Indian Patents. 231488:"A 2- PYRIDONE COMPOUND AND A PROCESS FOR PREPARING THE SAME THEREOF"

Title of Invention	"A 2- PYRIDONE COMPOUND AND A PROCESS FOR PREPARING THE SAME THEREOF"
Abstract	There are provided novel compounds of formula (I) wherein R1, R2, R4, R5, G1, G2, L, Y 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.

Full Text	Field of the Invention This invention relates to novel 2-pyridone compounds, processes for their preparation, pharmaceutical compositions comprising them, and their use in therapy. Background of the Invention Elastases are possibly the most destructive enzymes in the body, having the ability to degrade virtually all connective tissue components. The uncontrolled proteolytic degradation by elastases has been implicated in a number of pathological conditions. Human neutrophil elastase (hNE), a member of the chymotrypsin superfamily of serine proteases is a 33-KDa enzyme stored in the azurophilic granules of the neutrophils. In neutrophils the concentration of NE exceeded 5 mM and its total cellular amount has been estimated to be up to 3 pg. Upon activation, NE is rapidly released from the granules into the extracellular space with some portion remaining bound to neutrophil plasma membrane (See Kawabat et al. 2002, Eur. J. Pharmacol. 451,1-10). The main intracellular physiological function of NE is degradation of foreign organic molecules phagocytosed by neutrophils, whereas the main target for extracellular elastase is elastin (Janoff and Scherer, 1968, J. Exp. Med. 128,1137-1155). NE is unique, as compared to other proteases (for example, proteinase 3) in that it has the ability to degrade almost all extracellular matrix and key plasma proteins (See Kawabat et al. , 2002, Eur. .1. Pharmacol. 451,1-10). It degrades a wide range of extracellular matrix proteins such as elastin, Type 3 and type 4 collagen, laminin, fibronectin, cytokines, etc. (Ohbayashi, 11.. 2002, Expert Opin. Investig. Drugs, 11,965-980). NE is a major common mediator of many pathological changes seen in chronic lung disease including epithelial damage (Stockley, R. A. 1994. Am. J. Resp. Grit. Care Med. 150,109-113). The destructive role of NE was solidified almost 40 years ago when Laurell and Eriksson reported an association of chronic airflow obstruction and emphysema with deficiency of serum ai-antitrypsin (Laurell and Eriksson, 1963, Scand J. Clin. Invest 15,132-140). Subsequently it was determined that cct-antitrypsin is the most important endogenous inhibitor of human NE. The imbalance between human NE and endogenous antiprotease is believed to cause excess human NE hi pulmonary tissues which is considered as a major pathogenic factor in chronic obstructive pulmonary disease (COPD). The excessive human NE shows a prominent destructive profile and actively takes part in destroying the normal pulmonary structures, followed by the irreversible enlargement of the respiratory airspaces, as seen mainly in emphysema. There is an increase in neutrophil recruitment into the lungs which is associated with increased lung elastase burden and emphysema in oci-proteinase inhibitor-deficient mice (Cavarra et al., 1996, Lab. Invest. 75,273-280). Individuals with higher levels of the NE-cti protease inhibitor complex in bronchoalveolar lavage fluid show significantly accelerated decline in lung functions compared to those with lower levels . (Betsuyaku et al. 2000, Respiration, 67,261267). Instillation of human NE via the trachea in rats causes lung haemorrhage, neutrophil accumulation during acute phase and emphysematous changes during chronic phase (Karaki et al., 2002, Am. J. Resp. Grit Care Med., 166,496-500). Studies have shown that the acute phase of pulmonary emphysema and pulmonary haemorrhage caused by NE in hamsters can be inhibited by pre-treatment with inhibitors of NE (Fujie et al.,1999, brflamm. Res. 48,160-167). Neutrophil-predominant airway inflammation and mucus obstruction of the airways are major pathologic features of COPD, including cystic fibrosis and chronic bronchitis. NE impairs mucin production, leading to mucus obstruction of the airways. NE is reported to increase the expression of major respiratory mucin gene, MUC5AC (Fischer, B.M & Voynow, 2002, Am. J. Respir. Cell Biol,, 26,447-452). Aerosol administration of NE to guinea pigs produces extensive epithelial damage within 20 minutes of contact (Suzuki et al, 1996, Am. J. Resp. Grit Care Med., 153,1405-1411). Furthermore NE reduces the ciliary beat frequency of human respiratory epithelium in vitro (Smallman et al., 1984, Thorax, 39,663-667) which is consistent with the reduced mucociliary clearance that is seen in COPD patients (Currie et al., 1984, Thorax, 42,126-130). The instillation of NE into the airways leads to mucus gland hyperplasia in hamsters (Lucey et al., 1985, Am. Resp. Crit. Care Med., 132,362-366). A role for NE is also implicated in mucus hypersecretion in asthma. In an allergen sensitised guinea pig acute asthma model an inhibitor of NE prevented goblet cell degranulation and mucus hypersecretion (Nadel et al., 1999, Eur. Resp. 3., 13,190-196). NE has been also shown to play a role in the pathogenesis of pulmonary fibrosis. NE: oci.protenase inhibitor complex is increased in serum of patients with pulmonary fibrosis, which correlates with the clinical parameters in these patients (Yamanouchi et al., 1998, Eur. Resp. J. 11,120-125). In a murine model of human pulmonary fibrosis, a NE inhibitor reduced bleomycin-induced pulmonary fibrosis (Taooka et al., 1997, Am. J. Resp. Grit. Care Med., 156,260-265). Furthermore investigators have shown that NE deficient mice are resistant to bleomycin-induced pulmonary fibrosis (Dunsmore et al., 2001, Chest, 120,35S-36S). Plasma NE level was found to be elevated in patients who progressed to ARDS implicating the importance of NE in early ARDS disease pathogenesis. (Donnelly et al., 1995, Am. J. Res. Crit. Care Med., 151,428-1433). The antiproteases and NE complexed with antiprotease are increased in lung cancer area (Marchandise et al., 1989, Eur. Resp. J. 2, 623-629). Recent studies have shown that polymorphism in the promoter region of the NE gene are associated with lung cancer development (Taniguchi et al., 2002, Clin. Cancer Res., 8,1115-1120. Acute lung injury caused by endotoxin in experimental animals is associated with elevated levels of NE (Kawabata, et al., 1999, Am. J. Resp. Crit. Care, 161,2013-2018). Acute lung inflammation caused by intratracheal injection of lipopolysaccharide in mice has been shown to elevate the NE activity in bronchoalveolar lavage fluid which is significantly inhibited by a NE inhibitor (Fujie et al., 1999, Eur. J. Pharmacol., 374,117-125; Yasui, et al., 1995, Eur. Resp. J., 8,1293-1299). NE also plays an important role in the neutrophilinduced increase of pulmonary microvascular permeability observed in a model of acute lung injury caused by tumour necrosis factor «. (TNFa) and phorbol myristate acetate (PMA) in isolated perfused rabbit lungs (Miyazaki et al., 1998, Am. J. Respir. Crit. Care Med., 157, 89-94). A role for NE has also been suggested in monocrotoline-induced pulmonary vascular wall thickening and cardiac hypertrophy (Molteni et al., 1989, Biochemical Pharmacol. 38, 2411-2419). Serine elastase inhibitor reverses the monocrotaline-induced pulmonary hypertension and remodelling in rat pulmonary arteries (Cowan et al., 2000, Nature Medicine, 6,698-702). Recent studies have shown that serine elastase, that is, NE or vascular elastase are important in cigarette smoke-induced muscularisation of small pulmonary arteries in guinea pigs (Wright et al., 2002, Am. J. Respir. Crit. Care Med., 166, 954-960). NE plays a key role in experimental cerebral ischemic damage (Shimakura et al., 2000, Brain Research, 858,55-60), ischemia-reperfusion lung injury (Kishima et al., 1998, Ann. Thorac. Surg. 65, 913-918) and myocardial ischemia in rat heart (Tiefenbacher et al., 1997, Eur. J. Physiol., 433, 563-570). Human NE levels in plasma are significantly increased above normal in inflammatory bowel diseases, for example, Crohn's disease and ulcerative colitis (Adeyemi et al., 1985, Gut, 26,1306-1311). In addition NE has also been assumed to be involved in the pathogenesis of rheumatoid arthritis (Adeyemi et al., 1986, Rheumatol. Int., 6, 57). The development of collagen induced arthritis in mice is suppressed by a NE inhibitor (Kakimoto et al., 1995, Cellular Immunol. 165,26-32). Thus, human NE is known as one of the most destructive serine proteases and has been implicated in a variety of inflammatory diseases. The important endogenous inhibitor of human NE is cci-antitrypsin. The imbalance between human NE and antiprotease is believed to give rise to an excess of human NE resulting in uncontrolled tissue destruction. The protease/ antiprotease balance may be upset by a decreased availability of ocj-antitrypsin either through inactivation by oxidants such as cigarette smoke, or as a result of genetic inability to produce sufficient serum levels. Human NE has been implicated in the promotion or exacerbation of a number of diseases such as pulmonary emphysema, pulmonary fibrosis, adult respiratory distress syndrome (ARDS), ischemia reperfusion injury, rheumatoid arthritis and pulmonary hypertension. WO 02/053543 discloses pyridone derivatives having affinity for cannabinoid 2-type receptor. The present invention discloses novel 2-pyridione derivatives that are inhibitors of human neutrophil elastase and homologous serine proteases such as proteinase 3 and pancreatic elastase, and are thereby useful in therapy. Disclosure of the Invention The present invention provides a compound of formula (I) (Figure Removed) wherein: Y represents CR orN; R represents H or Cl to 6 alkyl; 2 R represents: 47 47 i) CN, NO2, OH, OSO2R , O-C2 to 6 alkanoyl, CO2R , CHO or C2 to 6 alkanoyl; or ii) C1 to 6 alkoxy optionally substituted by OH, Cl to 6 alkoxy, CN, NR54R55, 54 55 47 CONR R ,OCOR or one or more F atoms; or iii) C3 to 6 saturated or partially unsaturated cycloalkyl optionally further substituted by Cl to 6 alkyl; or iv) C4 to 7 saturated or partially unsaturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S(0)m and NR optionally further substituted by Cl to 6 alkyl; or v) CONR48R49, CONR5°NR48R49, C(=NOR5 V53, C(=NH)NHOR52 or NR^R49; or vi) C2 to 6 alkenyl or C2 to 6 alkynyl; said alkenyl or alkynyl group being optionally further substituted by Cl to 6 alkoxy or phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N; said pheny] or heteroaromatic ring being optionally further substituted by halogen, CN, Cl to 6 alkyl or Cl to 6 alkoxy; or vii) Cl to 6 alkyl substituted by one or more F atoms; or viii) Cl to 6 alkyl substituted by one or more groups selected from halogen, OH, oxo, azido, NR R , Cl to 6 alkoxy and Cl to 6 alkoxy substituted by one or more F atoms; or ix) Cl to 6 alkyl substituted by phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N; said phenyl or heteroaromatic ring being optionally further substituted by halogen, CN, Cl to 6 alkyl or Cl to 6 alkoxy; 48 49 R andR independently represent H, OH, Cl to 6 alkoxy, C3 to 6 cycloalkyl, CHO, C2 to 6 alkanoyl, CO2R }C(X)NR R or Cl to 6 alkyl; said alkyl being optionally further substituted by OH, Cl to 4 alkoxy, C3 to 6 cycloalkyl, CN or phenyl or a five- or sixmembered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N; said alkanoyl being optionally further substituted by CN; X represent O or S; or the group NR R together represents a saturated or partially unsaturated 5 to 7 membered azacyclic ring optionally incorporating one further heteroatom selected from 0, S and NR ; said azacyclic ring being optionally further substituted by one or more 57 substituents selected from OR and Cl to 4 alkyl; said alkyl being optionally further 57 substituted by OR ; R represents H or F; G represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N; R represents H, halogen, Cl to 6 alkyl, CN, Cl to 6 alkoxy, NO2, NR14R , Cl to 3 alkyl substituted by one or more F atoms or Cl to 3 alkoxy substituted by one or more F atoms; 14 15 R and R independently represent H or Cl to 3 alkyl; said alkyl being optionally further substituted by one or more F atoms; n represents an integer 1,2 or 3 and when n represents 2 or 3, each R group is selected independently; R represents H or Cl to 6 alkyl; said alkyl being optionally further substituted by OH or Cl to 6 alkoxy; or R and L are joined together such that the group -NR L represents a 5 to 7 membered azacycJic ring optionally incorporating one further heteroatom selected from O, S and NR ; said ring being optionally further substituted by Cl to 6 alkyl or NR R ;said alkyl being optionally further substituted by OH; 29 L represents a bond, O, NR or Cl to 6 alkyl; said alkyl optionally incorporating a heteroatom selected from O, S and NR ; and said alkyl being optionally further substituted by OH or OMe; 2 G represents a monocyclic ring system selected from: i) phenyl or phenoxy, ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S and N, iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms independently selected from 0, S(O)p and NR and optionally further incorporating a carbonyi group; or 2 G represents a bicyclic ring system in which each of the two rings is independently selected from: i) phenyl, ii) a S or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S and N, iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms independently selected from 0, S(O)p and NR 17and optionally further incorporating a carbonyi group; and the two rings are either fused together, or are bonded directly together or are separated by a linker group selected from O, S(O)q or CHa, said monocyclic or bicyclic ring system being optionally further substituted by one to three substituents independently selected from CN, OH, Cl to 6 alkyl, Cl to 6 alkoxy, halogen, It) NR18R19, N02, OS02R38, C02R2°, C(==NH)NH2, C(O)NR21R22, C(S)NR23R24, SC(==NH)NH2, NR31C(=NH)NH2, S(O)SR25, SO2NR26R27, Cl to 3 alkoxy substituted by one or more F atoms and Cl to 3 alkyl substituted by SO2R or by one or more F atoms; or when L does not represent an bond, G2 may also represent H; at each occurrence, m, p, q, s and t independently represent an integer 0,1 or 2; 18 19 32 R and R independently represent H, Cl to 6 alkyl, formyl, C2 to 6 alkanoyl, S(O)tR 33 34 or SO2NR R ; said alkyl group being optionally further substituted by halogen, CN, Cl to 4 alkoxy or CONR41R42; 25 R represents H, Cl to 6 alkyl or C3 to 6 cycloalkyl; said alkyl group being optionally further substituted by one or more substituents selected independently from OH, CN, CONR R ,CO2R ,OCOR , C3 to 6 cycloalkyl, a C4 to 7 saturated heterocyclic ring containing one or two heteroatams independently selected from O, S(O)p and NR4 3 and phenyl or a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from 0, S and N; said aromatic ring being optionally further substituted by one or more substituents selected independently from halogen, CN, Cl to 4 44 45 46 65 alkyl, Cl to 4 alkoxy, OH, CONR R , CO2R , S(O)SR and NHCOCH3; 32 R represents H, Cl to 6 alkyl or C3 to 6 cycloalkyl; R", R17, R20, R21, R32, R23, R24, R2, R27, R2', R31, R33, R34, R35, R36, R37 R38, R3', R40, R41, R42 R43, R44, R45, R4, R47 R50, R52, R53, R54, R55, R5', R57, E« R ,R ,R ,R andR independently represent H or Cl to 6 alkyl; JO ft and pharmaceutically acceptable salts thereof. The compounds of formula (I) may exist in enantiomeric and/or tautomeric forms. It is to be understood that all enantiomers, diastereomers, racemates, tautomers and mixtures thereof are included within the scope of the invention. Unless otherwise indicated, the term "Cl to 6 alky!" referred to herein denotes a straight or branched chain alkyl group having from 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl and hexyl. The terms "Cl to 3 alkyl" and "Cl to 4 alkyl" are to be interpreted analogously. Examples of "Cl to 3 alkyl substituted by one or more F atoms" include fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, pentafluoroethyl and 33.3-trifluoropropyl. Unless otherwise indicated, the term "Cl to 6 alkoxy" referred to herein denotes an oxygen substituent bonded to a straight or branched chain alkyl group having from 1 to 6 carbon atoms. Examples of such groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy and s-butoxy. The terms "Cl to 3 alkoxy" and "Cl to 4 alkoxy" are to be interpreted analogously. Examples of "Cl to 6 alkoxy substituted by one or more F atoms" include fluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy and 3,3,3-trifluoropropoxy. Unless otherwise indicated, the term "C2 to 6 alkanoyl" referred to herein denotes a straight or branched chain alkyl group having from 1 to 5 carbon atoms bonded to the molecule via a carbonyl group. Examples of such groups include acetyl, propionyl and pivaloyl. Unless otherwise indicated, the term "halogen" referred to herein denotes fluorine, chlorine, bromine and iodine. Examples of a five or six membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from 0, S and N include furan, thiophene, pyrrole, oxazole, oxadiazole, isoxazole, imidazole, thiazole, triazole, thiadiazole, pyridine, pyrimidine and pyrazine. Unless otherwise indicated, the term "C3 to 6 saturated or partially unsaturated cycloalkyl" referred to herein denotes a 3 to 6 membered non-aromatic carbocyclic ring optionally incorporating one or more double bonds. Examples include cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyelohexenyl. The term "five- or six-membered saturated or partially unsaturated cycloalkyl ring" is to be interpreted analogously. Unless otherwise indicated, the term "C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms independently selected from O, S(O)p and NR1 7 and optionally further incorporating a carbonyl group" referred to herein denotes a 4 to 7 membered non-aromatic heterocyclic ring optionally incorporating one or more double bonds and optionally incorporating a carbonyl group. 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 terms "five- or six-membered saturated or partially unsaturated heterocyclic ring containing one heteroatom selected from O, S and NR1 3" and "C4 to 7 saturated or partially unsaturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S(O)m and NR " are to be interpreted analogously. Examples of a "5 to 7 membered azacyclic ring optionally incorporating one further heteroatom selected from O, S and NR " include pyrrolidine, piperidine, morpholine, thiomorpholine and piperazine. In the definition of L, "Cl to 6 alkyl; said alkyl optionally incorporating a heteroatom selected from O, S and NR " embraces a straight or branched chain arrangement of 1 to 6 carbon atoms in which any two carbon atoms are optionally separated by O, S or NR . The definition thus includes, for example, methylene, ethylene, propylene, hexamethylene, ethylethylene, -CH2CH2O-CH2-> -CT2CH20-CH2-CH2-, -CH2CH2S- and -CH2CH2NR16-. Examples of bicyclic ring systems in which the two rings are either fused together, or are bonded directly together or are separated by a linker group selected from O, S(O)q or CH2 include biphenyl, thienylphenyl, pyrazolylphenyl, phenoxyphenyl, phenylcyclopropyl, naphthyl, indanyl, quinolyl, tetrahydroquinolyl, benzofuranyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, isoquinolyl, chromanyl, indenyl, quinazolyl, quinoxalyl, chromanyl, isocromanyl, 3Hindolyl, IH-indazolyl, quinuclidyl, tetrahydronaphthyl, dihydrobenzofaranyl, morpholine- 4-ylphenyl, 1,3-benzodioxolyl, l,l-dioxido-2,3-dihydro-l-benzothienyl, 2,3-dihydro-l,4- benzodioxinyl, 1,3-benzodioxinyl and 3^-dihydro-isochromenyl. 3 In one embodiment, Y in formula (I) represents CR . In another embodiment, Y represents N. In one embodiment, R in formula (I) represents Cl to 6 alkyl. In another embodiment, R represents CH3. 2 48 49 2 In one embodiment R in formula (I) represents CONR R . In another embodiment, R represents Cl to 6 alkoxy or Cl to 6 alkoxy substituted by OH, Cl to 6 alkoxy, or by one 2 or more F atoms. In yet another embodiment, R represents Cl to 6 alkyl substituted by 48 one or more F atoms or Cl to 6 alkyl substituted by OH, NR R4 9 , Cl to 6 alkoxy or Cl to 6 alkoxy substituted by one or more F atoms. 3 In one embodiment, R in formula (I) represents H. In one embodiment, G in formula (T) represents phenyl or pyridyl. In another embodiment, G in formula (0 represents phenyl. In one embodiment, R in formula (I) represents halogen, Cl to 6 alkyl, CN or Cl to 3 alkyl substituted by one or more F atoms. In another embodiment, R in formula (I) represents Cl, CHs, CN or CP$. In one embodiment, n represents the integer 1. In another embodiment, G in formula (I) represents phenyl, R represents CF3 and n represents the integer 1. 4 In one embodiment, R represents H. In one embodiment, L represents Cl to 6 alkyl (Cl to 6 alkylidene). In another 29 embodiment, L represents -CH2-. In another embodiment, L represents NR and R29 represents H. 2 In one embodiment, G represents an optionally substituted monocyclic ring system selected from: i) phenyl, ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S and N, iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two 17 heteroatoms independently selected from O, S(0)p and MR and optionally further incorporating a carbonyl group. 2 In another embodiment, G represents optionally substituted phenyl. In another o ag oe i^f. 27 embodiment, G represents phenyl substituted by OSO^R ,S(O)SR ,SC>2NR R , NR18R19 (wherein at least one of R18 and R19 represents S(O)tR32 or SOZNR3^34) or 39 2 Cl to 3 alkyl substituted by S(>2R - In another embodiment, G represents phenyl 25 25 substituted by S(O)sR andR represents Cl to 6 alkyl or C3 to 6 cycloalkyl and s represents the integer 2. 2 In another embodiment, G represents an optionally substituted bicyclic ring system in which each of the two rings is independently selected from: i) phenyl, ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S and N, iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms independently selected from O, S(O)p and MR and optionally further incorporating a carbonyl group; and the two rings are either fused together, or are bonded directly together or are separated by a linker group selected from O, S(O)q or CHa. 3 3 1 In one embodiment, Y in formula (I) represents CR and R represents H; R represents Cl to 6 alkyl; R represents CONR R or optionally substituted Cl to 6 alkoxy or substituted Cl to 6 alkyl; G represents phenyl; R represents halogen, Cl to 6 alky], CN 4 or Cl to 3 alkyl substituted by one or more F atoms; R represents H; L represents Cl to 6 alkyl; and G represents an optionally substituted monocyclic ring system selected from: i) phenyl, ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from 0, S and N, iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms independently selected from O, S(O)p and NR 17 and optionally further incorporating a carbonyl group. 3 3 1 In one embodiment, Y in formula (I) represents CR andR represents H; R represents 2 48 49 Cl to 6 alkyl; R represents CONR R or optionally substituted Cl to 6 alkoxy or substituted Cl to 6 alkyl; G represents phenyl; R represents halogen, Cl to 6 alkyl, CN 4 or Cl to 3 alkyl substituted by one or more F atoms; R represents H; L represents Cl to 6 o oo oc yf\ yj alkyl; and G represents phenyl substituted by OSC^R ,S(O)sR ,SC-2NR R , NR18R19 (wherein at least one of R18 and R19 represents S(O)tR32 or SO2NR33R34) or 39 Cl to 3 alkyl substituted by S(>2R . In one embodiment, Y in formula (T) represents CR3 and R3 represents H; R1 represents 2 48 49 methyl; R represents CONR R or optionally substituted Cl to 6 alkoxy or substituted Cl to 6 alkyl; G1 represents phenyl; R5 represents Cl, CHs, CN or CF3; R4 represents H; L 2 38 25 represents Cl to 6 alkyl; and G represents phenyl substituted by OSC^R ,S(O)SR , SO2NR26R27> NRI8R19 (wherein at least one of R18 and R19 represents S(O)tR32 or Ti 34 39 SO2NR R ) or Cl to 3 alkyl substituted by SO2R . 3 3 1 In one embodiment, Y in formula (I) represents CR and R represents H; R represents 2 48 49 1 5 methyl; R represents CONR R ;G represents phenyl; R represents Cl, CHs, CN or 4 2 CF3; R represents H; L represents Cl to 3 alkyl; and G represents phenyl substituted by 25 25 S(O)SR and R represents Cl to 6 alkyl or C3 to 6 cycloalkyl and s represents the integer 2. 3 3 1 In one embodiment, Y in formula (I) represents CR andR represents H; R represents 2 1 5 melhyl; R represents optionally substituted Cl to 6 alkoxy; G represents phenyl; R 4 2 represents Cl, CHs, CN or CFa; R represents H; L represents Cl to 3 alkyl; and G 25 25 represents phenyl substituted by S(O)SR and R represents Cl to 6 alkyl or C3 to 6 cycloalkyl and s represents the integer 2. 3 3 I In one embodiment, Y in formula (I) represents CR andR represents H; R represents 2 1 5 methyl; R represents substituted Cl to 6 alkyl; G represents phenyl; R represents Cl, 4 2 CHs, CN or CFa; R represents H; L represents Cl to 3 alkyl; and G represents phenyl 25 25 substituted by S(O)fiR and R represents Cl to 6 alkyl or C3 to 6 cycloalkyl and s represents the integer 2. 3 1 In one embodiment, Y in formula (I) represents CR or N; R represents H or Cl to 6 alkyl; R2 represents CN, NC-2, OH, CC>2R47, CHO, C2 to 6 alkanoyl, Cl to 6 alkoxy, Cl to 6 alkoxy substituted by one or more F atoms, C3 to 6 saturated or partially unsaturated cycloalkyl, C4 to 7 saturated or partially unsaturated heterocyclic ring containing 1 to 3 62 48 49 heteroatoms independently selected from O, S(O)m and NR ,CONR R , CONR5°NHR51, C(=NOR52)R53, NR58R59, C2 to 6 alkenyl or C2 to 6 alkynyl; said alkenyl or alkynyl group being optionally further substituted by Cl to 6 alkoxy or phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N; said phenyl or heteroaromatic ring being 2 optionally further substituted by halogen, CN, Cl to 6 alkyl or Cl to 6 alkoxy; or R represents Cl to 6 alkyl substituted by one or more F atoms; or Cl to 6 alkyl substituted by 58 59 OH, NR R , Cl to 6 alkoxy or Cl to 6 alkoxy substituted by one or more F atoms; or Cl to 6 alkyl substituted by phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N; said phenyl or heteroaromatic ring being optionally further substituted by halogen, CN, Cl to 6 alkyl or Cl to 6 alkoxy; 48 R represents H, OH, Cl to 6 alkoxy or Cl to 6 alkyl; said alkyl being optionally further 54 55 49 substituted by OH, Cl to 4 alkoxy or NR R ; R represents H or Cl to 6 alkyl; said 54 55 alkyl being optionally further substituted by OH, Cl to 4 alkoxy or NR R ; or the group 48 49 NR R together represents a 5 to 7 membered azacyclic ring optionally incorporating one further heteroatom selected from O, S and NR ; said azacyclic ring being optionally 57 further substituted by OR or Cl to 4 alkyl; said alkyl being optionally further substituted by OR ; R and R independently represent H, Cl to 6 alkyl, NR^R * or CONR R ; or the group NR K. together represents a 5 to 7 membered azacyclic ring 56 optionally incorporating one further beteroatom selected from O, S and NR ; said 57 azacyclic ring being optionally further substituted by OR or Cl to 4 alkyl; said alkyl 57 51 being optionally farther substituted by OR ; R represents C2 to 4 alkanoyl optionally 51 3 further substituted by CN, or R represents C(X)NH2 wherein X represents O or S; R represents H or F; G represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N; R represents H, halogen, Cl to 6 alkyl, CN, Cl to 6 alkoxy, NO2, NR14R* , Cl to 3 alkyl substituted by 14 15 one or more F atoms or Cl to 3 alkoxy substituted by one or more F atoms; R and R independently represent H or Cl to 3 alkyl; said alkyl being optionally further substituted by one or more F atoms; n represents an integer 1,2 or 3 and when n represents 2 or 3, 5 4 each R group is selected independently; R represents H or Cl to 6 alkyl; said alkyl being 4 optionally further substituted by OH or Cl to 6 alkoxy; or R and L are joined together 4 such that the group -NR L represents a 5 to 7 membered azacyclic ring optionally incorporating one further heteroatom selected from O, S and NR ; L represents a bond, O, NR2 9 or Cl to 6 alkyl; said alkyl optionally incorporating a heteroatom selected from O, S 11) ? and NR ; and said alkyl being optionally further substituted by OH 01 OMe; G represents a monocyclic ring system selected from: i) phenylorphenoxy, ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S andN, iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms independently selected from O, S(O)p and NR 17and optionally further incorporating a carbonyl group; or 2 G represents a bicyclic ring system in which each of the two rings is independently selected from: i) phenyl, ii) a S or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S and N, iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms independently selected from O, S(O)p and NR 17and optionally further incorporating a carbonyl group; and the two rings are either fused together, or are bonded directly together or are separated by a linker group selected from O, S(O)q or CKfe; said monocyclic or bicyclic ring system being optionally further substituted by one to three substituents independently selected 18 1Q ^R "?fl from CN, OH, Cl to 6 alkyl, Cl to 6 alkoxy, halogen, NR V , NO2, OS02R , CO2R , C(==NH)NH2, C(0)NR21R22, C 26 27 SO2NR R , Cl to 3 alkoxy substituted by one or more F atoms and Cl to 3 alkyl substituted by SO2R3 9 or by one or more F atoms; or when L does not represent an bond, 2 IS G may also represent H; m, p, q, s and t independently represent an integer 0,1 or 2; R 19 32 and R independently represent H, Cl to 6 alkyl, formyl, C2 to 6 alkanoyl, S(O)tR or 33 SO2NR R 34; said alkyl group being optionally further substituted by halogen, CN, Cl to 4 alkoxy or CONR41R42; R25 represents H, Cl to 6 alkyl or C3 to 6 cycloalkyl; said alkyl group being optionally further substituted by one or more substituents selected independently from OH, CN, CONR35R36, CC^R37, OCOR40, C3 to 6 cycloalkyl, a C4 to 7 saturated heterocyclic ring containing one or two heteioatoms independently selected from O, S(O)p and NR4 3 and phenyl or a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S and N; said aromatic ring being optionally further substituted by one or more substituents selected independently from halogen, CN, Cl to 4 alkyl, Cl to 4 alkoxy, OH, CONR^R45, CO2R46, S(O)SR65 and wy Irt 17 9ft 01 NHCOCH3; R represents H, Cl to 6 alkyl or C3 to 6 cycloalkyl; and R , R , R , R , 22 23 24 26 27 29 31 33 34 35 36 37 38 39 40 41 42 43 K. , It , JK. ,J\. ,Jx , Jv , K. , ts. , JR. , J\ , K. , JR. , JR. ,Jcv , K. , is. , Jx , tv. , independently represent H or Cl to 6 alkyl; In another aspect, the invention specifically provides any compound as described in the Examples herein, or the free base thereof or a pharmaceutically acceptable salt thereof. Particular compounds include: 5-cyancH6-methyl-NH^-(melhylsulfonyl)te^ dihydropyridine-3-carboxamide; 6-methyl-N-[4-(ni«thylsulfcmyl)benzyl]-S-nitro-2-oxo-l-[3-(trifluoroniethyl)phenyl]-l,2- dihydropyridine-3-carboxamide1, 5-(l-butoxyvinyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3- (trifluoromethyl)phenyl]-l ,2-dihydropyridine-3-carboxamide; 5-acetyl-6-methyl-N-[4-(melhyls!u^^ dihydropyridine-3-carboxamide; 5-[(lE>N-methoxyethaiumidoyl]--6-methyl-N-[4-(methylsulfonyl)benzyl>2-oxo-l-[3- (trifluoromethyl)phenyl3-l,2-dihydropyridine-3-carboxamide; 5-[(lE)-N-hydroxyethanimidoyl]-6-inelhyl-N-[4-(niethylsulfonyl)benzyl]-2-oxo-l-[3- (trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide; -20 > 6-metbyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-(pyridin-3-ylethynyl)-l-[3- (trifluoromethyl)phenyl]-l^-dihydropyridine-3-carboxamide; 6-methyl-N-[4-(methylsulfonyl)benzyI]-2-oxo-5-(2-pyridin-3-ylethyl)-l-[3- (trifluoromethyl)phenyl3-l^-(^ydropyridine-3-carboxainide; 6-methyl-N-[4KmethylsuIfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)pbenyl]-5-vinyl-l,2- dihydropyridine-3-carboxamide; ethyl 2-methyl-5-({ [4-(methyIsulfonyl)benzyl]amino }carbonyl)-6-oxo-l-[3- (trifluoromethyl)phenyl]-l,6-dihydropyridine-3-carboxylate; 5-(4-roethanesulfonyl-benzylcm-bamoyl)-2-methyl-6K)xo-l-(3-trifluoromethyI-phenyl)-l,6- dihydro-pyridine-3-carboxylic acid; 6-methyl-2-oxo-l-(3-trifluoromethyl-phenyl)-lhydro-pyridine-3>-dicarboxylicadd 5-dimethylamide3-(4-methanesulfonyl-benzyIamide); 6-metbyl-2-oxo-l-(3-trifluoromethyl-phenyl}-l ^-dihydro-pyridine-S^-dicarboxylic acid 5-amide 3-(4-methanesulfonyl-bcnzylamide); 6-methyl-2-oxo-ll,2Kiihydra-pyridine-3,5^carboxylicacid 3-(4-methanesulfonyl-benzylamide)5-inethylamide; fi-methyl^-oxo-HS-trifluoromethyl-phenyl-dihydro-pyridine-S.S-dicarboxylicacid 5-[(2-hydroxy^thyl)-methyl-amide]3-(4-methanesulfonyl-benzylamide); 6-methy]-2-oxo-l-(3-trifluoKmethyl-phenyl>l,2ihydro-pyridine-3,5-dicarboxylicacid 3-(4-methanesuIfonyl-benzylainide)5-(methyl-propyl-amide); 6-jnethyl-2-oxo-5-(pyrrolidine-l-carbonyl)-l-(3-trifluorometiiyl-phenyl)-l,2-dihydropyridine- 3,5-dicarboxylic acid 3-(4-methanesulfonyl-benzylaniide); 6-nMthyl-2-oxo-l3-lrifluoromethyl-phenyl>l,2-dihydro-pyridine-3,5-dicarboxylicacid 5-K2-dimethylamino^thyl)-methyl-ajnide]3-(4-methanesulfonyl-benzylamide); 5-((2jR)-2-hydroxymethyl-pyrrolidine-larbonyl)-6-methyl-2-oxo-l-(3-trifluoroinethylphenyl)- l,2-dihydro-pyridine-3-carboxylic acid 3-(4-methanesulfonyl -benzylamide); 5-(3-hydroxy-pyrrolidine-l-carbonyl)-6-methyl-2-oxo-l-(3-trifluoromethyI-phenyl)-l,2- dihydro-pyridine-3,5-dicarboxylic acid 3-(4-methanesulfonyl-benzylamide); N3-[(14-dioxido-23-dihydro-l'benzothien-5-yl)methyl]-N5^fs,6-trunethyl-2-oxo-l-[3- (trifluoromethyl)pbenyl}-l,2-dihydropyridine-3,5-dicarboxamide; 5-(N'-acetyl-hydrazinocarbonyl)-6-methyI-2-oxo-l-(3-trifluoromethyl-phenyl)-l dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide; 5-(2-cyano-acetyl)-bydrazinocarbonyI]-6-inethyl-2-oxo-l-(3-tiifluoromethyl-phenyl)- l,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide; 5-{f2-(aniin(x;arbonothioyl)hydrazino]carbonyl}-6-methylW-[4-(methylsalfonyl)benzyl3- 2-oxo-l-[3KtrifluoromeyI)phenyl]-l^-dihydropyridine-3^arboxarnide; 5-hydrazinocarbonyl^-methyl-2-oxo-l-(3-trifluoromeihy3-phenyl)-l,2-dihydro-pyridine- 3-carboxylic acid 4-methanesulfonyl-benzylamide; 5-({2-[(ethylamino)carbonyI]hydrazino}carbonyl)-6-methyl-Air-[4-(methylsulfonyl) benzyl]-2^xo-l-[3-(trifluoromethyl)phenyI]-l,2-dihydropyridine-3H:arboxamide; 5-({2-[(NJST-diniethylainino)Garbonyl]hydrazino}carboi)yl)-6-methyl^-[4- (methylsulfonyl)benzyl]-2-oxo-l-(3-(taifluoromethyl)phetiyl]-l,2-dihydropyridine-3- carboxamide; 5K33-dimethyI-ureido)-6-i»ethyl-2xc>-l-(3-trifluorQnietfiyl-phenyl)-l,2-dihydropyridfne- 3-carboxylic add 4-jnethanesulfonyl-benzylamide; 6-inethyl-5-(3-jnethy]-uieido)-2-oxo-l-(3-Mfluoromefcyl-phenyl)-l-dihydro-pyridine-3- carboxylic add 4-methanesulfonyl-benzylamide; 6-methyl-2-oxo-l-(3-triflucffon^hyl-phe3iyl)-5-ureido-l^dihydro-pyridine-3-caiboxyBc acid 4-methanesulfonyl-benzylamide; 5-anutio-6-methyl-2-oxo-l-(3-trifiuoromethyl-phenyl>l,2-dihydro-pyridine-3-carb^ acid 4-methanesulfonyl-benzylamide; 6-me%l-N-[4-(methylsutfonyl)bera^ l,2-dihydropyridine-3-carboxamide; 5-formyl-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-p-(trifluoromethyl)phenyl]-l,2- dihydropyiidine-3-carboxamide; 6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-(3-oxobutyl)-l-[3- (trifluoromethyl)phenyl)-l,2-dihydropyridine-3-carboxamide; 5-acetyl-N-[4-(isopropylsulfonyI)benzyl}-6-methyl-2-oxo-l-[3-(trifluoromethyI)phenyl]- 1,2-dihydropyridine-3-carboxamide; 5-acetyl-l-(3-cyano-phenyl)-6-methyl-2-oxo-l,2-dihydro-pyridine-3-carboxylicacid4- methanesulfonyl-benzylamide; 5-acetyl-l-(3-chloro-phenyl)-6-methyl-2-oxo-l,2-dihydro-pyridine-3-carboxylic acid 4- methanesulfonyl-benzylamide; 5-acetyl-6-methyl-2-oxo-l-m-tolyM,2-dihydro-pyridine-3-carboxylic acid 4- methanesulfonyl-benzylamide; 5-(l-hydroxyethyl)-6-methyl-N-[4-(methylsulfonyl)ben2yl]-2-oxo-l-t3- (trifluc>romethyI)phenyl>l^-dihydropyridine-3-carboxaniide; 5-(l-azidoethyl)-6-2neftyl-N-[4-(njesdiylsulfonyl)benzyl)-2-oxo-l-[3- (trifluoromethyl^henyll-l^-dihydropyridine-S-carboxamide; 6-methyI-N-[4-(methylsulfonyI)benzyl]-5-(l-morphoIin-4-ylethyl)-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide; 5-(l-hydroxypropyl)-6-methyI-N-[4-(methylsulfonyl)benzy]]-2-oxo-l-[3- (trifluc>romethyl)phenyl3-l,2-dihydropyridine-3-carboxamide; 5-(l-hydroxyethyl)-N-[4-(isopropylsulfonyl)benzyl]-6-methyl-2-oxo-l-[3- (trifluoromethyOphenyll-ljI-dihydropyridine-S-carboxamide; N-[4-(cycIopropylsulfonyl)beiizyl]-5-formyl-6-methyl-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-Ktihydropyridine-3 5-[(E)-(methoxyimino)methyl]^methyl-N-[4-(mcthylsuIf(Miyl)benzyl]-2-oxo-l-[3- (trifluorc>methyl)phenyl]4,2^hydix)pyridine-3^arboxaniide; 5-(hydroxymethyI)-^-metfiyl-N-[4-(niethylsuIfonyI)benzyl]-2-oxo-l-[3- (trifluoromethyl)phcnyl]-l^i-dihydropyridine-3-caiboxamide; 5-[(dime%lanuno)methyl>6-methyl-//-[4-(ittethylsulfonyl)benzyl]-2-oxo-l-[3^ (trifluoromethyl)phenyl]-l,2-dihydropyridine'3-catboxamide; 6-methyl-5-[(methylanuno)me&yl]-A^^^ (trifluoromethyl)phenyl]-l,2-dihydropyridme-3-carboxamide; 6-methyl-[4-(meAyJsulfonyl)benzyl]-5-(morpholin-4-yIraethyl)-2-oxo-l-[3- (trifluoromethyl)pheny]]-l,2-dihydropyridine-3-carboxamide; 5-{[(2-furylmethyl)aminolmethyl}-6-inethyl-^-[4-(mefliylsu]fonyl)beazyl]-2-oxo-l-[3- (trifluoromethyl)pheny]]-l,2-dihydropyridine-3-carboxamide; 5-[(cyclopropylamino)niethyl3-6-raethyl-A^-[4-(methyJsulfoiiyl)benzyl]-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide; 5-{[(2-hydroxypropyJ)amino]inethyl}-6-methyl--Ar-[4-(methyIsuIfonyl)benzyl]-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-dJhydropyridine-3-carboxamide; 5-[(cyc]opentyIanadno)methyl]-6-methyI-^-[4-(methylsulfonyl)benzyI3-2-oxo-l-[3- (trifiue)roinethyl)phenyl]-l,2-dihydropyridijie-3-carboxamide; 5-{[(2-hydroxyethyl)(methyl)amino]methyl}-6-methyl-/^~[4-(methylsulfonyl)benzyl]-2- oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide; 6-methyl-[4-(methylsulfonyl)beai2yl3-2-oxo-5-(pyrroKdin-l-ylmethyl)-l-[3- (trifluoromethyl)phenyl]-l^-dihydropyridine-3-carboxamide; 5-{ [methoxy(methyl)amino]methyl} -6-methyl-N-[4-(methylsulfonyl)benzyI]-2-oxo-l-[3- (trifluQromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide; 5- {[(cyanomethyl)amino]methyl }-6-methyl-^-[4-(methylsulfonyl)benzyl]-2-oxo-l -[3- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide; 5-{[(cyclopropylmethyl)airano]methyl}-6^^ [3-(trifluoromeliiy])phenyl]-l,2-dihydropyridine-3-carboxamide; 5-[(3rhydroxypyiroKdin-l-yI)methyl]-6-methyI-JV-[4^methylsulfonyI)benzyl]-2-oxo-l-[3- (trilfluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide; 5-(2-hydroxyethoxy)-N-[4-(isopropylsulfonyl)benzyl]-6-methyl-2-oxo-l-[3- (trifluoromethyl)phenyl]-l -dihydropyridine-3-carboxamide; 2-methyl-5 (trifluoromethyl)phenyl]-l ,6-dihydropyridin-3-yl acetate; 5-methoxy-6-methyl-^-[4-(methyIsidfonyl)ben2yl]-2-oxo-l-[3-(trifluoromethyl)phenyl]- l,2-dihydropyridine-3-carboxainide; 5-(3-methoxypropoxy)-6-methyl-N-[4-(methylsulfonyl)benzyl3-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide; 2-methyl-5-({[4-(methylsulfonyl)benzyI]arnino}carbonyl)-6-oxo-l-[3- (trifluoromethyl)phenyl]-l ,6-dihydropyridin-3-y] methanesulfonate; 5-ethoxy-6-methyl-N-[4-(methyisulfonyl)benzyl]-2-oxo-l-[3-(trifluoioinethyl)phenyl]-l,2- dihydrc^>yridine-3-carboxamide; S-(2-hydroxyethoxy)-6-methyl-N-[4-(methylsulfonyl)ben2yl]-2-oxo-l-[3- (trifluoromethyl)pheny]]-l^-dihydropyridine-3-carboxamide; 5-(cyanomethoxy)-6-methyl-N-[4-(methylsulfonyI)benzyl]-2-oxo-l-[3- (tiifluoromethyl)phenyIJ-l,2-dihydropyridine-3-carboxamide; 2-({ 2-methyI-5-({ [4-(methylsuIfonyl)benzyl]amino }carbonyl)-6-oxo-1 -[3- (trifluoromethyl)phenyl]-l,6-dihydropyridin-3-yl }oxy)ethyl acetate; 5-[2-(dimetfaylamino)-2-oxoethoxy]-6-ineAyl-N-[4-(jnethyIsulfonyl)beiizyl]-2-oxo-l-[3- (triflooromethyl)phenyl]-l,2-dihydropyridme-3-carboxamide; 5-(2-aminoethoxy)-N-[4-(isopropylsulfonyl)benzyl]-6-niethyl-2-oxo-l-[3- (trifluorometiiy])phenyl]-l,2-dihydropyridine-3-catboxainide; 5-(acetylamino)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3- (trifluaromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide; JV-[4-(isopropyIsulfonyi)benzyl]^nwthyl-5-[3^methylaraino)propoxy]-2-oxo-l-[3- (trifluoromethyl)phenyI]-l^-dihydropyridine-3-carboxainide; 5-(l-methoxyethyl)-6-methyl-AT-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3- (trifluoroinethyl)phenyl3-l,2-dihydropyridine-3-carboxamide; 5-(2-bromo-l-methoxyethyl6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3- (trifiuoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide; 5-(l-isopropoxyethyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3- (trifluoromethyl)phenyl]-l-dihydropyridine-3-carboxamide; 5-(N1-isobutyryl-hydrazinocaibonyl)-6-methyl-2-oxo-l-(3-trifluoromethyl-phenyl>l)2- dihydro-pyridine-3-carboxyJic acid 4-methanesulfonyl-benzylamide; JVy-methoxy-6-methyl-JVa-[4-(methylsulfonyl)benzyl^2-oxo-l-[3-(trifluoromeAyl)phenyy 1,2-dihydropyridine-35-dicarboxanjide; AT5-methoxy-A^t6-diinethyl--[4-l-[3- (trifluQromethyl)phenyl]-l,2-dihydropyridii»e-3,5-dicarboxaraide; 5-[(2,5-dimethyI-2,5-dihydro-lH-pyrrol-l-yI)carbonyl]-6-methyl-N-[4- (rae%lsulfonyl)benzyl]-2-oxo-l-[3-(trifluorotaethyl)phenyl]-l,2-^hydropyridine-3- carboxamide; 6-methyl-[4-(methy]sulfonyl)benzyl]-2xo-/^-pynx)lidin-l-yl-l-[3- (trifluoromethyl)phenyl]-l ,2-dihydropyridine-3,5-dicarboxamide; 6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-(piperidin-l-ylcaibonyl)-l-[3- (trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide; 6-methyl-//3-[4-(methylsulfonyl)benzyl]-A^5-morpholin-4-yl-2-oxo-l-[3- (trifluoromethyl)phenyI]-l,2-dihydropyridine-3,5-dicarboxamide; 6-methyl-5-[(4-methylpiperidin-l-yl)catbonyl]-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3- (trifluoromethyl)phenyl)-l ,2-dihydropyridine-3-carboxamide; 6-raethyl-A^-[4-(methy]sulfonyl)benzyl]-2-oxo-^Vs-piperidm-l-yl-l-[3- (trifluoromethyl)phenyl]-l12-dihydropyridine-3,5-dicarboxamide; 25 i JV5-(tert-butyI)-//,6-dimethyl-JV?-[4-(methylsuIfonyl)benzyI]-2-oxo-l-[3- (trifluoroniethyl)phenylH ,2-dihydropyridine-3 ,5-dicarboxamide; (ttifluororaethyl)phenyl]-l,2-dihydropyridine-3,5-dicarboxamide; ^-ethyl-A^-isopropyl-6-methyl-JVJ-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3- (trifluoromethyl)phenyl]- 1 ,2-dihydropyridine-3,5-dicarboxamide; 5-[N1-(fotmyl-hydrazinocarbonyl]-6-methyl-2-oxo-l-(3-trifluoromethyl-phenyl)-l,2- dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide; N1-[5-(4-methanesuIfonyl-benzylcarbamoyl)-2-methyl-6-oxo-l-(3-trifluoromethylphenyl)- l,6-dihydro-pyridine-3-carbonyl]-hydrazinecarboxylic acid ethyl ester, 5-({2-[(ethylamino)carbonothioyl]hydrazmo}carbonyI)-6-methyl-^-[4- (methylsulfonyl)ben2yl]-2K>xo-l-[3 carboxamide; 5-(isoxazolidin-2-ylcai^ony])-6-methyl-^-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3- (trifluoromethyl)phenyl]-l^-dihydropyridine-3-carboxaraide; 6-methyl-2-oxo-l-(3-trifIuoromethyl-phenyl)-l^^ihydro-pyridine-3^5-dicarboxy]ic acid 5-(methoxy-methyl-amide)3-[4-(propane-2-suIfcjnyl>benzylamide]; 6-methyl-2-oxo-l-(3-trifluoromethyl-phenyl)4,2-dihydro-pyridine-3,5-dicarboxylicacid 3-(4-ethanesulfonyl-benzylaraide)5-(methoxy-methyl-ainide); 6-methyl-2-oxo-l-(3-trifluc>romethyl-phenyl)-l,2-dihydK)-pyridine-3,5-dicarboxyKcacid3- (4-cyclopropanesulfonyl-beuzylamide)5-(methoxy-inethyl-amide); 6-methyl-2-oxo-l-(3-trifluoromethyl-phenyl)-l,2-dihydro-pyridine-3,5-dicaiboxyHcacid 5-[(2-hydroxy-ethyl)-amide]3-(4-methanesulfonyl-benzylamide; 5-(isoxazolidine-2-catbonyl>6-methyl-2-oxo-l-(3-trifluoromethyl-phenyl)l,2dihydropyridine- 3-carboxylic acid 4-ethanesulfonyl-benzylamide; 5-(isoxazolidine-2-carbonyl)-6-methyl-2-oxo-l-(3-trifluoromethylphenyl) ldihydropyridine-S-carboxylic acid 4-cyclopropanesulfonylbenzyIamide; 5-{N-hydroxycaTbamirnidoyI)-6-methyl-2-oxo-l-(3-trifluoromethyl-phenyl)-l,2-dihydropyridine- 3-carboxylic acid 4-methanesulfonyl-benzylamide; W3-(cyclohexy]methyI)-V5,Ar5,6-trimethyl-2-oxo- 1- [3-(trifluoromethyl)phenyI]-l ,2- dihydropyridine-3^5-dicarboxamide; 5,6-trimethyi-2-oxo-(pyridin-3-ylraethyl)-l-[3-(trifluoromethyl>phenyl]-l,2 dihydropyridine-3,5-dicarboxamide; AV,6-trimethyl-#3-(2-moiphoUn-4^ dihydropyridine-3,5-dicaiboxamide; AJ-trimethyl-JVS-morphoUn^ dihydropyridine-3,5-dicarboxamide; JVenzyl-A^JV^e-trinMthyW-o^ 3,5-dicarboxamide; JlHndol-S-ylJethy^AA-to dihydropyridine-3,5-dicarboxamide; dihydropyridine-3,5-dicarboxanride; dihydTOpyridine-3,5-dicarboxamide; J-trimethyl-aKao-A-Ka)- l,2-dihydropyridine-3^-dicarboxamide; l,2-dihydropyridine-3,5-dicarboxaraide; methyl)phenyl]-l,2-dihydropyridine-3,5-dicarboxainide; 5-{[4-(2-hydroxyethyl)piperazin-l-yl]carbonyI}-/7,W,2-trimethyl-6-oxo-l-[3- (trifluoromethyl)phenyl]"l,6-dihydropyridine-3-carboxaniide; methyl)phenyl]-l,2-dihydropyridine-3^-dicarboxamide; Ad-trimethyl-A-IS--me methyl)pbenyl]-l,2-dihydropyridine-3,5-dicarboxamide; N5,6-trimethyl-/V3-(l-naphthylmethyl)-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3 ,5-dicarboxamide; #3-(13-benzodioxol-5-ylmethyl)-AfX.6- l,2-dihydropyridine-3,5-dicarboxamide; ^r3K3,4^fluo^obenzyl)-JV5,W^^6-tlimethyl-2-oxo-l-[3-(trifluoroInethyl)phenyl]-l)2- dihydropyridine-3,5-dicarboxainide; fc N3K2-chloro4-fluorobenzyl)-A/5 >6-trimethyl-2-oxo-l-[3-(trifluoromethyl)-phenyl] dihydropyridine-3,5-dicarboxamide; Ve-trimethyW-oxo-jN^t^ dihydropyridine-3,5-dicarboxanHde; dihydropyridine-3,5-dicarboxainide; 1 ,2-dihydropyridine-3,5-dicarboxamide; 3-(2yclohex-ln-l-ylethyl)-,6-trimethy]-2-oxo-l-[3-(trifluoromethyl)-phenyl]- 1 ,2-dihydropyridine-3,5-dicarboxamide; ^r3-[^(4-cWorophenyl)ethyI]-/^^,6-trimethyl-2-oxo-l-[3 dihydropyridine-3,5-dicarboxarmde; methyl)phenyl3-l^Z-dihydropyridiiie-3,5HdicaiboxainJde; /^^^-trimethyl^^xo-^^pyridin^ylmethylVl-^trifluoromethyl^he dihydropyridine-3,5-dicarboxamide; /^^,2-trimethyl-6-oxo-5-[(4-pheny]piperazin-l-yJ)carbonyl]-l-[3-(trifliioromethyl) phenyl]-l,6-dihydropyriduie-3-caiboxamide; /ir^,2-triraethyl-6-oxo-5-[(4-pyridin-2-ylpipera2dn-l-yl)carbonyl]-l-[3-(trifluoromethyl) phenyl]-l,6-dihydropyridine-3-carboxamide; (trifluorojnethyl)phenyl3-l,2-dihydropyridine-3t5-dicarboxamide; methyl 4-{ [({5-[(dimethylamino)carbonyl]-6-methy!-2-oxo-l-[3-(trifluoromethyl) phenyl]-l ^-dihydropyridin-3-yl }carbonyl)amino]methyl}benzoate; 5-{ [3-(dimethylamino)pynx>lidin-l-yl]carbonyl }-AW2-trimethyl-6-oxo-l-[3- (trifluoromethyl)phenyl3-l,6-dihydropyridrae-3-carboxamide; JV5^,6-triinethyl-2-oxo-3-[2-(2-thienyl)ethyl]-l-[3-(trifluoromethyl)phenyl3-tf2- dihydropyridine-3,5-dicarboxamide; 5,6-triTnethyI-2-oxo-N3-(4-phenoxyben2yl)-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3,5-dicarboxamide; dihydropyridine-3,5-dicarboxamide; 28 ^ l,2-dihydropyridine-3,5-dicarboxainide; ^3-{2-[4-(aminosuIfonyI)phenyI]ethyl}-JVs^5,6-trimethyl-2-oxo-I-[3-(trifluoromethyl) phenyl]-l,2-dihydropyridine-3,5-dicarboxamide; l,2-dihydr(^)yridine-3,5-dicarboxainide; /^^,6-trimethyl-2-oxo-A^-phenoxy-l-[3-(trifluoromethyl)phenyl]-J,2-dihydro-pyridin 3,5-dicarboxaraide; (trifluoromethyl)phenyl]-l,2-dihydropyridine-3,5-dicarboxamide; JV3-[(6-fluoro-4/?-l,3-benzodioxin-8-yl)methylJ-^5^V5 t6-trimethyl-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3,5-dicarboxamide; //l-(l-benzothien-3-ylmethyl>Vi^,6-trimethyI-2^xo-l-[3-(trifluoromethyI>phenyl]- dihydropyridine-3,5-dicarboxamide; methyl)phenyl]-l,2-dihydropyridine-3,5-dicarboxamide; ^^^Mmethyl-^-tCl-methyl-l^pyrazoW-ylJmethyl methyl)phenyl]-l,2-dihydropyridine-3,5-dicari)oxamide; ^X.S-triinethyl^^xo-^-Kl-phenyl-L^-pyrazol-^ylJ methyl)phenyl]-l,2-dihydropyridine-3,5-dicarboxamide; ^ (trifluororaethyl)phenyi]-l,2-dihydropyridine-3^-dicarboxamide; A/3-(3-azepan-l-ylpropyI)-//5,A^,6-trimethyl-2^xo-l-[3^trifluoromethyl)phenyl]-l,2- dihydropyridine-3,5-dicarboxamide; Ar3-(4.cyanobenzyl)-A^,Afs,6-trimethyl-2-oxo-l-[3-(trifluoromethyl)phenyl3-l,2- dihydropyridine-3,5-dicarboxamide; A^^^^6-tri^lethyl-2-oxo-/^^3-[3-(5-oxo-4,5-dihydro-lJ¥-pyrazol-4-yI)prQpyl]-l-[3- (trifluoromethyDphenyll-l^-dihydi'opyridine-S.S-dicarboxamide; A^3-{[(2/?)4-ethylpyrroUdin-2-yl]methyl}-^5^,6-trimethyl-2-oxo-l-[3-(trifIuoromethyl) phenyl]-l,2-dihydropyridine-3,5-dicarboxamid6; 5-cyclopropyl-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3- (trifluoroniethyl)phenyl]-l,2-djhydropyridine-3-carboxamide; 6-methyl-5-(2-methyl-l,3-dioxolan-2-yl>N-[4-(methylsulfonyI)benzyl]-2-oxo-l-j;3- (trifluoromethyl)phenyl3-lt2-dihydropyridine-3-caiboxamide; 5-(4^-dihydro-oxazol-2-yl)-6-methyl-2-oxo-H3-trifluoromethyl-phenyl)-l,2-dihydropyridme- 3-carboxylic acid 4-methanesulfonyl-benzylaroide; 5^yclopropyl-6-methyl-N-{[5-(niethylsuIfonyl)pyridin-2-yl]methyl}-2-ox(>-l-[3- and pharmaceutically acceptable salts thereof. The present invention includes compounds of formula 0) in the form of salts, in particular acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable although salts of non-pharmaceutically acceptable acids may be of utility in the preparation and purification of the compound in question. Thus, preferred salts include those formed from hydrochloric, hydrobromic, sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids. In a further aspect the invention provides a process for the preparation of a compound of formula (I) which comprises: a) reacting a compound of formula OB) 2 with a nucleophilic equivalent of R , such as Cu(I)CN, an alkyl vinyl ether, an organo-tin compound, an organo boronic acid, a terminal alkyne or an alcohol and carbon monoxide; 1 ) A. \ 1 0 whereinR ,R ,R ,R , Y,G ,G , L and n are as defined in formula (I) and Hal represents a halogen atom, preferably bromo or iodo; or b) reacting a compound of formula (XV) (XV) wherein R ,R ,R ,n, G and Y are as defined in formula (I) and L represents a leaving group, with a compound of formula (DC) or a salt thereof R4 (IX) whereinR4 , G2 and L are as defined in formula (I); and where desired or necessary converting the resultant compound of formula (I), or another salt thereof, into a pharmaceutically acceptable salt thereof; or converting one compound of formula (I) into another compound of formula CD; and where desired converting the resultant compound of formula (I) into an optical isomer thereof. In process (a), the reaction is carried out at a suitable temperature, generally between 50 °C and 150 °C, in a suitable solvent such as toluene or N,N-dimethylformamide in the presence of a transition metal catalyst such as palladium or in the presence of a base such as potassium carbonate. In process (b), the reaction is carried out at a suitable temperature, generally between 0 °C and the boiling point of the solvent, in a suitable solvent such as dichloromethane or N-methylpyrrolidinone. The process is optionally carried out in the presence of a base and/or a coupling reagent such as HATU, HO AT, HOBT or DEEA. Suitable leaving groups L include OH and halogen. The man sldlled in the art will readily appreciate that many compounds of formula (I) may also be prepared by processes in which the final step or steps involve functional group 2 interchanges within the substituent R . Some such processes are detailed below. Other specific examples of such processes are described in the Examples section of this specification. All such processes form another aspect of the present invention. Compounds of formula (I) wherein R2 represents CONR^R49 or CONR5°NR48R49 can be prepared by reacting a compound of formula (IH) L-G2 (III) wherein R , R , R , Y , Q , G , L and n are as defined in formula (I); 48 49 50 48 49 with an amine of the general formula NHR R orNHR NR R . The process is carried out at a suitable temperature, generally between 0 °C and 50 °C in a suitable solvent such as 1,4-dioxane. Compounds of formula (ID) can be prepared by reacting a compound of formula (IV) (IV) wherein R , R , R , Y, G , G ,L and n are as defined in formula (I) and R represents an alkyl group; with an aqueous base such as sodium hydroxide followed by subsequent treatment of the product with a chlorinating agent such as thionyl chloride. The process is carried out at a suitable temperature, generally between 10 °C and 50 °C in a suitable solvent such as tetrahydrofuran or dichloromethane. Compounds of formula (I) wherein R is defined as NRHI can be prepared by reacting a compound of formula (V): .33- £H (V) wherein R , R , R , Y , G , G , L and n are as defined in formula (I); with an aqueous acid or an alkylamine. The process is carried out at a suitable temperature, generally between 50 °C and 150 °C in a suitable solvent such as toluene. The aqueous acid or alkylamine is added after heating for a time period of, typically between 0.5 and 16 hours. Compounds of formula (V) can be prepared by reacting a compound of formula (TV) wherein R is hydrogen with diphenylphosphoryl azide. The process is carried out at a suitable temperature, generally between 0 °C and 50 °C in a suitable solvent such as dichloromethane. Compounds of formula (IV) can be prepared by reacting a compound of formula (II) with carbon monoxide in the presence of an alcohol such as methanol or ethanol. The process is carried out at a suitable temperature, generally between 50 °C and 150 °C in a suitable solvent in a suitable solvent such as methanol or ethanol in a carbon monoxide atmosphere at elevated pressure, generally between 2 and 10 atmospheres. The reaction is performed in the presence of a transition metal catalyst such as palladium. 2 Compounds of formula (I) wherein R is C2 to 6 alkanoyl can be prepared by reacting a compound of formula (VI); 34 & RO R (VI) whereinR ,R ,R ,Y,G ,G , L and n are as defined in formula (I) and R is an alkyl group; with an aqueous base. The process is carried out at a suitable temperature, generally between 10 °C and 50 °C in a suitable solvent such as N,N-dimethylformamide. Compounds of formula (VI) can be prepared by reacting a compound of formula (IT) with an alkyl vinyl ether. The process is carried out at a suitable temperature, generally between 50 °C and 150 °C in a suitable solvent such as toluene or N,N-dirnethylformamide in the presence of a transition metal catalyst such as palladium. 2 52, 53 Compounds of formula (I) wherein R isC(=NOR jR can be prepared by reacting a 2 compound of formula (I) wherein R is C2 to 6 alkanoyl with an alkoxyamine or hydroxylamine. The process is carried out at a suitable temperature, generally between 50 °C and 150 °C in a suitable solvent such as orN,N-dimethylforniamide. 2 Compounds of formula (I) wherein R is CN can be prepared by reacting a compound of formula (H) with copper(I) cyanide. The process is carried out at a suitable temperature, generally between 100 °C and 150 °C in a suitable solvent in a suitable solvent such as 1- methyl-2-pyrrolidone. 2 Compounds of formula (I) wherein R is NQj can be prepared by reacting a compound of formula (VII) with a nitrating agent such as nitric acid. The process is carried out at a suitable temperature, generally between 10 °C and 50 °C in a suitable solvent in a suitable solvent such as acetic anhydride. Compounds of formula (IE) can be prepared by reacting a compound of formula (VII) (VII) wherein R , R , R , Y , G , G , L and n are as defined in formula (I); with a halogenating agent, such as N-iodosuccinimide in the presence of a strong acid such as trifluoromethanesulfonic acid. The process is carried out at a suitable temperature, generally between 0 °C and 50 °C in a suitable solvent such as acetonitrile in the presence of an acid such as trifluoromethanesulfonic acid. Compounds of formula (VII) can be prepared by reacting a compound of formula (VIQ) wherein R , R , Y, G and n are as defined in formula (I) and L represents a leaving group, with an amine of formula (DC) or a salt thereof R4 (IX) ,4 Ji wherein R , G and L are as defined in formula (I). The process is carried out at a suitable temperature, generally between 0 °C and the boiling point of the solvent, in a suitable solvent such as dichloromethane or N-methylpyrrolidinone. The process is optionally carried out in the presence of a base and/or a coupling reagent such as HATU, HOAT, HOST or DIEA. Suitable leaving groups L include OH and halogen. 3 1 3 Compounds of formula (VHD wherein Y is CR , L is OH and R is hydrogen can be prepared by condensing a compound of formula (X) (X) wherein R is as defined in formula (I), with a compound of f onnula (XI) (XI) wherein G , R and n ate as defined in formula (I), in the presence of a suitable base, such as sodium methoxide, in a suitable solvent, such as ethanol, followed by hydrolysis using a suitable base such as sodium hydroxide. In general, compounds of formulae (X) and (XI) are either known or may be prepared using methods that will be readily apparent to the man skilled in the art. For example, compounds of formula (X) can be prepared according to the methods of S,M Brombridge et al., Syntiietic Communications, 1993,23,487-494. And compounds of formula (XI) can be prepared according to the methods of Igor V. Ukrainets et al., Tetraliedron, 1994,50, 10331-10338. 3 1 1 Compounds of formula (VIH) wherein Y is CR , L is OH and R is hydrogen can be prepared by reacting a compound of formula (XII) NH° (XII) wherein G , R and n are as defined in formula fl), with a compound of formula (Xffl) (XIII) 3 wherein R is as defined in formula CD, at a suitable temperature, such as 160 °C> followed by base promoted cyclisation and acid hydrolysis. Compounds of formula (XHL) can be prepared according to US 3,838,155. Compounds of formula (VIE) wherein Y is CR3 , L is1 OH, R1 is methyl and R3 is hydrogen can be prepared by condensing a compound of formula CXIV) (R5)n H (XIV) wherein G , R and n are as defined in formula (I), with 4-methoxy-3-buten-2-one in the presence of a suitable base, such as l,4-diazabicyclo[2.2.2}octane, at a suitable temperature in a suitable solvent such as diethyleneglycol monomethy] ether, followed by acid hydrolysis. Salts of compounds of formula (I) may be formed by reacting the free base or a salt, enantiomer, tautomer or protected derivative thereof, with one or more equivalents of the appropriate acid. The reaction may be carried out in a solvent or medium in which the salt is insoluble, or in a solvent in which the salt is soluble followed by subsequent removal of the solvent in vacuo or by freeze drying. Suitable solvents include, for example, water, dioxane, ethanol, 2-propanol, tetrahydrofuran or diethyl ether, or mixtures thereof. The reaction may be a metathetical process or it may be carried out on an ion exchange resin. Compounds of formula (I) and intermediate compounds thereto may be prepared as such or in protected form. The protection and deprotection of functional groups is, for example, described in 'Protective Groups in Organic Chemistry', edited by J. W. F. McOmie, Plenum Press (1973), and 'Protective Groups in Organic Synthesis', 3rd edition, T. W. Greene & P. G. M. Wuts, Wiley-Interscience (1999). The compounds of the invention and intermediates may be isolated from their reaction mixtures, and if necessary further purified, by using standard techniques. The compounds of formula (I) may exist in enantiomeric or diastereoisomeric forms or mixtures thereof, all of which are included within the scope of the invention. The various optical isomers may be isolated by separation of a racemic mixture of the compounds using conventional techniques, for example, fractional crystallisation or HPLC. Alternatively, the individual enantiomers may be made by reaction of the appropriate optically active starting materials under reaction conditions that will not cause racemisation. Intermediate compounds may also exist in enantiomeric forms and may be used as purified enantiomers, diastereomers, racemates or mixtures thereof. 40 According to a further aspect of the invention we provide 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, ate useful because they possess pharmacological activity in animals. The compounds of formula (I) have activity as pharmaceuticals, in particular as modulators of human neutrophil elastase and homologous serine proteases such as proteinase 3 and pancreatic elastase, and as such are predicted to be useful in therapy. The compounds of formula (I) are particularly useful as inhibitors of human neutrophil elastase. They may thus be used in the treatment or prophylaxis of inflammatory diseases and conditions. Examples of these conditions are: adult respiratory distress syndrome CARDS), cystic fibrosis, pulmonary emphysema, chronic obstructive pulmonary disease (COPD) and ischaemic-reperfusion injury. The compounds of this invention may also be useful in the modulation of endogenous and/or exogenous biological irritants which cause and/or propagate atherosclerosis, diabetes, myocardial infarction; hepatic disorders including but not limited to cirrhosis, systemic lupus erythematous, inflammatory disease of lymphoid origin, including but not limited to T lymphocytes, B lymphocytes, thymocytes; autoimmune diseases, bone marrow; inflammation of the joint (especially rheumatoid arthritis, osteoarthritis and gout); inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis, pancreatitis and gastritis); inflammation of the skin (especially psoriasis, eczema, dermatitis); in tumour metastasis or invasion; in disease associated with uncontrolled degradation of the extracellular matrix such as osteoarthritis; in bone resorptive disease (such as osteoporosis and Paget's disease); diseases associated with aberrant angiogenesis; the enhanced collagen remodelling associated with diabetes, periodontal disease (such as gingivitis), cornea! ulceration, ulceration of the skin, post-operative conditions (such as colonic anastomosis) and dermal wound healing; demyelinating diseases of the central and peripheral nervous systems (such as multiple sclerosis); age related illness such as dementia, inflammatory diseases of cardiovascular origins; granulomatous diseases; renal diseases including but not limited to nephritis and polyarteritis; cancer; pulmonary hypertension, ingested poisons, skin contacts, stings, bites; asthma; rhinitis; HTV disease progression; for minimising the effects -41 of organ rejection in organ transplantation including but not limited to human organs; and replacement therapy of proteinase inhibitors. Thus, another aspect of the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of diseases or conditions in which inhibition of neutrophil elastase activity is beneficial; 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 a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis 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 a compound of formula (I) or a pharmaceutically acceptable salt thereof. In particular, the compounds of this invention may 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 gastric mucosal injury. Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition. For the above mentioned therapeutic indications, the dose of the compound to be administered will depend on the compound employed, the disease being treated, the mode of administration, the age, weight and sex of the patient. Such factors may be determined by the attending physician. However, in general, satisfactory results are obtained when the compounds are administered to a human at a daily dosage of between 0.1 mg/kg to 100 mg/kg (measured as the active ingredient). The compounds of formula (I) may be used on their own, or in the form of appropriate pharmaceutical formulations comprising the compound of the invention in combination with a pharmaceutically acceptable diluent, adjuvant or carrier. Particularly preferred are compositions not containing material capable of causing an adverse reaction, for example, an allergic reaction. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988. According to the invention, there is provided a pharmaceutical formulation comprising preferably less than 95% by weight and more preferably less than 50% by weight of a compound of formula (I) hi admixture with a pharmaceutically acceptable diluent or carrier. We also provide a method of preparation of such pharmaceutical formulations that comprises mixing the ingredients. The compounds may be administered topically, for example, to the lungs and/or the airways, in the form of solutions, suspensions, HFA aerosols or dry powder formulations, for example, formulations in the inhaler device known as the Turbuhaler®; or systemically, for example, by oral administration in the form of tablets, pills, capsules, syrups, powders or granules; or by parenteral administration, for example, in the form of sterile parenteral M'-l solutions or suspensions; or by rectal administration, for example, in the form of suppositories. Dry powder formulations and pressurized HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation. For inhalation, the compound is desirably finely divided. The finely divided compound preferably has a mass median diameter of less than 10 pan, and may be suspended in a propellent mixture with the assistance of a dispersant, such as a Cg-Cao fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, aperfluorinated or polyethoxylated surfactant, or other phannaceutically acceptable dispersant The compounds of the invention may also be administered by means of a dry powder inhaler. The inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler. One possibility is to mix the finely divided compound with a carrier substance, for example, a mono-, di- or polysaccharide, a sugar alcohol, or an other poiyol. Suitable carriers are sugars, for example, lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch. Alternatively the finely divided compound may be coated by another substance. The powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound. Another possibility is to process the finely divided powder into spheres which break up during the inhalation procedure. This spheronized powder may be filled into the drug reservoir of a multidose inhaler, for example, that known as the Turbuhaler® in which a dosing unit meters the desired dose which is then inhaled by the patient. With this system the active compound, with or without a carrier substance, is delivered to the patient For oral administration the active compound may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum, titanium dioxide, and the like. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent. For the preparation of soft gelatine capsules, the compound may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above mentioned excipients for tablets. Also liquid or semisolid formulations of the drug may be filled into hard gelatine capsules. Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, sacchanne and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art. The compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions. The following Examples are intended to illustrate, but in no way limit the scope of the invention. General Methods 3H NMR and 13C NMR spectra were recorded on a Varian Inava 400 MHz or a Varian Mercury-VX 300 MHz instrument. The central peaks of chloroform-^ (OH 7.27 ppm), diraethylsuIfoxide-& (6n 2.50 ppm), acetonitrile-ffe (OH 1.95 ppm) or methanol- (8n 331. ppm) were used as internal references. Column chromatography was carried out using /5'fC silica gel (0.040-0.063 mm, Meick). Unless stated otherwise, starting materials were commercially available. All solvents and commercial reagents were of laboratory grade and were used as received. The following abbreviations are used: HBTU O-(Benzotria2ol-l-yl)-N,N,N/JK/-tetramethyluronium hexafluorophosphate; HATU O-CT-Azabenzotriazol-l-yO-NJN'X-tetramethyluronium hexafluorophosphate; HOBT 1-Hydroxybenzotriazole; HOAT l-Hydroxy-7-azabenzotriazole; DIEA N,N-Diisopropylethylamine; NMP l-N-Methyl-2-pyrrolidinone; DME 1,2-Dimethoxyethane; THF Tetrahydrofuran; TFA Trifluoroacetic acid; DMF N,N-Dimethylfonnamide; DCM Dichloromethane. The following method was used for LC/MS analysis: Instrument Agilent 1100; Column Waters Symmetry 2.1 x 30 mm; Mass APCI; Flow rate 0.7 ml/min; Wavelength 254 nm; Solvent A: water + 0.1% TFA; Solvent B: acetonitrile + 0.1% TFA; Gradient 15-95%/B 8 min, 95% B 1 min. Analytical chromatography was run on a Symmetry Cig-column, 2.1 x 30 mm with 3.5 fim particle size, with acetonitrile/water/0.1% trifluoroacetic acid as mobile phase in a gradient from 5% to 95% acetonitrile over 8 minutes at a flow of 0.7 ml/min. Example 1 5-Cyano-6-methyl-N-f4-(methvlsulfonyl')benzyn-2-oxo-l-r3- toiflupromethyl) phenyll-1.2-dihvdropyridine-3-carboxamide a) Ethvl 3-oxo-3-f r3-> To an ice-cooled solution of 3-(trifluoromethyl)aniline (64.5 g, 0,40 mol) and triethylamine (60 ml) in acetone (700 ml) was added dropwise ethyl 3-chloro-3-oxopropanoate (63.6 g, 0.42 md) in acetone (50 ml). After the addition (approx. 30 minutes) stirring was continued at room temperature overnight. The solvents were removed and water (1200 ml) was added. The resulting precipitate was filtered off, thoroughly washed twice with water and then dried to afford the title compound as yellow powder (109 g, 99%). 'HNMR (CDC13): 8 9.52 (1H, s); 7.87 (1H, s); 7.78 (1H, d); 7.46 (1H, t); 7.39 (1H, d); 4.29 (2H, q); 3.50 (2H, s); 1.35 (3H, t). APCI-MS m/z: 276.1 [MR]. b) 6-Melhyl-2-oxo-l-f3^trirluorQniethyl)phenvn-l J-dihydropyridine-3-carboxyIic acid To a solution of ethyl 3H)xo-3-{[3 trifluoromethyl)phenyl]amino}propanoate (19,2 g,70 mmol) and sodium methoxide (7.6 g, 140 mmol) in EtOH (250 ml) was added 4-methoxybut-3-en-2-one (90%) (7.72 g, 77 mmol). After the addition, the reaction mixture was refluxed for 2 h and then cooled. Water (50 ml) and 2M NaOH were added and the mixture was stirred at room temperature overnight The organic solvents were removed and the reaction mixture was extracted (washed) with EtOAc. The water phases were acidified with hydrochloric acid to pH 3-4, an orange coloured precipitate appeared and was filtered off, washed with water and dried. Recrystallisation twice from heptane/EtOAc (4:1) afforded the title compound (12 g, 58%) as a white powder. JHNMR (CDCI3): 513.68 (1H, s); 8.54 (1H, d); 7.86 (1H, d); 7.79 (1H, t); 7.55 (1H, brs); 7.48 (1H, d); 6.58 (1H, d); 2.16 (3H, s), APCI-MS m/z: 298.1 [MHJ. c\ e-Methvl-N-r^fmethvlsulfonvltbenzvll^-oxo-l- r3-(trifluoromethvl')phenvn-l .2- dihvdropyridine-3-carboxamide A mixture of 6-methyl-2-oxo-l-[3-(trifluoromethyI)phenyl]-l,2-dihydropyridine-3- carboxylic acid (7.43 g, 25 mmol), HATU (10.5 g, 27.5 mmol), HOAT (3.75 g, 27.5 mmol) and DffiA (14.2 ml, 82.5 mmol) in NMP (65 ml) was reacted for 1 h, then .47 4-methyIsulphonylbenzyl amine hydrochloride (5.8 g, 26 mmol) was added. After 1 h, the reaction mixture was slowly poured into stirred ice water (1 L). A powder was formed, and the water mixture was acidified to pH 3 with citric acid (0.5 M), and stirring was continued for Ih. The precipitate was filtered off, washed with water and dried in vacuum overnight. Recrystallisation from EtOAc gave 8.1 g (70%). 'HNMR (CDC13): 8 10.00 (IH, brt); 8.60 (IH, d); 7.88 (2H, d); 7.83 (IH, d); 7.76 (IH, t); 7.53 (3H, m); 7.46 (IH, d); 6.49 (IH, d); 4.68 (2H, m); 3.03 (3H, s); 2.10 (3H, s). APCI-MS m/z: 465.1 [MH+]. 1 .2-dihydropyridine-3-carboxaniide To a solution of 6-raethyI-N-[4-(methyIsuIfonyI)benzyl]-2-oxo-l-[3- (Uifluoromethyl^hOTyl]-l^-dihydropyridine-3-carboxarnide (200 mg, 0.43 mmol) hi MeCN (1 .5 ml) at room temperature and under argon was added trifluoromethanesulfonic acid (1 ml) followed by N-iodosuccinimide (97 mg, 0.43 mmol). After 45 min, the reaction mixture was diluted with DCM, washed with aqueous NaHCCb, with aqueous NaS2O4 and water, dried (NaaSO), and evaporated to give the title compound (200 mg). H NMR (CDC13): 6 9.85 (IH, brt); 8.90 (IH, d); 7.88 (2H, d); 7.76 (2H, m); 7.50 (2H, d); 7.48 (IH, s); 7.40 (IH, d); 4.65 (2H, m); 3.03 (3H, s); 2.32 (3H, s). APCI-MS m/z: 591.0 [MH^]. e) 5-Cvano-6-methvl-N44-fmethvlsulfonvnbenzvn-2-oxo4-r3-ftrifluoromethvl')phenvll- 1.2-dihydropvrldine-3-carboxamide A mixture of 5-iodo-6-methyI-N-[4-(methyl6ulforiyl)benzyl]-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (120 mg, 0.20 mmol) and copper (I) cyanide (66.7 mg, 0.74 mmol) in NMP (2.5 ml) was stirred overnight at 140 °C. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was first purified by preparative HPLC and then by flash chromatography eluting with DCM/methanol (10:0.2) to give the title compound as a white solid (24 mg, 24 %). !HNMR (DMSO-d6): 5 9.55 (1H, t, J 6.1 Hz); 8.49 (1H, s); 7.96 (1H, s); 7.93 (1H, d, J 7.8 Hz); 7.88 - 7.81 (3H, ra); 7.77 (1H, d, J 8.0 Hz); 7.52 (2H, d, J 8.4 Hz); 4.56 (2H, d, J 6.2 Hz); 3.16 (3H, s); 2.22 (3H, s). APCI-MS m/z: 490 [MH+]. Example! 6-Methvl-N-f4-rmethvlsulfonvl)benzvn-5-nitro-2-oxo-l-r3- (Mflut>roinethyl)pheDvl1-l«2-di^ydropyridine-3-carboxamide To a solution of 6-methyl-N-[4-(methylsulfonyl)benzyl)-2-oxo-l-[3- (trifluororaethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (52 rag, 0.11 mmol) in acetic anhydride (2 ml) was added fuming nitric acid (0.1 ml, 2.1 mmol). The reaction mixture was stirred at room temperature for 40 rain. The mixture was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate. The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound as a yellow powder (13 mg, 23%). H NMR (CDC13): 8 9.47 (1H, t, J 5.6 Hz); 9.31 (1H, s); 7.92 - 7.86 (3H, m); 7.81 (1H, t, J 7.9 Hz); 7.54 - 7.48 (3H, m); 7.44 (1H, d, J 7.9 Hz); 4.69 (2H> dd, J 5.9,3.9 Hz); 3.03 (3H, s);2.52(3H,s). APCI-MS m/z: 510 [MR]. Example 3 5-(l-Bu^oxyvinvlV6-methvl-N-I4-(me^ylsujfQny\|)pcnzyl1-2-oxo-l-r3- (trifluoromethvnphenvl]-1.2-dihvdropvridine-3-carboxamide In a Schlenk vessel equipped with a magnetic stirring bar were placed 5-iodo-6-methyl-N - [4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxamide (101.5 mg, 0.17 mmol), bis[12-bis(diphenylphosphino)ethane]-palladram (0) (16.5 mg, 18.3 /unol), n-butyl vinyl ether (60 /il, 0.46 mmol), triethylamine (0.5 ml, 3.6 mmol) and DMF (6 ml). The vessel was purged with argon, sealed and heated at 100 °C overnight. The reaction mixture was cooled and partitioned between ethyl acetate and water, The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound as a white solid (27.3 mg, 28 %). H NMR (CDC13): 8 9.96 (1H, t, J 5.8 Hz); 8.64 (1H, s); 7.89 (2H, d, J 8.3 Hz); 7.82 (1H, d, J 8.0 Hz); 7.75 (1H, t, J 7.9 Hz); 7.56 - 7.50 (3H, m); 7.46 (1H, d, J 7.8 Hz); 4.69 (2H, ddd, J 22.1,15.7,6.2 Hz); 4.43 (1H, d, J 2.6 Hz); 4.26 (1H, d, J 2.6 Hz); 3.83 (2H, t, J 6.5 Hz); 3.03 (3H, s); 2.11 (3R s); 1.74 (2H, quintet, J 9.2 Hz); 1.46 (2H, sextet, J 9.1 Hz); 0.98(3H,t,J7.4Hz). APCI-MS m/z: 563 [MR]. Example 4 5-Acetvl-6-methvl-N-f4-fmethvlsu]fonvi')benzvI'>-2-oxo-l-r3- (trifluoromethyl)phenyl1-1.2-dihvdropyridiiie-3-cai:boxarnid6 To a solution of 5-(l-butoxyvinyI)-6-methyl-N-[4-(methylsulfoiiyl)benzyl3-2-oxo-l-l3- (trifluoiomethyl)phenyl]-l^-dihydropyridine-3-«irboxamide (38 mg, 67.5 /tmol) in DMF (0.5 ml) was added aqueous hydrochloric acid (2.0M, 50 jil). After 20 min. the solution was neutralized with aqueous sodium hydrogen carbonate. The reaction mixture was purified by preparative HPLC to give the tide compound as a white solid (17.6 mg, 51%). H NMR (CDC13): 5 9.75 (1H, t, J 5.7 Hz); 9.08 (1H, s); 7.90 (2H, d, J 83 Hz); 7.85 (1H, d, J 7.9 Hz); 7.78 (1H, t, J 7.9 Hz); 7.54 (2H, d, J 8.3 Hz); 7.50 (1H, s); 7.42 (1H, d, J 8.0 Hz); 4.70 (2H, t, J 6.0 Hz); 3.03 (3H, s); 2.66 (3H, s); 2.43 (3H, s). APCI-MS m/z: 507 [MH+]. Example 5 S-rflEVN-Metboxvethanimidoyll-e-methvl-N-r^fmethylsulfonvnbenzvl]- 2-oxo4-r3-ftrifluoromethynphenvl1-L2-dihvdropvridine-3-carboxamide A mixture of 5-acetyl-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (47.2 mg, 0.09 mmol), methoxylamine hydrochloride (22.9 mg, 0.27 mmol), potassium carbonate (36 mg, 0.26 mmol) and DMF (1 ml) was heated at 100 °C for 1 h. After cooling the reaction mixture was neutralized with aqueous 2.0M hydrochloric acid and purified by preparative HPLC to give the title compound as a white solid (9 mg, 18 %). .50 H NMR (CDC13): 8 9.91 (1H, t, 16.0 Hz); 8.58 (1H, s); 7.88 (2H, d, J 8.3 Hz); 7.82 (1H, d, J 8.3 Hz); 7.75 (IH, t, J 7.9 Hz); 7.54 - 7.49 (3H, m); 7.44 (IH, d, J 7.8 Hz); 4.67 (2H, t, J 5.9 Hz); 3.96 (3H, s); 3.02 (3H, s); 2.20 (3H, s); 2.14 (3H, s). APCI-MS m/z: 536 Example 6 S-ftlJ^N-HvdroxyethaniimdovlV^ ^ A mixture of 5-acetyl-6-methyl-N-[4-(methylsulfony])benzyl]-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxaTnide (34.7 mg, 68.5 jtunol), hydroxylamine hydrochloride (30.3 mg, 0.44 mmol), triethylamme (0.5 ml, 3.6 mrnol), tetrahydrofuran (1 ml) and methanol (0.5 ml) was heated at 70 °C for 48 h. The reaction mixture was cooled and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound as a white solid (8 mg, 22 %). H NMR (CDC13): 8 9.92 (IH, t, J 5.6 Hz); 8.59 (IH, s); 7.88 (2H, d, J 8.1 Hz); 7.82 (IH, d, J 7.7 Hz); 7.75 (IH, t, J 7.8 Hz); 7.52 (4H, d, J 4.2 Hz); 7.44 (IH, d, J 7.5 Hz); 4.68 (2H, ddd, J 21.2,15.3,6.0 Hz); 3.02 (3H, s); 2.25 (3H, s); 2.12 {3H, s). APCI-MS m/z: 522 [MR]. Example 7 6-Methyl-N-r4-(iqethylsutfony\|ty^ (trifluoromethyl)phenyn-1.2-dihydropyridine-3-carboxamide A mixture of 5-iodo-6-methyl-N-[4~(methylsulfonyl)benzyl)-2-oxo-l-[3- (trifluoromethy^phenyU-l^-dihydropyridine-S-carboxamide (86.7 mg, 0.15 mmol), copper® iodide (3.1 mg, 0.016 mmol), 1,10-phenanthroline monohydrate (5.9 mg, 0.03 mmol), ttiphenylphosphine (13.8 mg, 0.05 mmol), cesium carbonate (70 mg, 0.22 mmol)- tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol), 3-(trimethylsHylethynyl)pyridine (38.1 mg, 0.22 mmol) in toluene (15 ml) was heated at 100 °C under argon for 48 h. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was first purified by preparative HPLC on a kromasil column and then by flash chromatography eluting with DCM/methanol (10:0.25) to give the title compound as a white solid (29.7 mg, 36 %). HNMR (CDC13): 8 9.81 (1H, t, J 5.5 Hz); 8.76 (2H, d, J 113 Hz); 8.60 (ffl, d, J 4.7 Hz); 7.94 - 7-83 (3H, m); 7.83 - 7.75 (2H, m); 7.57 - 7.50 (3H, m); 7.47 (1H, d, J 7.7 Hz); 7.33 (1H, dd, 3 7.7, 5.0 Hz); 4.70 (2H, t, J 5.4 Hz); 3.03 (3H, s); 2.35 (3H, s). APCI-MS m/z: 566 [MH]. Example 8 6-Methvl-N--r4-fmethvlsulfonvl)benzvn-2-oxQ-5-f2-pvridin-3-vlethvD-l-f3- (trifiuoromethyDphenvlM^-dihvdropvridiTie-S-caTboxamide A suspension of 6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-(pyridin-3-ylethynyl)-l- [3-(trifluoromethyl)phenyl3-l,2-dihydiopyridine-3-carboxarnide (20 mg, 0.035 mmol), 5% palladium on carbon (10 mg) in ethanol (5 ml) and ethyl acetate (5 ml) was stirred vigorously under a hydrogen atmosphere for 48 h. The mixture was filtered through Celite, the filtrate was evaporated to dryness and the residue was purified by preparative HPLC to give the title compound as a white solid (1 1 mg, 55%). H NMR (DMSO-d6): 5 9.96 (1H, t, J 6.2 Hz); 8.45 (1H, d, J 1.8 Hz); 8.40 (1H, dd, J 4.8, 1.5 Hz); 8.29 (1H, s); 7.91 - 7.75 (5H> m); 7.72 - 7.60 (2H, m); 7.52 (2H, d, J 8.3 Hz); 7.34 - 7.27 (1H, m); 4.56 (2H, d, J 6.0 Hz); 3.16 (3H, s); 2.88 (4H, s); 1.87 (3H, s). APCI-MS m/z: 570 [MH]. Example 9 6-Mfithvl-N-r4-fmethvlsufo A mixture of 5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-t3- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (53 mg, 0.09 mmol),. tributyl(vinyl)tin (51 mg, 0.16 mmol), tetrakis(triphenylphosphine)panadium(0) (6.9 mg, 0.006 mmol) in toluene (10 ml) was heated at 100 °C under argon for 12 h. After cooling, the solvent was removed in vacuo and the residue was purified by preparative HPLC to give the title compound as a white solid (18 mg, 41%). JHNMR (CDC13): 8 9.98 (1H, t, J 5.9 Hz); 8.85 (1H, s); 7.87 (2H, dt, J 8.5, 1.9 Hz); 7.83 - 7.69 (2H, m); 7.54 - 7.47 (3H, m); 7.42 (1H, d, J 7.7 Hz); 6.69 (1H, dd, J 17.2, 11.0 Hz); .52 g' 5.73 (1H, d, J 17.2 Hz); 5.40 (1H, d, J 11.2 Hz); 4.67 (2H, dd, J 5.9,3.7 Hz); 3.01 (3H, s); 2.10 (3H, s). APCI-MS m/z: 491 [MH]. Example 10 Ethvl 2-aefliyi-5-Kr4^methvlsulfonvl)beiizvllaminolcarfaonylV6-oxo-l-r3- ftrifluoromethvI^phenvn-1.6-dihydropyridine-3-carboxylate In a stainless-steel autoclave (100 ml) were placed 5-iodo-6-methyl-N-[4- (methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoroinethyl)phenyI]-l^-dihydropyridine-3- carboxamide (108.1 mg, 0.18 mmol), palladium(n) acetate (3.8 mg, 0.02 mmol), triphenylphosphine (10.3 mg, 0.04 mmol), triethylamine (2ml, 14.4 mmol) and ethanol (6 ml). The reaction mixture was magnetically stirred at 100 °C under a carbon monoxide pressure of 4 atmospheres overnight. After cooling, the solvent was evaporated off and the residue was purified by preparative HPLC to give the title compound as a white solid (77.6 mg,79%). H NMR (CDC13): 5 9.73 (1H, t, J 5.9 Hz); 9.20 (1H, s); 7.90 (2H, d, J 8.3 Hz); 7.85 (1H, d, J 7.9 Hz); 7,78 (1H, t, J 7.8 Hz); 7.53 (2H, d, J 8.3 Hz); 7.50 (1H, s); 7.42 (1H, d, J 8.0 Hz); 4.69 (2H, t, J 5.9 Hz); 4.38 (2H, q, J 7.2 Hz); 3.03 (3H, s); 2.50 (3H, s); 1.42 (3H, t, J 7.2 Hz). APCI-MS m/z: 537 (MHj. Example 11 5-(4-Methane8ulfonyl"benzylcarbanioylV2-methvl'6-oxp-l-f3'- tr4Jlupromethyl-phenyl)-1.6-dihydro-pvridi^e--3-carboxyiicacid To a solution of ethyl 2-meltoyl-5-({[4-(methyIsulfonyl)benzyl]amino}carbonyI)-6-oxo-l- [3-(trifluoromethyl)phenyl]-l,6-dihydropyridine-3-carboxylate (0.70 g, 1.30 mmol) in THF (10 ml) and water (10 ml) was added 1M NaOH (2 ml, 2 mmol), and the mixture was stirred for 1 h at room temperature, monitoring the progress of the reaction by LC-MS. 20% conversion was observed, and another portion of 1M NaOH (1 ml, 1 mmol) was added, and the reaction was allowed to run for another 1 h. This procedure was repeated until complete conversion of the ester was observed (normally 3-4 hours). The outcome of the reaction is two compounds with the same mass, in a 95:5 proportion. The main product S3 3' is the subtitle compound, and the other is a regioisomer. The reaction mixture was evaporated to remove THF, and the residual water solution was acidified and extracted with EtOAc. The organic phase was collected and dried over NaaSO Filtration and evaporation gave a crude product 0.60 g (90%) as a yellowish solid, which can be used further without purification. A portion was purified by preparative HPLC, H NMR (CDC13): 5 9.90 (1H, t, J 6.2 Hz); 9.31 (1H, s); 7.9 (2H, d, J 8.2 Hz); 7.84 (1H, d, J 8.0 Hz); 7.77 (1H, t, J 8.0 Hz); 7.51 (2H, d, J 8.5 Hz); 4.5 (1H, s); 7.41 (1H, d, J 8.0 Hz); 4.92 (1H, bs); 4.78-4.63 (2H, m); 3.01 (3H, s); 2.53 (3H, s). APCI-MS m/z: 509.2 [MH+]. Example 12 6-Methvl-2-oxo-l-(3-trifiuoroniethyl-phenyl)-1.2-dihydro-pyridine-3.5- dicarboxylic acid 5-dimethyIamide 3-(4-metfaanesuIfonyl-benzvlamide) To 5-(4-memanesulfonyI-benzylcarbamoyl)-2-methyl-6-oxo-l-(3-trifluoromethyl-phenyl)- l,6-dihydro-pyridine-3-carboxylic acid in CHjCla (5 ml), SOCb (3 ml) was added, and the flask was sealed and stirred magnetically for 2 h. The crude mixture was evaporated in vacuo giving the intermediate acid chloride as a yellow solid. The solid was dissolved in 1,4-dioxan (5 ml, dried over molecular sieves) and dimethylamine (40% aqueous solution, 0.5 ml) was added quickly. The mixture was stirred for 5 minutes, and LC-MS showed complete formation of the title compound. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC, giving 0.008 g (76%) of the title compound as a white solid after freeze-drying the pure fractions. H NMR (CDC13): 8 9.86 (1H, t, J 5.9 Hz); 8.73 (1H, s); 7.89 (2H, d, J 8.3 Hz); 7.84 (1H, d, J 7.8 Hz); 7.77 (1H, t, J 7.8 Hz); 7.52 (2H, d, J 8.4 Hz); 7.51 (1H, s); 7.43 (1H, d, J 7.9 Hz); 6.16 (1H, bs); 4.75-4.63 (2H, m); 3.03 (3H, s); 3.02 (3H, d, J 4.3 Hz); 2.33 (3H, s). APCI-MS m/z: 536.2 [MH+]. Using the general method of Example 12, the compounds of Examples 13 to 20 and 22 to 25 were prepared. t, r \ 54 5 '• Example 13 6~Metjiyl-2H3xo-l-G-trifluorDmethvl-phenyD~1.2-difaydr^pffldine-3.5- dicarboxylic acid 5-amide 3-f4~methane8ulfonyl-benzylamide) HNMR (CDC13): 8 9.82 (1H, t, J 5.9 Hz); 8.80 (1H, s); 7.78 (2H, d, J 8.8 Hz); 7.84 (1H, d, J 8.1 Hz); 7.76 (1H, t, J 7.9 Hz); 7.51 (2H, d, J 8.9 Hz); 7.50 (1H, s); 7.42 (1H, d, J 7.8 Hz); 6.15 (1H, bs); 5.75 (1H, bs); 4.73-4.61 (2H, m); 3.02 (3H, s); 236 (3H, s). APCI-MS m/z: 508.2 [MB]. Example 14 6-MethyL-2^o-l-jf3-trifluoromethyl-phenylVl,2-di^vdro-pyridine-3.5- dicarboxvlic acid 3-(4-methanesulfonvl-benzvIamide') 5-methyIamide HNMR (CDCI3): 8 9.90 (1H, t, J 5.9 Hz); 8.54 (1H, s); 7.90 (2H, d, J 8.1 Hz); 7.84 (1H, d, J 7.9 Hz); 7.77 (1H, t, J 7.8 Hz); 7.53 (1H, s); 752 (2H, d, J 8.3 Hz); 7.45 (1H, d, J 7.9 Hz); 4,74-4.62 (2H, m); 3.15 (3H, s); 3.07 (3H, s); 3.02 (3H, s); 2.11 (3H, s). APQ-MS m/z: 522.3 [MH+J. Example 15 6-Methyl-2-oxo-l-(3^trifluorpme^iyl-phenyl')-l,2-dihvdro-pvridine-3.5- dicarboxylic acid S-rte-hydroxy^fcylVinethvI-amide) 3-(4-methaqesulfon vl-benzylamide) APCI-MS m/z: 566.2 [MH4]. Retention time 1.82 minutes. Example 16 6-Methvl-2-oxo-l-G-trifluoromethvI-phenvlVl^-dihvdro-pvridine-3^- dicarboxylic acid 3-(4-mctha^esuIfonyl-benzylainideV5-(methyI-propvl-amide') !H NMR (CDC13): 8 9.94-9.84 (1H, m); 8.50 (1H, s); 7.88 (2^ d, J 8.6 Hz); 7.83 (1H, d, J 7.9 Hz); 7.76 (1H, t, J 7.9 Hz); 7.52 (1H, s); 7,52 (2H, d, J 8.1 Hz); 7.44 (1H, d, J 7.9 Hz); 4.74-4.62 (2H, m); 3.52 (1.1H, t, J 7.5 Hz, part of rotameric system, retainer 1); 3.29 (0.9H, t, J 7.5 Hz, part of rotameric system, rotaraer 2); 3.10 (1.4H, s, part of rotameric system, rotamer 2); 3.02 (1.6H, s, part of rotameric system, rotamer 1); 3.02 (3H, s); 2.08 (3H, s); 1.75-1.60 (2H, m); 0.99 (1.6H, t, J 7.5 Hz, part of rotameric system, rotamer 1); 0.88(1.4H,t,J 7.5 Hz, part of rotameric system, rotamer 2). ,-. APCI-MS m/z: 564.3 [MR]. ,55 f Example 17 ^Methvl-2-oxc^5-(pyirolidine-lK:art)onYl)-I-(3-trifluoroinethyl-phenylV 12-dihvdro-pvridme-3.5-dicarboxylic acid 3-(4-methanesuIfanvI-beiizvlamide) H NMR (CDC13): 5 9.87 (1H, t, J 6.0 Hz); 8.59 (1H, s); 7.88 (2H, d, J 8.2 Hz); 7.82 (1H, d, J 7.9 Hz); 7.75 (1H, t, J 7.9 Hz); 7.54-7.48 (3H, m); 7.44 (1H, d, J 7.6 Hz); 4.73-4.61 (2H, m); 3.66 (2H, t, J 6.7 Hz); 3.46-3.39 (2H, m); 3.02 (3H, s); 2.14 (3H,.m); 2.06-1.95 (4H,m). APCI-MS m/z: 562.5 [MH+]. Example 18 6-Methvl'2-oxo-l-(3-trtfluoromethyl-phenylV1.2-dihydrQ-pyiidine-3.5- dicarbQxvlic acid S-^-dimethylaToino-ethvlVmethyl-amide] 3-(4-methanesulfonylbenzylaTnidej trifluoroacetic acid salt JH NMR (DMSO-dd): 5 9.88 (1H> t, J 6.1 Hz); 9,40 (1H, bs); 8.43 (1H, s); 8.00 (1H, s); 7.90 (1H, d, J 7.7 Hz); 7.87 (2H, d, J 8.2 Hz); 7.83-7.76 (2H, m); 7.53 (2H, d, J 8.2 Hz); 4.58 (2H, d, J 5.9 Hz); 4.05-3.70 (2H, m); 3.43-3.31 (2H, m); 3.16 (3H, s); 2.96 (3H, s); 2.89 (3H, s); 2.88 (3H, s); 1.92 (3H, s). APCI-MS m/z: 593.3 [MH+]. Example 19 5-(f2Je)-2-Hvdroxvmethvl-pvrroIidiTie-l-carbonvIV6-methvl-.2-oxo>l-f3- trifluoromethyl -phenylVl.2-dihydro-pvridine-3-caiboxylic acid 3-(4-methanesulfonyl - benzvlamide'li JH NMR (CDC13): 5 9.88 (1H, t, J 6.1 Hz); 8.59 (1H, d, J 3.3 Hz); 7.89 (2H, d, J 8.8 Hz); 7.84 (1H, d, J 7.7 Hz); 7.77 (1H, t, J 7.7 Hz); 7.51 (2H, d, J 8.6 Hz); 7.51 (1H, s); 7.44 (1H, d, J 7.8 Hz); 4.70-4.65 (2H, m); 4.44-4.35 (1H, m); 3.91-3.84 (1H, m); 3.74 (1H, p, J 5.7 Hz); 3.55-3.44 (2H> m); 3.02 (3H, s); 2.27-2.17 (1H, m); 2.15 (3H, s); 2.12-1.83 (3H, m); 1.82-1.71 (lH,m). APCI-MS m/z: 592.4 [MH]. Example 20 5"(3-Hvdroxv-pvrrolidine-l-carbonvI')-6-methvl-2-oxo--l-(3- trifluoromethvl-phenvlVl .2-dihvdro-pvridine-3.5-dicarboxvIic acid 3-C4-methanesulfonvIbenzvlamide') H NMR (CDC13): 8 9.96-9.89 (IH, m); 8.63-8.56 (IH, m); 7.88 (2H, d, J 8.5 Hz); 7.83 (IH, d, J 8.0 Hz); 7.76 (IH, t, J 7.6 Hz); 7.52 (IH, s); 7.51 (2H, d, J 8.0 Hz); 7.44 (IH, d, J 7.6 Hz); 4.67 (2H, d, J 5.7 Hz); 4.654.53 (IH, m); 3.92-338 (4H, m); 3.02 (3H, s); 2.19- 2.01 (2H, m); 2.14 (3H, s). APd-MS m/z: 578,3 [MH]. Retention time 1.95 minutes. Example 21 N3-rfl.l-Dioxido-2.3-dihvdro-l-benzothien-S-vnmethvn-N5.N5.6-trimethvl- 2-oxo-l~f3-(trifIuoromethvDphenvl1-L2-dihydropyridine-3.5-dicarbQxainide In a stainless-steel autoclave (100 ml) were placed N-[(l,l-dioxido-23-dihydro-lbenzotHen- 5-yl)methyl]-5-iodo-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l^- dihydropyridine-3-carboxamide (66.3 mg, 0.11 mmol), palladium(n)acetate (14.0 mg, 62.4 /imol), triphenylphosphine (25.1 mg, 95.7 jonol), dimethylamine (12 g, 27.8 mmol) and ethanol (10 ml). The reaction vessel was cooled to -50 °C, degassed by vacuum/carbon monoxide combined treatment, pressurized at 4 atmospheres with carbon monoxide, and then heated at 100 °C for 6 h. After cooling, the solution was evaporated and the residue was purified by preparative HPLC to give the tide compound as a white solid (11 mg, 18%). !H NMR (CDC13): § 9.85 (IH, t, J 5.9 Hz); 8.53 (IH, s); 7.84 (IH, d, J 7.7 Hz); 7.77 (IH, t, J 7.9 Hz); 7.68 (IH, d, J 8.0 Hz); 7.52 (IH, s); 7.44 (2H, t, J 8.6 Hz); 7.35 (IH, s); 4.65 (2H, dd, J 5.8,4.1 Hz); 3.49 (2H, t, J 6.8 Hz); 3.36 (2H, t, J6.9Hz); 3.15 (3H, s); 3.07 (3H, s);2.11(3H,s). APCI-MS m/z: 548 [MH]. Example 22 5-(N]-AcetyI-hydjrazinocarbonvlV6^nethyl-2-oxo-l-f3-trifluoromethy^ phenvlVl ,2-cUhvdro-pvridine-3-carboxvlic acid 4-methanesulfonvl-benzvlamide !H NMR (DMSO-d 7.93 (IH, s); 7.93-7.90 (IH, m); 7.87 (2H, d, J 8.4 Hz); 7.82 (IH, d, J 7.7 Hz); 7.74 (IH, d, J 8.0 Hz); 7.55 (2H, d, J 8.3 Hz); 4.59 (2H, d, J 6.2 Hz); 3.17 (3H, s); 2.18 (3H, s); 1.91 (3H, s). APCI-MS m/z: 565.2 [MH+]. Example23 5-rN-f2-Cvano-acetvlVhvdirainoc^ trifluoromethyl-pheDylVl^-dhvdrQ-pvridine-S-carboxvh'c.acid 4-methanesuIfonvlbenzvlamide HNMR (DMSO-dfi): 510.55 (1H, s); 10.42 (1H, s); 9.78 (1H, t, J 6.2 Hz); 8.51 (1H, s); 7.94 (1H, s); 7.92 (IE d, J 8.2 Hz); 7.87 (2H, d, J 8.2 Hz); 7.82 (1H, d, J 7.6 Hz); 7.75 (1H, d, J7.6 Hz); 7.55 (2H, d, J 8.2Hz); 4.59 (2H, d, J 6.0 Hz); 3.82 (2H, s); 3.17 (3H, s); 2.18 (3H, s). APCI-MS ra/z: 590.1 [MH+]. Example 24 5-( r24Amhiocarbonothiovl'>hvdra2:inolcarbonvl>-6-methvl-jy-f4- (methylsuI^vl)benzvll-2-oxo-l-F34triflu carboxamide NMR CDMSO-d): 510.31 (1H, s); 9.80 (1H, t, J 6.2 Hz); 9.32 (1H, s); 8.70 (1H, s); 7.92 (1H, d, J 7.8 Hz); 7.91 (1H, bs); 7.90 (1H, bs); 7.86 (2H, d, J 8.3 Hz); 7.83 (1H, d, J 8.3); 7.76 (1H, bs); 7.70 (1H, d, J 7.6 Hz); 7.54 (2H, d, J 8.1 Hz); 4.59 (2H, d, J 6.0 Hz); 3.17 (3H,s); 2.14 (3H,s). APCI-MS m/z: 582.1 [MH+]. Example 25 5-Hydraanocaib^^onyl-6-methyl'2-oxp-I-(3j-trifluoroinethvl-phgnyl)-1.2- dihydro-pvridine-3-caTboxylic acid 4-methanesulf^onvl-benzyJiamide APCI-MS na/z: 523.2 [MH]. Retention time 1.72 minutes. Example 26 5-({2-rfflthvIanrinok:arbonvl]hvd^ (methvlsulfonyI)ben2vI1-2-oxo-l-r3-(trifluoromethyDphenvl1-L2ihydbropyndin carboxaimde To5-bydrazmocarbonyl-6-methyl-2-oxo-l-(3-trifluoromethyI-phenyl)-l,2-dihydropyridine- 3-carboxylic acid 4-methanesulfonyJ-benzylamide (0.030 g, 0.057 romol) in 1,4-dioxan (10 ml) was added ethylisocyanate (0.016 g, 0.23 mmol), and the mixture was stirted at room temperature for 1 fa. The mixture was evaporated and the residue was purified on preparative HPLC giving 0.015 g (44%) of the title compound. H NMR (CDC13): 8 9.96-9.87 (1H, m); 8.82 (1H, s); 7.88 (1H, d, J 8.2 Hz); 7.84 (2H, d, I 7.9 Hz); 7.83-7.80 (1H, m); 7.77 (1H, t, J 7.9 Hz); 7.52 (1H, s); 7.47 (2H, d, J 8.2 Hz); 7.47-7.41 (1H, m); 4.70-4.55 (2H, m); 3.23 (2H, q, J 6.9 Hz); 3.01 (3H, s); 2.31 (3H, s); l.ll(3H,t,J7.1Hz). APCI-MS m/z: 594.2 [MH1]. Example 27 5-(f2-r(N.N-Dimefliylamino)carbonyllhydrazinolcarbonyll-6-methyl-A?:-f4- (methylsulfonyl^ benzvn-2-oxO"l-r3"(trifluorome1hyl)phenyn-1.2-dihydropyriding-3- carboxamide To5-hydrazinocarix>nyl-6-methyl-2-oxo-l-(3-trifluo«)methyl-phenyl)-l^-dihydi^ pyridine-3-carboxylic acid4-methanesulfonyl-benzylamide (0.030 g, 0.057 mmol) in THF (10 ml) was added N^-dimethylcarbamoyl chloride (0.0247 g, 0.23 mmol), and the mixture was stirred at 50 °C for 3 h. The mixture was evaporated and the residue was purified on preparative HPLC giving 0.020 g (60%) of the title compound. H NMR (DMSO-dtf): 5 9.92 (1H, bs); 9.80 (1H, t, J 6.2 Hz); 8.50 (1H, s); 8.48 (1H, s); 7.94-7.89 (2H, m); 7.87 (2H, d, J 8.5 Hz); 7.82 (1H, d, J 8.2 Hz); 7.73 (1H, d, J 7.8 Hz); 7.55 (2H, d, J 8.5 Hz); 4.59 (2H, d, J 6.0 Hz); 3.17 (3H, s); 2.85 (6H, s); 2.19 (3H, s). APCI-MS m/z: 594.1 [MH]. Example 28 5-f3.3-DimethvI-ureidoV6-methvl-2-oxo-l-(3-trifluoromethvl-phenvl')-1.2- dihvdro-pyridine-3-cajboxylic acid 4^mejhaiye$ulfonyl-benzvlamide a) 5-(4-MethanesuIfonvI-benzylcarbamoyD-2-methyl-6-Qxo-l-(3-trifluoromethyl-ph,enyl)- L6-dihydrp-pyridjne-3-carbonylazide To5-(4-methanesulfonyl-benzylcarbamoyl)-2-methyI-6-oxo-l-(3-trifluoromethyl-phenyl)- l,6-dihydro-pyridine-3-carboxylic acid (0.055 g, 0.108 mmol) in CHaCla (10 ml), triethylamine (0.020 g, 0.2 mmol) and diphenylphosphoryl azide (0.055 g, 0.2 mmol) were added, the flask was sealed, and the contents were stirred at room temperature overnight The volatiles were removed m vacua and the residue was purified on silica (heptane:EtOAc 2: 1 to 1 : 1 to 1:2) giving 0.012 g (21 %) of the title compound. XH NMR (CDC13): 5 9.58 (1H> t, J 5.8 Hz); 9.13 (1H, s); 7.88 (2H, d, J 8.2 Hz); 7.86-7.82 (1H, m); 7.77 (1H, t, J 7.9 Hz); 7.51 (2H, d, J 8.7 Hz); 7.49 (1H, s); 7.41 (1H, d, J 7.9 Hz); 4.73-4.61 (2H, m); 3.02 (3H, s); 2.53 (3H, s). APCI-MS m/z: decomposes. fr) 5-(3.3-Dimemvl-ureidoV6-methvl-2-oxo-l-G-^ pvridine-3-carooxvlic acid 4-m6thanesulfonvl-benzvlainide A mixture of 5-(4-methanesulfonyl-benzylcarbamoyl)-2-methyl-6-oxo-l-(3- trifluoromethyl-phenyI>-l,6-dihydro-pyridine-3-carbonylazide (0.005 g, 0.0094 mmol) and toluene (5 ml) was heated (120 °Q with stirring for 1 h, and then allowed to cool. The toluene was removed in vacuo and the residue was dissolved in acetonitrile (5 ml), dimethylamine (0.5 ml, 40% in water) was added quickly, and the resulting mixture was stirred for 5 minutes. Evaporation of the volatiles and purification by preparative HPLC gave 0.005 g (97%) of the title compound. H NMR (CDC13): 6 9.98 (1H, t, J 5.4 Hz); 8.47 (1H, s); 7.87 (2H, d, J 8.6 Hz); 7.80 (1H, d, J 7.7 Hz); 7.73 (1H, t, J 8.0 Hz); 7.53 (1H, s); 7.50 (2H, d, J 8.3 Hz); 7.46 (1H, d, J 8.0 Hz); 6.08 (1H, bs); 4.73-4.60 (2H, m); 3.05 (6H, s); 3.02 (3H, s); 2.02 (3H, s). APCI-MS m/z: 551 .2 [MH+]. Following the general method of Example 28, the compounds of Examples 29 and 30 were prepared: Example 29 6-Methvl-5-{3-methvKureidoV2-oxo-l-f3-trifluoromethvl-phenvlV1.2- dihydro-pyndme-3-carbqxylijcacid4-methan6sulfpnvl-benzyIamide ^NMR (CDG13): 8 10.13 (lH,t, J 6.1 Hz); 8.45 (1H, s); 7.87 (2H, d, J 8.1 Hz); 7.81 (1H, d, J 7.7 Hz); 7.73 (1H, t, J 7.7 Hz); 7.52 (1H, s); 7 .49 (2H, d, J 8.2 Hz); 7.45 (1H, d, J 7.4 Hz); 6.82 (1H, bs); 4.71-4.58 (2H, rn); 3.01 (3H, s); 2.80 (3H, s); 2.06 (3H, s). APCI-MS m/z: 537.1 [MH+]. Example 30 6-Methvl-2-oxo-l-f3-trifluQromethvI-DhenvlV5-nreido-1.2-dihvdrO" pyridine-3-carboxvHcacid4-methanesulfonvl-ben2vlamide H NMR (DMSO-d d, J 8.5 Hz); 7.84-7.79 (2H, m); 7.69 (1H, d, J 7.8 Hz); 7.52 (2H, d, J 8.2 Hz); 5.94 (2H,s); 4.58 (2H, d, J 6.2Hz); 3.15 (3H, s); 1.89 (3H, s). APCI-MS m/z: 523.1 [MH]. Example 31 5-Amino-6-methyl-2-oxo-l-(3-trifluorometfavl"phenyl>-1.2-dihvdropyridine- 3-carboxylic acid 4-methanesulfonvl-bcnzvlamide To a solution of 5-(4-methanesulfonyl-benzylcarbamoyl)-2-methyl-6-oxo-l-(3- trifluoromethyl-phenyl^l^-dihydro-pyridine-S-carboxylic acid (0.055 g, 0.108 mmol) in tert-butanol (15 ml), triethylamine (0.020 g, 0.2 mmol) and diphenylphosphoryl azide (0.055 g, 0.2 mmol) were added, the flask was equipped with a reflux condenser, and the mixture was heated with stirring at 100 °C overnight. LC-MS showed a complex mixture of products, where one was identified by mass to be the title compound. The compound was isolated by preparative HPLC, and pure fractions were freeze-dried, to give 0.006 g (12%) of an yellow solid. H NMR (DMSO-dtf): 810.28 (IE t, J 6.1 Hz); 8.22 (IH, s); 7.86 (2H, d, J 8.2 Hz); 7.85 (IH, s); 7.80 (IH, s); 7.78 (IH, d, J 8.0 Hz); 7.64 (IH, d, J 7.7 Hz); 7.53 (2H, d, J 8.4 Hz); 4.64 (2H, s); 4.57 (2H, d, J 6.2 Hz); 3.17 (3H, s); 1.84 (3H, s). APCI-MS m/z: 480.1 [MH]. Example 32 6-Methvl-JV-r4-rmethvlsulfonvl>benzvn-2-oxo-5-propionvl-l-r3- (trifluoromethyDphenvn-l^-dihydropyridine-S-carboxamide A solution of 5-iodo-6-methyl-^-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3- (trifluoromethyl)phenyl3-l,2-dihydropyridine-3-carboxamide (1500 mg, 2.5 mmol), bis[l,2-bis(diphenylphosphino)ethane]palladium (230 mg, 0.25 mmol), triethylamine (7.5 ml, 54 mmol) and ethylpropenyl ether (900 #1,7.5 mmol) in DMF (45 ml) were heated at 100 °C overnight. After cooling the reaction mixture was poured into water and extracted with ethyl acetate. The extracts were separated and evaporated under reduced pressure. The crude product was dissolved in DMF (25 ml) and 2M HC1 (25 ml) and then stirred for 1.5 h. The reaction mixture was then poured into aqueous NaHCO3 and extracted with ethyl acetate The extracts were evaporated under reduced pressure and the residue was chromatographed on silica using ethyl acetate/heptane (2/1, 4/1, 10/1) as eluent. Fractions containing the product were combined and evaporated to give 1.3 g (>99%) of the title compound HNMR (CDC13): 5 9.76 (1H, t); 9.06 (1H, s); 7.89 (2H, d); 7.84 (1H, d); 7.76 (1H, t); 7.52 (2H, d); 7.49 (1H, s); 7.40 (1H, d); 4.68 (2H, m); 3.02 (3H, s); 3.00 (2H, q); 2.39 (3H, s);1.22(3H,t). Example 33 5-Formvl-6-methvl-N-f4-finethvlsulfonvl>)benzvl1-2-oxo-l-f3- The title compound was prepared using a procedure analogous to that described for Example 44. NMR (CDC13): S 10.06 (1H, s); 9.57 (1H, t, J 5.9 Hz); 9.06 (1H, s); 7.89 (2H, d, J 8.2 Hz); 7.86 (1H, s); 7.79 (1H, t, J 7.9 Hz); 7.52 (3H, d, J 8.2 Hz); 7.43 (1H, d, J 8.2 Hz); 4.69 (2H, m); 3.04 (3H, s); 2.52 (3H, s). APCI-MS m/z: 493.2 [MH+]. Example 34 6-Methvl-N-r4-(methvlsuhconvnbenzvn-2-oxo-5-f3-oxobutvl1-l-r3- (triflaoromethvl)pbenyll-1.2-dihydropyridine-3rcarboxajmde In a Schlenk vessel equipped with a magnetic stirring bar were placed 5-iodo-6-methyl-N - [4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(tritluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxamide (564.3 mg, 0.96 mmol), bis[1.2-bis(diphenylphosphino)ethane]-palladium (0) (19.9 mg, 0.02 mmol), 3-buten-2-ol (499 mg, 6.9 mmol), triethylamine (1.2 ml, 8.6 mmol) and DMF (6 ml). The vessel was purged with argon, sealed and heated at 105 °C overnight. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound as a white solid (255 mg, 50 %). HNMR (CDC13): S 10.05 (IH, t, J 5.8 Hz); 8.49 (IH, s); 7.87 (2H, d, J 8.4 Hz); 7.80 (IH, d, J 7.9 Hz); 7.73 (IH, t, J 7.9 Hz); 7.51 (2H, d, J 8.4 Hz); 7.48 (IH, s); 7.41 (IH, d, J 7.9 Hz); 4.69 (2H, m); 3.01 (3H, s); 2.81 (4H, s); 2.20 (3H, s); 2.10 (3H, s). APCI-MS m/z: 535.1 [MH]. Example 35 5-Acetvl-N-r4-(isopropylsulfonyI')ben2vn-6-methyl-2-QXO-i-r3- ftrifluoromethyDphenyI1-1.2-dihvdropTOdine-3-carboxanude a) N-f4-(Isopropylsulfonyl)benzy]V6-methyl-2-Qxo-l-r3rftrifluoromethyl)phenyll-1.2- dihydropvridine-3-caTboxamide To a mixture of 6^memyI-2xo-l-E3-(trifluoromethyl)phenyl3-l^-dihydropvridine-3- carboxylic acid (16.27 g, 54.5 mmo]) in DCM was added thionyl chloride (12 ml, 165 mmol) under argon. The colour of the reaction mixture turned black. After 50 minutes stirring at ambient temperature, the solvent was removed by evaporation. The last traces of thionyl chloride were removed by azeotropic evaporation with toluene. To an ice cooled solution of the residue in DCM, was added dropwise a mixture of l-[4- (isopropylsulfonyl)phenyl] methanamine (11.8 g, 55.4 mmol) and triethylamine (30 ml, 215 mmol) in DCM under vigorous stirring. After the addition, the dark suspension was allowed to warm up to room temperature. After 30 minutes stirring at ambient temperature the reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo, giving a dark oil which crystallized on standing. The solid was triturated with ethyl acetate, filtered, washed with ethyl acetate, ether, heptane, and dried under vacuo to give the title compound as a light yellow powder (15.3 g). The filtrates were collected, concentrated and further purified by flash chromatography on silica, eluting with a gradient of tert-butyl methyl ether to 5% methanol in tert-butyl methyl ether to provide an additional 8.78 g of the crude product. The solids were combined to give (24.1 g, 89 %) of the title compound. H NMR (CDC13): 8 9.96 (IH, t, / 5.5 Hz); 8.57 (IH, d, /7.4 Hz); 7.78 (3H, t, /4.1 Hz); 7.72 (IH, t, J7.9 Hz); 7.52 - 7.45 (3H, m); 7.43 (IH, d, J 7.7 Hz); 6.46 (IH, d, /7.6 Hz); 4.67 (2H, ddd, / 22.0 15.7 6.2 Hz); 3.13 (IH, septet, J 9.8 Hz); 2.07 (3H, s); 1 .26 (6H, d, J 6.9 Hz). APCI-MS m/z: 493.2 [MH]. b> 5-Iodo-N-f4-(isopropvlsulfonyI')benzvl1-6-methvl-2-oxo-l-\|'3-(trifluaromethvl>phenyn- 1.2-dihydropyridine-3-carboxamJde To a stirred solution of N-[4-(isopropylsulfonyl)benzyl]-6-methyl-2-oxo-l-[3- (ttifluorojnethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (23.98 g, 48.73 mmol) and TFA (90 ml) in DCM (90 ml) was added N-iodosuccinimide (1 1 .03 g, 49.14 mmol). After 2 h the reaction was complete and the solvent was removed by evaporation. To the residue was added ethyl acetate (100 ml) and saturated aqueous sodium hydrogencarbonate solution (60 ml) under stirring. The yellow solid was collected by suction filtration, washed with water, air dried for 30 min, washed again with diethyl ether, heptane and vacuum dried to give the title compound as a light yellow powder (29.67 g, 98 %). H NMR (CDC13): 8 9.83 (IH, t, J 6.0 Hz); 8.90 (IH, s); 7.83 - 7.76 (3H, m); 7.73 (IH, t, J 7.8 Hz); 7.47 (3H, d, J 8.0 Hz); 7.39 (IH, d, J 7.7 Hz); 4.66 (2H, ddd, J 22.3, 15.8 and 6.3 Hz); 3.13 (IH, septet, J 9.0 Hz); 2.29 (3H, s); 1.26 (6H, d, J 6.9 Hz). APCI-MS m/z: 619.1 [MH+]. c) 5-Acetvl-N-r4-(isopropvlsulfonvl')benzvn-6-methvl-2-oxo-l-r3- (fluoromethyDphenyll-l^-dihvdropvridine^-carboxamide A mixture of 5-iodo-N-[4-(isopropylsulfonyl)benzyl]-6-methyl-2-oxo-l-[3- (trifluoromethyl)phenyl3-l,2-dihydropyridine-3-carboxamide (3.55 g, 5.7 mmol), bis[1.2- bis(diphenylphosphino)ethane]-palladium (0) (24.5 mg, 0.03 mmol), n-butyl vinyl ether (1.16 g, 11.6 mmol), triethylamine (4 ml, 28.7 mmol) in DMF (14 ml) was stirred at 100 °C under argon for 19 h. The reaction mixture was cooled and concentrated in vacuo. The residue was dissolved in methanol (20 ml) and 2M hydrochloric acid (2 ml) was added. After 1 h stirring at room temperature the mixture was partitioned between ethyl acetate/water and basified with saturated aqueous sodium bicarbonate solution. The water layer was extracted with ethyl acetate (2 x 50 ml) and DCM (1 x 30 ml). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica elating with tert-butyl methyl ether/methanol (10:0.2) to give the title compound as a light yellow solid (2.5 g, 82%). H NMR (CDC13): 5 9.71 (1H, t, J 5.7 Hz); 9.05 (1H, s); 7.85 - 7.78 (3H, m); 7.75 (1H, t, J 7.9 Hz); 7.51 - 7.44 (3H, m); 7.39 (1H, d, J 8.2 Hz); 4.68 (2H, ddd, J 22.4, 15.8 and 6.2 Hz); 3.14 (1H, septet, J 7.7 Hz); 2.63 (3H, s); 2.40 (3H, s); 1.26 (6H, d, J 6.9 Hz). APCI-MS m/z: 535.2 JMH]. The compounds of Examples 36 to 38 were prepared using a procedure analogous to that described for Example 4. Example 36 5-Acetvl"l-(3-CArano-phenvlV6-methvl-2-oxo-1.2-dihvdro-pvridine-3- carboxvlic acid4-methanesulfonvl-benzvlamide H NMR (CDC13): £ 9.67 (1H, t, 75.7 Hz); 9.07 (1H, s); 7.90-7.86 (3H, m); 7.76 (1H, t, J=7,9 Hz); 7.53-7.45 (4H, m); 4.74-4.64 (2H, m); 3.02 (3H, s); 2.65 (3H, s); 2.42 (3H, s). APCI-MS m/z: 464 [MH]. Example 37 5-Acetvl-l-(3-chloro-phenvl>-6-methyl-2-QXQ-1.2-dihvdro-pvridine-3- carboxvlic acid 4-methanesulfonl-ben2vlamide NMR (CDC13): $ 9.77 (1H, t, J 5.8 Hz); 9.04 (1H, s); 7.89 (2H, d, / 8.3 Hz); 7.56-7.51 (4H, m); 7.22 (1H, s); 7.10-7.08 (1H, m); 4.69 (2H, d, J 6.0 Hz); 3.02 (3H, s); 2.64 (3H, s); 2.44 (3H, s). APCI-MS m/z: 473 [MH+]. Example 38 5-AcetyJ-6-methyI-2-oxQ-l-m-tQlyL-1.2-dihvdro-pvridine--3-caiboxvUcacid 4-methanesulfonvl-faenzvlainide HNMR (CDC13): 5 9.89 (IH, t, / 5.5 Hz); 9.04 (IH, s); 7.88 (2H, d, J 8.3 Hz); 7.53-7.47 (3H, m); 7.37-7.35 (IH, m); 6.98-6.96 (2H, m); 4.68 (2H, d, / 6.0 Hz); 3.02 (3H, s); 2.64 (3H, s); 2.44 (3H, s), 2.43 (3H, s). APCI-MS m/z: 453 [MB]. Example 39 S-fl-HvdroxvethvlV6-methvl-N-r4-(methvlsuIfonvl)benzvn-2-oxo-l-r3- ftrifluofomethvDphenyl1-1.2-dihvdropvridine-3-carboxamide A mixture of 5-acetyl-6-methyl-JV-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3- (trifluoromethyl)phenyl}-l,2-dihydropyridine-3-carboxamide (Example 4,180 mg, 0.35 mmol) and aluminum tri-sec-butoxide (0.2 mg, 0.79 mmol) in anhydrous isopropanol (30 ml) was stirred at 85 °C under a nitrogen atmosphere for 48 h. The reaction mixture was cooled to room temperature, water (0.2 ml) was added and the mixture was then concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound as a white solid (134 mg, 74 %). H MMR (CDC13): 8 10.01 (ia t, J 5.7 Hz); 8,84 (IH, d, J 1.9 Hz); 7.87 (2H, d, J 8.3 Hz); 7.81 (IH, d, J 7.8 Hz); 7.74 (IH, t, J 8.0 Hz); 7.52 (2H, d, J 8.3 Hz); 7.50 (IH, s); 7.42 (IH, d, J 7.9 Hz); 5.03 (IH, dd, J 10.9 1.6 Hz); 4.67 (2H, q, J 6.3 Hz); 3.02 (3H, s); 2.12 (3H, s); 1.91 (IH, t, J 3.9 Hz); 1.58 (3H, dd, J 6.4 2.6 Hz). APCI-MS m/z: 509.2 [MH+]. Example 40 5-(l-Azidoethyl)-6-methvl-N-f4-(methylsuIfonyDbenzvn-2-oxo-l-f3- (trifluorQmethynphenyn-1.2-dihydropyridine-3-carboxarnide To a solution of 5-(l-hydroxyethyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (29.1 mg, 0.06 mmol) in DCM (1.5 ml) was added thionylchloride (0.15 ml, 2.1 mmol) under an argon atmosphere. After 40 minutes stirring at ambient temperature, the solvent was removed in vacuo. The last traces of thionyl chloride were removed by azeotropic evaporation with toluene. The residue was dissolved in anhydrous DMF (1 ml) and sodium azide (20 mg, 0.3 mmol) was added. After 1 h stirring at room temperature the reaction mixture was diluted with water and purified by preparative HPLC giving the title compound as a white solid (11.5 mg, 37 %). 66 £-" JH NMR (CDC13): 5 9.94 (1H, t, J 5.9 Hz); 8,73 (1H, d, J 2.0 Hz); 7.88 (2H, dt, J 8.4 1.9 Hz); 7.83 (1H, d, J 8.1 Hz); 7.76 (1H, td, J 7.9 3.5 Hz); 7.55 - 7.48 (3H, m); 7.43 (1H, t, J 14.1 Hz); 4.81 - 4.59 (3H, m); 3.02 (3H, s); 2.13 (3H, s); 1.63 (3H, dd, J 6.91.6 Hz). APCI-MS m/z: 534.2 [MH]. Example 41 6-Methyl-N-r4-(methy\|suIfonyDbenzyl1--5--(l'-morpholin-4-ylethylV2-oxo-lf3>( trifluoromethvnphaiyn-1.2-dihydropyridine-3-cart>oxanude To a solution of 5-(l-hydroxyethyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3-cartx)xainide (15 mg, 0.03 ramol) in DCM (2 ml) was added thionyl chloride (0.5 ml, 6.9 mmol) under an argon atmosphere. After 1 h stirring at ambient temperature, the solvent was removed in vacuo. The last traces of thionyl chloride were removed by azeotropic evaporation with toluene. The residue was dissolved in anhydrous DMF (1 ml) and morpholine (0.3 ml, 3,4 nunol) was added. After 35 minutes stirring at room temperature the reaction mixture was diluted with water and further purified by preparative HPLC giving the title compound as a white solid (4.3 mg, 25%). H NMR (CDC13): 810.05 (1H, t, J 5.9 Hz); 8.78 (1H, d, J 1.0 Hz); 7.87 (2H, d, J 8.3 Hz); 7.81 (1H, d, J 7.9 Hz); 7.74 (1H, t, J 8.0 Hz); 7,53 (2H, d, J 8.1 Hz); 7.50 (1H, s); 7.43 (1H, t, J 7.3 Hz); 4.67 (2H, td, J 24.2 5.9 Hz); 3.70 (4H, dd, J 20.6 11.4 Hz); 3.48 (1H, m); 3.02 (3H, s); 2.53 (2H, s); 2.43 (2H, m); 2.12 (3H, s); 1.36 (3H, dd, J 6.6 1.3 Hz). APCI-MS m/z: 578.3 [MB]. Example 42 5-fl-Hvdroxypropv]V6-methyl"N-r4-(methvIsulfonynbenzyn-2-oxo-l-f3- (triflucromethvDphenyl]-!t..2-dihydropyridine-3-carboxarnide The title compound was prepared using a procedure analogous to that described for Example 39. H NMR (CDC13): 5 10.01 (1H, t, J 5.9 Hz); 8.79 (1H, d, J 1.7 Hz); 7.87 (2H, d, J 8.3 Hz); 7.81 (2H, d, J 7.9 Hz); 7.74 (2H, t, J 7.8 Hz); 7.52 (2H, d, J 8,3 Hz); 7.49 (1H, s, ); 7.42 (1H, d, J = 7.5 Hz); 4.77 - 4.59 (3H, m); 3.01 (3H, s); 2.10 (3H, s); 2.00 (1H, t, J - 4.5 Hz); 1.98 -1.74 (2H, m); 1.01 (3H, td, J 7.4 2.5 Hz). APCI-MS m/z: 523.2 [MR]. Example 43 5-(l-HvdroxyethvlVN-r4-(isopropvlsulfonvDbenzvn-6-methvl-2-oxo-l-r3- (trifluoromethvDphenvn-l^-dihvdropvfidine-S-carboxainide The title compound was prepared using a procedure analogous to that described for Example 39. H NMR (CDd3): 5 10.02 (1H, t, J 5.9 Hz); 8.85 (1H, d, J 1.7 Hz); 7.81 (3H, d, J 30.8 Hz); 7.74 (1H, t, J 7.9 Hz); 7.50 (3H, d, J 19.2 Hz); 7.43 (1H, d, J 7.6 Hz); 5.03 (1H, t, J 5.4 Hz); 4.69 (2H, dd, J 29.1 9.7 Hz); 3.15 (1H, quintet, J 6.8 Hz); 2.12 (3H, s); 1.98 (1H, t, J 4.4 Hz); 1.58 (3H, dd, J 6.4 2.2 Hz); 1.28 (6H, d, J 6.9 Hz). APCI-MS m/z: 578.3 [MB]. Example 44 N-r4-CCvclopropvlsulfonvI>benzvn-5-formvl-6-methvl-2-oxo-l-r3- rtrifluorometfavDphenvn-l^-dihvdropvridine-S-carboxamide N-[4-(Cyclopropylsulfonyl)benzylJ-5-iodo-6-memyl-2-oxo-l-[3-(trifluoromefliyl)phenyI]- l,2-dihydropyridine-3-carboxamide [2.6 g, 4.2 mmol; prepared by a procedure analogous to that described for Example 35 (b)], tris(dibenzylideneacetone) dipalladium (0) (81.9 mg, 0.09 mmol), triphenylphosphine (263.8 mg, 1.0 mmol) and toluene (28 ml) were added to a 100 ml single-neck round bottomed flask. The flask was fitted with a 30 ml dropping funnel with pressure-equalizer containing tnbutyltin hydride (2.3 g, 7.8 mmol) and toluene (20ml). The system was thoroughly flushed with carbon monoxide by repeated evacuation and filling and was then pressurized at 2.5 atmospheres carbon monoxide and heated at 95 °C with vigorous stirring. The tnbutyltin hydride solution was added dropwise over a period of 3 h. After the addition was complete, the reaction mixture was allowed to reach room temperature and then the carbon monoxide was flushed out with argon. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica, eluting with tert-butyl methyl ether/methanol (10:0.2) to give the title compound as a white solid (1.6 g, 73%). NMR (CDa3): 510.06 (IH, s); 9.56 (IH, t, J 5.8 Hz); 9.06 (IH, s); 7.89 - 7.78 (4H, m); 7.54 - 7.47 (3H, m); 7.44 (IH, d, J 7.8 Hz); 4.68 (2H, ddd, J 21.5 15.4 6.2 Hz); 2.51 (3H, s); 2.42 (IH, m); 1.33 (2H, m); 1.01 (2H, m). APCI-MS m/z: 519.2 [MR]. Example 45 5-r(E)-(Mefopftyirmno>metfoI1^ oxo-l-r3^ttifluoroinet^yl)phenyl1-1.2-dihydrDpyridine-3-carboxamidg A mixture of 5-fonnyl-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-t3- (trifluorojnethyl)phenyl]-l,2-dihydropyridine-3-carboxaniide (Example 33,14.7 rag, 0.03 mmol), O-methylhydroxylamine hydrochloride (17.2 mg, 0.21 mmol), potassium acetate (42.7 mg, 0.44 mmol) and water (0.1 ml) in ethanol (1.5 ml) was heated at 60 °C for 2 h. The reaction mixture was cooled, concentrated in vacuo and the residue was purified by preparative HPLC to give the title compound as a white solid (6.2 mg, 39 %). H NMR (DMSO-ds): 5 9.80 (IH, t, J 6.0 Hz); 8.76 (IH, s); 8.44 (IH, s); 7.95 - 7.79 (5H, m); 7.74 (IH, d, J 8.0 Hz); 7.54 (2H, d, J 8.3 Hz); 4.58 (2H, d, J 6.1 Hz); 3.90 (3H, s); 3.17 (3H, s); 2.10 (3H, s). APCI-MS m/z: 522.2 [MR]. Example 46 5-n^ydrojtymethyIV6-metbyl-N-r4-fmethylsuIfpnyDbenzy]il-2^xj>-\|-r3" (triguoromethyl^henylVl^-dihydropyridine-S-carboxamide The title compound was prepared using a procedure analogous to that described for Example 39. H NMR (CDC13): 8 9.98 (IH, t, J 28.4 Hz); 8.66 (IH, s); 7.87 (2H, d, J 8.3 Hz); 7.82 (IH, d, J 8.0 Hz); 7.75 (IH, t, J 7.9 Hz); 7.51 (3H, d, J 8.4 Hz); 7.43 (IH, d, J 8.1 Hz); 4.67 (4H, m); 3.02 (3H, s); 2.16 (3H, s); 2.01 (IH, t, J 5.3 Hz). APCI-MS ni/z: 495.1 [MH+], Example 47 5-rfDimethvlamino)methvn-6-methvl-7^-r4~(methvlsulfonvl)benzvn-2-oxol- f3-ftrifluQromethv^phenvl]-L2-dihvdrQPVridine-3-carboxamide -697 a) 5-CChlQromethvl)-6-methvl-^-f4-(methvlsulfonvl')benzyn-2-oxo-l-r3- (trifluorQmethvnphenvll-1.2-dihvdropvridiTie-3~(;arhnxflmide 5-(Hydroxymethyl)-6-methyl-N-[4-(methylsulfonyl)benzyJ]-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxainide (Example 46,990 mg, 2.0 mmol) was treated with thionyl chloride (476 mg, 4.0 mmol) to give the title compound (1.0 g, 97%). APCI-MS m/z: 513.2 [ME]. b) 54fl^methvIaniino)methvl1-6-methvl-.//-r4-fmethvlsuIfonvnbenzvl1-2-oxo-l-r3- rtrifluoromethvl)phenvn-1.2-dihvdropvridine-3-carboxamide A solution of S-^hloromethyO-o^methyl-A^-^-Onethylsulfony^benzy^^oxo-l-IS- (trifluoromethyl)phenyl]-l^-dihydropyridine-3-carboxamide (5 mg, 0.097 mmol) and dimethylamine in ethanol (0.5 ml, 33 %) was heated in a microwave for 10 minutes at 50 °C. The mixture was then purified by preparative HPLC to give the title compound as a white solid (4mg,79%). H NMR (DMSO-d6): 5 9.96 (1H, t, J 6.0 Hz); 8.34 (1H, s); 7.90 - 7.85 (4H, m); 7.80 (1H, t, J 7.8 Hz); 7.70 (1H, d, J 8.0 Hz); 7.53 (2H, d, J 8.3 Hz); 4.58 (2H, d, J 6.2 Hz); 3.57 (2H, s); 3.17 (3H, s,); 2.18 (6H, s ); 2.02 (3H, s). APCI-MS m/z: 522.1 [MH+]. . Example 48 6-Methyl-5-r(methvlamino')methvl1-^-r4-(methvlsulfoiivBbenzyI1-.2-oxo-l- [3-(trifluoromemyl)phenvn-1.2-dihvdropvridine-3^arbQxarnide The title compound was prepared using a procedure analogous to that described for Example 47. JH NMR (DMSO-dg) 8 9.97 (1H, t, J 6.0 Hz); 8.43 (1H, s); 7.94 - 7.85 (4H, m); 7.81 (1H, t, J 7.8 Hz); 7.67 (1H, d, J 7.9 Hz); 7.53 (2H, d, J 8.2 Hz); 4.58 (2H, d, J 6.0 Hz); 3.57 (2H, s); 3.17 (3H, s); 2.30 (3H, s); 2.02 (3H, s). APCI-MS m/z: 508.1 [MH+]. ,70 Example 49 e-Methvl-^-r^methvlsulfonvDbenzvn-S-dnorpholin^-vImethvn^-oxo-lf3- ftrifluorom^yDphenyl1-lJ-dihvdropvridine-3-car^oxanude A solution of S-CchloromethyO-e-methyl-A/'-t^methylsulfonyl^enzyy^-oxo-l-tS- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (Example 47, 8 rag, 0.016 mmol ) and morpholine (5.5 mg, 0.062 mrool) in DMF (1 ml) was heated in a microwave oven for 10 minutes at 50 °C. The mixture was then purified by preparative HPLC to give the title compound as a white solid (4 mg, 45 %). !H NMR (CDC13): 8 10.03 (1H, t, ); 8.56 (1H, s, ); 7.87 (2H, d, J=8.2 Hz); 7.81 (1H, d, J=7.8 Hz); 7.75 (2H, t, J=7.9 Hz); 7.52 (3H, d, J=8.2 Hz); 4.67 (2H, m ); 3.72 (4H, m ); 337 (2H, m ); 3.01 (3H, s, ); 2.50 (3H. s ); 2.13 (2H, m ); 1.57 (2H, s). APCI-MS m/z: 564.2 " The compounds of Examples 50 to 59 were prepared using a procedure analogous to that described for Example 49. Example 50 5-1 r(2-FurvlmethvI)amino1meQiyl ) -6-methvl"JV-f4-(roethylsulfonynbenzyl\|- 2K)xo-l-r3-(trifluoromeftynphenyl]-1.2-dihydrppyrjdine-3 H NMR (DMSO-dg): 8 9.64 (1H, t, J 6.1 Hz); 8.12 (1H, s); 7.58 - 7.47 (5H, ra); 7.35 (1H, d, J 7.7 Hz); 7.24 - 7.20 (3H, m); 6.07 (1H, dd, J 3.1, 1.8 Hz); 5.95 (1H, d, J 3.0 Hz); 4.26 (2H, d, J 6.1 Hz); 3.40 (2H, s); 3.29 (2H, s); 2.85 (3H, s); 1.66 (3H, s). APCI-MS m/z: 574.2 [MH+]. Example 51 54(CvclopropvIamino)methvll-6-methvl^-r4-fmethvlsuIfonvnbenzvn-2- oxo-l-r3-(trifluoromethynphenyl1-L2-dihvdropyridine-3M:arboxamide H NMR (DMSO-de): 8 9.97 (1H, t, J 6.0 Hz); 8.43 (1H, s); 7.90 - 7.84 (4H, m); 7,81 (IH.t, J7.9Hz);7.66(lH,d, J 7.8 Hz); 7.53 (2H, d, J8.3Hz);4.58(2H,d, J 6.0 Hz); 3.65 (2H, s); 3.17 (3H, s); 2.11 - 2.07 (1H, m); 2.02 (3H, s); 0.38 - 0.35 (2H, m, ); 0.26 - 0.23 (2H, m). APCI-MS m/z: 534.2 [MH]. Example 52 5-f \(2-HvdroxyptopvI)aminolmethvl > -e-met fmethvlsulfonvnbenzvI1'2-oxo-l-f34trifluoromethvDphenvD-1.2-dihvdropvridine~3- carboxamide H NMR (DMSO-ds): 8 9.97 (1H, t, J 6.1 Hz); 8.45 (1H, s); 7.90 - 7.85 (4H, m); 7.81 (1H, t, J 7.8 Hz); 7.68 (1H, d, J 8.1 Hz); 7.53 (2H, d, J 8.4 Hz); 4.58 (2H, d, J 6.0 Hz); 4.49 (1H, d, J 4.4 Hz); 3.72 - 3.68 (1H, m,); 3.63 (2H, s); 3.17 (3H, s); 2.49 - 2.46 (2H, m); 2.02 (3H, s); 1.05 (3H, d, J 6.2 Hz). APCI-MS m/z: 552.2 [MB]. Example 53 5-r(Cyclopentylanuno)methy^ oxo-l-f3-(Uifluoromethynphenyl1-1.2-dihydropyridine-3-carboxamide H NMR (DMSO-d6): S 9.97 (1H, t, J 6.1 Hz); 8.45 (1H, s); 7.90 - 7.85 (4H, m); 7.81 (1H, t, J 7.9 Hz);7.67 (1H, d, J 8.0 Hz); 7.53 (2H, d, J 8.3 Hz); 4.58 (2H, d, J 6.0Hz); 3.57 (2H, s); 3.17 (3H, s); 3.05 (1H, t, J 6.1 Hz); 2.02 (3H, s); 1.77 - 1.70 (2H, m); 1.64 - 1.60 (2H, m); 1.49 -1.45 (2H, m ); 1.39 - 1.33 (2H, m). APCI-MS m/z: 562.2 [MH]. Example 54 5-frf2-HvdroxvethvI')(methvDaminoilmethvll-6-methvI-jy-r4- (methylsulfonvnbengyI1-2-oxo-l'r3-ftrifluoromethyl)phenyn-1.2-dihvdropyridine-3-- carboxamide !H NMR (DMSO-dg): 5 9.97 (1H, t, J 6.0 Hz); 8.36 (1H, s); 7.89 - 7.85 (4H, m); 7.80 (1H, t, J 8.2 Hz); 7.69 (1H, d, J 8.4 Hz); 7.54 (2H, d, J 8.3 Hz); 4.58 (2H, d, J 6.0Hz); 4.41 (1H, t, J 5.2 Hz); 3.52 (2H, q, J 5.9 Hz); 3.46 (2H, d, J 30.9 Hz); 3.17 (3H, s); 2.47 (2H, d); 2.18 (3H, s); 2.03 (3H, s). APCI-MS m/z: 552.2 [MH+]. Example 55 6-MethyI-JVr-r4-(roethv!sulfonvl')benzvn-2-oxo-5-(pvrrolidin-l-vlmethvlVl- DrftrifluorQmethvltohenvll-l^-dihvdropvridine-S-carboxamide J727?.) ]HNMR (DMSO-dc): 89.97 (IH, t, J 6.1 Hz); 8.37 (1H, s); 7.90 - 7.85 (4H, m); 7.80 (1H, t, 3 7.8 Hz); 7.70 (1H, d, J 7.9 Hz); 7.53 (2H, d, J 8.4 Hz); 4.57 (2H, d, 1 6.1 Hz); 3.51 (2H, s); 3.17 (3H, s); 2.47 - 2,44 (4H, m); 2.03 (3H, s); 1.70 (4H, m ). APCI-MS m/z: 548.2 [MH4]. Example 56 5-(rMethoxyfmethvl)amino1methvll-6-n>ethyl-jy-r4" carboxamide H NMR (DMSO-de): 8 9.94 (1H, t, J 6.0 Hz); 8.39 (1H, s); 7.90 - 7.85 (4H, m); 7.81 (1H, t, J 8.1 Hz); 7.69 (1H, d, J 7.9 Hz); 7.54 (2H, d, J 8.4 Hz); 4.58 (2H, d, J 6.0 Hz); 3.72 (2H, s); 3.17 (3H, s); 2.58 (3H, s, ); 2.04 (3H, s). APCI-MS m/z: 538.2 [MH]. Examples? 5- J rfCvanomfithvnaminolni&thvl l-6-metfavl-^-r4-fmethvlsulfonvlVbenzvn- ^ r3-(trifluorometiivl>hen vU- 1 NMR (DMSO-de): 8 9.78 (1H, t, J 6.2 Hz); 8.25 (1H, s ); 7.74 - 7.64 (5H, m ); 7.51 (iH, d, J 8.1 Hz); 7.37 (2H, d, J 8.3 Hz); 4.42 (2H, d, J 5.7 Hz); 3.53 (2H, d, J 5.7 Hz); 3.48 (2H, d, J 7.1 Hz); 3.01 (3H, a)', 1.87 (3H, s ). APCI-MS m/z: 533.2 [MH+]. Example 58 5-f [(Cvclopropylmethvnaminolmetbvl l-6-methvl-JV-r4- carboxamide NMR (DMSO-de): 8 9.98 (IH, t, J 6.0 Hz); 8.46 (IH, s); 7.88 (4H, dd, J 10.5, 8.5 Hz); 7.81 (IH, t, J 7.9 Hz); 7.68 (IH, d, J 7.9 Hz); 7.53 (2H, d, J 8.3 Hz); 4.58 (2H, d, J 6.0 Hz); 3.62 (2H, s); 3.17 (3H, s); 2.42 (2H, d, J 6.7 Hz); 2.02 (3H, s); 0.91 (lH,s ); 0.43 - 038 (2H, m); 0.14 - 0.10 (2H, m). APCI-MS m/z: 548.2 [MH]. Example 59 5-rG-HvdroxvDvrroHdin4-vnmetbvl1-6>methvl-^-r4- (metfaylsulfonvDbenzvlV2-oxo-l-f34trifluoroinethyDphenvn-1.2-dihvdfopvridine-3- carboxamide ^NMR (DMSO-dfi): 5 9.97 (1H, t, J 6.1 Hz); 8.37 (1H, s); 7.90 - 7.85 (4H, m); 7.80 (1H, t, J 7.9 Hz); 7.70 (1H, d, J 7.9 Hz); 7.54 (2H, d, J 8.3 Hz); 4.71 (1H, d, J 4.2 Hz); 4.58 (2H, d, J 6.1 Hz); 4.20 (1H, dt, J 9.7, 3.7 Hz); 3.49 (2H, s); 3.17 (3H, s); 2.79 - 2.74 (1H, m); 2.58 (1H, t, J 7.6 Hz); 2.50 - 2.45 (1H, in); 2.35 - 2.32 (1H, m); 2.03 (3H, s); 2.00 - 1.97 (1H, m); 1.57 - 1.53 (1H, m). APCI-MS m/z: 564.2 [MH]. Example 60 5-f2-HvdroxvethQXvVN-r4~fisoDropylsulfonyl'ybenzvn-6-methvl-2-oxo-lrMtriflioromethvI>pheaivl1--1.2-dih\dropvridine-3-carboxamide at 5-Hvdroxv-N-r4-('isorovlsulfonvl>benzvn-6-met:hvl-2-oxo>l-f3- To ice-cooled 35% hydrogen peroxide (11.11 g, 114.4 tnmol) was added concentrated sulphuric acid (8.92 g, 91.0 mmol) and 5-acetyl-N-[4-(isopropylsulfonyl)benzyl]-6-methyl- 2-oxo-l-[3-(trifluoromethyl)phenyl]4,2^ihydropyridine-3-^arboxainide (Example 35 (c), 2.2 g, 4.1 mmol) in DCM (3 ml). The mixture was stirred vigorously and heated at 45 °C for 1.5 h. The reaction mixture was cooled to room temperature and then added dropwise to an ice cooled mixture of ethyl acetate (100 ml) and saturated aqueous sodium carbonate solution under stirring. The organic layer was collected and the water layer was extracted with ethyl acetate (2 x 60 ml). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on siKca eluting with tert-butyl methyl ether/methanol (10:0.2) to give the title compound as a yellow solid (1.1 g, 52 %). !H NMR (CDC13): 5 10.66 (1H, t, J 6.0 Hz); 8.97 (1H, s); 8.16 (1H, s); 7.81 (3H, m); 7.74 (1H, t, J 7.8 Hz); 7.51 (3H, t, J 4.1 Hz); 7.43 (1H, d, J 7.8 Hz); 4.68 (2H, td, J 9.5 4.5 Hz); 3.16 (1H, quintet, J 6.9 Hz); 2.04 (3H, s); 1.28 (6H, d, J 6.9 Hz). APCI-MS m/z: 509.1 CMH]. J74 b) 2~f (S-(f f4-(Isopropvlsulfonvl^benzyJ1aniino)carbonvlV2-niethvI-6-oxo-l-f3- (trifIuoromethvnphMvn-1.6-dihvdropvridin-.3-vlloxv^ethvl acetate A mixture of 5-hydroxy-N-[4-(isopropylsijlfonyl)benzy]]-6-methyl-2-oxo-l-[3- (trifluoromethyl)phenyl3-l^^hydropyridine-3^arboxainide (1.05 g, 2.06 mmol), 2- bromoethyl acetate (1.03 g, 6.17 mmol), l,8-diazabicyclo[5.4.0]iJndec-7-ene (0.94 g, 6.17 mrnol) in anhydrous DMF (2.5 ml) was heated at 80 °C for 25 min under argon. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography elutmg with a gradient of ten-butyl methyl ether to 2.5% methane! in tert-butyl methyl ether to provide the title compound as a light green solid (0.87 g, 71%). H NMR (CDC13): 8 10.11 (1H, t, J 5.8 Hz); 8.58 (1H, s); 7.79 (3H, d, J 8.4 Hz); 7.73 (1H, t, J 7.9 Hz); 7.48 (3H, d, J 8.2 Hz); 7.41 (1H, d, J 7.9 Hz); 4.67 (2H, ddd, J 21.7, 15.6 and 6.1 Hz); 4.38 (2H, dd, J 5,4 4.0 Hz); 4.21 (2H, dd, J 5.2, 3.7 Hz); 3.13 (1H, septet, J 9.0 Hz); 2.10 (3H, s); 2.04 (3H, s); 1.26 (6H, d, J » 6.9 Hz). APCI-MS m/z: 595.1 [MH]. (trifluorometh vDphenyll- 1 .2-dihvdropyridine-3-carboxamide A mixture of 2-({5-({ [4-(isopropylsulfonyl)benzyl]amino}carbonyl)-2-methyl-6-oxo-l-[3- (trifluoromethyl)phenyl]-l,6-dihydropyridin-3-yl}oxy)ethyl acetate (0.87 g, 1.46 mmol), methanol (5 ml) and 2M sodium hydroxide solution (0.2 ml, 0.4 mmol) was stirred at ambient temperature for 20 min. The solution was acidified with acetic acid, diluted with water and purified by preparative HPLC to give the title compound as a light green solid (0.65 g, 82%). XHNMR (CDC13): 6 10.13 (1H, t, J 5.7 Hz); 8.59 (1H, s); 7.79 (3H, d, J 8.4 Hz); 7.73 (1H, t, J 7.9 Hz); 7.51 - 7.46 (3H, m); 7.42 (1H, d, J 7.8 Hz); 4.67 (2H, ddd, J 21.7 15.6 6.1 Hz); 4.12 (2H, t, J 4.5 Hz); 3.96 (2H, septet, J 9.6 Hz); 3.14 (1H, septet, J 9.6 Hz); 2.06 (3H, s); 1.83 (1H, t, J 6.0 Hz); 1.26 (6H, d, J 6.9 Hz). APCI-MS m/z: 553.1 " Example 61 2-Methyl-5-(U4-(methylsulfonvDbenzvl1ammQlcarbonvlV6-oxo-l~f3- (trifluoromethvDphenvn-1.6-dihvdropvridin-3-vl acetate The title compound was obtained as a byproduct during the synthesis of 5-hydroxy-6- melhyl-A^[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromBthyl)phenyl]-l,2- dihydropyridine-3-carboxamide when the latter compound was prepared by a procedure analogous to that described for Example 60 (a). H NMR (DMSO-dg): S 9.93 (1H, t,36.1 Hz); 8.33 (1H, s); 7.96 - 7.80 (4H, m); 7.75 (2H, d, J 8.2 H); 7.54 (2H, d, J 8.3 Hz); 4.59 (2H, d, 3 6.2 Hz); 3.17 (3H, s); 2.32 (3H, s); 1.89 (3H,s). APCI-MS m/z; 523.3 [MH+]. Example 62 5-Methoxv-6-methvl-J^-r4-(methvlsulfon-yI')benzvn-2-oxo-l-r3- ftrifiuorQmethyl)phenyll-L2-dihydropyridine-3-carbbxamide A solution of 5-hydroxy-6-methyl-JV-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-^ihydK>pyridine-3-carboxamide(Example 61,15 mg, 0.031 mmol) and K2CO3 (13.8 mg, 0.1 mmol) in acetone (1 ml) was heated to 60 °C. After 15 minutes the mixture was cooled to room temperature, iodomethane (7 mg, 0.050 nanol) was added, and the reaction mixture was heated for an additional 30 minutes at 60 °C. The mixture was then purified by preparative HPLC to give the title compound as a white sou'd (14mg,90%). ^ NMR (DMSO-de): 510.11 (1H, t, J-5.9 Hz); 8.39 (1H, s,); 7.90 - 7.85 (5H, m,); 7.81 (4H,t, J=7.9Hz);7.71(lH,d, J=8.0 Hz); 7.54 (3H, d, J-8.3 Hz); 4.59 (2H, d, J=6.0 Hz); 3.81 (3H, s,); 3.18 (4H, s,); 1.95 (3H, s,). APCI-MS m/z: 495.5 [MH]. Example 63 5-(3-Methoxvpropoxv)-6-methvl-JVr-r4-(methylsulfonvl')benzvn-2-oxo-l-r3- (trifiuororaethvl^phenvn-l^-dihvdropvridine-S-carboxamide To a solution of 5-hydroxy-6-methyl-AT-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3- (trifluoromethy^phenyli-l^-dihydropyridme-S-carboxamide (Example 61,10 mg, 0.02 mmol), lithium iodide (2.7 mg, 0.02 mmol) and l,8-diazabicyclo[5.4.0]undec~7-ene (7 mg, 0.04 mmol) in DMF (1 ml), l-bromo-3-methoxypropane (6.1 mg, 0.04 mmol) was added, ,76 and the reaction mixture was heated for 60 minutes at 40 °C. The mixture was then purified by preparative HPLC to give the title compound as a white solid (5 mg, 45 %). H NMR (CDC13): 5 8.58 (1H, s); 10.2 (1H, t); 7.87 (2H, d, J 8.3 Hz); 7.80 (1H, d); 7.74 (1H, t,); 7.52 (3H, d, J 8.4 Hz); 7.4 (1H, d); 4.67 (2H, t, J 5.6 Hz); 4.10 (2H, t, J 6.3 Hz); 3.56 (2H, t, J 6.1 Hz); 3.37 (3H, s); 3.02 (3H, s,); 2.05 (3H,s). APCI-MS ra/z: 553.2 [MH]. Example 64 2-Methyl-5 (trifluoromethvl)phenyl1-I.6-dihvdropvridin-3-vlmethanesdfQnate To a solution of 5-hydroxy-6-methyl-JV-[4-(methylsuifonyl)benzyl]-2-oxo-l-[3- (trifluoromethyl)phenyl3-l,2-dihydropyridine-3-carboxamide (5 mg, 0.01 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (3 mg, 0.02mmol) inDCM (1 ml), 2-chloroethylamine hydrochloride (2.3 mg, 0.02 mmol) was added and the reaction mixture was heated for 60 minutes at 40 °C. The mixture was then purified by preparative HPLC to give the title compound as a white solid (3 mg, 54 %). HNMR (CDCls): 5 7.88 (2H, d, J 8.4 Hz); 7.83 (1H, s); 7.77 (1H, ); 7.55 - 7.50 (3H, m); 7.48 - 7.43 (1H, m,); 4.67 (2H, t, J 6.3 Hz); 3.33 (3H, s); 3.02 (3H, s); 2.15 (3H, s). APCI-MS ra/z: 559.1 [MR]. Example 65 5-Ethoxv-6-methvl-N44-fmethvlsulfonv^benzvl1-2-oxO'l"f3- ftrifluoromemvl')phenvI1-1.2"dihvdropvridine-3-carboxaniide A mixture of 5-hydroxy-6-methyl-JV-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxarnide (Example 61,40.7 mg, 0.08 mmol), iodoethane (0.4 ml, 5.0 mmol), l,8-diazabicyclo[5.4.0]undec-7-ene (0.6 g, 4.1 mmol) in DMF (1.5 ml) was stirred at 85 °C for 30 minutes under argon. The reaction mixture was cooled, diluted with water and purified by preparative HPLC to give the title compound as a white solid (11.5 mg, 26 %). H NMR (CDC13): 510.19 (1H, t, J 5.8 Hz); 8.57 (1H, s); 7.87 (2H, d, J 8.3 Hz); 7.81 (1H, 4/8.0 Hz); 7.74 (1H, t, /7.9 Hz); 7.52 (3H, d, J 8.4 Hz); 7.43 (1H, d, J 7.7 Hz); 4.69 (2H, m); 4.09 (2H, q, J 7.0 Hz); 3.01 (3H, s); 2.05 (3H, s); 1.41 (3H, t, / 7.0 Hz). 77 7ft APCI-MS m/z: 509.0 (MR]. Example 66 5-f2-Hvdroxyethoxv)-6-methyl-N-f4-(methvlsulfonvl')benzvll-2-oxo-l-r3- Ctrifluoromethvl)phenvn-1.2-dihvdropvridine-3-carboxamide The title compound was obtained by a procedure analogous to that described for Example 60. H NMR (CDC13): 6 10.15 (1H, t, J 5.9 Hz); 8.60 (1H, s); 7.87 (2H, d, J 8.3 Hz); 7.81 (1H, d, J 7.8 Hz); 7.74 (1H, t, J 7.8 Hz); 7.52 (3H, d, J 8.3 Hz); 7.43 (1H, d, J 7.8 Hz); 4.67 (2H, m); 4.13 (2H, t, J 4.5 Hz); 3.98 (2H, q, J 20.3 Hz); 3.02 (3H, s); Z08 (3H, s); 1.86 (1H, t> J 6.0 Hz). API-MS m/z: 525.1 [MR]. Example 67 S-jCyanomeftpxyVd-methvl-N-r^fmethylsulfonyDbenzyll^-oxQ-l-fS-- flrifluoromethvKphenvJ'l-l .2~dihydropvridme-3-carboxamide trifluoroacetate The title compound was obtained using analogous conditions to those described in Example 65. H NMR (CDCI3): 8 10.12 (1H, t, / 5.6 Hz); 8.61 (1H, s); 7.89 (2H, d, / 8.3 Hz); 7.84 (1H, d, J 7.9 Hz); 7.76 (1H, t, J 7.9 Hz); 7.51 (3H, d, J 8.2 Hz); 7.45 (1H, d, J 8.0 Hz); 4.82 (2H, s); 4.69 (2H, ddd, /21.5 15.4 6.1 Hz); 3.02 (3H, s); 2.14 (3H, s). APCI-MS m/z: 520.0 [MH]. Example 68 2>(/2-Methvl-5-(f/r4-(methylsulfonvl)benzvl]aminolcarbonvl')-6-oxo-l-f3- (trifluoromemvl')phenyn-1.6-dihvdropvridin-3-vnoxvlethvl acetate The title compound was obtained under similar conditions to those described in Example . 60. !HNMR (CDC13): 810.13 (1H, t, J 5.7 Hz); 8.59 (1H, s); 7.88 (2H, d, J 8.4Hz); 7.81 (1H, d, J 8.0 Hz); 7.75 (1H, t, J 7.9 Hz); 7.52 (3H, d, J 8.4 Hz); 7.43 (1H, d, J 8.0 Hz); 4.67 (2H, t, J 5.7 Hz); 4.40 (2H, dd, J 5.4 3.9 Hz); 4.22 (2H, dd, J 5.2 3.8 Hz); 3.02 (3H, s); 2.12 (3H, s); 2.05 (3H, s). APCI-MS m/z: 567.2 [MH]. 78 Example 69 542-fl3jmethvIaniinoV2-oxoethoxyl-6-methyI-N-r4- oarboxamide a) tert-Butvl ({2-m^hyl-5-(U4-(methvlsulfQnyl'>benzynanunolcarfaonyI')-6-Qxo-l--f3- The title compound was obtained under similar conditions to those described in Example 60. H NMR (CDC13): 8 10.15 (1H, t, J 5.9. Hz); 8.51 (1H, s); 7.87 (2H, d, J 8.4 Hz); 7.81 (IH, d, J 8.0 Hz); 7.74 (1H, t, J 7.9 Hz); 7.51 (3H, m); 7.43 (1H, d, J 7.8 Hz); 4.67 (2H, ddd, J 20.6, 15.2 and 5,8 Hz); 4.57 (2H, s); 3.01 (3H, s); 2.14 (3H, s); 1.51 (9H, s). APCI-MS m/z: 595.3 [MH]. fr) (\ 2-Methyl-5-(f f 4-(mefty\|sulfonyl)benzynamino >carbonyl)r6-oxo-l -f3- (trifljioromethyl Vphenyll-ljD^dihydropyridin-S-yl ) oxytacedc acid To a solution of tert-butyl ({2-methyl-5-({[4-(methylsulfonyl)benzyl]amino}carbonyl)-6- oxo4-[3-(trifluoromethyl)phenyl]-l,6-dihydrbpyridin-3-yl}oxy)acetate (103 mg, 0.17 mmol) in THF (3 ml) and methanol (2 ml) was added 2M aqueous sodium hydroxide solution (0.6 ml, 1.2 mmol). After stirring for 1 h, the reaction mixture was acidified with acetic acid and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound as a white solid (87.7 mg, 95 %). JH NMR (CDC13): 8 10.48 (1H, t, J 5.9 Hz); 8.58 (1H, s); 7.87 (2H, d, J 8.4 Hz); 7.82 (1H, d, J 8.1 Hz); 7.75 (1H, t, J 7.9 Hz); 7.51 (3H, d, J 23.6 Hz); 7.44 (1H, d, J 7.9 Hz); 4.78 (2H, s); 4.67 (2H, ddd, J 21.7 15.5 6.1 Hz); 3.02 (3H, s); 2.14 (3H, s). APCI-MS m/z: 539.1 [MH]. c) 5jJ2-(Dimethylan^no^-pxoethoxyV6^me^tli[yI-I f3-(trifluoromethvl1phenvU-^J2-dihvdropvridine-3-carbpxamide A mixture of ({2-methyl-5-({[4-(methylsulfonyl)benzyl]amino}carbonyl)-6-oxo-l-[3- (trifluoromethyl)phenyl]-l,6-dihydropyridin-3-yl}oxy)acetic acid (87.5 mg, 0.16 mmol) and thionyl chloride (0.6 ml, 8.24 mmol) in DCM (5 ml) was stirred at 35 °C for 30 minutes under an argon atmosphere. The mixture was cooled and concentrated in vacuo. The last traces of thionyl chloride were removed by azeotropic evaporation with toluene. The residue was dissolved in DCM (4 ml) and dimethylamine (0.5 ml) was added. After 30 minutes stirring at ambient temperature the reaction mixture was concentrated and purified by preparative HPLC to give the title compound as a white solid (47.7 mg, 53 %). H NMR (CDC13): 810.19 (1H, t, J 5.9 Hz); 8.48 (1H, s); 7.87 (2H, d, J 8.3 Hz); 7.80 (1H, d, J 7.9 Hz); 7.73 (1H, t, J 7.8 Hz); 7.51 (3H, d, J 8.1 Hz); 7.44 (1H, d, J 8.3 Hz); 4.81 (2H, s); 4.66 (2H, dd, J 20.7 9.5 Hz); 3.02 (6H, d, J 4.8 Hz); 2.99 (3H, s); 2.16 (3H, s). APCI-MS m/z: 566.2 [MH+]. Example 70 5^2-AnunoethoxyVN-r4-fisorm)pylsulfQnvDbenzvl1-6-methyl-2-oxo-l-r3- (trifluoromethyl)phenyn-1.2-dihydropyridine-3-carboxamide To a solution of 5-hydroxy-6-methyl-JV-[4-(isopropylsulfonyl)benzyl)-2-oxo-l-[3- (trifluoromethyl)phenyl]-l^-dihydropyridine-3-carboxamide (Example 60 (a), 25 mg, 0.049 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (15 mg, 0.099 mmol) in NMP (1.5 ml), 2-chloroethylamine hydrochloride (11.5 mg, 0.099 mmol) was added and the reaction mixture was heated in a microwave oven for 10 minutes at 70 °C. The mixture was then purified by preparative HPLC to give the title compound as a white solid (8 mg, 25 %). 'HNMR (DMSO-ds): 5 10.11 (1H, t, J=6.1 Hz); 8.38 (1H, s,); 7.90 (2H, d, J=7.8 Hz); 7.83 - 7.78 (3H, m,); 7.72 (1H, d, J=8.0 Hz); 7.54 (2H, d, J=8.3 Hz); 4.61 (2H, d, J=6.2 Hz); 3.93 (2H, t, J=5.6 Hz); 3.42 - 3.31 (2H, m,); 2.86 (2H, t, J=5.6 Hz); 1.97 (3H, s, J=4.6 Hz); 1.14 (3H, s,); 1.12 (3H, s,). APCI-MS m/z: 552.2 [MH+]. Example 71 5-(Acetylarnino')-6-rnethyl-N-r4-('methvlsulfonvl')benzyn-2-oxo-l-r3- (trifluoromethyl)phenvl1-1.2-dihvdropvridine-3-carbQxamide A mixture of d-methyl-A/'-ethylsulfonyObenzyll-S-nitro-oxo-l-p- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (Example 2,15.3 mg, 0.03 mmol) and iron powder (20 mg, 0.36 mmol) in acetic acid (1.5 ml) was stirred at ambient temperature for 1 h. The iron powder was filtered off and the filtrate was concentrated in vacuo. Acetic anhydride (0.25 ml, 2.6 mmol), DMF (1 ml) and saturated aqueous sodium hydrogencarbonate solution were added to the residue. After stirring the reaction mixture at room temperature for 30 minutes, it was neutralized with aqueous sodium hydroxide solution and purified by preparative HPLC to give the title compound as a white solid (3.5 mg, 22 %). H NMR (CDC13): 8 9.94 (1H, t, J 6.0 Hz); 8.47 (1H, s); 7.87 (2H, d, J 8.4 Hz); 7.81 (1H, d, / 7.9 Hz); 7.74 (1H, t, J 7.9 Hz); 7.53 (1H, s); 7.50 (2H, d, J 8.4 Hz); 7.46 (1H, d, J 7.9 Hz); 7.13 (1H, s); 4.68 (2H, m); 3.02 (3H, s); 2.20 (3H, s); 1.99 (3H, s). APCI-MS rn/z: 522.1 [MH+J. Example 72 #-f4-Q[sopropvlsutfonyDbenzyl1-6^methvl-5-r3-(^ l-l a) 543-BromQpropoxy'>-A[-r4-(isopropvlsulfortvnbenzvl1-6-methyl-2K)Xo-l-r3-- (trifluorom6thyl>phenyt1-1.2-dihyo^opyridine-3-carboxamide A solution of 5-hydroxy-/-[4-(isopropylsulfonyl)benzyl]-6-methyl-2-oxo-l-[3- (trifluoromethyl)phenyJ]-ldihyopyridine-3-carboxainide (500 mg, 0.98 mmol), (1.28 mg, 3.94 mmol) and 1,3 dibromopropane (795 mg, 3.94mmol) in DMF (6 ml) was heated to 70 °C for 30 minutes. After cooling the mixture was purified by preparative HPLC to give the title compound as a white solid (100 mg, 16 %). APCI-MS m/z: 629.2 [MR]. (trifluoromethvl')phenyn-L2-dihvdropvridine-3-carboxaniide A solution of 5-(3-bromopropoxy)-jlV-[4-(isopropylsulfonyl)benzyl]-6-niethyl-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (30 mg, 0.048 mmol) and methanamine (0.5 ml, 2M in THF) was heated in a microwave oven for 60 minutes at 50 °C. The mixture was then purified by preparative HPLC to give the title compound as a white solid (13 mg, 46%). H NMR (CDC13): 5 10.06 (1H, t, J 6.0 Hz); 8.43 (1H, 3); 7.68 ~ 7.66 (3H, m); 7.61 (1H, t, J 7.8 ); 7.37 (3H, d, J 8.4 Hz); 7.31 (1H, d, J 7.6 Hz); 4.55 (2H, t, J 5.8 Hz); 3.98 (2H, t, J 6.1 Hz); 3.06 - 3.00 (IH, m); 2.75 (2H, t, J 7.0 Hz); 2.40 (3H, s); 1.95 (2H, t); 1.91 (3H, s); 1.15 (3H,s); 1.14 (3H,s). APCI-MS m/z: 580.2 [MH]. Example 73 5-fl-MethoxvethvlV6-methvI-Ar-f4-(methvlsuIfonvl)benzvn-2-oxo-l-r3« (trifluoromethyl)phenvn-1.2-dihydropvridine-3-carboxamide To a solution of 6-methyl-N-[4-(methyIsulfonyl)benzyl]-2-oxo-l-[3- (trifluoromethyl)phenyl]-5-vinyl-l,2-dihydropyridine-3-carboxairiide (Example 9,20.7 mg, 0.04 mmol) in methanol (2 ml) was added concentrated sulphuric acid (0.05 ml). The mixture was stirred at 65 °C overnight and then neutralized with aqueous sodium hydrogencarbonate solution. The reaction mixture was purified by preparative HPLC to give the title compound as white solid (5.9 mg, 27 %). HNMR (CDC13): 8 10.01 (IH, t, J 5.8 Hz); 8.72 (IH, s); 7.87 (2H, d, J 8.3 Hz); 7.81 (IH, d, J 7.8 Hz); 7.75 (IH, t, J 7.8 Hz); 7.52 (3H, d, J 28.4 Hz); 7.44 (IH, t, J 6.6 Hz); 4.67 (2H, m); 4.44 (IH, dq, J 0.1 6.3 Hz); 3.29 (3H, d, J 1.0 Hz); 3.01 (3H, s); 2.09 (3H, s); 1.48 (3H,dd,J6.52.1Hz). APa-MS m/z: 523.0 [MH+]. Example 74 5-(2-Bromo-l-methoxvethvl')-6-methvl-N-r4-fmethvlsulfonvl')benzvn-2- oxo-l-f3-(trifluoromethyI)phenyn-l,2-dihydit)pvridhie-3-carboxainide A mixture of 6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]- 5-vinyH,2-dihydropyridine-3-carboxamide (Example 9,66.9 mg, 0.14 mmol), N-broraosuccinimide (37.7 mg, 0.21 mmol) and dibenzoyl peroxide (7.1 mg, 0.03 mmol) in methanol (2 ml) was stirred at ambient temperature for 1.5 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC to give the title compound as white solid (44 mg, 52 %). !H NMR (CDC13): 8 9.94 (IH, t, J 5.9 Hz); 8.69 (IH, d, J 0.8 Hz); 7.88 (2H, d, J 8.3 Hz); 7.83 (IH, d, J 8.0 Hz); 7.76 (IH, t, J 7.9 Hz); 7.52 (2H, d, J 8.2 Hz); 730 (IH, s); 7.44 (IH, t, J 7.2 Hz); 4.68 (2H, m); 4.54 (IH, t, J 6.7 Hz); 3.67 (IH, m); 3.46 (IH, m); 3.37 (3H, d, J 1.1 Hz); 3.02 (3H, s); 2.13 (3H, s). APCI-MS m/z: 600.1,601.1,602.1,603.2 \ME+]. Example 75 5-(l-Isopropoxvethvl)^-methvl--N-r4-(met?iylsuyonyl)benzy\|l-2-QXo-143-- (trifluoromethyl)phenvl7-L2-dihydropyridine-3--carboxamide The title compound was prepared by a procedure analogous to that described for Example !H NMR (CDC13): 810.02 (1H, t, J 5.8 Hz); 8.76 (1H, s); 7.87 (2H, d, J 8.3 Hz); 7.81 (1H, d, J 7.8 Hz); 7.74 (1H, t, J 7.9 Hz); 7.52 (3H, d, J 25.3 Hz); 7.43 (1H, t, J 6.7 Hz); 4.68 (3H, m); 3.56 (1H, td, J 6.1 3.7 Hz); 3.01 (3H, s); 2.10 (3H, s); 1.44 (3H, dd, J 6.5 and 2.2 Hz); 1.18 (6H, dd, J 10.8 and 6.1 Hz). APCI-MS m/z: 551.2 [MH]. Example 76 S-fNMspbutyrvl-hydrariQocaifoQnylV phenvlVl^-dihvdrO"pyridine»3-carboxylic acid 4-methanesulfonyl-beii2vlamide a) 5-Hvdrazinc 3-carboxvlic acid 4-mernanesulfonvl-hen7vlamide The compound obtained in Example 11 (0.051 g, 0.14 mmol) in DCM (5 ml) was treated with SOCli (5 ml) and the flask was sealed and stirred magnetically for 2 h, when LC-MS showed that the reaction was complete. The crude mixture was evaporated in vacuo, giving the intermediate acid chloride as a yellow solid. The solid was dissolved in 1,4-dioxane (5 ml, dried over molecular sieves) and hydrazine hydrate (0.05 g, 1.0 mmol) was added. The mixture was stirred for 10 minutes, and LC-MS showed complete formation of the title compound. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC giving the title compound (0.036 g, 70%) as a white solid after freezedrying the pure fractions. APCI-MS m/z: 523.2 fMH+]. by 5-(Nl4sobutviyI4iydra.zinocarbonylV6-m dihvdro-pvridine-3-carboxvlic acid 4-methanesulfonvI-benzvlamide The compound obtained in step (a) (0.025 g, 0.047 mmol) in dry THF (10 ml) was stirred and isobutyric anhydride (0.040 g, 0.25 mmol) was added. The obtained mixture was stirred for 15 minutes, and LC-MS showed complete conversion of the starting material to the desired amide. The solvent was evaporated and the residue was purified by preparative HPLC giving the subtitle compound (0,024 g, 85%) as a white powder after freeze-drying the pure fractions. HNMR (DMSO-d6): 810.25 (1H, bs); 9.89 (1H, bs); 9.79 (1H, t, 76.2 Hz); 8.50 (1H, s); 7.93 (1H, s); 7.94-7.90 (1H, m); 7.87 (2H, d, J 8.5 Hz); 7.84 (1H, t, 77.7 Hz); 7.74 (1H, d, 77.7 Hz); 7.55 (2H, d, 78.3 Hz); 4.63-4.56 (2H, m); 3.18 (3H, s); 2.55-2.49 (1H, p, 76.8 Hz); 2.18 (3H, s); 1.08 (6H, d, 76.8 Hz). APCI-MS m/z: 593.2 [MR]. The compounds of Examples 77 to 87 and 91 to 97 were prepared using a procedure analogous to that described for Example 12. Example 77 JvJ-Methoxv-6-methvl-^-r4-(methvlsulfonvl)benzvn-2-oxo-l-r3- (trifluoromethynphenvn-l^-dihydrQpvridine-S^-dicarboxamide XHNMR (DMSO-de): 8 11.74 (1H, bs); 9.79 (1H, t); 8.41 (1H, s); 7.95-7.70 (6H, m); 7.54 (2H, d); 4.58 (2H, d); 3.70 (3H, s); 3.18 (3H, s); 2.13 (3H, s). APCI-MS m/z: 538.1 [MH]. Example 78 JV5-Methoxv-A^.6-dimethvl-A^-r4-(methvlsuIfonvnbenzvl1-2-oxo-l-r3- (teifluorornethvDphenyI1-1.2-dihydropyridine-3,5-dicarboxamide HNMR (DMSO-ds): 8 9.83 (1H, t); 8.36 (1H, s); 8.01 (1H, bs); 7.94-7.76 (5H, m); 7.54 (2H, d); 4.58 (2H, d); 3.59 (3H, s); 3.28 (3H, s); 3.18 (3H, s); 2.00 (3H, s). APCI-MS m/z: 552.2 [MH+]. Example 79 5-r(2.5-Pimethvl-2.5-dihvdro-lH-pvrrol-l-vDcarbonvn-6-methvl-N-r4- (methylsulfonvl)benzy]1-2-oxo-l-r3-(trifluoromethyl)phenvn-1.2-dihvdropyridine-3- carboxamide H NMR (DMSO-d6): 5 9.86 (1H, q); 8.29 (0.5H, d); 8.26 (0.5H, s); 8.06 (0.5H, bs); 8.01 (0.5H, bs); 7.95-7.74 (5H, m); 7.55 (2H, d); 5.83 (2H, dt); 4.80 (1H, bt); 4.58 (2H, d); 4.49 (1H, bd); 3.17 (3H, s); 2.03 (1H, d); 1.92 (1H, d);U4 (3H, d); 1.08 (2H, d); 1.05 (1H, m). APCI-MS m/z: 588.2 [MH+]. Example 80 6~Methvl-A/J-f4-fmethvlsulfonvDbenzvl1-2-oxo-//5-Dvrrolidin-l-vl--l--r3- (trifluorometh^l)phenvl1-1.2-dihvdropyridine--3.t5-dicarboxatnide JH NMR (DMSO-de): 5 9.84 (2H, bt); 8.43 (1H, s); 7.99-7.78 (5H, m); 7.72 (1H, d); 7.54 (2H, d); 4.58 (2H, d); 3.18 (3H, s); 3.02 (4H, bs); 2.13 (3H, s); 1.80 (4H, bs). APCI-MS m/z: 577.2 [MH+]. Example 81 6-Methvl-N-f4-(mfethvlsiUfonvnbenzvl1-2-oxo-54piperidin-l-vlcarbonvlV l-r3-(trifluoro\|nethyl)phenyl1--1.2-dihydrQpyndinc-3-carbox^inide ^NMR (DMSO-dtf): 5 9.88 (1H, t); 8.20 (1H, s); 8.03 (1H, d); 7.94-7.74 (5H, m); 7.54 (2H, d); 4.58 (2H, bs); 3.79-3.22 (4H, m); 3.18 (3H, s); 1.93 (3H, s); 1.69-1.36 (6H, m). APQ-MS m/z: 576.2 [MH4]. Example 82 6-Methyl-JVJ-r4-(methylsulfonyl)benzyn-j?\^-roorpholin-4-^-2-oxo-l-r3- (trifluorpmethyl)phenyl1-1.2^iJiydropyridipe-3.^--dicarboxgmide ^NMR (DMSO-d6): 8 9.82 (1H, t); 9.57 (0.8H, s); 9.22 (0.2H, s); 8.41 (0.8H, s); 8.36 (0.2H, s); 8.00-7.76 (5H, m); 7.72 (1H, d); 7.54 (2H, d); 4.58 (2H, d); 3.66 (4H, m); 3.17 (3H, s); 2.84 (3.2H, m); 2.73 (0.8H, bs); 2.11 (0.8H, s); 2.02 (0.2H, s). APCI-MS m/z: 593.2 rMH+J. Example 83 6-Methvl-5-rf4-m?thvlpiperidin-l-vDcarbonvll-N-r4- (methvlsulfonyDbenzyl1-2-oxo-l-F3-(trifluoromethyDphenyl1-L2-dihyclropyfldine-3- carboxamide . (DMSO-d (2H, d); 4.58 (2H, bs); 4.43 (1H, bs); 3.72 (1H, bs); 3.17 (3H, s); 3.05 (1H, m); 2.76 (1H, m); 1.93 (3H, d); 1.77-1.55 (3H, m); 1.19-0.80 (5H, m). APCI-MS m/z: 590.2 [MB]. Example 84 6-Methvl-J\^-r4-(metfavlsulfonvl>)benzvn-2-oxo-A?!?-piperidm-l-vI-l-r3- (trifluoromethyl')phenvn-1.2-dihvdropvridine-3.5-dicarboxamide JHNMR (DMSO-dg): 5 9.82 (1H, t); 9.64 (0.8H, s); 9.12 (0.2H, s); 8.39 (0.8H, s); 8.35 (0.2H, s); 8.00-7.77 (5H, m); 7.72 (1H, d); 7.54 (2H, d); 4.58 (2H, d); 3.19 (3H, s); 2.84 (3H, m); 2.11 (0.8H, bs); 2.02 (0.2H, s); 1.66-1.53 (4H, m); 1.53-1.32 (3H, m). APCI-MS m/z: 591.2 [MH]. Example 85 jy?-rtert-ButvlV^?.6-dimethvI-^?-r4-(methvlsulfonv])benzvn-2-oxo-l-r3- (trifluoromethyl)phenyn-1.2-dihvdropvridine-3.5-dicarboxamide JHNMR (DMSO-de): 8 9.88 (1H, t); 8.19 (1H, s); 7.99 (1H, d); 7.91-7.73 (5H, m); 7.54 (2H, d); 4.58 (2H, bs); 3.18 (3H, s); 2.91 (3H, s); 1.95 (3H, s); 1.45 (9H, s). APCI-MS m/z: 578.2 [MH+j. Example 86 JVJ-Butvl-^V5.6-dimethvl-N3-r4-rmethvlsulfonvl)benzvn-2-oxo-143- (trifluoromethyl)phenyn-lt2-dihydropyridme-3,5-dicarboxamide ^NMR (DMSO-dc): 5 9.88 (1H, t); 8.19 (1H, d); 8.01 (1H, s); 7.95-7.74 (5H, m); 7.54 (2H, d); 4.58 (2H, bs); 3.18 (3H, s); 2.95 (1.2H, s); 2.94 (1.8H, s); 1.92 (1.8H, s); 1.91 (1.2H, s); 1.63-1.40 (2H, m); 1.40-1.10 (2H, m); 0.92 (1.8H, t); 0.83 (1.2Ht). APCI-MS m/z: 578.2 [MH]. Example 87 Ar?-Ethvl-A^-isopropyl-6-methvl-JV?-r4-(methv]suIfonvnbenzvn-2-oxo-l-r3- (trifluoromethvDDhenvn-l^-dihvdropvridine-S^-dicarboxamide H NMR (DMSO-de): 5 9.90 (1H, t); 8,20 (0.3H, s); 8.15 (0.7H, s); 8.10-7.95 (1H, m); 7.95-7.75 (5H, m); 7.54 (2H, d); 4.58 (2H, bs); 4.02 (1H, bs); 3.36 (2H, bs); 3.18 (3H, s); 1.91 (3H, s); 1.32-0.96 (9H, m). APCI-MS m/z: 578.2 [MH"]. The compounds of Examples 88 to 90 were prepared using a procedure analogous to that described for Example 76. Example 88 5-iN1-(Fonnyl-hydrazmocarboriyI1-6-inethyI-2-oxo-l-(3-trifluorornethvlphenylV1.2- dihydro-pvrioMne^3-carboxylicacid4-methan6sulfonvl-benzylamide H NMR (DMSO-ds): 5 10.43 (1H, s); 10.13 (1H, s); 9.79 (1H, t, / 6.2 Hz); 8.52 (1H, s); 8.11 (1H, s); 7.93 (1H, s); 7.94-7.89 (1H, s); 7.87 (2H, d, J 8.65 Hz); 7.87 (1H, d, J 8.21); 7.74 (1H, d, / 8.21 Hz); 7.55 (2H, d, J 8.21 Hz); 4.63-4.54 (2H, m); 3,17 (3H, s); 2.18 (3H, APCI-MS m/z: 551.2 [MH+]. Example 89 N1-r5-(4-Me1faanesuIfonvl-benzvlcarbamovIV2-methvI-6-oxo-l-(3- trifluoromethvl-phenvlVL6-dihvdro-pvridine-3-carbonvl1-hvdrazi7iecarboxvHcacidetiivl ester 1H NMR (DMSO-dtf): 8 10.23 (1H, s); 9.79 (1H, t, J 6.1 Hz); 9.23 (1H, s); 8.47 (1H, s); 7.94 (1H, s); 7.94-7.89 (1H, d, / 8.2 Hz); 7.87 (2H, d, J 8.4 Hz); 7.82 (1H, d, 77.7 Hz); 7.74 (1H, d, / 7.8 Hz); 7.54 (2H, d, / 8.4 Hz); 4.65^.55 (2H, m); 4.14-4.01 (2H, m); 3.17 (3H, s); 2.16 (3H, s); 1.25-1.15 (3H, m). APCI-MS m/z: 595.2 [MR]. Example 90 5-( 1 2-rrEthvlamino)carbonothiovnhvdrazino ) carbonvl^-6-meth vl-Ar4- (metliyIsu]fonynb6nzyl1-2-oxo-l-r3-ftrifluoromethvDphenvl1-1.2-dihydrppyridine^ carboxamide .-87 !H NMR (DMSO-d 8.14 (1H, bs); 7.95-7.81 (4H, m); 7.71 (1H, d, / 8.0 Hz); 7.55 (2H, d, J 8.3 Hz); 4.60 (2H, d, 7 6.1 Hz); 3.54-3.44 (2H, m); 3.18 (3H, s); 2.16 (3H, s); 1.08 (3H, t, .7 7.1 Hz) APCI-MS m/z: 610.2 [MR]. Example 91 5-(Isoxazolidin-2-vlcarbonvlV6-methyI-//-r4-(methvlsulfonvl'>benzvn-2- oxo-l-rS-ftrifluorom&thvDphenvn-l^-dihvdfopvridine-S-carboxainide !H NMR (DMSO-dg): 8 9.79 (1H, t); 8.41 (1H, s); 7.99 (1H, s); 7.93-7.74 (5H, m); 7.54 (2H, d); 4.58 (2H, d); 3.96 (2H, t); 3.76 (2H, m); 3.17 (3H, s); 2.31 (2H, p); 2.05 (3H, s). APCI-MS m/z: 564.3 [MR]. Example 92 6'Methvl-2-oxo-l-f3-trifluoromethyI-phenylVl^-dihvdro-pvridin&-3T5- dicaiboxvlic acid 54methoxy-mefbyl-aipide) 3-r4-(propan&-2-sulfonvl)-benzylamide1 !HNMR (CDCb): 6 9.87 (1H, bt); 8.67 (1H, s); 7.84-7.74 (4H, m); 7.52-7.49 (3H, bd); 7.45-7.43 (1H, bd); 4.74-4.64 (2H, m); 3.62 (3H, s); 3.38 (3H, s); 3.19-3.13 (1H, m); 2.13 (3H,s);1.28(6H,d,J6.8Hz). APCI-MS m/z: 580 [MH+], Example 93 6-MethvI-2-oxo-l-(3-trifluQromethvl-phenvlV1.2-dihvdro-pvridine-3.5- dicartooxvlic acid 3-(4-ethanesulfonvl-benzyIamide) 5-(methoxv-methyl-amide1 ^NMR (CDC13): 5 9.87 (1H, bt); 8.67 (1H, s); 7.86-7.82 (3H, m); 7.78-7.74 (1H, bt); 7.53-7.50 (3H, m); 7.45-7.43 (1H, bd); 4.74-4.64 (2H, m); 3.66 (3H, s); 3.38 (3H, s); 3.09 (2H, q, 77.5 Hz); 2.13 (3H, s); 1.26 (3H, t, 77.5 Hz). APCI-MS m/z: 566 [MH+]. Example 94 6-Methvl-2-oxo-l-G-triflucaromethvl-phenvlV1.2-dihvdro-pvridme-3.5- dicarboxvlicacid3-(4-cvcIopropanesulfonvl-benzvlamide)5-('methoxv-methvl-amide') H NMR (CDCls): 5 9.86 (1H, bt); 8.67 7.51-7.49 (3H, bd); 7.45-7.43 (1H, bd); 4.73-4.63 (2H, m); 3,66 (3H, s); 3.38 (3H, s); 2.46- 2.39 (1H, m); 1.35-1-31 (2H, m); 1.04-0.99 (2H, m). APCI-MS m/z: 578 [MH+], Example 95 g-Methyj^-oxo- l-(3-trifluorometfayl-phenvlM .2-dihydrQ-pyridige-3,5- dicarboxvlic acid 5-rf2-hvdroxv-ethvn-amidel 3-(4-methanesulfonvl-benzvlamide H NMR (DMSO-ds): 6 9.82 (1H, t, 7 6.0 Hz); 8.48 (1H, s); 8.48 (1H, t, 7 5.6 Hz); 7.93- 7.89 (1H, m); 7.90 (1H, s); 7.87 (2H, d, 7 8.2 Hz); 7.83 (1H, t, 7 7.6 Hz); 7,72 (1H, d, 7 7.9 Hz); 7.54 (2H, d, 7 8.2 Hz); 4.74 (1H, bs); 4.64-4.54 (2H, m); 3.50 (2H, t, 7 6.2 Hz); 3.32- 3.25 (2H, m); 3.17 (3H, s); 2.14 (3H, s). APCI-MS m/z: 552.2 [MH+]. Example 96 5-fl5oxazQlidine-2-catbony^-6-methyI-2-oxo-l-(3-triflorQmethylphenyni. 2diydro-pvridine-3-ca^)oxvlic acid 4-ethanesulfonvl-benzvlamide !H NMR (CDC13): 8 9.83 (1H, bt); 8.70 (1H, s); 7.85-7.81 (3H, m); 7.77-7.73 (1H> bt); 7.53-7.50 (3H, m); 7.45-7.43 (1H, bd); 4.73-4.63 (2H, m); 4.06 (2H, t, J 7.2 Hz); 3.91 (2H, t, 77.2 Hz); 3.08 (2H, q, 77.7 Hz); 2.48-2.41 (2H, m); 2.19 (3H, s); 1.26 (3H, t, 77.7 Hz). APCI-MS m/z: 579 [MB]. Example 97 5-(Isoxazolidme-2-carbonyn-6-metfayI-2-oxo-l-f3-trifluorometh-y]phenyn 1.2dihydropvridine-3-carboxvlic acid 4-cvclQDropane8ulfonvlbenzvlamide !H NMR (CDC13): 8 9.81 (1H, bt); 8.70 (1H, s); 7.84-7.81 (3H, m); 7.77-7.73 (1H, bt); 7.52-7.48 (3H, m); 7.45-7.43 (1H, bd); 4.73-4.62 (2H, m); 4.06 (2H, t, 76.8 Hz); 3.91 (2H, t, 7 7.2 Hz); 2.48-2.39 (3H, m); 2.19 (3H, s); 1.35-1.31 (2H, m); 1.04-0.99 (2H, m), APCI-MS m/z: 590[MH+). Example 98 5-(N-Hydroxvcarbaininiidoy]V6-methyl-2-oxo-l-(3-trifluoromethylphenvl'- 1.2-dihvdro-Dvridine-3-carboxvlicacid4-methanesulfonvI-benzv]amide ,89 °)c 5-Cyano-6-methyl-2-oxo- 1 -(3-triflucMromethyl-phenyl)-l ,2-dihydro-pyridine-3-carboxylic acid 4-melhanesulfonyl-benzylainide Example 1, 0.040 g, 0.082 mmol), hydroxylamine hydrochloride (0.015 g, 0.209 mmol), NaOAc (0.017 g, 0.209 mmol), ethano! (3 ml), water (0.1 ml) and a magnetic stirrer were placed in a vial. The mixture was heated at 90 °C overnight. LC-MS showed a 50:50 mixture of two components, one of which had the expected MW. The product was isolated by preparative HPLC giving 0,012 g (28%) of the title compound. !H NMR (DMSO-d Hz); 7.86 (2H, d, J 8.2 Hz); 7.85 (1H, s); 7.83 (1H, t, J 7.8 Hz); 7.69 (1H, d, J 7.8 Hz); 7.54 (2H, d, / 8.3 Hz); 5.88 (2H, bs); 464-4.55 (2H, m); 3.17 (3H, s); 2.07 (3H, s). APCI-MS m/z: 523.2 Example 99 {trifIuoromethYl>phenYl1-1.2-dihydgppyri a> Ethvl 6-methvl-2-oxo-l -r3-ftrifluorometfavl)phenvll-l .2-dihvdropvridme-3-carboxvlate A suspension of 6-methyl-2-oxo- l-[3-(trifluoromethyl)phenyl3-l,2-dihydropyridine-3- carboxyKc acid (Example 1 (b), 13.1 g, 43.9 mmol), sodium carbonate (5.2 g, 48.3 mmol) and iodoethane (10.6 g, 67.7 mmol) in NMP (60 ml) was stirred at ambient temperature for 19 h under a nitrogen atmosphere. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was collected, washed with water and brine, dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash cnromatography on silica eluting with tert-butyl methyl ether/methanol (10:0.4) to give the title compound as a light brown solid (12.5 g, 87%). !H NMR (CDC13); S 8.21 (1H, d, J 7.4 Hz); 7.75 (1H, d, J 7.8 Hz); 7.68 (1H> t, J 7.8 Hz); 7.49 (1H, s); 7.42 (1H, d, / 7.8 Hz); 6.25 (1H, d, / 7.4 Hz); 4.36 (2H, q, J 7.2 Hz); 2.03 (3H,s);1.37(3H,t,77.2Hz). APCI-MS m/z: 326.1 [MH]. b)_ Ethyl 5Modo-6.fflemyl-2^xo-I-(3r carboxvlate To a solution ethyl 6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxylate (9.9 g, 30.5 mmol) in CHaCl2 (45 ml) and TFA (38 ml) was added N-iodosuccinimide (6.89 g, 30.6 mmol) under a nitrogen atmosphere. After 19 h stirring at ambient temperature the solvent was concentrated in vacuo. To the residue were added ethyl acetate and saturated aqueous sodium hydrogencarbonate to neutralize the remaining TFA. The organic phase was collected, washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica eluting with DCM/methanol (10:0.2) to give the title compound as a yellow solid (11.4 g, 83%). H NMR (CDC13): 8 8.52 (1H, s); 7.76 (1H, d, J 7.8 Hz); 7.69 (1H, t, J 7.9 Hz); 7.46 (1H, s); 7.38 (1H, d, 77.7 Hz); 4.36 (2H, q, Jl.l Hz); 2.26 (3H, s); 1.37 (3H, t, /7.2 Hz). APCI-MS m/z: 452.0 [MH]. c) Eth,yl 5-r(dimethylarninokarbonvl1-6^inethyl-2-oxo-l-r3-('trifluorornethvnphenvI1-l.2- dihydropvridine-3-carboxv3ate Ethyl 5-iodo-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyI]-l ,2-dihydropyridine-3- carboxylate (2.6 g, 5.76 mmol), palladium triphenylphosphine (38.7 mg, 0.15 mmol), anhydrous dimethylamine (5 ml) and anhydrous ethanol (20 ml) were placed in a stainless-steel autoclave (100 ml). The reaction mixture was stirred at 85 °C under a carbon monoxide pressure of 5 J atmospheres for 2 h. After cooling, excess carbon monoxide was released into a fume hood and the solvent was concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound as a white solid (1.3 g, 58 %). H NMR (CDC13): 8 8.16 (1H, s); 7.77 (1H, d, J 7.9 Hz); 7.70 (1H, t, /7.8 Hz); 7.49 (1H, s); 7.41 (1H, d, J7.9 Hz); 4.36 (2H, q, J7.1 Hz); 3.09 (6H, 4/30.2 Hz); 2.04 (3H, s); 1.37(3H,t,J7.2Hz). APCI-MS m/z: 397.2 [MH+]. d 5-rfl3imethvlaminoV;arbonvn-6-methvl-2-oxo-l-r3-ftrifluoromethvDphenvn-2- dihvdropvridine-3-carboxvlie acid To a solution of ethyl 5-[(dimethyIamino)carbonyl]-6-methyl-2-oxo-l-[3- (trifluoromethyl)phenyl]-l^-dihydropyridine-3-carboxylate (1.28 g, 3.2 mmol) in THF (5 ml) and water (1 ml) was added dropwise 2M sodium hydroxide (1.7 ml, 3.4 mmol) over 1 h. After an additional 2 h stirring at ambient temperature, the solution was acidified to pH 1 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound as a white solid (0.92 g, 77 %). HNMR (CDC13): 8 8.47 (1H, s); 7.88 (1H, d, J7.8 Hz); 7.80 (1H, t, 77.9 Hz); 7.56 (1H, s); 7.48 (1H, d, /7.9 Hz); 3.12 (6H, d, .7 36.0 Hz); 2.15 (3H, s). APCI-MS m/z: 369.1 [MR]. e) NVCyclohexvlmethvlVJV5JV^6-trimethvl-2-oxo-l-r3-(trifluoromethvl)phenyn-1.2- dihydropyridine-3 J-dicarboxamide A mixture of 5-[(dmiemylamino)carbonyl]-6-methyl-2-oxo-l-[3-(trifluromethyl)-phenyl]- l,2-dihydropyridine-3-carboxylic acid (12 mg, 0.03 mmol), HATU (15 mg, 0.04 mmol), HOAT (7 mg, 0.04 mmol) and DffiA (13 mg, 0.1 mmol) in NMP (160 ul) was added to (cyclohexylmethyl)amine in NMP (135 fil, 0.3M, 0.04 mmol). The reaction mixture was stirred for 17 h at room temperature. The solvent was removed in vacuo, and the residue was dissolved in acetonitrile/water, 50/50, to a total volume of 1.6 ml, and purified using preparative HPLC to give the title compound (8 mg, 58%). RT (CJ8, UV 220 nm): 7.3 min. APCI-MS m/z: 464.2 [MH+]. The compounds of Examples 100 to 146 were prepared using a procedure analogous to that described for Example 99. Example 100 N5.^5.6-Trimethvl-2-oxo-N3-(pvridin-3-vlmethvn-l-r3-(trifluoromethvnphenylM, 2-dihydropyridine-3.5-dicarboxamide RT (Cis, UV 220 nm): 5.0 min. APCI-MS m/z: 459.2 Example 101 .(trifluoromethvjVp)ienyn-1.2-dihvdropvridtne-3.5-dicarboxQnude RT (C18, UV 220 nm): 4.9 min. APCI-MS m/z: 481.1 [MR J. Example 102 AJV5>6-Trimethvl-JV3-(3-morolm-4-vlt>ropvlV2--Qxo>l-T3- RT (C18, UV 220 nm): 5.0 min. APCI-MS m/z: 495.2 [MB]. Example 103 JV3-BenzvI-^.Ns.6-trimethvl-2-oxo-l-r3-(trifluoromethynphenvn-l>2- dihydyo-pyridine-S^S-dicarboxamide RT (C18, UV 220 nm): 6.8 min. APCI-MS m/z: 458.2 [MR]. Example 104 fllff-fodol-S-vnethvn-JS RT (Cia, UV 220 nm): 65 min. APCI-MS m/z: 511.1 [MH+]. Example 105 1 .2-djhydropyridine-3 .5~dicarboxamide RT (Cis, UV 220 nm): 7.0 min. APCI-MS m/z: 472.3 [MR]. Example 106 ^5J^.6-TrimethvI-2K>xo-^3-(2-t>henvlethvIVl--r3-(trifluorometh-vl')dien\ll- 1 RT (C18, UV 220 nm): 5.3 min. APCI-MS m/z: 472.1 [MH+], Example 107 A/sJVs.6-Trimethvl-2-oxo-JV34(2J?V2-phenvlcvclopropvll-1-r3- (trifluoromethylVphenyl1-1.2-dihvdropviidme-3,5-dicarboxamide RT (Cis, UV 220 nm): 5.5 min. APCI-MS m/z: 484.1 [MH]. Example 108 ftrifluoromethyD-phenvn- 1 ,2-dihydropvridine-3.5-dicarboxainide RT (C18, UV 220 nm): 5.4 min. APCI-MS m/z: 484.1 [MH+]. Example 109 ^-r2-n3-Beiizodioxoi-5-vnethvn-/^.Ar^6-trimethvl-2-oxo-l-f3-ftrifluoromethyl> phenyn-1.2-dihvdropvridine-3^-dicarboxamide RT (Ci8, UV 220 nm): 5.2 min. APCI-MS m/z: 516.2 [MH+], Example 110 5-f r4-(2-Hvdroxvethvl>pipeTazin-l-vl1caibonvU-jyjy.2-trimetfavl-6-oxo-l-- r3-ftrifluoromemvl)phenyl14.6-dihydropvridiiie-3-cafboxa3nide RT (C18, UV 220 nm): 3.1 min. APCI-MS m/z: 481.3 [MH+3. Example 111 J/3-ra-Eth\lpvrrolidin-2-vl>methvn-^5JN?a.6--trimethvl-2-oxo-l-r3- ftriflaoro-methynphenvn-1.2-dihydropyridine-3.5-dicarboxamide RT (Cig, UV 220 nm): 3.5 min. APCI-MS m/z: 479.2 Example 112 JV5JV5.6-Trimethvl^3-r3-(2-methvlpiperidin-l-v])propvn-2-oxo-l-f3- (trifluoro-methyl^phenyn-1.2-dihvdropyridine-3.5-dicarboxamide RT (C,8, UV 220 nm): 3.7 min. APCI-MS m/z: 507.2 [MH+]. Example 113 JV5JV5.6-Trimethvl-jy3-fl-naphthv]methvlV2-oxo.l-r3- (trifluoTomethyl>phenvn-lJi^hy^ropyridme-3.5-dicarboxamide RT (Cig, UV 220 nm): 5.7 min. APCI-MS m/z: 508.1 [MR]. Example 114 methyljpfaenyll-l^^dihydropyridine-S.S-dicarboxamide RT (Cig, UV 220 ran): 5.1 min. APCI-MS m/z: 502.1 [MH]. Example 115 A- rMfluorometfavnpheByl1-1.2-d;hydropvridine-3.5-dicarboxamide RT (Ci8> UV 220 nm): 5.4 min. APCI-MS m/z: 494.2 [MH]. Example 116 3-f2-ChlcMP^flporobenzvlVJVs.A/5.64iimethvl-2-oxo-l-r3- RT (Cig, UV 220 nm): 5.6 min. APCI-MS m/z: 510.1 [MH+]. Example 117 ftrifluoromemvnpenvn-1.2-dihvdropvridine-3.5-dicarboxamide RT (Cia, UV 220 nm): 5.0 min. APCI-MS m/z: 464.2 [MH+]. Example 118 JV3-f3.4>DichIorobenzvn-5.Ag.6-trimethvl-2-oxo-l-r3- (trifluoromethyl>phenylV2-dihydropviidine-3t5- RT (Cia, UV 220 nm): 5.9 min. APCI-MS m/z: 526.1 [MH+]. Example 119 ^3-r2-(2.4-Dichlorophenvl)etfavll-^5^s.6-trimetfavl-2-oxo-143- {trifluoromethylVphenyl1--L2-dihvdn)Pvridine-3.5-dicarboxamide RT (Ci8, UV 220 nm): 6.0 rain. APCI-MS m/z: 540.1 [MH+J. Example 120 (trifluoromethylVphenyn-l^-dihvdropvridine-3.S-dicarboxamide RT (C,8, UV 220 nm): 5.7 min. APCI-MS m/z: 476.2 [MH+J. Example 121 ^3-ri-f4-Chlorophenvnethvn-JV5JVs.6-trimethvl-2-oxo-l-r3- Ctrifluoromethyl)-phenyl1-1.2-dihvdropvridine-3.5-dicaiboxamide RT (Cig, UV 220 nm): 5.8 min. APCI-MS m/z: 506.2 [MH+]. Example 122 ^sJVs.6-Ttimethvl-2-oxo-JV3-r3--r2-oxopvrrolidin--l-vl)propvn-l-r3- ftrifluoro-methvl)phenvI1'1.2-dihydropyiidine-33^icarboxaniide RT (Cis, UV 220 ran): 4.0 min. APCI-MS m/z: 493.3 [MR]. Example 123 A^J^^-Trimethyl^-oxo-^-fpyiidm^ylmethyl^-l-fSftrifluog) methyl)phenyn-1.2-dihydropyridine-3.5-dicarboxaniide RT (C]8, UV 220 nm): 3.3 min. APCI-MS m/z: 459.2 [MH+j. Example 124 7/^.2-TrimethvI-6-oxo-5-r(4-phenvlpiperazin-l-vl)carbonvn-l-r3- (trifluorQ-methyl)phenyn-L6-dihydropyridine-3-carboxamide RT (Cjs, UV 220 nm): 4,1 min. APCI-MS m/z: 513.2 [MR]. Example 125 ^^.2-Trimethv]-6-oxo>5-f(4-Pvridin-2>vlpipCfazin-l-vlV;arbonvn-l-f3- (trifluoro-methyDphenyn-L6-di^vdrgpvridine-3-carbQxamide RT (da, UV 220 nm): 3.2 min. APCI-MSm/z: 514.3 [MH+]. Example 126 /V3-(2.3-Dihvdro-l-benzofuran-5-vlmeihvlVNsJV5.6-trimethyl-2-oxo-l-f3- (tiifluoroinethynphenyn-1.2-dihvdropvridine>-3.5-dicarboxamide RT (Cis, UV 220 nm): 5,1 min. APCI-MS m/z: 500.2 [MH]. Example 127 Methy) 4-{ f (\ S-f(dimethylamino'k;arbonvn-6-methvl-2-oxo-f3-(trifluofomethl) hen]l-l ^-dihvdroridin-3-'l Icarbonaminolinethl benzoate RT (Cia, UV 220 nm): 5.1 min. APCI-MS m/z: 516.2 [MH]. Example 128 5-1 r3-fl>imethvlamino^pvrrolidin-l-vlleafbonvl \-JVJ/2-trimethvl-6-oxo-l F3-f trifluoromethyDphenvn- 1 .6-dih vdtQpyridine-3-cayboxamide RT (Cis, UV 220 nm): 3.1 min. APCI-MS m/z: 465.2 [MH]. Example 129 JVsJVs.6-Trimethvl-2-oxo-jy3-r2-(2-thiegynethvn-l-r3- (triflaoromethvnphenvn-1.2-dihvdtopvridine-3.5-dicarboxamide RT (Ci8> UV 220 nm): 5.2 min. APCI-MS m/z: 478.1 [MH], Example 130 JV5JVg>6-TrimethvI-2-oxo-?/3-(4-phenoxvbenzvD-l-r3- (trjfluorQmethvDphenyl1-1.2-dihydropvridine-3.5-dicarboxamide RT (Cja, UV 220 nm): 6.0 min. APCI-MS m/z: 550,3 [MH+]. Example 131 ArsJV5.6-Trimethvl-2-oxo-JV3-f3-thienvlmethvn-l-r3- (trifluoromgthvI)phenvn-1.2-dihvdropvridine-3.5-dicarbox8nade RT (Cig, UV 220 am): 5.0 min. APCI-MS m/z: 464.2 [MR]. Example 132 A^-f2-(4-ferf-Butvlphenvl'>etfivll-/»/5JV5.6-trimethvl-2-oxo-l-r3- (trifluoromethvlVphenvI1-1.2-dihydropyridine-3.5-dicarfaoxamide RT (Cis, UV 220 nm): 6.3 min. APCI-MS m/z: 528.2 [MB]. Example 133 N3-(244-(AminosuIfonvl)phenvl1ethvU"JV5JV5.6>tritaethvl-2-oxo-l-r3-- RT (Ci8, UV 220 nm): 4.4 min. APCI-MS m/z: 551.2 [MH+]. Example 134 JVsJV5.6-Trimethvl-2-oxo^-r4-flg-pvrazoI-l-vnbenzvn-l-r3- (t\|ifluoromethyIVphenyl1-1.2-dihydrop\ridine-3T5-dicarboxapMde RT (da, UV 220 nm): 5.0 min. APCI-MS m/z: 524.2 [MH+]. Example 135 dihvdro-Dvridine-3.5-dicarboxamide RT (Cig, UV 220 nm): 5.1 min. APCI-MS m/z: 460.1 [MH+]. Example 136 /J/3-(f2.3-Pihvdro-1.4-benzodioxin-2-vlmethvlVAr5.A?5.6-trimethv3-2-oxo-l- [S-ftrifluoromethyl^phenvn-l^-dihvdropvridine-S^-dicarboxamide RT (Cig, UV 220 nm): 5.4 min. APCI-MS m/z: 516.2 [MH]. Example 137 J73-f(6-Huoro-4H-1.3-benzodioxin-8-vl'>methvll-N5./^.6-trimethvI-2-QXQ-lf3^ trifluoromethvIJphenvI1-1.2-dihvdropyridine-3,5-dicarboxainide RT (Cis, UV 220 nm): 5.2 min. APCI-MS m/z: 534.2 [MH+]. Example 138 JV3-a-Ben20thien-3-vlmethvn-MjV5.6-trimethvl-2-oxo-l-r3- (trifIuoromethylVphenyll-L2-dihydropyQdine-3^-dicarboxamide RT (Cis, UV 220 nm): 5.6 min. APCI-MS m/z: 514.1 [MH]. Example 139.A.6-Triniethyl-2-oxo-Ar3-r2-ftetrahvdro-2g-.pvran-4-vnethvl1-l-r3- RT (Ca, UV 220 nm): 4.5 min. APCI-MS m/z: 480.2 [MH}. Example 140 JVsJV5.6-Trmiethvl--A?3-r(l-methvl-lfl-pvrazoI-4-vnmethvl1-2-oxo-l-r3- (trif]iuorO"methynph€nvI1-L2'dihvdropvridin6-3,5-dicarboxamide RT (Ci8 UV 220 nm): 4.0 min. APCI-MS m/z: 462.2 [MH]. Example 141 (trifluoio-methvl')phenyll-lJ2-dihydropyridine-3,5-dicarboxamide RT (Cig, UV 220 nm): 5.1 min. APCI-MS m/z: 524.2 [MH+], Example 142 /^-Ff5-Methoxv-4-oxo-4flr-pvran-2~vDmethvl1-^s.//i.6-trimethvl-2-oxo-lr3-( trifluoromethvl)phenyI1-1.2-dihydropyridine-3.5-dicarboxamide RT (Cis, UV 220 nm): 3.9 min. APCI-MS m/z: 506.2 [MH]. Example 143 rtrifluoromethvl)phenvn-1.2-dihvdropvridine-3.5-dicarboxamide RT (C18, UV 220 nm): 3.7 min. APCI-MS m/z: 507.2 [MH+]. Example 144 JV3-(4-Cyanobenzvl>-JVsJV5.6-trirnethvl-2-oxo-l-r3-(trifiuoromethvDphenyIV lT2-dihydropyridine-3.5-dicarboxamide RT (Gig, UV 220 nm): 5.0 min. APCI-MS m/z: 483.2 [MH+j. Example 145 J^Jv^-Trimernvl^-oxcKA^-ra-fS^ yI)pTopyl]-l-r3-(trifluoromemyI)p^^^ RT (Cis, UV 220 nm): 3.8 min. APCI-MS m/z: 492.2 [MH+]. Example 146 JV3-! r(2/^l-EmvlpwoMn-2-vl1methvl l-A^.JV5.6-trimethvl-2-oxo-l-r3- (trifluorQ-methvDphenvl1"lJ-djhydropyri6^ne-3.5-dcarboxamide RT (Cj8, UV 220 nm): 3.4 min. APCI-MS m/z: 479.2 [MH+]. Example 147 5-Cvclopropvl-6-methvl-N-f4"fhiethvlsulfonvl)benzvn-2-oxo-l-r3- (trifluorojnethvI)phenvl1-1.2rdihydrppvridine-3-carboxamidet A mixture of 5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (Example 1 (d), 120.4 mg, 0.20 mmol), cyclopropylboronic acid (48.7 mg, 0.57 mmol), potassium phosphate (195.3 mg, 0.85 mmol), tricyclohexylphosphine (19.9 mg, 0.07 mmol) and palladium acetate (8.5 mg, 0.03 mmol) in toluene (4 ml) and water (0.08 ml) was stirred at 100 °C under an argon atmosphere for 2 h. The reaction mixture was cooled and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound as a white solid (36mg,35%). H NMR (CDCb): 610.06 (IH, t, J 5.9 Hz); 8.48 (IH, s); 7.87 (2H, d, J 8.4 Hz); 7.81 (IH, d, J 7.8 Hz); 7.74 (IH, t, J 7.8 Hz); 7.51 (3H, d, J 8,4 Hz); 7.42 (IH, d, J 7.7 Hz); 4.67 (2H, m); 3.01 (3H, s); 2.20 (3H, s); 1.76 (IH, dd, J 13.6 3.0 Hz); 0.99 (2H, m); 0.70 (2H, q, J 5.1 Hz). APCI-MS m/z: 505.1 [MB]. Example 148 6-Methvl-5-f2-methvl-1.3-dioxolan-2-vlVN-r4-(methvlsulfonvnbenzvn-2- oxo-l-r3-ftrifluoromethvilDhenvn-1.2-dihvdropvridine-3-carboxamide 5-Acetyl-6-methyl-/^-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyI)phenyl]-l,2- dihydropyridine-3-carboxamide (Example 4,55 mg, 0.11 mmol), ethane-l,2-diol (482 mg, 8,7 mmol), toluene-4-sulfonic acidmonohydrate (21 mg, 0.11 mmol) and toluene (50 ml) were placed in a round-bottomed flask (100 ml) equipped with a Dean and Stark water separator, reflux condenser and magnetic stirrer. The reaction mixture was heated at reflux for 48 h. After cooling, the mixture was neutralized with aqueous sodium hydrogen carbonate solution and the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound as a white solid (31.5 mg, 52 %). XH NMR (CDC13): 8 9.99 (IH, t); 8.90 (IH, s); 7.87 (2H, d); 7.81 (IH, d); 7.74 (IH, t); 7.52 (2H, d); 7.50 (IH, s); 7.42 (IH, d); 4.67 (2H, m); 4.07 (2H, m); 3.85 (2H, m); 3.01 (3H, s); 2.23 (3H, s); 1.67 (3H, s). APCI-MS m/z: 551.0 [MH]. Example 149 5-(4.5-Dihvdro-oxazol-2-vl'>-6-methvl-2-oxo-l>(3-trifluoromethvl-phenvlV 1.2-dihvdro-pvridine-3-carboxvlic acid 4-methane8ulfonyl-benzvIamide The compound obtained in Example 95 (0.022 g, 0.04 mmol) was dissolved in dry DCM (2 ml). To this solution was added one drop of SOCfe, and the mixture was allowed to stand for 1 h. LC-MS showed complete consumption of the starting material. Evaporation and subsequent purification on preparative HPLC afforded the title compound 0.004 g (20%) as a white solid after freeze-drying the pure fractions. H NMR CDMSO-dg): 6 9.74 (IH, t, J6.1 Hz); 8.78 (IH, s); 7.96 (IH, s); 7.91 (IH, d, J 7.6 Hz); 7.86 (2H, d, J 8.2 Hz); 7.83 (IH, t, J1.& Hz); 7.76 (IH, d, 77.8 Hz); 7.54 (2H, d, J PCT/SE2004/001336 8.2 Hz); 4.65-4.55 (2H, m); 4.38 (2H, t, / 9.2 Hz); 3.99 (2H, t, J 9.2 Hz); 3.17 (3H, s); 2.40 3H,s). APCI-MS ra/z: 534.1 [ME], Example 150 5-CycIopropvl-6-methvl-N-(f5--(methvlsulfonvl'>pvridin-2-vnmethvl)-2- O^o-l-r3-ftrifluoromethyl)ph^yl1-1.2rdihydropyridine-3^aflrboxamide a) 5-Cyclopropyl'6-methyl-2^xo-l-f3'(teifluoromethyl)phenyll-1.2--dihydrQpvridine-3- cafboxylic acid Ethyl 5-iodo-6-methyI-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxylate (Example 99 (b), 0.77 g, 1.6 mmol), toluene (35 ml), cyclopropyl-boronic acid (0.257 g, 3 mmol), Pd(OAc)2 (0.072 g, 0.35 mmol), P(c-Hex>3 (0.169 g, 0.6 mmol), K^O, monohydrate (1.6 g, 6.9 mmol), water (0.7 ml) and a magnetic stirrer bar were placed in a pressure safe glass vessel. The vessel was sealed and heated (130 °C) with stirring overnight LC-MS showed complete formation of the intermediate ethyl ester. The mixture was allowed to cool and the phases were diluted with EtOAc (50 ml) and water (50 ml) and the phases were allowed to separate. The organic phase was washed with water and brine, and further dried with Na^SO* Filtration and evaporation gave a crude intermediate. This material was dissolved in THF (10 ml) and water (5 ml). To this solution was added NaOH (1M, 3 ml, 3 mmol) and the mixture was stirred for 2 h at 50 °C. The THF was evaporated and the residual aqueous phase was acidified and extracted with EtOAc (2 x 20 ml). The extracts were washed with water and brine and finally dried over NaSC Filtration and evaporation gave the required carboxylic acid (0.19 g, 33%). APCI-MS m/z: 338.1 [MH+]. Retention time 2.35 minutes. b^ 5-(Methvlthio>pyridine-2-<:arbonitrile> 5-Bromo-pyridine-2-carbonitrile (2.63 g, 13.7mmol), sodium methanethiolate (1.44 g, 20.5 mmol), potassium carbonate (3.79 g, 27.4 mmol) in NMP (60 ml) were stirred in a sealed flask overnight. The mixture was partitioned between ethyl acetate and water! "the organic phase was washed with water several times, brine and dried over sodium sulphate. The solvent was removed in vacuo to afford the title compound as a yellow solid (2.0 g, 99%). H NMR (CD3OD): 6 8.54 (1H, d, J 2.3 Hz); 7.83 - 7.71 (2H, m); 2.60 (3H, s). c) 5-(Methylsulfony]')pyridine-2-carbonittile 5-(Methylthio)pyridine-2-carbonitrile (2.0 g, 13.3 mmol) was dissolved in DCM (20 ml) and cooled to -15 °C and 3-chloroperoxybenzoic acid (6.75 g, 27.4 mmol) was added in portions while the temperature was kept between -15 °C to -10 °C When the addition was complete, the cooling bath was removed and the mixture was stirred at room temperature for 2 h. 2M KOH and DCM were added. The organic phase was separated, washed twice with 2M KOH, water and brine, dried over sodium sulphate and evaporated to afford the title compound as a white solid (2.15 g, 89%). H NMR (CD3OD): 5 9.22 (1H, d, J 2.3 Hz); 8.54 (1H, dd, J 8.1,23 Hz); 8.13 (1H, d, J 8.3Hz);3.27(3H,s). d) {r5-fMethylsulfonvl)pyridin-2-ynmemyl} amine hvdrochloride 5-(MethylsulfonyI)pyridine-2-carbonitriIe (2.15 g, 11.8 mmol) was dissolved in methanol (230 ml). 6M HCI (1 ml) and 10% palladium on carbon (234 mg) were added and the mixture was stirred under an atmospheric pressure of hydrogen overnight. The catalyst was removed by filtration through celite and the solvent was evaporated, water was added and the solution was freeze-dried to afford the title compound as a yellow powder (2.34 g, H NMR (CD3OD): 5 9.10 (1H, d, J 2.2 Hz); 8.36 (1H, dd, J 8.2,2.4 Hz); 7.68 (1H, d, J 8.8 Hz); 4.29 (2H, s); 3.22 (3H, s). eli _5_-Cyclopropyl»6-methy\|-N- ([5^(mediyIsuIfonyl1pvridin-2-ynmethvl 1 -2-oxo-l -f 3- 1-1.2-dihvdropvridine-3-carboxamide 5-Cyclopropyl-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxylic acid, {[5-(methylsulfonyl)pyridin-2-yl]methyl}amine hydrochloride, HBTU and D1EA in NMP were reacted together overnight. Purification by HPLC gave the title compound. 1H NMR (DMSO): 8 10.14 (IH, t, J 5.8 Hz); 8.98 (IH, d, J 2.3 Hz); 8.26 (IH, dd, J 8.2, 2.4 Hz); 8.18 (IH, s); 7.94 - 7.79 (3H, m); 7.74 - 7.68 (IH, m); 7.55 (IH, d, J 8.4 Hz); 4.69 (2H, d, J 5.9 Hz); 3.29 (3H, s); 2.13 (3H, s); 1.90 - 1.78 (IH, m); 0.99 - 0.90 (2H, m); 0.64 -0.56(2H,m). APCI-MS m/z: 506.1 [MR]. Human Neutrophil Elastase Quenched-FRET Assay The assay uses Human Neutrophil Elastase (HNE) purified from serum (Calbiochem art. 324681; Ref. Baugh, RJ. et at, 1976, Biochemistry. 15,836-841). HNE was stored in 50 mM NaOAc, 200 mM Nad, pH 5.5 with added 30% glycerol at -20 °C. The protease substrate used was Elastase Substrate V Fluorogenic, MeOSuc-AAPV-AMC (Calbiochem art. 324740; Ref. Castillo, M.J. et aL, 1979, Anal. Biochem. 99,53-64). The substrate was stored in DMSO at -20 °C. The assay additions were as follows: Test compounds and controls were added to black 96-well flat-bottom plates (Greiner 655076), 1 jtLin 100% DMSO, followed by 30 jL HNE in assay buffer with 0.01% TritonX-100. The assay buffer constitution was: 100 mM Tris (pH 7.5) and 500 mM NaCl. The enzyme and the compounds were incubated at room temperature for 15 minutes. Then 30 fj,\ substrate in assay buffer was added. The assay was stopped after 30 minutes incubation at room temperature by adding 60 fi\ stop solution (140 mM acetic acid, 200 mM sodium monochloroacetate, 60 mM sodium acetate, pH 4.3). Fluorescence was measured on a Wallac 1420 Victor 2 instrument at settings: Excitation 380 nm, Emission 460 nm. IC5Q values were determined using Xlfit curve fitting using model 205. When tested in the above screen, the compounds of the Examples gave ICso values for inhibition of human neutrophil elastase activity of less than 30 jxM, indicating that the 464100 compounds of the invention are expected to possess useful therapeutic properties. Specimen results are shown in the following Table: Compound (Table Removed) WE CLAIM; 1. A 2-pyridone compound of formula (I) used as inhibitors of human neutrophil elastase and homologous serine proteases and a pharmaceutically acceptable salts thereof; (Formula Removed) wherein: Y represents CR3 or N; R1 represents H or Cl to C6 alkyl; R2 represents: i) CN, NO2, OH, OSO2R47, O-C2 to C6 alkanoyl, CO2R47, CHO or C2 to C6 alkanoyl; or ii) Cl to C6 alkoxy is unsubstituted or substituted by OH, C1 to C6 alkoxy, CN, NR54R55, CONR54R55, OCOR47 or one or more F atoms; or iii) C3 to C6 saturated or partially unsaturated cycloalkyl is unsubstituted or substituted by C1 to C6 alkyl; or iv) C4 to C7 saturated or partially unsaturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S(O)m and NR62 is unsubstituted or substituted by C1 to C6 alkyl; or v) CONR48R49, CONR50NR48R49, C(=NOR52)R53, C(=NH)NHOR52 or NR48R49; or vi) C2 to C6 alkenyl or C2 to C6 alkynyl; said alkenyl or alkynyl group is unsubstituted or substituted by C1 to C6 alkoxy or phenyl or a five- or six- membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N; said phenyl or heteroaromatic ring being is unsubstituted or substituted by halogen, CN, C1 to C6 alkyl or C1 to C6 alkoxy; or vii) C1 to C6 alkyl substituted by one or more F atoms; or viii) C1 to C6 alkyl substituted by one or more groups selected from halogen, OH, oxo, azido, NR48R49 , C1 to C6 alkoxy and C1 to C6 alkoxy substituted by one or more F atoms; or ix) C1 to C6 alkyl substituted by phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N; said phenyl or heteroaromatic ring is unsubstituted or substituted by halogen, CN, C1 to C6 alkyl or C1 to C6 alkoxy; R48 and R49 independently represent H, OH, C1 to C6 alkoxy, C3 to C6 cycloalkyl, CHO, C2 to C6 alkanoyl, CO2R50, C(X)NR63R64 or Cl to C6 alkyl; said alkyl is unsubstituted or substituted by OH, C1 to C4 alkoxy, C3 to C6 cycloalkyl, CN or phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N; said alkanoyl is unsubstituted or substituted by CN; X represent O or S; or the group NR48R49 together represents a saturated or partially unsaturated 5 to 7 membered azacyclic ring is unsubstituted or substituted by one heteroatom selected from O, S and NR56; said azacyclic ring is unsubstituted or substituted by one or more substituents selected from OR57 and C1 to C4 alkyl; said alkyl is unsubstituted or substituted by OR57; R3 represents H or F; G1 represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N; R5 represents H, halogen, Cl to C6 alkyl, CN, Cl to C6 alkoxy, NO2, NRI4R15, Cl to C3 alkyl substituted by one or more F atoms or C1 to C3 alkoxy substituted by one or more F atoms; R14 and R15 independently represent H or C1 to C3 alkyl; said alkyl is unsubstituted or substituted by one or more F atoms; n represents an integer 1, 2 or 3 and when n represents 2 or 3, each R5 group is selected independently; R4 represents H or C1 to C6 alkyl; said alkyl is unsubstituted or substituted by OH or C1 to C6 alkoxy; or R4 and L are joined together such that the group —NR4L represents a 5 to 7 membered azacyclic ring is unsubstituted or substituted by one heteroatom selected from O, S and NR16 ; said ring is unsubstituted or substituted by C1 to C6 alkyl or NR60R61 ; said alkyl is unsubstituted or substituted by OH; L represents a bond, O, NR29 or CI to C6 alkyl; said alkyl is unsubstituted or substituted by one heteroatom selected from O, S and NR16 and said alkyl is unsubstituted or substituted by OH or OMe; G2 represents a monocyclic ring system selected from: i) phenyl or phenoxy, ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S and N, iii) a C3 to C6 saturated or partially unsaturated cycloalkyl, or iv) a C4 to C7 saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms independently selected from O, S(O)p and NR and is unsubstituted or substituted by incorporating a carbonyl group; or G represents a bicyclic ring system in which each of the two rings is independently selected from: i) phenyl, ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S and N, iii) a C3 to C6 saturated or partially unsaturated cycloalkyl, or iv) a C4 to C7 saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms independently selected from O, S(0)p and NR17 and is unsubstituted or substituted by incorporating a carbonyl group; and the two rings are either fused together, or are bonded directly together or are separated by a linker group selected from O, S(0)q or CH2, said monocyclic or bicyclic ring system is substituted by one to three substituents independently selected from CN, OH, C1 to C6 alkyl, C1 to C6 alkoxy, halogen, NR18R19, NO2, OSO2R38, CO2R20, C(=NH)NH2, C(O)NR2lR22, C(S)NR23R24, SC(=NH)NH2, NR31C(=NH)NH2, S(O)sR25, SO2NR26R27, Cl to C3 alkoxy substituted by one or more F atoms and Cl to C3 alkyl substituted by SO2R39 or by one or more F atoms; or when L does not represent an bond, G also represent H; at each occurrence, m, p, q, s and t independently represent an integer 0, 1 or 2; R18 and R19 independently represent H, Cl to C6 alkyl, formyl, C2 to C6 alkanoyl, S(O)tR32 or SO2NR33R34 ; said alkyl group is unsubstituted or substituted by halogen, CN, Cl to C4 alkoxy or CONR41R 42; R25 represents H, Cl to C6 alkyl or C3 to C6 cycloalkyl; said alkyl group is unsubstituted or substituted by one or more substituents selected independently from OH, CN, CONR35R36, CO2R37, OCOR40, C3 to C6 cycloalkyl, a C4 to C7 saturated heterocyclic ring containing one or two heteroatoms independently selected from O, S(O)p and NR43 and phenyl or a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S and N; said aromatic ring is unsubstituted or substituted by one or more substituents selected independently from halogen, CN, C1 to C4 alkyl, C1 to C4 alkoxy, OH, CONR44R45, CO2R46, S(O)sR65 and NHCOCH3 R32 represents H, C1 to C6 alkyl or C3 to C6 cycloalkyl; R16, R17, R20, R21, R22 R23, R24, R26, R27, R29, R3\ R33, R34, R35, R36, R37, R38, R39 R40 R 41 R42 R43 R44 R45 R46 R47 R50 R52 R53 R54 R55 R56 R57 R60 R61 ,R62 ,R63 ,R64 and R65 independently represent H or C1 to 6 alkyl. 2. A compound as claimed in claim 1, wherein Y is CR . 3. A compound as claimed in claim 1 and 2, wherein G1 represents phenyl. 4. A compound as claimed in any one of claims 1 to 3, wherein R5 represents Cl, CH3, CN or CF3. 5. A compound as claimed in claims 1 to 4 used as inhibitors of human neutrophil elastase and homologous serine proteases. 6. A pharmaceutical formulation comprising a compound of formula (I) as claimed in claims 1 to 4, or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable diluent or carrier. 7. A process for preparing compounds as claimed in claims 1 to 4, and pharmaceutically acceptable salts thereof, which comprise: a. reacting a compound of formula (II) (Formula Removed) b. with a nucleophile providing R group selected from Cu(I)CN, an alkyl vinyl ether, an organo-tin compound, an organo-boronic acid, a terminal alkyne or an alcohol and carbon monoxide; wherein R1, R2, R4, R5, Y, G1, G2, L and n are defined in formula (I) and Hal represents a halogen atom, preferably bromo or iodo, to obtain a compound of formula (I).

Full Text

Field of the Invention
This invention relates to novel 2-pyridone compounds, processes for their preparation, pharmaceutical compositions comprising them, and their use in therapy.
Background of the Invention
Elastases are possibly the most destructive enzymes in the body, having the ability to degrade virtually all connective tissue components. The uncontrolled proteolytic degradation by elastases has been implicated in a number of pathological conditions.
Human neutrophil elastase (hNE), a member of the chymotrypsin superfamily of serine proteases is a 33-KDa enzyme stored in the azurophilic granules of the neutrophils. In neutrophils the concentration of NE exceeded 5 mM and its total cellular amount has been estimated to be up to 3 pg. Upon activation, NE is rapidly released from the granules into the extracellular space with some portion remaining bound to neutrophil plasma membrane (See Kawabat et al. 2002, Eur. J. Pharmacol. 451,1-10). The main intracellular physiological function of NE is degradation of foreign organic molecules phagocytosed by neutrophils, whereas the main target for extracellular elastase is elastin (Janoff and Scherer, 1968, J. Exp. Med. 128,1137-1155). NE is unique, as compared to other proteases (for example, proteinase 3) in that it has the ability to degrade almost all extracellular matrix and key plasma proteins (See Kawabat et al. , 2002, Eur. .1. Pharmacol. 451,1-10). It degrades a wide range of extracellular matrix proteins such as elastin, Type 3 and type 4 collagen, laminin, fibronectin, cytokines, etc. (Ohbayashi, 11.. 2002, Expert Opin.
Investig. Drugs, 11,965-980). NE is a major common mediator of many pathological changes seen in chronic lung disease including epithelial damage (Stockley, R. A. 1994. Am. J. Resp. Grit. Care Med. 150,109-113).
The destructive role of NE was solidified almost 40 years ago when Laurell and Eriksson reported an association of chronic airflow obstruction and emphysema with deficiency of

serum ai-antitrypsin (Laurell and Eriksson, 1963, Scand J. Clin. Invest 15,132-140).
Subsequently it was determined that cct-antitrypsin is the most important endogenous
inhibitor of human NE. The imbalance between human NE and endogenous antiprotease is
believed to cause excess human NE hi pulmonary tissues which is considered as a major
pathogenic factor in chronic obstructive pulmonary disease (COPD). The excessive human
NE shows a prominent destructive profile and actively takes part in destroying the normal
pulmonary structures, followed by the irreversible enlargement of the respiratory airspaces,
as seen mainly in emphysema. There is an increase in neutrophil recruitment into the lungs
which is associated with increased lung elastase burden and emphysema in oci-proteinase
inhibitor-deficient mice (Cavarra et al., 1996, Lab. Invest. 75,273-280). Individuals with
higher levels of the NE-cti protease inhibitor complex in bronchoalveolar lavage fluid show
significantly accelerated decline in lung functions compared to those with lower levels .
(Betsuyaku et al. 2000, Respiration, 67,261*267). Instillation of human NE via the trachea
in rats causes lung haemorrhage, neutrophil accumulation during acute phase and
emphysematous changes during chronic phase (Karaki et al., 2002, Am. J. Resp. Grit Care
Med., 166,496-500). Studies have shown that the acute phase of pulmonary emphysema
and pulmonary haemorrhage caused by NE in hamsters can be inhibited by pre-treatment
with inhibitors of NE (Fujie et al.,1999, brflamm. Res. 48,160-167).
Neutrophil-predominant airway inflammation and mucus obstruction of the airways are
major pathologic features of COPD, including cystic fibrosis and chronic bronchitis. NE
impairs mucin production, leading to mucus obstruction of the airways. NE is reported to
increase the expression of major respiratory mucin gene, MUC5AC (Fischer, B.M &
Voynow, 2002, Am. J. Respir. Cell Biol,, 26,447-452). Aerosol administration of NE to
guinea pigs produces extensive epithelial damage within 20 minutes of contact (Suzuki et
al, 1996, Am. J. Resp. Grit Care Med., 153,1405-1411). Furthermore NE reduces the
ciliary beat frequency of human respiratory epithelium in vitro (Smallman et al., 1984,
Thorax, 39,663-667) which is consistent with the reduced mucociliary clearance that is
seen in COPD patients (Currie et al., 1984, Thorax, 42,126-130). The instillation of NE
into the airways leads to mucus gland hyperplasia in hamsters (Lucey et al., 1985, Am.
Resp. Crit. Care Med., 132,362-366). A role for NE is also implicated in mucus
hypersecretion in asthma. In an allergen sensitised guinea pig acute asthma model an
inhibitor of NE prevented goblet cell degranulation and mucus hypersecretion (Nadel et al.,
1999, Eur. Resp. 3., 13,190-196).
NE has been also shown to play a role in the pathogenesis of pulmonary fibrosis.
NE: oci.protenase inhibitor complex is increased in serum of patients with pulmonary
fibrosis, which correlates with the clinical parameters in these patients (Yamanouchi et al.,
1998, Eur. Resp. J. 11,120-125). In a murine model of human pulmonary fibrosis, a NE
inhibitor reduced bleomycin-induced pulmonary fibrosis (Taooka et al., 1997, Am. J. Resp.
Grit. Care Med., 156,260-265). Furthermore investigators have shown that NE deficient
mice are resistant to bleomycin-induced pulmonary fibrosis (Dunsmore et al., 2001, Chest,
120,35S-36S). Plasma NE level was found to be elevated in patients who progressed to
ARDS implicating the importance of NE in early ARDS disease pathogenesis. (Donnelly
et al., 1995, Am. J. Res. Crit. Care Med., 151,428-1433). The antiproteases and NE
complexed with antiprotease are increased in lung cancer area (Marchandise et al., 1989,
Eur. Resp. J. 2, 623-629). Recent studies have shown that polymorphism in the promoter
region of the NE gene are associated with lung cancer development (Taniguchi et al., 2002,
Clin. Cancer Res., 8,1115-1120.
Acute lung injury caused by endotoxin in experimental animals is associated with elevated
levels of NE (Kawabata, et al., 1999, Am. J. Resp. Crit. Care, 161,2013-2018). Acute
lung inflammation caused by intratracheal injection of lipopolysaccharide in mice has been
shown to elevate the NE activity in bronchoalveolar lavage fluid which is significantly
inhibited by a NE inhibitor (Fujie et al., 1999, Eur. J. Pharmacol., 374,117-125; Yasui, et
al., 1995, Eur. Resp. J., 8,1293-1299). NE also plays an important role in the neutrophilinduced
increase of pulmonary microvascular permeability observed in a model of acute
lung injury caused by tumour necrosis factor «. (TNFa) and phorbol myristate acetate
(PMA) in isolated perfused rabbit lungs (Miyazaki et al., 1998, Am. J. Respir. Crit. Care
Med., 157, 89-94).
A role for NE has also been suggested in monocrotoline-induced pulmonary vascular wall
thickening and cardiac hypertrophy (Molteni et al., 1989, Biochemical Pharmacol. 38,
2411-2419). Serine elastase inhibitor reverses the monocrotaline-induced pulmonary
hypertension and remodelling in rat pulmonary arteries (Cowan et al., 2000, Nature
Medicine, 6,698-702). Recent studies have shown that serine elastase, that is, NE or
vascular elastase are important in cigarette smoke-induced muscularisation of small
pulmonary arteries in guinea pigs (Wright et al., 2002, Am. J. Respir. Crit. Care Med., 166,
954-960).
NE plays a key role in experimental cerebral ischemic damage (Shimakura et al., 2000,
Brain Research, 858,55-60), ischemia-reperfusion lung injury (Kishima et al., 1998, Ann.
Thorac. Surg. 65, 913-918) and myocardial ischemia in rat heart (Tiefenbacher et al., 1997,
Eur. J. Physiol., 433, 563-570). Human NE levels in plasma are significantly increased
above normal in inflammatory bowel diseases, for example, Crohn's disease and ulcerative
colitis (Adeyemi et al., 1985, Gut, 26,1306-1311). In addition NE has also been assumed
to be involved in the pathogenesis of rheumatoid arthritis (Adeyemi et al., 1986,
Rheumatol. Int., 6, 57). The development of collagen induced arthritis in mice is
suppressed by a NE inhibitor (Kakimoto et al., 1995, Cellular Immunol. 165,26-32).
Thus, human NE is known as one of the most destructive serine proteases and has been
implicated in a variety of inflammatory diseases. The important endogenous inhibitor of
human NE is cci-antitrypsin. The imbalance between human NE and antiprotease is
believed to give rise to an excess of human NE resulting in uncontrolled tissue destruction.
The protease/ antiprotease balance may be upset by a decreased availability of
ocj-antitrypsin either through inactivation by oxidants such as cigarette smoke, or as a
result of genetic inability to produce sufficient serum levels. Human NE has been
implicated in the promotion or exacerbation of a number of diseases such as pulmonary
emphysema, pulmonary fibrosis, adult respiratory distress syndrome (ARDS), ischemia
reperfusion injury, rheumatoid arthritis and pulmonary hypertension.
WO 02/053543 discloses pyridone derivatives having affinity for cannabinoid 2-type
receptor.
The present invention discloses novel 2-pyridione derivatives that are inhibitors of human
neutrophil elastase and homologous serine proteases such as proteinase 3 and pancreatic
elastase, and are thereby useful in therapy.
Disclosure of the Invention
The present invention provides a compound of formula (I)
(Figure Removed)
wherein:
Y represents CR orN;
R represents H or Cl to 6 alkyl;
2
R represents:
47 47
i) CN, NO2, OH, OSO2R , O-C2 to 6 alkanoyl, CO2R , CHO or C2 to 6
alkanoyl; or
ii) C1 to 6 alkoxy optionally substituted by OH, Cl to 6 alkoxy, CN, NR54R55,
54 55 47
CONR R ,OCOR or one or more F atoms; or
iii) C3 to 6 saturated or partially unsaturated cycloalkyl optionally further substituted
by Cl to 6 alkyl; or
iv) C4 to 7 saturated or partially unsaturated heterocyclic ring containing 1 to 3
heteroatoms independently selected from O, S(0)m and NR optionally further
substituted by Cl to 6 alkyl; or
v) CONR48R49, CONR5°NR48R49, C(=NOR5 V53, C(=NH)NHOR52 or NR^R49;
or
vi) C2 to 6 alkenyl or C2 to 6 alkynyl; said alkenyl or alkynyl group being optionally
further substituted by Cl to 6 alkoxy or phenyl or a five- or six-membered
heteroaromatic ring containing 1 to 3 heteroatoms independently selected from
O, S and N; said pheny] or heteroaromatic ring being optionally further
substituted by halogen, CN, Cl to 6 alkyl or Cl to 6 alkoxy; or
vii) Cl to 6 alkyl substituted by one or more F atoms; or
viii) Cl to 6 alkyl substituted by one or more groups selected from halogen, OH, oxo,
azido, NR R , Cl to 6 alkoxy and Cl to 6 alkoxy substituted by one or more
F atoms; or
ix) Cl to 6 alkyl substituted by phenyl or a five- or six-membered heteroaromatic
ring containing 1 to 3 heteroatoms independently selected from O, S and N;
said phenyl or heteroaromatic ring being optionally further substituted by
halogen, CN, Cl to 6 alkyl or Cl to 6 alkoxy;
48 49
R andR independently represent H, OH, Cl to 6 alkoxy, C3 to 6 cycloalkyl, CHO, C2
to 6 alkanoyl, CO2R }C(X)NR R or Cl to 6 alkyl; said alkyl being optionally further
substituted by OH, Cl to 4 alkoxy, C3 to 6 cycloalkyl, CN or phenyl or a five- or sixmembered
heteroaromatic ring containing 1 to 3 heteroatoms independently selected from
O, S and N; said alkanoyl being optionally further substituted by CN;
X represent O or S;
or the group NR R together represents a saturated or partially unsaturated 5 to 7
membered azacyclic ring optionally incorporating one further heteroatom selected from 0,
S and NR ; said azacyclic ring being optionally further substituted by one or more
57
substituents selected from OR and Cl to 4 alkyl; said alkyl being optionally further
57
substituted by OR ;
R represents H or F;
G represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3
heteroatoms independently selected from O, S and N;
R represents H, halogen, Cl to 6 alkyl, CN, Cl to 6 alkoxy, NO2, NR14R* , Cl to 3 alkyl
substituted by one or more F atoms or Cl to 3 alkoxy substituted by one or more F atoms;
14 15
R and R independently represent H or Cl to 3 alkyl; said alkyl being optionally further
substituted by one or more F atoms;
n represents an integer 1,2 or 3 and when n represents 2 or 3, each R group is selected
independently;
R represents H or Cl to 6 alkyl; said alkyl being optionally further substituted by OH or
Cl to 6 alkoxy;
or R and L are joined together such that the group -NR L represents a 5 to 7 membered
azacycJic ring optionally incorporating one further heteroatom selected from O, S and
NR ; said ring being optionally further substituted by Cl to 6 alkyl or NR R ;said
alkyl being optionally further substituted by OH;
29 L represents a bond, O, NR or Cl to 6 alkyl; said alkyl optionally incorporating a
heteroatom selected from O, S and NR ; and said alkyl being optionally further
substituted by OH or OMe;
2
G represents a monocyclic ring system selected from:
i) phenyl or phenoxy,
ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms
independently selected from O, S and N,
iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or
iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two
heteroatoms independently selected from 0, S(O)p and NR and optionally further
incorporating a carbonyi group; or
2
G represents a bicyclic ring system in which each of the two rings is independently
selected from:
i) phenyl,
ii) a S or 6 membered heteroaromatic ring containing one to three heteroatoms
independently selected from O, S and N,
iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or
iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two
heteroatoms independently selected from 0, S(O)p and NR 17and optionally further
incorporating a carbonyi group;
and the two rings are either fused together, or are bonded directly together or are separated
by a linker group selected from O, S(O)q or CHa,
said monocyclic or bicyclic ring system being optionally further substituted by one to three
substituents independently selected from CN, OH, Cl to 6 alkyl, Cl to 6 alkoxy, halogen,
It)
NR18R19, N02, OS02R38, C02R2°, C(==NH)NH2, C(O)NR21R22, C(S)NR23R24,
SC(==NH)NH2, NR31C(=NH)NH2, S(O)SR25, SO2NR26R27, Cl to 3 alkoxy substituted by
one or more F atoms and Cl to 3 alkyl substituted by SO2R or by one or more F atoms;
or
when L does not represent an bond, G2 may also represent H;
at each occurrence, m, p, q, s and t independently represent an integer 0,1 or 2;
18 19 32
R and R independently represent H, Cl to 6 alkyl, formyl, C2 to 6 alkanoyl, S(O)tR
33 34
or SO2NR R ; said alkyl group being optionally further substituted by halogen, CN, Cl
to 4 alkoxy or CONR41R42;
25
R represents H, Cl to 6 alkyl or C3 to 6 cycloalkyl; said alkyl group being optionally
further substituted by one or more substituents selected independently from OH, CN,
CONR R ,CO2R ,OCOR , C3 to 6 cycloalkyl, a C4 to 7 saturated heterocyclic ring
containing one or two heteroatams independently selected from O, S(O)p and NR4 3 and
phenyl or a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms
independently selected from 0, S and N; said aromatic ring being optionally further
substituted by one or more substituents selected independently from halogen, CN, Cl to 4
44 45 46 65
alkyl, Cl to 4 alkoxy, OH, CONR R , CO2R , S(O)SR and NHCOCH3;
32
R represents H, Cl to 6 alkyl or C3 to 6 cycloalkyl;
R", R17, R20, R21, R32, R23, R24, R2*, R27, R2', R31, R33, R34, R35, R36, R37 R38,
R3', R40, R41, R42 R43, R44, R45, R4*, R47 R50, R52, R53, R54, R55, R5', R57, E«
R ,R ,R ,R andR independently represent H or Cl to 6 alkyl;
JO ft
and pharmaceutically acceptable salts thereof.
The compounds of formula (I) may exist in enantiomeric and/or tautomeric forms. It is to
be understood that all enantiomers, diastereomers, racemates, tautomers and mixtures
thereof are included within the scope of the invention.
Unless otherwise indicated, the term "Cl to 6 alky!" referred to herein denotes a straight or
branched chain alkyl group having from 1 to 6 carbon atoms. Examples of such groups
include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl and hexyl. The
terms "Cl to 3 alkyl" and "Cl to 4 alkyl" are to be interpreted analogously.
Examples of "Cl to 3 alkyl substituted by one or more F atoms" include fluoromethyl,
difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, pentafluoroethyl
and 33.3-trifluoropropyl.
Unless otherwise indicated, the term "Cl to 6 alkoxy" referred to herein denotes an
oxygen substituent bonded to a straight or branched chain alkyl group having from 1 to 6
carbon atoms. Examples of such groups include methoxy, ethoxy, n-propoxy, i-propoxy,
n-butoxy, i-butoxy and s-butoxy. The terms "Cl to 3 alkoxy" and "Cl to 4 alkoxy" are to
be interpreted analogously.
Examples of "Cl to 6 alkoxy substituted by one or more F atoms" include fluoromethoxy,
trifluoromethoxy, 2,2,2-trifluoroethoxy and 3,3,3-trifluoropropoxy.
Unless otherwise indicated, the term "C2 to 6 alkanoyl" referred to herein denotes a
straight or branched chain alkyl group having from 1 to 5 carbon atoms bonded to the
molecule via a carbonyl group. Examples of such groups include acetyl, propionyl and
pivaloyl.
Unless otherwise indicated, the term "halogen" referred to herein denotes fluorine,
chlorine, bromine and iodine.
Examples of a five or six membered heteroaromatic ring containing 1 to 3 heteroatoms
independently selected from 0, S and N include furan, thiophene, pyrrole, oxazole,
oxadiazole, isoxazole, imidazole, thiazole, triazole, thiadiazole, pyridine, pyrimidine and
pyrazine.
Unless otherwise indicated, the term "C3 to 6 saturated or partially unsaturated cycloalkyl"
referred to herein denotes a 3 to 6 membered non-aromatic carbocyclic ring optionally
incorporating one or more double bonds. Examples include cyclopropyl, cyclopentyl,
cyclopentenyl, cyclohexyl and cyelohexenyl. The term "five- or six-membered saturated or
partially unsaturated cycloalkyl ring" is to be interpreted analogously.
Unless otherwise indicated, the term "C4 to 7 saturated or partially unsaturated
heterocyclic ring containing one or two heteroatoms independently selected from O, S(O)p
and NR1 7 and optionally further incorporating a carbonyl group" referred to herein denotes
a 4 to 7 membered non-aromatic heterocyclic ring optionally incorporating one or more
double bonds and optionally incorporating a carbonyl group. 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 terms "five- or six-membered saturated
or partially unsaturated heterocyclic ring containing one heteroatom selected from O, S and
NR1 3" and "C4 to 7 saturated or partially unsaturated heterocyclic ring containing 1 to 3
heteroatoms independently selected from O, S(O)m and NR " are to be interpreted
analogously.
Examples of a "5 to 7 membered azacyclic ring optionally incorporating one further
heteroatom selected from O, S and NR " include pyrrolidine, piperidine, morpholine,
thiomorpholine and piperazine.
In the definition of L, "Cl to 6 alkyl; said alkyl optionally incorporating a heteroatom
selected from O, S and NR " embraces a straight or branched chain arrangement of 1 to 6

carbon atoms in which any two carbon atoms are optionally separated by O, S or NR .
The definition thus includes, for example, methylene, ethylene, propylene, hexamethylene,
ethylethylene, -CH2CH2O-CH2-> -CT2CH20-CH2-CH2-, -CH2CH2S- and
-CH2CH2NR16-.
Examples of bicyclic ring systems in which the two rings are either fused together, or are
bonded directly together or are separated by a linker group selected from O, S(O)q or CH2
include biphenyl, thienylphenyl, pyrazolylphenyl, phenoxyphenyl, phenylcyclopropyl,
naphthyl, indanyl, quinolyl, tetrahydroquinolyl, benzofuranyl, indolyl, isoindolyl,
indolinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl,
isoquinolyl, chromanyl, indenyl, quinazolyl, quinoxalyl, chromanyl, isocromanyl, 3Hindolyl,
IH-indazolyl, quinuclidyl, tetrahydronaphthyl, dihydrobenzofaranyl, morpholine-
4-ylphenyl, 1,3-benzodioxolyl, l,l-dioxido-2,3-dihydro-l-benzothienyl, 2,3-dihydro-l,4-
benzodioxinyl, 1,3-benzodioxinyl and 3^-dihydro-isochromenyl.
3
In one embodiment, Y in formula (I) represents CR . In another embodiment, Y represents
N.
In one embodiment, R in formula (I) represents Cl to 6 alkyl. In another embodiment, R
represents CH3.
2 48 49 2 In one embodiment R in formula (I) represents CONR R . In another embodiment, R
represents Cl to 6 alkoxy or Cl to 6 alkoxy substituted by OH, Cl to 6 alkoxy, or by one
2
or more F atoms. In yet another embodiment, R represents Cl to 6 alkyl substituted by
48 one or more F atoms or Cl to 6 alkyl substituted by OH, NR R4 9 , Cl to 6 alkoxy or Cl to
6 alkoxy substituted by one or more F atoms.
3
In one embodiment, R in formula (I) represents H.
In one embodiment, G in formula (T) represents phenyl or pyridyl. In another
embodiment, G in formula (0 represents phenyl.
In one embodiment, R in formula (I) represents halogen, Cl to 6 alkyl, CN or Cl to 3
alkyl substituted by one or more F atoms. In another embodiment, R in formula (I)
represents Cl, CHs, CN or CP$.
In one embodiment, n represents the integer 1.
In another embodiment, G in formula (I) represents phenyl, R represents CF3 and n
represents the integer 1.
4
In one embodiment, R represents H.
In one embodiment, L represents Cl to 6 alkyl (Cl to 6 alkylidene). In another
29 embodiment, L represents -CH2-. In another embodiment, L represents NR and R29
represents H.
2
In one embodiment, G represents an optionally substituted monocyclic ring system
selected from:
i) phenyl,
ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms
independently selected from O, S and N,
iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or
iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two
17
heteroatoms independently selected from O, S(0)p and MR and optionally further
incorporating a carbonyl group.
2
In another embodiment, G represents optionally substituted phenyl. In another
o ag oe i^f. 27
embodiment, G represents phenyl substituted by OSO^R ,S(O)SR ,SC>2NR R ,
NR18R19 (wherein at least one of R18 and R19 represents S(O)tR32 or SOZNR3^34) or
39 2 Cl to 3 alkyl substituted by S(>2R - In another embodiment, G represents phenyl
25 25 substituted by S(O)sR andR represents Cl to 6 alkyl or C3 to 6 cycloalkyl and s
represents the integer 2.
2
In another embodiment, G represents an optionally substituted bicyclic ring system in
which each of the two rings is independently selected from:
i) phenyl,
ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms
independently selected from O, S and N,
iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or
iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two
heteroatoms independently selected from O, S(O)p and MR and optionally further
incorporating a carbonyl group;
and the two rings are either fused together, or are bonded directly together or are separated
by a linker group selected from O, S(O)q or CHa.
3 3 1 In one embodiment, Y in formula (I) represents CR and R represents H; R represents
Cl to 6 alkyl; R represents CONR R or optionally substituted Cl to 6 alkoxy or
substituted Cl to 6 alkyl; G represents phenyl; R represents halogen, Cl to 6 alky], CN
4
or Cl to 3 alkyl substituted by one or more F atoms; R represents H; L represents Cl to 6
alkyl; and G represents an optionally substituted monocyclic ring system selected from:
i) phenyl,
ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms
independently selected from 0, S and N,
iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or
iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two
heteroatoms independently selected from O, S(O)p and NR 17 and optionally further
incorporating a carbonyl group.
3 3 1
In one embodiment, Y in formula (I) represents CR andR represents H; R represents
2 48 49
Cl to 6 alkyl; R represents CONR R or optionally substituted Cl to 6 alkoxy or
substituted Cl to 6 alkyl; G represents phenyl; R represents halogen, Cl to 6 alkyl, CN
4
or Cl to 3 alkyl substituted by one or more F atoms; R represents H; L represents Cl to 6
o oo oc *yf\ *yj
alkyl; and G represents phenyl substituted by OSC^R ,S(O)sR ,SC-2NR R ,
NR18R19 (wherein at least one of R18 and R19 represents S(O)tR32 or SO2NR33R34) or
39
Cl to 3 alkyl substituted by S(>2R .
In one embodiment, Y in formula (T) represents CR3 and R3 represents H; R1 represents
2 48 49 methyl; R represents CONR R or optionally substituted Cl to 6 alkoxy or substituted
Cl to 6 alkyl; G1 represents phenyl; R5 represents Cl, CHs, CN or CF3; R4 represents H; L
2 38 25 represents Cl to 6 alkyl; and G represents phenyl substituted by OSC^R ,S(O)SR ,
SO2NR26R27> NRI8R19 (wherein at least one of R18 and R19 represents S(O)tR32 or
Ti 34 39 SO2NR R ) or Cl to 3 alkyl substituted by SO2R .
3 3 1 In one embodiment, Y in formula (I) represents CR and R represents H; R represents
2 48 49 1 5 methyl; R represents CONR R ;G represents phenyl; R represents Cl, CHs, CN or
4 2 CF3; R represents H; L represents Cl to 3 alkyl; and G represents phenyl substituted by
25 25
S(O)SR and R represents Cl to 6 alkyl or C3 to 6 cycloalkyl and s represents the
integer 2.
3 3 1
In one embodiment, Y in formula (I) represents CR andR represents H; R represents
2 1 5
melhyl; R represents optionally substituted Cl to 6 alkoxy; G represents phenyl; R
4 2
represents Cl, CHs, CN or CFa; R represents H; L represents Cl to 3 alkyl; and G
25 25
represents phenyl substituted by S(O)SR and R represents Cl to 6 alkyl or C3 to 6
cycloalkyl and s represents the integer 2.
3 3 I
In one embodiment, Y in formula (I) represents CR andR represents H; R represents
2 1 5
methyl; R represents substituted Cl to 6 alkyl; G represents phenyl; R represents Cl,
4 2
CHs, CN or CFa; R represents H; L represents Cl to 3 alkyl; and G represents phenyl
25 25
substituted by S(O)fiR and R represents Cl to 6 alkyl or C3 to 6 cycloalkyl and s
represents the integer 2.
3 1
In one embodiment, Y in formula (I) represents CR or N; R represents H or Cl to 6 alkyl;
R2 represents CN, NC-2, OH, CC>2R47, CHO, C2 to 6 alkanoyl, Cl to 6 alkoxy, Cl to 6
alkoxy substituted by one or more F atoms, C3 to 6 saturated or partially unsaturated
cycloalkyl, C4 to 7 saturated or partially unsaturated heterocyclic ring containing 1 to 3
62 48 49
heteroatoms independently selected from O, S(O)m and NR ,CONR R ,
CONR5°NHR51, C(=NOR52)R53, NR58R59, C2 to 6 alkenyl or C2 to 6 alkynyl; said
alkenyl or alkynyl group being optionally further substituted by Cl to 6 alkoxy or phenyl
or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms
independently selected from O, S and N; said phenyl or heteroaromatic ring being
2
optionally further substituted by halogen, CN, Cl to 6 alkyl or Cl to 6 alkoxy; or R
represents Cl to 6 alkyl substituted by one or more F atoms; or Cl to 6 alkyl substituted by
58 59
OH, NR R , Cl to 6 alkoxy or Cl to 6 alkoxy substituted by one or more F atoms; or Cl
to 6 alkyl substituted by phenyl or a five- or six-membered heteroaromatic ring containing
1 to 3 heteroatoms independently selected from O, S and N; said phenyl or heteroaromatic
ring being optionally further substituted by halogen, CN, Cl to 6 alkyl or Cl to 6 alkoxy;
48
R represents H, OH, Cl to 6 alkoxy or Cl to 6 alkyl; said alkyl being optionally further
54 55 49
substituted by OH, Cl to 4 alkoxy or NR R ; R represents H or Cl to 6 alkyl; said
54 55
alkyl being optionally further substituted by OH, Cl to 4 alkoxy or NR R ; or the group
48 49
NR R together represents a 5 to 7 membered azacyclic ring optionally incorporating
one further heteroatom selected from O, S and NR ; said azacyclic ring being optionally
57
further substituted by OR or Cl to 4 alkyl; said alkyl being optionally further substituted
by OR ; R and R independently represent H, Cl to 6 alkyl, NR^R * or
CONR R ; or the group NR K. together represents a 5 to 7 membered azacyclic ring
56
optionally incorporating one further beteroatom selected from O, S and NR ; said
57
azacyclic ring being optionally further substituted by OR or Cl to 4 alkyl; said alkyl
57 51
being optionally farther substituted by OR ; R represents C2 to 4 alkanoyl optionally
51 3
further substituted by CN, or R represents C(X)NH2 wherein X represents O or S; R
represents H or F; G represents phenyl or a five- or six-membered heteroaromatic ring
containing 1 to 3 heteroatoms independently selected from O, S and N; R represents H,
halogen, Cl to 6 alkyl, CN, Cl to 6 alkoxy, NO2, NR14R* , Cl to 3 alkyl substituted by
14 15
one or more F atoms or Cl to 3 alkoxy substituted by one or more F atoms; R and R
independently represent H or Cl to 3 alkyl; said alkyl being optionally further substituted
by one or more F atoms; n represents an integer 1,2 or 3 and when n represents 2 or 3,
5 4
each R group is selected independently; R represents H or Cl to 6 alkyl; said alkyl being
4
optionally further substituted by OH or Cl to 6 alkoxy; or R and L are joined together
4
such that the group -NR L represents a 5 to 7 membered azacyclic ring optionally
incorporating one further heteroatom selected from O, S and NR ; L represents a bond, O,
NR2 9 or Cl to 6 alkyl; said alkyl optionally incorporating a heteroatom selected from O, S
11) *? and NR ; and said alkyl being optionally further substituted by OH 01 OMe; G
represents a monocyclic ring system selected from:
i) phenylorphenoxy,
ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms
independently selected from O, S andN,
iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or
iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two
heteroatoms independently selected from O, S(O)p and NR 17and optionally further
incorporating a carbonyl group; or
2
G represents a bicyclic ring system in which each of the two rings is independently
selected from:
i) phenyl,
ii) a S or 6 membered heteroaromatic ring containing one to three heteroatoms
independently selected from O, S and N,
iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or
iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two
heteroatoms independently selected from O, S(O)p and NR 17and optionally further
incorporating a carbonyl group;
and the two rings are either fused together, or are bonded directly together or are separated
by a linker group selected from O, S(O)q or CKfe; said monocyclic or bicyclic ring system
being optionally further substituted by one to three substituents independently selected
18 1Q ^R "?fl from CN, OH, Cl to 6 alkyl, Cl to 6 alkoxy, halogen, NR V , NO2, OS02R , CO2R ,
C(==NH)NH2, C(0)NR21R22, C 26 27 SO2NR R , Cl to 3 alkoxy substituted by one or more F atoms and Cl to 3 alkyl
substituted by SO2R3 9 or by one or more F atoms; or when L does not represent an bond,
2 IS G may also represent H; m, p, q, s and t independently represent an integer 0,1 or 2; R
19 32 and R independently represent H, Cl to 6 alkyl, formyl, C2 to 6 alkanoyl, S(O)tR or
33 SO2NR R 34; said alkyl group being optionally further substituted by halogen, CN, Cl to
4 alkoxy or CONR41R42; R25 represents H, Cl to 6 alkyl or C3 to 6 cycloalkyl; said alkyl
group being optionally further substituted by one or more substituents selected
independently from OH, CN, CONR35R36, CC^R37, OCOR40, C3 to 6 cycloalkyl, a C4 to
7 saturated heterocyclic ring containing one or two heteioatoms independently selected
from O, S(O)p and NR4 3 and phenyl or a 5 or 6 membered heteroaromatic ring containing
one to three heteroatoms independently selected from O, S and N; said aromatic ring being
optionally further substituted by one or more substituents selected independently from
halogen, CN, Cl to 4 alkyl, Cl to 4 alkoxy, OH, CONR^R45, CO2R46, S(O)SR65 and
wy Irt 17 9ft 01
NHCOCH3; R represents H, Cl to 6 alkyl or C3 to 6 cycloalkyl; and R , R , R , R ,
22 23 24 26 27 29 31 33 34 35 36 37 38 39 40 41 42 43
K. , It , JK. ,J\. ,Jx , Jv , K. , ts. , JR. , J\ , K. , JR. , JR. ,Jcv , K. , is. , Jx , tv. ,
independently represent H or Cl to 6 alkyl;
In another aspect, the invention specifically provides any compound as described in the
Examples herein, or the free base thereof or a pharmaceutically acceptable salt thereof.
Particular compounds include:
5-cyancH6-methyl-NH^-(melhylsulfonyl)te^
dihydropyridine-3-carboxamide;
6-methyl-N-[4-(ni«thylsulfcmyl)benzyl]-S-nitro-2-oxo-l-[3-(trifluoroniethyl)phenyl]-l,2-
dihydropyridine-3-carboxamide1,
5-(l-butoxyvinyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l ,2-dihydropyridine-3-carboxamide;
5-acetyl-6-methyl-N-[4-(melhyls!u^^
dihydropyridine-3-carboxamide;
5-[(lE>N-methoxyethaiumidoyl]--6-methyl-N-[4-(methylsulfonyl)benzyl>2-oxo-l-[3-
(trifluoromethyl)phenyl3-l,2-dihydropyridine-3-carboxamide;
5-[(lE)-N-hydroxyethanimidoyl]-6-inelhyl-N-[4-(niethylsulfonyl)benzyl]-2-oxo-l-[3-
(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;
-20 >
6-metbyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-(pyridin-3-ylethynyl)-l-[3-
(trifluoromethyl)phenyl]-l^-dihydropyridine-3-carboxamide;
6-methyl-N-[4-(methylsulfonyl)benzyI]-2-oxo-5-(2-pyridin-3-ylethyl)-l-[3-
(trifluoromethyl)phenyl3-l^-(^ydropyridine-3-carboxainide;
6-methyl-N-[4KmethylsuIfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)pbenyl]-5-vinyl-l,2-
dihydropyridine-3-carboxamide;
ethyl 2-methyl-5-({ [4-(methyIsulfonyl)benzyl]amino }carbonyl)-6-oxo-l-[3-
(trifluoromethyl)phenyl]-l,6-dihydropyridine-3-carboxylate;
5-(4-roethanesulfonyl-benzylcm-bamoyl)-2-methyl-6K)xo-l-(3-trifluoromethyI-phenyl)-l,6-
dihydro-pyridine-3-carboxylic acid;
6-methyl-2-oxo-l-(3-trifluoromethyl-phenyl)-lhydro-pyridine-3>-dicarboxylicadd
5-dimethylamide3-(4-methanesulfonyl-benzyIamide);
6-metbyl-2-oxo-l-(3-trifluoromethyl-phenyl}-l ^-dihydro-pyridine-S^-dicarboxylic acid
5-amide 3-(4-methanesulfonyl-bcnzylamide);
6-methyl-2-oxo-ll,2Kiihydra-pyridine-3,5^carboxylicacid
3-(4-methanesulfonyl-benzylamide)5-inethylamide;
fi-methyl^-oxo-HS-trifluoromethyl-phenyl-dihydro-pyridine-S.S-dicarboxylicacid
5-[(2-hydroxy^thyl)-methyl-amide]3-(4-methanesulfonyl-benzylamide);
6-methy]-2-oxo-l-(3-trifluoKmethyl-phenyl>l,2ihydro-pyridine-3,5-dicarboxylicacid
3-(4-methanesuIfonyl-benzylainide)5-(methyl-propyl-amide);
6-jnethyl-2-oxo-5-(pyrrolidine-l-carbonyl)-l-(3-trifluorometiiyl-phenyl)-l,2-dihydropyridine-
3,5-dicarboxylic acid 3-(4-methanesulfonyl-benzylaniide);
6-nMthyl-2-oxo-l3-lrifluoromethyl-phenyl>l,2-dihydro-pyridine-3,5-dicarboxylicacid
5-K2-dimethylamino^thyl)-methyl-ajnide]3-(4-methanesulfonyl-benzylamide);
5-((2jR)-2-hydroxymethyl-pyrrolidine-larbonyl)-6-methyl-2-oxo-l-(3-trifluoroinethylphenyl)-
l,2-dihydro-pyridine-3-carboxylic acid 3-(4-methanesulfonyl -benzylamide);
5-(3-hydroxy-pyrrolidine-l-carbonyl)-6-methyl-2-oxo-l-(3-trifluoromethyI-phenyl)-l,2-
dihydro-pyridine-3,5-dicarboxylic acid 3-(4-methanesulfonyl-benzylamide);
N3-[(14-dioxido-23-dihydro-l'benzothien-5-yl)methyl]-N5^fs,6-trunethyl-2-oxo-l-[3-
(trifluoromethyl)pbenyl}-l,2-dihydropyridine-3,5-dicarboxamide;
5-(N'-acetyl-hydrazinocarbonyl)-6-methyI-2-oxo-l-(3-trifluoromethyl-phenyl)-l
dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide;
5-(2-cyano-acetyl)-bydrazinocarbonyI]-6-inethyl-2-oxo-l-(3-tiifluoromethyl-phenyl)-
l,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide;
5-{f2-(aniin(x;arbonothioyl)hydrazino]carbonyl}-6-methylW-[4-(methylsalfonyl)benzyl3-
2-oxo-l-[3Ktrifluorome*yI)phenyl]-l^-dihydropyridine-3^arboxarnide;
5-hydrazinocarbonyl^-methyl-2-oxo-l-(3-trifluoromeihy3-phenyl)-l,2-dihydro-pyridine-
3-carboxylic acid 4-methanesulfonyl-benzylamide;
5-({2-[(ethylamino)carbonyI]hydrazino}carbonyl)-6-methyl-Air-[4-(methylsulfonyl)
benzyl]-2^xo-l-[3-(trifluoromethyl)phenyI]-l,2-dihydropyridine-3H:arboxamide;
5-({2-[(NJST-diniethylainino)Garbonyl]hydrazino}carboi)yl)-6-methyl^-[4-
(methylsulfonyl)benzyl]-2-oxo-l-(3-(taifluoromethyl)phetiyl]-l,2-dihydropyridine-3-
carboxamide;
5K33-dimethyI-ureido)-6-i»ethyl-2xc>-l-(3-trifluorQnietfiyl-phenyl)-l,2-dihydropyridfne-
3-carboxylic add 4-jnethanesulfonyl-benzylamide;
6-inethyl-5-(3-jnethy]-uieido)-2-oxo-l-(3-Mfluoromefcyl-phenyl)-l-dihydro-pyridine-3-
carboxylic add 4-methanesulfonyl-benzylamide;
6-methyl-2-oxo-l-(3-triflucffon^hyl-phe3iyl)-5-ureido-l^dihydro-pyridine-3-caiboxyBc
acid 4-methanesulfonyl-benzylamide;
5-anutio-6-methyl-2-oxo-l-(3-trifiuoromethyl-phenyl>l,2-dihydro-pyridine-3-carb^
acid 4-methanesulfonyl-benzylamide;
6-me%l-N-[4-(methylsutfonyl)bera^
l,2-dihydropyridine-3-carboxamide;
5-formyl-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-p-(trifluoromethyl)phenyl]-l,2-
dihydropyiidine-3-carboxamide;
6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-(3-oxobutyl)-l-[3-
(trifluoromethyl)phenyl)-l,2-dihydropyridine-3-carboxamide;
5-acetyl-N-[4-(isopropylsulfonyI)benzyl}-6-methyl-2-oxo-l-[3-(trifluoromethyI)phenyl]-
1,2-dihydropyridine-3-carboxamide;
5-acetyl-l-(3-cyano-phenyl)-6-methyl-2-oxo-l,2-dihydro-pyridine-3-carboxylicacid4-
methanesulfonyl-benzylamide;
5-acetyl-l-(3-chloro-phenyl)-6-methyl-2-oxo-l,2-dihydro-pyridine-3-carboxylic acid 4-
methanesulfonyl-benzylamide;
5-acetyl-6-methyl-2-oxo-l-m-tolyM,2-dihydro-pyridine-3-carboxylic acid 4-
methanesulfonyl-benzylamide;
5-(l-hydroxyethyl)-6-methyl-N-[4-(methylsulfonyl)ben2yl]-2-oxo-l-t3-
(trifluc>romethyI)phenyl>l^-dihydropyridine-3-carboxaniide;
5-(l-azidoethyl)-6-2neftyl-N-[4-(njesdiylsulfonyl)benzyl)-2-oxo-l-[3-
(trifluoromethyl^henyll-l^-dihydropyridine-S-carboxamide;
6-methyI-N-[4-(methylsulfonyI)benzyl]-5-(l-morphoIin-4-ylethyl)-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide;
5-(l-hydroxypropyl)-6-methyI-N-[4-(methylsulfonyl)benzy]]-2-oxo-l-[3-
(trifluc>romethyl)phenyl3-l,2-dihydropyridine-3-carboxamide;
5-(l-hydroxyethyl)-N-[4-(isopropylsulfonyl)benzyl]-6-methyl-2-oxo-l-[3-
(trifluoromethyOphenyll-ljI-dihydropyridine-S-carboxamide;
N-[4-(cycIopropylsulfonyl)beiizyl]-5-formyl-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-Ktihydropyridine-3 5-[(E)-(methoxyimino)methyl]^methyl-N-[4-(mcthylsuIf(Miyl)benzyl]-2-oxo-l-[3-
(trifluorc>methyl)phenyl]4,2^hydix)pyridine-3^arboxaniide;
5-(hydroxymethyI)-^-metfiyl-N-[4-(niethylsuIfonyI)benzyl]-2-oxo-l-[3-
(trifluoromethyl)phcnyl]-l^i-dihydropyridine-3-caiboxamide;
5-[(dime%lanuno)methyl>6-methyl-//-[4-(ittethylsulfonyl)benzyl]-2-oxo-l-[3^
(trifluoromethyl)phenyl]-l,2-dihydropyridine'3-catboxamide;
6-methyl-5-[(methylanuno)me&yl]-A^^^
(trifluoromethyl)phenyl]-l,2-dihydropyridme-3-carboxamide;
6-methyl-[4-(meAyJsulfonyl)benzyl]-5-(morpholin-4-yIraethyl)-2-oxo-l-[3-
(trifluoromethyl)pheny]]-l,2-dihydropyridine-3-carboxamide;
5-{[(2-furylmethyl)aminolmethyl}-6-inethyl-^-[4-(mefliylsu]fonyl)beazyl]-2-oxo-l-[3-
(trifluoromethyl)pheny]]-l,2-dihydropyridine-3-carboxamide;
5-[(cyclopropylamino)niethyl3-6-raethyl-A^-[4-(methyJsulfoiiyl)benzyl]-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide;
5-{[(2-hydroxypropyJ)amino]inethyl}-6-methyl--Ar-[4-(methyIsuIfonyl)benzyl]-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dJhydropyridine-3-carboxamide;
5-[(cyc]opentyIanadno)methyl]-6-methyI-^-[4-(methylsulfonyl)benzyI3-2-oxo-l-[3-
(trifiue)roinethyl)phenyl]-l,2-dihydropyridijie-3-carboxamide;
5-{[(2-hydroxyethyl)(methyl)amino]methyl}-6-methyl-/^~[4-(methylsulfonyl)benzyl]-2-
oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide;
6-methyl-[4-(methylsulfonyl)beai2yl3-2-oxo-5-(pyrroKdin-l-ylmethyl)-l-[3-
(trifluoromethyl)phenyl]-l^-dihydropyridine-3-carboxamide;
5-{ [methoxy(methyl)amino]methyl} -6-methyl-N-[4-(methylsulfonyl)benzyI]-2-oxo-l-[3-
(trifluQromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide;
5- {[(cyanomethyl)amino]methyl }-6-methyl-^-[4-(methylsulfonyl)benzyl]-2-oxo-l -[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide;
5-{[(cyclopropylmethyl)airano]methyl}-6^^
[3-(trifluoromeliiy])phenyl]-l,2-dihydropyridine-3-carboxamide;
5-[(3rhydroxypyiroKdin-l-yI)methyl]-6-methyI-JV-[4^methylsulfonyI)benzyl]-2-oxo-l-[3-
(trilfluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide;
5-(2-hydroxyethoxy)-N-[4-(isopropylsulfonyl)benzyl]-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l -dihydropyridine-3-carboxamide;
2-methyl-5 (trifluoromethyl)phenyl]-l ,6-dihydropyridin-3-yl acetate;
5-methoxy-6-methyl-^-[4-(methyIsidfonyl)ben2yl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-
l,2-dihydropyridine-3-carboxainide;
5-(3-methoxypropoxy)-6-methyl-N-[4-(methylsulfonyl)benzyl3-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide;
2-methyl-5-({[4-(methylsulfonyl)benzyI]arnino}carbonyl)-6-oxo-l-[3-
(trifluoromethyl)phenyl]-l ,6-dihydropyridin-3-y] methanesulfonate;
5-ethoxy-6-methyl-N-[4-(methyisulfonyl)benzyl]-2-oxo-l-[3-(trifluoioinethyl)phenyl]-l,2-
dihydrc^>yridine-3-carboxamide;
S-(2-hydroxyethoxy)-6-methyl-N-[4-(methylsulfonyl)ben2yl]-2-oxo-l-[3-
(trifluoromethyl)pheny]]-l^-dihydropyridine-3-carboxamide;
5-(cyanomethoxy)-6-methyl-N-[4-(methylsulfonyI)benzyl]-2-oxo-l-[3-
(tiifluoromethyl)phenyIJ-l,2-dihydropyridine-3-carboxamide;
2-({ 2-methyI-5-({ [4-(methylsuIfonyl)benzyl]amino }carbonyl)-6-oxo-1 -[3-
(trifluoromethyl)phenyl]-l,6-dihydropyridin-3-yl }oxy)ethyl acetate;
5-[2-(dimetfaylamino)-2-oxoethoxy]-6-ineAyl-N-[4-(jnethyIsulfonyl)beiizyl]-2-oxo-l-[3-
(triflooromethyl)phenyl]-l,2-dihydropyridme-3-carboxamide;
5-(2-aminoethoxy)-N-[4-(isopropylsulfonyl)benzyl]-6-niethyl-2-oxo-l-[3-
(trifluorometiiy])phenyl]-l,2-dihydropyridine-3-catboxainide;
5-(acetylamino)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-
(trifluaromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide;
JV-[4-(isopropyIsulfonyi)benzyl]^nwthyl-5-[3^methylaraino)propoxy]-2-oxo-l-[3-
(trifluoromethyl)phenyI]-l^-dihydropyridine-3-carboxainide;
5-(l-methoxyethyl)-6-methyl-AT-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-
(trifluoroinethyl)phenyl3-l,2-dihydropyridine-3-carboxamide;
5-(2-bromo-l-methoxyethyl6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-
(trifiuoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide;
5-(l-isopropoxyethyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l-dihydropyridine-3-carboxamide;
5-(N1-isobutyryl-hydrazinocaibonyl)-6-methyl-2-oxo-l-(3-trifluoromethyl-phenyl>l)2-
dihydro-pyridine-3-carboxyJic acid 4-methanesulfonyl-benzylamide;
JVy-methoxy-6-methyl-JVa-[4-(methylsulfonyl)benzyl^2-oxo-l-[3-(trifluoromeAyl)phenyy
1,2-dihydropyridine-35-dicarboxanjide;
AT5-methoxy-A^t6-diinethyl--[4-l-[3-
(trifluQromethyl)phenyl]-l,2-dihydropyridii»e-3,5-dicarboxaraide;
5-[(2,5-dimethyI-2,5-dihydro-lH-pyrrol-l-yI)carbonyl]-6-methyl-N-[4-
(rae%lsulfonyl)benzyl]-2-oxo-l-[3-(trifluorotaethyl)phenyl]-l,2-^hydropyridine-3-
carboxamide;
6-methyl-[4-(methy]sulfonyl)benzyl]-2xo-/^-pynx)lidin-l-yl-l-[3-
(trifluoromethyl)phenyl]-l ,2-dihydropyridine-3,5-dicarboxamide;
6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-(piperidin-l-ylcaibonyl)-l-[3-
(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;
6-methyl-//3-[4-(methylsulfonyl)benzyl]-A^5-morpholin-4-yl-2-oxo-l-[3-
(trifluoromethyl)phenyI]-l,2-dihydropyridine-3,5-dicarboxamide;
6-methyl-5-[(4-methylpiperidin-l-yl)catbonyl]-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-
(trifluoromethyl)phenyl)-l ,2-dihydropyridine-3-carboxamide;
6-raethyl-A^-[4-(methy]sulfonyl)benzyl]-2-oxo-^Vs-piperidm-l-yl-l-[3-
(trifluoromethyl)phenyl]-l12-dihydropyridine-3,5-dicarboxamide;
25 i
JV5-(tert-butyI)-//,6-dimethyl-JV?-[4-(methylsuIfonyl)benzyI]-2-oxo-l-[3-
(trifluoroniethyl)phenylH ,2-dihydropyridine-3 ,5-dicarboxamide;
(ttifluororaethyl)phenyl]-l,2-dihydropyridine-3,5-dicarboxamide;
^-ethyl-A^-isopropyl-6-methyl-JVJ-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-
(trifluoromethyl)phenyl]- 1 ,2-dihydropyridine-3,5-dicarboxamide;
5-[N1-(fotmyl-hydrazinocarbonyl]-6-methyl-2-oxo-l-(3-trifluoromethyl-phenyl)-l,2-
dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide;
N1-[5-(4-methanesuIfonyl-benzylcarbamoyl)-2-methyl-6-oxo-l-(3-trifluoromethylphenyl)-
l,6-dihydro-pyridine-3-carbonyl]-hydrazinecarboxylic acid ethyl ester,
5-({2-[(ethylamino)carbonothioyl]hydrazmo}carbonyI)-6-methyl-^-[4-
(methylsulfonyl)ben2yl]-2K>xo-l-[3 carboxamide;
5-(isoxazolidin-2-ylcai^ony])-6-methyl-^-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l^-dihydropyridine-3-carboxaraide;
6-methyl-2-oxo-l-(3-trifIuoromethyl-phenyl)-l^^ihydro-pyridine-3^5-dicarboxy]ic acid
5-(methoxy-methyl-amide)3-[4-(propane-2-suIfcjnyl>benzylamide];
6-methyl-2-oxo-l-(3-trifluoromethyl-phenyl)4,2-dihydro-pyridine-3,5-dicarboxylicacid
3-(4-ethanesulfonyl-benzylaraide)5-(methoxy-methyl-ainide);
6-methyl-2-oxo-l-(3-trifluc>romethyl-phenyl)-l,2-dihydK)-pyridine-3,5-dicarboxyKcacid3-
(4-cyclopropanesulfonyl-beuzylamide)5-(methoxy-inethyl-amide);
6-methyl-2-oxo-l-(3-trifluoromethyl-phenyl)-l,2-dihydro-pyridine-3,5-dicaiboxyHcacid
5-[(2-hydroxy-ethyl)-amide]3-(4-methanesulfonyl-benzylamide;
5-(isoxazolidine-2-catbonyl>6-methyl-2-oxo-l-(3-trifluoromethyl-phenyl)l,2dihydropyridine-
3-carboxylic acid 4-ethanesulfonyl-benzylamide;
5-(isoxazolidine-2-carbonyl)-6-methyl-2-oxo-l-(3-trifluoromethylphenyl)
ldihydropyridine-S-carboxylic acid 4-cyclopropanesulfonylbenzyIamide;
5-{N-hydroxycaTbamirnidoyI)-6-methyl-2-oxo-l-(3-trifluoromethyl-phenyl)-l,2-dihydropyridine-
3-carboxylic acid 4-methanesulfonyl-benzylamide;
W3-(cyclohexy]methyI)-V5,Ar5,6-trimethyl-2-oxo- 1- [3-(trifluoromethyl)phenyI]-l ,2-
dihydropyridine-3^5-dicarboxamide;
5,6-trimethyi-2-oxo-(pyridin-3-ylraethyl)-l-[3-(trifluoromethyl>phenyl]-l,2
dihydropyridine-3,5-dicarboxamide;
AV,6-trimethyl-#3-(2-moiphoUn-4^
dihydropyridine-3,5-dicaiboxamide;
AJ-trimethyl-JVS-morphoUn^
dihydropyridine-3,5-dicarboxamide;
JVenzyl-A^JV^e-trinMthyW-o^
3,5-dicarboxamide;
JlHndol-S-ylJethy^AA-to
dihydropyridine-3,5-dicarboxamide;
dihydropyridine-3,5-dicarboxanride;
dihydTOpyridine-3,5-dicarboxamide;
J-trimethyl-aKao-A-Ka)-
l,2-dihydropyridine-3^-dicarboxamide;
l,2-dihydropyridine-3,5-dicarboxaraide;
methyl)phenyl]-l,2-dihydropyridine-3,5-dicarboxainide;
5-{[4-(2-hydroxyethyl)piperazin-l-yl]carbonyI}-/7,W,2-trimethyl-6-oxo-l-[3-
(trifluoromethyl)phenyl]"l,6-dihydropyridine-3-carboxaniide;
methyl)phenyl]-l,2-dihydropyridine-3^-dicarboxamide;
Ad-trimethyl-A-IS--me
methyl)pbenyl]-l,2-dihydropyridine-3,5-dicarboxamide;
N5,6-trimethyl-/V3-(l-naphthylmethyl)-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-
dihydropyridine-3 ,5-dicarboxamide;
#3-(13-benzodioxol-5-ylmethyl)-AfX.6-
l,2-dihydropyridine-3,5-dicarboxamide;
^r3K3,4^fluo^obenzyl)-JV5,W^^6-tlimethyl-2-oxo-l-[3-(trifluoroInethyl)phenyl]-l)2-
dihydropyridine-3,5-dicarboxainide;
fc
N3K2-chloro4-fluorobenzyl)-A/5
>6-trimethyl-2-oxo-l-[3-(trifluoromethyl)-phenyl]
dihydropyridine-3,5-dicarboxamide;
Ve-trimethyW-oxo-jN^t^
dihydropyridine-3,5-dicarboxanHde;
dihydropyridine-3,5-dicarboxainide;
1 ,2-dihydropyridine-3,5-dicarboxamide;
3-(2yclohex-ln-l-ylethyl)-,6-trimethy]-2-oxo-l-[3-(trifluoromethyl)-phenyl]-
1 ,2-dihydropyridine-3,5-dicarboxamide;
^r3-[^(4-cWorophenyl)ethyI]-/^^,6-trimethyl-2-oxo-l-[3 dihydropyridine-3,5-dicarboxarmde;
methyl)phenyl3-l^Z-dihydropyridiiie-3,5HdicaiboxainJde;
/^^^-trimethyl^^xo-^^pyridin^ylmethylVl-^trifluoromethyl^he
dihydropyridine-3,5-dicarboxamide;
/^^,2-trimethyl-6-oxo-5-[(4-pheny]piperazin-l-yJ)carbonyl]-l-[3-(trifliioromethyl)
phenyl]-l,6-dihydropyriduie-3-caiboxamide;
/ir^,2-triraethyl-6-oxo-5-[(4-pyridin-2-ylpipera2dn-l-yl)carbonyl]-l-[3-(trifluoromethyl)
phenyl]-l,6-dihydropyridine-3-carboxamide;
(trifluorojnethyl)phenyl3-l,2-dihydropyridine-3t5-dicarboxamide;
methyl 4-{ [({5-[(dimethylamino)carbonyl]-6-methy!-2-oxo-l-[3-(trifluoromethyl)
phenyl]-l ^-dihydropyridin-3-yl }carbonyl)amino]methyl}benzoate;
5-{ [3-(dimethylamino)pynx>lidin-l-yl]carbonyl }-AW2-trimethyl-6-oxo-l-[3-
(trifluoromethyl)phenyl3-l,6-dihydropyridrae-3-carboxamide;
JV5^,6-triinethyl-2-oxo-3-[2-(2-thienyl)ethyl]-l-[3-(trifluoromethyl)phenyl3-tf2-
dihydropyridine-3,5-dicarboxamide;
5,6-triTnethyI-2-oxo-N3-(4-phenoxyben2yl)-l-[3-(trifluoromethyl)phenyl]-l,2-
dihydropyridine-3,5-dicarboxamide;
dihydropyridine-3,5-dicarboxamide;
28 ^
l,2-dihydropyridine-3,5-dicarboxainide;
^3-{2-[4-(aminosuIfonyI)phenyI]ethyl}-JVs^5,6-trimethyl-2-oxo-I-[3-(trifluoromethyl)
phenyl]-l,2-dihydropyridine-3,5-dicarboxamide;
l,2-dihydr(^)yridine-3,5-dicarboxainide;
/^^,6-trimethyl-2-oxo-A^-phenoxy-l-[3-(trifluoromethyl)phenyl]-J,2-dihydro-pyridin
3,5-dicarboxaraide;
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3,5-dicarboxamide;
JV3-[(6-fluoro-4/?-l,3-benzodioxin-8-yl)methylJ-^5^V5
t6-trimethyl-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3,5-dicarboxamide;
//l-(l-benzothien-3-ylmethyl>Vi^,6-trimethyI-2^xo-l-[3-(trifluoromethyI>phenyl]-
dihydropyridine-3,5-dicarboxamide;
methyl)phenyl]-l,2-dihydropyridine-3,5-dicarboxamide;
^^^Mmethyl-^-tCl-methyl-l^pyrazoW-ylJmethyl
methyl)phenyl]-l,2-dihydropyridine-3,5-dicari)oxamide;
^X.S-triinethyl^^xo-^-Kl-phenyl-L^-pyrazol-^ylJ
methyl)phenyl]-l,2-dihydropyridine-3,5-dicarboxamide;
^
(trifluororaethyl)phenyi]-l,2-dihydropyridine-3^-dicarboxamide;
A/3-(3-azepan-l-ylpropyI)-//5,A^,6-trimethyl-2^xo-l-[3^trifluoromethyl)phenyl]-l,2-
dihydropyridine-3,5-dicarboxamide;
Ar3-(4.cyanobenzyl)-A^,Afs,6-trimethyl-2-oxo-l-[3-(trifluoromethyl)phenyl3-l,2-
dihydropyridine-3,5-dicarboxamide;
A^^^^6-tri^lethyl-2-oxo-/^^3-[3-(5-oxo-4,5-dihydro-lJ¥-pyrazol-4-yI)prQpyl]-l-[3-
(trifluoromethyDphenyll-l^-dihydi'opyridine-S.S-dicarboxamide;
A^3-{[(2/?)4-ethylpyrroUdin-2-yl]methyl}-^5^,6-trimethyl-2-oxo-l-[3-(trifIuoromethyl)
phenyl]-l,2-dihydropyridine-3,5-dicarboxamid6;
5-cyclopropyl-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-
(trifluoroniethyl)phenyl]-l,2-djhydropyridine-3-carboxamide;
6-methyl-5-(2-methyl-l,3-dioxolan-2-yl>N-[4-(methylsulfonyI)benzyl]-2-oxo-l-j;3-
(trifluoromethyl)phenyl3-lt2-dihydropyridine-3-caiboxamide;
5-(4^-dihydro-oxazol-2-yl)-6-methyl-2-oxo-H3-trifluoromethyl-phenyl)-l,2-dihydropyridme-
3-carboxylic acid 4-methanesulfonyl-benzylaroide;
5^yclopropyl-6-methyl-N-{[5-(niethylsuIfonyl)pyridin-2-yl]methyl}-2-ox(>-l-[3-
and pharmaceutically acceptable salts thereof.
The present invention includes compounds of formula 0) in the form of salts, in particular
acid addition salts. Suitable salts include those formed with both organic and inorganic
acids. Such acid addition salts will normally be pharmaceutically acceptable although salts
of non-pharmaceutically acceptable acids may be of utility in the preparation and
purification of the compound in question. Thus, preferred salts include those formed from
hydrochloric, hydrobromic, sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic,
succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids.
In a further aspect the invention provides a process for the preparation of a compound of
formula (I) which comprises:
a) reacting a compound of formula OB)
2
with a nucleophilic equivalent of R , such as Cu(I)CN, an alkyl vinyl ether, an organo-tin
compound, an organo boronic acid, a terminal alkyne or an alcohol and carbon monoxide;
1 *) A. *\ 1 0
whereinR ,R ,R ,R , Y,G ,G , L and n are as defined in formula (I) and Hal
represents a halogen atom, preferably bromo or iodo; or
b) reacting a compound of formula (XV)
(XV)
wherein R ,R ,R ,n, G and Y are as defined in formula (I) and L represents a leaving
group,
with a compound of formula (DC) or a salt thereof
R4
(IX)
whereinR4 , G2 and L are as defined in formula (I);
and where desired or necessary converting the resultant compound of formula (I), or another
salt thereof, into a pharmaceutically acceptable salt thereof; or converting one compound of
formula (I) into another compound of formula CD; and where desired converting the resultant
compound of formula (I) into an optical isomer thereof.
In process (a), the reaction is carried out at a suitable temperature, generally between 50 °C
and 150 °C, in a suitable solvent such as toluene or N,N-dimethylformamide in the
presence of a transition metal catalyst such as palladium or in the presence of a base such
as potassium carbonate.
In process (b), the reaction is carried out at a suitable temperature, generally between 0 °C
and the boiling point of the solvent, in a suitable solvent such as dichloromethane or
N-methylpyrrolidinone. The process is optionally carried out in the presence of a base
and/or a coupling reagent such as HATU, HO AT, HOBT or DEEA. Suitable leaving groups
L include OH and halogen.
The man sldlled in the art will readily appreciate that many compounds of formula (I) may
also be prepared by processes in which the final step or steps involve functional group
2
interchanges within the substituent R . Some such processes are detailed below. Other
specific examples of such processes are described in the Examples section of this
specification. All such processes form another aspect of the present invention.
Compounds of formula (I) wherein R2 represents CONR^R49 or CONR5°NR48R49 can
be prepared by reacting a compound of formula (IH)
L-G2
(III)
wherein R , R , R , Y , Q , G , L and n are as defined in formula (I);
48 49 50 48 49 with an amine of the general formula NHR R orNHR NR R .
The process is carried out at a suitable temperature, generally between 0 °C and 50 °C in a
suitable solvent such as 1,4-dioxane.
Compounds of formula (ID) can be prepared by reacting a compound of formula (IV)
(IV)
wherein R , R , R , Y, G , G ,L and n are as defined in formula (I) and R represents an
alkyl group;
with an aqueous base such as sodium hydroxide followed by subsequent treatment of the
product with a chlorinating agent such as thionyl chloride. The process is carried out at a
suitable temperature, generally between 10 °C and 50 °C in a suitable solvent such as
tetrahydrofuran or dichloromethane.
Compounds of formula (I) wherein R is defined as NRHI can be prepared by reacting
a compound of formula (V):
.33- £H
(V)
wherein R , R , R , Y , G , G , L and n are as defined in formula (I);
with an aqueous acid or an alkylamine. The process is carried out at a suitable temperature,
generally between 50 °C and 150 °C in a suitable solvent such as toluene. The aqueous
acid or alkylamine is added after heating for a time period of, typically between 0.5 and 16
hours.
Compounds of formula (V) can be prepared by reacting a compound of formula (TV)
wherein R is hydrogen with diphenylphosphoryl azide. The process is carried out at a
suitable temperature, generally between 0 °C and 50 °C in a suitable solvent such as
dichloromethane.
Compounds of formula (IV) can be prepared by reacting a compound of formula (II)
with carbon monoxide in the presence of an alcohol such as methanol or ethanol. The
process is carried out at a suitable temperature, generally between 50 °C and 150 °C in a
suitable solvent in a suitable solvent such as methanol or ethanol in a carbon monoxide
atmosphere at elevated pressure, generally between 2 and 10 atmospheres. The reaction is
performed in the presence of a transition metal catalyst such as palladium.
2
Compounds of formula (I) wherein R is C2 to 6 alkanoyl can be prepared by reacting a
compound of formula (VI);
34 &
RO
R
(VI)
whereinR ,R ,R ,Y,G ,G , L and n are as defined in formula (I) and R is an alkyl
group;
with an aqueous base.
The process is carried out at a suitable temperature, generally between 10 °C and 50 °C in
a suitable solvent such as N,N-dimethylformamide.
Compounds of formula (VI) can be prepared by reacting a compound of formula (IT) with
an alkyl vinyl ether. The process is carried out at a suitable temperature, generally between
50 °C and 150 °C in a suitable solvent such as toluene or N,N-dirnethylformamide in the
presence of a transition metal catalyst such as palladium.
2 52, 53 Compounds of formula (I) wherein R isC(=NOR jR can be prepared by reacting a
2
compound of formula (I) wherein R is C2 to 6 alkanoyl with an alkoxyamine or
hydroxylamine. The process is carried out at a suitable temperature, generally between 50
°C and 150 °C in a suitable solvent such as orN,N-dimethylforniamide.
2
Compounds of formula (I) wherein R is CN can be prepared by reacting a compound of
formula (H) with copper(I) cyanide. The process is carried out at a suitable temperature,
generally between 100 °C and 150 °C in a suitable solvent in a suitable solvent such as 1-
methyl-2-pyrrolidone.
2
Compounds of formula (I) wherein R is NQj can be prepared by reacting a compound of
formula (VII) with a nitrating agent such as nitric acid. The process is carried out at a
suitable temperature, generally between 10 °C and 50 °C in a suitable solvent in a suitable
solvent such as acetic anhydride.
Compounds of formula (IE) can be prepared by reacting a compound of formula (VII)
(VII)
wherein R , R , R , Y , G , G , L and n are as defined in formula (I);
with a halogenating agent, such as N-iodosuccinimide in the presence of a strong acid such
as trifluoromethanesulfonic acid.
The process is carried out at a suitable temperature, generally between 0 °C and 50 °C in a
suitable solvent such as acetonitrile in the presence of an acid such as
trifluoromethanesulfonic acid.
Compounds of formula (VII) can be prepared by reacting a compound of formula (VIQ)
wherein R , R , Y, G and n are as defined in formula (I) and L represents a leaving
group, with an amine of formula (DC) or a salt thereof
R4
(IX)
,4 Ji wherein R , G and L are as defined in formula (I).
The process is carried out at a suitable temperature, generally between 0 °C and the boiling
point of the solvent, in a suitable solvent such as dichloromethane or
N-methylpyrrolidinone. The process is optionally carried out in the presence of a base
and/or a coupling reagent such as HATU, HOAT, HOST or DIEA. Suitable leaving groups
L include OH and halogen.
3 1 3 Compounds of formula (VHD wherein Y is CR , L is OH and R is hydrogen can be
prepared by condensing a compound of formula (X)
(X)
wherein R is as defined in formula (I), with a compound of f onnula (XI)
(XI)
wherein G , R and n ate as defined in formula (I), in the presence of a suitable base, such
as sodium methoxide, in a suitable solvent, such as ethanol, followed by hydrolysis using a
suitable base such as sodium hydroxide.
In general, compounds of formulae (X) and (XI) are either known or may be prepared
using methods that will be readily apparent to the man skilled in the art. For example,
compounds of formula (X) can be prepared according to the methods of S,M Brombridge
et al., Syntiietic Communications, 1993,23,487-494. And compounds of formula (XI) can
be prepared according to the methods of Igor V. Ukrainets et al., Tetraliedron, 1994,50,
10331-10338.
3 1 1
Compounds of formula (VIH) wherein Y is CR , L is OH and R is hydrogen can be
prepared by reacting a compound of formula (XII)
NH°
(XII)
wherein G , R and n are as defined in formula fl), with a compound of formula (Xffl)
(XIII)
3
wherein R is as defined in formula CD, at a suitable temperature, such as 160 °C> followed
by base promoted cyclisation and acid hydrolysis. Compounds of formula (XHL) can be
prepared according to US 3,838,155.
Compounds of formula (VIE) wherein Y is CR3 , L is1 OH, R1 is methyl and R3 is
hydrogen can be prepared by condensing a compound of formula CXIV)
(R5)n H
(XIV)
wherein G , R and n are as defined in formula (I), with 4-methoxy-3-buten-2-one in the
presence of a suitable base, such as l,4-diazabicyclo[2.2.2}octane, at a suitable temperature
in a suitable solvent such as diethyleneglycol monomethy] ether, followed by acid
hydrolysis.
Salts of compounds of formula (I) may be formed by reacting the free base or a salt,
enantiomer, tautomer or protected derivative thereof, with one or more equivalents of the
appropriate acid. The reaction may be carried out in a solvent or medium in which the salt
is insoluble, or in a solvent in which the salt is soluble followed by subsequent removal of
the solvent in vacuo or by freeze drying. Suitable solvents include, for example, water,
dioxane, ethanol, 2-propanol, tetrahydrofuran or diethyl ether, or mixtures thereof. The
reaction may be a metathetical process or it may be carried out on an ion exchange resin.
Compounds of formula (I) and intermediate compounds thereto may be prepared as such or
in protected form. The protection and deprotection of functional groups is, for example,
described in 'Protective Groups in Organic Chemistry', edited by J. W. F. McOmie,
Plenum Press (1973), and 'Protective Groups in Organic Synthesis', 3rd edition, T. W.
Greene & P. G. M. Wuts, Wiley-Interscience (1999).
The compounds of the invention and intermediates may be isolated from their reaction
mixtures, and if necessary further purified, by using standard techniques.
The compounds of formula (I) may exist in enantiomeric or diastereoisomeric forms or
mixtures thereof, all of which are included within the scope of the invention. The various
optical isomers may be isolated by separation of a racemic mixture of the compounds using
conventional techniques, for example, fractional crystallisation or HPLC. Alternatively, the
individual enantiomers may be made by reaction of the appropriate optically active starting
materials under reaction conditions that will not cause racemisation.
Intermediate compounds may also exist in enantiomeric forms and may be used as purified
enantiomers, diastereomers, racemates or mixtures thereof.
40
According to a further aspect of the invention we provide 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, ate useful because
they possess pharmacological activity in animals. The compounds of formula (I) have
activity as pharmaceuticals, in particular as modulators of human neutrophil elastase and
homologous serine proteases such as proteinase 3 and pancreatic elastase, and as such are
predicted to be useful in therapy. The compounds of formula (I) are particularly useful as
inhibitors of human neutrophil elastase. They may thus be used in the treatment or
prophylaxis of inflammatory diseases and conditions.
Examples of these conditions are: adult respiratory distress syndrome CARDS), cystic
fibrosis, pulmonary emphysema, chronic obstructive pulmonary disease (COPD) and
ischaemic-reperfusion injury. The compounds of this invention may also be useful in the
modulation of endogenous and/or exogenous biological irritants which cause and/or
propagate atherosclerosis, diabetes, myocardial infarction; hepatic disorders including but
not limited to cirrhosis, systemic lupus erythematous, inflammatory disease of lymphoid
origin, including but not limited to T lymphocytes, B lymphocytes, thymocytes;
autoimmune diseases, bone marrow; inflammation of the joint (especially rheumatoid
arthritis, osteoarthritis and gout); inflammation of the gastrointestinal tract (especially
inflammatory bowel disease, ulcerative colitis, pancreatitis and gastritis); inflammation of
the skin (especially psoriasis, eczema, dermatitis); in tumour metastasis or invasion; in
disease associated with uncontrolled degradation of the extracellular matrix such as
osteoarthritis; in bone resorptive disease (such as osteoporosis and Paget's disease);
diseases associated with aberrant angiogenesis; the enhanced collagen remodelling
associated with diabetes, periodontal disease (such as gingivitis), cornea! ulceration,
ulceration of the skin, post-operative conditions (such as colonic anastomosis) and dermal
wound healing; demyelinating diseases of the central and peripheral nervous systems (such
as multiple sclerosis); age related illness such as dementia, inflammatory diseases of
cardiovascular origins; granulomatous diseases; renal diseases including but not limited to
nephritis and polyarteritis; cancer; pulmonary hypertension, ingested poisons, skin
contacts, stings, bites; asthma; rhinitis; HTV disease progression; for minimising the effects
-41
of organ rejection in organ transplantation including but not limited to human organs; and
replacement therapy of proteinase inhibitors.
Thus, another aspect of the invention provides the use of a compound of formula (I) or a
pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the
treatment or prophylaxis of diseases or conditions in which inhibition of neutrophil elastase
activity is beneficial; 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 a compound of formula (I) or a pharmaceutically
acceptable salt thereof.
In another aspect, the invention provides the use of a compound of formula (I) or a
pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the
treatment or prophylaxis 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 a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In particular, the compounds of this invention may 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
gastric mucosal injury.
Prophylaxis is expected to be particularly relevant to the treatment of persons who have
suffered a previous episode of, or are otherwise considered to be at increased risk of, the
disease or condition in question. Persons at risk of developing a particular disease or
condition generally include those having a family history of the disease or condition, or
those who have been identified by genetic testing or screening to be particularly
susceptible to developing the disease or condition.
For the above mentioned therapeutic indications, the dose of the compound to be
administered will depend on the compound employed, the disease being treated, the mode
of administration, the age, weight and sex of the patient. Such factors may be determined
by the attending physician. However, in general, satisfactory results are obtained when the
compounds are administered to a human at a daily dosage of between 0.1 mg/kg to 100
mg/kg (measured as the active ingredient).
The compounds of formula (I) may be used on their own, or in the form of appropriate
pharmaceutical formulations comprising the compound of the invention in combination
with a pharmaceutically acceptable diluent, adjuvant or carrier. Particularly preferred are
compositions not containing material capable of causing an adverse reaction, for example,
an allergic reaction. Conventional procedures for the selection and preparation of suitable
pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science
of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
According to the invention, there is provided a pharmaceutical formulation comprising
preferably less than 95% by weight and more preferably less than 50% by weight of a
compound of formula (I) hi admixture with a pharmaceutically acceptable diluent or
carrier.
We also provide a method of preparation of such pharmaceutical formulations that
comprises mixing the ingredients.
The compounds may be administered topically, for example, to the lungs and/or the
airways, in the form of solutions, suspensions, HFA aerosols or dry powder formulations,
for example, formulations in the inhaler device known as the Turbuhaler®; or systemically,
for example, by oral administration in the form of tablets, pills, capsules, syrups, powders
or granules; or by parenteral administration, for example, in the form of sterile parenteral
M'-l
solutions or suspensions; or by rectal administration, for example, in the form of
suppositories.
Dry powder formulations and pressurized HFA aerosols of the compounds of the invention
may be administered by oral or nasal inhalation. For inhalation, the compound is desirably
finely divided. The finely divided compound preferably has a mass median diameter of less
than 10 pan, and may be suspended in a propellent mixture with the assistance of a
dispersant, such as a Cg-Cao fatty acid or salt thereof, (for example, oleic acid), a bile salt, a
phospholipid, an alkyl saccharide, aperfluorinated or polyethoxylated surfactant, or other
phannaceutically acceptable dispersant
The compounds of the invention may also be administered by means of a dry powder
inhaler. The inhaler may be a single or a multi dose inhaler, and may be a breath actuated
dry powder inhaler.
One possibility is to mix the finely divided compound with a carrier substance, for
example, a mono-, di- or polysaccharide, a sugar alcohol, or an other poiyol. Suitable
carriers are sugars, for example, lactose, glucose, raffinose, melezitose, lactitol, maltitol,
trehalose, sucrose, mannitol; and starch. Alternatively the finely divided compound may be
coated by another substance. The powder mixture may also be dispensed into hard gelatine
capsules, each containing the desired dose of the active compound.
Another possibility is to process the finely divided powder into spheres which break up
during the inhalation procedure. This spheronized powder may be filled into the drug
reservoir of a multidose inhaler, for example, that known as the Turbuhaler® in which a
dosing unit meters the desired dose which is then inhaled by the patient. With this system
the active compound, with or without a carrier substance, is delivered to the patient
For oral administration the active compound may be admixed with an adjuvant or a carrier,
for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch,
corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or
polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium
stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into
tablets. If coated tablets are required, the cores, prepared as described above, may be
coated with a concentrated sugar solution which may contain, for example, gum arabic,
gelatine, talcum, titanium dioxide, and the like. Alternatively, the tablet may be coated
with a suitable polymer dissolved in a readily volatile organic solvent.
For the preparation of soft gelatine capsules, the compound may be admixed with, for
example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain
granules of the compound using either the above mentioned excipients for tablets. Also
liquid or semisolid formulations of the drug may be filled into hard gelatine capsules.
Liquid preparations for oral application may be in the form of syrups or suspensions, for
example, solutions containing the compound, the balance being sugar and a mixture of
ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may
contain colouring agents, flavouring agents, sacchanne and/or carboxymethylcellulose as a
thickening agent or other excipients known to those skilled in art.
The compounds of the invention may also be administered in conjunction with other
compounds used for the treatment of the above conditions.
The following Examples are intended to illustrate, but in no way limit the scope of the
invention.
General Methods
3H NMR and 13C NMR spectra were recorded on a Varian Inava 400 MHz or a Varian
Mercury-VX 300 MHz instrument. The central peaks of chloroform-^ (OH 7.27 ppm),
diraethylsuIfoxide-& (6n 2.50 ppm), acetonitrile-ffe (OH 1.95 ppm) or methanol- (8n 331.
ppm) were used as internal references. Column chromatography was carried out using
/5'fC
silica gel (0.040-0.063 mm, Meick). Unless stated otherwise, starting materials were
commercially available. All solvents and commercial reagents were of laboratory grade
and were used as received.
The following abbreviations are used:
HBTU O-(Benzotria2ol-l-yl)-N,N,N/JK/-tetramethyluronium hexafluorophosphate;
HATU O-CT-Azabenzotriazol-l-yO-NJN'X-tetramethyluronium hexafluorophosphate;
HOBT 1-Hydroxybenzotriazole;
HOAT l-Hydroxy-7-azabenzotriazole;
DIEA N,N-Diisopropylethylamine;
NMP l-N-Methyl-2-pyrrolidinone;
DME 1,2-Dimethoxyethane;
THF Tetrahydrofuran;
TFA Trifluoroacetic acid;
DMF N,N-Dimethylfonnamide;
DCM Dichloromethane.
The following method was used for LC/MS analysis:
Instrument Agilent 1100; Column Waters Symmetry 2.1 x 30 mm; Mass APCI; Flow rate
0.7 ml/min; Wavelength 254 nm; Solvent A: water + 0.1% TFA; Solvent B: acetonitrile +
0.1% TFA; Gradient 15-95%/B 8 min, 95% B 1 min.
Analytical chromatography was run on a Symmetry Cig-column, 2.1 x 30 mm with 3.5 fim
particle size, with acetonitrile/water/0.1% trifluoroacetic acid as mobile phase in a gradient
from 5% to 95% acetonitrile over 8 minutes at a flow of 0.7 ml/min.
Example 1 5-Cyano-6-methyl-N-f4-(methvlsulfonyl')benzyn-2-oxo-l-r3-
toiflupromethyl) phenyll-1.2-dihvdropyridine-3-carboxamide
a) Ethvl 3-oxo-3-f r3-> To an ice-cooled solution of 3-(trifluoromethyl)aniline (64.5 g, 0,40 mol) and triethylamine
(60 ml) in acetone (700 ml) was added dropwise ethyl 3-chloro-3-oxopropanoate (63.6 g,
0.42 md) in acetone (50 ml). After the addition (approx. 30 minutes) stirring was
continued at room temperature overnight. The solvents were removed and water (1200 ml)
was added. The resulting precipitate was filtered off, thoroughly washed twice with water
and then dried to afford the title compound as yellow powder (109 g, 99%).
'HNMR (CDC13): 8 9.52 (1H, s); 7.87 (1H, s); 7.78 (1H, d); 7.46 (1H, t); 7.39 (1H, d);
4.29 (2H, q); 3.50 (2H, s); 1.35 (3H, t).
APCI-MS m/z: 276.1 [MR*].
b) 6-Melhyl-2-oxo-l-f3^trirluorQniethyl)phenvn-l J-dihydropyridine-3-carboxyIic acid
To a solution of ethyl 3H)xo-3-{[3
trifluoromethyl)phenyl]amino}propanoate (19,2 g,70
mmol) and sodium methoxide (7.6 g, 140 mmol) in EtOH (250 ml) was added
4-methoxybut-3-en-2-one (90%) (7.72 g, 77 mmol). After the addition, the reaction
mixture was refluxed for 2 h and then cooled. Water (50 ml) and 2M NaOH were added
and the mixture was stirred at room temperature overnight The organic solvents were
removed and the reaction mixture was extracted (washed) with EtOAc. The water phases
were acidified with hydrochloric acid to pH 3-4, an orange coloured precipitate appeared
and was filtered off, washed with water and dried. Recrystallisation twice from
heptane/EtOAc (4:1) afforded the title compound (12 g, 58%) as a white powder.
JHNMR (CDCI3): 513.68 (1H, s); 8.54 (1H, d); 7.86 (1H, d); 7.79 (1H, t); 7.55 (1H, brs);
7.48 (1H, d); 6.58 (1H, d); 2.16 (3H, s),
APCI-MS m/z: 298.1 [MH*J.
c\ e-Methvl-N-r^fmethvlsulfonvltbenzvll^-oxo-l- r3-(trifluoromethvl')phenvn-l .2-
dihvdropyridine-3-carboxamide
A mixture of 6-methyl-2-oxo-l-[3-(trifluoromethyI)phenyl]-l,2-dihydropyridine-3-
carboxylic acid (7.43 g, 25 mmol), HATU (10.5 g, 27.5 mmol), HOAT (3.75 g, 27.5
mmol) and DffiA (14.2 ml, 82.5 mmol) in NMP (65 ml) was reacted for 1 h, then
.47
4-methyIsulphonylbenzyl amine hydrochloride (5.8 g, 26 mmol) was added. After 1 h, the
reaction mixture was slowly poured into stirred ice water (1 L). A powder was formed, and
the water mixture was acidified to pH 3 with citric acid (0.5 M), and stirring was continued
for Ih. The precipitate was filtered off, washed with water and dried in vacuum overnight.
Recrystallisation from EtOAc gave 8.1 g (70%).
'HNMR (CDC13): 8 10.00 (IH, brt); 8.60 (IH, d); 7.88 (2H, d); 7.83 (IH, d); 7.76 (IH, t);
7.53 (3H, m); 7.46 (IH, d); 6.49 (IH, d); 4.68 (2H, m); 3.03 (3H, s); 2.10 (3H, s).
APCI-MS m/z: 465.1 [MH+].
1 .2-dihydropyridine-3-carboxaniide
To a solution of 6-raethyI-N-[4-(methyIsuIfonyI)benzyl]-2-oxo-l-[3-
(Uifluoromethyl^hOTyl]-l^-dihydropyridine-3-carboxarnide (200 mg, 0.43 mmol) hi
MeCN (1 .5 ml) at room temperature and under argon was added trifluoromethanesulfonic
acid (1 ml) followed by N-iodosuccinimide (97 mg, 0.43 mmol). After 45 min, the reaction
mixture was diluted with DCM, washed with aqueous NaHCCb, with aqueous NaS2O4 and
water, dried (NaaSO*), and evaporated to give the title compound (200 mg).
*H NMR (CDC13): 6 9.85 (IH, brt); 8.90 (IH, d); 7.88 (2H, d); 7.76 (2H, m); 7.50 (2H, d);
7.48 (IH, s); 7.40 (IH, d); 4.65 (2H, m); 3.03 (3H, s); 2.32 (3H, s).
APCI-MS m/z: 591.0 [MH^].
e) 5-Cvano-6-methvl-N44-fmethvlsulfonvnbenzvn-2-oxo4-r3-ftrifluoromethvl')phenvll-
1.2-dihydropvrldine-3-carboxamide
A mixture of 5-iodo-6-methyI-N-[4-(methyl6ulforiyl)benzyl]-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (120 mg, 0.20 mmol)
and copper (I) cyanide (66.7 mg, 0.74 mmol) in NMP (2.5 ml) was stirred overnight at 140
°C. The reaction mixture was cooled and partitioned between ethyl acetate and water. The
organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The
residue was first purified by preparative HPLC and then by flash chromatography eluting
with DCM/methanol (10:0.2) to give the title compound as a white solid (24 mg, 24 %).
!HNMR (DMSO-d6): 5 9.55 (1H, t, J 6.1 Hz); 8.49 (1H, s); 7.96 (1H, s); 7.93 (1H, d, J 7.8
Hz); 7.88 - 7.81 (3H, ra); 7.77 (1H, d, J 8.0 Hz); 7.52 (2H, d, J 8.4 Hz); 4.56 (2H, d, J 6.2
Hz); 3.16 (3H, s); 2.22 (3H, s).
APCI-MS m/z: 490 [MH+].
Example! 6-Methvl-N-f4-rmethvlsulfonvl)benzvn-5-nitro-2-oxo-l-r3-
(Mflut>roinethyl)pheDvl1-l«2-di^ydropyridine-3-carboxamide
To a solution of 6-methyl-N-[4-(methylsulfonyl)benzyl)-2-oxo-l-[3-
(trifluororaethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (52 rag, 0.11 mmol) in acetic
anhydride (2 ml) was added fuming nitric acid (0.1 ml, 2.1 mmol). The reaction mixture
was stirred at room temperature for 40 rain. The mixture was partitioned between ethyl
acetate and aqueous sodium hydrogen carbonate. The organic layer was washed with
water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was
purified by preparative HPLC to give the title compound as a yellow powder (13 mg,
23%).
*H NMR (CDC13): 8 9.47 (1H, t, J 5.6 Hz); 9.31 (1H, s); 7.92 - 7.86 (3H, m); 7.81 (1H, t, J
7.9 Hz); 7.54 - 7.48 (3H, m); 7.44 (1H, d, J 7.9 Hz); 4.69 (2H> dd, J 5.9,3.9 Hz); 3.03 (3H,
s);2.52(3H,s).
APCI-MS m/z: 510 [MR*].
Example 3 5-(l-Bu^oxyvinvlV6-methvl-N-I4-(me^ylsujfQny|)pcnzyl1-2-oxo-l-r3-
(trifluoromethvnphenvl]-1.2-dihvdropvridine-3-carboxamide
In a Schlenk vessel equipped with a magnetic stirring bar were placed 5-iodo-6-methyl-N -
[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-
carboxamide (101.5 mg, 0.17 mmol), bis[12-bis(diphenylphosphino)ethane]-palladram
(0) (16.5 mg, 18.3 /unol), n-butyl vinyl ether (60 /il, 0.46 mmol), triethylamine (0.5 ml, 3.6
mmol) and DMF (6 ml). The vessel was purged with argon, sealed and heated at 100 °C
overnight. The reaction mixture was cooled and partitioned between ethyl acetate and
water, The organic layer was dried over sodium sulphate, filtered and concentrated in
vacuo. The residue was purified by preparative HPLC to give the title compound as a white
solid (27.3 mg, 28 %).
*H NMR (CDC13): 8 9.96 (1H, t, J 5.8 Hz); 8.64 (1H, s); 7.89 (2H, d, J 8.3 Hz); 7.82 (1H,
d, J 8.0 Hz); 7.75 (1H, t, J 7.9 Hz); 7.56 - 7.50 (3H, m); 7.46 (1H, d, J 7.8 Hz); 4.69 (2H,
ddd, J 22.1,15.7,6.2 Hz); 4.43 (1H, d, J 2.6 Hz); 4.26 (1H, d, J 2.6 Hz); 3.83 (2H, t, J 6.5
Hz); 3.03 (3H, s); 2.11 (3R s); 1.74 (2H, quintet, J 9.2 Hz); 1.46 (2H, sextet, J 9.1 Hz);
0.98(3H,t,J7.4Hz).
APCI-MS m/z: 563 [MR*].
Example 4 5-Acetvl-6-methvl-N-f4-fmethvlsu]fonvi')benzvI'>-2-oxo-l-r3-
(trifluoromethyl)phenyl1-1.2-dihvdropyridiiie-3-cai:boxarnid6
To a solution of 5-(l-butoxyvinyI)-6-methyl-N-[4-(methylsulfoiiyl)benzyl3-2-oxo-l-l3-
(trifluoiomethyl)phenyl]-l^-dihydropyridine-3-«irboxamide (38 mg, 67.5 /tmol) in
DMF (0.5 ml) was added aqueous hydrochloric acid (2.0M, 50 jil). After 20 min. the
solution was neutralized with aqueous sodium hydrogen carbonate. The reaction mixture
was purified by preparative HPLC to give the tide compound as a white solid (17.6 mg,
51%).
*H NMR (CDC13): 5 9.75 (1H, t, J 5.7 Hz); 9.08 (1H, s); 7.90 (2H, d, J 83 Hz); 7.85 (1H,
d, J 7.9 Hz); 7.78 (1H, t, J 7.9 Hz); 7.54 (2H, d, J 8.3 Hz); 7.50 (1H, s); 7.42 (1H, d, J 8.0
Hz); 4.70 (2H, t, J 6.0 Hz); 3.03 (3H, s); 2.66 (3H, s); 2.43 (3H, s).
APCI-MS m/z: 507 [MH+].
Example 5 S-rflEVN-Metboxvethanimidoyll-e-methvl-N-r^fmethylsulfonvnbenzvl]-
2-oxo4-r3-ftrifluoromethynphenvl1-L2-dihvdropvridine-3-carboxamide
A mixture of 5-acetyl-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (47.2 mg, 0.09 mmol),
methoxylamine hydrochloride (22.9 mg, 0.27 mmol), potassium carbonate (36 mg, 0.26
mmol) and DMF (1 ml) was heated at 100 °C for 1 h. After cooling the reaction mixture
was neutralized with aqueous 2.0M hydrochloric acid and purified by preparative HPLC to
give the title compound as a white solid (9 mg, 18 %).
.50
H NMR (CDC13): 8 9.91 (1H, t, 16.0 Hz); 8.58 (1H, s); 7.88 (2H, d, J 8.3 Hz); 7.82 (1H,
d, J 8.3 Hz); 7.75 (IH, t, J 7.9 Hz); 7.54 - 7.49 (3H, m); 7.44 (IH, d, J 7.8 Hz); 4.67 (2H, t,
J 5.9 Hz); 3.96 (3H, s); 3.02 (3H, s); 2.20 (3H, s); 2.14 (3H, s).
APCI-MS m/z: 536
Example 6 S-ftlJ^N-HvdroxyethaniimdovlV^
^
A mixture of 5-acetyl-6-methyl-N-[4-(methylsulfony])benzyl]-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxaTnide (34.7 mg, 68.5 jtunol),
hydroxylamine hydrochloride (30.3 mg, 0.44 mmol), triethylamme (0.5 ml, 3.6 mrnol),
tetrahydrofuran (1 ml) and methanol (0.5 ml) was heated at 70 °C for 48 h. The reaction
mixture was cooled and concentrated in vacuo. The residue was purified by preparative
HPLC to give the title compound as a white solid (8 mg, 22 %).
*H NMR (CDC13): 8 9.92 (IH, t, J 5.6 Hz); 8.59 (IH, s); 7.88 (2H, d, J 8.1 Hz); 7.82 (IH,
d, J 7.7 Hz); 7.75 (IH, t, J 7.8 Hz); 7.52 (4H, d, J 4.2 Hz); 7.44 (IH, d, J 7.5 Hz); 4.68 (2H,
ddd, J 21.2,15.3,6.0 Hz); 3.02 (3H, s); 2.25 (3H, s); 2.12 {3H, s).
APCI-MS m/z: 522 [MR*].
Example 7 6-Methyl-N-r4-(iqethylsutfony|ty^
(trifluoromethyl)phenyn-1.2-dihydropyridine-3-carboxamide
A mixture of 5-iodo-6-methyl-N-[4~(methylsulfonyl)benzyl)-2-oxo-l-[3-
(trifluoromethy^phenyU-l^-dihydropyridine-S-carboxamide (86.7 mg, 0.15 mmol),
copper® iodide (3.1 mg, 0.016 mmol), 1,10-phenanthroline monohydrate (5.9 mg, 0.03
mmol), ttiphenylphosphine (13.8 mg, 0.05 mmol), cesium carbonate (70 mg, 0.22 mmol)-
tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol),
3-(trimethylsHylethynyl)pyridine (38.1 mg, 0.22 mmol) in toluene (15 ml) was heated at
100 °C under argon for 48 h. The reaction mixture was cooled and partitioned between
ethyl acetate and water. The organic layer was dried over sodium sulphate, filtered and
concentrated in vacuo. The residue was first purified by preparative HPLC on a kromasil
column and then by flash chromatography eluting with DCM/methanol (10:0.25) to give
the title compound as a white solid (29.7 mg, 36 %).
*HNMR (CDC13): 8 9.81 (1H, t, J 5.5 Hz); 8.76 (2H, d, J 113 Hz); 8.60 (ffl, d, J 4.7 Hz);
7.94 - 7-83 (3H, m); 7.83 - 7.75 (2H, m); 7.57 - 7.50 (3H, m); 7.47 (1H, d, J 7.7 Hz); 7.33
(1H, dd, 3 7.7, 5.0 Hz); 4.70 (2H, t, J 5.4 Hz); 3.03 (3H, s); 2.35 (3H, s).
APCI-MS m/z: 566 [MH*].
Example 8 6-Methvl-N--r4-fmethvlsulfonvl)benzvn-2-oxQ-5-f2-pvridin-3-vlethvD-l-f3-
(trifiuoromethyDphenvlM^-dihvdropvridiTie-S-caTboxamide
A suspension of 6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-(pyridin-3-ylethynyl)-l-
[3-(trifluoromethyl)phenyl3-l,2-dihydiopyridine-3-carboxarnide (20 mg, 0.035 mmol), 5%
palladium on carbon (10 mg) in ethanol (5 ml) and ethyl acetate (5 ml) was stirred
vigorously under a hydrogen atmosphere for 48 h. The mixture was filtered through Celite,
the filtrate was evaporated to dryness and the residue was purified by preparative HPLC to
give the title compound as a white solid (1 1 mg, 55%).
*H NMR (DMSO-d6): 5 9.96 (1H, t, J 6.2 Hz); 8.45 (1H, d, J 1.8 Hz); 8.40 (1H, dd, J 4.8,
1.5 Hz); 8.29 (1H, s); 7.91 - 7.75 (5H> m); 7.72 - 7.60 (2H, m); 7.52 (2H, d, J 8.3 Hz); 7.34
- 7.27 (1H, m); 4.56 (2H, d, J 6.0 Hz); 3.16 (3H, s); 2.88 (4H, s); 1.87 (3H, s).
APCI-MS m/z: 570 [MH*].
Example 9 6-Mfithvl-N-r4-fmethvlsufo
A mixture of 5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-t3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (53 mg, 0.09 mmol),.
tributyl(vinyl)tin (51 mg, 0.16 mmol), tetrakis(triphenylphosphine)panadium(0) (6.9 mg,
0.006 mmol) in toluene (10 ml) was heated at 100 °C under argon for 12 h. After cooling,
the solvent was removed in vacuo and the residue was purified by preparative HPLC to
give the title compound as a white solid (18 mg, 41%).
JHNMR (CDC13): 8 9.98 (1H, t, J 5.9 Hz); 8.85 (1H, s); 7.87 (2H, dt, J 8.5, 1.9 Hz); 7.83 -
7.69 (2H, m); 7.54 - 7.47 (3H, m); 7.42 (1H, d, J 7.7 Hz); 6.69 (1H, dd, J 17.2, 11.0 Hz);
.52 g*'
5.73 (1H, d, J 17.2 Hz); 5.40 (1H, d, J 11.2 Hz); 4.67 (2H, dd, J 5.9,3.7 Hz); 3.01 (3H, s);
2.10 (3H, s).
APCI-MS m/z: 491 [MH*].
Example 10 Ethvl 2-aefliyi-5-Kr4^methvlsulfonvl)beiizvllaminolcarfaonylV6-oxo-l-r3-
ftrifluoromethvI^phenvn-1.6-dihydropyridine-3-carboxylate
In a stainless-steel autoclave (100 ml) were placed 5-iodo-6-methyl-N-[4-
(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoroinethyl)phenyI]-l^-dihydropyridine-3-
carboxamide (108.1 mg, 0.18 mmol), palladium(n) acetate (3.8 mg, 0.02 mmol),
triphenylphosphine (10.3 mg, 0.04 mmol), triethylamine (2ml, 14.4 mmol) and ethanol (6
ml). The reaction mixture was magnetically stirred at 100 °C under a carbon monoxide
pressure of 4 atmospheres overnight. After cooling, the solvent was evaporated off and the
residue was purified by preparative HPLC to give the title compound as a white solid (77.6
mg,79%).
*H NMR (CDC13): 5 9.73 (1H, t, J 5.9 Hz); 9.20 (1H, s); 7.90 (2H, d, J 8.3 Hz); 7.85 (1H,
d, J 7.9 Hz); 7,78 (1H, t, J 7.8 Hz); 7.53 (2H, d, J 8.3 Hz); 7.50 (1H, s); 7.42 (1H, d, J 8.0
Hz); 4.69 (2H, t, J 5.9 Hz); 4.38 (2H, q, J 7.2 Hz); 3.03 (3H, s); 2.50 (3H, s); 1.42 (3H, t, J
7.2 Hz).
APCI-MS m/z: 537 (MH*j.
Example 11 5-(4-Methane8ulfonyl"benzylcarbanioylV2-methvl'6-oxp-l-f3'-
tr4Jlupromethyl-phenyl)-1.6-dihydro-pvridi^e--3-carboxyiicacid
To a solution of ethyl 2-meltoyl-5-({[4-(methyIsulfonyl)benzyl]amino}carbonyI)-6-oxo-l-
[3-(trifluoromethyl)phenyl]-l,6-dihydropyridine-3-carboxylate (0.70 g, 1.30 mmol) in THF
(10 ml) and water (10 ml) was added 1M NaOH (2 ml, 2 mmol), and the mixture was
stirred for 1 h at room temperature, monitoring the progress of the reaction by LC-MS.
20% conversion was observed, and another portion of 1M NaOH (1 ml, 1 mmol) was
added, and the reaction was allowed to run for another 1 h. This procedure was repeated
until complete conversion of the ester was observed (normally 3-4 hours). The outcome of
the reaction is two compounds with the same mass, in a 95:5 proportion. The main product
S3 3'
is the subtitle compound, and the other is a regioisomer. The reaction mixture was
evaporated to remove THF, and the residual water solution was acidified and extracted
with EtOAc. The organic phase was collected and dried over NaaSO* Filtration and
evaporation gave a crude product 0.60 g (90%) as a yellowish solid, which can be used
further without purification. A portion was purified by preparative HPLC,
*H NMR (CDC13): 5 9.90 (1H, t, J 6.2 Hz); 9.31 (1H, s); 7.9 (2H, d, J 8.2 Hz); 7.84 (1H,
d, J 8.0 Hz); 7.77 (1H, t, J 8.0 Hz); 7.51 (2H, d, J 8.5 Hz); 4.5 (1H, s); 7.41 (1H, d, J 8.0
Hz); 4.92 (1H, bs); 4.78-4.63 (2H, m); 3.01 (3H, s); 2.53 (3H, s).
APCI-MS m/z: 509.2 [MH+].
Example 12 6-Methvl-2-oxo-l-(3-trifiuoroniethyl-phenyl)-1.2-dihydro-pyridine-3.5-
dicarboxylic acid 5-dimethyIamide 3-(4-metfaanesuIfonyl-benzvlamide)
To 5-(4-memanesulfonyI-benzylcarbamoyl)-2-methyl-6-oxo-l-(3-trifluoromethyl-phenyl)-
l,6-dihydro-pyridine-3-carboxylic acid in CHjCla (5 ml), SOCb (3 ml) was added, and the
flask was sealed and stirred magnetically for 2 h. The crude mixture was evaporated in
vacuo giving the intermediate acid chloride as a yellow solid. The solid was dissolved in
1,4-dioxan (5 ml, dried over molecular sieves) and dimethylamine (40% aqueous solution,
0.5 ml) was added quickly. The mixture was stirred for 5 minutes, and LC-MS showed
complete formation of the title compound. The mixture was concentrated in vacuo and the
residue was purified by preparative HPLC, giving 0.008 g (76%) of the title compound as a
white solid after freeze-drying the pure fractions.
*H NMR (CDC13): 8 9.86 (1H, t, J 5.9 Hz); 8.73 (1H, s); 7.89 (2H, d, J 8.3 Hz); 7.84 (1H,
d, J 7.8 Hz); 7.77 (1H, t, J 7.8 Hz); 7.52 (2H, d, J 8.4 Hz); 7.51 (1H, s); 7.43 (1H, d, J 7.9
Hz); 6.16 (1H, bs); 4.75-4.63 (2H, m); 3.03 (3H, s); 3.02 (3H, d, J 4.3 Hz); 2.33 (3H, s).
APCI-MS m/z: 536.2 [MH+].
Using the general method of Example 12, the compounds of Examples 13 to 20 and 22 to
25 were prepared.
t, r \ 54 5 '•
Example 13 6~Metjiyl-2H3xo-l-G-trifluorDmethvl-phenyD~1.2-difaydr^pffldine-3.5-
dicarboxylic acid 5-amide 3-f4~methane8ulfonyl-benzylamide)
*HNMR (CDC13): 8 9.82 (1H, t, J 5.9 Hz); 8.80 (1H, s); 7.78 (2H, d, J 8.8 Hz); 7.84 (1H,
d, J 8.1 Hz); 7.76 (1H, t, J 7.9 Hz); 7.51 (2H, d, J 8.9 Hz); 7.50 (1H, s); 7.42 (1H, d, J 7.8
Hz); 6.15 (1H, bs); 5.75 (1H, bs); 4.73-4.61 (2H, m); 3.02 (3H, s); 236 (3H, s).
APCI-MS m/z: 508.2 [MB*].
Example 14 6-MethyL-2^o-l-jf3-trifluoromethyl-phenylVl,2-di^vdro-pyridine-3.5-
dicarboxvlic acid 3-(4-methanesulfonvl-benzvIamide') 5-methyIamide
*HNMR (CDCI3): 8 9.90 (1H, t, J 5.9 Hz); 8.54 (1H, s); 7.90 (2H, d, J 8.1 Hz); 7.84 (1H,
d, J 7.9 Hz); 7.77 (1H, t, J 7.8 Hz); 7.53 (1H, s); 752 (2H, d, J 8.3 Hz); 7.45 (1H, d, J 7.9
Hz); 4,74-4.62 (2H, m); 3.15 (3H, s); 3.07 (3H, s); 3.02 (3H, s); 2.11 (3H, s).
APQ-MS m/z: 522.3 [MH+J.
Example 15 6-Methyl-2-oxo-l-(3^trifluorpme^iyl-phenyl')-l,2-dihvdro-pvridine-3.5-
dicarboxylic acid S-rte-hydroxy^fcylVinethvI-amide) 3-(4-methaqesulfon vl-benzylamide)
APCI-MS m/z: 566.2 [MH4]. Retention time 1.82 minutes.
Example 16 6-Methvl-2-oxo-l-G-trifluoromethvI-phenvlVl^-dihvdro-pvridine-3^-
dicarboxylic acid 3-(4-mctha^esuIfonyl-benzylainideV5-(methyI-propvl-amide')
!H NMR (CDC13): 8 9.94-9.84 (1H, m); 8.50 (1H, s); 7.88 (2^ d, J 8.6 Hz); 7.83 (1H, d, J
7.9 Hz); 7.76 (1H, t, J 7.9 Hz); 7.52 (1H, s); 7,52 (2H, d, J 8.1 Hz); 7.44 (1H, d, J 7.9 Hz);
4.74-4.62 (2H, m); 3.52 (1.1H, t, J 7.5 Hz, part of rotameric system, retainer 1); 3.29
(0.9H, t, J 7.5 Hz, part of rotameric system, rotaraer 2); 3.10 (1.4H, s, part of rotameric
system, rotamer 2); 3.02 (1.6H, s, part of rotameric system, rotamer 1); 3.02 (3H, s); 2.08
(3H, s); 1.75-1.60 (2H, m); 0.99 (1.6H, t, J 7.5 Hz, part of rotameric system, rotamer 1);
0.88(1.4H,t,J 7.5 Hz, part of rotameric system, rotamer 2). ,-.
APCI-MS m/z: 564.3 [MR*].
,55 f
Example 17 ^Methvl-2-oxc^5-(pyirolidine-lK:art)onYl)-I-(3-trifluoroinethyl-phenylV
12-dihvdro-pvridme-3.5-dicarboxylic acid 3-(4-methanesuIfanvI-beiizvlamide)
*H NMR (CDC13): 5 9.87 (1H, t, J 6.0 Hz); 8.59 (1H, s); 7.88 (2H, d, J 8.2 Hz); 7.82 (1H,
d, J 7.9 Hz); 7.75 (1H, t, J 7.9 Hz); 7.54-7.48 (3H, m); 7.44 (1H, d, J 7.6 Hz); 4.73-4.61
(2H, m); 3.66 (2H, t, J 6.7 Hz); 3.46-3.39 (2H, m); 3.02 (3H, s); 2.14 (3H,.m); 2.06-1.95
(4H,m).
APCI-MS m/z: 562.5 [MH+].
Example 18 6-Methvl'2-oxo-l-(3-trtfluoromethyl-phenylV1.2-dihydrQ-pyiidine-3.5-
dicarbQxvlic acid S-^-dimethylaToino-ethvlVmethyl-amide] 3-(4-methanesulfonylbenzylaTnidej
trifluoroacetic acid salt
JH NMR (DMSO-dd): 5 9.88 (1H> t, J 6.1 Hz); 9,40 (1H, bs); 8.43 (1H, s); 8.00 (1H, s);
7.90 (1H, d, J 7.7 Hz); 7.87 (2H, d, J 8.2 Hz); 7.83-7.76 (2H, m); 7.53 (2H, d, J 8.2 Hz);
4.58 (2H, d, J 5.9 Hz); 4.05-3.70 (2H, m); 3.43-3.31 (2H, m); 3.16 (3H, s); 2.96 (3H, s);
2.89 (3H, s); 2.88 (3H, s); 1.92 (3H, s).
APCI-MS m/z: 593.3 [MH+].
Example 19 5-(f2Je)-2-Hvdroxvmethvl-pvrroIidiTie-l-carbonvIV6-methvl-.2-oxo>l-f3-
trifluoromethyl -phenylVl.2-dihydro-pvridine-3-caiboxylic acid 3-(4-methanesulfonyl -
benzvlamide'li
JH NMR (CDC13): 5 9.88 (1H, t, J 6.1 Hz); 8.59 (1H, d, J 3.3 Hz); 7.89 (2H, d, J 8.8 Hz);
7.84 (1H, d, J 7.7 Hz); 7.77 (1H, t, J 7.7 Hz); 7.51 (2H, d, J 8.6 Hz); 7.51 (1H, s); 7.44 (1H,
d, J 7.8 Hz); 4.70-4.65 (2H, m); 4.44-4.35 (1H, m); 3.91-3.84 (1H, m); 3.74 (1H, p, J 5.7
Hz); 3.55-3.44 (2H> m); 3.02 (3H, s); 2.27-2.17 (1H, m); 2.15 (3H, s); 2.12-1.83 (3H, m);
1.82-1.71 (lH,m).
APCI-MS m/z: 592.4 [MH*].
Example 20 5"(3-Hvdroxv-pvrrolidine-l-carbonvI')-6-methvl-2-oxo--l-(3-
trifluoromethvl-phenvlVl .2-dihvdro-pvridine-3.5-dicarboxvIic acid 3-C4-methanesulfonvIbenzvlamide')
*H NMR (CDC13): 8 9.96-9.89 (IH, m); 8.63-8.56 (IH, m); 7.88 (2H, d, J 8.5 Hz); 7.83
(IH, d, J 8.0 Hz); 7.76 (IH, t, J 7.6 Hz); 7.52 (IH, s); 7.51 (2H, d, J 8.0 Hz); 7.44 (IH, d, J
7.6 Hz); 4.67 (2H, d, J 5.7 Hz); 4.654.53 (IH, m); 3.92-338 (4H, m); 3.02 (3H, s); 2.19-
2.01 (2H, m); 2.14 (3H, s).
APd-MS m/z: 578,3 [MH*]. Retention time 1.95 minutes.
Example 21 N3-rfl.l-Dioxido-2.3-dihvdro-l-benzothien-S-vnmethvn-N5.N5.6-trimethvl-
2-oxo-l~f3-(trifIuoromethvDphenvl1-L2-dihydropyridine-3.5-dicarbQxainide
In a stainless-steel autoclave (100 ml) were placed N-[(l,l-dioxido-23-dihydro-lbenzotHen-
5-yl)methyl]-5-iodo-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l^-
dihydropyridine-3-carboxamide (66.3 mg, 0.11 mmol), palladium(n)acetate (14.0 mg, 62.4
/imol), triphenylphosphine (25.1 mg, 95.7 jonol), dimethylamine (12 g, 27.8 mmol) and
ethanol (10 ml). The reaction vessel was cooled to -50 °C, degassed by vacuum/carbon
monoxide combined treatment, pressurized at 4 atmospheres with carbon monoxide, and
then heated at 100 °C for 6 h. After cooling, the solution was evaporated and the residue
was purified by preparative HPLC to give the tide compound as a white solid (11 mg,
18%).
!H NMR (CDC13): § 9.85 (IH, t, J 5.9 Hz); 8.53 (IH, s); 7.84 (IH, d, J 7.7 Hz); 7.77 (IH,
t, J 7.9 Hz); 7.68 (IH, d, J 8.0 Hz); 7.52 (IH, s); 7.44 (2H, t, J 8.6 Hz); 7.35 (IH, s); 4.65
(2H, dd, J 5.8,4.1 Hz); 3.49 (2H, t, J 6.8 Hz); 3.36 (2H, t, J6.9Hz); 3.15 (3H, s); 3.07 (3H,
s);2.11(3H,s).
APCI-MS m/z: 548 [MH*].
Example 22 5-(N]-AcetyI-hydjrazinocarbonvlV6^nethyl-2-oxo-l-f3-trifluoromethy^
phenvlVl ,2-cUhvdro-pvridine-3-carboxvlic acid 4-methanesulfonvl-benzvlamide
!H NMR (DMSO-d 7.93 (IH, s); 7.93-7.90 (IH, m); 7.87 (2H, d, J 8.4 Hz); 7.82 (IH, d, J 7.7 Hz); 7.74 (IH, d,
J 8.0 Hz); 7.55 (2H, d, J 8.3 Hz); 4.59 (2H, d, J 6.2 Hz); 3.17 (3H, s); 2.18 (3H, s); 1.91
(3H, s).
APCI-MS m/z: 565.2 [MH+].
Example23 5-rN-f2-Cvano-acetvlVhvdirainoc^
trifluoromethyl-pheDylVl^-dhvdrQ-pvridine-S-carboxvh'c.acid 4-methanesuIfonvlbenzvlamide
*HNMR (DMSO-dfi): 510.55 (1H, s); 10.42 (1H, s); 9.78 (1H, t, J 6.2 Hz); 8.51 (1H, s);
7.94 (1H, s); 7.92 (IE d, J 8.2 Hz); 7.87 (2H, d, J 8.2 Hz); 7.82 (1H, d, J 7.6 Hz); 7.75
(1H, d, J7.6 Hz); 7.55 (2H, d, J 8.2Hz); 4.59 (2H, d, J 6.0 Hz); 3.82 (2H, s); 3.17 (3H, s);
2.18 (3H, s).
APCI-MS ra/z: 590.1 [MH+].
Example 24 5-( r24Amhiocarbonothiovl'>hvdra2:inolcarbonvl>-6-methvl-jy-f4-
(methylsuI^vl)benzvll-2-oxo-l-F34triflu carboxamide
NMR CDMSO-d*): 510.31 (1H, s); 9.80 (1H, t, J 6.2 Hz); 9.32 (1H, s); 8.70 (1H, s);
7.92 (1H, d, J 7.8 Hz); 7.91 (1H, bs); 7.90 (1H, bs); 7.86 (2H, d, J 8.3 Hz); 7.83 (1H, d, J
8.3); 7.76 (1H, bs); 7.70 (1H, d, J 7.6 Hz); 7.54 (2H, d, J 8.1 Hz); 4.59 (2H, d, J 6.0 Hz);
3.17 (3H,s); 2.14 (3H,s).
APCI-MS m/z: 582.1 [MH+].
Example 25 5-Hydraanocaib^^onyl-6-methyl'2-oxp-I-(3j-trifluoroinethvl-phgnyl)-1.2-
dihydro-pvridine-3-caTboxylic acid 4-methanesulf^onvl-benzyJiamide
APCI-MS na/z: 523.2 [MH*]. Retention time 1.72 minutes.
Example 26 5-({2-rfflthvIanrinok:arbonvl]hvd^
(methvlsulfonyI)ben2vI1-2-oxo-l-r3-(trifluoromethyDphenvl1-L2ihydbropyndin
carboxaimde
To5-bydrazmocarbonyl-6-methyl-2-oxo-l-(3-trifluoromethyI-phenyl)-l,2-dihydropyridine-
3-carboxylic acid 4-methanesulfonyJ-benzylamide (0.030 g, 0.057 romol) in
1,4-dioxan (10 ml) was added ethylisocyanate (0.016 g, 0.23 mmol), and the mixture was
stirted at room temperature for 1 fa. The mixture was evaporated and the residue was
purified on preparative HPLC giving 0.015 g (44%) of the title compound.
*H NMR (CDC13): 8 9.96-9.87 (1H, m); 8.82 (1H, s); 7.88 (1H, d, J 8.2 Hz); 7.84 (2H, d, I
7.9 Hz); 7.83-7.80 (1H, m); 7.77 (1H, t, J 7.9 Hz); 7.52 (1H, s); 7.47 (2H, d, J 8.2 Hz);
7.47-7.41 (1H, m); 4.70-4.55 (2H, m); 3.23 (2H, q, J 6.9 Hz); 3.01 (3H, s); 2.31 (3H, s);
l.ll(3H,t,J7.1Hz).
APCI-MS m/z: 594.2 [MH1].
Example 27 5-(f2-r(N.N-Dimefliylamino)carbonyllhydrazinolcarbonyll-6-methyl-A?:-f4-
(methylsulfonyl^ benzvn-2-oxO"l-r3"(trifluorome1hyl)phenyn-1.2-dihydropyriding-3-
carboxamide
To5-hydrazinocarix>nyl-6-methyl-2-oxo-l-(3-trifluo«)methyl-phenyl)-l^-dihydi^
pyridine-3-carboxylic acid4-methanesulfonyl-benzylamide (0.030 g, 0.057 mmol) in THF
(10 ml) was added N^-dimethylcarbamoyl chloride (0.0247 g, 0.23 mmol), and the
mixture was stirred at 50 °C for 3 h. The mixture was evaporated and the residue was
purified on preparative HPLC giving 0.020 g (60%) of the title compound.
*H NMR (DMSO-dtf): 5 9.92 (1H, bs); 9.80 (1H, t, J 6.2 Hz); 8.50 (1H, s); 8.48 (1H, s);
7.94-7.89 (2H, m); 7.87 (2H, d, J 8.5 Hz); 7.82 (1H, d, J 8.2 Hz); 7.73 (1H, d, J 7.8 Hz);
7.55 (2H, d, J 8.5 Hz); 4.59 (2H, d, J 6.0 Hz); 3.17 (3H, s); 2.85 (6H, s); 2.19 (3H, s).
APCI-MS m/z: 594.1 [MH*].
Example 28 5-f3.3-DimethvI-ureidoV6-methvl-2-oxo-l-(3-trifluoromethvl-phenvl')-1.2-
dihvdro-pyridine-3-cajboxylic acid 4^mejhaiye$ulfonyl-benzvlamide
a) 5-(4-MethanesuIfonvI-benzylcarbamoyD-2-methyl-6-Qxo-l-(3-trifluoromethyl-ph,enyl)-
L6-dihydrp-pyridjne-3-carbonylazide
To5-(4-methanesulfonyl-benzylcarbamoyl)-2-methyI-6-oxo-l-(3-trifluoromethyl-phenyl)-
l,6-dihydro-pyridine-3-carboxylic acid (0.055 g, 0.108 mmol) in CHaCla (10 ml),
triethylamine (0.020 g, 0.2 mmol) and diphenylphosphoryl azide (0.055 g, 0.2 mmol) were
added, the flask was sealed, and the contents were stirred at room temperature overnight
The volatiles were removed m vacua and the residue was purified on silica
(heptane:EtOAc 2: 1 to 1 : 1 to 1:2) giving 0.012 g (21 %) of the title compound.
XH NMR (CDC13): 5 9.58 (1H> t, J 5.8 Hz); 9.13 (1H, s); 7.88 (2H, d, J 8.2 Hz); 7.86-7.82
(1H, m); 7.77 (1H, t, J 7.9 Hz); 7.51 (2H, d, J 8.7 Hz); 7.49 (1H, s); 7.41 (1H, d, J 7.9 Hz);
4.73-4.61 (2H, m); 3.02 (3H, s); 2.53 (3H, s).
APCI-MS m/z: decomposes.
fr) 5-(3.3-Dimemvl-ureidoV6-methvl-2-oxo-l-G-^
pvridine-3-carooxvlic acid 4-m6thanesulfonvl-benzvlainide
A mixture of 5-(4-methanesulfonyl-benzylcarbamoyl)-2-methyl-6-oxo-l-(3-
trifluoromethyl-phenyI>-l,6-dihydro-pyridine-3-carbonylazide
(0.005 g, 0.0094 mmol) and toluene (5 ml) was heated (120 °Q with stirring for 1 h, and
then allowed to cool. The toluene was removed in vacuo and the residue was dissolved in
acetonitrile (5 ml), dimethylamine (0.5 ml, 40% in water) was added quickly, and the
resulting mixture was stirred for 5 minutes. Evaporation of the volatiles and purification by
preparative HPLC gave 0.005 g (97%) of the title compound.
*H NMR (CDC13): 6 9.98 (1H, t, J 5.4 Hz); 8.47 (1H, s); 7.87 (2H, d, J 8.6 Hz); 7.80 (1H,
d, J 7.7 Hz); 7.73 (1H, t, J 8.0 Hz); 7.53 (1H, s); 7.50 (2H, d, J 8.3 Hz); 7.46 (1H, d, J 8.0
Hz); 6.08 (1H, bs); 4.73-4.60 (2H, m); 3.05 (6H, s); 3.02 (3H, s); 2.02 (3H, s).
APCI-MS m/z: 551 .2 [MH+].
Following the general method of Example 28, the compounds of Examples 29 and 30 were
prepared:
Example 29 6-Methvl-5-{3-methvKureidoV2-oxo-l-f3-trifluoromethvl-phenvlV1.2-
dihydro-pyndme-3-carbqxylijcacid4-methan6sulfpnvl-benzyIamide
^NMR (CDG13): 8 10.13 (lH,t, J 6.1 Hz); 8.45 (1H, s); 7.87 (2H, d, J 8.1 Hz); 7.81 (1H,
d, J 7.7 Hz); 7.73 (1H, t, J 7.7 Hz); 7.52 (1H, s); 7 .49 (2H, d, J 8.2 Hz); 7.45 (1H, d, J 7.4
Hz); 6.82 (1H, bs); 4.71-4.58 (2H, rn); 3.01 (3H, s); 2.80 (3H, s); 2.06 (3H, s).
APCI-MS m/z: 537.1 [MH+].
Example 30 6-Methvl-2-oxo-l-f3-trifluQromethvI-DhenvlV5-nreido-1.2-dihvdrO"
pyridine-3-carboxvHcacid4-methanesulfonvl-ben2vlamide
*H NMR (DMSO-d d, J 8.5 Hz); 7.84-7.79 (2H, m); 7.69 (1H, d, J 7.8 Hz); 7.52 (2H, d, J 8.2 Hz); 5.94 (2H,s);
4.58 (2H, d, J 6.2Hz); 3.15 (3H, s); 1.89 (3H, s).
APCI-MS m/z: 523.1 [MH*].
Example 31 5-Amino-6-methyl-2-oxo-l-(3-trifluorometfavl"phenyl>-1.2-dihvdropyridine-
3-carboxylic acid 4-methanesulfonvl-bcnzvlamide
To a solution of 5-(4-methanesulfonyl-benzylcarbamoyl)-2-methyl-6-oxo-l-(3-
trifluoromethyl-phenyl^l^-dihydro-pyridine-S-carboxylic acid (0.055 g, 0.108 mmol) in
tert-butanol (15 ml), triethylamine (0.020 g, 0.2 mmol) and diphenylphosphoryl azide
(0.055 g, 0.2 mmol) were added, the flask was equipped with a reflux condenser, and the
mixture was heated with stirring at 100 °C overnight. LC-MS showed a complex mixture
of products, where one was identified by mass to be the title compound. The compound
was isolated by preparative HPLC, and pure fractions were freeze-dried, to give 0.006 g
(12%) of an yellow solid.
*H NMR (DMSO-dtf): 810.28 (IE t, J 6.1 Hz); 8.22 (IH, s); 7.86 (2H, d, J 8.2 Hz); 7.85
(IH, s); 7.80 (IH, s); 7.78 (IH, d, J 8.0 Hz); 7.64 (IH, d, J 7.7 Hz); 7.53 (2H, d, J 8.4 Hz);
4.64 (2H, s); 4.57 (2H, d, J 6.2 Hz); 3.17 (3H, s); 1.84 (3H, s).
APCI-MS m/z: 480.1 [MH*].
Example 32 6-Methvl-JV-r4-rmethvlsulfonvl>benzvn-2-oxo-5-propionvl-l-r3-
(trifluoromethyDphenvn-l^-dihydropyridine-S-carboxamide
A solution of 5-iodo-6-methyl-^-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-
(trifluoromethyl)phenyl3-l,2-dihydropyridine-3-carboxamide (1500 mg, 2.5 mmol),
bis[l,2-bis(diphenylphosphino)ethane]palladium (230 mg, 0.25 mmol), triethylamine (7.5
ml, 54 mmol) and ethylpropenyl ether (900 #1,7.5 mmol) in DMF (45 ml) were heated at
100 °C overnight. After cooling the reaction mixture was poured into water and extracted
with ethyl acetate. The extracts were separated and evaporated under reduced pressure. The
crude product was dissolved in DMF (25 ml) and 2M HC1 (25 ml) and then stirred for 1.5
h. The reaction mixture was then poured into aqueous NaHCO3 and extracted with ethyl
acetate The extracts were evaporated under reduced pressure and the residue was
chromatographed on silica using ethyl acetate/heptane (2/1, 4/1, 10/1) as eluent. Fractions
containing the product were combined and evaporated to give 1.3 g (>99%) of the title
compound
*HNMR (CDC13): 5 9.76 (1H, t); 9.06 (1H, s); 7.89 (2H, d); 7.84 (1H, d); 7.76 (1H, t);
7.52 (2H, d); 7.49 (1H, s); 7.40 (1H, d); 4.68 (2H, m); 3.02 (3H, s); 3.00 (2H, q); 2.39 (3H,
s);1.22(3H,t).
Example 33 5-Formvl-6-methvl-N-f4-finethvlsulfonvl>)benzvl1-2-oxo-l-f3-
The title compound was prepared using a procedure analogous to that described for
Example 44.
NMR (CDC13): S 10.06 (1H, s); 9.57 (1H, t, J 5.9 Hz); 9.06 (1H, s); 7.89 (2H, d, J 8.2
Hz); 7.86 (1H, s); 7.79 (1H, t, J 7.9 Hz); 7.52 (3H, d, J 8.2 Hz); 7.43 (1H, d, J 8.2 Hz); 4.69
(2H, m); 3.04 (3H, s); 2.52 (3H, s).
APCI-MS m/z: 493.2 [MH+].
Example 34 6-Methvl-N-r4-(methvlsuhconvnbenzvn-2-oxo-5-f3-oxobutvl1-l-r3-
(triflaoromethvl)pbenyll-1.2-dihydropyridine-3rcarboxajmde
In a Schlenk vessel equipped with a magnetic stirring bar were placed 5-iodo-6-methyl-N -
[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(tritluoromethyl)phenyl]-l,2-dihydropyridine-3-
carboxamide (564.3 mg, 0.96 mmol), bis[1.2-bis(diphenylphosphino)ethane]-palladium
(0) (19.9 mg, 0.02 mmol), 3-buten-2-ol (499 mg, 6.9 mmol), triethylamine (1.2 ml, 8.6
mmol) and DMF (6 ml). The vessel was purged with argon, sealed and heated at 105 °C
overnight. The reaction mixture was cooled and partitioned between ethyl acetate and
water. The organic layer was washed with water, brine, dried over sodium sulfate, filtered
and concentrated in vacuo. The residue was purified by preparative HPLC to give the title
compound as a white solid (255 mg, 50 %).
*HNMR (CDC13): S 10.05 (IH, t, J 5.8 Hz); 8.49 (IH, s); 7.87 (2H, d, J 8.4 Hz); 7.80 (IH,
d, J 7.9 Hz); 7.73 (IH, t, J 7.9 Hz); 7.51 (2H, d, J 8.4 Hz); 7.48 (IH, s); 7.41 (IH, d, J 7.9
Hz); 4.69 (2H, m); 3.01 (3H, s); 2.81 (4H, s); 2.20 (3H, s); 2.10 (3H, s).
APCI-MS m/z: 535.1 [MH*].
Example 35 5-Acetvl-N-r4-(isopropylsulfonyI')ben2vn-6-methyl-2-QXO-i-r3-
ftrifluoromethyDphenyI1-1.2-dihvdropTOdine-3-carboxanude
a) N-f4-(Isopropylsulfonyl)benzy]V6-methyl-2-Qxo-l-r3rftrifluoromethyl)phenyll-1.2-
dihydropvridine-3-caTboxamide
To a mixture of 6^memyI-2xo-l-E3-(trifluoromethyl)phenyl3-l^-dihydropvridine-3-
carboxylic acid (16.27 g, 54.5 mmo]) in DCM was added thionyl chloride (12 ml, 165
mmol) under argon. The colour of the reaction mixture turned black. After 50 minutes
stirring at ambient temperature, the solvent was removed by evaporation. The last traces of
thionyl chloride were removed by azeotropic evaporation with toluene. To an ice cooled
solution of the residue in DCM, was added dropwise a mixture of l-[4-
(isopropylsulfonyl)phenyl] methanamine (11.8 g, 55.4 mmol) and triethylamine (30 ml,
215 mmol) in DCM under vigorous stirring. After the addition, the dark suspension was
allowed to warm up to room temperature. After 30 minutes stirring at ambient temperature
the reaction mixture was concentrated in vacuo and the residue was partitioned between
ethyl acetate and water. The organic layer was washed with water, dried over sodium
sulfate, filtered and concentrated in vacuo, giving a dark oil which crystallized on standing.
The solid was triturated with ethyl acetate, filtered, washed with ethyl acetate, ether,
heptane, and dried under vacuo to give the title compound as a light yellow powder (15.3
g). The filtrates were collected, concentrated and further purified by flash chromatography
on silica, eluting with a gradient of tert-butyl methyl ether to 5% methanol in tert-butyl
methyl ether to provide an additional 8.78 g of the crude product. The solids were
combined to give (24.1 g, 89 %) of the title compound.
*H NMR (CDC13): 8 9.96 (IH, t, / 5.5 Hz); 8.57 (IH, d, /7.4 Hz); 7.78 (3H, t, /4.1 Hz);
7.72 (IH, t, J7.9 Hz); 7.52 - 7.45 (3H, m); 7.43 (IH, d, J 7.7 Hz); 6.46 (IH, d, /7.6 Hz);
4.67 (2H, ddd, / 22.0 15.7 6.2 Hz); 3.13 (IH, septet, J 9.8 Hz); 2.07 (3H, s); 1 .26 (6H, d, J
6.9 Hz).
APCI-MS m/z: 493.2 [MH*].
b> 5-Iodo-N-f4-(isopropvlsulfonyI')benzvl1-6-methvl-2-oxo-l-|'3-(trifluaromethvl>phenyn-
1.2-dihydropyridine-3-carboxamJde
To a stirred solution of N-[4-(isopropylsulfonyl)benzyl]-6-methyl-2-oxo-l-[3-
(ttifluorojnethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (23.98 g, 48.73 mmol) and
TFA (90 ml) in DCM (90 ml) was added N-iodosuccinimide (1 1 .03 g, 49.14 mmol). After
2 h the reaction was complete and the solvent was removed by evaporation. To the residue
was added ethyl acetate (100 ml) and saturated aqueous sodium hydrogencarbonate
solution (60 ml) under stirring. The yellow solid was collected by suction filtration,
washed with water, air dried for 30 min, washed again with diethyl ether, heptane and
vacuum dried to give the title compound as a light yellow powder (29.67 g, 98 %).
*H NMR (CDC13): 8 9.83 (IH, t, J 6.0 Hz); 8.90 (IH, s); 7.83 - 7.76 (3H, m); 7.73 (IH, t, J
7.8 Hz); 7.47 (3H, d, J 8.0 Hz); 7.39 (IH, d, J 7.7 Hz); 4.66 (2H, ddd, J 22.3, 15.8 and 6.3
Hz); 3.13 (IH, septet, J 9.0 Hz); 2.29 (3H, s); 1.26 (6H, d, J 6.9 Hz).
APCI-MS m/z: 619.1 [MH+].
c) 5-Acetvl-N-r4-(isopropvlsulfonvl')benzvn-6-methvl-2-oxo-l-r3-
(fluoromethyDphenyll-l^-dihvdropvridine^-carboxamide
A mixture of 5-iodo-N-[4-(isopropylsulfonyl)benzyl]-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl3-l,2-dihydropyridine-3-carboxamide (3.55 g, 5.7 mmol), bis[1.2-
bis(diphenylphosphino)ethane]-palladium (0) (24.5 mg, 0.03 mmol), n-butyl vinyl ether
(1.16 g, 11.6 mmol), triethylamine (4 ml, 28.7 mmol) in DMF (14 ml) was stirred at 100
°C under argon for 19 h. The reaction mixture was cooled and concentrated in vacuo. The
residue was dissolved in methanol (20 ml) and 2M hydrochloric acid (2 ml) was added.
After 1 h stirring at room temperature the mixture was partitioned between ethyl
acetate/water and basified with saturated aqueous sodium bicarbonate solution. The water
layer was extracted with ethyl acetate (2 x 50 ml) and DCM (1 x 30 ml). The combined
organic layers were washed with water, brine, dried over sodium sulfate, filtered and
concentrated in vacuo. The residue was purified by flash chromatography on silica elating
with tert-butyl methyl ether/methanol (10:0.2) to give the title compound as a light yellow
solid (2.5 g, 82%).
*H NMR (CDC13): 5 9.71 (1H, t, J 5.7 Hz); 9.05 (1H, s); 7.85 - 7.78 (3H, m); 7.75 (1H, t, J
7.9 Hz); 7.51 - 7.44 (3H, m); 7.39 (1H, d, J 8.2 Hz); 4.68 (2H, ddd, J 22.4, 15.8 and 6.2
Hz); 3.14 (1H, septet, J 7.7 Hz); 2.63 (3H, s); 2.40 (3H, s); 1.26 (6H, d, J 6.9 Hz).
APCI-MS m/z: 535.2 JMH*].
The compounds of Examples 36 to 38 were prepared using a procedure analogous to that
described for Example 4.
Example 36 5-Acetvl"l-(3-CArano-phenvlV6-methvl-2-oxo-1.2-dihvdro-pvridine-3-
carboxvlic acid4-methanesulfonvl-benzvlamide
*H NMR (CDC13): £ 9.67 (1H, t, 75.7 Hz); 9.07 (1H, s); 7.90-7.86 (3H, m); 7.76 (1H, t,
J=7,9 Hz); 7.53-7.45 (4H, m); 4.74-4.64 (2H, m); 3.02 (3H, s); 2.65 (3H, s); 2.42 (3H, s).
APCI-MS m/z: 464 [MH*].
Example 37 5-Acetvl-l-(3-chloro-phenvl>-6-methyl-2-QXQ-1.2-dihvdro-pvridine-3-
carboxvlic acid 4-methanesulfonl-ben2vlamide
NMR (CDC13): $ 9.77 (1H, t, J 5.8 Hz); 9.04 (1H, s); 7.89 (2H, d, / 8.3 Hz); 7.56-7.51
(4H, m); 7.22 (1H, s); 7.10-7.08 (1H, m); 4.69 (2H, d, J 6.0 Hz); 3.02 (3H, s); 2.64 (3H, s);
2.44 (3H, s).
APCI-MS m/z: 473 [MH+].
Example 38 5-AcetyJ-6-methyI-2-oxQ-l-m-tQlyL-1.2-dihvdro-pvridine--3-caiboxvUcacid
4-methanesulfonvl-faenzvlainide
*HNMR (CDC13): 5 9.89 (IH, t, / 5.5 Hz); 9.04 (IH, s); 7.88 (2H, d, J 8.3 Hz); 7.53-7.47
(3H, m); 7.37-7.35 (IH, m); 6.98-6.96 (2H, m); 4.68 (2H, d, / 6.0 Hz); 3.02 (3H, s); 2.64
(3H, s); 2.44 (3H, s), 2.43 (3H, s).
APCI-MS m/z: 453 [MB*].
Example 39 S-fl-HvdroxvethvlV6-methvl-N-r4-(methvlsuIfonvl)benzvn-2-oxo-l-r3-
ftrifluofomethvDphenyl1-1.2-dihvdropvridine-3-carboxamide
A mixture of 5-acetyl-6-methyl-JV-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-
(trifluoromethyl)phenyl}-l,2-dihydropyridine-3-carboxamide (Example 4,180 mg, 0.35
mmol) and aluminum tri-sec-butoxide (0.2 mg, 0.79 mmol) in anhydrous isopropanol (30
ml) was stirred at 85 °C under a nitrogen atmosphere for 48 h. The reaction mixture was
cooled to room temperature, water (0.2 ml) was added and the mixture was then
concentrated in vacuo. The residue was purified by preparative HPLC to give the title
compound as a white solid (134 mg, 74 %).
*H MMR (CDC13): 8 10.01 (ia t, J 5.7 Hz); 8,84 (IH, d, J 1.9 Hz); 7.87 (2H, d, J 8.3 Hz);
7.81 (IH, d, J 7.8 Hz); 7.74 (IH, t, J 8.0 Hz); 7.52 (2H, d, J 8.3 Hz); 7.50 (IH, s); 7.42 (IH,
d, J 7.9 Hz); 5.03 (IH, dd, J 10.9 1.6 Hz); 4.67 (2H, q, J 6.3 Hz); 3.02 (3H, s); 2.12 (3H, s);
1.91 (IH, t, J 3.9 Hz); 1.58 (3H, dd, J 6.4 2.6 Hz).
APCI-MS m/z: 509.2 [MH+].
Example 40 5-(l-Azidoethyl)-6-methvl-N-f4-(methylsuIfonyDbenzvn-2-oxo-l-f3-
(trifluorQmethynphenyn-1.2-dihydropyridine-3-carboxarnide
To a solution of 5-(l-hydroxyethyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (29.1 mg, 0.06 mmol) in
DCM (1.5 ml) was added thionylchloride (0.15 ml, 2.1 mmol) under an argon atmosphere.
After 40 minutes stirring at ambient temperature, the solvent was removed in vacuo. The
last traces of thionyl chloride were removed by azeotropic evaporation with toluene.
The residue was dissolved in anhydrous DMF (1 ml) and sodium azide (20 mg, 0.3 mmol)
was added. After 1 h stirring at room temperature the reaction mixture was diluted with
water and purified by preparative HPLC giving the title compound as a white solid (11.5
mg, 37 %).
66 £-"
JH NMR (CDC13): 5 9.94 (1H, t, J 5.9 Hz); 8,73 (1H, d, J 2.0 Hz); 7.88 (2H, dt, J 8.4 1.9
Hz); 7.83 (1H, d, J 8.1 Hz); 7.76 (1H, td, J 7.9 3.5 Hz); 7.55 - 7.48 (3H, m); 7.43 (1H, t, J
14.1 Hz); 4.81 - 4.59 (3H, m); 3.02 (3H, s); 2.13 (3H, s); 1.63 (3H, dd, J 6.91.6 Hz).
APCI-MS m/z: 534.2 [MH*].
Example 41 6-Methyl-N-r4-(methy|suIfonyDbenzyl1--5--(l'-morpholin-4-ylethylV2-oxo-lf3>(
trifluoromethvnphaiyn-1.2-dihydropyridine-3-cart>oxanude
To a solution of 5-(l-hydroxyethyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-cartx)xainide (15 mg, 0.03 ramol) in DCM
(2 ml) was added thionyl chloride (0.5 ml, 6.9 mmol) under an argon atmosphere. After 1 h
stirring at ambient temperature, the solvent was removed in vacuo. The last traces of
thionyl chloride were removed by azeotropic evaporation with toluene. The residue was
dissolved in anhydrous DMF (1 ml) and morpholine (0.3 ml, 3,4 nunol) was added. After
35 minutes stirring at room temperature the reaction mixture was diluted with water and
further purified by preparative HPLC giving the title compound as a white solid (4.3 mg,
25%).
*H NMR (CDC13): 810.05 (1H, t, J 5.9 Hz); 8.78 (1H, d, J 1.0 Hz); 7.87 (2H, d, J 8.3 Hz);
7.81 (1H, d, J 7.9 Hz); 7.74 (1H, t, J 8.0 Hz); 7,53 (2H, d, J 8.1 Hz); 7.50 (1H, s); 7.43 (1H,
t, J 7.3 Hz); 4.67 (2H, td, J 24.2 5.9 Hz); 3.70 (4H, dd, J 20.6 11.4 Hz); 3.48 (1H, m); 3.02
(3H, s); 2.53 (2H, s); 2.43 (2H, m); 2.12 (3H, s); 1.36 (3H, dd, J 6.6 1.3 Hz).
APCI-MS m/z: 578.3 [MB*].
Example 42 5-fl-Hvdroxypropv]V6-methyl"N-r4-(methvIsulfonynbenzyn-2-oxo-l-f3-
(triflucromethvDphenyl]-!t..2-dihydropyridine-3-carboxarnide
The title compound was prepared using a procedure analogous to that described for
Example 39.
*H NMR (CDC13): 5 10.01 (1H, t, J 5.9 Hz); 8.79 (1H, d, J 1.7 Hz); 7.87 (2H, d, J 8.3 Hz);
7.81 (2H, d, J 7.9 Hz); 7.74 (2H, t, J 7.8 Hz); 7.52 (2H, d, J 8,3 Hz); 7.49 (1H, s, ); 7.42
(1H, d, J = 7.5 Hz); 4.77 - 4.59 (3H, m); 3.01 (3H, s); 2.10 (3H, s); 2.00 (1H, t, J - 4.5 Hz);
1.98 -1.74 (2H, m); 1.01 (3H, td, J 7.4 2.5 Hz).
APCI-MS m/z: 523.2 [MR*].
Example 43 5-(l-HvdroxyethvlVN-r4-(isopropvlsulfonvDbenzvn-6-methvl-2-oxo-l-r3-
(trifluoromethvDphenvn-l^-dihvdropvfidine-S-carboxainide
The title compound was prepared using a procedure analogous to that described for
Example 39.
*H NMR (CDd3): 5 10.02 (1H, t, J 5.9 Hz); 8.85 (1H, d, J 1.7 Hz); 7.81 (3H, d, J 30.8
Hz); 7.74 (1H, t, J 7.9 Hz); 7.50 (3H, d, J 19.2 Hz); 7.43 (1H, d, J 7.6 Hz); 5.03 (1H, t, J
5.4 Hz); 4.69 (2H, dd, J 29.1 9.7 Hz); 3.15 (1H, quintet, J 6.8 Hz); 2.12 (3H, s); 1.98 (1H,
t, J 4.4 Hz); 1.58 (3H, dd, J 6.4 2.2 Hz); 1.28 (6H, d, J 6.9 Hz).
APCI-MS m/z: 578.3 [MB*].
Example 44 N-r4-CCvclopropvlsulfonvI>benzvn-5-formvl-6-methvl-2-oxo-l-r3-
rtrifluorometfavDphenvn-l^-dihvdropvridine-S-carboxamide
N-[4-(Cyclopropylsulfonyl)benzylJ-5-iodo-6-memyl-2-oxo-l-[3-(trifluoromefliyl)phenyI]-
l,2-dihydropyridine-3-carboxamide [2.6 g, 4.2 mmol; prepared by a procedure analogous
to that described for Example 35 (b)], tris(dibenzylideneacetone) dipalladium (0) (81.9 mg,
0.09 mmol), triphenylphosphine (263.8 mg, 1.0 mmol) and toluene (28 ml) were added to a
100 ml single-neck round bottomed flask. The flask was fitted with a 30 ml dropping
funnel with pressure-equalizer containing tnbutyltin hydride (2.3 g, 7.8 mmol) and toluene
(20ml). The system was thoroughly flushed with carbon monoxide by repeated evacuation
and filling and was then pressurized at 2.5 atmospheres carbon monoxide and heated at 95
°C with vigorous stirring. The tnbutyltin hydride solution was added dropwise over a
period of 3 h. After the addition was complete, the reaction mixture was allowed to reach
room temperature and then the carbon monoxide was flushed out with argon. The solvent
was removed in vacuo and the residue was purified by flash chromatography on silica,
eluting with tert-butyl methyl ether/methanol (10:0.2) to give the title compound as a white
solid (1.6 g, 73%).
NMR (CDa3): 510.06 (IH, s); 9.56 (IH, t, J 5.8 Hz); 9.06 (IH, s); 7.89 - 7.78 (4H,
m); 7.54 - 7.47 (3H, m); 7.44 (IH, d, J 7.8 Hz); 4.68 (2H, ddd, J 21.5 15.4 6.2 Hz); 2.51
(3H, s); 2.42 (IH, m); 1.33 (2H, m); 1.01 (2H, m).
APCI-MS m/z: 519.2 [MR*].
Example 45 5-r(E)-(Mefopftyirmno>metfoI1^
oxo-l-r3^ttifluoroinet^yl)phenyl1-1.2-dihydrDpyridine-3-carboxamidg
A mixture of 5-fonnyl-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-t3-
(trifluorojnethyl)phenyl]-l,2-dihydropyridine-3-carboxaniide (Example 33,14.7 rag, 0.03
mmol), O-methylhydroxylamine hydrochloride (17.2 mg, 0.21 mmol), potassium acetate
(42.7 mg, 0.44 mmol) and water (0.1 ml) in ethanol (1.5 ml) was heated at 60 °C for 2 h.
The reaction mixture was cooled, concentrated in vacuo and the residue was purified by
preparative HPLC to give the title compound as a white solid (6.2 mg, 39 %).
*H NMR (DMSO-ds): 5 9.80 (IH, t, J 6.0 Hz); 8.76 (IH, s); 8.44 (IH, s); 7.95 - 7.79 (5H,
m); 7.74 (IH, d, J 8.0 Hz); 7.54 (2H, d, J 8.3 Hz); 4.58 (2H, d, J 6.1 Hz); 3.90 (3H, s); 3.17
(3H, s); 2.10 (3H, s).
APCI-MS m/z: 522.2 [MR*].
Example 46 5-n^ydrojtymethyIV6-metbyl-N-r4-fmethylsuIfpnyDbenzy]il-2^xj>-|-r3"
(triguoromethyl^henylVl^-dihydropyridine-S-carboxamide
The title compound was prepared using a procedure analogous to that described for
Example 39.
*H NMR (CDC13): 8 9.98 (IH, t, J 28.4 Hz); 8.66 (IH, s); 7.87 (2H, d, J 8.3 Hz); 7.82 (IH,
d, J 8.0 Hz); 7.75 (IH, t, J 7.9 Hz); 7.51 (3H, d, J 8.4 Hz); 7.43 (IH, d, J 8.1 Hz); 4.67 (4H,
m); 3.02 (3H, s); 2.16 (3H, s); 2.01 (IH, t, J 5.3 Hz).
APCI-MS ni/z: 495.1 [MH+],
Example 47 5-rfDimethvlamino)methvn-6-methvl-7^-r4~(methvlsulfonvl)benzvn-2-oxol-
f3-ftrifluQromethv^phenvl]-L2-dihvdrQPVridine-3-carboxamide
-697
a) 5-CChlQromethvl)-6-methvl-^-f4-(methvlsulfonvl')benzyn-2-oxo-l-r3-
(trifluorQmethvnphenvll-1.2-dihvdropvridiTie-3~(;arhnxflmide
5-(Hydroxymethyl)-6-methyl-N-[4-(methylsulfonyl)benzyJ]-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxainide (Example 46,990 mg, 2.0
mmol) was treated with thionyl chloride (476 mg, 4.0 mmol) to give the title compound
(1.0 g, 97%).
APCI-MS m/z: 513.2 [ME*].
b) 54fl^methvIaniino)methvl1-6-methvl-.//-r4-fmethvlsuIfonvnbenzvl1-2-oxo-l-r3-
rtrifluoromethvl)phenvn-1.2-dihvdropvridine-3-carboxamide
A solution of S-^hloromethyO-o^methyl-A^-^-Onethylsulfony^benzy^^oxo-l-IS-
(trifluoromethyl)phenyl]-l^-dihydropyridine-3-carboxamide (5 mg, 0.097 mmol) and
dimethylamine in ethanol (0.5 ml, 33 %) was heated in a microwave for 10 minutes at 50
°C. The mixture was then purified by preparative HPLC to give the title compound as a
white solid (4mg,79%).
*H NMR (DMSO-d6): 5 9.96 (1H, t, J 6.0 Hz); 8.34 (1H, s); 7.90 - 7.85 (4H, m); 7.80 (1H,
t, J 7.8 Hz); 7.70 (1H, d, J 8.0 Hz); 7.53 (2H, d, J 8.3 Hz); 4.58 (2H, d, J 6.2 Hz); 3.57
(2H, s); 3.17 (3H, s,); 2.18 (6H, s ); 2.02 (3H, s).
APCI-MS m/z: 522.1 [MH+]. .
Example 48 6-Methyl-5-r(methvlamino')methvl1-^-r4-(methvlsulfoiivBbenzyI1-.2-oxo-l-
[3-(trifluoromemyl)phenvn-1.2-dihvdropvridine-3^arbQxarnide
The title compound was prepared using a procedure analogous to that described for
Example 47.
JH NMR (DMSO-dg) 8 9.97 (1H, t, J 6.0 Hz); 8.43 (1H, s); 7.94 - 7.85 (4H, m); 7.81 (1H,
t, J 7.8 Hz); 7.67 (1H, d, J 7.9 Hz); 7.53 (2H, d, J 8.2 Hz); 4.58 (2H, d, J 6.0 Hz); 3.57
(2H, s); 3.17 (3H, s); 2.30 (3H, s); 2.02 (3H, s).
APCI-MS m/z: 508.1 [MH+].
,70
Example 49 e-Methvl-^-r^methvlsulfonvDbenzvn-S-dnorpholin^-vImethvn^-oxo-lf3-
ftrifluorom^yDphenyl1-lJ-dihvdropvridine-3-car^oxanude
A solution of S-CchloromethyO-e-methyl-A/'-t^methylsulfonyl^enzyy^-oxo-l-tS-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (Example 47, 8 rag, 0.016
mmol ) and morpholine (5.5 mg, 0.062 mrool) in DMF (1 ml) was heated in a microwave
oven for 10 minutes at 50 °C. The mixture was then purified by preparative HPLC to give
the title compound as a white solid (4 mg, 45 %).
!H NMR (CDC13): 8 10.03 (1H, t, ); 8.56 (1H, s, ); 7.87 (2H, d, J=8.2 Hz); 7.81 (1H, d,
J=7.8 Hz); 7.75 (2H, t, J=7.9 Hz); 7.52 (3H, d, J=8.2 Hz); 4.67 (2H, m ); 3.72 (4H, m );
337 (2H, m ); 3.01 (3H, s, ); 2.50 (3H. s ); 2.13 (2H, m ); 1.57 (2H, s).
APCI-MS m/z: 564.2 "
The compounds of Examples 50 to 59 were prepared using a procedure analogous to that
described for Example 49.
Example 50 5-1 r(2-FurvlmethvI)amino1meQiyl ) -6-methvl"JV-f4-(roethylsulfonynbenzyl|-
2K)xo-l-r3-(trifluoromeftynphenyl]-1.2-dihydrppyrjdine-3 *H NMR (DMSO-dg): 8 9.64 (1H, t, J 6.1 Hz); 8.12 (1H, s); 7.58 - 7.47 (5H, ra); 7.35 (1H,
d, J 7.7 Hz); 7.24 - 7.20 (3H, m); 6.07 (1H, dd, J 3.1, 1.8 Hz); 5.95 (1H, d, J 3.0 Hz);
4.26 (2H, d, J 6.1 Hz); 3.40 (2H, s); 3.29 (2H, s); 2.85 (3H, s); 1.66 (3H, s).
APCI-MS m/z: 574.2 [MH+].
Example 51 54(CvclopropvIamino)methvll-6-methvl^-r4-fmethvlsuIfonvnbenzvn-2-
oxo-l-r3-(trifluoromethynphenyl1-L2-dihvdropyridine-3M:arboxamide
*H NMR (DMSO-de): 8 9.97 (1H, t, J 6.0 Hz); 8.43 (1H, s); 7.90 - 7.84 (4H, m); 7,81
(IH.t, J7.9Hz);7.66(lH,d, J 7.8 Hz); 7.53 (2H, d, J8.3Hz);4.58(2H,d, J 6.0 Hz);
3.65 (2H, s); 3.17 (3H, s); 2.11 - 2.07 (1H, m); 2.02 (3H, s); 0.38 - 0.35 (2H, m, ); 0.26 -
0.23 (2H, m).
APCI-MS m/z: 534.2 [MH*].
Example 52 5-f \(2-HvdroxyptopvI)aminolmethvl > -e-met
fmethvlsulfonvnbenzvI1'2-oxo-l-f34trifluoromethvDphenvD-1.2-dihvdropvridine~3-
carboxamide
*H NMR (DMSO-ds): 8 9.97 (1H, t, J 6.1 Hz); 8.45 (1H, s); 7.90 - 7.85 (4H, m); 7.81 (1H,
t, J 7.8 Hz); 7.68 (1H, d, J 8.1 Hz); 7.53 (2H, d, J 8.4 Hz); 4.58 (2H, d, J 6.0 Hz); 4.49
(1H, d, J 4.4 Hz); 3.72 - 3.68 (1H, m,); 3.63 (2H, s); 3.17 (3H, s); 2.49 - 2.46 (2H, m);
2.02 (3H, s); 1.05 (3H, d, J 6.2 Hz).
APCI-MS m/z: 552.2 [MB*].
Example 53 5-r(Cyclopentylanuno)methy^
oxo-l-f3-(Uifluoromethynphenyl1-1.2-dihydropyridine-3-carboxamide
*H NMR (DMSO-d6): S 9.97 (1H, t, J 6.1 Hz); 8.45 (1H, s); 7.90 - 7.85 (4H, m); 7.81 (1H,
t, J 7.9 Hz);7.67 (1H, d, J 8.0 Hz); 7.53 (2H, d, J 8.3 Hz); 4.58 (2H, d, J 6.0Hz); 3.57
(2H, s); 3.17 (3H, s); 3.05 (1H, t, J 6.1 Hz); 2.02 (3H, s); 1.77 - 1.70 (2H, m); 1.64 - 1.60
(2H, m); 1.49 -1.45 (2H, m ); 1.39 - 1.33 (2H, m).
APCI-MS m/z: 562.2 [MH*].
Example 54 5-frf2-HvdroxvethvI')(methvDaminoilmethvll-6-methvI-jy-r4-
(methylsulfonvnbengyI1-2-oxo-l'r3-ftrifluoromethyl)phenyn-1.2-dihvdropyridine-3--
carboxamide
!H NMR (DMSO-dg): 5 9.97 (1H, t, J 6.0 Hz); 8.36 (1H, s); 7.89 - 7.85 (4H, m); 7.80 (1H,
t, J 8.2 Hz); 7.69 (1H, d, J 8.4 Hz); 7.54 (2H, d, J 8.3 Hz); 4.58 (2H, d, J 6.0Hz); 4.41
(1H, t, J 5.2 Hz); 3.52 (2H, q, J 5.9 Hz); 3.46 (2H, d, J 30.9 Hz); 3.17 (3H, s); 2.47 (2H,
d); 2.18 (3H, s); 2.03 (3H, s).
APCI-MS m/z: 552.2 [MH+].
Example 55 6-MethyI-JVr-r4-(roethv!sulfonvl')benzvn-2-oxo-5-(pvrrolidin-l-vlmethvlVl-
DrftrifluorQmethvltohenvll-l^-dihvdropvridine-S-carboxamide
J727?.)
]HNMR (DMSO-dc): 89.97 (IH, t, J 6.1 Hz); 8.37 (1H, s); 7.90 - 7.85 (4H, m); 7.80 (1H,
t, 3 7.8 Hz); 7.70 (1H, d, J 7.9 Hz); 7.53 (2H, d, J 8.4 Hz); 4.57 (2H, d, 1 6.1 Hz); 3.51
(2H, s); 3.17 (3H, s); 2.47 - 2,44 (4H, m); 2.03 (3H, s); 1.70 (4H, m ).
APCI-MS m/z: 548.2 [MH4].
Example 56 5-(rMethoxyfmethvl)amino1methvll-6-n>ethyl-jy-r4"
carboxamide
*H NMR (DMSO-de): 8 9.94 (1H, t, J 6.0 Hz); 8.39 (1H, s); 7.90 - 7.85 (4H, m); 7.81 (1H,
t, J 8.1 Hz); 7.69 (1H, d, J 7.9 Hz); 7.54 (2H, d, J 8.4 Hz); 4.58 (2H, d, J 6.0 Hz); 3.72
(2H, s); 3.17 (3H, s); 2.58 (3H, s, ); 2.04 (3H, s).
APCI-MS m/z: 538.2 [MH*].
Examples? 5- J rfCvanomfithvnaminolni&thvl l-6-metfavl-^-r4-fmethvlsulfonvlVbenzvn-
^ r3-(trifluorometiivl>hen vU- 1
NMR (DMSO-de): 8 9.78 (1H, t, J 6.2 Hz); 8.25 (1H, s ); 7.74 - 7.64 (5H, m ); 7.51
(iH, d, J 8.1 Hz); 7.37 (2H, d, J 8.3 Hz); 4.42 (2H, d, J 5.7 Hz); 3.53 (2H, d, J 5.7 Hz);
3.48 (2H, d, J 7.1 Hz); 3.01 (3H, a)', 1.87 (3H, s ).
APCI-MS m/z: 533.2 [MH+].
Example 58 5-f [(Cvclopropylmethvnaminolmetbvl l-6-methvl-JV-r4-
carboxamide
NMR (DMSO-de): 8 9.98 (IH, t, J 6.0 Hz); 8.46 (IH, s); 7.88 (4H, dd, J 10.5, 8.5 Hz);
7.81 (IH, t, J 7.9 Hz); 7.68 (IH, d, J 7.9 Hz); 7.53 (2H, d, J 8.3 Hz); 4.58 (2H, d, J 6.0
Hz); 3.62 (2H, s); 3.17 (3H, s); 2.42 (2H, d, J 6.7 Hz); 2.02 (3H, s); 0.91 (lH,s ); 0.43 -
038 (2H, m); 0.14 - 0.10 (2H, m).
APCI-MS m/z: 548.2 [MH*].
Example 59 5-rG-HvdroxvDvrroHdin4-vnmetbvl1-6>methvl-^-r4-
(metfaylsulfonvDbenzvlV2-oxo-l-f34trifluoroinethyDphenvn-1.2-dihvdfopvridine-3-
carboxamide
^NMR (DMSO-dfi): 5 9.97 (1H, t, J 6.1 Hz); 8.37 (1H, s); 7.90 - 7.85 (4H, m); 7.80 (1H,
t, J 7.9 Hz); 7.70 (1H, d, J 7.9 Hz); 7.54 (2H, d, J 8.3 Hz); 4.71 (1H, d, J 4.2 Hz); 4.58
(2H, d, J 6.1 Hz); 4.20 (1H, dt, J 9.7, 3.7 Hz); 3.49 (2H, s); 3.17 (3H, s); 2.79 - 2.74 (1H,
m); 2.58 (1H, t, J 7.6 Hz); 2.50 - 2.45 (1H, in); 2.35 - 2.32 (1H, m); 2.03 (3H, s); 2.00 -
1.97 (1H, m); 1.57 - 1.53 (1H, m).
APCI-MS m/z: 564.2 [MH*].
Example 60 5-f2-HvdroxvethQXvVN-r4~fisoDropylsulfonyl'ybenzvn-6-methvl-2-oxo-lrMtriflioromethvI>pheaivl1--1.2-dih\dropvridine-3-carboxamide
at 5-Hvdroxv-N-r4-('isorovlsulfonvl>benzvn-6-met:hvl-2-oxo>l-f3-
To ice-cooled 35% hydrogen peroxide (11.11 g, 114.4 tnmol) was added concentrated
sulphuric acid (8.92 g, 91.0 mmol) and 5-acetyl-N-[4-(isopropylsulfonyl)benzyl]-6-methyl-
2-oxo-l-[3-(trifluoromethyl)phenyl]4,2^ihydropyridine-3-^arboxainide (Example 35 (c),
2.2 g, 4.1 mmol) in DCM (3 ml). The mixture was stirred vigorously and heated at 45 °C
for 1.5 h. The reaction mixture was cooled to room temperature and then added dropwise
to an ice cooled mixture of ethyl acetate (100 ml) and saturated aqueous sodium carbonate
solution under stirring. The organic layer was collected and the water layer was extracted
with ethyl acetate (2 x 60 ml). The combined organic layers were washed with water and
brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was
purified by flash chromatography on siKca eluting with tert-butyl methyl ether/methanol
(10:0.2) to give the title compound as a yellow solid (1.1 g, 52 %).
!H NMR (CDC13): 5 10.66 (1H, t, J 6.0 Hz); 8.97 (1H, s); 8.16 (1H, s); 7.81 (3H, m); 7.74
(1H, t, J 7.8 Hz); 7.51 (3H, t, J 4.1 Hz); 7.43 (1H, d, J 7.8 Hz); 4.68 (2H, td, J 9.5 4.5 Hz);
3.16 (1H, quintet, J 6.9 Hz); 2.04 (3H, s); 1.28 (6H, d, J 6.9 Hz).
APCI-MS m/z: 509.1 CMH*].
J74
b) 2~f (S-(f f4-(Isopropvlsulfonvl^benzyJ1aniino)carbonvlV2-niethvI-6-oxo-l-f3-
(trifIuoromethvnphMvn-1.6-dihvdropvridin-.3-vlloxv^ethvl acetate
A mixture of 5-hydroxy-N-[4-(isopropylsijlfonyl)benzy]]-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl3-l^^hydropyridine-3^arboxainide (1.05 g, 2.06 mmol), 2-
bromoethyl acetate (1.03 g, 6.17 mmol), l,8-diazabicyclo[5.4.0]iJndec-7-ene (0.94 g, 6.17
mrnol) in anhydrous DMF (2.5 ml) was heated at 80 °C for 25 min under argon. The
reaction mixture was cooled and partitioned between ethyl acetate and water. The organic
layer was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo.
The residue was purified by flash chromatography elutmg with a gradient of ten-butyl
methyl ether to 2.5% methane! in tert-butyl methyl ether to provide the title compound as a
light green solid (0.87 g, 71%).
*H NMR (CDC13): 8 10.11 (1H, t, J 5.8 Hz); 8.58 (1H, s); 7.79 (3H, d, J 8.4 Hz); 7.73 (1H,
t, J 7.9 Hz); 7.48 (3H, d, J 8.2 Hz); 7.41 (1H, d, J 7.9 Hz); 4.67 (2H, ddd, J 21.7, 15.6 and
6.1 Hz); 4.38 (2H, dd, J 5,4 4.0 Hz); 4.21 (2H, dd, J 5.2, 3.7 Hz); 3.13 (1H, septet, J 9.0
Hz); 2.10 (3H, s); 2.04 (3H, s); 1.26 (6H, d, J » 6.9 Hz).
APCI-MS m/z: 595.1 [MH*].
(trifluorometh vDphenyll- 1 .2-dihvdropyridine-3-carboxamide
A mixture of 2-({5-({ [4-(isopropylsulfonyl)benzyl]amino}carbonyl)-2-methyl-6-oxo-l-[3-
(trifluoromethyl)phenyl]-l,6-dihydropyridin-3-yl}oxy)ethyl acetate (0.87 g, 1.46 mmol),
methanol (5 ml) and 2M sodium hydroxide solution (0.2 ml, 0.4 mmol) was stirred at
ambient temperature for 20 min. The solution was acidified with acetic acid, diluted with
water and purified by preparative HPLC to give the title compound as a light green solid
(0.65 g, 82%).
XHNMR (CDC13): 6 10.13 (1H, t, J 5.7 Hz); 8.59 (1H, s); 7.79 (3H, d, J 8.4 Hz); 7.73 (1H,
t, J 7.9 Hz); 7.51 - 7.46 (3H, m); 7.42 (1H, d, J 7.8 Hz); 4.67 (2H, ddd, J 21.7 15.6 6.1 Hz);
4.12 (2H, t, J 4.5 Hz); 3.96 (2H, septet, J 9.6 Hz); 3.14 (1H, septet, J 9.6 Hz); 2.06 (3H, s);
1.83 (1H, t, J 6.0 Hz); 1.26 (6H, d, J 6.9 Hz).
APCI-MS m/z: 553.1 "
Example 61 2-Methyl-5-(U4-(methylsulfonvDbenzvl1ammQlcarbonvlV6-oxo-l~f3-
(trifluoromethvDphenvn-1.6-dihvdropvridin-3-vl acetate
The title compound was obtained as a byproduct during the synthesis of 5-hydroxy-6-
melhyl-A^[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromBthyl)phenyl]-l,2-
dihydropyridine-3-carboxamide when the latter compound was prepared by a procedure
analogous to that described for Example 60 (a).
*H NMR (DMSO-dg): S 9.93 (1H, t,36.1 Hz); 8.33 (1H, s); 7.96 - 7.80 (4H, m); 7.75 (2H,
d, J 8.2 H); 7.54 (2H, d, J 8.3 Hz); 4.59 (2H, d, 3 6.2 Hz); 3.17 (3H, s); 2.32 (3H, s); 1.89
(3H,s).
APCI-MS m/z; 523.3 [MH+].
Example 62 5-Methoxv-6-methvl-J^-r4-(methvlsulfon-yI')benzvn-2-oxo-l-r3-
ftrifiuorQmethyl)phenyll-L2-dihydropyridine-3-carbbxamide
A solution of 5-hydroxy-6-methyl-JV-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-^ihydK>pyridine-3-carboxamide(Example 61,15 mg, 0.031
mmol) and K2CO3 (13.8 mg, 0.1 mmol) in acetone (1 ml) was heated to 60 °C. After 15
minutes the mixture was cooled to room temperature, iodomethane (7 mg, 0.050 nanol)
was added, and the reaction mixture was heated for an additional 30 minutes at 60 °C. The
mixture was then purified by preparative HPLC to give the title compound as a white sou'd
(14mg,90%).
^ NMR (DMSO-de): 510.11 (1H, t, J-5.9 Hz); 8.39 (1H, s,); 7.90 - 7.85 (5H, m,); 7.81
(4H,t, J=7.9Hz);7.71(lH,d, J=8.0 Hz); 7.54 (3H, d, J-8.3 Hz); 4.59 (2H, d, J=6.0
Hz); 3.81 (3H, s,); 3.18 (4H, s,); 1.95 (3H, s,).
APCI-MS m/z: 495.5 [MH*].
Example 63 5-(3-Methoxvpropoxv)-6-methvl-JVr-r4-(methylsulfonvl')benzvn-2-oxo-l-r3-
(trifiuororaethvl^phenvn-l^-dihvdropvridine-S-carboxamide
To a solution of 5-hydroxy-6-methyl-AT-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-
(trifluoromethy^phenyli-l^-dihydropyridme-S-carboxamide (Example 61,10 mg, 0.02
mmol), lithium iodide (2.7 mg, 0.02 mmol) and l,8-diazabicyclo[5.4.0]undec~7-ene (7 mg,
0.04 mmol) in DMF (1 ml), l-bromo-3-methoxypropane (6.1 mg, 0.04 mmol) was added,
,76
and the reaction mixture was heated for 60 minutes at 40 °C. The mixture was then purified
by preparative HPLC to give the title compound as a white solid (5 mg, 45 %).
*H NMR (CDC13): 5 8.58 (1H, s); 10.2 (1H, t); 7.87 (2H, d, J 8.3 Hz); 7.80 (1H, d); 7.74
(1H, t,); 7.52 (3H, d, J 8.4 Hz); 7.4 (1H, d); 4.67 (2H, t, J 5.6 Hz); 4.10 (2H, t, J 6.3 Hz);
3.56 (2H, t, J 6.1 Hz); 3.37 (3H, s); 3.02 (3H, s,); 2.05 (3H,s).
APCI-MS ra/z: 553.2 [MH*].
Example 64 2-Methyl-5 (trifluoromethvl)phenyl1-I.6-dihvdropvridin-3-vlmethanesdfQnate
To a solution of 5-hydroxy-6-methyl-JV*-[4-(methylsuifonyl)benzyl]-2-oxo-l-[3-
(trifluoromethyl)phenyl3-l,2-dihydropyridine-3-carboxamide (5 mg, 0.01 mmol) and
l,8-diazabicyclo[5.4.0]undec-7-ene (3 mg, 0.02mmol) inDCM (1 ml), 2-chloroethylamine
hydrochloride (2.3 mg, 0.02 mmol) was added and the reaction mixture was heated for 60
minutes at 40 °C. The mixture was then purified by preparative HPLC to give the title
compound as a white solid (3 mg, 54 %).
*HNMR (CDCls): 5 7.88 (2H, d, J 8.4 Hz); 7.83 (1H, s); 7.77 (1H, ); 7.55 - 7.50 (3H,
m); 7.48 - 7.43 (1H, m,); 4.67 (2H, t, J 6.3 Hz); 3.33 (3H, s); 3.02 (3H, s); 2.15 (3H, s).
APCI-MS ra/z: 559.1 [MR*].
Example 65 5-Ethoxv-6-methvl-N44-fmethvlsulfonv^benzvl1-2-oxO'l"f3-
ftrifluoromemvl')phenvI1-1.2"dihvdropvridine-3-carboxaniide
A mixture of 5-hydroxy-6-methyl-JV-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxarnide (Example 61,40.7 mg, 0.08
mmol), iodoethane (0.4 ml, 5.0 mmol), l,8-diazabicyclo[5.4.0]undec-7-ene (0.6 g, 4.1
mmol) in DMF (1.5 ml) was stirred at 85 °C for 30 minutes under argon. The reaction
mixture was cooled, diluted with water and purified by preparative HPLC to give the title
compound as a white solid (11.5 mg, 26 %).
*H NMR (CDC13): 510.19 (1H, t, J 5.8 Hz); 8.57 (1H, s); 7.87 (2H, d, J 8.3 Hz); 7.81 (1H,
4/8.0 Hz); 7.74 (1H, t, /7.9 Hz); 7.52 (3H, d, J 8.4 Hz); 7.43 (1H, d, J 7.7 Hz); 4.69
(2H, m); 4.09 (2H, q, J 7.0 Hz); 3.01 (3H, s); 2.05 (3H, s); 1.41 (3H, t, / 7.0 Hz).
77 7ft
APCI-MS m/z: 509.0 (MR*].
Example 66 5-f2-Hvdroxyethoxv)-6-methyl-N-f4-(methvlsulfonvl')benzvll-2-oxo-l-r3-
Ctrifluoromethvl)phenvn-1.2-dihvdropvridine-3-carboxamide
The title compound was obtained by a procedure analogous to that described for Example
60.
*H NMR (CDC13): 6 10.15 (1H, t, J 5.9 Hz); 8.60 (1H, s); 7.87 (2H, d, J 8.3 Hz); 7.81 (1H,
d, J 7.8 Hz); 7.74 (1H, t, J 7.8 Hz); 7.52 (3H, d, J 8.3 Hz); 7.43 (1H, d, J 7.8 Hz); 4.67 (2H,
m); 4.13 (2H, t, J 4.5 Hz); 3.98 (2H, q, J 20.3 Hz); 3.02 (3H, s); Z08 (3H, s); 1.86 (1H, t> J
6.0 Hz).
API-MS m/z: 525.1 [MR*].
Example 67 S-jCyanomeftpxyVd-methvl-N-r^fmethylsulfonyDbenzyll^-oxQ-l-fS--
flrifluoromethvKphenvJ'l-l .2~dihydropvridme-3-carboxamide trifluoroacetate
The title compound was obtained using analogous conditions to those described in
Example 65.
*H NMR (CDCI3): 8 10.12 (1H, t, / 5.6 Hz); 8.61 (1H, s); 7.89 (2H, d, / 8.3 Hz); 7.84 (1H,
d, J 7.9 Hz); 7.76 (1H, t, J 7.9 Hz); 7.51 (3H, d, J 8.2 Hz); 7.45 (1H, d, J 8.0 Hz); 4.82 (2H,
s); 4.69 (2H, ddd, /21.5 15.4 6.1 Hz); 3.02 (3H, s); 2.14 (3H, s).
APCI-MS m/z: 520.0 [MH*].
Example 68 2>(/2-Methvl-5-(f/r4-(methylsulfonvl)benzvl]aminolcarbonvl')-6-oxo-l-f3-
(trifluoromemvl')phenyn-1.6-dihvdropvridin-3-vnoxvlethvl acetate
The title compound was obtained under similar conditions to those described in Example .
60.
!HNMR (CDC13): 810.13 (1H, t, J 5.7 Hz); 8.59 (1H, s); 7.88 (2H, d, J 8.4Hz); 7.81 (1H,
d, J 8.0 Hz); 7.75 (1H, t, J 7.9 Hz); 7.52 (3H, d, J 8.4 Hz); 7.43 (1H, d, J 8.0 Hz); 4.67 (2H,
t, J 5.7 Hz); 4.40 (2H, dd, J 5.4 3.9 Hz); 4.22 (2H, dd, J 5.2 3.8 Hz); 3.02 (3H, s); 2.12 (3H,
s); 2.05 (3H, s).
APCI-MS m/z: 567.2 [MH*].
78
Example 69 542-fl3jmethvIaniinoV2-oxoethoxyl-6-methyI-N-r4-
oarboxamide
a) tert-Butvl ({2-m^hyl-5-(U4-(methvlsulfQnyl'>benzynanunolcarfaonyI')-6-Qxo-l--f3-
The title compound was obtained under similar conditions to those described in Example
60.
*H NMR (CDC13): 8 10.15 (1H, t, J 5.9. Hz); 8.51 (1H, s); 7.87 (2H, d, J 8.4 Hz); 7.81 (IH,
d, J 8.0 Hz); 7.74 (1H, t, J 7.9 Hz); 7.51 (3H, m); 7.43 (1H, d, J 7.8 Hz); 4.67 (2H, ddd, J
20.6, 15.2 and 5,8 Hz); 4.57 (2H, s); 3.01 (3H, s); 2.14 (3H, s); 1.51 (9H, s).
APCI-MS m/z: 595.3 [MH*].
fr) (\ 2-Methyl-5-(f f 4-(mefty|sulfonyl)benzynamino >carbonyl)r6-oxo-l -f3-
(trifljioromethyl Vphenyll-ljD^dihydropyridin-S-yl ) oxytacedc acid
To a solution of tert-butyl ({2-methyl-5-({[4-(methylsulfonyl)benzyl]amino}carbonyl)-6-
oxo4-[3-(trifluoromethyl)phenyl]-l,6-dihydrbpyridin-3-yl}oxy)acetate (103 mg, 0.17
mmol) in THF (3 ml) and methanol (2 ml) was added 2M aqueous sodium hydroxide
solution (0.6 ml, 1.2 mmol). After stirring for 1 h, the reaction mixture was acidified with
acetic acid and concentrated in vacuo. The residue was purified by preparative HPLC to
give the title compound as a white solid (87.7 mg, 95 %).
JH NMR (CDC13): 8 10.48 (1H, t, J 5.9 Hz); 8.58 (1H, s); 7.87 (2H, d, J 8.4 Hz); 7.82 (1H,
d, J 8.1 Hz); 7.75 (1H, t, J 7.9 Hz); 7.51 (3H, d, J 23.6 Hz); 7.44 (1H, d, J 7.9 Hz); 4.78
(2H, s); 4.67 (2H, ddd, J 21.7 15.5 6.1 Hz); 3.02 (3H, s); 2.14 (3H, s).
APCI-MS m/z: 539.1 [MH*].
c) 5jJ2-(Dimethylan^no^-pxoethoxyV6^me^tli[yI-I f3-(trifluoromethvl1phenvU-^J2-dihvdropvridine-3-carbpxamide
A mixture of ({2-methyl-5-({[4-(methylsulfonyl)benzyl]amino}carbonyl)-6-oxo-l-[3-
(trifluoromethyl)phenyl]-l,6-dihydropyridin-3-yl}oxy)acetic acid (87.5 mg, 0.16 mmol)
and thionyl chloride (0.6 ml, 8.24 mmol) in DCM (5 ml) was stirred at 35 °C for 30
minutes under an argon atmosphere. The mixture was cooled and concentrated in vacuo.
The last traces of thionyl chloride were removed by azeotropic evaporation with toluene.
The residue was dissolved in DCM (4 ml) and dimethylamine (0.5 ml) was added. After 30
minutes stirring at ambient temperature the reaction mixture was concentrated and purified
by preparative HPLC to give the title compound as a white solid (47.7 mg, 53 %).
*H NMR (CDC13): 810.19 (1H, t, J 5.9 Hz); 8.48 (1H, s); 7.87 (2H, d, J 8.3 Hz); 7.80 (1H,
d, J 7.9 Hz); 7.73 (1H, t, J 7.8 Hz); 7.51 (3H, d, J 8.1 Hz); 7.44 (1H, d, J 8.3 Hz); 4.81 (2H,
s); 4.66 (2H, dd, J 20.7 9.5 Hz); 3.02 (6H, d, J 4.8 Hz); 2.99 (3H, s); 2.16 (3H, s).
APCI-MS m/z: 566.2 [MH+].
Example 70 5^2-AnunoethoxyVN-r4-fisorm)pylsulfQnvDbenzvl1-6-methyl-2-oxo-l-r3-
(trifluoromethyl)phenyn-1.2-dihydropyridine-3-carboxamide
To a solution of 5-hydroxy-6-methyl-JV-[4-(isopropylsulfonyl)benzyl)-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l^-dihydropyridine-3-carboxamide (Example 60 (a), 25 mg,
0.049 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (15 mg, 0.099 mmol) in NMP (1.5
ml), 2-chloroethylamine hydrochloride (11.5 mg, 0.099 mmol) was added and the reaction
mixture was heated in a microwave oven for 10 minutes at 70 °C. The mixture was then
purified by preparative HPLC to give the title compound as a white solid (8 mg, 25 %).
'HNMR (DMSO-ds): 5 10.11 (1H, t, J=6.1 Hz); 8.38 (1H, s,); 7.90 (2H, d, J=7.8 Hz);
7.83 - 7.78 (3H, m,); 7.72 (1H, d, J=8.0 Hz); 7.54 (2H, d, J=8.3 Hz); 4.61 (2H, d, J=6.2
Hz); 3.93 (2H, t, J=5.6 Hz); 3.42 - 3.31 (2H, m,); 2.86 (2H, t, J=5.6 Hz); 1.97 (3H, s,
J=4.6 Hz); 1.14 (3H, s,); 1.12 (3H, s,).
APCI-MS m/z: 552.2 [MH+].
Example 71 5-(Acetylarnino')-6-rnethyl-N-r4-('methvlsulfonvl')benzyn-2-oxo-l-r3-
(trifluoromethyl)phenvl1-1.2-dihvdropvridine-3-carbQxamide
A mixture of d-methyl-A/'-ethylsulfonyObenzyll-S-nitro-oxo-l-p-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (Example 2,15.3 mg, 0.03
mmol) and iron powder (20 mg, 0.36 mmol) in acetic acid (1.5 ml) was stirred at ambient
temperature for 1 h. The iron powder was filtered off and the filtrate was concentrated in
vacuo. Acetic anhydride (0.25 ml, 2.6 mmol), DMF (1 ml) and saturated aqueous sodium
hydrogencarbonate solution were added to the residue. After stirring the reaction mixture
at room temperature for 30 minutes, it was neutralized with aqueous sodium hydroxide
solution and purified by preparative HPLC to give the title compound as a white solid (3.5
mg, 22 %).
*H NMR (CDC13): 8 9.94 (1H, t, J 6.0 Hz); 8.47 (1H, s); 7.87 (2H, d, J 8.4 Hz); 7.81 (1H,
d, / 7.9 Hz); 7.74 (1H, t, J 7.9 Hz); 7.53 (1H, s); 7.50 (2H, d, J 8.4 Hz); 7.46 (1H, d, J 7.9
Hz); 7.13 (1H, s); 4.68 (2H, m); 3.02 (3H, s); 2.20 (3H, s); 1.99 (3H, s).
APCI-MS rn/z: 522.1 [MH+J.
Example 72 #-f4-Q[sopropvlsutfonyDbenzyl1-6^methvl-5-r3-(^
l-l
a) 543-BromQpropoxy'>-A[-r4-(isopropvlsulfortvnbenzvl1-6-methyl-2K)Xo-l-r3--
(trifluorom6thyl>phenyt1-1.2-dihyo^opyridine-3-carboxamide
A solution of 5-hydroxy-/-[4-(isopropylsulfonyl)benzyl]-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyJ]-ldihyopyridine-3-carboxainide (500 mg, 0.98 mmol),
(1.28 mg, 3.94 mmol) and 1,3 dibromopropane (795 mg, 3.94mmol) in DMF (6 ml) was
heated to 70 °C for 30 minutes. After cooling the mixture was purified by preparative
HPLC to give the title compound as a white solid (100 mg, 16 %).
APCI-MS m/z: 629.2 [MR*].
(trifluoromethvl')phenyn-L2-dihvdropvridine-3-carboxaniide
A solution of 5-(3-bromopropoxy)-jlV-[4-(isopropylsulfonyl)benzyl]-6-niethyl-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (30 mg, 0.048 mmol) and
methanamine (0.5 ml, 2M in THF) was heated in a microwave oven for 60 minutes at 50
°C. The mixture was then purified by preparative HPLC to give the title compound as a
white solid (13 mg, 46%).
*H NMR (CDC13): 5 10.06 (1H, t, J 6.0 Hz); 8.43 (1H, 3); 7.68 ~ 7.66 (3H, m); 7.61 (1H, t,
J 7.8 ); 7.37 (3H, d, J 8.4 Hz); 7.31 (1H, d, J 7.6 Hz); 4.55 (2H, t, J 5.8 Hz); 3.98 (2H, t, J
6.1 Hz); 3.06 - 3.00 (IH, m); 2.75 (2H, t, J 7.0 Hz); 2.40 (3H, s); 1.95 (2H, t); 1.91 (3H, s);
1.15 (3H,s); 1.14 (3H,s).
APCI-MS m/z: 580.2 [MH*].
Example 73 5-fl-MethoxvethvlV6-methvI-Ar-f4-(methvlsuIfonvl)benzvn-2-oxo-l-r3«
(trifluoromethyl)phenvn-1.2-dihydropvridine-3-carboxamide
To a solution of 6-methyl-N-[4-(methyIsulfonyl)benzyl]-2-oxo-l-[3-
(trifluoromethyl)phenyl]-5-vinyl-l,2-dihydropyridine-3-carboxairiide (Example 9,20.7
mg, 0.04 mmol) in methanol (2 ml) was added concentrated sulphuric acid (0.05 ml). The
mixture was stirred at 65 °C overnight and then neutralized with aqueous sodium
hydrogencarbonate solution. The reaction mixture was purified by preparative HPLC to
give the title compound as white solid (5.9 mg, 27 %).
*HNMR (CDC13): 8 10.01 (IH, t, J 5.8 Hz); 8.72 (IH, s); 7.87 (2H, d, J 8.3 Hz); 7.81 (IH,
d, J 7.8 Hz); 7.75 (IH, t, J 7.8 Hz); 7.52 (3H, d, J 28.4 Hz); 7.44 (IH, t, J 6.6 Hz); 4.67
(2H, m); 4.44 (IH, dq, J 0.1 6.3 Hz); 3.29 (3H, d, J 1.0 Hz); 3.01 (3H, s); 2.09 (3H, s); 1.48
(3H,dd,J6.52.1Hz).
APa-MS m/z: 523.0 [MH+].
Example 74 5-(2-Bromo-l-methoxvethvl')-6-methvl-N-r4-fmethvlsulfonvl')benzvn-2-
oxo-l-f3-(trifluoromethyI)phenyn-l,2-dihydit)pvridhie-3-carboxainide
A mixture of 6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-
5-vinyH,2-dihydropyridine-3-carboxamide (Example 9,66.9 mg, 0.14 mmol),
N-broraosuccinimide (37.7 mg, 0.21 mmol) and dibenzoyl peroxide (7.1 mg, 0.03 mmol)
in methanol (2 ml) was stirred at ambient temperature for 1.5 h. The solvent was removed
in vacuo and the residue was purified by preparative HPLC to give the title compound as
white solid (44 mg, 52 %).
!H NMR (CDC13): 8 9.94 (IH, t, J 5.9 Hz); 8.69 (IH, d, J 0.8 Hz); 7.88 (2H, d, J 8.3 Hz);
7.83 (IH, d, J 8.0 Hz); 7.76 (IH, t, J 7.9 Hz); 7.52 (2H, d, J 8.2 Hz); 730 (IH, s); 7.44 (IH,
t, J 7.2 Hz); 4.68 (2H, m); 4.54 (IH, t, J 6.7 Hz); 3.67 (IH, m); 3.46 (IH, m); 3.37 (3H, d, J
1.1 Hz); 3.02 (3H, s); 2.13 (3H, s).
APCI-MS m/z: 600.1,601.1,602.1,603.2 \ME+].
Example 75 5-(l-Isopropoxvethvl)^-methvl--N-r4-(met?iylsuyonyl)benzy|l-2-QXo-143--
(trifluoromethyl)phenvl7-L2-dihydropyridine-3--carboxamide
The title compound was prepared by a procedure analogous to that described for Example
!H NMR (CDC13): 810.02 (1H, t, J 5.8 Hz); 8.76 (1H, s); 7.87 (2H, d, J 8.3 Hz); 7.81 (1H,
d, J 7.8 Hz); 7.74 (1H, t, J 7.9 Hz); 7.52 (3H, d, J 25.3 Hz); 7.43 (1H, t, J 6.7 Hz); 4.68
(3H, m); 3.56 (1H, td, J 6.1 3.7 Hz); 3.01 (3H, s); 2.10 (3H, s); 1.44 (3H, dd, J 6.5 and 2.2
Hz); 1.18 (6H, dd, J 10.8 and 6.1 Hz).
APCI-MS m/z: 551.2 [MH*].
Example 76 S-fNMspbutyrvl-hydrariQocaifoQnylV
phenvlVl^-dihvdrO"pyridine»3-carboxylic acid 4-methanesulfonyl-beii2vlamide
a) 5-Hvdrazinc 3-carboxvlic acid 4-mernanesulfonvl-hen7vlamide
The compound obtained in Example 11 (0.051 g, 0.14 mmol) in DCM (5 ml) was treated
with SOCli (5 ml) and the flask was sealed and stirred magnetically for 2 h, when LC-MS
showed that the reaction was complete. The crude mixture was evaporated in vacuo, giving
the intermediate acid chloride as a yellow solid. The solid was dissolved in 1,4-dioxane (5
ml, dried over molecular sieves) and hydrazine hydrate (0.05 g, 1.0 mmol) was added. The
mixture was stirred for 10 minutes, and LC-MS showed complete formation of the title
compound. The mixture was concentrated in vacuo and the residue was purified by
preparative HPLC giving the title compound (0.036 g, 70%) as a white solid after freezedrying
the pure fractions.
APCI-MS m/z: 523.2 fMH+].
by 5-(Nl4sobutviyI4iydra.zinocarbonylV6-m
dihvdro-pvridine-3-carboxvlic acid 4-methanesulfonvI-benzvlamide
The compound obtained in step (a) (0.025 g, 0.047 mmol) in dry THF (10 ml) was stirred
and isobutyric anhydride (0.040 g, 0.25 mmol) was added. The obtained mixture was
stirred for 15 minutes, and LC-MS showed complete conversion of the starting material to
the desired amide. The solvent was evaporated and the residue was purified by preparative
HPLC giving the subtitle compound (0,024 g, 85%) as a white powder after freeze-drying
the pure fractions.
*HNMR (DMSO-d6): 810.25 (1H, bs); 9.89 (1H, bs); 9.79 (1H, t, 76.2 Hz); 8.50 (1H, s);
7.93 (1H, s); 7.94-7.90 (1H, m); 7.87 (2H, d, J 8.5 Hz); 7.84 (1H, t, 77.7 Hz); 7.74 (1H, d,
77.7 Hz); 7.55 (2H, d, 78.3 Hz); 4.63-4.56 (2H, m); 3.18 (3H, s); 2.55-2.49 (1H, p, 76.8
Hz); 2.18 (3H, s); 1.08 (6H, d, 76.8 Hz).
APCI-MS m/z: 593.2 [MR*].
The compounds of Examples 77 to 87 and 91 to 97 were prepared using a procedure
analogous to that described for Example 12.
Example 77 JvJ-Methoxv-6-methvl-^-r4-(methvlsulfonvl)benzvn-2-oxo-l-r3-
(trifluoromethynphenvn-l^-dihydrQpvridine-S^-dicarboxamide
XHNMR (DMSO-de): 8 11.74 (1H, bs); 9.79 (1H, t); 8.41 (1H, s); 7.95-7.70 (6H, m); 7.54
(2H, d); 4.58 (2H, d); 3.70 (3H, s); 3.18 (3H, s); 2.13 (3H, s).
APCI-MS m/z: 538.1 [MH*].
Example 78 JV5-Methoxv-A^.6-dimethvl-A^-r4-(methvlsuIfonvnbenzvl1-2-oxo-l-r3-
(teifluorornethvDphenyI1-1.2-dihydropyridine-3,5-dicarboxamide
*HNMR (DMSO-ds): 8 9.83 (1H, t); 8.36 (1H, s); 8.01 (1H, bs); 7.94-7.76 (5H, m); 7.54
(2H, d); 4.58 (2H, d); 3.59 (3H, s); 3.28 (3H, s); 3.18 (3H, s); 2.00 (3H, s).
APCI-MS m/z: 552.2 [MH+].
Example 79 5-r(2.5-Pimethvl-2.5-dihvdro-lH-pvrrol-l-vDcarbonvn-6-methvl-N-r4-
(methylsulfonvl)benzy]1-2-oxo-l-r3-(trifluoromethyl)phenvn-1.2-dihvdropyridine-3-
carboxamide
*H NMR (DMSO-d6): 5 9.86 (1H, q); 8.29 (0.5H, d); 8.26 (0.5H, s); 8.06 (0.5H, bs); 8.01
(0.5H, bs); 7.95-7.74 (5H, m); 7.55 (2H, d); 5.83 (2H, dt); 4.80 (1H, bt); 4.58 (2H, d); 4.49
(1H, bd); 3.17 (3H, s); 2.03 (1H, d); 1.92 (1H, d);U4 (3H, d); 1.08 (2H, d); 1.05 (1H, m).
APCI-MS m/z: 588.2 [MH+].
Example 80 6~Methvl-A/J-f4-fmethvlsulfonvDbenzvl1-2-oxo-//5-Dvrrolidin-l-vl--l--r3-
(trifluorometh^l)phenvl1-1.2-dihvdropyridine--3.t5-dicarboxatnide
JH NMR (DMSO-de): 5 9.84 (2H, bt); 8.43 (1H, s); 7.99-7.78 (5H, m); 7.72 (1H, d); 7.54
(2H, d); 4.58 (2H, d); 3.18 (3H, s); 3.02 (4H, bs); 2.13 (3H, s); 1.80 (4H, bs).
APCI-MS m/z: 577.2 [MH+].
Example 81 6-Methvl-N-f4-(mfethvlsiUfonvnbenzvl1-2-oxo-54piperidin-l-vlcarbonvlV
l-r3-(trifluoro|nethyl)phenyl1--1.2-dihydrQpyndinc-3-carbox^inide
^NMR (DMSO-dtf): 5 9.88 (1H, t); 8.20 (1H, s); 8.03 (1H, d); 7.94-7.74 (5H, m); 7.54
(2H, d); 4.58 (2H, bs); 3.79-3.22 (4H, m); 3.18 (3H, s); 1.93 (3H, s); 1.69-1.36 (6H, m).
APQ-MS m/z: 576.2 [MH4].
Example 82 6-Methyl-JVJ-r4-(methylsulfonyl)benzyn-j?\^-roorpholin-4-^-2-oxo-l-r3-
(trifluorpmethyl)phenyl1-1.2^iJiydropyridipe-3.^--dicarboxgmide
^NMR (DMSO-d6): 8 9.82 (1H, t); 9.57 (0.8H, s); 9.22 (0.2H, s); 8.41 (0.8H, s); 8.36
(0.2H, s); 8.00-7.76 (5H, m); 7.72 (1H, d); 7.54 (2H, d); 4.58 (2H, d); 3.66 (4H, m); 3.17
(3H, s); 2.84 (3.2H, m); 2.73 (0.8H, bs); 2.11 (0.8H, s); 2.02 (0.2H, s).
APCI-MS m/z: 593.2 rMH+J.
Example 83 6-Methvl-5-rf4-m?thvlpiperidin-l-vDcarbonvll-N-r4-
(methvlsulfonyDbenzyl1-2-oxo-l-F3-(trifluoromethyDphenyl1-L2-dihyclropyfldine-3-
carboxamide
. (DMSO-d (2H, d); 4.58 (2H, bs); 4.43 (1H, bs); 3.72 (1H, bs); 3.17 (3H, s); 3.05 (1H, m); 2.76 (1H,
m); 1.93 (3H, d); 1.77-1.55 (3H, m); 1.19-0.80 (5H, m).
APCI-MS m/z: 590.2 [MB*].
Example 84 6-Methvl-J\^-r4-(metfavlsulfonvl>)benzvn-2-oxo-A?!?-piperidm-l-vI-l-r3-
(trifluoromethyl')phenvn-1.2-dihvdropvridine-3.5-dicarboxamide
JHNMR (DMSO-dg): 5 9.82 (1H, t); 9.64 (0.8H, s); 9.12 (0.2H, s); 8.39 (0.8H, s); 8.35
(0.2H, s); 8.00-7.77 (5H, m); 7.72 (1H, d); 7.54 (2H, d); 4.58 (2H, d); 3.19 (3H, s); 2.84
(3H, m); 2.11 (0.8H, bs); 2.02 (0.2H, s); 1.66-1.53 (4H, m); 1.53-1.32 (3H, m).
APCI-MS m/z: 591.2 [MH*].
Example 85 jy?-rtert-ButvlV^?.6-dimethvI-^?-r4-(methvlsulfonv])benzvn-2-oxo-l-r3-
(trifluoromethyl)phenyn-1.2-dihvdropvridine-3.5-dicarboxamide
JHNMR (DMSO-de): 8 9.88 (1H, t); 8.19 (1H, s); 7.99 (1H, d); 7.91-7.73 (5H, m); 7.54
(2H, d); 4.58 (2H, bs); 3.18 (3H, s); 2.91 (3H, s); 1.95 (3H, s); 1.45 (9H, s).
APCI-MS m/z: 578.2 [MH+j.
Example 86 JVJ-Butvl-^V5.6-dimethvl-N3-r4-rmethvlsulfonvl)benzvn-2-oxo-143-
(trifluoromethyl)phenyn-lt2-dihydropyridme-3,5-dicarboxamide
^NMR (DMSO-dc): 5 9.88 (1H, t); 8.19 (1H, d); 8.01 (1H, s); 7.95-7.74 (5H, m); 7.54
(2H, d); 4.58 (2H, bs); 3.18 (3H, s); 2.95 (1.2H, s); 2.94 (1.8H, s); 1.92 (1.8H, s); 1.91
(1.2H, s); 1.63-1.40 (2H, m); 1.40-1.10 (2H, m); 0.92 (1.8H, t); 0.83 (1.2Ht).
APCI-MS m/z: 578.2 [MH*].
Example 87 Ar?-Ethvl-A^-isopropyl-6-methvl-JV?-r4-(methv]suIfonvnbenzvn-2-oxo-l-r3-
(trifluoromethvDDhenvn-l^-dihvdropvridine-S^-dicarboxamide
*H NMR (DMSO-de): 5 9.90 (1H, t); 8,20 (0.3H, s); 8.15 (0.7H, s); 8.10-7.95 (1H, m);
7.95-7.75 (5H, m); 7.54 (2H, d); 4.58 (2H, bs); 4.02 (1H, bs); 3.36 (2H, bs); 3.18 (3H, s);
1.91 (3H, s); 1.32-0.96 (9H, m).
APCI-MS m/z: 578.2 [MH*"].
The compounds of Examples 88 to 90 were prepared using a procedure analogous to that
described for Example 76.
Example 88 5-iN1-(Fonnyl-hydrazmocarboriyI1-6-inethyI-2-oxo-l-(3-trifluorornethvlphenylV1.2-
dihydro-pvrioMne^3-carboxylicacid4-methan6sulfonvl-benzylamide
*H NMR (DMSO-ds): 5 10.43 (1H, s); 10.13 (1H, s); 9.79 (1H, t, / 6.2 Hz); 8.52 (1H, s);
8.11 (1H, s); 7.93 (1H, s); 7.94-7.89 (1H, s); 7.87 (2H, d, J 8.65 Hz); 7.87 (1H, d, J 8.21);
7.74 (1H, d, / 8.21 Hz); 7.55 (2H, d, J 8.21 Hz); 4.63-4.54 (2H, m); 3,17 (3H, s); 2.18 (3H,
APCI-MS m/z: 551.2 [MH+].
Example 89 N1-r5-(4-Me1faanesuIfonvl-benzvlcarbamovIV2-methvI-6-oxo-l-(3-
trifluoromethvl-phenvlVL6-dihvdro-pvridine-3-carbonvl1-hvdrazi7iecarboxvHcacidetiivl
ester
1H NMR (DMSO-dtf): 8 10.23 (1H, s); 9.79 (1H, t, J 6.1 Hz); 9.23 (1H, s); 8.47 (1H, s);
7.94 (1H, s); 7.94-7.89 (1H, d, / 8.2 Hz); 7.87 (2H, d, J 8.4 Hz); 7.82 (1H, d, 77.7 Hz);
7.74 (1H, d, / 7.8 Hz); 7.54 (2H, d, / 8.4 Hz); 4.65^.55 (2H, m); 4.14-4.01 (2H, m); 3.17
(3H, s); 2.16 (3H, s); 1.25-1.15 (3H, m).
APCI-MS m/z: 595.2 [MR*].
Example 90 5-( 1 2-rrEthvlamino)carbonothiovnhvdrazino ) carbonvl^-6-meth vl-Ar4-
(metliyIsu]fonynb6nzyl1-2-oxo-l-r3-ftrifluoromethvDphenvl1-1.2-dihydrppyridine^
carboxamide
.-87
!H NMR (DMSO-d 8.14 (1H, bs); 7.95-7.81 (4H, m); 7.71 (1H, d, / 8.0 Hz); 7.55 (2H, d, J 8.3 Hz); 4.60 (2H,
d, 7 6.1 Hz); 3.54-3.44 (2H, m); 3.18 (3H, s); 2.16 (3H, s); 1.08 (3H, t, .7 7.1 Hz)
APCI-MS m/z: 610.2 [MR*].
Example 91 5-(Isoxazolidin-2-vlcarbonvlV6-methyI-//-r4-(methvlsulfonvl'>benzvn-2-
oxo-l-rS-ftrifluorom&thvDphenvn-l^-dihvdfopvridine-S-carboxainide
!H NMR (DMSO-dg): 8 9.79 (1H, t); 8.41 (1H, s); 7.99 (1H, s); 7.93-7.74 (5H, m); 7.54
(2H, d); 4.58 (2H, d); 3.96 (2H, t); 3.76 (2H, m); 3.17 (3H, s); 2.31 (2H, p); 2.05 (3H, s).
APCI-MS m/z: 564.3 [MR*].
Example 92 6'Methvl-2-oxo-l-f3-trifluoromethyI-phenylVl^-dihvdro-pvridin&-3T5-
dicaiboxvlic acid 54methoxy-mefbyl-aipide) 3-r4-(propan&-2-sulfonvl)-benzylamide1
!HNMR (CDCb): 6 9.87 (1H, bt); 8.67 (1H, s); 7.84-7.74 (4H, m); 7.52-7.49 (3H, bd);
7.45-7.43 (1H, bd); 4.74-4.64 (2H, m); 3.62 (3H, s); 3.38 (3H, s); 3.19-3.13 (1H, m); 2.13
(3H,s);1.28(6H,d,J6.8Hz).
APCI-MS m/z: 580 [MH+],
Example 93 6-MethvI-2-oxo-l-(3-trifluQromethvl-phenvlV1.2-dihvdro-pvridine-3.5-
dicartooxvlic acid 3-(4-ethanesulfonvl-benzyIamide) 5-(methoxv-methyl-amide1
^NMR (CDC13): 5 9.87 (1H, bt); 8.67 (1H, s); 7.86-7.82 (3H, m); 7.78-7.74 (1H, bt);
7.53-7.50 (3H, m); 7.45-7.43 (1H, bd); 4.74-4.64 (2H, m); 3.66 (3H, s); 3.38 (3H, s); 3.09
(2H, q, 77.5 Hz); 2.13 (3H, s); 1.26 (3H, t, 77.5 Hz).
APCI-MS m/z: 566 [MH+].
Example 94 6-Methvl-2-oxo-l-G-triflucaromethvl-phenvlV1.2-dihvdro-pvridme-3.5-
dicarboxvlicacid3-(4-cvcIopropanesulfonvl-benzvlamide)5-('methoxv-methvl-amide')
*H NMR (CDCls): 5 9.86 (1H, bt); 8.67 7.51-7.49 (3H, bd); 7.45-7.43 (1H, bd); 4.73-4.63 (2H, m); 3,66 (3H, s); 3.38 (3H, s); 2.46-
2.39 (1H, m); 1.35-1-31 (2H, m); 1.04-0.99 (2H, m).
APCI-MS m/z: 578 [MH+],
Example 95 g-Methyj^-oxo- l-(3-trifluorometfayl-phenvlM .2-dihydrQ-pyridige-3,5-
dicarboxvlic acid 5-rf2-hvdroxv-ethvn-amidel 3-(4-methanesulfonvl-benzvlamide
*H NMR (DMSO-ds): 6 9.82 (1H, t, 7 6.0 Hz); 8.48 (1H, s); 8.48 (1H, t, 7 5.6 Hz); 7.93-
7.89 (1H, m); 7.90 (1H, s); 7.87 (2H, d, 7 8.2 Hz); 7.83 (1H, t, 7 7.6 Hz); 7,72 (1H, d, 7 7.9
Hz); 7.54 (2H, d, 7 8.2 Hz); 4.74 (1H, bs); 4.64-4.54 (2H, m); 3.50 (2H, t, 7 6.2 Hz); 3.32-
3.25 (2H, m); 3.17 (3H, s); 2.14 (3H, s).
APCI-MS m/z: 552.2 [MH+].
Example 96 5-fl5oxazQlidine-2-catbony^-6-methyI-2-oxo-l-(3-triflorQmethylphenyni.
2diydro-pvridine-3-ca^)oxvlic acid 4-ethanesulfonvl-benzvlamide
!H NMR (CDC13): 8 9.83 (1H, bt); 8.70 (1H, s); 7.85-7.81 (3H, m); 7.77-7.73 (1H> bt);
7.53-7.50 (3H, m); 7.45-7.43 (1H, bd); 4.73-4.63 (2H, m); 4.06 (2H, t, J 7.2 Hz); 3.91 (2H,
t, 77.2 Hz); 3.08 (2H, q, 77.7 Hz); 2.48-2.41 (2H, m); 2.19 (3H, s); 1.26 (3H, t, 77.7 Hz).
APCI-MS m/z: 579 [MB*].
Example 97 5-(Isoxazolidme-2-carbonyn-6-metfayI-2-oxo-l-f3-trifluorometh-y]phenyn
1.2dihydropvridine-3-carboxvlic acid 4-cvclQDropane8ulfonvlbenzvlamide
!H NMR (CDC13): 8 9.81 (1H, bt); 8.70 (1H, s); 7.84-7.81 (3H, m); 7.77-7.73 (1H, bt);
7.52-7.48 (3H, m); 7.45-7.43 (1H, bd); 4.73-4.62 (2H, m); 4.06 (2H, t, 76.8 Hz); 3.91 (2H,
t, 7 7.2 Hz); 2.48-2.39 (3H, m); 2.19 (3H, s); 1.35-1.31 (2H, m); 1.04-0.99 (2H, m),
APCI-MS m/z: 590[MH+).
Example 98 5-(N-Hydroxvcarbaininiidoy]V6-methyl-2-oxo-l-(3-trifluoromethylphenvl'-
1.2-dihvdro-Dvridine-3-carboxvlicacid4-methanesulfonvI-benzv]amide
,89 °)c
5-Cyano-6-methyl-2-oxo- 1 -(3-triflucMromethyl-phenyl)-l ,2-dihydro-pyridine-3-carboxylic
acid 4-melhanesulfonyl-benzylainide Example 1, 0.040 g, 0.082 mmol), hydroxylamine
hydrochloride (0.015 g, 0.209 mmol), NaOAc (0.017 g, 0.209 mmol), ethano! (3 ml), water
(0.1 ml) and a magnetic stirrer were placed in a vial. The mixture was heated at 90 °C
overnight. LC-MS showed a 50:50 mixture of two components, one of which had the
expected MW. The product was isolated by preparative HPLC giving 0,012 g (28%) of the
title compound.
!H NMR (DMSO-d Hz); 7.86 (2H, d, J 8.2 Hz); 7.85 (1H, s); 7.83 (1H, t, J 7.8 Hz); 7.69 (1H, d, J 7.8 Hz);
7.54 (2H, d, / 8.3 Hz); 5.88 (2H, bs); 464-4.55 (2H, m); 3.17 (3H, s); 2.07 (3H, s).
APCI-MS m/z: 523.2
Example 99
{trifIuoromethYl>phenYl1-1.2-dihydgppyri a> Ethvl 6-methvl-2-oxo-l -r3-ftrifluorometfavl)phenvll-l .2-dihvdropvridme-3-carboxvlate
A suspension of 6-methyl-2-oxo- l-[3-(trifluoromethyl)phenyl3-l,2-dihydropyridine-3-
carboxyKc acid (Example 1 (b), 13.1 g, 43.9 mmol), sodium carbonate (5.2 g, 48.3 mmol)
and iodoethane (10.6 g, 67.7 mmol) in NMP (60 ml) was stirred at ambient temperature for
19 h under a nitrogen atmosphere. The reaction mixture was partitioned between ethyl
acetate and water. The organic phase was collected, washed with water and brine, dried
over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash
cnromatography on silica eluting with tert-butyl methyl ether/methanol (10:0.4) to give the
title compound as a light brown solid (12.5 g, 87%).
!H NMR (CDC13); S 8.21 (1H, d, J 7.4 Hz); 7.75 (1H, d, J 7.8 Hz); 7.68 (1H> t, J 7.8 Hz);
7.49 (1H, s); 7.42 (1H, d, / 7.8 Hz); 6.25 (1H, d, / 7.4 Hz); 4.36 (2H, q, J 7.2 Hz); 2.03
(3H,s);1.37(3H,t,77.2Hz).
APCI-MS m/z: 326.1 [MH*].
b)_ Ethyl 5Modo-6.fflemyl-2^xo-I-(3r
carboxvlate
To a solution ethyl 6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-
carboxylate (9.9 g, 30.5 mmol) in CHaCl2 (45 ml) and TFA (38 ml) was added
N-iodosuccinimide (6.89 g, 30.6 mmol) under a nitrogen atmosphere. After 19 h stirring at
ambient temperature the solvent was concentrated in vacuo. To the residue were added
ethyl acetate and saturated aqueous sodium hydrogencarbonate to neutralize the remaining
TFA. The organic phase was collected, washed with water and brine, dried over sodium
sulfate, filtered and concentrated in vacuo. The residue was purified by flash
chromatography on silica eluting with DCM/methanol (10:0.2) to give the title compound
as a yellow solid (11.4 g, 83%).
*H NMR (CDC13): 8 8.52 (1H, s); 7.76 (1H, d, J 7.8 Hz); 7.69 (1H, t, J 7.9 Hz); 7.46 (1H,
s); 7.38 (1H, d, 77.7 Hz); 4.36 (2H, q, Jl.l Hz); 2.26 (3H, s); 1.37 (3H, t, /7.2 Hz).
APCI-MS m/z: 452.0 [MH*].
c) Eth,yl 5-r(dimethylarninokarbonvl1-6^inethyl-2-oxo-l-r3-('trifluorornethvnphenvI1-l.2-
dihydropvridine-3-carboxv3ate
Ethyl 5-iodo-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyI]-l ,2-dihydropyridine-3-
carboxylate (2.6 g, 5.76 mmol), palladium triphenylphosphine (38.7 mg, 0.15 mmol), anhydrous dimethylamine (5 ml) and anhydrous
ethanol (20 ml) were placed in a stainless-steel autoclave (100 ml). The reaction mixture
was stirred at 85 °C under a carbon monoxide pressure of 5 J atmospheres for 2 h. After
cooling, excess carbon monoxide was released into a fume hood and the solvent was
concentrated in vacuo. The residue was purified by preparative HPLC to give the title
compound as a white solid (1.3 g, 58 %).
*H NMR (CDC13): 8 8.16 (1H, s); 7.77 (1H, d, J 7.9 Hz); 7.70 (1H, t, /7.8 Hz); 7.49 (1H,
s); 7.41 (1H, d, J7.9 Hz); 4.36 (2H, q, J7.1 Hz); 3.09 (6H, 4/30.2 Hz); 2.04 (3H, s);
1.37(3H,t,J7.2Hz).
APCI-MS m/z: 397.2 [MH+].
d 5-rfl3imethvlaminoV;arbonvn-6-methvl-2-oxo-l-r3-ftrifluoromethvDphenvn-2-
dihvdropvridine-3-carboxvlie acid
To a solution of ethyl 5-[(dimethyIamino)carbonyl]-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l^-dihydropyridine-3-carboxylate (1.28 g, 3.2 mmol) in THF (5
ml) and water (1 ml) was added dropwise 2M sodium hydroxide (1.7 ml, 3.4 mmol) over 1
h. After an additional 2 h stirring at ambient temperature, the solution was acidified to pH
1 and concentrated in vacuo. The residue was purified by preparative HPLC to give the
title compound as a white solid (0.92 g, 77 %).
*HNMR (CDC13): 8 8.47 (1H, s); 7.88 (1H, d, J7.8 Hz); 7.80 (1H, t, 77.9 Hz); 7.56 (1H,
s); 7.48 (1H, d, /7.9 Hz); 3.12 (6H, d, .7 36.0 Hz); 2.15 (3H, s).
APCI-MS m/z: 369.1 [MR*].
e) NVCyclohexvlmethvlVJV5JV^6-trimethvl-2-oxo-l-r3-(trifluoromethvl)phenyn-1.2-
dihydropyridine-3 J-dicarboxamide
A mixture of 5-[(dmiemylamino)carbonyl]-6-methyl-2-oxo-l-[3-(trifluromethyl)-phenyl]-
l,2-dihydropyridine-3-carboxylic acid (12 mg, 0.03 mmol), HATU (15 mg, 0.04 mmol),
HOAT (7 mg, 0.04 mmol) and DffiA (13 mg, 0.1 mmol) in NMP (160 ul) was added to
(cyclohexylmethyl)amine in NMP (135 fil, 0.3M, 0.04 mmol). The reaction mixture was
stirred for 17 h at room temperature. The solvent was removed in vacuo, and the residue
was dissolved in acetonitrile/water, 50/50, to a total volume of 1.6 ml, and purified using
preparative HPLC to give the title compound (8 mg, 58%).
RT (CJ8, UV 220 nm): 7.3 min.
APCI-MS m/z: 464.2 [MH+].
The compounds of Examples 100 to 146 were prepared using a procedure analogous to that
described for Example 99.
Example 100 N5.^5.6-Trimethvl-2-oxo-N3-(pvridin-3-vlmethvn-l-r3-(trifluoromethvnphenylM,
2-dihydropyridine-3.5-dicarboxamide
RT (Cis, UV 220 nm): 5.0 min.
APCI-MS m/z: 459.2
Example 101
.(trifluoromethvjVp)ienyn-1.2-dihvdropvridtne-3.5-dicarboxQnude
RT (C18, UV 220 nm): 4.9 min.
APCI-MS m/z: 481.1 [MR* J.
Example 102 AJV5>6-Trimethvl-JV3-(3-morolm-4-vlt>ropvlV2--Qxo>l-T3-
RT (C18, UV 220 nm): 5.0 min.
APCI-MS m/z: 495.2 [MB*].
Example 103 JV3-BenzvI-^.Ns.6-trimethvl-2-oxo-l-r3-(trifluoromethynphenvn-l>2-
dihydyo-pyridine-S^S-dicarboxamide
RT (C18, UV 220 nm): 6.8 min.
APCI-MS m/z: 458.2 [MR*].
Example 104 fllff-fodol-S-vnethvn-JS
RT (Cia, UV 220 nm): 65 min.
APCI-MS m/z: 511.1 [MH+].
Example 105
1 .2-djhydropyridine-3 .5~dicarboxamide
RT (Cis, UV 220 nm): 7.0 min.
APCI-MS m/z: 472.3 [MR*].
Example 106 ^5J^.6-TrimethvI-2K>xo-^3-(2-t>henvlethvIVl--r3-(trifluorometh-vl')dien\ll-
1
RT (C18, UV 220 nm): 5.3 min.
APCI-MS m/z: 472.1 [MH+],
Example 107 A/sJVs.6-Trimethvl-2-oxo-JV34(2J?V2-phenvlcvclopropvll-1-r3-
(trifluoromethylVphenyl1-1.2-dihvdropviidme-3,5-dicarboxamide
RT (Cis, UV 220 nm): 5.5 min.
APCI-MS m/z: 484.1 [MH*].
Example 108
ftrifluoromethyD-phenvn- 1 ,2-dihydropvridine-3.5-dicarboxainide
RT (C18, UV 220 nm): 5.4 min.
APCI-MS m/z: 484.1 [MH+].
Example 109 ^-r2-n3-Beiizodioxoi-5-vnethvn-/^.Ar^6-trimethvl-2-oxo-l-f3-ftrifluoromethyl>
phenyn-1.2-dihvdropvridine-3^-dicarboxamide
RT (Ci8, UV 220 nm): 5.2 min.
APCI-MS m/z: 516.2 [MH+],
Example 110 5-f r4-(2-Hvdroxvethvl>pipeTazin-l-vl1caibonvU-jyjy.2-trimetfavl-6-oxo-l--
r3-ftrifluoromemvl)phenyl14.6-dihydropvridiiie-3-cafboxa3nide
RT (C18, UV 220 nm): 3.1 min.
APCI-MS m/z: 481.3 [MH+3.
Example 111 J/3-ra-Eth\lpvrrolidin-2-vl>methvn-^5JN?a.6--trimethvl-2-oxo-l-r3-
ftriflaoro-methynphenvn-1.2-dihydropyridine-3.5-dicarboxamide
RT (Cig, UV 220 nm): 3.5 min.
APCI-MS m/z: 479.2
Example 112 JV5JV5.6-Trimethvl^3-r3-(2-methvlpiperidin-l-v])propvn-2-oxo-l-f3-
(trifluoro-methyl^phenyn-1.2-dihvdropyridine-3.5-dicarboxamide
RT (C,8, UV 220 nm): 3.7 min.
APCI-MS m/z: 507.2 [MH+].
Example 113 JV5JV5.6-Trimethvl-jy3-fl-naphthv]methvlV2-oxo.l-r3-
(trifluoTomethyl>phenvn-lJi^hy^ropyridme-3.5-dicarboxamide
RT (Cig, UV 220 nm): 5.7 min.
APCI-MS m/z: 508.1 [MR*].
Example 114
methyljpfaenyll-l^^dihydropyridine-S.S-dicarboxamide
RT (Cig, UV 220 ran): 5.1 min.
APCI-MS m/z: 502.1 [MH*].
Example 115 A-
rMfluorometfavnpheByl1-1.2-d;hydropvridine-3.5-dicarboxamide
RT (Ci8> UV 220 nm): 5.4 min.
APCI-MS m/z: 494.2 [MH*].
Example 116 3-f2-ChlcMP^flporobenzvlVJVs.A/5.64iimethvl-2-oxo-l-r3-
RT (Cig, UV 220 nm): 5.6 min.
APCI-MS m/z: 510.1 [MH+].
Example 117
ftrifluoromemvnpenvn-1.2-dihvdropvridine-3.5-dicarboxamide
RT (Cia, UV 220 nm): 5.0 min.
APCI-MS m/z: 464.2 [MH+].
Example 118 JV3-f3.4>DichIorobenzvn-5.Ag.6-trimethvl-2-oxo-l-r3-
(trifluoromethyl>phenylV2-dihydropviidine-3t5- RT (Cia, UV 220 nm): 5.9 min.
APCI-MS m/z: 526.1 [MH+].
Example 119 ^3-r2-(2.4-Dichlorophenvl)etfavll-^5^s.6-trimetfavl-2-oxo-143-
{trifluoromethylVphenyl1--L2-dihvdn)Pvridine-3.5-dicarboxamide
RT (Ci8, UV 220 nm): 6.0 rain.
APCI-MS m/z: 540.1 [MH+J.
Example 120
(trifluoromethylVphenyn-l^-dihvdropvridine-3.S-dicarboxamide
RT (C,8, UV 220 nm): 5.7 min.
APCI-MS m/z: 476.2 [MH+J.
Example 121 ^3-ri-f4-Chlorophenvnethvn-JV5JVs.6-trimethvl-2-oxo-l-r3-
Ctrifluoromethyl)-phenyl1-1.2-dihvdropvridine-3.5-dicaiboxamide
RT (Cig, UV 220 nm): 5.8 min.
APCI-MS m/z: 506.2 [MH+].
Example 122 ^sJVs.6-Ttimethvl-2-oxo-JV3-r3--r2-oxopvrrolidin--l-vl)propvn-l-r3-
ftrifluoro-methvl)phenvI1'1.2-dihydropyiidine-33^icarboxaniide
RT (Cis, UV 220 ran): 4.0 min.
APCI-MS m/z: 493.3 [MR*].
Example 123 A^J^^-Trimethyl^-oxo-^-fpyiidm^ylmethyl^-l-fSftrifluog)
methyl)phenyn-1.2-dihydropyridine-3.5-dicarboxaniide
RT (C]8, UV 220 nm): 3.3 min.
APCI-MS m/z: 459.2 [MH+j.
Example 124 7/^.2-TrimethvI-6-oxo-5-r(4-phenvlpiperazin-l-vl)carbonvn-l-r3-
(trifluorQ-methyl)phenyn-L6-dihydropyridine-3-carboxamide
RT (Cjs, UV 220 nm): 4,1 min.
APCI-MS m/z: 513.2 [MR*].
Example 125 ^^.2-Trimethv]-6-oxo>5-f(4-Pvridin-2>vlpipCfazin-l-vlV;arbonvn-l-f3-
(trifluoro-methyDphenyn-L6-di^vdrgpvridine-3-carbQxamide
RT (da, UV 220 nm): 3.2 min.
APCI-MSm/z: 514.3 [MH+].
Example 126 /V3-(2.3-Dihvdro-l-benzofuran-5-vlmeihvlVNsJV5.6-trimethyl-2-oxo-l-f3-
(tiifluoroinethynphenyn-1.2-dihvdropvridine>-3.5-dicarboxamide
RT (Cis, UV 220 nm): 5,1 min.
APCI-MS m/z: 500.2 [MH*].
Example 127 Methy) 4-{ f (\ S-f(dimethylamino'k;arbonvn-6-methvl-2-oxo-f3-(trifluofomethl)
hen]l-l ^-dihvdroridin-3-'l Icarbonaminolinethl benzoate
RT (Cia, UV 220 nm): 5.1 min.
APCI-MS m/z: 516.2 [MH*].
Example 128 5-1 r3-fl>imethvlamino^pvrrolidin-l-vlleafbonvl \-JVJ/2-trimethvl-6-oxo-l
F3-f trifluoromethyDphenvn- 1 .6-dih vdtQpyridine-3-cayboxamide
RT (Cis, UV 220 nm): 3.1 min.
APCI-MS m/z: 465.2 [MH*].
Example 129 JVsJVs.6-Trimethvl-2-oxo-jy3-r2-(2-thiegynethvn-l-r3-
(triflaoromethvnphenvn-1.2-dihvdtopvridine-3.5-dicarboxamide
RT (Ci8> UV 220 nm): 5.2 min.
APCI-MS m/z: 478.1 [MH*],
Example 130 JV5JVg>6-TrimethvI-2-oxo-?/3-(4-phenoxvbenzvD-l-r3-
(trjfluorQmethvDphenyl1-1.2-dihydropvridine-3.5-dicarboxamide
RT (Cja, UV 220 nm): 6.0 min.
APCI-MS m/z: 550,3 [MH+].
Example 131 ArsJV5.6-Trimethvl-2-oxo-JV3-f3-thienvlmethvn-l-r3-
(trifluoromgthvI)phenvn-1.2-dihvdropvridine-3.5-dicarbox8nade
RT (Cig, UV 220 am): 5.0 min.
APCI-MS m/z: 464.2 [MR*].
Example 132 A^-f2-(4-ferf-Butvlphenvl'>etfivll-/»/5JV5.6-trimethvl-2-oxo-l-r3-
(trifluoromethvlVphenvI1-1.2-dihydropyridine-3.5-dicarfaoxamide
RT (Cis, UV 220 nm): 6.3 min.
APCI-MS m/z: 528.2 [MB*].
Example 133 N3-(244-(AminosuIfonvl)phenvl1ethvU"JV5JV5.6>tritaethvl-2-oxo-l-r3--
RT (Ci8, UV 220 nm): 4.4 min.
APCI-MS m/z: 551.2 [MH+].
Example 134 JVsJV5.6-Trimethvl-2-oxo^-r4-flg-pvrazoI-l-vnbenzvn-l-r3-
(t|ifluoromethyIVphenyl1-1.2-dihydrop\ridine-3T5-dicarboxapMde
RT (da, UV 220 nm): 5.0 min.
APCI-MS m/z: 524.2 [MH+].
Example 135
dihvdro-Dvridine-3.5-dicarboxamide
RT (Cig, UV 220 nm): 5.1 min.
APCI-MS m/z: 460.1 [MH+].
Example 136 /J/3-(f2.3-Pihvdro-1.4-benzodioxin-2-vlmethvlVAr5.A?5.6-trimethv3-2-oxo-l-
[S-ftrifluoromethyl^phenvn-l^-dihvdropvridine-S^-dicarboxamide
RT (Cig, UV 220 nm): 5.4 min.
APCI-MS m/z: 516.2 [MH*].
Example 137 J73-f(6-Huoro-4H-1.3-benzodioxin-8-vl'>methvll-N5./^.6-trimethvI-2-QXQ-lf3^
trifluoromethvIJphenvI1-1.2-dihvdropyridine-3,5-dicarboxainide
RT (Cis, UV 220 nm): 5.2 min.
APCI-MS m/z: 534.2 [MH+].
Example 138 JV3-a-Ben20thien-3-vlmethvn-MjV5.6-trimethvl-2-oxo-l-r3-
(trifIuoromethylVphenyll-L2-dihydropyQdine-3^-dicarboxamide
RT (Cis, UV 220 nm): 5.6 min.
APCI-MS m/z: 514.1 [MH*].
Example 139.A.6-Triniethyl-2-oxo-Ar3-r2-ftetrahvdro-2g-.pvran-4-vnethvl1-l-r3-
RT (Ca, UV 220 nm): 4.5 min.
APCI-MS m/z: 480.2 [MH*}.
Example 140 JVsJV5.6-Trmiethvl--A?3-r(l-methvl-lfl-pvrazoI-4-vnmethvl1-2-oxo-l-r3-
(trif]iuorO"methynph€nvI1-L2'dihvdropvridin6-3,5-dicarboxamide
RT (Ci8 UV 220 nm): 4.0 min.
APCI-MS m/z: 462.2 [MH*].
Example 141
(trifluoio-methvl')phenyll-lJ2-dihydropyridine-3,5-dicarboxamide
RT (Cig, UV 220 nm): 5.1 min.
APCI-MS m/z: 524.2 [MH+],
Example 142 /^-Ff5-Methoxv-4-oxo-4flr-pvran-2~vDmethvl1-^s.//i.6-trimethvl-2-oxo-lr3-(
trifluoromethvl)phenyI1-1.2-dihydropyridine-3.5-dicarboxamide
RT (Cis, UV 220 nm): 3.9 min.
APCI-MS m/z: 506.2 [MH*].
Example 143
rtrifluoromethvl)phenvn-1.2-dihvdropvridine-3.5-dicarboxamide
RT (C18, UV 220 nm): 3.7 min.
APCI-MS m/z: 507.2 [MH+].
Example 144 JV3-(4-Cyanobenzvl>-JVsJV5.6-trirnethvl-2-oxo-l-r3-(trifiuoromethvDphenyIV
lT2-dihydropyridine-3.5-dicarboxamide
RT (Gig, UV 220 nm): 5.0 min.
APCI-MS m/z: 483.2 [MH+j.
Example 145 J^Jv^-Trimernvl^-oxcKA^-ra-fS^
yI)pTopyl]-l-r3-(trifluoromemyI)p^^^
RT (Cis, UV 220 nm): 3.8 min.
APCI-MS m/z: 492.2 [MH+].
Example 146 JV3-! r(2/^l-EmvlpwoMn-2-vl1methvl l-A^.JV5.6-trimethvl-2-oxo-l-r3-
(trifluorQ-methvDphenvl1"lJ-djhydropyri6^ne-3.5-dcarboxamide
RT (Cj8, UV 220 nm): 3.4 min.
APCI-MS m/z: 479.2 [MH+].
Example 147 5-Cvclopropvl-6-methvl-N-f4"fhiethvlsulfonvl)benzvn-2-oxo-l-r3-
(trifluorojnethvI)phenvl1-1.2rdihydrppvridine-3-carboxamidet
A mixture of 5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (Example 1 (d), 120.4 mg,
0.20 mmol), cyclopropylboronic acid (48.7 mg, 0.57 mmol), potassium phosphate (195.3
mg, 0.85 mmol), tricyclohexylphosphine (19.9 mg, 0.07 mmol) and palladium acetate (8.5
mg, 0.03 mmol) in toluene (4 ml) and water (0.08 ml) was stirred at 100 °C under an argon
atmosphere for 2 h. The reaction mixture was cooled and concentrated in vacuo.
The residue was purified by preparative HPLC to give the title compound as a white solid
(36mg,35%).
H NMR (CDCb): 610.06 (IH, t, J 5.9 Hz); 8.48 (IH, s); 7.87 (2H, d, J 8.4 Hz); 7.81 (IH,
d, J 7.8 Hz); 7.74 (IH, t, J 7.8 Hz); 7.51 (3H, d, J 8,4 Hz); 7.42 (IH, d, J 7.7 Hz); 4.67 (2H,
m); 3.01 (3H, s); 2.20 (3H, s); 1.76 (IH, dd, J 13.6 3.0 Hz); 0.99 (2H, m); 0.70 (2H, q, J 5.1
Hz).
APCI-MS m/z: 505.1 [MB*].
Example 148 6-Methvl-5-f2-methvl-1.3-dioxolan-2-vlVN-r4-(methvlsulfonvnbenzvn-2-
oxo-l-r3-ftrifluoromethvilDhenvn-1.2-dihvdropvridine-3-carboxamide
5-Acetyl-6-methyl-/^-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyI)phenyl]-l,2-
dihydropyridine-3-carboxamide (Example 4,55 mg, 0.11 mmol), ethane-l,2-diol (482 mg,
8,7 mmol), toluene-4-sulfonic acidmonohydrate (21 mg, 0.11 mmol) and toluene (50 ml)
were placed in a round-bottomed flask (100 ml) equipped with a Dean and Stark water
separator, reflux condenser and magnetic stirrer. The reaction mixture was heated at reflux
for 48 h. After cooling, the mixture was neutralized with aqueous sodium hydrogen
carbonate solution and the solvent was removed in vacuo. The residue was purified by
preparative HPLC to give the title compound as a white solid (31.5 mg, 52 %).
XH NMR (CDC13): 8 9.99 (IH, t); 8.90 (IH, s); 7.87 (2H, d); 7.81 (IH, d); 7.74 (IH, t);
7.52 (2H, d); 7.50 (IH, s); 7.42 (IH, d); 4.67 (2H, m); 4.07 (2H, m); 3.85 (2H, m); 3.01
(3H, s); 2.23 (3H, s); 1.67 (3H, s).
APCI-MS m/z: 551.0 [MH*].
Example 149 5-(4.5-Dihvdro-oxazol-2-vl'>-6-methvl-2-oxo-l>(3-trifluoromethvl-phenvlV
1.2-dihvdro-pvridine-3-carboxvlic acid 4-methane8ulfonyl-benzvIamide
The compound obtained in Example 95 (0.022 g, 0.04 mmol) was dissolved in dry DCM (2
ml). To this solution was added one drop of SOCfe, and the mixture was allowed to stand
for 1 h. LC-MS showed complete consumption of the starting material. Evaporation and
subsequent purification on preparative HPLC afforded the title compound 0.004 g (20%)
as a white solid after freeze-drying the pure fractions.
*H NMR CDMSO-dg): 6 9.74 (IH, t, J6.1 Hz); 8.78 (IH, s); 7.96 (IH, s); 7.91 (IH, d, J 7.6
Hz); 7.86 (2H, d, J 8.2 Hz); 7.83 (IH, t, J1.& Hz); 7.76 (IH, d, 77.8 Hz); 7.54 (2H, d, J
PCT/SE2004/001336
8.2 Hz); 4.65-4.55 (2H, m); 4.38 (2H, t, / 9.2 Hz); 3.99 (2H, t, J 9.2 Hz); 3.17 (3H, s); 2.40
3H,s).
APCI-MS ra/z: 534.1 [ME*],
Example 150 5-CycIopropvl-6-methvl-N-(f5--(methvlsulfonvl'>pvridin-2-vnmethvl)-2-
O^o-l-r3-ftrifluoromethyl)ph^yl1-1.2rdihydropyridine-3^aflrboxamide
a) 5-Cyclopropyl'6-methyl-2^xo-l-f3'(teifluoromethyl)phenyll-1.2--dihydrQpvridine-3-
cafboxylic acid
Ethyl 5-iodo-6-methyI-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-
carboxylate (Example 99 (b), 0.77 g, 1.6 mmol), toluene (35 ml), cyclopropyl-boronic acid
(0.257 g, 3 mmol), Pd(OAc)2 (0.072 g, 0.35 mmol), P(c-Hex>3 (0.169 g, 0.6 mmol), K^O,
monohydrate (1.6 g, 6.9 mmol), water (0.7 ml) and a magnetic stirrer bar were placed in a
pressure safe glass vessel. The vessel was sealed and heated (130 °C) with stirring
overnight LC-MS showed complete formation of the intermediate ethyl ester. The mixture
was allowed to cool and the phases were diluted with EtOAc (50 ml) and water (50 ml)
and the phases were allowed to separate. The organic phase was washed with water and
brine, and further dried with Na^SO* Filtration and evaporation gave a crude intermediate.
This material was dissolved in THF (10 ml) and water (5 ml). To this solution was added
NaOH (1M, 3 ml, 3 mmol) and the mixture was stirred for 2 h at 50 °C. The THF was
evaporated and the residual aqueous phase was acidified and extracted with EtOAc (2 x 20
ml). The extracts were washed with water and brine and finally dried over NaSC
Filtration and evaporation gave the required carboxylic acid (0.19 g, 33%).
APCI-MS m/z: 338.1 [MH+]. Retention time 2.35 minutes.
b^ 5-(Methvlthio>pyridine-2-<:arbonitrile> 5-Bromo-pyridine-2-carbonitrile (2.63 g, 13.7mmol), sodium methanethiolate (1.44 g, 20.5
mmol), potassium carbonate (3.79 g, 27.4 mmol) in NMP (60 ml) were stirred in a sealed
flask overnight. The mixture was partitioned between ethyl acetate and water! "the organic
phase was washed with water several times, brine and dried over sodium sulphate. The
solvent was removed in vacuo to afford the title compound as a yellow solid (2.0 g, 99%).
*H NMR (CD3OD): 6 8.54 (1H, d, J 2.3 Hz); 7.83 - 7.71 (2H, m); 2.60 (3H, s).
c) 5-(Methylsulfony]')pyridine-2-carbonittile
5-(Methylthio)pyridine-2-carbonitrile (2.0 g, 13.3 mmol) was dissolved in DCM (20 ml)
and cooled to -15 °C and 3-chloroperoxybenzoic acid (6.75 g, 27.4 mmol) was added in
portions while the temperature was kept between -15 °C to -10 °C When the addition was
complete, the cooling bath was removed and the mixture was stirred at room temperature
for 2 h. 2M KOH and DCM were added. The organic phase was separated, washed twice
with 2M KOH, water and brine, dried over sodium sulphate and evaporated to afford the
title compound as a white solid (2.15 g, 89%).
*H NMR (CD3OD): 5 9.22 (1H, d, J 2.3 Hz); 8.54 (1H, dd, J 8.1,23 Hz); 8.13 (1H, d, J
8.3Hz);3.27(3H,s).
d) {r5-fMethylsulfonvl)pyridin-2-ynmemyl} amine hvdrochloride
5-(MethylsulfonyI)pyridine-2-carbonitriIe (2.15 g, 11.8 mmol) was dissolved in methanol
(230 ml). 6M HCI (1 ml) and 10% palladium on carbon (234 mg) were added and the
mixture was stirred under an atmospheric pressure of hydrogen overnight. The catalyst was
removed by filtration through celite and the solvent was evaporated, water was added and
the solution was freeze-dried to afford the title compound as a yellow powder (2.34 g,
H NMR (CD3OD): 5 9.10 (1H, d, J 2.2 Hz); 8.36 (1H, dd, J 8.2,2.4 Hz); 7.68 (1H, d, J
8.8 Hz); 4.29 (2H, s); 3.22 (3H, s).
eli _5_-Cyclopropyl»6-methy|-N- ([5^(mediyIsuIfonyl1pvridin-2-ynmethvl 1 -2-oxo-l -f 3-
1-1.2-dihvdropvridine-3-carboxamide
5-Cyclopropyl-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-
carboxylic acid, {[5-(methylsulfonyl)pyridin-2-yl]methyl}amine hydrochloride, HBTU
and D1EA in NMP were reacted together overnight. Purification by HPLC gave the title
compound.
1H NMR (DMSO): 8 10.14 (IH, t, J 5.8 Hz); 8.98 (IH, d, J 2.3 Hz); 8.26 (IH, dd, J 8.2,
2.4 Hz); 8.18 (IH, s); 7.94 - 7.79 (3H, m); 7.74 - 7.68 (IH, m); 7.55 (IH, d, J 8.4 Hz); 4.69
(2H, d, J 5.9 Hz); 3.29 (3H, s); 2.13 (3H, s); 1.90 - 1.78 (IH, m); 0.99 - 0.90 (2H, m); 0.64
-0.56(2H,m).
APCI-MS m/z: 506.1 [MR*].
Human Neutrophil Elastase Quenched-FRET Assay
The assay uses Human Neutrophil Elastase (HNE) purified from serum (Calbiochem art.
324681; Ref. Baugh, RJ. et at, 1976, Biochemistry. 15,836-841). HNE was stored in
50 mM NaOAc, 200 mM Nad, pH 5.5 with added 30% glycerol at -20 °C. The protease
substrate used was Elastase Substrate V Fluorogenic, MeOSuc-AAPV-AMC (Calbiochem
art. 324740; Ref. Castillo, M.J. et aL, 1979, Anal. Biochem. 99,53-64). The substrate was
stored in DMSO at -20 °C. The assay additions were as follows: Test compounds and
controls were added to black 96-well flat-bottom plates (Greiner 655076), 1 jtLin 100%
DMSO, followed by 30 j*L HNE in assay buffer with 0.01% TritonX-100. The assay
buffer constitution was: 100 mM Tris (pH 7.5) and 500 mM NaCl. The enzyme and the
compounds were incubated at room temperature for 15 minutes. Then 30 fj,\ substrate in
assay buffer was added. The assay was stopped after 30 minutes incubation at room
temperature by adding 60 fi\ stop solution (140 mM acetic acid, 200 mM sodium
monochloroacetate, 60 mM sodium acetate, pH 4.3). Fluorescence was measured on a
Wallac 1420 Victor 2 instrument at settings: Excitation 380 nm, Emission 460 nm. IC5Q
values were determined using Xlfit curve fitting using model 205.
When tested in the above screen, the compounds of the Examples gave ICso values for
inhibition of human neutrophil elastase activity of less than 30 jxM, indicating that the
464100
compounds of the invention are expected to possess useful therapeutic properties.
Specimen results are shown in the following Table:
Compound
(Table Removed)

WE CLAIM;
1. A 2-pyridone compound of formula (I) used as inhibitors of human neutrophil elastase and homologous serine proteases and a pharmaceutically acceptable salts thereof;

(Formula Removed)
wherein:
Y represents CR3 or N;
R1 represents H or Cl to C6 alkyl;
R2 represents:
i) CN, NO2, OH, OSO2R47, O-C2 to C6 alkanoyl, CO2R47, CHO or C2 to C6
alkanoyl; or ii) Cl to C6 alkoxy is unsubstituted or substituted by OH, C1 to C6 alkoxy, CN,
NR54R55, CONR54R55, OCOR47 or one or more F atoms; or iii) C3 to C6 saturated or partially unsaturated cycloalkyl is unsubstituted or
substituted by C1 to C6 alkyl; or iv) C4 to C7 saturated or partially unsaturated heterocyclic ring containing 1 to
3 heteroatoms independently selected from O, S(O)m and NR62 is
unsubstituted or substituted by C1 to C6 alkyl; or v) CONR48R49, CONR50NR48R49, C(=NOR52)R53, C(=NH)NHOR52 or
NR48R49; or vi) C2 to C6 alkenyl or C2 to C6 alkynyl; said alkenyl or alkynyl group is
unsubstituted or substituted by C1 to C6 alkoxy or phenyl or a five- or six-
membered heteroaromatic ring containing 1 to 3 heteroatoms independently
selected from O, S and N; said phenyl or heteroaromatic ring being is

unsubstituted or substituted by halogen, CN, C1 to C6 alkyl or C1 to C6
alkoxy; or vii) C1 to C6 alkyl substituted by one or more F atoms; or viii) C1 to C6 alkyl substituted by one or more groups selected from halogen,
OH, oxo, azido, NR48R49 , C1 to C6 alkoxy and C1 to C6 alkoxy substituted
by one or more F atoms; or ix) C1 to C6 alkyl substituted by phenyl or a five- or six-membered
heteroaromatic ring containing 1 to 3 heteroatoms independently selected
from O, S and N; said phenyl or heteroaromatic ring is unsubstituted or
substituted by halogen, CN, C1 to C6 alkyl or C1 to C6 alkoxy;
R48 and R49 independently represent H, OH, C1 to C6 alkoxy, C3 to C6 cycloalkyl, CHO, C2 to C6 alkanoyl, CO2R50, C(X)NR63R64 or Cl to C6 alkyl; said alkyl is unsubstituted or substituted by OH, C1 to C4 alkoxy, C3 to C6 cycloalkyl, CN or phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N; said alkanoyl is unsubstituted or substituted by CN;
X represent O or S;
or the group NR48R49 together represents a saturated or partially unsaturated 5 to 7 membered azacyclic ring is unsubstituted or substituted by one heteroatom selected from O, S and NR56; said azacyclic ring is unsubstituted or substituted by one or more substituents selected from OR57 and C1 to C4 alkyl; said alkyl is unsubstituted or substituted by OR57;
R3 represents H or F;
G1 represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N;
R5 represents H, halogen, Cl to C6 alkyl, CN, Cl to C6 alkoxy, NO2, NRI4R15, Cl to C3 alkyl substituted by one or more F atoms or C1 to C3 alkoxy substituted by one or more F atoms;

R14 and R15 independently represent H or C1 to C3 alkyl; said alkyl is unsubstituted or substituted by one or more F atoms;
n represents an integer 1, 2 or 3 and when n represents 2 or 3, each R5 group is selected independently;
R4 represents H or C1 to C6 alkyl; said alkyl is unsubstituted or substituted by OH or C1 to C6 alkoxy;
or R4 and L are joined together such that the group —NR4L represents a 5 to 7 membered azacyclic ring is unsubstituted or substituted by one heteroatom selected from O, S and NR16 ; said ring is unsubstituted or substituted by C1 to C6 alkyl or NR60R61 ; said alkyl is unsubstituted or substituted by OH;
L represents a bond, O, NR29 or CI to C6 alkyl; said alkyl is unsubstituted or substituted by one heteroatom selected from O, S and NR16 and said alkyl is unsubstituted or substituted by OH or OMe;
G2 represents a monocyclic ring system selected from:
i) phenyl or phenoxy,
ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S and N,
iii) a C3 to C6 saturated or partially unsaturated cycloalkyl, or
iv) a C4 to C7 saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms independently selected from O, S(O)p and NR and is unsubstituted or substituted by incorporating a carbonyl group; or
G represents a bicyclic ring system in which each of the two rings is independently selected from:
i) phenyl,

ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms
independently selected from O, S and N, iii) a C3 to C6 saturated or partially unsaturated cycloalkyl, or iv) a C4 to C7 saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms independently selected from O, S(0)p and NR17 and is unsubstituted or substituted by incorporating a carbonyl group;
and the two rings are either fused together, or are bonded directly together or are separated by a linker group selected from O, S(0)q or CH2,
said monocyclic or bicyclic ring system is substituted by one to three substituents independently selected from CN, OH, C1 to C6 alkyl, C1 to C6 alkoxy, halogen, NR18R19, NO2, OSO2R38, CO2R20, C(=NH)NH2, C(O)NR2lR22, C(S)NR23R24, SC(=NH)NH2, NR31C(=NH)NH2, S(O)sR25, SO2NR26R27, Cl to C3 alkoxy substituted by one or more F atoms and Cl to C3 alkyl substituted by SO2R39 or by one or more F atoms; or
when L does not represent an bond, G also represent H;
at each occurrence, m, p, q, s and t independently represent an integer 0, 1 or 2;
R18 and R19 independently represent H, Cl to C6 alkyl, formyl, C2 to C6 alkanoyl, S(O)tR32 or SO2NR33R34 ; said alkyl group is unsubstituted or substituted by halogen, CN, Cl to C4 alkoxy or CONR41R 42;
R25 represents H, Cl to C6 alkyl or C3 to C6 cycloalkyl; said alkyl group is unsubstituted or substituted by one or more substituents selected independently from OH, CN, CONR35R36, CO2R37, OCOR40, C3 to C6 cycloalkyl, a C4 to C7 saturated heterocyclic ring containing one or two heteroatoms independently selected from O, S(O)p and NR43 and phenyl or a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S and N; said aromatic ring is unsubstituted or substituted

by one or more substituents selected independently from halogen, CN, C1 to C4 alkyl, C1 to C4 alkoxy, OH, CONR44R45, CO2R46, S(O)sR65 and NHCOCH3
R32 represents H, C1 to C6 alkyl or C3 to C6 cycloalkyl;
R16, R17, R20, R21, R22 R23, R24, R26, R27, R29, R3\ R33, R34, R35, R36, R37, R38, R39 R40 R 41 R42 R43 R44 R45 R46 R47 R50 R52 R53 R54 R55 R56 R57 R60

R61 ,R62 ,R63 ,R64 and R65 independently represent H or C1 to 6 alkyl.
2. A compound as claimed in claim 1, wherein Y is CR .
3. A compound as claimed in claim 1 and 2, wherein G1 represents phenyl.
4. A compound as claimed in any one of claims 1 to 3, wherein R5 represents Cl, CH3, CN or CF3.
5. A compound as claimed in claims 1 to 4 used as inhibitors of human neutrophil elastase and homologous serine proteases.
6. A pharmaceutical formulation comprising a compound of formula (I) as claimed in claims 1 to 4, or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable diluent or carrier.
7. A process for preparing compounds as claimed in claims 1 to 4, and pharmaceutically acceptable salts thereof, which comprise:
a. reacting a compound of formula (II)

(Formula Removed)

b. with a nucleophile providing R group selected from Cu(I)CN, an alkyl vinyl ether, an organo-tin compound, an organo-boronic acid, a terminal alkyne or an alcohol and carbon monoxide;
wherein R1, R2, R4, R5, Y, G1, G2, L and n are defined in formula (I) and Hal represents a halogen atom, preferably bromo or iodo, to obtain a compound of formula (I).

Documents:

2073-DELNP-2006-Abstract-(18-12-2008).pdf

2073-DELNP-2006-Abstract-(20-11-2008).pdf

2073-DELNP-2006-Abstract-(23-12-2008).pdf

2073-Delnp-2006-Abstract-17-04-2008.pdf

2073-delnp-2006-abstract.pdf

2073-DELNP-2006-Claims-(04-12-2008).pdf

2073-DELNP-2006-Claims-(18-12-2008).pdf

2073-DELNP-2006-Claims-(20-11-2008).pdf

2073-DELNP-2006-Claims-(23-12-2008).pdf

2073-Delnp-2006-Claims-17-04-2008.pdf

2073-delnp-2006-claims.pdf

2073-delnp-2006-complete specification (granted).pdf

2073-DELNP-2006-Correspondence-Others-(18-12-2008).pdf

2073-DELNP-2006-Correspondence-Others-(20-11-2008).pdf

2073-Delnp-2006-Correspondence-Others-17-04-2008.pdf

2073-DELNP-2006-Correspondence-Others.pdf

2073-DELNP-2006-Description (Complete)-(18-12-2008).pdf

2073-delnp-2006-description (complete)-(23-12-2008).pdf

2073-delnp-2006-description (complete).pdf

2073-DELNP-2006-Form-1-(18-12-2008).pdf

2073-DELNP-2006-Form-1-(20-11-2008).pdf

2073-DELNP-2006-Form-1-(23-12-2008).pdf

2073-delnp-2006-form-1.pdf

2073-DELNP-2006-Form-18.pdf

2073-DELNP-2006-Form-2-(20-11-2008).pdf

2073-DELNP-2006-Form-2-(23-12-2008).pdf

2073-Delnp-2006-Form-2-17-04-2008.pdf

2073-delnp-2006-form-2.pdf

2073-Delnp-2006-Form-26-17-04-2008.pdf

2073-delnp-2006-form-3.pdf

2073-delnp-2006-form-5.pdf

2073-delnp-2006-pct-210.pdf

2073-delnp-2006-pct-304.pdf

2073-DELNP-2006-Petition-137-(18-12-2008).pdf

2073-Delnp-2006-Petition-137-17-04-2008.pdf

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Patent Number

231488

Indian Patent Application Number

2073/DELNP/2006

PG Journal Number

13/2009

Publication Date

27-Mar-2009

Grant Date

05-Mar-2009

Date of Filing

17-Apr-2006

Name of Patentee

ASTRAZENECA AB

Applicant Address

S-151 85 SODERTALJE, SWEDEN,

Inventors:

#	Inventor's Name	Inventor's Address
1	HANS LONN	ASTRAZENECA R&D LUND, SE-221 87 LUND, SWEDEN,
2	ANTONIOS NIKITIDIS	ASTRAZENECA R&D LUND, SE-221 87 LUND, SWEDEN,
3	PETER HANSEN	ASTRAZENECA R&D LUND, SE-221 87 LUND, SWEDEN,
4	KAROLINA LAWITZ	ASTRAZENECA R&D LUND, SE-221 87 LUND, SWEDEN,

PCT International Classification Number

C07D 211/86

PCT International Application Number

PCT/SE2004/001336

PCT International Filing date

2004-09-15

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	0302487-4	2003-09-18	Sweden