz); 6.63 (IN, a, 9 7.6 Hz); 4.52 (2H, 8,); 2.74 (6H, 5,); 2.09 (ZN, c).

F, HIAT-MS ti/: 509.3 MN. Example 60 6-Methyl-Nm-4-Imethyl(methylsulfonyl)amino|benzyl)-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboboxamide

In a mixture of b-methyl-M-(4-(methylsulfonyl)amino|benzyl)-2-oxo-1-3-3-trifluoromethyl)-phenyl/|-1,2-dihydropyridine-3-carbox copper (10 mg, O0 0.02 mmol) in dichloromethane add iodomethane (4 mg, 0.00 mol) and DIPE (3.9 mg, 0.0 mol). The reaction mixture is stirred for 10 minutes at 602C in the microwave. After evaporation of the solvent, the residue 65 is dissolved in a mixture of CH with CM/water and purified on a HiepassfRger MS C8 column (19x50mm) using a gradient of a SNUSM/water mixture at a flow rate of 20ml/min. Sublimation of the mixture gives the title compound (bmg, -58v-

bean). "H-NMR (400MHz, DMSO-4b) 5 9.83 (IN, 6, at 5.9Hz), 8.38 (IN, a, 9 7.5Hz), 7.89 (2H, a, U 8 ,7Hz), 7.80 (IN, B 9 7.7Hz), 7.71 (IN, a, yuyu 8.0Hz), 7.32 (4H, t), 6.62 (IN, a, 7 7 ,5Hz), 4.48 (2H, a, 59Hz), 3.20 (ZH, 5), 2.91 (ZH, 5), 2.01 (ZH, c)

HIAT-MS ti/: 494.1 MN.

Next, by the general method of example 60, the compounds of examples 60.1-60.7 are obtained:

Example 60.1

M-K4-(butyl(methylsulfonyl)amino|phenyl|methyl|d-1,2-dihydro-b6-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-3-pyride 70 incarboxamide

Using 1-iodobutane. Exit (7mg, 43905). "H-NMR (400 MHz, DMSO-4b) 5 9.86 (IN, 5); 8.38 (IN, a, at 13Hz); 7.89 (2H, a, 9 9.5Hz); 7.80 (IN, U 74Hz; 7.72 (IN, a, U 8.2Hz); 7.32 (4H, 5); 6.63 (IN, a, 9 7.2Hz); 449 (2H, a, 2 58HC); 3.58 (2H, z8v,; 2.91 (ZN, 8,); 2.02 (ZN, 8,); 1.27 (AN, c,); 0.81 (ZN, U 6 ,2Hz).

HIAT-MS ti/ 536.4 (Mn.

Example 60.2 1,2-dihydro-6-methyl-M-K4-(1-methylethylmethylsulfonyl)-amino|phenyl|methyl|-2-oxo-1-I(3--trifluoromethyl)phenyl 1-3-pyridinecarboxamide

Using 2-iodopropane. Output (1Omg, 38905). 720 "H-NMR (400MHz, DMSO-sdv) 5 9.88 (2H, y, U 6.0Hz); 8.39 (2H, a, 9 7.4Hz); 7.89 (4H, a, 711 ,6Hz); 7.80 (ZH, 6 9 7.8Hz); 7.72 (2H, a, 9 8.1Hz); 7.33 (4H, a, at 8.3Hz); 7.22 (4H , a, at 8.3Hz); 6.63 (2H, a, 9 7.6Hz); 4.52 (AN, a, U 6.1Hz); 4.30 (2H, quintet, U 6.7Hz) 3.02 (7H, c), 2.02 (6H, 5), 1.04 (12H, a, U 6.8Hz).

HIAT-MS t/z 522.4 MN". p

Example 60.3

M-(4-(2-Methocaethyl)xmethylsulfonylamino|benzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyride o yn-3-carboxamide

Using 2-bromomethyl-methyl ether. Output (15mg, 3390).

TN-NMR (400MHz, DMSO-4v) δ 9.86 (IN. i, U 5.9Hz); 8.38 (IN, a, at 7.4Hz); 7.89 (2H, a, 9 93Hz); 7.0 "e-

IN, Bu 7vgsh); 7.2 bedrooms, rent 79 UAH; 7.32 (4H, a); 662 (IN, a, 9 7.5Hz); 4.49 (2n, a, yuyu 6boHshch; 3.73 (2N, 9 5.8Hz); 3.29 (2N, i, U 5.7Hz); 3.17 (ZN, v,); 2.98 (ZN, 58); 2.02 (ZN, 5). -

HIAT-MS ti/: 538.4 MN. with

Example 60.4 - -(4-(2-Cyanoethylumethylsulfonyl)amino|benzyl)-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl|-1,2-dihydropyridine n-33-carboxamide (he )

Using 3-bromopropionitrile. Exit (Zmg, 19965). "H-NMR (400MHz, DMSO-4v) 5 9.86 (IN, her); 8.39 (IN, a, at 7.4Hz); 7.89 (2H, a, 9 9.3Hz); 7 ... ... 02 (ZH, 5). 70 HIAT-MS t/: 533.1 (Mn. 8 s Example 60.5: z» MI (ethyl(methylsulfonyl)amino|benzyl)-b-metal-2-oxo-1 - I3--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carb oxamide

Applying iodethane. Exit: (bmg, 5995). so 15 "H-NMR (400MHz, DMSO-4v) 5 9.86 (1H, 6 3 5.9Hz); 8.38 (1H, a, 9 7.4Hz); 7.89 (2H, a, U 93Hz); 7.80

Mon, B 9 78hz; 7.72 (IN, a, 81 Hz); 7.32 (4H, aa, 711.6, 8.7Hz); 6.62 (1H, a, 77.5Hz); 449 (2H, a,» -y 6b,OGts); 3.62 (2H, a, U 7.1Hz); 2.93 (ZN, in,); 2.02 (ZN, in,); 0.96 (ZN, i, U 71Gu);

He HIAT-MS ti/: 508.4 MN.

Example 60.6 - 1,2-Dihydro-6-methyl-N-(4-(methylsulfonyl)propylamino|-phenyl)|-2-oxo-1-3-(trifluoromethyl)phenyl|-3-pyridinecarboxamide

Using 1-iodopropane. Exit (bmg, 57905).

TN-NMR (400MHz, DMSO-iv) δ 9.86 (IN, 6, 96.0Hz); 8.38 (IN, a, 9 7.5Hz); 7.89 (2H, a, at 8.8Hz); 7.80

IN, BU 7vGgu); 72 (1H, a, at 82Hz); 7.32 (4H, 5); 6.62 (1H, y, 9 7.7Gu); 4.49 (2H, a, at 6.0Hz); 3.54 (2H, M, U 7.1Hz); 2.92 (ZN, v8,); 2.01 (ZN, in,); 1.91 (2H, a, U 7.2Hz); 0.80 (ZN, E, U 7.3 Hz). o HIAT-MS t/z: 522.4 MN). Example 60.7

M-K4-(3-Amino-3-oxopropylmethylsulfonyl)amino|-methyldihydro-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyld|-3 60 -pyridinecarboxamide

Using 3-bromopropionamide. Exit (7mg, 30905). "H-NMR (400 MHz, DMSO-iv) 5 9.86 (IN, 6 9 6.0 GHz); 8.39 (1H, a, U 7.5 Hz); 37.89 (2H, 4, U 10, 5Hz); 7.80

IN, 69 7, ig); 7.72 (IN, a yuyu 7v8Hz; 7.32 (5H, aa, in 11.0, 88Hz); 6.81 (IN, in,); 6.63 (IN, a, 9U7.6Gu); 4 .50 (2H, a, 96.0Hz); 3.80 (2H, i, 9 7.5Hz); 2.96 (ZH, c); 2.17 (2H, i, U 1.6Hz); 2 ,02 (ZN, c). because HIAT-MS t/": 551.4 (MN.

Example 61 1,2-dihydro-b6-methyl-N-(4-methylsulfonyl)oxy|phenyl,2-(trifluoromethyl)phenyl|-3-pyridinecarboxamide a). M-(4-Hydroxybenzyl)-6-methyl-2-oxo-1-3-"-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

In a mixture of 1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (g, 3.3 mmol), GATU (1.28 g,

3.5 mmol), GOAT (457mg, 3.3bmmol) and DIPE (1.7g, 13.3bmmol) in M-MP (10ml) add (4-hydroxybenzyl)amine hydrobromide (68bmg, 3.3bmmol) in M-MP (5 ml). The reaction mixture was stirred for 12 hours at room temperature.

The reaction mixture was diluted with water (75.0 ml) and extracted with EtOAc, the organic phase was dried with magnesium sulfate 7/0, filtered and evaporated to give the title compound (1.2 g, 8990). "H-NMR (400MHz, DMSO-iv) 5 9.66 (IN, 6, U 5.7Hz); 9.27 (1H, 85); 8.36 (IN, 4, U 7.4Hz); 7 ... ,z3Hz); 6.67 (2Н, а, у 8.5Hz); 6.60 (1Н, а, 9 7.4Hz); 4.33 (2Н, а, У 5.8Hz); 1.99 ( ZN, c).

HIAT-MS ti/: 403.3 MN.

B) 1,2-Dihydro-6-methyl-N-(4-Kmethylsulfonyl)oxy|phenyl)methyl)-2-oxo-1-3-(trifluoromethyl)phenyl|-3-pyridinecar boxamide

The title compound is obtained by Kk!

M-(4-Hydroxybenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide and methanesulfonyl chloride as in example 57 (20Omg, 8490). "H-NMR (400MHz, DMSO-4dv) 5 9.87 (IN, B in bogtz); 8.38 (IN, a, in 7.5Hz); 7.89 (2H, a. 78.9Hz); 7.80

IN, Bu 78hshsh; 7.72 (1H, a, 9 7.9 Hz); 739 (2H, a, in 86Htssh); 7.29 (2H, a, at 8.6Hz); 6.62 (1H, a, 9 7.5Gu); 4.50 (2H, a, U 6.0Hz); 3.35 (ZN, 5); 2.02 (ZN, c).

HIAT-MS t/z: 481.3 MN. p 29 Example 62 2-Propanesulfonic acid (4-CC2dihydro-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-3-pyridinium|carbonylamino|methyl|phenyl ester

The title compound is obtained by Kk!

M-(4-hydroxybenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide and isopropylsulfonyl chloride as in example 57. -- "H-NMR ( 400MHz, DMSO-yv) 5 9.83 (IN, her); 8.35 (IN, a, 9 7.5Hz); 7.86 (2H, a, 9 87Hz); 778 (IN in 7.7Hz) ; 7.69 (IN, а, 9У 7.3Hz); 7.35 (2Н, а, у 8.5Hz); 7.22 (2Н, а, У 86Hz); 6.6О (1IN, а, 9 7.3Hz); 4.46 (2H, sch a, U 6.2Hz); 3.66 (1H, t); 1.99 (ZH, 5); 1.38 (6H, a, U 6.9Hz ).

HIAT-MSti/ 509.4 MN". --

Example 63 so

IM-(01,1-Dioxido-2,3-dihydro-1-benzothien-5-yl)umethyl/|-6-methyl-2-oxo-1-3--trifluoromethyl)phenyl|)|-1,2 -dihydropyridine-3-carboxamide a) 2,3-Dihydro-1-benzothiophene-5-carbaldehyde and 2,3-Dihydro-1-benzothiophene-7-carbaldehyde

The sub-title compounds are obtained by the method described in (MO 01/126021. "c) 2,3-Dihydro-1-benzothien-5-ipmethanol and 2,3-Dihydro-1-benzothien-7-ylmethanol -o c The title compounds are obtained by mixing mixture of 2,3-dihydro-1-benzothiophene-5-carbaldehyde and 2,3-dihydro-1-benzothiophene-7-carbaldehyde (4.3 g, 2 mmol) with sodium borohydride (3.78 g, 1000 mmol) in THF: (100ml) and water (1Oml) at room temperature overnight. 1M hydrochloric acid is added slowly to quench excess borohydride. The mixture was extracted with E(OAc) and washed with water. The solvents were removed in vacuo and the residue was purified by column chromatography on silica using heptane/g(OAc (4:1) as eluent to give 2,3-dihydro-1-benzothien-5 -ylmethanol (1.84 g): "H-NMR. (SOS): 6 7.22 (1H, gg); 7.20 (1H, d, at 8.3Hz); 7.11 (1H, Bha, at 8.3Hz); 4.61 (2H, c); 3.41-3.25 (4H, t); - and 2,3-dihydro-1-benzothien-7-ylmethanol (1.18g) (total yield 7095): name) "H-NMR (SOSIv): 5 7.18 (1H, a, U 7.5Hz); 7.15 (1H, a, U 7.5Hz); 7.05 (1H, i, In 7.5 Hz); 4.63 (2H 5); 3.41-3.28 (AN, t). - 20 s) 1,1-Dioxido-2,3-dihydro-1-benzothien-5-yl )umethanol

The title compound is obtained by mixing 2,3-dihydro-1-benzothien-5-ylmethanol (1.08g, 6.38mmol), "6-oxone (5.8g, 9.4mmol), aqueous EDTA (22ml, 0.4mM), and sodium hydrogen carbonate (4.8g) in a mixture of acetone and water at pH 7.5 at room temperature overnight. The reaction mixture was extracted with EtOAc and washed with water. The solvents were removed in vacuo and the residue was purified by silica column chromatography using heptane/g (OAc (4:1) as eluent to give the sub-title compound (1.0 g, 7990).

F! "H-NMR (SOSIV): 5 7.70 (1H, a, U 7.9Hz); 7.43 (1H, a, y 7.9Hz); 7.42. (1H, c); 4.79 (2H, c); 3.53-3.36 (AN, t). a) 5-(bromomethyl)-2,3-dihydro-1-benzothiophene-1,1-dioxide o The title compound is obtained by boiling under (1,1-dioxido-2,3-dihydro-1-benzothien-5-yl)umethanol (1.0g, bmmol) with phosphorus tribromide (0.524g, 0.188ml, b0 2mmol) in dry toluene (200ml) for 71 hours. Water was added and the crude mixture was extracted with EtOAc, washed with water and brine and dried. The solvents were removed in vacuo to give the sub-title compound (1.15g, 8896).

NMR (SOCI5): 6 7.73 (IN, a, 9 8.0 Hz); 7.51 (IN, a, at 8.0Hz); 7.43 (IN, 58); 4.51 (2H, 58); 3.53 (2H, U 6.8Hz); 3.43 (2H, i, U 6.8Hz). bo f) (1,1-dioxido-2,3-dihydro-1-benzothien-5-yl)umethylamine

The title compound is obtained by mixing 5-(bromomethyl)-2,3-dihydro-1-benzothiophene 1,1-dioxide (1.14g, 4.5 mmol) with aqueous ammonia (43ml) in a 1:1 methanol/THF mixture (30ml) overnight. The solvents were removed in vacuo to give the sub-title compound (700mg, 8190).

TN-NMR (SOCI3): δ 8.05 (2H, bgv); 7.82 (1H, a, 9 8.3Hz); 7.63 (IN, B); 7.61 (1H, a, U 8.3Hz); 4.15 (2H, a); 3.62 (2H, i, 7 6.9Hz); 3.36 (2H, E, U 6.9Hz).

HIAT-MS t/g2:198 (ML. 9

(1,1-dioxido-2,3-dihydro-1-benzothien-5-yl)umethyl)-b-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2-dihydropyr 70 din-3-carboxamide

Starting with β-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxylic acid (74 µgH, 2.5 mmol) and (1,1-dioxido-2,3- dihydro-1-benzothien-5-yl)umethylamine (500 mg, 2.5 mmol) by the method described in Example 17, the title compound (1.05 g, 88965) is obtained.

TN-NMR (SOSIv): 5 9.94 (1H, B U bogtz); 8.39 (IN, a, at 7.5Hz); 7.93 (1H, 85); 7.91(1Н, а, 97.7Г); 75 7.83 (1H, 6 07.7Hz); 7.74 (1H, a, 9 11hz)y; 7.70 (IN, a, 9 8 Hz); 7.45 (1H, a, at 80Hz); 7.43 (1H, c); 6.64

PN, a, 2 7.5Gu); 4.58 (2H, a, 9 6.0Hz); 3.57(2H, i, U 6.9Hz); 3.34(2H, i, U 6.9Hz); 2.04 (ZH, c).

HIAT-MS t/2:477 (MN.

Example 64

IM-(O1,1-dioxido-2,3-dihydro-1-benzothien-5-yl)umethyl|-5-iodo-6-methyl-2-oxo-1-IZ--trifluoromethyl)phenyl|d|- 1,2-dihyde ropyridine-3-carboxamide

In solution

IM-(01,1-dioxido-2,3-dihydro-1-benzothien-5-yl)umethyl|-b-methyl-2-oxo-2-3--trifluoromethyl)phenyl)-1,2-dihydropyr dyne-3-carboxamide (102mg, 0.21mmol), dichloromethane (1.8ml) and TFOK (0.9ml). add M-iodosuccinimide (47 mgHg, 0.21 mmol). The mixture was stirred at room temperature for 4 hours and the solvent was then removed under vacuum at 29°C. The residue is distributed between EOAc and an aqueous solution of sodium hydrogen carbonate, and the organic Ge) extract is washed with water, dried, filtered and evaporated. The crude product was purified by preparative HPLC to give the title compound as a white solid (87mg, 69905). 7TH-NMR (SOSIz): 5 9.85 (IN, 6 at 5.7 Hz); 8.91 (IN, 8); 7.83 (IN, a, 9 8 Hz); 7.76 (IN, 6 U 8.0Gu); - 20 7.68 (IN, a, 9 8.0Hz); 7.49 (IN, 5); 7.41 (2H, a, 9 8.0); 7.34 (IN, 5); 4.64 (2H, i, 9 6.5Hz); 3.48 (2H, i, - 6.9Hz); 3.35 (2H, i, U 7.0Gsh); 2.32 (ZN, 5). -

HIAT-MS t/2:603 МН. with

Example 65 5-Iodo-M-4-(isopropyl(methylsulfonyl)amino|benzyl)-b-methyl-2-oxo-1-3-(trifluoromethyl)phenyl|-1,2-dihydropyride-yn-3-carboxamide so

The title product is obtained as described in Example 64, but starting with Kk!

M-4-(isopropyl(methylsulfonyl)-amino|benzyl)b-methyl-2-oxo-1-3-(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-k arboxamide.

White powder (4mg, 6890). 7"H-NMR (400MHz, DMSO-yv) a 9.77 (IN, 5, 9 b1GHz); 8.61 (IN, 8); 7.90 (2H, 6 in 82ghshsh; 751 (Nu Zh s 7.9Hz); 7.72 (IN, a, U 7.9G); 7.33 (2H, a, at 82Hz); 721 (2H, a, U 893Hz); 4.51 (2H, a, 9 god); 4.30 (1H, th quintet, U 6.7 Hz); 3.02 (ZH, c); 2.20 (ZH, c); 1.04 (6H, a, U 6.7 Hz). "» HIAT-MS t/2:648 МН.

Example 66 1,2-dihydro-b6-methyl-N-(4-(methylsulfonyl)methyl|phenyl|-methyl|/|-2-oxo-1-3--trifluoromethyl)phenyl|-3-pyridine (ee) rboxamide - a) 6-Methyl-M-(4-(methylthio)methyl|benzyl)-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide and a mixture of 1-(C -methylphenyl)-2-oxo-4,2-dihydropyridine-Z-carboxylic acids (412mg, 2.39mmol), VTTU (527mg, -1 50 1.39mmol) and DIPE (719mg, 5.5bmmol) in M-MP add (methylthio)methyl|benzene (232mg, 1.39mmol) in M-MP (1ml), stir the reaction mixture for 1 hour at room temperature, then dilute with water - and (15ml) and extract E(Ac. The organic phase is dried magnesium sulfate, filtered and evaporated to give the crude title compound (620 mg), which was used directly in the next step.

B) 1,2-Dihydro-6-methyl-N-(4-(methylsulfonyl)methyl|phenyl|-methyl|/|-2-oxo-1-3--trifluoromethyl)phenyl|-3-pyridine rboxamide. o To crude imi) b-methyl-1M4-4-Kmethylthio)methyl|benzyl)-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide (620mg 1.39mmol) in M-chloroperoxybenzoic acid (48 µg, 2.8 mmol) is added to CHNCl" (1 Oml), cooled to -1509С. The mixture is stirred for 30 minutes and then overnight at room temperature. The reaction mixture is further diluted with CHCl and water, washed with sodium thiosulfate, sodium hydrogen carbonate and brine. The solvent is removed under vacuum and 25 mg of the residue is dissolved in a mixture of CH with CM/water (2.Oml) and purified on a Hiegae FRger MS C8 column (19X50Ωm) using a gradient of the mixture of CH with CM/water at a flow rate of 20 ml/min. Sublimation of the mixture afforded the title compound (15mgH). b5 7"H-NMR (400MHz, DMSO-yv) 5 9.66 (IN, i, U 5.7Hz); 9.27 (1H, 8); 8.36 (IN, a, 9 7.4Hz); 7 .86 (2H, a, u

4.5Hz); 7.78 (IN, i, U 8.0Gsh); 7.68 (IN, a, 9 7.9 Hz); 7.06 (2H, a, 9 8, z3Hz); 6.67 (2H, a, at 8.5 Hz); 6.60 (1N. a, U 7.4 Hz); 4.33 (2H, a, U 5.8Hz); 1.99 (ZN, c).

HIAT-MS ti/: 479.3 MN.

Example 67 b-Chloro-5-methyl-4-3-methylphenyl-N-(4-(methylsulfonyl)benzyl|-3-oxo-3,4-dihydropyrazine-2-carboxamide a) 6b-Chloro-5-methyl- 4-3-methylphenyl)-3-oxo-3,4-dihydropyrazine-2-carbonitrile

The title compound is prepared as described in substance (Sbirvzop, ei a). 9. Ogud. Spent 1994, 59, 1072-1077 and

Nootaegiei a!. Teigapedgop, 1990, 46, 5715-5732). 70 c) 6-Chloro-5-methyl-4-(3-methylphenyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid.

A solution of b-chloro-5-methyl-4-(3-methylphenyl)-3-oxo-3,4-dihydropyrazine-2-carbonitrile (100 mg, 0.3 mmol) in 11M sulfuric acid (1 Oml) is heated at 902C for 16 hours . Water (200 ml) is added. The aqueous phase is extracted with dichloromethane. The organic layer was dried, filtered and evaporated to give the sub-title compound (2Omg, 19906).

HIAT-MS t/: 279.2 |IMH7,

VERH Spgotoiy zreeakoo KR 18e 50-4 bmm, flow 2.5ml/minute, wavelength 254nm, time 1.93 minutes. c) 6-Chloro-5-methyl-4-(3-methylphenyl-M-I(4--(methylsulfonyl)benzyl)-3-oxo-3,4-dihydropyrazine-2-carboxamide

The title compound is obtained starting with Kk! b-chloro-5-methyl-4-(3-methylphenyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid and (4-methylsulfonyl)benzylamine, as described in example 17. "H-NMR (DMSO -yv): 5 9.68 (IN, 0; 7.87 (2H, a); 7.57 (2H, a); 7.49 (IN, 0; 7.36 (IN, 4); 7, 19 (2H, 4); 4.59 (2H, a); 3.18 (ZN; 5); 2.36 (ZN, 58); 2.11 (ZN, c).

HIAT-MS ti/: 446.3 (MN.

Example 68 p 29 5-Bromo-6-(difluoromethyl)-M-I4--"methylsulfonyl)benzyl)-2-oxo-1-3-"-trifluoromethyl)phenyl|-1,2-dihydropyridine He)-3- carboxamide a) Ethyl b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxylate

The title compound is obtained by mixing a mixture of b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxylic acid (20.8g, 7Omol) with sodium carbonate (8.16g , 7/mmol) in M-MP (15OmL). Ethyl iodide (15.6g, 100mmol) was added slowly (about 10-15 minutes) and the mixture was stirred at room temperature for 4 hours. Water was added and the crude product was extracted with E(OAc, washed with water and dried and filtered. The solvent was removed in vacuo and the residue was triturated with diethyl ether (10 mL), filtered, washed with diethyl ether and dried to give the -(chee subtitle compound (18g, 7995) as a white solid). "H- NMR (SOSIZU 8 8.21 (IN, 4, 9 7AGCsu 7.75 (IN, a, 9 1.9Hz) .25 (1H, a, 9 7.4Hz); 4.36 (2H, a, U 7.2Hz); 2.03 (ZH, c); 1.37 (ZH, , U 7.2Hz).

HIAT-MS pi/: 326 (MN.

B) Ethyl 5-bromo-6-(bromomethyl)-2-oxa-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxylate

The sub-title compound (3.25g, 9896) was obtained by mixing ethyl with b-methyl-2-oxa-1-3-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxylate (2.25g, b, 9mmol ) with

M-bromosuccinimide (2.45 g, 13.8 mmol) and benzoyl peroxide (35 mg, 0.14 mmol) in carbon tetrachloride (40 mL) at 702 for 4 hours. "H-NMR (SOCI3): 5 8.33 (1H, 8); 7.82 (1IN, 4, U 7.9Hz); 7.72 (1H, 6 9 7.9Hz); 7.62 (1H , c); 7.56 (1H, ad,

And 1.9Hz); 4.38 (2H, a, U 7.1Hz); 4.16-4.08 (2H, t); 1.37 (ZN, i, U 71Gu). so HIAT-MS t/g: 482/484/486 (Mn. - s) Ethyl 5-bromo-6-(hydroxymethyl)-2-oxo-1-3--trifluoromethyl)phenyl|-1,2-dihydropyridine- 3-carboxylate

The sub-title compound is obtained in quantitative yield by mixing ethyl ime) 5-Bromo-6-(bromomethyl)-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxylate with aqueous sodium - 50 hydrogen carbonate in aqueous THF at 602C overnight. 7"H-NMR (SOCI3): 5 8.35 (1H, 8); 7.78 (1H, a, 9 7.9Hz); 7.65 (IN, 6U 7.9Hz); 7.17 ( 1H, 8); 7.50 (1H, a, tya - 7.9Hz); 4.45-4.33 (4H, t); 1.37 (ZH, U 7.1Hz).

HIAT-MS: 420/422 MH 7. a) Ethyl 5-Bromo-6-formyl-2-oxo-1-3-trifluoromethyl)phenyl (1,2-dihydropyridine-3-carboxylate)

Dimethylsulfoxide (1.14g, 1.03bml, 14.bmmol) is added dropwise to a solution of oxalyl chloride (0.93g, 0.b4ml,

HF) 7.Zmmol) in dry СНоСі» (40 ml) at -702С in an argon atmosphere. After stirring for 10 minutes, add ethyl g 5-Bromo-6-(hydroxymethyl)-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxylate (2.8 g, 6.6 mmol) in SiOCl" (10 mL) and stirring is continued for 20 minutes, then triethylamine (3.34 g, 4.bml, in 33 mmol) is added. After another 15 minutes at low temperature, the reaction mixture is allowed to reach -159C and water (20 mL) is added. Stirring is continued until the reaction mixture reaches room temperature. It is then extracted with water and SiO 2 , washed with brine, dried and filtered. The solvents are removed in vacuo and the residue is purified by silica column chromatography using CH 2 SiO 2 as eluent to afford the title compound (1 ,46g, 52965). 65 TN-NMR (SOSI8): 5 9.74 (1H, 5); 8.31 (IN, 85); 7.75 (1H, a, U 13Hz); 7.65 (1H . 6, In 71Gu).

HIAT-MS t/l: 418/420 MN. f) Ethyl 5-bromo-6-(difluoromethyl)-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxylate.

The subtitle compound is obtained by stirring with ethyl

3-Bromo-6-formyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxylate (0.98g, 2.34mmol) with (diethylamino)sulfur trifluoride (SAZT) 1378mg , 2.34 mmol) in dry SOCl (20 ml) overnight. Water is added and the reaction mixture is extracted with CHClCl. The solvents were removed in vacuo to give 1.06 ug (10095) of the sub-title compound. "H-NMR (SOSISCH): 5 8.29 (IN, B 91 Hz); 7.77 (IN, a, in vyg); 7.65 (IN, 6 U 81 Hz); 7.53 (1H, in ); 70.TAv(H, 678.1Hz); 6.82 (1H, 5, U 55.1Hz); 4.39 (2H, a, U 7.1Hz); 1.38 (2H, a, U 7.1Hz).

HIAT-MS: 440/442 МН 7. 9 5-Bromo-6-difluoromethyl)-M-I4-(methylsulfonyl)benzyl)-2-oxo-1-3-trifluoromethyl)phenyl)-1, 2-dihydropyridine-

Z-carboxamide

The title compound is obtained from 5-

Bromo-6-(difluoromethyl)-2-oxo-1-3-"-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxylic acid (obtained from ethyl 5-Bromo-6-(difluoromethyl)-2- oxo-1-III-(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxylate by alkaline hydrolysis) and 4-(methylsulfonyl)benzylamine hydrochloride by the method described in example 17.

TN -NMR (SOSIv): 5 9.79 (1H, Bi, U 52Hz); 8.78 (1H, 8); 7.89 (2H, a, U 8.4Hz); 7.82 (IN, a, U 7.8Gu); 770 (1H, 6 at 7.8Hz); 7.55 (1H, 8); 7.50 (2H, a, U 84Hz); 7.47 (IN, a, U 7.8Hz); 6.92 (IN, 5 V 51.9 Hz); 4.67 (2H, t); 3.02 (ZN, c).

HIAT-MS ti/»: 579/581 МН 7.

Example 69 in 6-"Difluoromethyl)-IM-4-"methylsulfonyl)benzyl|-2-oxo-1-III--trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide (HO)

The title compound was obtained by hydrogenation of 5-Bromo-6-difluoromethyl)-N-(4-methylsulfonyl)benzyl|-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide with palladium on coal (Ra/C) and ammonium formate in methanol. - zo 7TN-NMR (SOSIz): 5 10.00 (1H, B 9 5.8Hz); 8.76 (1H, a, 9 7.5Hz); 7.89 (2H, a, U 82Hz); 7.87 (1H, a, at 7.9 GHz); 7.77 (IN, 6 9 7.9 UAH); 7.58 (IN, 8); 7.52 (IN, a, 9 7.9Hz); 7.51 (2H, a, 9 82Hz); 6.98 (IN, a, 7. i- 7.5 Hz); 6.10 (1H, E, U 53.0Hz); 4.70 (ZN, c). high school

HIAT-MS ti/g: 501 (MN.

The compounds of examples 70.1-70.50 were obtained by a method similar to that described in examples 1 and 2: --

Example 70.1 p

IM-(2,3-Dihydro-1,4-benzodioxin-b-ylmethyl)-b-methyl-2-oxo-1-3-rifluoromethyl)phenyl|-1,2-dihydropyridine-3-carb oxamide

TN NMR (DMSO-iv): 5 9.93 (IN, 9; 8.38 (IN, a); 7.88 (2H, 4); 7.80 (1H, 9; 7.70 (IN, a ); 6.79-6.70 (ZH, "t); 6.62 (1H, 4); 4.34 (2H, 4); 4.18 (4H, 5).

HIAT-MS p/z: 466.3 (Mn. o) s Example 70.2 "» 6-Methyl-M-3-"methylsulfonyl)benzyl|-2-oxo-1-3--trifluoromethyl)phenyl|- 1,2-dihydropyridine-3-carboxamide " "IN NMR (DMSO-di5): 5 9.93 (1H, 0; 8.38 (1H, a); 7.95-7.45 (BH, t); 6.62 (1H, 4); 4.58 (2H, 49); 3.18 (ZH, c).

Example 70.3 6-Methyl-M'-(4-methylsulfonyl)phenyl)|-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carbohydrazide with TN NMR (DMSO -yv): 5 10.80 (IN, 8); 9.62 (IN, a); 7.99-7.74 (4H, t); 7.65 (2H, 4); 6.80 (2H, a); 6.67th (IN, 49); 3.07 (ZN, c). 7 Example 70.4

M'-(4-bromophenyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carbohydrazide - T"H NMR (DMSO-dibbv): 5 10 .69 (1H, c); 8.35 (1H, a); 7.99-7.73 (4H, t); 7.29 (2H, a); 5.66 (ZH, ad). -" ZM Example 70.5

M-(5-Methoxy-4-oxo-4H-pyran-2-yl)umethyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridin-3-carb oxamide

HIAT-MS pi/l: 435.2 MN.

Example 70.6 o M-(4-Cyanobenzyl)-6-methyl-2-oxo-1-III--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide iso) HIAT-MS n/z: 412 ,3 (MN.

Example 70.7 60 0/0 M-13-(4-Methoxyphenyl)isoxazol-5-yl|methyl|-bmethyl-2-oxo-1-3--trifluoromethyl)phenyl|-1,2-dihydropyridin-3- car boxamide

HIAT-MS p/z: 484.4 MN).

Example 70.8

M'-(4-Cyanophenyl)-6-methyl-2-oxo-1-3-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carbohydrazide, HIAT-MS pi/l: 413.3 (MH .

Example 70.9 6-Methyl-2-oxo-M-(1-phenyl-1H-pyrazol-4-yl)methyl)-1-(3-"-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3 -carboxamide

HIAT-MS pi/l: 467.3 (Mn.

Example 70,10

IM-(2,3-dihydro-1,4-benzodioxin-1-ylmethyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridin-3-carb oxamide

HIAT-MS pi/l: 445.2 MN.

Example 70,11 70. 6-Methyl-M-(1-(3-methylphenyl)-1H-pyrazol-4-yl)methyl)-2-oxo-1-3-trifluoromethyl)phenyl|-1,2 -dihydropyridine-3-ka rboxamide

HIAT-MS p/z: 467.3 (MN.

Example 70,12

M'-(4-Chlorophenyl)-6-methyl-2-oxo-1-I(3-trifluoromethylphenyl|-1,2-dihydropyridine-3-carbohydrazide 19 HIAT-MS p/z 422.2 (MH.

Example 70.13 6-Methyl-2-oxo-M-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxami d

HIAT-MS pi/l: 409.4 MN.

Example 70,14

M-(1-Ethyl-1H-pyrazol-4-yl)umethyl/|-b-methyl-2-oxo-1-(3-"-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide

HIAT-MS p/z: 405.2 (Mn.

Example 70,15

M-K4-Benzylmorpholin-2-yl)methyl)-b-methyl-2-oxo-1-3-"-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide sch » HIAT-MS ti/: 4863 (MN. Fr

Example 70.16 6-Methyl-M-|3-(-2-methylpiperidine-1-lylpropyl)-2-oxo-1-3--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxami d «- from HIAT-MS pi/l: 436.3 (Mn.

Example 70.17 Methyl 2-C(b-methyl-2-oxo-1-3-trifluoromethyl)phenyl(1,2-dihydropyridin-3-yl)-carbonyl)amino|methyl)-3-furoate with

HIAT-MS pi/g: 558.3 MNI.

Example 70.18 -- 6-Methyl-Mm-(1-methyl-1H-pyrazol-4-yl)methyl-1|-2-oxo-1-3--trifluoromethyl)phenyl|-1,2-dihydropyridin-3- Carboxami so d

HIAT-MS p/z: 391.2 (MN.

Example 70.19 "

M-13-Azepan-1-ylpropyl)-6-methyl-2-oxo-1-13-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 436.3 (Mn. - s Example 70.20 a 6-Methyl-M-(2-morpholin-4-ylpropyl)-2-oxo-1-3--trifluoromethyl)phenyl|- 1,2-dihydropyridine-3-carboxamide HIAT-MS pi/l: 424.3 (M.N.

Example 70,21 8-Methyl-2-oxo-M-(3-piperidin-1-ylpropyl)-1-I(3-trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide with HIAT-MS p/z: 422.3 MN. - Example 70,22

IM-IZ-(3,5-Dimethyl-1H-pyrazol-1-yl)propyl)-b-methyl-2-oxo-1-IZ--trifluoromethyl)phenyl|-1,2-dihydropyridin-3-carb de oxamide - 2 HIAT-MS ti/: 433.3 (Mn. ah Example 70.23 IM-IZ-(2-7" Ethylpiperidin-1-yl)propyl)-b-methyl-2-oxo-1-IZ- "-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 450.4 MN.

Example 70.24 6-Methyl-m-(2-(1-methyl-1H-imidazol-5-yl)ethyl)-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridin-3 -carboxam (F. id g HIAT-MS pi/l: 405.2 MN.

Example 70.25 in M-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)methyl|-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine -3-carb oxamide

HIAT-MS p/z: 419.2 (MN.

Example 70,26

IM-(4-(Acetylamino)benzyl)|-b-methyl-2-oxo-1-III-"-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide 65 HIAT-MS pi/l: 444 ,2 MN.

Example 70,27

6-Methyl-2-oxo-M-I(3-(1H-pyrazol-1-yl)propyl I|-1-(3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 405.2 MN.

Example 70.28 8-Methyl-2-oxo-N-(pyridin-2-ylmethyl)-1-I(3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

HIAT-MS ti/: 3883 (MN.

Example 70.29 6-Methyl-M-11-(4-methylphenyl)-1H-pyrazol-4-yl|methyl)-2-oxo-1-3--trifluoromethyl)phenyl|-1,2-dihydropyridine-3 - car boxamide

HIAT-MS pi/l: 467.3 (Mn.

Example 70,30 6-Methyl-M'-14-methylphenyl)-2-oxo-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carbohydrazide

HIAT-MS pi/l: 402.2 MN.

Example 70,31 79. v-Methyl-M-I33-(4-methylpiperidin-1-yl)propyl|-2-oxo-1-13--trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxami d

HIAT-MS p/z 436.3 MN")

Example 70.32 6-Methyl-2-oxo-IM-I3-(5-oxo-4,5-dihydro-1H-pyrazol-4-yl)propyl|-1-(3-"'trifluoromethyl)phenyl|- 1,2-dihydropyridine-

Z-carboxamide

HIAT-MS p/z: 421.3 (MH,

Example 70.33 Ethyl 5-methyl-4-(((6b-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridin-3-yl)carbonyl))amino|methyl)- 2-furoa ts » HIAT-MS pi/l: 463.3 (M. o

Example 70,34

M-Kb-Fluoro-4H-1,3-benzodioxin-8-yl)methyl/|-6-methyl-2-oxo-1-3--trifluoromethyl)phenyl/|-1,2-dihydropyridin-3-ka rboxamide "- by HIAT-MS pi/l: 463.3 (Mn.

Example 70.35 - 6-Methyl-2-oxo-N-(2-pyridin-3-ylethyl)-1-(3-"-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide c

HIAT-MS pi/l: 402.2 MN.

Example 70,36 -

M-((1,3-Dimethyl-1H-pyrazol-4-yl)methyl|-b-methyl-2-oxo-1-3--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carbox c amide

HIAT-MS p/z: 405.2 (Mn.

Example 70.37 "6-Methyl-2-oxo-N-(2-pyridin-4-ylethyl)-1-(3-"-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide

HIAT-MS pi/l: 402.2 MN. t s Example 70.38 h» M'-(4-Fluorophenyl)-6-methyl-2-oxo-1-3--trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carbohydrazide" HIAT-MS pi /l: 406.2 MN.

Example 70.39 v-Methyl-M-(1-methyl-1H-pyrrol-2-yl)umethyl)|-2-oxo-1-3-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carboxamide

Me HIAT-MS ti/g: 390.3 (Mn. - Example 70.40 6-Methyl-2-oxo-M'-phenyl-1-3-trifluoromethyl)phenyl)|-1,2-dihydropyridine-3 - caribsite drazid

HIAT-MS pi/: 388.3 MN. name)

Example 70,41 - and 50 M-(1-Ethyl-5-methyl-1H-pyrazol-4-yl)umethyl|-6-methyl-2-oxo-1-3--trifluoromethyl)phenylI-1,2- dihydropyridine-3-carb also oxamide

HIAT-MS p/z: 419.2 (MN.

Example 70.42 6-Methyl-m-(2-(1-methyl-1H-imidazol-4-yl)ethyl|-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridin-3 -carboxam

ID

(F, HIAT-MS p/z: 405.2 (Mn. ka Example 70.43

IM-(2-(1,3-Dioxolan-2-yl)ethyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide in HIAT-MS pi/: 397.3 (MN.

Example 70,44

M-(1-Benzothien-3-ylmethyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl)-1,2-dihydropyridin-3-carboxamide

HIAT-MS p/z: 443 (MN.

Example 70.45 65 M-(1,5-Dimethyl-1H-pyrazol-4-yl)umethyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridin-3 -carbox amide

HIAT-MS p/z: 405.2 (Mn.

Example 70,46

1-(2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl|-6-methyl-2-oxo-1-3-"(trifluoromethyl)phenyl|-1,2-dihydropyridin-3- karbok samid

HIAT-MS p/z 419.2 (MN).

Example 70.47

I-(2-(3,5-Dimethylisoxazol-4-yl)ethyl|-6-methyl-2-oxo-1-3--trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxa copper

HIAT-MS pi/l: 420.3 (M.N.

Example 79,48

IM-(3,4-dihydro-1H-isochromen-1-ylmethyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridin-3-carboxamide

HIAT-MS pi/l: 443.2 MN. 19 Example 70,49

M-((2K)-1-Ethylpyrrolidin-2-yl|methyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxami d

HIAT-MS pi/l: 408.3 (M.N.

Example 70.50 6-Methyl-2-oxo-M-((2K)-tetrahydrofuran-2-ylmethyl)-1-III--trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxami d

HIAT-MS p/z: 381.2 (MN.

Example 70.51 5-Chloro-M-4-(dimethylamino)sulfonyl)benzyl)-6-methyl-2-oxo-1-III-(trifluoromethyl)phenyl|-1,2-dihydropyridine-3 sch 29-carboxamide Ge) a). M-(4-(Benzylthio)benzyl|-6-methyl-2-oxo-1-3--(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

The subtitle compound is prepared as described for

I-(4-(benzylsulfonyl)benzyl|-6-methyl-2-oxo-1-3-(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide (Example 27 (B)), but without the step oxidation The subtitle product is purified by preparative HPLC column -- (eta, 0.295 ammonia, acetonitrile) to give the title compound.-

TN NMR (DMSO): 5 9.78 (IN, 6 9 6bHz); 8.37 (IN, a, at 7.5 Hz); 7.91-7.68 (4H, t); 7.35-7.16 (9H, t); sch 6.62 (1H, a, 7 7.6 Hz); 4.47-4.37 (2H, t); 4.20 (2H, 8); 2.01 (ZN, c).

HIAT-MS ti/: 509 (MN. --

B) so 5-Chloro-M-4-(dimethylamino)-sulfonyl)benzyl)-b-methyl-2-oxo-1-3-"-trifluoromethyl)phenyl)-1,2-dihydropyridine-

Z-carboxamide

A mixture of 5095 formic acid/water (13 ml) and СНоСиИ» (U9 ml). The reaction mixture is cooled to -202С and blown with chlorine gas for 1 minute. After evaporation of excess chlorine for 8 seconds, the reaction mixture is distributed between CHNClCl and water. The organic phase is washed with a 0.5 M aqueous solution of sodium bicarbonate and brine, and then dried. After filtration, the solvent is removed under vacuum and the residue is dissolved in ethanol (10 mL). 5.6 M Dimethylamine in ethanol (2500 µL) is added and the mixture is stirred at room temperature overnight. After removal of the solvent, the residue is purified by preparative HPLC (x-Eta, 0.295 ammonia , acetonitrile), yielding the title compound (41 mg, 43965). 8.65 (1H, c); 7.85-7.67 (4H, t); 7.51-7.39 (4H, t); 4.73-4.59 (2H, - t); 2.68 (6H, 5); 2.19 (ZN, c).

HIAT-MS pi/: 528 (MN. name) Example 72 -I 20 M-4-(Dimethylamino)sulfonyl|benzyl)-b-methyl-2-oxo-1-III-"-trifluoromethyl)-phenyl/|- 1,2-dihydropyridine-3-carboxamide "-5-Chloro-M-4-(Dimethylamino)sulfonyl|benzyl)-b-methyl-2-oxo-1-III-"-trifluoromethyl)phenyl|-1, 2-Dihydropyrides n-3-carboxamide (15mg, 0.028mmol) was dissolved in hot methanol (mL). After cooling to room temperature, ammonium formate (bmg, 0.immol) and 1095 palladium on carbon (Zmg) were added. The reaction mixture 22 was stirred in a sealed flask at room temperature for 4 hours After filtering through celite

F! the solvent is evaporated and the residue is purified by column chromatography on silica using a mixture of СНоSiO/methanol (98:2) as eluent to give the title compound (bmg, 43905). o TN NMR (SOSIV): 5 10.01-9.92 (IN, t); 8.59 (IN, a, U 7.5Hz); 7.85-7.66 (4H, t); 7.55 7.41 (4H, t); 6.48 (IN, a, 9 7.5Gu); 4.75-4.59 (2H, t); 2.68 (6H, 5); 2.09 (ZN, c). 60 HIAT-MO downy (MN)

Example 73 5-Chloro-6-methyl-2-oxo-M-I4-(piperazin-1-ylsulfonyl)benzyl)-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridin-3-k arboxamide in The title compound is obtained by the general method of example 71.

TN NMR (SOSIS): 5 9.99-9.82 (2H, t); 8.64 (IN, a, 9 8.2 Hz); 7.86-7.62 (4H, t); 7.53-7.39 (4H, t);

4.76-4.55 (2H, t); 3.86-2.92 (8H, t); 2.19 (ZN, c).

HIAT-MS ti/2:569 MN.

The compounds of examples 74-78 are obtained by the general method of example 72:

Example 74 6-Methyl-2-oxo-M-I(4-(piperazin-1-ylsulfonyl)benzyl|-1-III-"trifluoromethyl)-phenyl/|-1,2-dihydropyridin-3-carboxamide" YAN YMR (SOSIV8): 5 10.11-9.79 (2H, t); 8.67-8.50 (1H, t); 7.89-7.38 (8H, t); 6.52-6.43 (1IN, t); 4.78-4.52 (2H, t); 3.89-3.62 (2H, t); 3.49-2.94 (6H, t); 2.09 (ZN, 5).

HIAT-MS pi/: 535 (MN.

Example 75 6-Methyl-Mm-I4-(Mlrpholin-4-ylsulfonyl)benzyl)-2-oxo-1-3--trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxamide "YAN NMR ( SOSIv): 5 10.05-95995 (IN, t); 8.58 (IN, a, at 7.5Hz); 7.84-7.64 (4H, t); 7.54-7.41 ( 4H t); 6.48 (TN, aa, 9 7.4, 0.8Hz); 4.75-4.59 (2H, t); 3.76-3.69 (4H, t); 3, 01-2.94 (4H, t); 2.09 (ZH, 5).

HIAT-MS t/h: 536 MN")

Example 76 6-Methyl-2-oxo-M-I4-(piperidin-1-ylsulfonyl)benzyl|-1-3-"trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide by TN NMR (SOCIs) : 5 10.02-9.92 (IN, t); 8.60 (IN, a, 9 7.3Hz); 7.84-7.64 (4Н, т); 7.54 7.41 (4Н , t); 6.48 (IN, aa, 9 7.5, 0.5 Hz); 4.74-4.59 (2H, t); 2.99 - 2.91 (4H, t); 2, 09 (ZH, 5); 1.68-1.35 (6H, t).

HIAT-MS pi/: 534 (MN.

Example 77 with 8-Methyl-M-(4-(methylamino)sulfonial)benzyl)-2-oxo-1-I(3-trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxa with copper.

TN NMR (SOSIV): 5 10.02-9.92 (1IN, t); 8.59 (IN, a, 9 7.3Hz); 7.86-7.70 (4H, t); 7.54-7.41 (4H, t); 6.48 (IN, a, 2 7.3Hz); 4.7-4.58 (2H, t); 4.29 (1H, 5); 2.63 (ZN, 5); 2.09 (ZN, 5).

HIAT-MS pi/l: 480 (M. --

Example 78 - 6-Methyl-2-oxo-N-4-(pyrrolidin-1-ylsulfonyl)benzyl|)-1-3-trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxa copper with

IN NMR (SOSIs): 5 10.00-9.91 (IN, t); 8.60 (IN, a, at 7.5 Hz); 7.85-7.68 (4H, t); 7.53-7.40 (4H, t); 648 "- (IN, aa, 9 7.5, 0.7Hz); 4.76-4.58 (2H, t); 3.26-3.16 (4H, t); 2.09 (ZH, 5); 1.80-1.70 (4H, t).

HIAT-MS pu: 520 (Mn. co

Example 79 5-chloro-6-methyl-2-oxo-M-I4-(Pyrrolidin-1-ylsulfonyl)benzyl)-1-III-"trifluoromethyl)phenyl|-1,2-dihydropyridin-3-k arboxamide" The title compound is obtained by the general method of example 71. 8.66 (1H, c); 7.86-7.72 (4H, t); 7.52-7.40 (4H, t); 4.74-4.59 (2H, t); 3.25-3.17 (4H, t); 2.19 (ZN, c); 1.78-1.72 (4H, t) ;" HIAT-MS ti/g: 554 (MN).

Example 80

3-Chloro-b-methyl-M-I4-(methylsulfonyl)benzyl)-2-oxo-1-3-"trifluoromethyl)-phenyl)-1,2-dihydropyridine-3-carbox o amide 6-Methyl-M- 14-methylsulfonyl)benzylidene-2-oxo-1-3-trifluoromethylphenyl)-1,2-dihydropyridine-3-carboxamide - Example 1.1) (5mg, 0.108mmol) is dissolved in acetonitrile (ml) and cool to 020. KMO»z (16bmg, co 0.1bmmol) and sulfuryl chloride (13p, 1.0.1bmmol) are added. The reaction mixture is stirred for 1 hour at 09C, and then a saturated aqueous solution of sodium carbonate and diethyl ether are added. I ate the water phase. extracted with diethyl ether and the combined organic phase washed with brine and dried. After filtration, the solvent is removed under vacuum, the residue is dissolved in methanol, a white precipitate forms, which is filtered off and dried to give the title compound (22mg, 4196). "YAN iNMR (SOSIV): 5 9.93-9.80 (1H, t); 8.64 (1H, c); 7.94-7.69 (4H, t); 7.57-7.37 (4H, t); 4.75-4.57 (2H, t); 3.01 (ZH, 5); 2.19 (ZH, c).

GF) HIAT-MS pti/: 499 (MN).

Example 81 M-4-(Acetylamino)sulfonyl|benzyl)-b-methyl-phenyl)-1,2-dihydropyridine-3-carboxamide o IM-(4--Aminosulfonyl)benzyl|-bmethyl-2-oxo-1- 3(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

Example 1.51) (1 mg, O0.034 mmol) is dissolved in CHCl (ml). KOH powder (bmg, 0.11 mmol) and 1090 60 acetyl chloride in CH2ClCl (25 μl, 0.035 mmol) were added and the mixture was stirred at room temperature for 1.5 hours. Water and 0.5M aqueous solution of hydrochloric acid are added. The reaction mixture is extracted with СНоСи». The organic phase is washed with water, brine and dried. The solvent was removed in vacuo and the residue was purified by preparative HPLC (x-(egta, 0.290 ammonia, acetonitrile)) to give the title compound (7mg, 41965).

TN NMR (SOSI): 5 10.03-9996 (IN, t); 8.58 (1H, a, 9 7.4Hz); 8.16 (1H, 5); 7.98-7.93 (2H, t); 7.83-7.71 b5 (2H, t); 7.53-7.42 (4H, t); 6.47 (1H, a, U 7.4Hz); 4.72-4.59 (2H, t); 2.08 (ZN, c); 2.02 (ZN, c).

HIAT-MS ti/: 508 (MN.

The compounds of examples 82 and 83 are obtained by the inflammatory method of example 10:

Example 82

M-I4-(Isopropylsulfonyl)benzyl)-5-iodo-b-methyl-2-ocoo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

TN NMR (SOSIi): 5 9.90 (IN, B U 5.7Hz); 8.91 (IN, 8); 7.83-7.80 (ZN, t); 7.76 (IN, 6 V 7.9Hz); 7.50-7.48 (ZN, t); 7.41 (IN. a, U 7.8Hz); 4.68 (2H, her, U 6.2Hz); 3.15 (1H, t); 2.31 (ZN, 5); 1.28 (6H, a, U 6.89Gu).

HIAT-MS p/z: 619 (MN.

Example 83

IM-(4-"Cyclopropylsulfonyl)benzyl)-5-iodo-6-methyl-2-ocoo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-car boxamide

TN NMR (SOSIi): 5 9.86 (IN, B 9 5.8 Hz); 8.90 (IN, c); 7.83-7.80 (ZN, t); 7.75 (IN, 5 U 7.8Gu); 7.49-7.47 (ZN, t); 7.40 (1H, a, 7 7.8Hz); 4.66 (2H, her, U 5.7Hz); 2.42 (1H, t); 2.91 (ZN, 5); 1.32 (2H,t); 1.01 (2H, t). 719 HIAT-MS m/x: 617 (MN.

Example 84 1,2-Dihydro-b6-methyl-N-(4-(methylsulfonyl)oxylphenyl)methyl|-2-oxo-1-I(3--trifluoromethyl)phenyl|-3-pyridinecar boxamide

The title compound (31mg, 4690) is obtained from Kk) 720 M-(4-hydroxybenzyl)-6-methyl-2-okeo-1-3-trifluoromethyl)phenyl I-1,2-dihydropyridine-3-carboxamide and benzenesulfonyl chloride by the general method of the example 61.

TN nMR (DMSO-y5) δ 9.87 (IN, y, 9 6b, oGHz); 8.38 (IN, a, 9 7.5 Hz); 7.89 (2H, a, 9 8.9 Hz); 7.80 (IN, at 7.8Hz); 7.72 (IN, a, 9U 7.9Hz); 7.39 (2H, a, at 8.6 Hz); 7.29 (2H, a, U 86Hz); 6.62 (IN, a, 9U 7.5Hz); 4.50 (2Н, с ге З, 6, ОГу); 3.35 (ZN, 8,); 2.02 (ZN, c). at

HIAT-MS ti/: 5433 МН 7.

Example 85

IM-I(I4-(1,1-Deuxidoisothiazolidin-2-yl)benzyl|-b-methyl-2-oxo-1--3--trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-car boxamide "--

The title compound (12mg, 9.590) is obtained by Kk)

M-(4-aminobenzyl)-6-methyl-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydroproline-3-carboxamide and -

C-chloropropanesulfonyl chloride by the general method of example 56. Ha

TN NMR (DMSO-yv) δ 9.78 (IN, y, 15.8Hz); 8.37 (IN, a, 9 7.4Hz); 7.88 (2H, a, 9 7.6Hz); 7.79 (IN, i, at 7.8Hz); 7.70 (IN, a, U 82G); 7.28 (2H, a, at 8.6Hz); 7.14 (2H, a, U 8.5Hz); 6.61 (IN, a, 9U 7.5Hz); 443 (2H, -- a,»B5vHz); 3.69 (2H, i, U 6.5 Hz); 3.47 (2H, i, 7 7.4 Hz); 2.38 (2H, quintet, U 7.0Hz); 2.01 (ZN, 5). (uh)

HIAT-MS t/z 5063 MN.

Example 86 6-Methyp-2-oxo-M-((4-(4-pyridinylsulfonyl)phenyl|methyl|c-1-3-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carb « oxamide a) 1 -I4-(Pyridin-4-ylsulfonyl)phenyl|methanamine C c To a mixture of 4-mercaptopyridine (0.8 g, 7.2 mmol) and potassium carbonate (2.0 g, 14.4 mmol) in M-MP, add "» 4 -fluorobenzaldehyde (0.99g, 8.0mmol). The mixture is then stirred at 702C for 3 hours. After cooling, the reaction mixture is diluted with water (5.0ml) and extracted with E(OAc). The organic solvent is evaporated and the residue is dissolved in methanol. Sodium borohydride (0.57g, 115mmol) are added and the mixture is stirred for 3 hours at room temperature. After the addition of water, the methanol is removed under vacuum and the residue is extracted with CH 2 . The organic phase is dried over anhydrous magnesium sulfate, filtered, and evaporated and the residue is dissolved in toluene - (1Oml). The toluene solution is heated to 402, phosphorus tribromide (0.125g, 0.92mmol) is added and the temperature is increased to 1002 for 30 minutes. After cooling, water (5Oml) is added and the mixture is extracted with E(OAc. o The organic phase is evaporated, the residue is dissolved in methanol and 2595 ammonia (15ml) in -I 20 methanol (1Oml) is slowly added to the mixture. After stirring for 3 hours at room temperature, the sub-title compound x is obtained. (0.30g, 37905) as a white solid). 7 HIAT-MS ti/: 217.2 (MN"Y

B) 6-Methyl-2-oxo-M-((4-(4-pyridinylsulfonyl)phenyl|methyl-1-3-"-trifluoromethyl)phenyl-1,2-dihydropyridine-3-carb oxamide

HF) In a mixture of /6β-methyl-2-ox-1-3-trifluoromethyl)phenyl/|-1,2-dihydropyridine-3-carboxylic acid/(0.28 g,

HF 0.92mMmol), GBTU (0.35g, 0.92mMmmol) and DEEA (0.24g, 1.84mmol) in M-MP add 1-(4-(pyridin-4-ylsulfonyl)phenyl|methanamine (0, 20g, 0.92mmol) in M-MP (ml). The reaction mixture is stirred for 1 hour at room temperature, then diluted with water (15ml) and extracted with E(OAc). The organic phase is dried with magnesium sulfate, filtered and evaporated. The residue is dissolved in CHCl" (1 Oml), cooled to -159C, M-chloroperoxybenzoic acid (0.48 g, 2.7 mmol) was added. The mixture was stirred for 30 minutes and then overnight at room temperature. The reaction mixture was further diluted with CHCl" and water, washed

Ma»52Oz, an aqueous solution of sodium hydrogen carbonate and brine. The solvent is removed under vacuum, and 25 mg of the residue is dissolved in a mixture of acetonitrile/water (2.0 ml) and purified on a Hiegtäger MS C8 column (19X5 Ω) using a gradient of an acetonitrile/water mixture at a flow rate of 20 ml/min. Sublimation of the mixture gave the title compound (12mg, 4996).

TN NMR (DMSO-iv) 5 9.92 (IN, 6 9 6.oHz); 3.85 (2Н, ай, В 4,4,1,6Hz); 8.34 (1H, a, at 7.5Hz); 7.96 (2H, aa, 9U 6.7, 1.7Hz); 7.90 (4H, t); 7.87 (IN, 6 9 44, 1.6 Gsh); 7.71 (IN, a, 97.9Hz); 7.54 (2H, a, 9 84Gu); 6.61 (2H,a,9 8.2Hz); 4.55 (2H, a, U 6.0Hz); 2.01 (ZN, 5).

HIAT-MS ti/: 528.4 MN.

Starting from /β-methyl-2-oxo-1--3-trifluoromethyl)phenyl/)|-1,2-dihydropyridine-3-carboxylic acid and a suitable methanamine derivative, by the general method of example 86, the compounds of examples 87-91,924 are obtained (B) and 93(B):

Example 87 6-Methyl-2-oxo-M-I4-(phenylsulfonyl)benzyl)-1-(3-trifluoromethyl)phenyl)|-1,2-dihydropyridine-3-carboxamide.

The title compound (Za4mg, 2195) is obtained using 1-I4-(phenylthio)phenyl|methanamine (from thiophenol and 4-fluorobenzaldehyde). "YAN NMR (SOSIv) 5 9.90 (IN, 5, U 6.O0Hz); 8.34 (1Н, а, 9 7.5Hz); 7.90 (6Н, t); 7.80 (IN, 6 U 8yHz); 7.78 19. (2H, t); 7.59 (2H, i, U 7.5Hz); 7.49 (2H, d, U 8.4Hz); 6.60 (1H, 4, 9 7.7Gu); 4.53 (2H, y, U 6.2Hz); 2.01 (ZH, c).

HIAT-MS t/z: 527.4 MN.

Example 88 6-Methyl-2-oxo-IM-I4-(/1,3-thiazol-2-ylsulfonyl)benzyl|-1-3-"-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

The title compound (5Omg, 2195) was obtained using 1-|4-(1,3-thiazol-2-ylsulfonyl)phenyl|methanamine (from 2-mercaptothiazole and 4-fluorobenzaldehyde).

TN NMR (400 MHz, DMSO-sdv) δ 9.91 (1H, 6 U b1Hz); 8.32 (1H, a, at 11.8Hz); 8.23 (1H, a, at 7.9Hz); 8.06 (IN, a, 31g); 7.95 (2H, a, 84gu); 7.87 (2H, a, yuyu 72hz); 7.78 (IN, 6 9 7.9 Hz); 7.68 (IN, 6 9 7.5Gu); sch re 7.54 (2H, a. U 8.4Hz); 6.59 (1H, a, 9 7.7 Hz); 4.54 (2H, a, U 64Hz); 1.99 (ZN, 5).

HIAT-MS t/: 534.3 MN. and)

Example 89 6-Methyl-2-oxo-M-I4-(pyrimidin-2-ylsulfonyl)benzyl)-1-3-(trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide The title compound (1Omg, 2395) is obtained using 1-(4-(pyrimidin-2-ylsulfonyl)phenyl|methanamine (from 2-mercaptopyrimidine and 4-fluorobenzaldehyde). - "IN NMR (DMSO-div): 5 9.63 (IN, 6 9 6b1hz); 8.69 (1Н, а, У 4.9Hz); 8.05 (IN, а, 9 7.5Hz); 7.60 (4Н, 4.9 схШ with 8.6Hz); 7 .45 (ZH, t); 7.23 (2H, a, U 8.3Hz); 630 (1H, a, U 7.4Hz); 4.27 (2H, a, 9 6.6Hz); 1, 70 (ZN, 5).

HIAT-MS ti/: 529.3 MN. -

Example 90 (ge)

I-I(I4-(1H-Imidazol-2-ylsulfonyl)benzyl)|-b-methyl-2-oxo-1-III-"-trifluoromethyl)phenyl)-1,2-dihydropyridin-3-carboxamide

The title compound (8mg, 1695) was obtained using 1-I4-(1H-imidazol-2-ylsulfonyl)phenyl|methanamine (from 2-mercaptoimidazole and 4-fluorobenzaldehyde).

TN NMR (DMSO-iv) δ 9.91 (IN, 6 at 62Hz); 8.35 (2H, a, at 7.4Hz); 7.88 (4H, 5, U 8.4Hz); 7.80 (IN, B in Z with 7, 7gsd)u; 7.72 (IN, a, yuyu 79g); 7.52 (2H, a, in 8.3Gsh); 7.27 (1H, 8); 6.61 (IN, a, 9 7.5 Hz); 5.75 (1H, c); 4.54 » (2Н, а, 7 6.0Hz); 2.02 (ZN, 5).

HIAT-MS t/z: 517.3 MN.

Example 91 6-Methyl-Mm-(4-(1-methyl-1H-1,2,4-triazol-5-yl)usulfonyl)benzyl)-2-oxo-1-3-trifluoromethyl)phenyl)- 1,2-dihydropyridine-3-carboxamide - The title compound (bmg, 15965) is obtained using 1-4-((1-methyl-THN-1,2,4-triazol-5-yl)usulfonyl|phenylmethanamine (from 3-mercapto-4-methyl-4H-1,2,4--riazole and di-4-fluorobenzaldehyde). - and 250 NMR (DMSO-a5) 8 9.95 (IN, Her, 9 6.0 Hz); 8 ... 80 (2H, B in 7); 7.72 (IN, a, 7vhz); 7.59 (2H, a, 9 84HPu); 6.62 (IN, a, in 7" 7, HZ); 4, 59 (2H, a, U 6.3 Hz); 3.86 (ZH, 5); 2.02 (ZH, 5).

HIAT-MS ti/ 532.3 МН 7.

Example 92 6-Methyl-Mm-I4-(5-methyl-1,3-oxazol-4-yl)usulfonalibenzyl|)|-2-oxo-1-3--trifluoromethyl)phenyl)|-1,2-dihydropyrides

HF) n-Z-carboxamide 7 a). 1--(4--(5-Methyl-1,3-oxazol-4-yl)sulfonyl|phenyl)methanamine

To 5-methyl-4-(4-methylphenyl)sulfonyl|-1,3-oxazole (obtained according to U. Spet. bos, RegKip Tgapv. 1, 2000, 527-531) (3.7g, 15.bmmol ) in chlorobenzene, add M-bromosuccinimide (3.5 g, 196 mmol) and 60 2,2'-azobis(2-methylpropingryl) (0.27 g, 1.6 mmol). The reaction mixture is then stirred and heated to 602C. Bromine (0.104g, 0.6b5mmol) and the mixture are heated to 9092 for another 2 hours. After cooling, 295 aqueous Manzo with (1Oml) and water (40ml) are added and the mixture is extracted with E(Ac) The organic phase is evaporated, the residue is dissolved in methanol and 2595 ammonia (15O0ml) in methanol (10Oml) is slowly added to the mixture. After stirring for 3 hours at 65 rt, ammonia was removed under vacuum and the aqueous phase was extracted with EtOAc.The organic phase was dried over magnesium sulfate, filtered and evaporated to give the sub-title compound (2g, 5190).

B) 6-Methyl-M-(4-(5-methyl-1,3-oxazol-4-yl)usulfonyl)benzyl|-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyrides n-3-carboxamide

The title compound (7mg, 2190) was obtained using 1-4-(5-methyl-1,3-oxazol-4-yl)usulfonyl|phenyl)methanamine.

TN NMR (DMSO-iv) 5 9.92 (IN, 5 U 6.0Hz); 8.39 (IN, 8); 8.35 (IN, 4, U 7.4Hz); 7.88 (4H, 6U54Gu); 7.0 (IN, 6 U 82); 7-71 (IN, a, at 82Hz; 7.52 (2H, a, 9 81Hz); 661 (IN, a, 9 7.5Hz); 4.55 (2H, a» 6.1Hz); 2 .64 (ZN, 5); 2.02 (ZN, 5); 1.91 (2H, 5).

HIAT-MS t/: 532.3 MN.

Example 93 6-Methyl-M-16-(methylsulfonyl)pyridin-3-yl|methyl)-2-oxo-1-13-"'trifluoromethyl)phenyl|-1,2-dihydropyridin-3-carboxamide a) 1 -(6--"Methylsulfonyl)pyridin-3-yl|methanamine

To 2-chloropyridine-5-carboxaldehyde (0.50g, 3.bmol) in THF (bBml) was added sodium methanethiolate (0.50Hg, 7.00mmol). The mixture is then stirred at 70°C overnight. After cooling, the reaction mixture is diluted with water (15 mL) and extracted with E(Ac. The organic phase is evaporated and the residue is dissolved in methanol. Sodium borohydride (0.26 g, 7.0 mmol) is added and the mixture is stirred for 3 hours at room temperature. After the addition of water, the methanol was removed in vacuo and the residue was extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered, evaporated and treated with dichloromethane (50 mL). To the mixture in dichloromethane was added phosphorus tribromide (0.25 g, 0.92 mmol) and the mixture was stirred overnight at room temperature. Water (50ml) is then added and the mixture is extracted with E(OAc). Finally, the organic phase is evaporated, the residue is dissolved in methanol and 25956 ammonia (200ml) in methanol (20ml) is slowly added to the mixture. After stirring for 3 hours at room temperature, the subtitle is obtained c) (o) 6-Methyl-M-16-(methylsulfonyl)pyridin-3-yl)methyl)|-2-oxo-1-3--trifluoromethyl)phenyl|-1,2-dihydropyridin- 3-car boxamide

The title compound (12 mg, 2495) was obtained using |b-(methylsulfonyl)pyridin-3-yl|methylamine.

TN-NMR (DMSO-y5) δ 9.98 (IN, Cu bgc); 8.71 (1H, 5); 8.36 (IN, a, 9 7.5 Hz); 8.01 (2H, 8); 7.90 (2Н, 7-7 а о взгц)у; 781 (IN, 6 V 7.7 Hz); 7.72 (IN, a, 9 7.9Gsh); 6.62 (IN, 4, 9 7.5Hz); 4.61 (2H, a, U by GHz); 325 che (ZN, 5); 2.03 (ZN, c).

HIAT-MS ti/: 466.3 MN. see

Example 94 h 5-Fluoro-6-methyl-M-I4-(methylsulfonyl)benzyl|-2-oxo-1-3-"-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide d)

To b-methyl-M-I(4-"methylsulfonyl)benzyl|)|-2-oxo-1-3--trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxamide

Example 1711 (0.25 g, 0.54 mmol) in acetonitrile (4.5 ml) under argon is added "1-chloromethyl-4-fluoro-1,4-diazonium dicyclo!|2,2,2|octane-bis(tetrafluoroborate) ( 0.45g, 1.27mmol). The reaction mixture - about 70 is heated at 809 for 2 hours. Water is then added and the product is purified on a HiegaFfRger MO C8s column (19x500mm) using an acetonitrile/water gradient at a flow rate of 20ml/min. Sublimation of the mixture gave the title compound (75 mg, 2995). "YAN NMR (SOSIz) 5 10.02 (IN, i at 54Hz); 8.57 (IN, a, At 9.0Hz); 7.88 (2H, a. at 84Hz); 7.54 (1H, a, in 8І1Г4); 7.76 (IN, 6 In 1.9Hz); 7.51 (4Н, а, in 84Hz); 7.44 (IN, а, in 3.0Hz); 4.67 (2Н, 6 9 57Hz); 3.05 (ZN, o 8); 2.08 (ZN, a, U 3.3Hz). - from HIAT-MS t/l: 483.3 МН.

Example 95 1-(4-"("methylsulfonyl)benzyl)-2-oxo-6-(2-oxoethyl)-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carboxam id -i F. I . phosphorus oxychloride (1.8 ml, 19./7 mmol) is added dropwise under argon with stirring to an ice-cooled solution of dry M,M-dimethylformamide (2.8 ml). After addition, cooling is stopped and the mixture is stirred at room temperature for 30 minutes. Dry dichloromethane (1 Oml) is added and the solution is cooled to -2096, 6-Methyl-M-(4-(methylsulfonyl)benzyl|-2-oxo-1-3-"-trifluoromethyl)phenyl/|-1,2-dihydropyridine- 3-carboxamide (1.27, 24 mmol) is added in small portions at such a rate that the temperature does not rise above 1260. After 15 minutes, at 09, potassium carbonate (3.4 g, 24, mmol) is added ) and the mixture is heated to boiling temperature under reflux for 20 minutes. The reaction mixture is cooled and poured into a cooled solution of 5095 aqueous sodium carbonate (200 ml) and stirred at room temperature for 5 hours. 60 The mixture is extracted with ethyl acetate. The organic layers are washed with water, brine , dried, filtered and concentrated under reduced pressure to give a dark oil.Part of the oil was purified by preparative HPLC to give the title compound as a yellow solid.

TN NMR (SOSIv): 5 10.06 (IN, i, U 5.3 Hz); 9.47 (2H, 8); 8.66 (2H, a, at 7.4 Hz); 7.89 (2H, a, U 8.2Gu); 7.82 (IN, a, 9 81g); 7.71 (IN, 6 9 7.9 Hz); 7.53-7.49 (ZN, t); 7.41 (IN, a, 9 82 Hz); 6.50 (IN, a, because 74 Hz); 4.69 (2H, i, / 5.6Hz); 3.60 (2H, c); 3.02 (ZN, c).

HIAT-MS p/z: 493 (MN.

Example 96 5-Ethyl-6-methyl-N-(4-(methylsulfonyl)benzyl)-2-oxo-1-3-trifluoromethyl)phenyl|-1,2-dihydropyridine-3-carbox

Med

A mixture of b-methyl-M-I(4--"methylsulfonyl)benzyl|)|-2-oxo-1-3--trifluoromethyl)phenyl|-5-vinyl-1,2-dihydropyridine-3-carboxy copper ( patent application ZE 0302487-4 (58mg, 0.12mmol), 595 palladium on charcoal (11mg) in ethanol (15ml) and EtOAc (15ml) were vigorously stirred under a hydrogen atmosphere for 16 hours. The mixture was filtered through celite, the filtrate was evaporated to dry state and the residue was purified by preparative HPLC to give the title compound as a white solid (ZZmg, 56905).

NMR (SOCI5): 5 10.09 (IN, 6 9 5.7Gsh); 8.55 (1H,. 3; 7.87 (2H, ayu vsGhshsh: 780 (IN, a, 7.8Hz); 7.74 (IN, 6 9 7.9Hsh; 7.52 (2H, a, U 84Hz); 7.50 (IN, 5); 7.43 (IN, a, 9 7.6Hz; 4.67 (2H, 6 9 64Hz); 3.01 (ZH, c); 2.59 (2H , a, U 7.5 Hz); 2.04 (ZN, 5); 1.23 (ZN, i, U 7.5 Hz).

HIAT-MS pi/l: 493 (MN.

Screening

EKET quenching study of human neutrophil elastase

The research used human neutrophil elastase (NEP), purified from the serum of ISaiYirBiospet agi. 324681; Kei. Vashi, K...ei ai., 1976, Viospetivighu. 15, 836-841). NEL is stored in 5HOMM of MaoOAc, 200mM of sodium chloride, pH5.5 with the addition of 3095 glycerol at -202C. The applied substrate of the protease is the substrate of elastase M

RIsogodepis, MeObZys-AARM-AMS (|SaiYiriospet ay. 324740; Kei. SaviSho, M. eyi ai.,, 1979, ApaYi. Viospet. 99, 53-64). The substrate is stored in DMSO at -202С. Additions during the study are carried out as follows: test compounds and controls are added to black 96-cell flat-bottom planilets (Ogeipeg 655076) in 100956 DMSO, and then

100 ml of NEL in assay buffer with 0.0195 TpIopX-100. The research buffer consists of: 100 mM Tris s (pH 5) and 500 mM sodium chloride. The enzyme and compounds are incubated at room temperature for 15 minutes. at

Then add 3 µl of the substrate in the assay buffer. The study is stopped after 30 minutes of incubation at room temperature by adding bOml stop solution (140mM acetic acid, 200mM sodium monochloroacetate, bOmM sodium acetate, pH 4.3). Fluorescence is measured on a Ouayas 1420 Misiog 2 device under the following conditions: Excitation 38 Ohm, emission 4 bOhm. The IR 50 value was determined by fitting the HIN curve - using model 205.

When tested in the above screening, the compounds of the examples gave an IC 50 value for human neutrophil elastase inhibitory activity of less than ZOmMkM, showing that the compounds of the invention are expected to have useful therapeutic properties. Examples of results are shown in the following Table: "- with human neutrophil elastase IS. em) BO "

WITH

"o - xz" (ee)

Claims (10)

Formula of the invention - 1. The compound of formula (I) about about V. with her- YAKA: - with X in! "bu ri F) yu - (vn that 60 where: X represents O or 5; U" represents M or SV, and when V! represents OH, U" can also represent MAE in tautomeric form; Ug? represents SEZ, and when U" represents SC, U? can also represent M; 65 He represents H or C 4. alkyl; the indicated alkyl, as an option, is replaced by one or more substituents independently selected from the group: halogen, CM, CHO, OB, Meee9, ( 0819 and HOMA B; and when U! represents M, B can also represent OH; c' represents H, C 46 alkyl or phenyl; said phenyl is optionally further substituted with a substituent selected from the group consisting of halogen, C 1 -alkyl and C 1 -alkyl oxy; 2 represents H, halogen or C. alkyl; VZ represents H or E; WITH! represents phenyl or a five- or six-membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, C and M; or 5 represents a five- or six-membered saturated or partially unsaturated 70 cycloalkyl ring; or (3 represents a five- or six-membered saturated or partially unsaturated heterocyclic ring containing one heteroatom selected from 0, 5 and MA"Z, where KZ represents H or C, alkyl; B? represents H, halogen, C 4alkyl . ; the specified alkyl is optionally further substituted by one or more E atoms; n is an integer of 1, 2, or 3, and when n is 2 or 3, each E? group is independently selected; БЕ" and 9 independently represent H or C . valkyl; said alkyl is optionally additionally substituted with OH or C valkoxyl; or B" and | are joined together so that the group -MA7I. represents a 5-7-membered azacyclic ring, which optionally contains another a heteroatom selected from O, 5 and Me 75; Y represents a bond, O, MK 293 or C. alkyl; said alkyl optionally contains a heteroatom selected from O, 5 and ME E; and, as varied nt, the indicated alkyl is additionally substituted with a substituent selected from the group: OH or OMe; Ha 2 represents a monocyclic ring system selected from the group: o i) phenyl or phenoxyl, i) a 5- or b--linked heteroaromatic ring containing one to three heteroatoms, independently selected from 0, 5 there, iii) Cz. saturated or partially unsaturated cycloalkyl, or i) Si saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms "7 independently selected from О, 5(О)р and МВ 7, and optionally additionally containing a carbonyl group ; or ich- 2 represents a dicyclic ring system in which each of the two rings is independently selected from the group: І) phenyl, c і) 5- or b--linked heteroaromatic ring containing one to three heteroatoms, independently selected from О, 5 there , 4 days iii) Sz. saturated or partially unsaturated cycloalkyl, or (Z) C, a saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms independently selected from O, C(O)"p and M" and optionally additionally containing a carbonyl group ; and the two rings are fused together, either joined together directly, or separated by a linking group selected from 0, 5(O)u4 or CH", "a monocyclic or dicyclic ring system is indicated, optionally, in addition substituted by one- by three - 70 substituents, independently selected from the group: SM, OH, S. valkyl, Si valcoxyl, halogen, MA 'Z87Z, MO», 050238, с Сов? с(еМНИМНо, С(ОМ? в, с(в)MAZv ?I, 5C(-MNIMNo, MAZ'SE(-MNIMNo, 5(0)5829, 5О2МЕ29827, with C. zaloxyl, substituted by one or more E atoms, and C. zalkyl, substituted by group 502839 or by one or more E atoms; or (ee) when GI. does not represent a bond, 2 can also represent H; - т, р, а, з and Я are independently equal to the whole number 0, 1 or 2; E8 and VE? independently represent H, C..alkyl, formyl or Co alkanoyl; the specified alkyl, as an option, in addition to the name) is substituted by phenyl, as an option, substituted by a substituent selected from the group: halogen, C ..alkyl, Si. valkoxyl -00720 or ZO; that the MEZVU group together represents a 5-7-membered azacyclic ring containing, optionally, one more heteroatom selected from 0, 5 and ME28; 2" and KE"? independently represent H, C. valkyl, formyl, Co valcanoyl, (OX 7 or 502 MAZ23; the indicated alkyl, as an option, is additionally substituted by a substituent selected from the group: halogen, CM, C.i. daloxyl or cOoMme" in; h represents H , C..alkyl or C.sub.3 cycloalkyl; the specified alkyl is optionally additionally substituted with one or more substituents independently selected from the group: OH, CM, COM, CO, OSOV, Ca.cycloalkyl, where C is a saturated heterocyclic ring, containing one or two heteroatoms independently selected from OO, 5(O)p, and ME, and a phenyl or 5-6-membered heteroaromatic ring containing one to three heteroatoms independently selected from O, 5, and M; specified the aromatic ring is optionally further substituted with one or more substituents independently selected from the group consisting of: halogen, CM, C. dalalkyl, C. alkyl, OH, COMEV5, CO2825, 5(0)5877, and MNSOSN"; 225 and EC?" independently represent H, S. alkyl, formyl or Co-balkanoyl; 22 represents H, C, alkyl or C3, cycloalkyl; 65 He represents H, C 4 alkyl or phenyl; the indicated phenyl is optionally additionally substituted with a substituent selected from the group: halogen, C-alkyl or C-alkyl; Vo, V", v", vv, V, o, V, r, r, Gay ov go, v, v, v, di Gay i, v, v, vl, V, v, VZ, v, V, 5 and "7 independently represent H or C. alkyl; and their pharmaceutically acceptable salts, provided that the following compounds are excluded: M-benzyl-5,6-dimethyl-2-oxo-1-phenyl-1,2-dihydropyridine- 3-carboxamide; M-(2-phenethyl)-5,6-dimethyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide; M-(2-hydroxyethyl)-2,4-dioxo- 3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide; 5-carboxamide; 4-I2-C1,2-dihydro-1-(4-methylcyclohexyl)-2-oxo-3-pyridinylIcarbonylamino|ethyl|-benzoic acid, 70 4-I2-CZ(1-cyclohexyl-1,2 -dihydro-2-oxo-3-pyridinylcarbonylamino|ethyl|-benzoic acid, M-benzyl-1-cyclohexyl-5,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxamide and (2-phenethyl) -1-cyclohexyl-5,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxamide. 2. Compound according to claim 1, where X represents 0. 3. Compound according to claim 1 or 2, where is each EC? and KZ is represented by N. 4. The compound of formula (I) according to any of claims 1-3, where C! represents phenyl or pyridyl. 5. The compound of formula (I) according to claim 1 or its pharmaceutically acceptable salt for use as a medicine. 6. A pharmaceutical composition containing a compound of formula (I) as defined in any of claims 1-4, or a pharmaceutically acceptable salt thereof, optionally in admixture with a pharmaceutically acceptable diluent or carrier. 7. A method of treating or reducing the risk of a disease or human condition in which inhibition of neutrophil elastase activity is beneficial, in which a therapeutically effective amount of a compound of formula (I) as defined in any of claims 1-4, or a pharmaceutically acceptable salt thereof. 8. Use of a compound of formula (I) as defined in any of claims 1-4, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of human diseases or conditions in which inhibition of neutrophil elastase activity is beneficial. d) 9. Use of a compound of formula (I) as defined in any of claims 1-4, or a pharmaceutically acceptable salt thereof, in the production of a medicament for the treatment or prevention of inflammatory diseases or conditions. 10. The method of obtaining the compound of formula (I), which is defined in any of claims 1-4, and its optical isomers, racemates and tautomers and its pharmaceutically acceptable salts, in which the reaction of the compound of formula (II) is carried out -- a cha cha ve s ХК «- xx z5 so A E shchi « zo Vi - s ! ! . where B", 22, U, U2, X, C! and n are defined in claim 1, and Y represents a leaving group, with an amine of the formula (III) "" or its Neua salt and - 5 bore IV - where KU, 02 and | defined in claim 1, when it is necessary or necessary to convert the formed compound of formula (I) or its other salt into its 5p pharmaceutically acceptable salt; or conversion of one compound of formula (I) into another compound of formula (I); and when Ш- is required, conversion of the formed compound of formula (I) into its optical isomer. - Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2008, M 21, 25.12.2008. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. F) name) 60 b5