Indian Patents
Title of Invention

"A 2-PYRIDONE COMPOUND"
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 derivatives, 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. J. Pharmacol. 451,1-10). It degrades a wide range of extracellular matrix proteins such as elastin, Type 3 and type 4 collagens, laminin, fibronectin, cytokines, etc. (Ohbayashi, H., 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. Crit. 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 tti-antitrypsin (Laurell and Eriksson, 1963, Scand. J. Clin. Invest 15,132-140). Subsequently it was determined that cci-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 in 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 (Xi-proteinase inhibitor-deficient mice (Cavatra et al., 1996, Lab. Invest 75,273-280). Individuals with higher levels of me NE-cti protease inhibitor complex in bronchoalveolar lavage fluid show sigtiifbaiitly accelerated decline in lung functions compared to those with lower levels (Betsuyoku et al. 2000, Respiration, 67,261-267). Instillation of human NE via the trachea in r?.ts 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-trcatment with inhibitors of NE.( Fujie et al.,1999, Inflamm. Res. 48,160-167).
Nputrophil-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, BM & Voynow, 2002, Am. J. Respir. Cell Bid., 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. Crit. 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. J., 13,190-196).
NE has been also shown to play a role in the pathogenesis of pulmonary fibrosis. NE: di.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 amurine model of human pulmonary fibrosis, aNE inhibitor reduced bleomychi-induced pulmonary fibrosis (Taooka et al., 1997, Am. J. Resp. Grit Care Med, 156,260-265). Furthermore investigators have shown mat 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). Jhe antiproteases and NE complexed with antiprotease are increased in lung cancer area (Merchandise 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 endotoxiu in experimental animals is associated with elevated levels of NE (Kawabata, et al., 1999,. Ajm. J. Resp. Crit. Care, 161,2013-2018). Acute lung inflammation caused by intratracheal injection of lipdpolysaccharide 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 neutrophil-induced increase of pulmonary microvascular permeability observed in a model of acute lung injury caused by tumour necrosis factor a (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.T 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 ulcerau've 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. Inf., 6, 57). The development of collagen induced arthritis in mice is suppressed by a NE inhibitor (Kakimoto et al., 1995, Cellular Lnmunol. 165,26-32).
Thus, humon 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 ai-antitrypain. 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 cci-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-rype receptor.
The present invention discloses novel 2-pyridione derivatives that are inhibitors of human neutropnil 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)
represents CR orN;
R represents H or Cl to 6 alkyl;
2 R represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to 4
heteroatoms independently selected from O, S and N; said aromatic ring being optionally substituted by 1 to 3 substituents selected independently from OH, halogen, Cl to 6 alkyl,
Cl to 6 alkoxy, NR58COR5°, COOR51, COR52, CONR R and NR4 R ; said alkyl being optionally further substituted by OH, Cl to 6 alkoxy, CN or CO2R ;
R and R independently represent H, Cl to 6 alkyl or C2 to 6 alkanoyl;
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, NC2, NR R1 , 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 C1 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;
4
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
azacyclic ring optionally incorporating one further heteroatom selected from O, S and NR16;
L represents a bond, O, S(O)p, 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 O, S(O)p and NR and optionally further 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 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(O)p and NR 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 CEfe,
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,
NR18R19, NO2, OS02R38, CO2R2°, C(=NH)NH2, C(O)NR21R22, C(S)NR23R24, SC(=NH)NH2, NR31C(=NH)NH2, S(O)SR25, SC>2NR26R27, Cl to 3 alkoxy substituted by
one or more F atoms and C1 to 3 alkyl substituted by SO2R , NR R or by one or more
F atoms; or
2 when L does not represent an bond, G may also represent H;
At each occurrence, p, q, s and t independently represent an integer 0,1 or 2;

R and R independently represent H, Cl to 6 alkyl, formyl, C2 to 6 alkanoyl, S(O)tR
33 34 or SO^NR 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,
CONR35R36, CO2R37, OCQR40, C3 to 6 cycloalkyl, a C4 to 7 saturated heterocyclic ring
43 containing one or two heteroatoms independently selected from O, S(O)p and NR and
phenyl or a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O. S and N; said aromatic zing being optionally further substituted by one or more subatituents selected independently from halogen, CN, Cl to 4
alkyl, Cl to 4 alkoxy, OH, CONR R , O^R , S(O)SR and NHCOCH3;
32 R represents H, Cl to 6 alkyl or C3 to 6 cycloalkyl;
58 and R independently represent H or Cl to 6 alkyl;
and pharmaceutically acceptable salts thereof.
The compounds of fonnula (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 alkyl" 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 3,3,3-trifluoropropyl.
Unless otherwise indicated, the term "Cl to 6 alkoxy " referred to herein denotes an oxygen substituent bonded to a straight or branched chain aBtyl 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 3 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 4 heteroatoms independently selected from O, S and N include furan, thiophene, pyrrole, oxazole,

1,2,4-oxadiazole, 1,3,4-oxadiazole, isoxazole, imidazole, pyrazole, thiazole, triazole, thiadiazole, pyridine, pyrimidine, pyrazine and tetrazole. 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, 1,2,4-oxadiazole, 1,3,4-oxadiazole, isoxazole, imidazole, pyrazole, 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, cyclopenteny], cyclohexyl and cyclohexenyl. The term "five- or six-membered saturated or partially unsaturated cycloalkyl ring" is to be interpreted analogously.
Unless otherwise indicated, the tenn "C4 to 7 saturated or partially unsaturated
heterocyclic ring containing one or two heteroatoms independently selected from O, S(O)p
17 and NR 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, Ictrahydropyran, 41oxo-4H-pyran, pyrrolidine, pyrroline, imidazolidine, dihydro-oxazole, dihydropyrazole, 1,3-dioxoIane, piperidine, piperazine, morpholine, perhydroazepine, pyrrolidone and piperidone. The term "five- or six-membered saturated or partially unsaturated heterocyclic ring containing one
heteroatom selected from O, S and NR " is 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; saidalkyJ 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, -^2CH2O-CH2-, -CH2CH2O-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, 3H-indolyl, IH-indazolyl, quinuclidyl, tetrahydronaphthyl, dihydrobenzofuranyl, morpholine-4-ylphenyl, 1,3-benzodioxolyl, l,l-dioxido-23-dihydro-l-benzothienyl, 23--dihydro-l,4-benzodioxinyl, 1,3-benzodioxinyl, and 3,4-dihydro-isochromenyl.
3 In one embodiment, Y in formula 00 represents OR . In another embodiment, Y represents
N.
In one embodiment, R in formula (D represents Cl to 6 alkyl. In another embodiment, R represents CBkj.
2 In one embodiment, R in formula (I) represents optionally substituted phenyl. In another
2 embodiment, R in formula (I) represents an optionally substituted five- or six-membered
heteroaromatic ring containing 1 to 4 heteroatoms selected independently from O, S and N.
In another embodiment, R in formula (I) represents an optionally substituted five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms selected independently from
2 O, S and N. In another embodiment, R in formula (I) represents an optionally substituted
five-membered heteroaromatic ring containing 2 or 3 heteroatoms selected independently

2 from 0, S and N. In another embodiment, R in formula (I) represents optionally
substituted furan, pyridine, pyrimidinc, pyrrole, thiophene, thiazolo, isoxazole, oxadiazole
2 or thiadiazole. In another embodiment, R in formula CO represents optionally substituted
isoxazole.
3 In one embodiment, R in formula CO represents H.
In one embodiment, G in formula CO represents phenyl or pyridyl. In another embodiment, G in formula (I) represents phenyl.
In one embodiment, R in formula CO 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, 0% CN or CF3-
In one embodiment, n represents the integer 1.
In another embodiment, O in formula CO represents phenyl, R* represents CFs and n represents the integer 1.
4 In one embodiment, R represents H.
In one embodiment, L represents Cl to 6 alkyl. In another embodiment, L represents
-CH2- In another embodiment, L represents NR and R 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 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
17 heteroatoms independently selected from 0, S(O)p and NR and optionally further
incorporating a carbonyl group.
2 In another embodiment, G represents optionally substituted phenyl. In another
embodiment, G represents phenyl substituted by OSO2R ,S(O)SR .SC^NR R ,
NR18R19 (wherein at least one of R18 and R19 represents S(O)tR32 or SO2NR33R34) or
Cl io 3 alkyl substituted by SO2R . In another embodiment, G 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.
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
17 heteroatoms independently selected from O, S(O)p and NR 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 0, S(O)q or CH2.
In one embodiment, Y in formula (I) represents CR and R represents H; R represents
2 Cl to 6 alkyl; R represents an optionally substituted five- or six-membered
heteroaromatic ring containing 1 to 3 heteroatoms selected independently from O, S and N;
G represents phenyl; R represents halogen, Cl to 6 alkyl, CN or Cl to 3 alkyl substituted
by one or more F atoms; R represents H; L represents Cl to 6 alkyl; and O 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(O)p and NR and optionally further
incorporating a carbonyl group.
In one embodiment, Y in formula CO represents CR andR represents H; R represents
Cl to 6 alkyl; R represents an optionally substituted fivs-membered heteroaromatic ring containing 1 to 3 heteroatoms selected independently from O, S and N; G represents
phenyl; R represents halogen, Cl to 6 alkyl, CN or Cl to 3 alkyl substituted by one or

more F atoms; R represents H; L represents Cl to 6 alkyl; and G represents phenyl
substituted by OSO2R ,S(O)SR ,SO2NR R ,NR R (wherein at least one of R
and R19 represents S(O)tR32 or SO2NR33R34) or Cl to 3 alkyl substituted by SO2R39.
In one embodiment, Yin formula (I) represents CR andR represents H; R represents
2 methyl; R represents an optionally substituted five-membered heteroaromatic ring
containing 2 or 3 heteroatoms selected independently from O, S and N; G represents
phenyl; R represents Cl, CHs, CN or CFs; R represents H; L represents Cl to 6 alkyl;
and G2 represents phenyl substituted by OSC^R38, StO^R25, SC^NR^R27, NR18R19
(wherein at least one of R18 and R19 represents S(O)tR32 or SO2NR33R34) or Cl to 3
alkyl substituted by SO^R .
In one embodiment, Y in formula (I) represents CR andR represents H; R represents
methyl; R represents an optionally substituted isoxazole ring; G represents phenyl; R

represents Cl, 0*3, CN or CP^; R represents H; L represents Cl to 3 alkyl; and G
represents phenyl substituted by OSO2R ,S(O)SR ,SO2NR R ,NR R. (wherein at
least one of R andR1 represents S(O)tR32 or SO2NR R ) or Cl to 3 alkyl substituted
bySC^R
In one embodiment, Y in formula (0 represents CR andR represents H; R represents
2 methyl; R represents an optionally substituted five-membered heteroaromatic ring
containing 2 or 3 heteroatoms selected independently from O, S and N; G represents
pheuyl; R represents Cl, CH3, CN or CF& R represents H; L represents Cl to 6 alkyl;

and G represents phenyl substituted by S(O)SR and R represents Cl to 6 alkyl ot C3
to 6 cycloalkyl and s represents the integer 2.
In one embodiment, Y in formula (I) represents CR andR represents H; R represents
methyl; R represents an optionally substituted isoxazole ring; G represents phenyl; R

represents Cl, CH3, CN or CF^; R represents H; L represents Cl to 3 alkyl; and G
represents phenyl substituted by S(O)SR andR represents Cl to 6 aikyl or C3 to 6
cycloalkyl and s represents the integer 2.
In one embodiment, Y in formula (I) represents CR or N; R represents H or Cl to 6
2 alkyl; R represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to
4 heteroatoms independently selected from O, S and N; said aromatic ring being optionally
substituted by 1 to 3 substituents selected independently from OH, halogen, Cl to 6 alkyl,
Cl to 6 alkoxy, NCOR , COOR , COR , CONR R and MR R ; said alkyl being
optionally further substituted by OH, CN or CO2R ;R andR independently represent
H, Cl to 6 alkyl or C2 to 6 alkanoyl; 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,
14 15 -
NR R , Cl to 3 alkyl substituted by 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, 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 azacyclic ring optionally incorporating one further heteroatom selected from O,
5 and NR ; L represents a bond, 0, 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; 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
17 heteroatoms independently selected from O, S(O)p and NR and 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 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(O)p and NR 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 CBk; 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, NR18R19, N(2, OSC^R38,
C(=NH)NH2. CCO^^R22, C^NR^R24, SC(=NHJNH2, NR31C(=NH)NH2,
SO^NR R" , Cl to 3 alkoxy substituted by one or more F atoms and Cl to 3 alkyl
39 substituted by SC^R or by one or more F atoms; or when L does not represent an bond,
G may also represent H; p, q, s and t independently represent an integer 0, 1 or 2; R
and R independently represent H, Cl to 6 alkyl, formyl, C2 to 6 alkanoyl, S(O),;R or
33 34 SO2NR R ; said alkyl group being optionally further substituted by halogen, CN, Cl to
4 alkoxy or CONR *R ; 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, CONR35R36, CO2R37, OCOR40, C3 to 6 cycloalkyl, a C4 to
7 saturated heterocyclic ring containing one or two heteroatoms independently selected
43 from O, S(O)p and NR 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 R , CO2R , S(O)SR and

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:
6^methyl-W-[4-(methylsulfonyl)benzyl]-^
dihydropyridine-3-carboxamide;
5-[4-(hydroxymemy])phenyl3-6-methyl-Ar-[4Xmethylsulfonyl)benzyl]-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l ^-dihydropyridine-3-carboxamide;
carboxylic acid 4-methanesulfonyl-benzylamide;
6'-methoxy-2-mernyl-W^4XmethylsulfonyI)ben^
l,6-dihydro-33'-bipYridine-5-carboxamide;
5-(2-methoxypyrimidin-5-yl)^niethyI-Ar-[4Kmethylsulfonyl)benzyl3-2-oxo^
(trifluoromethyl)phenyl]-l^-dihydropyridine-3-carboxamide;
5-[4-(acetylamino)phenyl]-6H(nethyl-N-[4-(methylsulfonyl)ben2yI3 2-oxo-l-[3-
(tnfluoromethyI)phenyl]-l^-dihydropyridine-3-carboxamide;
6-methyl-2^xo-5-(lH-pyrrol-3-yl)-l-(3-trifluoromethylphenyl)-l^-dihydro-pyridine-3-
carboxylic acid 4-methanesulfonyl-benzylamide;
5-furan-2-yW-methyl-2 carboxylic acid 4-methanesulfonyl-benzylamide;
6-methyl-2-oxo-5-tWophen-3-yl-l-(3-trifluoromethylphenyl)-l,2-dihydro-pyridine--3-
carboxylic acid 4-methanesulfonyl-benzylamide;
6-methyl-2-oxo-5-thiophen-2-yl-l-(3-trifluoromethylphenyl)-12-dihydro-pyridine-3-
carboxylic acid 4-methanesulfonyl-benzylamide;
5-(3,5-dimethyl-isoxazol-4-yI)-6-methyl-2-oxo-l-(3-trifluoromethylphenyl)-l,2-dihydro-
pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide;
5-(2,4-dimethoxy-pyrimidin-5-yl)-6-methy]-2-oxo-l-(3-tiifluoromethylphenyl)-l,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyI-benzylamide; 5-(2,4-dioxo-1^3,4-telrahydro-pyrinudin-5-yl>6-methyl-2-oxo-l-(3-trifluoromethyl-phenyl)-l,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide; 6-methyl-5K5-roethyl-[13,4]oxadiazol-2-yl)-2-oxo-l-(3-trifluoromethylphenyI)-l^-dihydro-pyridine-3-carboxyIic acid 4-methanesulfonyl-benzylamide; 6-ioethyl-2-oxo-5-(5-propyl-[l^,4]oxadia2ol-2-yl)-l-(3-trifluoromethylphenyl)-l^-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide; {5-[5-(4-methanesulfonyl-benzylcarbamoyl)-2-methyl-6-oxo-l-(3-trifluoK)methyl-phenyl)-l,6-dihydro-pyridin-3-yl]-[13,4]oxadiazol-2-yl}-acetic acid ethyl ester, 5-(5-cyanomethyl-[13,4]oxadiazol-2-yl)-6-methyl-2-oxo-l--(3-trifIuoroniethylphenyl)-l^-dihydro-pyridme-3-carboxylic acid 4-methanesulfonyl-benzylamide; 5-(5-^amino-[l,3.4]oxadiazol-2-yl)-6-memyl-2-oxo-l--(3-trifluoromethylphenyl)-l^-dihydro-pyridiDe-3-catboxylic acid 4-methanesulfonyl-benzylamide;
dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide;
5-(5-eUiylaimno-[13,4]oxadiazol-2-yl)-6-methyl-2-oxo-l- dihydit>-pyridine'-3-carb6xylic acid 4-methanesulfonyl-benzylamide;
5-(5-N,N -dimethylamino-[l ,3,4]oxadiazol-2-yl)-6-methyl-2-oxo- l-(3-trifluoromethyl -
phenyl)-! ,2-dihydro-pyridirie-3-carboxylic acid 4-methanesulfonyl-benzylamide;
6-methyl-N-[4-(metliylsulfonyi)benzyl]-2-oxo-5-pyrazin-2-yl-l-[3-(trifluoro-
methyl)phenyl]-l,2-dihydropyridine-3-carboxamide;
6-methyl-5-oxazol-2-yl-2-oxo-l-(3-trifluoromethylphenyl)-l,2-dihydro-pyridine-3-
carboxylic acid 4-methanesulfonyl-benzylamide;
6-memyl-5-(l-methyl-lH-imidazol-2-yl)-2-oxo-l-(3-trifluoromethylphenyl)-1^2-dihydro-
pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide;
6-memyl-2-oxo-5-(lH-pyrazol-4-yl)-l-(3-trifluoromethylphenyl)-l,2-dihydro-pyridine-3-
carboxylic acid 4-methanesulfonyl-benzylamide;
6-methyl-N-[4-(methylsulfonyI)benzyl3-2-oxo-5-pyrimidin-2-yl-l-[3-(trifluoro-
naethyl)phenyl]-l,2-dihydropyridine-3-carboxamide;
5-methyl-5-(2-methyl-2H-pyrazol-3-yl)-2-oxo-l-(trifluoromethylphenyl)-l,2-dihydro-
pyridine-S-carboxylic acid 4-methanesulfonyl-benzylamide;
6-methyl-5-(3-inethyUsoxazoM-yl)-^-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-
(trifluoromelhyl)phenyl]-l^^lihydiopyridine-3-carboxamide;
6-methyl-5-4]oxadiazol-5-yl)-2-oxo-l-(3-trifluoroinethylphenyl)-l,2-
dihydro-pyridine-3-carboxylic acid 4-mathanesulfonyl-benzylamide;
6-methyl-5-(3-methylisoxazol-5-yl)-^-[4- (trifluoromethyl)phenyl]-l-dihydropyridine-3-carboxaniide;
5-(3,5-dimethylisoxazolyl)-JV^[4^isopropylsulfonyl)benzylI-6--methyl-2-oxc>-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-caTboxainide;
5-(3^^methylisoxazol^yl)-7^-[4-(ethyIsiilfonyl)benzyl]-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl]-1^2-dihydropyridine-3-cart)oxamide;
JV-[4-(cyclopropy]sulfonyl)benzyl]-5-(3,5^me1liyUsoxazol-^yl)-6-methyl-2-oxo-l-[3-
(trifluorbmetfiyl)phenyl]-l-dihydropyridine-3-carboxamide;
l-(3yanophenyl)-5-(31iinethyUsoxaz
2-oxo-i ,2-dihydropyridine-3-carboxamide;
3-carboxylic acid 4-methanesulfonyl-benzylamide;
carboxylic add 4-methanesulfonyl-benzylamide;
5-(5-isopropyl-[l,3,4]oxadiazol-2-yl>6-inethyl-2-oxo-l-(3-trifluoromethylphdnyl-i,2-
dihydro-pyiidine-3-carboxylic acid 4-methanesulfonyl-benzylamide;
6-methyl-5-[l ,3t4]oxadiazol-2-yl)-2-oxo-l-(3-trifluoromethylphenyl)-l ,2-dihydro-
pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide;
5-(5-hydroxy-[13,4]oxadiazol-2-yl)-6-methyl-2-oxo-l-(3-trifluoromethylphenyl)-l,2-
dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide;
6^memyl-5-(5-methyl-4H-[l,2,4]triazol-3-yl)-2-oxo-l-(3-trifluoromethylphenyl)-l^-
dihydro-pyridine-3-carboxylic acid 4-methylsulfonyl-benzylamide;
5-(4,5-cUmethyl-4H-Cl>2,4]triazol-3-yl)-6-raethyl-2-oxo-l-(3-trifluoromethylphenyl)-l>
dihydro-pyridine-3-carboxylic acid 4-methaTiesulfonyl-benzylamide;
5-(5-methoxymethyl-[l,3}43oxadiazol-2-yl)-6-methyl-2-oxo-l-(3-trifluoromethylphenyl)-
l,2-dihydro-pyridine-3-cafboxylic acid 4-methanesulfonyl-benzylamide;
N-[4-(isopropylsulfonyl)benzyl]-6-methyl-5-(5-methyl-l,3i4~oxadiazol-2-yl)-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide;
N-[4-(ethylsulfonyl)benz3d]-6-methyl-5-(5-methyl-l,3,4-oxadiazol-2-yl)-2-oxo-l-[3-
(trifluOTomethyl)phenyl]-l^-dihydropyridine-3-carboxaniide;
^-[4-(cycIopropylsulfonyl)benzyl]-6-methyl-5-(5-methyl-13,4-oxadia2ol-2-yI)-2-oxo-l-
[3-(trifluoromethyl)phenyl3-l,2-dihydropyridine-3-carboxamide;
6-methyl-5-[l,3,4]oxadiazol-2-yl-2K)xo-l-(3-trifluoromelhylpheiiyl)-l^-^ihydro-pyridine-
3-carboxylic acid 4-(propane-2-sulfonyl)-benzylamide;
6-methyl-5-[l,3,4]oxadiazol-2-yl-2-oxo-l-(3-trifluoromethylphenyI)-l^-dihydro-pytidine-
3-carboxylic acid 4-cyclopropanesuIfonyl-benzylamide;
6-methyl-5-(2-methyl-13-oxazoW-yl)-JV-[4-(methylsulfonyl)benzyl]-2^xo-l-[3-
(trifluoromethyl)phenyl]-l ^-dihydropyridine-3-carboxamide;
6-methyl-^-[4-(methylsulfonyl)benzyl]-5-(l,3-oxazol-4-yl)-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l^-dihydi-6pyridine-3-carboxamide;
5-(2-aminthia2ol-yl)-6-methyI-2-oxo-l-(3-trifluoromefeylpbfinyll hydK
pyridiiie-3-carboxylic acid 4-methanesulfonyl-benzylarnide;
5K2^-dimethyl-O-oxazol-4-yl)methyl-//-[4KmethyIsulf(myI)benzyl]-2
(trifluor6methyl^henylJ-l^^hydropyridine-3-carboxamide;
6-methyl-5-(5-methyl-13-oxazoI^yl)^-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-
(trifluoromethyl)phenyi]-l ,2-dihydropyridine-3-carboxamide;
5-(2-aimno-5-nifcthyI-tMazol^
dihydro-'pyridinerS-carboxylic acid 4-methanesulfonyl-benzylamide;
l,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide; 6-methyl-5-(5-methyl-[l,2,4]oxadiazol-3-yI)-2-oxo-l-(3-trifluoromethylphenyl)-l^-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide; 6-methyI-5-[l,2,4]oxadiazol-3-yl-2-oxo-l-(3-trifluoromethylphenyl)-l,2^hydK^pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide;
6-methyl-2-oxo-5-(lH-te1razol-5-yl)-l-(3-trifluoromethylphenyl)-l,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide;
6-methyl-5-(4-methyl-oxazol-2-yl)-2-oxo-l-(3-trifluoromethylphenyl)-lJ2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide;
5-(4,5-dimethyl-oxazol-2-yl)-6-methyl-2-oxo-l-(3-trifluoromethylphenyl)-l,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylainide;
-(cyclohexylmethyl)-6-methyl-2-oxo-5-phenyl-l-[3-(tiifluOTomethyl)phenyl]-l,2-
dihydropyridine-3-carboxamide;
6-methyl-N-(2-morpholin-4-ylethyI)-2-oxo-5-phenyl-l-[3-(trifluoromeAyl)phenyl]- 1,2-
dihydropyridine-3-carboxamide;
6-methyl-2-oxo-5-phenyl-N-lH-l,2,4-triazol-3-yl-l-[3-(trifluoromethyl)phenyl]-l,2-
dihydropyridine-3-carboxamide;
N-[2-(lH4ndol-3-yl)ethyl]-6-methyl-2-oxo-5-phenyl-l-[3-(trifluoromethyl)phenyl]-l^-
dihydropyridine-3-carboxamide;
6-methyl-2-oxo-5-phenyl-N-(l-phenylethyl)-l-[3-(trifluoromethyl)phenyl]-l^-
dihydropyridine-3-carboxamide;
6-methyI-2-oxo-5-phenyI-N-(2-phenylethyl)-l-[3-(trifluoromethyl)phenyl]-l,2-
dihy(tropyiidine-3-carboxamide;
6-inetliyl-2^xo-5-phenyl-N-[(2R>2-phenylcyclopropyl]-l-[3Ktrifluoromethyl)phenyI]-
l^-dihydiopyiidine-3-carboxamide;
N-(23-dihydio-lH-inden-2-yI)n«thyl-2-oxo-5-phenyl-l-j3-(trifluoroine&
1 ^--dihydropyridine-3-carboxaniide;
N-[(l^thylpym>lidin-2-yl)methyI]-6-methyl-2-oxo-5-phenyl-l-[3-(trifluorcOTiethy])-
phenyl]-l,2-dihydropyridine-3-carboxamide;
6-methyI-N-(l-naphthylmethyl)-2-oxo-5-phenyl-l-[3-(trifluoromethyl)phenyl]-l,2-
dihydropyridine-3-carboxamide;
N-(l,3'benzodioxol-5-ylraethyl)-6-methyl-2-oxo-5-phenyl-l-[3-(trifluoromethyJl)phenyl]-
1,2-dihydropyridine-3-carboxamide;
N-(2-chloro-4-fluorobenzyl)-6-methyl-2-oxo-5-phenyl-l-[3-(trifluoromethyl)phenyl]-l,2-
dihydropyridine-3-carboxamide;
6-methyl-2-oxo-5-phenyl-N-(2-thienylinethyl)-l-[3-(triflucM:omethyl)phenyl]-l,2-
dihydropyridine-3-carboxainide;
N-(2-cyclohex-l-en-l-ylethyl)-6-methyl-2-oxo-5-phenyl-l-[3-(trifluoromethyI)phenyI]-
1,2-dihydropyridine-3-carboxamide;
6-methyl-2-oxo-N-(4-phenoxybenzyl)-5-phenyl-l-[3-(trifluoromethyl)phenyl]-l,2-
dihydropyridine-3-carboxamide;
N-[(2,5-dimethyl-3-furyl)methyl]-6-methyl-2-oxo-5-phenyl-l-[3-(trifluoromethyl>
phenyl]-l,2-dihydropyridine-3-carboxamide;
N-{2-[4-(aminosulfonyl)phenyI]ethyl}-6-methyl-2-oxo-5-phenyl-l-[3-(trifluorometfiy])-
phenyl]-l,2-dihydropyridine-3-carboxamide;
6-methyl-2-oxo-5-phenyl-N-[4-(lH-pyrazol-l-yl)benzyl]-l-[3-(trifluoromethyl)phenyl]-
1,2-dihydropyridine-3-carboxamide;
6-methyl-2-oxo-N-phenoxy-5-phenyl-l-[3-(trifluoromethyl)phenyl]-l,2-dihydro-pyridine-
3-carboxamide;
N-[(6-fluoro-4H-l^-benzodioxin-8-yl)methyI]-6-methyl-2-oxo-5-phenyl-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxaniide;
6-methyl-2^xo-5-phenyI-N-[2^tetrahydro-2H-pyran-^yl)ethyl]-l-[3-(trifluoromethyl)-
phenyl]-l,2-dihydropyridine-3-carboxamide;
6-methyl-2-oxo-5-phenyl-N-[3-(lH-pyrazol-l-yl)propyl]-l-[3-(trifluoromethyl)phenyl]-
1 ^-dihydropyridine'S^carboxamide;
6-methyl-N-[(l-inethyl-lH-pyrazol-4-yl)methyl]-2T-oxo-5-phcnyI-l-[3-(trifluoiomethyl)-
phenyl]-l,2-dihydropyndine^3-carboxanude;
6-methyl-2^xo-5-phenyI-N-[(l-phenyl-lH-pyrazol-^yl)methyl]-l-[3-(trifluoromefliyl)-
phenyl]-! ,2-dihydr6pyridine-3-caiboxamide;
N-[(5-methoxy-4-oxo-4H-pyran-2-yi)methyl]-6-methyl-2-oxo-5-phenyl-l-[3-
(trifIuoromethyI)phenyl]-Jj2-dihydropyridine-3-carboxamide;
N-(3-azepan-l-ylpn>pyl)-6--methyl-2-c-»xp-5-phenyl-l-[3-(trifluoromethyl)phenyl]-l^-
dihydropyridine-3-carboxamide;
N-(4-cyanobenzyl)-6-methyi-2-oxo-5-phenyl-l^[3-(trifluoromethyl)phenyl]-l,2-
dihydropyridine-3-carboxamide;
6-methyl-2-oxo-N-[3-(5-oxo-4,5-dihydro-lH-pyrazol-4-yl)propyl]-5-phenyl-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide;
6-raethyl-5-(2-methyl-2H-pyrazol-3-yl)-2-oxo-l-(3-trifluoroinethylphenyl>l^-dihydro-
pyridine-3-carboxylic acid (3-methyl-isoxazol-5-ylmethyl)-aniide;
6-methyl-5-(2-methyl-2H-pyrazol-3-yl)-2-oxo-l-(3-trifluoromethyIphenyl)-l^-dihydro-
pyridine-3-carboxylicacid(5-methanesulfonylmethyl-[l,2,4]oxadiazol-3-ylmethyl)-amide;
6-methyl-5-(2-methyl-2H-pyrazol-3-yl)-2-oxo-l-(3-trifluoromethylphenyI)-l,2-dihydro-
pyridine-3-carboxyIic acid ([l,2,4]oxadiazol-3-ylmethyl)-amide;
6-methyl-5-(l-methyl-lH-pyrazol-5-yl)-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-
oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide;
5-(3^-d^methylisoxazol4-yl)^methyl-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1 -[3-(trifluoromethyl)phenyl]-l ,2-dihydropyridine-3-carboxamide; acceptable salts thereof.
The present invention includes compounds of formula (I) 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: is a) reacting a compound of formula (II)
(Figure Removed)
wherein 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;
with a nucleophile R -M wherein R is as defined in formula (I) and M represents an
organo-tin or organo boronic acid group; or
b) when R represents a 13,4-oxadiazol-2-yl or a l,3,4-thiadiazol-2-yl ring, reacting a compound of formula (HI)

(Figure Removed)

•X"') whereinR ,R ,R ,Y,G ,G , Land n are as defined in formula (I), Z represents O or S
47 48" 47 48
and X represented to 6 alkyl or NR R andR andR are as defined in formula (I);
with a suitable dehydrating agent such as phosphoryl chloride or trimethylsilyl polyphosphate; or
c) reacting a compound of formula (XV)

(Figure Removed)

(XV) wherein R , R , R , n, G and Y are as defined in formula (1) and L represents a leaving
group,
with a compound of formula (EX) or a salt thereof

wherein R ,G and L are as defined in fonnula (I);
and where desired or necessary converting the resultant compound of fonnula (I), or another salt thereof, into a pharmaceutically acceptable salt thereof; or converting one compound of fonnula CO into another compound of formula (I); and where desired converting the resultant compound of fonnula 00 into an optical isomer thereof.
Tn 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 in the presence of a transition metal catalyst such as palladium. Optionally, the reaction may be carried out in the presence of a base such as potassium carbonate.
In process (b), the reaction is carried out at a suitable temperature, generally between 20 °C and 10G °C in a suitable solvent such as dichloromethane, if necessary, using a sealed vial.
The man skilled in the art will readily appreciate that compounds of formula (I) wherein
2 R represents a five-membered heteroaromatic ring other than a 13,4-oxadiazol-2-yl or a
l,3,4-thiadiazol-2-yl ring may also be prepared by processes in which the final step is the ring closure of the five-membered heteroaromatic ring. Specific examples of such processes are described in the Examples section of this specification. Such processes form another aspect of the present invention.
In process (c), 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, HOAT, HOST or D1EA. Suitable leaving groups L include OH and halogen.
Compounds of formula (in) may be prepared by reacting a compound of formula (IV)

(Figure Removed)
wherein R,R,R,Y, G,G,L and n arc as defined in formula (I); with a compound of the general formula (V)
wherein X is defined in formula (in)- This reaction may be carried out at a suitable temperature, generally between 0 °C and 50 CC in a suitable solvent such as 1,4-dioxane.
Compounds of formula (IV) may be prepared by reacting a compound of formula (VI)
(Figure Removed)
(VI) whereinR ,R ,R ,Y,G ,G , L and n are as defined in formula (I) and R represents Cl
to 6 alkyl;
with an aqueous base such as sodium hydroxide, followed by subsequent treatment of the product with a chlorinating agent such as thionyl chloride. This process may be carried out at a suitable temperature, generally between 10 °C and 50 °C in a suitable solvent such as tetrahydrofuran cr dichloromethane.
Compounds of formula (VI) may be prepared by reacting a compound of formula (II) with carbon monoxide in the presence of an alcohol such as methanol or ethanol and in the presence of a suitable transition metal catalyst This process may be carried out at a suitable temperature, generally between 50 °C and 150 °C 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.
Compounds of formula (Q) may be prepared by reacting a compound of formula (VII)
(Figure Removed)

£ J O
wherein R*, R"*, R , Y, G , G , L and n are as defined in formula (I), with a halogenating
agent, such as N-iodosuccinimide. This 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 add.
Compounds of formula (VH) can be prepared by reacting a compound of formula (VET)

(Figure Removed)
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
4 2 wherein R , G and L are as defined in formula CO. The process is carded out at a suitable
temperature, generally between 0 °C and the boiling point of the solvent, in a suitable solvent such as dichloromethane orN-methylpyirolidinone. The process is optionally carried out in the presence of a base and/or a coupling reagent such as HATU, HO AT,
HOBT or DIBA. Suitable leaving groups L include OH and halogen.
Compounds of formula (VIE) wherein Y is CR , L is OH and R is hydrogen can be
prepared by condensing a ctfmpound of formula
(Figure Removed)
wherein R is as defined in formula (I); with a compound of formula (XI)

(Figure Removed)
wherein G , R and n are 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., Synthetic Communications, 1993,23,487-494. And compounds of formula (XI) can be prepared according to the methods of Igor V. Ukrainets et al., Tetrahedron, 1994,50, 10331-10338.
Compounds of formula (VIE) wherein Y is CR , L is OH and R is hydrogen can be
prepared by reacting a compound of formula (Xfl)
wherein G , R and n are as defined in formula (I), with a compound of formula (XHI)
(Figure Removed)
wherein R is as defined in formula (I), at a suitable temperature, such as 160 °C, followed
by base promoted cyclisation and acid hydrolysis. Compounds of formula (XHE) can be prepared according to US 3,838,155.
Compounds of formula (VM) wherein Y is CR , L is OH, R is methyl and R is
hydrogen can be prepared by condensing a compound of fonnula (XTV)

(Figure Removed)
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 monomethyl 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 hi which the salt is soluble followed by subsequent removal of the solvent in vacua or by freeze drying. Suitable solvents include, for example, water, dioxane, ethanol, 2-propanoI, tetehydrofuran 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 isoraers 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.
According to a further aspect of the invention we provide a compound.of formula (I) or a phannaceutically acceptable salt thereof, for use as a medicament
The compounds of formula (I), and their pharmaceutically acceptable salts, are useful because they possess pharmacological activity in animals. The compounds of formula CO 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 hi 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 (ARDS), 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 gastro-intestinal traet (especially inflammatory bowel disease, ulcerative colitis, pancreatitis and gastritis); inflammation of
the sicin (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; HIV disease progression; for minimising the effects 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 neutropliil 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 00 or a pharmaceutically acceptable salt thereof.
In particular, the^ompounds of this invention may be used in the treatment t>f 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).
Hie compounds of formula CO may be used on their own, or in the form of appropriate
\, J
pharmaceutical formulations comprising the compound of the invention in combination with a phannaceutically 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) in 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 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 i*m, and may be suspended in a propellaut 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, a perfluorinated or polyethoxyiated surfactant, or other pharmaceutically 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 polyol. 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 Icnown 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 aroylopecthi; a cellulose derivative; a binder, for example, gelatine or poly vinylpyrrolidone; 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 arabicy 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, saccharine 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
JH NMR and 13C NMR spectra were recorded on a Varian Inova 400 MHz or a Varian Mercury-VX 300 MHz instrument. The central peaks of chloroform-rf (6H 7.27 ppm), dimethylsulfoxide-cfe (8H 2.50 ppm), acetonitrile-Jj (5H 1.95 ppm) or methanol-d* (8fl 331 ppm) were used as internal references. Column chromatography was carried out using silica gel (0.040-0.063 mm, Merck). 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-(Benzotriazol-l-yl>-N^^^Sf'-tetramethyluron>um hexafluorophosphate;
HATU O-(7-Azabenzotriazol-l-yl>N^^'^-tetracoemylviromiim hexafluorophosphate;
HOBT 1-Hydroxybenzotriazole;
HOAT l-Hydroxy-7-azabenzotriazole;
DIEA N,N-Dusopropylethylamine;
NMP l-N-MethyW-pyrrolidinone;
DME 1,2-Dimethoxyethane;
THF Tetrahydrofuran;
TFA Trifluoroacetic acid;
DMF N,N-Dimethylformamide;
DCM Dichloromethane.
The following method was used for LC/MS analysis:
Instrument Agilent 1100; Column Waters Symmetry 2.1 x 30 mm; Mass APCI; How rate 0.7 mJ/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 Cis-column, 2.1 x 30 mm with 3.5 um 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 ^Methyl-JV-f^frnethvlsulfonvllbenzvll^-oxo-S-phenyl-l-rS-(trifluoromethvl)phenvl1-1.2-dihvdi^vridine-3^arboxaimde
a) Ethvl 3-oxo-3-ir3-(triiluoromethvDphenYnamino}propanoatc
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 mol) 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 compoimd as yellow powder (109 g, 99%).
; 1H NMR (CDCfe): 5 9.52 (1H, s); 7.87 (1H, s); 7.78 (1H, d); 7.46 (1H, t); 739 (1H, d); 4.29 (2H, q); 3.50 (2H, s); 135 (3H, t). APCI-MS ra/z: 276.1 [MH*].
b) 6-Methyl'2-oxo-l-r3-ftrifluoromethvl>phenvn-l .2-dihvdropvridine-3-carboxylic acid
To a solution of ethyl S-oxo-S-llMtrifluoro^ethyDphenyyaminoJpropanoate (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.
'HNMR (CDC13): 613.68 (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+].
dihvdropvridine-3-carboxamide
A mixture of 6-methyl-2-oxo-l-[3-(trifluoromethyl)phenylJ-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 DEEA (14.2 ml, 82.5 mmol) in NMP (65 ml) was reacted for 1 h, then 4-methylsulphonylbenzyl 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 lh. The precipitate was filtered off, washed with water and dried in vacuum overnight. Recrystaffisation from BtOAc gave 8.1 g (70%).
JHNMR (CDC13): 5 10.00 (1H, brt); 8.60 (1H, d); 7.88 (2H, d); 7.83 (1H, d); 7.76 (1H, t); 7.53 (3H, m); 7.46 (1H, d); 6.49 (1H, d); 4.68 (2H, m); 3.03 (3H, s); 2.10 (3H, s). APCI-MS m/z: 465.1 [MH+].
d) 5-Iodo-6-methvl-JV^r4^memvlsulfonyl)benzyn-2-oxo-l-r3-(trifluoromerhyDphenvl1-
1 .2-dihydropvridine-3-carboxamide
To a solution of 6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l^-dihydropyridine-3-caiboxamide (200 mg, 0.43 mmol) in
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 NaHC03> with aqueous Na$204 and
water, dried (NazSO^, and evaporated to give the title compound (200 mg).
!H NMR (CDC13): 5 9.85 (1H, brt); 8.90 (1H, d); 7.88 (2H, d); 7.76 (2H, m); 7.50 (2H, d);
7.48 (1H, s); 7.40 (1H, d); 4.65 (2H, m); 3.03 (3H, s); 2.32 (3H, s).
APCI-MS m/z: 591.0 [MH+].
e) 6-Methvl-^-r4-(methvlsulfonvnben2vl1-2-oxo-5-phenv]--l-r3-(trifluoromethvI>|)hetiYll
1 .2-dihvdropvridine-3-carboxamide
A mixture of phenylboronic acid (25 mg, 0.20 mmol),
1,1' bis(diphenylphosphino)ferrocenedichloropalladium(n) (4 mg, 0.005 mmol), 5-iodo-6-
methy 1-AT- [4 dihydropyridine-3-carboxamide (100 mg 0.17 mmol), toluene (1 ml), ethanol (99%, 0.25
ml) and NajCCb (2M, 0.25 ml) was stirred at 80 °C overnight, concentrated and the
residue was purified by flash chromatography to give the title compound (70 mg, 76%).
'HNMR (CDC13): 8 10.04 (1H, brt); 8.64 (1H, s); 7.88 (2H, d); 7.82 (1H, d); 7.76 (IH, t);
7.58 (IH, s); 7.54-739 (6H, m); 731 (2H, d); 4.69 (2H, m); 3.02 (3H, s); 2.03 (3H, s).
APCI-MS m/z:
Example 2 5-I^an-3-vl-6-nMthvl-2-c^o-l-(3-tiifluoromc^yl-phenvlVl^-dihvdrb-pyridine-3-carboxvlic acid 4-methanesulfonvl-benzvlamide A mixture of 5-4odo-6-methyl-JV-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethy^phenyll-l^-dihydropyridine-S-carboxamide (Example 1 (d), 0.0413 g, 0,07 lomol), furan-3-boronic acid (0.009 g, 0.08 mmol), Pd(PPh3)4 (0.004 g, 3.46 nmol), DME (2 ml) and Na^CDs (2 ml, 2M) was vigorously stirred under nitrogen in a sealed vial at 80 °C for 2 h. Another ^portion of foran-3-boronic acid (0.005 g) and PdOPPha^ (0.004 g) was added and the reaction was allowed to go for another hour. The mixture was allowed to cool, and was then partitioned between EtOAc and water. The organic phase was collected and the aqueous phase was extracted with another portion of EtOAc (10 ml). The combined organic phases were washed with water, brine, and dried over NaaSO* Filtration and evaporation gave a crude oil which was purified on silica (heptane : EtOAc 2:1 to 1:1 to 1:2), which after evaporation of pure fractions gave 0.023 g (62%) of the title compound as a white solid.
'HNMR (DMSO-dd): 8 9.94 (IH, t, J6.0 Hz); 8.36 (1H, s); 7.96-7.73 (7H, m); 7.54 (2H, d, J 8.14 Hz); 7.46 (IH, d, J7.4 Hz); 6.73 (IH, s); 4.59 (2H, d, J 6.13 Hz); 3.17 (3H, s); 2.06 (3H, s). APCI-MS m/z: 5313 \MH+].
Using the general method of Example 1, the compounds of Examples 3 to 6 were prepared:
Example 3 5-r4-fliydroxvmemvl)p^envl1-6-methvl-A^r4-(methvlsuIfonvl)benzyl'|'-2-
oxQ-l-r3-ftrifluoromethvl^phenvn-1.2-dihvdropvridine-3-carboxamide
!H NMR (CDC13): 6 10.04 (1H, brs); 8.64 (1H, bra); 7.88-7.77 (4H, m); 7.58-7.47 (6H, m);
7.32 (2H, bra); 4.78 (2H, s) 4.70 (2H, brs); 3.02 (3H, s); 2.03 (3H, s).
APCI-MS m/z: 571 [MH4].
Example 4
(trjfluort)methynphenvll-1.6-dihvdro-33'-bipvridine-5-carboxamide
.'H NMR (CDC13): 8 10.00 (1H, t); 8.58 (1H, s); 8.12 (1H, d); 7.89-7.74 (4H, m); 7.58-7.49
(5H, m); 6.85 (1H, d); 4.69 (2H, m); 4.00 (3H, s); 3J02 (3H, s); 2.02 (3H, s).
APa-MS m/z: 572(MH+J.
Example 5 5-f2-Methoxypyrimidin-5-yl)^inemyl-^-f4-(memvisulfonvl)ben2yl1-^
oxo-1 -rS-ftrifluoromettiyl^phenyll-lJt-dihvdropvridine-S-carboxamide
'H NMR (CDC13): 5 9.93 (1H, brt); 8.56 (1H, s); 8.51 (2H, s); 7.89-7.75 (4H, m); 7.57-
7.48 (4H, m); 4.69 (2H, m); 4.09 (3H, s); 3.02 (3H, s); 2.02 (3H, s).
APCI-MS m/z: 573[MH+].
Example 6 5-r4-(Acetvlamino')phenvn-6-methvl-N-r4-fmethvIsulfonvl)benzvn-2-oxo-
l-r3-(trifluoromethyl)phenvn-1.2-dihvdrQpvridine-3-carbQxamide
JH NMR (CDC13): 8 10.05 (1H, brt); 8.61 (1H, s); 7.89-7.73 (4H, m); 7.61-7.49 (6H, m);
7.39 (1H, s); 7.24(1H, s) 4.69 (2H, m); 3.02 (3H, s); 2.21 (3H, s); 2.02 (3H, s).
APCI-MS m/z: 598[MH+].
Example 7
dihvdro-pyridine-3-carboxvIic acid 4-methanesulfonvl-benzvlamide
A mixture of 5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l^^hydropyridine-3-cartx)xarnide (0.060 g, 0.10 mmol), l-trimethylsilyl-lH-pyrrol-3-yl-boronic acid (0.033 g, 0.12 mmol), Pd(PPh3)4 (0.005 g,-4.34 nmol), DME (2 ml) and Na2CO3 (2 ml, 2M) was vigorously stirred under nitrogen in a sealed vial at 80 °C for 2 h. Another portion of l-trimethylsilyl-lH-pyrrol-3-yl-boronic acid (0.005 g) and Pd(PPha)4 (0.004 g) was added and the reaction was allowed to go for another hour. The mixture was allowed to cool and partitioned between EtOAc and water. The organic phase was collected and the aqueous phase was extracted with another portion of EtOAc. The combined organic phases were washed with water and brine, and were then dried over Na2SO4. Filtration and evaporation gave a crude oil which was purified on silica (heptane: EtOAc 2:1 to 1:1 to 1:2), which after evaporation of pure fractions gave 0.08 g (80%) of the intermediate as a white solid. A solution of this solid in THF (10 ml) containing tetrabutylarnmoniumfluoride trihydrate (0.025 g, 0.08 mmol) was stirred at room temperature for 1 h. Evaporation and purification on silica (heptane: EtOAc 2:1 to 1:1 to 1:2) provided 0.02 g (47%) of the title compound as a white solid, which darkened on standing.
'H NMR (CDClj): 810.12 (1H, t, J 55 Hz); 8.68 (1H, s); 8.53 (1H, bs); 7.86 (2H, d, / 83 Hz); 7.79 (1H, d, J7.8 Hz); 7.73 Using the general method of Example 2, the compounds of Examples 8 to 12 were ; prepared:
Example 8 5-Furan-2-yl-6-methyl-2-oxo-l-(3-trifluoromethvl-phenvlV1.2-dihvdro-pyridine-3-carboxvlic acid 4-methanesulfonvI-benzvlamide
*H NMR (CDC13): 8 9.96 (1H, t, /5.8 Hz); 8.85 (1H, s); 7.89 (2H, d, / 8.7 Hz); 7.84 (1H, d, 77.7 Hz); 7.77 (1H, t, J7.7 Hz) 7.56 (1H, s); 7.54 (2H, d, J8.0Hz); 7.48 (1H, d, 77.7 Hz); 6.55-6.49 (2H, m); 4.76-4.64 (2H, m); 3.03 (3H, s); 2.23 (3H, s).
APCI-MS m/z: 531.1 [MH4].
Example 9 6-Methvl-2-oxo-5-thiooheD-3-vl-l-f3-trifluoromethvl-phenvlV1.2-dihvdro-
pyridine-3-carboxylic acid 4-methanesulfonvI-benzylarnide
'H NMR (CDC13): 8 10.02 (1H, t, J 5.9 Hz); 8.65 (1H, s); 7.88 (2H, d, J 8.2 Hz); 7.82 (IB
d, 77.8 Hz); 7.76 (1H, t, 77.8 Hz); 7.57 (1H, s); 7.53( 2H, d, J S3 Hz); 7.49 (1H, d, 77.8
Hz); 7.46-7.42 (1H, m); 7.27-7.25 (1H, m); 7.10 (1H, dd, 75.0 Hz and 1.2 Hz); 4.75-4.62
(2H, m); 3.02 (3H, s); 2.07 (3H, s).
APCI-MS m/z: 547 [MR*].
Example 10 6-MethvI-2-oxo-5-thiophen-2-vl-l-(3-trifluoromethyI-pheQyl)-1.2-dihvdro-
pyridine -3~carboxylic acid 4-methanesulfonvl-benzylamide
*H NMR (CDC13): 5 9.95 (1H, t, 7 5.8 Hz); 8.68. (1H, s); 7.87 (2H, d, 7 8 J Hz); 7.83 (1H,
d, 77.8 Hz); 7.75 (1H, t, 77.8 Hz); 7.56 (1H, s); 7.51 (2H, d, 7 8.5 Hz); 7.48 (1H, d, 7 8 J
Hz); 7.42-7.39 (1H, m); 7.12-7.08 (1H, m); 7.04-7.01 (1H, m); 4.74-4.62 (2H, ra);
3.01(3H,s);2.11(3H,s).
APCI-MS m/z: 547
Example 11 5-(3^-Dimethvl-isoxazoI^yl^6-ii»thyl-2K)xo-l-('3-trifluorometfiyl-phenvlV1.2-dihvdro-pvridme-3-catboxvlic acid 4-methanesulfonvl-benzvIamide 'HNMR (CDC13): S 9.93 (1H, t, 75.8 Hz); 8.41 (1H, s); 7.86 (2H, d, 78.7 Hz); 7.82 (1H, d, 77.7 Hz); 7.76 (1H, t, 7 7.7 Hz); 7.54 (1H, bs); 7.50 (2H, d, 7 8.7 Hz); 7.49-7.44 (1H, m); 4.73-4.60 (2H, m); 3.01 (3H, s); 2.34-2.28 (3H, ds); 2.20-2.14 (3H, ds); 1.90 (3H, s). APCI-MS m/z: 560.1 [MR4].
Example 12 S-f2^4-Diinetiioxv-pvriniidin-5-vl'>-6-methvI-2-oxQ-l-(3-trifluoromethvl-p^envD-1.2-dihydro-pyridine-3-carboxvlic^cid4-methanesulfonvI-benzylamide 'HNMR (CDC13): S 9.98 (IH, t, 75.8 Hz); 8.49 (1H, s); 8.16 (1H, s); 7.87 (2H, d, 7 8.8 Hz); 7.83 (1H, d, 7 7.8 Hz); 7.76 (1H, t, 7 7.7 Hz); 7.58 (1H, s); 7.52 (2H, d, 7 8.2 Hz); 7.49 (1H, s); 4.76-4.60 (2H, m); 4.07 (3H, s); 4.02 (3H, s); 3.02 (3H, s); 1.91 (3H, s).
APCI-MS m/z: 603.1 [MH"].
Example 13 542.4-Pioxo-1.23.4-tetrahvdiD-pvriaiiidin-5-vlV6-inethvl-2-oxo-l-(3-trifluoromethylphenylVL2-dihvdro-pyridine-3-carboxvIic acid 4-rnethanesulfonvl-benzvlamide
A mixture of 5-iodo-6-methyl-JV-[4-(methyIsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (0.075 g, 0.127 mmol), 2,4-di-te/t-butyloxy-pyrimidine-5-boronic acid (0.044 g, 0.152 mmol), Pd(PPh3)4 (0.010 g, 8.69 mnol), DME (2 ml) and NaaCOa (2 ml, 2M aqueous solution) was vigorously stirred under nitrogen in a sealed vial at 80 °C for 2 h. Then another portion of 2,4-di-te/f-butyloxy-pyrimidiiie-5-boronic acid (0.010 g) and Pd(PPh3)4 (0.004 g) were added. After an additional hour the mixture was allowed to cool and was then partitioned between EtOAc and water. The organic phase was collected and the aqueous phase was extracted with another portion of EtOAc. The combined organic phases were washed with water and brine, and dried over Na^SO* Filtration and evaporation followed by purification on silica (heptane: EtOAc 2:1 to 1:1 to 1:2) gave 0.060 g (69%) of the tot-butyl protected intermediate as a white,solid. To a.solution of the solid in THF (5 ml), TFA (5 ml) was added in one poitipn and the mixture was stirred for 30 minutes. The reaction mixture was concentrated and EtOAc .was added io the residue. The obtained suspension was stirred for 10 minutes and the title compound was collected by filtration. Yield 0.045 g (100%) as an off-white solid.
*H NMR (DMSO-ds): 8 11.31 (1H, s); 11.13 (1H, d, / 6.0); 9.91 (1H, t, J 6.2 Hz); 8.24 (1H, s); 7.90 (1H, d, / 8.0Hz); 7.86 (2H, d, J 8.4 Hz); 7.81 (1H, d, /7.8 Hz); 7.70 (1H, d, .77.6 Hz); 7.65-7.59 (1H, m); 7.53 (2H, d, J 8.4 Hz); 7.52 (1H, d, J 6.0 Hz); 4.58 (2H, d, / 6.2 Hz); 3.17 (3H, s); 1.91 (3H, s). APCI-MS m/z: 575.1 [MH*3.
Example 14 6-Methvl-5-f5-methvl-rL3.41oxadiazol-2-vlV2-oxo-l-(3-trifluoromethvl-phenvlVl .2-dihvdro-pvridine-3-carboxvlic acid 4-methanesulfonvl-benzvlamide
a) Ethyl 2-methvI-5-ff r4-rmethvIsulfonvl>ben2vnamino}carbonvl)-6-oxo-l-r3-
(trifluoromethyl)phenyl1-L6-dihydropyrjdine-3-carboxy]ate
In a stainless-steel autoclave (100 ml) were placed 5-iodo-6-methyl-N-[4-
(memylsulfonyl)benzyl]-2K>xo-l-[3 carboxamide (108.1 mg, 0.18 mmol), palladium(II)acetate (3.8 mg, 0.02 rnmol),
triphenylphosphine (10.3 mg, 0.04 mmol), triethylamine (2 ml, 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 (CDCIs): 8 9.73 (1H, t, / 5.9 Hz); 9.20 (1H, s); 7.90 (2H, d, J 83 Hz); 7.85 (1H,
d, / 7.9 Hz); 7.78 (1H, t, J 7.8 Hz); 7.53 (2H, d, J 83 Hz); 7.50 (1H, s); 7.42 (1H, d, J 8.0
Hz);4.69 (2H, t,/53Hz);438 (2H,q, J72Hz);3.03 (3H,s);2.50(3H, s); 1.42(3H,t,J
7.2Hz).
APCI-MS m/z: 537 [MB*].
• b) S-(4-Mftthanesulfonyl"ben2yIcarbamoyJV2-ir4CthyI-6-oxQ-l-Q-trifhioromethyl-phenylV 1^6-dihvdro-pvridine-3-carboxylic acid
To a solution of ethyl 2-memyl-5-({[4-(methylsiilfonyl)benzyI]amino}carbonyl)-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 NaOH (1M, 2 ml, 2 mmol), and the mixture was stirred for 1 h at room temperature, monitoring the progress of me reaction by LC-MS. 20% conversion was observed and another portion of NaOH (1M, 1 ml, 1 mmol) was added, and the reaction was allowed to run for another hour. This process 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 is the subtitle compound, and the other is a regioisomer. The reaction mixture was evaporated in order to remove THF, and the residual water solution was acidified and then extracted into EtOAc. The organic phase was collected and dried over Na2SC>4. Filtration
and evaporation gave a crude product 0.60 g (90%) of a yellowish solid, which was used further without purification. A portion of the product was purified using preparative HPLC. 'H NMR (CDC1*): 8 9.90 (1H, t, J 6.2 Hz); 9.31 (1H, s); 7.89 (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); 4.49 (1H, s); 7.41 (1H, d, 78.0 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
dihydro-pyriding-3-carboxvlic acid 4-methanesulfonyl-benzvlamide
A solution of 5-(4-methanesulfonyl-benzylcarbanioyl)-2-methyl-6-oxo-l-(3-
trifluoromethyl-phenyl)-l,6-dihydra-pyridine-3-carboxylic acid (0.071 g, 0.14 mmol) hi
DGM (5 ml) containing SOCfe (5 ml) was stirred ia^a sealed flask for 2 h and then
concentrated. The obtained solid in 1,4-dioxaae (5 ml, dried over molecular sieves) and
acetylhydrazide (0.1 g, 1.35 mmol) were stirred for 10 minutes and concentrated. The
residue was purified by preparative HPLC giving 0.041 g (52%) of the title compound as a
white solid.
'HNMR (DMSO-d*): 5 10.26 (1H, s); 9.95 (IK, s); 9.79 (1H, t, J6.0 Hz); 8.50 (1H, s);
7.93 (1H, s); 7.93-7.90 (1H. m);.7.87 (2H, d, J 8.4 Hz); 7.82 (1H, d, / 7.7 Hz); 7.74 (1H, d,
J 8.0 Hz); 7.55 (2H, d, J 8.3 Hz); 4.59 C2H, d, J 6.2 Hz); 3.17 (3H, s); 2.18 (3H, s); 1.91
(3H,s).
APQ-MS m/z: 565.2 [MH+].
d) 6-Methvl-5-f5-methvI-ri.3.41oxadiazol-2-vlV2-oxo-l-
was washed with brine, dried (Na2S04), filtered, and concentrated. The solid material was purified by preparative HPLC to give the title compound as a white solid (0.019 g, 66%). 1HNMR (DMSO-dtf): 5 9.74 (1H, t, 76.2 Hz); 8.78 (1H, s); 8.01 (1H, s); 7.94 (1H, d, J 7.8 Hz); 7.87 (2H, d; J 8.1 Hz); 7.82 (1H, t, 77.7 Hz); 7.55 (2H, d, J 83 Hz); 4.61 (2H, d, 76.1 Hz); 3.13 (3H, s); 2.59 (3H, s); 2.43 (3H, s). APCI-MS ra/z: 547.2 [MR*].
Using the general method of Example 14, the compounds of Examples 15 to 19 were prepared:
Example 15 6-Methvl~2-oxo-5- phenvIM ,2-dihYdro-gvridine-3-carboxvlic acid 4-methanesulfonvl-henzylanyde
JH NMR (DMS04j): 8 9.75 (1H, t, 76.33 Hz); 8.78 (1H, s); 8.00 (1H, s); 7.94 (1H, d, J
8.1 Hz); 7.87 (2H d, 7 8.2 Hz); 7.86-7.83 (1H, m); 7.82 (1H, t, J 8.4 Hz); 7.55 (2H, d, J
8.4); 4.60 (2H, d, 76.1 Hz); 3.17 (3H, s); 2.92 (2H, t, 77.3 Hz); 2.42 (3H, s); 1.78 (2H,
sext, / 7.3 Hz); 0.99 (3H, t, J13 Hz).
APCI-MS in/z: 575.2iMH*].
Example 16 l5~f5-C4^-Methanesulfonyl-benzylcaroamoyD-2-nie(hyl-6yOxo-l-(3-trirluoromethvl-phenvlVl^-dihvdro-pvridin-S^vn^rO^loxadiazol^vIl-aceticacidethvl
*H NMR (DMSO-dtf): 8 9.73 (1H, t, J 6.0 Hz);-8.77 (1H, s); 8.01 (1H, s); 7.94 (1H, d, 77.8 Hz); 7.87 (2H, d, 7 8.1 Hz); 7.86-7.80 (2H, m); 7.55 (2H, d, 7 8.1); 4.61 (2H, d, 7 6.3 Hz); 4.30 (2H, s); 4.17(2H, q, 772 Hz); 3.17(3H, s); 2.44 (3H, s); 1.22 (3H, t, 772 Hz). APCI-MS m/z: 619.2 [MH+].
Example 17 5-(5-Cvanomethvl-ri 3.41oxadiazoI-2-vn-6-methvl-2-oxo-l -G-
trifluoromethvl-phenyl)-lJ2-djhydro-pvridine-3-car^oxylicacid4-methanesulfgnvl-
benzvlamide
'H NMR pMSO-dtf): 5 9.73 (1H, t, J 6.2 Hz); 8.76 (1H, s); 8.02 (1H, s); 7.94 (1H, d, 77.6 Hz); 7.87 (2H, d, J 8.1 Hz); 7.86-7.80 (2H, m); 7.55 (2H, d, J 8.3 Hz); 4.70 (2H, s); 4.61 (2H, d, / 6.1 Hz); 3.17 (3H, s); 2.42 (3H, s).
APCI-MS m/z: 572.2 [MH*].
Example 18 545-Amino-ri3.41oxadiazoI-2-vlV6-methvl-2-oxo-l-f3-trifluoromethvl-
phenvlV1.2-dihydro-pvridine-3-carboxvIic acid 4-methanesulfonvl-benzvlamide
*H NMR (DMSO-dfi): 5 9.81 (1H, t, J 6.1 Hz); 8.71 (1H, s); 8.00 (1H, s); 7.94 (1H, d, J 8.0
Hz); 7.88 (2H, d, / 8.0 Hz); 7.86-7.82 (1H, m); 7.80 (1H, df / 8.3 Hz); 7.56 (2H, d, J 8.2
Hz); 7.29 (2H, s); 4.62 (2H, 6.09 Hz); 3.18 (3H, s); 2.40 (3H, s).
APa-MS m/z: 548.2 [MH*].
Example 19 5-(S-Aimno-ri3.411hiadiazdl-2-vlV6-itffithvr-2-dxo-l-(3-trifluoromethvl-phenvlV1.2-dihvdro-Dvridine-3-carboxvHc acid 4-methanesuIfonvl-benzvl amide JH NMR (DMSO-dtf): 5 9.83 (1H, t, J 6.2 Hz); 8,46 (1H, s); 7.99 (1H, s); 7.92 (1H, d, 77.4 Hz); 7.87 (2H, d, J8.2); 7.83 (1H, d, J7-.6Hz); 7.79 (1H, d,/8.0Hz); 7.55 (2H, d> J83
Hz); 7.42 (2H, s); 4.60 (2H, d, J 6.1 Hz); 3.17 (3H, s); 2,21 (3H, s). APCI-MS m/z: 564.1 [MH+].
Example 20 5-f5-Ethvlamino-ri3.41oxadiazol-2-viV6-methvl-2-oxo"l-(3-trifluoromethyl-phenyl)-! .2-dihydro-pyridine-3-carboxvlic acid 4-metfianesulfonvI-bcnzvlamide
a) 5-HvdrazmocarbonvI-6-melfayl-2"Oxo-l-f3-trifluoromethyl-phenvIV1.2-dihydro-
pyridine-3-catboxylic acid 4-methaTiesulfonvl-benzvlamide
The title compound was prepared as described in Examples 14 (c) and 38 (a). APCI-MS m/z: 523.2 [MH*]. Retention time 1.72 minutes.
b) 5-({2-r(Ethvlamino)carbonynhydrazinolcarboi]VlV6-methvI-JV-r4-fmethylsulfonyI)
bsnzvl1-2-oxo-l-l'3-(trifluoromethvl')Phenvn-1.2-dihvdropvtidme-3-carboxainide
To5-hydrazinocarbonyl-6-methyl-2-oxo-l-(3-trifluoromethy]--pbenyl)-l,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyI-benzylamide (0.030 g, 0.057 mmol) in 1,4-dioxane (10 ml) was added ethyl isocyanate (0.016 g, 023 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was evaporated and the residue was purified by preparative HPLC giving 0.015 g (44%) of the title compound. 'HNMR (CDC13): 5 9.96-9.87 (1H, m); 8.82 (1H, s); 7.88 (1H, d, J8.2 Hz); 7.84 (2H, d, / 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, /6.8 Hz); 3.01 (3H, s); 2.31 (3H, s); l.ll(3H,t,77.1Hz). APd-MS m/z: 594,2 [MH+].
c) 545 •Ethylamino-f 1 3.41oxadiazoI-2-yD-6-methyl-2-oxo-l -(3-trifluoromemvl-phenyl V
lJ2-dihvdrD-pvria1ne-3-carboxvlicacid4-methanesulfonvI-benzvIamide
The title compound was prepared from 5-({2-[(ethylamino)carbonyl]hydrazino}carbonyl)-
6-methyl -#-[4-(metfiyJsulfonyI) benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l ,2-
dihydropyridine-3-carbo.xamide using an analogous method to that described in Example
14(d).
1H NMR (DMSO-d Hz); 7:87 (2H, d, J 8.5 Hz); 7.'84 (1H, d, / 8.0 Hz); 7.81-7.75 (2H, m); 7.55 (2H, d, / 8.1
Hz); 4.60 (2H, d, J 6.1 Hz); 3.26 (2H, p, 76.6 Hz); 3.17 (3H, s); 2.38 (3H, s); 1.18 (3H, t, /
7.1 Hz).
APCI-MS m/z: 5763 [MH+].
Example 21
trifluoromethyl -phenyJVl^-dihvdro-pvridine-S-carboxvIic acid 4-methanesu!fonvl-benzylamide
a) 5f(2-r(NJ-Dimethvlamino')carbonvIll)ydrazino)carfaonyl)-6-methvI-Jv'-r4-
(methylsulfonyDbenzyil^-oxo-l-rS-ftTifluorornethvnphenvn-l.Z-dihydropyridiqe-Sj-
carboxamide
To5-hydrazinocarbonyl-6-methyl-2-oxo-l-(3-trifluoromethyl-phenyl)-l,2-dihydro-pyridine-3-carboxylic acid4-methanesulfonyl-benzylamide (0.030 g, 0.057 mmol) in THF (10 ml) was added N,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 by preparative HPLC giving 0.020 g (60%) of the title compound JH NMR (DMSO-d5): 8 9.92 (1H, bs); 9.80 (1H, t, 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, J8.5 Hz); 4.59 (2H, d, 76.0Hz); 3.17 (3H, s); 2.8 (6H, s); 2.19 (3H, s). APCI-MS m/z: 594.1 [MH4].
b) 5-C5-N^I-Diniethvlamino-ri.3.41oxadiazol-2-vl>-6-methvI-2-oxo-l-(3-trifluoromethvl-
phenvlM.2-dihvdro-pvridine-3-carboxvlic acid 4-methanesiilfonvI-ben2vlamide
The title compound was prepared from 5-({2-[(N,N-
diinemylamrno)carbonyl]hydrazino}rarto
oxo-l-[3-(trifluoromemyl)phenyl]-l,2-dihydropyridme-3^carboxamide using the general
method described in Example 14 (d).
JH NMR (DMSO-dtf): 6 9.79 (1H, t, J 6.2 Hz); 8:69 (1H, s); 8.00 (1H, s); 7.93( 1H, d, J 7.9
Hz); 7.87 (2H, d, J 8.4 Hz); 7.85 (1H, t, J7.7 Hz); 7.80 (1H, d, .7.7,7 Hz); 7.55 (2H, d, J
8.4 Hz); 4.59 (2H, d, J 6.2 Hz); 3.17 (3H, s); 3.06 (6H, s); 2.36 (3H, s). ,
APCI-MS m/z: 576.3 [MH+].
Example 22 6-Methvl-N-r4-(methvlsulfonvnbenzvn-2-oxo-5-fpvrazin-2-vlVl-r3-(trifluoro-methvnphenyn-1.2-dihvdropyridine-3-carboxamide
Tris(dibenzylidene-acetone)dipalladium(0) (1 mg) was added to 5-iodo-6-methyl-N-[4-
i
(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoro-methyl)phenyl]-l,2-dihydropyridine-3-carboxamide (Example 1 (d), 20 mg, 0.034 mmol), 2-(tributylstannyl)pyrazine (25 mg, 0.068 mmol) and triphenylphosphine (1.6 mg, 0.006 mmol) in toluene (1.5 ml) under argon and the mixture was stirred in a sealed vial at 100 °C overnight. After cooling, the mixture was filtered through celite and evaporated. The residue was dissolved in toluene and ether was added. The precipitate was filtered off and dried in vacuo (5 mg, 27%).
1H NMR (CDC13): 5 9.93 - 9.85 (IH, m); 8.82 - 8.77 (2H, m); 8.68 - 8.64 (IH, m); 8.60 (IH, d, J 14.0 Hz); 7.91 - 7.73 (4H, m); 7.59 - 7.46 (4H, m); 4.76 - 4.62 (2H, m); 3.01 (3H, s); 2.18 (3H, s).
APd-MS m/z 543.3 [MR*].
Example 23 6-MethvI-5-(oxazoI-2-vlV2-^xo-l- 5-Iodo^meftyl-N-[4 APCI-MS m/z: 532.2 [MH*]:
Example 25 6-MethvI-5-fl-methvl-lH-imidazol-2-yn-2-oxo-l-f3-trifluorornethvl-phenvlV1.2-dihvdro-pvridine-3-carboxvlic acid4-methajiesulfonvl-benzylamide 54odo-6-methyl-N-[4-(methylsulfonyI)benzyl]-2-oxo-l-[3-(trifluoro-methyl)phenyl]-l,2-dihydropyridine-3-carboxamide (0.06 g, 0.1 mmol), l-methyl-2-tributylstannyl-lH-imidazole (0.11 g, 0.5 mmol, prepared according to literature procedures), Pd(PPh3)4 (0.015 g, 0.012 mmol), DME (2 ml) and a magnetic stirrer bar were placed in a vial. The suspension was degassed and the vial was sealed, and subsequently heated (100 °C) with stirring overnight. LC-MS confirmed the conversion of the iodide to the desired product, and the solvents were removed in vacuo. Purification on preparative HPLC afforded the title compound (0.005 g, 10%) as a white solid after freeze-drying the pure fractions.
'H NMR (DMSO-dtf): 8 9.88 (1H, t, 76.2 Hz); 8.30 (1H, s); 8.03 (1H, s); 7.94-7.89 (1H, m); 7.87 (2H, d, / 8.5 Hz); 7.85-7.81 (2H, m); 7.55 (2H, d, J 8.5 Hz); 7.31 (1H, s); 7.06 (1H, s); 4.66-4.55 (2H, m); 3.58 (3H, s); 3.17 (3H, s); 1.85 (3H, s).
APCI-MS m/z: 545.2 [MH+].
Example 26 6-Methvl-2-oxo-5-(lH-pvrazol-4-vD-l-f3-trifluoromethvl-phenvIV1.2-dihvdro-pvridine-3-carboxylic acid 4-methanesuIfonvl-benzylamide 5-Iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(triflaoromethyl)-phenyl]-l,2-dihydropyridine-3-carboxamide (0.080 g, 0.135 mmol), 4-tributylstannyl-l-trityl-lH-pyrazole (0.08 g, 0.13 mmol, prepared according to literature procedures), Pd(PPh3)4 (0.020 g, 0.017 mmol), DME (3 ml) and a magnetic stirrer bar were placed in a vial. The reactor was degassed, the vial sealed and the reaction was heated (95 °C) with stirring overnight LC-MS showed that almost all starting iodide had been consumed to give a main product. The crude mixture was evaporated and the residual oil was purified on silica (heptane:EtOAc 1:2), giving 0.060 g of the intermediate trityl protected product. The intermediate was dissolved in DCM (3 ml) and TFA (3 ml) was added. The mixture was heated (50 °C) with stirring for 30 minutes. The reaction was quenched by the addition of methanol (5 ml). Purification on preparative HPLC gave the title compound (0.016 g, 22%) as a white solid after freeze-drying the pure fractions.
'H NMR (DMSO-dtf): 8 9.98 (1H, t, J 6.2 Hz); 8.38 (1H, s); 7.94 (1H, s); 7.91 (1H, d, / 8.1 Hz); 7.87 (2H, d, J 8.3 Hz); 7.84-7.80 (2H, m); 7.75 (1H, d, J 7.9 Hz); 7.55 (2H, d, / 8.4 Hz); 5.76 (1H, s); 4.64-4.55 (2H, m); 3.17 (3H, s); 2.06 (3H, s).
APCI-MS m/z: 531.1 [MH+].
Example 27 6-Methvl-N-r4-(methvlsulfonvl^benzvn-2-oxo-5-Dvrimidin-2-vI-l-r3-(trifluoro-methvDphenyn-1.2-dihvdropvridine-3-carboxarnide Tris(dibenzylideneacetone)-dipalladium(0) (1 mg) was added to 5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)-phenyl]-l,2-dihydropyridine-3-carboxamide (20 mg, 0.034 mmol), 2-(tributyl-stannyl)pyrimidine (25 mg, 0.068 mmol) and triphenylphosphine (1.9 mg, 0.007 mmol) in toluene (1.6 ml) under argon and the mixture was stirred at 100 °C overnight. After cooling, the mixture was filtered through
celite and evaporated. The residue was purified by preparative HPLC. Pure fractions were
freeze-dried to give the title compound (5 mg, 27%).
'HNMR (CDC13): 8 9.91-9.85 (IH, m); 9.28 (1H, s); 8.84 (2H, d, J 5.2 Hz); 7.90-7.73
(4H, m); 7.57 - 7.45 (4H, m); 7.29 - 7.25 (IH, m); 4.76 - 4.62 (2H, m); 3.01 (3H, s); 2.40
(3H,s).
APCI-MS m/z: 543.1 [MH+].
Example 28 6-Methyl-5-(2-mel^vl-2H-pvrazol-3-vl'b2-oxo-l--(trifluoromethvI-phenvl)-l^-dihydro-pvridine-3-carboxvlic acid 4-methanesulfonyl^benzvIamide 5-Iodo-6-methyl-N-[4-(methyIsulfonyl)benzyI]-2-oxo-l-[3-(trifluoromethyl>phenyl3-l^-dihydropyridine-3-carboxainide (0.06 g, 0.1 mmol), l-methyl-5-trimethylstannyl-lH-pyrazole (0.07 g, 0.3 mmol, prepared according to literature procedures), Pd(PPhs)4 (0.015 g, 0.012 mmol), DME (2 ml) and a magnetic stirrer bar were placed in a vial. The suspension was degassed and the vial was sealed, and subsequently heated (100 °C) with stirring overnight. LC-MS confirmed the conversion of the iodide to the desired product, and the solvents were removed in vacuo. Purification on silica (heptaneiEtOAc 1:2 to 13) afforded the title compound (0.040 g, 75%) as a white solid, which was subsequently freeze-dried.
'H NMR (DMSO-dtf): 5 9.89 APCI-MS m/z: 545.2 [MH*].
Example 29 6-Methvl-5-(3-memylisoxazoI-4-vl)-JV^r4-fmemvlsidfonvl')benzyn-2-oxQ7l-.r3-arifluoromemvl)phenvn-l^-dihvdropvridine-3-carboxamide 5-Iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (25 mg, 0.042 mmol), tetrakis(triphenylphosphine) palladium (2.5 mg, 0.0022 mmol) and 3-methyl-4-(tributylstannyl)isoxazole [synthesized as described by D. Ucniyama in Heterocycles, 43, 6,1301,1996] (32 mg, 0.086 mmol) were mixed in DME (0.45 ml) in an argon filled vial. The vial was closed and heated with stirring at 100 °C for 24 h. The reaction mixture was
poured into a mixture of ethyl acetate and water. The mixture was shaken, the water phase was removed and the organic phase was dried over sodium sulphate. The product was purified by preparative HPLC. Yield: 12 mg, 0.022 mmol (52 %).
XH NMR (DMSO-ds): 6 9.91 (1H, t, J 6.0 Hz,); 8.24 (1H, s ); 8.96 (1H, s); 7.98 - 7.77
(6H, m); 1.54 (2H, d, J 8.4 Hz); 4.59 (2H, d, J 6.2 Hz); 3.17 (3H, s); 2.21 (3H, s); 1.88 (3H, s).
APCI-MS m/z: 546.5 [MH+].
Example 30 6-Methyl-5-f3-methvl-ri.2.41oxadiazoI-5-vlV2-oxo-l~f3-trirluororaethvl-phenyn-1.2-dihvdro-pvridine-3^carboxylic acid 4-mathanesuIfonvl-benzvlamide 5-Iodo-6-methyl-N-[4-(mc^ylsulfonyl)benzyl]-2-oxo-l-[3-(triJ3uorornethyl)phenyl] 1,2-dihydropyridine-3-carboxamide (0.236 g, 0.4 mmol), acetamide oxime (0.088 g, 1.2 mmol), Pd(PPh3)2Cl2 (0.014 g, 0.020 mmol), triethylarnine (0.081 g,10.8 mmol), toluene
• ..* .r> (15 ml) and a magnetic stirrer bar were loaded into a pressure safe steel reactor. The
reactor was degassed with CO, and when all air had been removed, a 4 atmospheres
pressure of CO was applied, and the reactor was heated to 95 °C, The reaction was allowed
to proceed overnight. LC-MS showed that almost all starting iodide had been consumed to
give a main product. The crude mixture was evaporated and the'residual oil Was partitioned
between EtOAc and water. The organic phase was collected, and was dried and
evaporated. Purification on silica (heptanetEtOAc 1:2) gave pure material (0 083 g, 38%)
as a white solid. y
JH NMR (DMSO-d6): 5 9.68 (1H, t, J 6.2 Hz); 8.91 (1H, s); 8.01 (1H, s); 7.95 (1H, d, J 8.1 Hz); 7.87 (2H, d, J 8.02 Hz); 7.86 (1H, t, J7.16 Hz); 7.81 (1H, d, 77.86 Hz); 7.55 (2H, d, J 8.3 Hz); 4.67-455 (2H, m); 3.17 (3H, s); 2.47 (3H, s); 2.41 (3H, s).
APCI-MS m/z: 547.0 [MR*].
Example 31 6-Methvl-5-(3-methyIisoxazol-5-vD-JV-r4-(methvlsulfonvl')benzyn-2-oxo-l-
f3-(trifluoromethyl>phenyl1-1.2-dihydropvridine-3-carbDxamide
The title compound was synthesized in the same way as Example 29 but starting from
5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]:2-oxo-l-[3-(trifiuorornetnyl)phenyl)-l,2-
dihydropyridine-3-carboxamide (50 mg, 0.085 mmol),
tetrakis(triphenylphosphine)palladium (5 mg, 0.0043 mmol) and 3-methyl-5-(tributylstannyl)isoxazole [synthesized as described in Tetrahedron, 47, 28, 5111, 1991] (63 mg, 0.169 mmol) in DME (0.85 ml). Yield: 15 mg, 0.033 mmol (39 %). *H NMR (DMSO-dfi): 8 9.79 (1H, t, J=r6.0 Hz); 8.57 (1H, s); 7.99 (1H, s); 7.94 - 7.79 (5H,
m); 7.55 (2H, d, J=8.4 Hz); 6.67 (1H, s); 4.60 (2H, d, J=6.2 Hz); 3.17 (3H, s); 2.30 (3H, s); 2.17 (3H,s).
APCI-MS m/z: 546.4 [MH+].
The compounds of Examples 32 to 37 were prepared using analogous methods to those described in Examples 1 (a) to 1 (d) and 2.
Example 32 5-|3.5-DimethyUsojcazol-^vl'l!-7V-f4-(Tsopropvlsulfonyl)benzyll-6-methyl-2-oxo-l-f3-(trifluoromethvl>phenvn-l^-dihvdropvridine-3-carboxamide
*H NMR (CDC13): 8 10.12 (1H, bt, ); 8.44 (1H, s); 7.86-7.67 (4H, m); 7.56 (1H, bs,); 7.51-
7.47 (3H, m); 4.76-4.66 (2H, m); 3.21-3.11 (1H, m,); 2.34 (3H, d, 76.8 Hz); 2.20 (3H, d, J 6.8 Hz); 1.93 (3H, s): 1.27 (6H, d, J 7.0 Hz).
APCI-MS m/z: 588
Example 33
l-F3-(trifluoromej^vDphenyn-l,2-dihydropyridine-3-carboxamide
!H NMR (CDC13): 8 10.15 (1H, bt, ); 8.43 (1H, s); 7.86-7.83 (3H, m); 7.78 (1H, bt,); 7.57
(1H, bs,) 7.53-7.47 (3H, m); 4.73-4.69 (2H, m); 3.09 (2H, q, J 7.4 Hz,); 234 (3H, d, J 6.9 Hz); 2.20 (3H, d, J 6.9 Hz); 1.94 (3H, s): 1.26 (3H, t, J 7.4 Hz).
APCI-MS m/z: 574 [MH+].
Example 34 JV-f4-(CvclopropylsuIfonvnbenzvl1-5-(3.5-dimethvlisoxazQl-4-vlV6-methvl-2-oxo-l-f3-(trifluoromethvlVhenvn-^2-dihvdropvridine-3-carboxarnide
1H NMR (CDC13): 8 10.06 (1H, bt, ); 8.43 (1H, s); 7.88-7.76 (4H, m); 7.56 (1H, bs,) 7.51-
7.47 (3H, m); 4.74-4.63 (2H, m); ); 2.45-2.38 (1H, m); 2.33 (3H, d, J 6.7 Hz); 2.19 (3H, d, J 6.7 Hz); 1.92 (3H, s): 1.35-1.30 (2H, m); 1.07-0.99 (2H, m).
APCI-MS m/z: 586 [MH+].
Example 35 1 -C3-CvanophenvD-5-(3.5-dimernylisoxazo]-4-vn-6-methyl-#- f4-(methylsulfonvl)benzvI1-2-oxo-1.2-dihvdropyiidine-3-catboxarnide
^NMR (CDC13): 5 9.88 (IH, bt,); 8.44 (IH, s); 7.90-7.86 (3H, m); 7.77 (IH, bt,); 7.62-
7.51 (4H, m); 4.74-4.63 (2H, m); 3.02 (3H, s); 2.33 (3H, d, 75.7 Hz); 2.19 (3H, d, 75.6 Hz); 1.93 (3H, s).
APCI-MS m/z: 517 [MB*].
Example 36 l-f3-C^lorophenvl)-5-G.5-dimethyl-isgjcazol-4-yl)-6-methv]-2-oxo-L2-(lihydro-pvridine-3-carboxvlic acid 4-methanesulfonvl-benzvlamide
!H NMR (CDC13): 5 9.98 (IH, bt,); 8.42 (IH, s); 7.88 (2H, d, 7 8.4 Hz); 7.57-7 52 (4H, m);
730-729 (IH, m); 7.19-7.17 (IH, m); 4.68 (2H, d, 75.6 Hz); 3.02 (3H, s); 232 (3H, d, 7 4.0Hz); 2.18 (3H, d, 74.2Hz); 1.95 (3H, s).
APCI-MS m/z: 526 [MH*j.
Example 37 5-f3.5^imethvl-isoxazoI-4-vD-6-methyl-2-oxo-l-m-tblj1^1.2-dihYdn>-pvridine-3-carboxvlic acid 4-methanesulfonvl-benzvlamide
'"HNMR (CDC13): 5 10.11 (IH, bt,); 8.40 (IH, s); 7.87 (2H, d, 7 8.4 Hz); 7.54-7.47 (3H,
m); 7.35 (IH, d, 7 7.7 Hz); 7.06-7.03 (2H, m); 4.67 (2H, d, 7 5.9 Hz); 3.02 (3H, s); 2.46 (3H, s); 2.32 (3H, d, 7 2.5 Hz); 2.18 (3H, d, 73.0 Hz); 1.93 (3H, s).
APCI-MS m/z: 506 [MR*;}.
Example 38 5-(5-Isopropvl-ri.3.41oxadiazoI-2-yD-6-methyl-2-oxo-l-(3-trifluoromethyl-phenvlVl a") 5-Hydrazinocarbonvl-6-methvl-2-oxo-l-f3-triflaQromethyI-phenylV1.2-dihvdrD-pvridine-3-carboxylic acid 4-methanesulfonvl-benzvlamide The compound obtained in Example 14 (b) (0.051 g, 0.14 mmol) in DCM (5 ml) was treated with SOCIz (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 freeze-drying the pure fractions.
APCI-MS m/z: 523.2 [MR*"].
fr) S-fN^IsobutyrvI-hydrazinraarixmv^ dihydro-pvridine-3-carfaoxvlic acid 4-methanesulfonvl-benzylamide 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.
*H NMR (DMSO-d*): 810.25 (IH, bs); 9.89 (IH, bs); 9 79 (IH, t, J6.2 Hz); 8.50 (IH, s);
7.93 (IH, s); 7.94-7.90 (IH, m); 7.87 (2H, d, 78.5 Hz); 7.84 (IH, t,77.7 Hz);7.74 (IH,d, 77.7 Hz); 7.55 (2H, d, J 8.3 Hz); 4.63-4.56 (2H, m); 3.18 (3H, s); 2.55-2.49 (IH, p, 76.8 Hz); 2.18 (3H, s); 1.08 ,(6H, d, 7 6.8 Hz).
APCI-MS m/z: 593.2 [MH+].
c> 5-(5-Isopropvl-ri.3.41oxadiazoI-2-vD-6-methvI-2-oxo-l-(3-trifluoromethvl-phenvlV 1.2-dihvdro-T>vridine-3-carboxvlic acid 4-methanesulfonvl-benzvlamide The compound obtained in step (b) (0.02 g, 0.034 mmol) in TMS-polyphosphate (3 ml, PPSE in DCM, Synthesis 1982, page 591-592) was stirred in a sealed vial and heated at 70 °C for 3 h. LC-MS showed complete conversion of the linear starting material to a compound with the expected MW. The cooled solution was diluted with DCM (10 ml) and was washed with water (10 ml). The organic phase was collected and the aqueous phase was extracted with another portion of DCM (10 ml). The combined organic phase was
washed with brine and was then dried with NaaSCU. Filtration and evaporation of the solution gave a white solid. Purification of this material by preparative HPLC provided pure fractions which were freeze-dried. The title compound was obtained as a white solid (0.015 g, 77%).
'HNMR (DMSO-dtf): 8 9.76 (1H, t, J=6.29 Hz); 8.77 (1H, s); 8.01 (1H, s); 7.94 (1H, d, / 7.6 Hz); 7.87 (2H, d, J 8.6 Hz); 7.84-7.78 (2H, m); 7.55 (2H, d, J 8.4 Hz); 4.65-4.56 (2H, m); 3.30 (1H, p, J 6.9 Hz); 3.18 (3H, s); 2.41 (3H, s); 1.36 (6H, d, J 7.0 Hz).
APCI-MS m/z: 575.2 [MH+].
Example 39 6-Methvl-5-ri.3.41oxadiazoI-2-vD-2-oxo-l-(3-trifluoromethvl-phenvl>-1.2-dihvdro-pvridine-3-carboxylic acid 4-methanesulfonyl-benzvlamide
a) S-fN'-ffiormvl-hvdrazrnocarrwm
dihvdro-pyridine-3-caiboxylic acid 4-methanesulfonyl-benzvlamide
The compound obtained in Example 38 (a) (0.025 g, 0.048 mmol) in dry THF (10 ml) was stirred and mixed formylacetyl anhydride (0.06 g, 0.68 mmol; prepared according to literature procedures) was added. The mixture was stirred for 20 minutes and LG-MS showed full conversion of the starting material. Evaporation and purification on preparative HPLC, and subsequent freeze-drying, afforded the sub-title compound (0.022 g, 83%) as a white powder.
^NMR (DMSO-d 8.11 (1H, s); 7.93 (1H, s); 7.94-7.89 (1H, s); 7.8y (2H, d, J 8.65 Hz); 7.87 (1H, d, / 8.21); 7.74 (1H, d, J 8.21 Hz); 7.55 (2H, d, J 8.21 Hz); 4.63-4.54 (2H, m); 3.17 (3H, s); 2.18 (3H, s).
APCI-MS m/z: 551.2 [MH*].
b) 6-Methvl-5-ri.3.41oxadiazol-2-vlV2-oxo-l-(3-trifluoromethvI-phenvD-l,2-dihvdrD-
pvridine-3-carboxylic acid 4-methanesulfonyl-benzylamide
The title compound was prepared according to the procedure described in Example 38 (c) starting from 0.020 g (0.036 mmol) of the compound obtained in step (a). The title
compound was obtained as a white solid (0.010 g, 52%) after purification on preparative HPLC and freeze-drying of the pure fractions.
'H NMR (DMSO-d5): 8 9.74 (1H, t, J 6.3 Hz); 9.38 (1H, s); 8.82 (1H, s); 8.01 (1H, s); 7.94 (1H, d, J 7.7 Hz); 7.87 (2H, d, J 8.0 Hz); 7.87-7.84 (1H, m); 7.81 (1H, d, J 7.9 Hz); 7.55 (2H, d, / 8.0 Hz); 4.65-4.55 (2H, m); 3.17 (3H, s); 2.45 (3H, s).
APCI-MS m/z: 533.2 [MH*].
Example 40 5-f5-Hvdroxv-ri.3.41oxadiazol-2-vlV6-methvl-2-oxo-l-('3-trifluoromethvl-phenyD-1 .2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonvl-benzvIamide
a) N'-fS^-Methanesulfonyl-benzvlcarbamovn^-methvl-o^oxo-l-CS-trifluoromethyl-
phenylV1.6-dhydrc>-pyridine-3-carboriyn-hydrazinecarfao^yIic acid ethvl ester
The compound obtained in Example 38 (a) (0.025 g, 0.048 mmol) in dry THF (2 ml) was
stirred and diethyl pyrocarbonate (0.023 g, 0.14 mmoi) was added. The vial was sealed and
was stirred at 40 °C for 3 h, monitoring the reaction by LC-MS. The mixture was
evaporated and was then purified by preparative HPLC, giving the sub-title compound
(0.023 g, 80%) as a white solid after freeze-drying the pure fractions.
JH NMR (DMSO-dd): 6 10.23 (1H, s); 9.79 (1H, t, J 6,1 H*); 9.23 (1H, s); 8.47 (1H, s);
7.94 (1H, s); 7.94-7.89 (1H, d, J 8.2 Hz); 7.87 (2H, d, / 8.4 Hz); 7.82 (1H, d, J 7.7 Hz);
7.74 (1H, d, J 7.8 Hz); 7.54 (2H, d, J 8.4 Hz); 4.65-4.55 (2H, m); 4.14-4.01 (211, m); 3.17
(3H, s); 2.16 (3H, s); 1.25-1.15 (3H, m).
APCI-MS m/z: 5952 [MH+J.
V) 5-(5-Hvdroxv-ri.3.41oxadiazol-2-vlV6-methvl-2-oxo-l-(3-trifluoromethvl-ohenvlV1.2-dihvdro-pvridine-3-carboxvlic acid 4-methanesulfonyI-bjenzylamide The title compound was prepared according to the procedure described in Example 38 (c) starting from O.OlSg (0.025 mmol) of the compound obtained in step (a). The reaction time was 4 days. The product was obtained as a white solid (0.008 g, 58%) after purification on preparative HPLC and freeze-drying of the pure fractions.
1HNMR (DMSO-dtf): δ12.61 (1H, bs); 9.73 (1H, t, 76.2 Hz); 8.63 (1H, s); 7.99 (1H, s); 7.93 (1H, d, J 8.0 Hz); 7.87 (2H, d, J 8.2 Hz); 7.85 (1H, t, J 7.8 Hz); 7.78 (1H, d, J7.8 Hz); 7.55 (2H, d, J 8.2 Hz); 4.64-4.55 (2H, m); 3.17 (3H, s); 2.30 (3H, s).
APCI-MS m/z: 549.1 [MR*].
Example 41 6-Methyl-5-(5-metfayMH-ri^.41triazol-3-vlV2-oxo^l-(3-trifluoroinethyl--
phemvlVl .2-dihvdro-pyridine-3-carboxylic acid 4-methvlsulfonvl-benzvIamide
The compound of Example 38 (a) (0.017 g, 0.0325 minol), toluene (1 ml), NMP (0.5 ml),
triethylamine (0.5 ml), ethyl acetamidate hydrochloride (0.030 g, 0.24 mmol) and a
magnetic stirrer bar were placed in a glass vial. The vial was sealed and the mixture was
healed with stirring at 100 °C overnight. The mixture was allowed to cool and was then
concentrated in vacuo. Purification by preparative HPLC and subsequent freeze-drymg of
the pure fractions afforded the title compound (0.005 g. 28%) as a white solid.
1H NMR (DMSO-dtf): δ13.79 (1H, bs); 9.89 (1H, t, 7 6.0 Hz); 8.99 (1H, s); 7.97 (III, s);
7.90 (1H, d, 7 8.0 Hz); 7.87 (2H, d, 7 8.2 Hz); 7.83 (1H, t, 7 7.9 Hz); 7.78 (1H, d, 7 7.9
Hz); 7.55 (2H, d, 7 8.3 Hz); 4.67-4.55 (2H, m); 3.17 (3H, s); 2.41 (3H, s); 2.41 (3H, s).
APCI-MS m/z: 546.2 [MH*].
Example 42 5-f4.5-Dimethvl-4H-r 1.2.41triazol-3-vn-6-methvl-2-oxo-l-f3-tTifiuoromethvl-phenvlVl .2-dihvdro-pvridine-3-carboxylic acid 4-methanesulfonvl -• benzvlamide
A solution of POC13 (0.030 g, 0.2 mmol) in CHC13 (1 ml) and pyridine (1 ml) was added to N-methylacetamide (0.015 g, 0.2 mmol) and the mixture was cooled in an ice-water bath and stirred for 90 minutes. To this solution was added a solution of 5-hydrazinocarbonyl-6-memyl-2-oxo-l-(3-trifluoromethyl-phenyl)-1^2-dihydro-pyridine-3-carboxylicacid4-methanesulfonyl-benzylamide (Example 38 (a), 0.040 g, 0.076 mmol) in CHCls (2 ml) and the mixture was stirred overnight at room temperature. Purification by preparative HPLC gave the linear intermediate (0.020 g). This material was suspended in EtOAc (2 ml) and was heated (90 °C) with stirring for 4 h, giving rise to a mixture of three components. This mixture was purified on preparative HPLC giving the title compound (0.003 g, 7%) after freeze-drying the pure fractions.

1HNMR (DMSO-dtf): δ 9.89 (IH, t, 76.1 Hz); 8.29 (IH, s); 8.04 (IH, s); 7.94-7.89 (IH, m); 7.87 (2H, d, J 8.6 Hz); 7.87-7.83 (2H, m); 7.55 (2H, d, 78.3 Hz); 4.66-4.55 (2H, m); 3.45 (3H, s); 3.17 (3H, s); 2.39 (3H, s); 1.87 (3H, s).
APCI-MS m/z: 560.2 [MH+].
Example 43 5-fS-MethoxvmethvI-n.3.41oxadiazol-2-vlV6-niethvl-2-oxo-l-f3-trifiuoromethyl-phenylVl .2-dihvdro-pvridine-3-carboxvlic acid 4-methanesulfonyI-benzvlamide
a) 5-rN1-f2-Methoxv-acetvlVhvdrazinocarfaonvl1-6^rnethvI-2-oxo-l-(3-trifluQiomethyl-
phenylVl .2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonvl-benzvIamide
The compound obtained in Example 38 (a) (0.028 g, 0.053 mmol) in dry THF (2 ml) was treated with triethylamine (0.020 g, 0.20 mmol) and 2-raethoxyacetyl chloride (0.02 g, 0.18 mmol). The mixture was stirred for 5 minutes and LC-MS showed complete conversion of the starting material to a mixture of three compounds. The reaction was quenched by the addition of MeOH, and subsequent evaporation and purification on preparative HPLC afforded the subtitle compound (0.015 g, 47%) as a white solid after freeze-drying the pure fractions.
1HNMR (DMSO-dtf): δ 10.29 (IH, s); 9.95 (IH, s); 9.79 (1H, t, 76.3 Hz); 8.51 (IH, s); 7.93 (IH, s); 7.94-7.89 (IH, m); 7.87 (2H, d, J 8.3 Hz); 7.82 (IH, d, J 7.8 Hz); 7.74 (IH, d, J 7.7 Hz); 7.55 (2H, d, 7 8.1 Hz); 4.65-4.55 (2H, m); 3.97 (2H, s); 3.36 (3H, s); 3.17 (3H, s);2.18(3H,s).
APCI-MS m/z: 595.2 [MH*].
b) 5-f5-Met3ioxvmethvl-ri3.41oxadiazo]-2-vlV6-methvl-2-oxo-l-G-trifluoromethvl-
phenyD-L2-dihydro-pvridine-3-carboxvIicacid4-methanesulfonvl-benzvlamide
Prepared according to the procedure described in Example 38 (c) starting from 0.015 g
(0.025 mmol) of the compound obtained in step (a). The title compound (0.011 g, 80%)
was obtained as a white solid after purification on preparative HPLC and freeze-drying of
the pure fractions.
1H NMR (DMSO-dtf): δ 9.73 (1H, t, J6.1 Hz); 8.79 (1H, s); 8.01 (1H, s); 7.94 (1H, d, y 7.9 Hz); 7.87 (2H, d, J 8.14 Hz); 7.86-7.84 (1H, m); 7.71 (1H, d, J 7.9 Hz); 7.56 (2H, d, J 8.1 Hz); 4.75 (2H, s); 4.65-4.55 (2H, m); 3.39 (3H, s); 3.17 (3H, s); 2.45 (3H, s).
APCI-MS m/z: 577.2 \MB+l
Example 44 N-f4-(IsoptppvlsuIfonvI')benzvl1-6-roethvI-5-(5-methyl-13.4-oxadiagol-2-
vlV2-oxo-l-r34trifluoromethyl')phenyl1--1.2-dihvdropyridine-3-carboxajQide
The title compound was prepared by an analogous method to that described in Example 14.
1H NMR (CDC13): δ 9.96 (1H, bt, ); 9.08 (1H, s); 7.89-7.78 (4H, m); 7.55-7.45 (4H, m);
4.78-4.65 (2H, m); 3.20-3.13 (1H, m,); 2.68 (3H, s); 2.62 (3H, s); 1.28 (6H, d, J 6.9 Hz).
APCI-MS m/z: 575 [ME*].
Example 45 N-r4-fEthvIsulfonvDberavl1-6-methvl-5-f5-methvl-13.4-oxadiazol-2-vlV2-
oxo-l-r3-(trifluoromethyl^henvl1-1.2-dihvdropvridine-3-carboxamide
The title compound was prepared by an analogous method to that described in Examplel4.
1H NMR (CDC13): δ 9.80 - 9.71 (1H, m); 9.09 (1H, s); 7.90 - 7.74 (4H, m); 7.56 - 7.42
(4H, m); 4.79 - 4.63 (2H, m); 3.08 (2H, q, J 7.5 Hz); 2.64 (3H, s); 2.62 (3H, s); 1.27 (3H, t,
J7.4HZ).
,\PCI-MS m/z: 561.1
Example 46 JV-r4-(Cvclopropvlsulfonyl')benzvll-6-methyl-5-f5-methvl-L3.4-oxadiazQL;
2-vlV2-oxo-l-f3-ftrifluoromemyl)phenyn-1.2-dihvdropyridine-3-carboxamide
The title compound was prepared by an analogous method to that described in £xamplel4.
1H NMR (CDC13): δ 9.74 (1H, bt, ); 9.09 (1H, s); 7.87-7.77 (4H, m); 7.54-7.45 (4H, m);
4.75-4.64 (2H, m); 2.64 (3H, s); 2.62 (3H, s); 2.46-2.39 (1H, m); 1.35-1.31 (2H, m); 1.04-
0.99 (2H, m).
APCI-MS m/z: 573 [MH+].
Example 47 6-Methvl-5-ri.3.41oxadiazoI-2-vI-2-oxo-l-(3-trifluoromethvl-phenvlVlJ2-dihvdro-pvridine-3-carboxvIic acid 4-fpropane-2-sulfonvn-benzvlamide
The title compound (0.025 g, 64%) was prepared by an analogous method to that described in Example 39.
1H NMR (DMSO-dd): δ 9.75 (1H, t, J 62 Hz); 938 (1H, s); 8.82 (1H, s); 8.02 (1H, s); 134 (1H, d, J 7.5 Hz); 7.89-7.82 (2H, m); 7.80 (2H, d, / 8 2 Hz); 7.56 (2H, d, / 8.2 Hz); 4.68-4.56 (2H, m); 337 (1H, p, J 6.8 Hz); 2.45 (3H, s); 1.13 (6H, d, /62 Hz).
APCI-MS m/z: 561.2 [MH*"].
Example 48 6-Methvl-5-fl3.41o^adiazol-2-yl-2-oxo-l-f3-trifluoroniethvl-phenvn-lJZ-
dihyd|X)-pyridine-3-cart>oxylic acid 4-cyclopropanesuIfonyl-benzyIamide
The title compound (0.023 g, 80%) was prepared by an analogous method to that described
in Example 39.
1H NMR (DMSO-dtf): δ 9.74 (1H, t, J62 Hz); 938 (1H, s); 8.82 (1H, s); 8.01 (1H, s); 7.94
(1H, d, J 7.7 Hz); 7.89-7.80 (2H, rr, 7.84 (2H, d, J 8.2 Hz); 7.55 (2H, d, J 8.2 Hz); 4.66-
4.56 (2H, m); 2.84-2.77 (1H, m); 2.44 (3H, s); 1.12-1.05 (2H, m); 1.05-0.97 (2H, m).
APCI-MS m/z: 559.2 [MB*].
Example 50 6-Methvl-5-f2-methvl~13-oxazol-4-vn-N-r4-fmeth'sdsulfonvnbenzyn-2-oxo-l-f3-(trifluoromemynphen\11-l.g-dihvdropyridine-3-carboxamid&
a> S-fl-Butoxwinvn-6-methvl-N-r4-rmethvlsuIfonvl')benzvn-2-oxo-l-r3-(trifluoromethynphenyn-1.2-dihydropvridine-3-carboxamide
5-Iodo-6-methyl-N-[4-(methylsuIfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (Example 1 (d), 101.5 mg, 0.17 mmol), bis[1.2-bis(diphenylphosphino)ethane3-palladium (0) (16.5 mg, 18.3 /tmol), n-butyl vinyl ether (60 jil, 0.46 mmol), triethylamine (0.5 ml, 3.6 mmol) and DMF (6 ml) were placed in a Schlenk vessel equipped with a magnetic stirring bar. 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 (273 mg, 28 %).
H NMR (CDC13): δ 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); 426 (1H, d, J 2.6 Hz); 3.83 (2H, t, J 6.5 Hz); 3.03 (3H, s); 2.11 (3H, 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 [MH+J.
b") 5-Acetyl-6-methyl-N-r4-(metbvlsulfonvnbenzvl1-2-oxo^l-r3-(trifluoromethvI^phenyn-
1.2-dihv&opyridine-3'-carboxamide
Aqueous hydrochloric acid (2.0M, 50 /il) was added to a solution of 5-(l-butoxyvinyl)-6-
methyl-N-[4^(j]ifithyisulfonyl)beiizyl]-2-oxo-I-[3-(trifluoroinethyl)pheny]3-l^-
dihydropyridine-3-carboxamide (38 mg, 67.5 /wnol) in DMF (0.5 ml). After 20 min. the
solution was neutralized with aqueous sodium hydrogen carbonate. The reaction mixture
was purified by preparative HPLC to give the title compound as a white solid (17.6 mg,
51%).
1H NMR (CDC13): δ 9.75 (1H, t, J 5J Hz); 9.08 (1H, s); 7.90 (2H, d, J 8.3 Hz); 7.85 (1H,
d, J7.9Hz);7.78 (1H,t, J7.9Hz);7.54(2H,d, J8.3Hz);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 tti/z: 507 [MR*].
c) 5-Bromoacetvl-6-methyl-A^-r4-fmethvlsulfonyl')benzvn-2-oxo-l-r3-(tnfluorometbvDphenvn-1.2-dihvdropvridine-3-carbQxamide
Bromine (34 jul, 0.66 mmol) in THF (5 ml) was added to a solution of 5-acetyl-6-methyl-//-[4Kmemylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (320 mg, 0.63 mmol) in THF (10 ml). After 2h, the yellow colour had disappeared. The reaction mixture was partitioned between water and ethyl acetate, the organic phase was separated, evaporated, and the residue was chromatographed on silica using ethyl acetate/heptane (1/1,2/1,4/1) as eluent. Fractions containing the product were combined and evaporated to give the title compound (150 mg, 41%).
1HNMR (CDC13): δ 9.67 (IH, t); 9.00 (IH, s); 7.89 (2H, d); 7.86 (IH, d); 7.78 (IH, t); 7.52 (2H4); 7.50 (IH, s); 7.42 (IH, d); 4.69 (2H, m); 4.41 (2H, s); 3.02 (3H, s); 2.42 (3H, s).
d') 6-Methyl-5-(2-methvl-13-oxa2pl-4-vlVA(-r4-(methvlsalfonvl')ben2vn-2-oxo-l-B-
A mixture of 5-(bromoacetyl)-6-methyl-JV-[4-(methylsulfonyI)benzyl]-2-oxo-.l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (90 mg, 0.15 mmol) and acetamide (44 mg, 0.75 mmol), xylene (300 fil) and cone. H2SO4 (10 /*!) was heated with stirring for 3 h. The reaction was diluted with water and CHaCN and purified on preparative HPLC affording the title compound (37 mg, 45%). 1H NMR (CDC13): δ10.08 (IH, t); 8.69 (IH, s); 7.88 (2H, d); 7.82 (IH, d); 7.76 (IH, t); 7.72 (IH, s); 7.54 (IH, s); 7.52 (2H, d); 7.46 (IH, d); 4.69 (2H, m); 3.02 (3H, s): 2,56 (3H, s);2.19(3H,s).
APCI-MS m/z: 546.4 [MH*].
(trifluoromethylphenvn-l-dihvdropvridine-S-carboxamide
A-mixture of 5-(bromoacetyl)-6-methyl-^V-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (Example 50 (c)/100 mg,
0.17 mmol), fonnamide (135 pi, 3.4 mmol), xylene (300 ;tl) and cone. H2SO4 (10 /il) was
heated with stirring for 2 h. The reaction was diluted with water and CH3CN and purified
on preparative HPLC, affording the title compound (23 mg, 31%).
1HNMR (CDC13): δ 9.95 (IH, t); 8.75 (IH, s); 7.99 (IH, d); 7.88 (2H, d); 7.86 (IH, d);
.7.83 (IH, d); 7.76 (IH, t); 7.72 (IH, s); 7.52 (2H, d); 7.47 (IH, d); 4.69 (2H, m); 3.03 (3H,
s); 2.24 (3H, s).
APCI-MS m/z: 523.3 [MB*].
Example 52 5-f2-Amino-thiazol-4-vn-6-methvI-2-Qxo-l-f3-trifluoromethvl-phenvl')-1.2-dihvdro-DVridine-3-carboxvlic acid 4-methanesulfonvl-benzvlamide
5-BromoacetyI-6-inethyl-2-oxo-l-(3-trifluoromethyl-phenyl)-l,2-dihydro-pyridine-3-carboxylic acid ^methanesulfonyl-benzylamide (Example 50 (c), 0.04 g, 0.067 mmol), thiourea (0.0067 g, 0.086 mmol), NaOAc (0.011 g, 0.136 mmoIX EtOH (2 ml) and a magnetic stirrer bar were placed in a tube designed for microwave synthesis. The vial was sealed and the mixture was heated in a CEM Discover Microwave apparatus (100W, 90 °C) for 20 minutes, giving complete conversion of the starting material to a single product according to LC-MS. The solvents were evaporated to give a crude mixture which was purified on preparative HPLC giving the title compound (0.026 g, 66%) as a slightly yellowish solid after freeze-drying the pure fractions.
1H NMR (DMSO-ds): δ 9.92 (1H, t, / 6.1 Hz); 8.64 (1H, s); 7.94 (1H, s); 7.90 (1H, d, / 8.( Hz); 7.87 (2H, d, J 8.3 Hz); 7,81 (1H, d, / 7.7 Hz); 7.75 (1H, d, J 7.75 Hz); 7.54 (2H, d, J 8.2 Hz); 7.11 (2H, bs); 6.64 (1H, s); 4.65-4.55 (2H, m); 3.17 (3H, s); 2.17 (3H, s).
APCI-MSm/z: 563 [MB*].
Example 53. 5-(2J5-DimethvM 3-oxazol^vlV6^methvl-jy-r4-fmemvlsiilfonvnbenzvl1-2-oxo-l-f3-ftdfluoromemynphenvll-1.2^hvdropvridine'3-carboxamide
a") 6^Methyl-JVr-r4-(raethylsulfoaynbenzylV2-oxo-5-propionyI-l-f3-(trifluoron»thvl^heovlV1.2Hiihydropyridme-3-carboxamide Asolua'oTiof54odo-6-msthyl-]V-[4-(memykulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (Example 1 (d), 1500 mg, 2J mmol), bis[l^-bis(diphenylphosphino)ethane]palladiuni(0) (230 mg, 0.25 mmol), triethylamine (7.5 ml, 54 mmol) and ethylpropenyl ether (900 /al,.7.5 mmol) in DMF (45 ml) was heated at 100 °C overnight. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate and the solvent was removed under reduced pressure. The crude product was men dissolved in DMF (25 ml) and 2M HC1 (25 ml) and then stirred for 1.5h. The reaction mixture was then poured into aqueous NaHCOa and extracted with ethyl acetate. The extracts were separated, 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 the title compound (1.3 g, 99%).
1HNMR (CDC13): δ 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 (3R s); 3.00 (2H. q); 2.39 (3H, s); 1.22 (3H, t).
M 5-(2^Bromopropanovl')-6--methvl-/y-r4-(methylsulfonyl^benzyIV2-oxo-l-f3-
ftrifluoromethvnphenvn-1.2-dihvdropvridine-3-carboxamide
Bromine (84 til, 1 .61 mmol) in THF (5 ml) was added to a solution of 6-methyl-//-[4-
(methylsulfonyl)benzyI]-2-oxo-5-propionyl-l-[3-(trifluoromethyl)phenyl]-l^-
dihydropyridine-3-carboxamide (700 mg, 1.34 mmol) in THF (10 ml). After 2h, the yellow
colour had disappeared. The reaction mixture was partitioned between water and ethyl
acetate, the organic phase was separated, dried and evaporated under reduced pressure to
give the title compound (800 mg, 99 %).
1H NMR (CDC13): 5δ9.71 (1H, t); 8.97 (1H, d); 7.89 (2H, d); 7.85 (1H, d); 7.77 (1H, t);
7.52 (2H, d); 7.46 (IH, d); 7.40 (1H, d); 5.28 (1H, q); 4.69 (2H, m); 3.02 (3H, s); 2 36 (3H,
s); 1.90 (3H, d).
c) 5-(2.5-Dimethyl-13-oxazoj^yl)^m^
(trifluoromedivl)pherjvll-L2^hvdropyridine-3-carboxarnide
A mixture of 5'24>romopropanoyl)-6-methyl-JV-[4-(methyisulfonyl)benzyl]-2-oxo-l-i3-
(trifluoromethyl)phenyl]-l^-dihydropyridine-3-carboxamide (130 mg, 0.22 mmol),
acetamide (262 mg, 4.4 mmol), xylene (300 jtl) and cone. HaSO* (10 /il) was heated with
stirring for 2 h. The reaction was diluted with water and CHsCN and purified on
preparative HPLC, affording the title compound (45 mg, 36 %).
'HNMR (CDC13): δ 10.00 (IH, t); 8.54 (1H, s); 7.88 (2H, d); 7.82 (1H, d); 7.75 (1H, t);
7.54 (IH, d); 7.52 (2H, d); 7.47 (IH, d); 4.68 (2H, m); 3.02 (3H, s); 2.51 (3H, s); 2.34 (3H,
s);2.11(3H,s).
APCI-MS m/z: 560.4 [MR*].
Example 54 6-Methvl-5-('5-methvl-13-oxazol-4-v]VJV-r4-(methvlsulfonvnbenzvn-2-oxo-l-f3-(trifluoromethvnphenvn-lJ2-dihvdroDvridine-3-carboxamide
A mixture of 5-(2-bromopropanoyl)-6-methy]-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l^-dihydropyridine-3-carboxamide (Example 53 (b), 130 mg,
022 mmol), fonnamide (176 yd, 4.4 mmol), xylene (300 /*1) and cone. H2SO4 (10 /il) was
heated with stirring for 2 h. The reaction was diluted with water and CHaCN and purified
on preparative HPLC, affording the title compound (27 mg, 23 %).
1H NMR (CDC13): δ10.02 (1H, t); 8.57 (la d); 7.89 (1H, s); 7.88 (2H, d); 7.83 (1H, d);
7.76 (1H, t); 7.55 (1H, d); 7.52 (2H, d); 7.48 (1H, d); 4.69 (2H, m); 3.02 (3H, s); 2.41 (3H,
s); 2.09 (3H, s).
APCI-MS m/z: 546.3 [MH+].
Example 55 5-f2-Amino-5-metfayI-i:hiazol-4-yI)-6-methyI-2-oxo-l-(3-trifluoromethyI-phenvl>-L2-dihydro-pvridine-3-carboxvlic acid 4-methanesulfonvl-benzylamide 5-(2-Bromopropanoyl)-6-metiiyl-JV^[4-(nMthylsulfonyl)benzyI]-2-oxo-l-I3-(trifluoromethyl)pheny!3-l^-dinydropyridine-3-carboxainide (Example 53 (b), 0.04 g, 0.067 mmol), thiourea (0.0067 g, 0.0^6 mmol), NaOAc (0.011 g, 0.136 mrnol), EtOH (2 ml) and a magnetic stirrer bar were placed in a tube designed for microwave synthesis. The vial was sealed and the mixture was heated in a GEM Discover Microwave apparatus (100W, 90 °C) for 20 minutes, giving complete conversion of the starting material to a
single product according to LC-MS. The solvents were evaporated to give a crude mixture which was purified on preparative HPLG, giving the title compound (0.026 g, 66%) as a slightly yellowish solid after freeze-drying the pure fractions.
'HNMR (DMSO-dtf): δ 9.90 (1H, t, J 6.2 Hz); 8.32 (1H, s); 7.98 (1H, s); 7.91 (1H, d, .7 7.9 Hz); 7.87 (2H, d, / 8.3 Hz); 7.83 (1H, t, / 7.8 Hz); 7.77 (1H, d, J 7.8 Hz); 7.54 (2H, d, / 8.2 Hz); 4.67-4.55 (2H, m); 3.18 (3H, s); 2.12 (3H, s); 1.91 (3H, s).
APCI-MS m/z: 577.1 [MH+].
Example 56 5-(2-HvdroxvmethvI-5-methvl-thiazol-4-vlV6-methvl-2-oxo-l-(r3-trifluoromethvl-phenvlVl.2-dihvdro-pvridine-3-carboxvlic acid 4-methanesulfonvl-benzvlamide
5-(2-Bromopropanoyl)-6-methyl-A^-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (Example 53 (b), 0.06 g, 0.10
mmol), 2-amino-2-thioxoethyl pivalate (0.022 g, 0.125 mmol), EtOH (2 ml) and a magnetic stirrer bar were placed in a tube designed for microwave synthesis. The vial was sealed and the mixture was heated in a GEM Discover Microwave apparatus (100W, 80 °C) for 40 minutes, giving complete conversion of the starting material to a single product according to LC-MS. The solvents were evaporated to give a crude mixture which was purified on silica giving 0.045 g (76%) of the intermediate pivalyl ester. This compound was dissolved in THF (2 ml) and water (2 ml). To this solution was added NaOH (0.2 mmol, 0. 1 ml of a 2M solution), and the mixture was stirred at room temperature overnight The THF was evaporated off and the water phase was acidified, extracted, and the extracts were evaporated. Purification by preparative HPLC gave pure fractions which were freeze-dried to give the title compound (0.040 g, 68%) as a white solid. *H NMR (DMSO-'-dtf): δ 9.92 (1H, t, .7 6.2 Hz); 8.30 (1H, s); 8.02 (1H, s); 7.92-7.88 (1H, d); 7.87 (2H, d, 78.5 Hz); 7.88-7.78 (2H, m); 7.54 (2H, d, J 8.4 Hz); 6.02 (1H, J 5.8 Hz); 4.69 (2H, d, J 5.8 Hz); 4.64-4.54 (2H, m); 3.17 (3H, s); 234 (3H, s); 1.89 (3H, s)
APCI-MS m/z: 592.1 [MH*].
Example 57 6-Methvl-5-(5-meth yl-(l 3. ,41oxadiazol-3- vl V2-oxo-l -(3-trifluoromethvl-pheiwlV1.2-dfavdro-pvridine-3-carboxvlicadd4-m^
a) 5^yano-&-mernyl-N-f4-(meth^te 1 .2-dihvdropyridine-3-carboxainide
A mixture of 5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l^-dihydropyridine-3-carboxamide (Example 1 (d), 120 mg, 020 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 dichloromethane/methanol (10:0.2) to give the title compound as a white solid (24 mg, 24 %).
JH NMR (DMSO-d6): δ 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, m); 7.77 (1H, d, J 8.0 Hz); 7.52 (2H, d, J 8.4 Hz); 4 56 (2H, d, J 62 Hz); 3.16 (3H, s); 2.22 (3H, s).
APCI-MS m/z: 490 [MR4].
b) 5-^-HydroxvcarbamimidovlV6-memyI-2-oxo-l-G-trifluoromethyl-phen'ylV1.2-dihvdro-pyridine-3-carboxvlic acid 4-methanesulfonyl-benzvl amide 5-Cyano-6-methyl-N-[4-(methylsu]fonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (0.040 g, 0.082 mmol), hydroxylamine hydrochloride (0.015 g, 0.209 mmol), NaOAc (0.017 g, 0.209 mmol), ethanol (3 ml), water (0.1 ml) and a magnetic stirrer bar were placed in a vial. The mixture was heated (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 intermediate N-hydroxyamidine.
1R NMR (DMSO-dtf): δ9.85 (lH,t, J62 Hz); 9.53 :(1H, s); 8.33 (1H, s);7.91 (lH,d,/7.6 Hz); 7.86 (2H, d, / 8.2 Hz); 7.85 (1H, s); 7.83 APCI-MS m/z: 523.2
c 6-Methvl-5-f5-methvl-ri .2.41oxadiazol-3-vlV2-oxo-i -f3-trifluoromethyl-|>henvlVl 2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonvl-benzylamide 5-(N-Hydroxycarbarnimidoyl)-6-methyl-2-oxo-l-(3-trifluoromethyl-phenyI)-1^2-dihydro-pyiidine-3-carboxylic acid4-methanesulfonyl-benzylamide (0.011 g, 0.021 mmol), acetic anhydride (0.02 g, 0.195 mmol), toluene (2 ml) and a magnetic stirrer bar were placed in a vial. The vial was sealed and was heated (110 °C) with stirring for 5 h. LC-MS confirmed the consumption of the starting material and the formation of a product with the expected MW. Evaporation and purification on preparative HPLC gave the title compound (0.004 g, 35%) as a white solid after freeze-drying the pure fractions.
JH NMR (DMSO-dd): δ 9.77 (1H, t, /6.2 Hz); 8.90 (1H, s); 8.01 (1H, s); 7.93 (1H, d, J7.5 Hz); 7.87 (2H, d, J 8.3 Hz); 7.87-7.79 (2H, m); 7.55 (2H, d, 78.3 Hz); 7.67-7.53 (2H, m); 3.17 (3H, s); 2.69 (3H, s); 2.37 (3H, s).
APQ-MS m/z: 547.2
Example 58 6-Methvl-5-rL2.41oxadiazol-3-vl-2-oxo-l-f3-trifluoromethvl-phenvlVl^-dihvdro-pyridine-3-carboxvlic acid 4-methanesulfonvl-benzvlamide 5-Cyano-6^methyl-N-[4-(methylsulfonyl)ben2yl]-2K)xo-l-[3^trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxainide (Example 57 (a), 0.040 g, 0.082 mmol), hydroxylamine hydrochloride (0.015 g, 0.209 mmol), NaOAc (0.017 g, 0.209 mmol), ethanol (3 ml), water (0.1 ml) and a magnetic stirrer bar were placed in a vial. The mixture was heated (90 °C) overnight The solvents were evaporated hi vacuo. The residue was dissolved in triethyl-orthoformate (3 ml) in a vial and a magnetic stirrer bar was added. The vial was sealed and heated (130 °C) with stirring for 2 h. LC-MS confirmed formation of a product with the expected MW, The volatiles were removed in vacuo, and the residue was purified on preparative HPLC giving the title compound (0.012 g, 27%) as a white solid after freeze-drying the pure fractions.
]HNMR (DMSO-dtf): δ 9.78 (1H, s); 9.77 (1H, t, J6.2 Hz); 8.93 (1H, s); 8.03 (1H, s); 7.93 (1H, d, / 7.7 Hz); 7.87 (2H, d, / 8.2 Hz); 7.86-7.80 (2H, m); 7.56 (2H, d, / 8.2 Hz); 4.65-4.55 (2H, m); 3.17 (3H, s); 2.39 (3H, s).
APCO-MS irtx 533.2 [MH+].
Example 59 6-Methvl-2-oxc>-5-aH-tetrazol-5-vn-l-(r3-trifluoromethvl-phenvlV1.2-dihvdro-pvridiae-3-carboxvIic acid 4^methanesulfonyl-benzvlamide 5-^ano-6-methyl-N-[4-(rnethylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (Example 57 (a), 0.018 g, 0.037 mmol), NaNa (0.020 g, 0.307 mraoJ), NHiCI (0.016 g, 0.307 mmol), NMP (1 ml) and a magnetic stirrer bar •were placed in a tube designed for microwave synthesis. The vial was sealed and the mixture was heated in a CEM Discover Microwave apparatus (100W, 140 °C) for 30 minutes, giving complete conversion of the nitrile according to LC-MS. The crude mixture was dissolved in acetonitrile (2 ml) and water (2 ml) and was purified directly on preparative HPLC under acidic conditions, giving the title compound (0.012 g, 61%) as a beige solid after freeze-drying the pure fractions.
'HNMR (DMSO-dtf): δ 9.81 (1H, t, J6.1 Hz); 8.79 (1H, bs); 8.02 (1H, bs); 7.93 (1H, d, J 7.89 Hz); 7.87 (2H, d, / 8.5 Hz); 7.88-7.85 (1H, m); 7.82 (1H, d, J 8.2 Hz); 7.56 (2H, d, J 8.4 Hz); 4.67-4.55 (2H, m); 3.17 (3H, s); 2.34 (3H, s).
APCI-MS ro/z: 533.2 [MH+].
Example 60 6-Mcthvl-5-(4-methYl~oxazol-2-vlV2-oxo-l-f3-trifluoromethvl-phenvIV12-dihvdro-pyridine-3-carboxvlic acid 4-methanesulfonvl-benzvlamide 6-Methyl-2-oxo-l-(3-trifluaromethyl-phenyl)-l,2-dihydro-pyridine-3,5-dicarboxylicacid 5-amide 4-methanesulfonyl-benzylamide [prepared from the acid chloride of 5-(4-methanesulfonyl-benzylcaibamoyl)-2-methyl-6-oxo-l-(3-trifluoromethyl-phenyl)-l,6-dihydro-pyridine-3-carboxylic acid [described in Example 14 (b)] and ammonia] (0.05 g, 0.098 mmol), 1-chloroacetone (0.025 g, 0.27 mmol), CaCQj (0.015 g, 0.15 mmol), NMP
(1.5 ml) and a magnetic stiner bar were placed in a tube designed for microwave synthesis. The vial was sealed and the mixture was heated in a GEM Discover Microwave apparatus (100W, 155 °C) for 60 minutes, giving complete conversion of the amide according to LC-MS. The crude mixture was dissolved in acetonitrile (2 ml) and water (2 ml) and was purified directly on preparative HPLC giving the title compound (0.006 g, 11%) as a solid after freeze-drying the pure fractions,
!HNMR (DMSO-dtf): δ 9.79 (1H, t, / 6.1 Hz); 8.89 (1H, s); 7.98 (1H, bs); 7.97-7.95 (1H, m); 7.92 (1H, d, J 7.8 Hz); 7.87 (2H, d, J 8.1 Hz); 7-85 (Ifi; t, J7.9 Hz); 7.79 (1H, d, /7.9 Hz); 7.55 (2H, d, / 8.2 Hz); 4.66-4.55 (2H, m); 3.17 (3H, s); 2.45 (3H,.s); 2.17 (3H, s).
APQ-MS m/z: 546.2 [MH+].
Example 61 5-(4.5-Dimethvl-oxazol-2-vn-6-methvl-2-oxo-l-f3-trifluoromethvl-phenvlV '1.2-dihvdro-pvridine-3-carboxvlic acid 4-methanesulfonv]-benzvlamide 6-Methyl-2-oxo-l-(3-trifluoromethyl-phenyl)-l,2-dihydro-pyridine-3,5-dicarboxylicacid 5-amide 4-methanesulfonyl-benzylamide (see Example 60,0.05 g, 0.098 mmol), 3-bromo-2-butanone (0.020 g, 0.20 mmol), CaCO3 (0.015 g, 0.15 mmol), NMP (1.5 ml) and a magnetic stirrer bar were placed in a tube designed for microwave synthesis. The vial was sealed and the mixture was heated in a GEM Discover Microwave apparatus (100W, 140 °C) for 2h. The reaction was stopped and the crude mixture was dissolved in acetonitrile (2

ml) and water (2 ml) and was purified directly on preparative HPLC, giving the title
compound (0.007 g, 13%) as a slightly brownish solid after freeze-drying the pure
fractions.
1H NMR (DMSO-dd): δ 9.81 (1H, t, J 6.1 Hz); 8.85 (1H, s); 7.98 (1H, bs); 7.92 (1H, d, /
7.8 Hz); 7.87 (2H, d, /8.1 Hz); 7.85 (1H, t, J7.8 Hz); 7.78 (1H, d, 77.9 Hz); 7.55 (2H, d,
J 8.2 Hz); 4.66-4.55 (2H, m); 3.17 (3H, s); 2.44 (3H, s); 2.33 (3H, s); 2.17 (3H, s)
APCI-MS m/z: 560.2 [MB*].
Example 63 JSr-(CvcIohexvlmethvD-6-methvl-2-oxo-5-phenvl-l-f3-(trifluoromethyl')phenvll-1.2-dihvdropvridine-3-carboxamide
a) Ethvl6-methvl-2-oxo-I-r3-ftrifluoromemvnphenvn-L2-dihvdroDvridine-3-carboxvlate A suspension of 6^rnethyl-2K>xo-l-[3-(trifluoromethyl)phenyl]-l^^hydropyridine-3-carboxylic acid (Example 1 (b), 13.1 g, 43.9 mmol), sodium carbonate (5.2 g, 483 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 ?ud concentrated in vacuo. The residue was purified by flash chromatography en 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 (CDCla): δ 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, J 7.8 Hz); 6.25 (1H, d, J 7.4 Hz); 4.36 (2H, q, J12 Hz); 2.03 (3H,s);1.37(3H,t,J7.2Hz).
APCI-MS m/z: 326.1 EMH*].
by Ethyl 5-iodo-6-methvl-2-oxo-l-f3-(trifluoromethvl')phenvn-L2-dihydropyridine-3-
carboxvlate
N-Iodosuccinimide (6.89 g, 30.6 mmol) was added to a solution of ethyl 6-methyl-2-oxo-
l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxylate (9.9 g, 30.5 mmol) in
DCM (45 ml) and TFA (38 ml) under a nitrogen atmosphere. After 19 h stirring at ambient
temperature the solvent was concentrated in vacuo. Saturated aqueous sodium hydrogen

carbonate solution and ethyl acetate were added to the residue 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): δ 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, J 7.7 Hz); 4.36 (2H, q, J 7.1 Hz); 2.26 (3H, s); 1.37 (3H, t, J 7.2 Hz). APCI-MS m/z: 452.0 \MR+].
c") Ethyl 6-mefcyl-2-oxo-5-phenvl-l-r3-(trifluoromethvnphenvl1-1.2-dihvdropvridine-3-carboxylate
Ethyl 5-iodo-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-
carboxylate (2.6 g, 5.76 mmol), phenyltributylstannane (2.24 mg, 6.10 mnaolX
tetrakis(triphenylphosphine)palladium(0) (17.3 mg, 0.02 mmol), toluene (15 ml) and
anhydrous DME (1.5 ml) were placed in a Schlenk vessel equipped with a magnetic
stirring bar. The vessel was purged with argon, sealed and heated at 100 °C overnight.
After cooling to room temperature, the mixture was partitioned between ethyl acetate and
water. The organic layer was washed with water and 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 (0.8 g, 35%).
1HNMR (CDC13): δ 826 (1H, s); 7.72 (2H, m); 7.56 (1H, s); 7.51 - 736 (4H, m); 734 -7.28 (2H, m); 4.37 (2H, q, J 7.1 Hz); 1.97 (3H, s); 1.37 (3H, t). APCI-MS m/z: 402.3 [MH+].
d) 6-Methvl-2-oxo-5-phenvl-l-r3-('trifluoromethvI')phenvl1-l,2-dihvdroDvridine-3-carboxvlic acid
Aqueous 2M sodium hydroxide solution (2.5 ml, 5.0 mmol) was added to a solution of ethyl 6-methyl-2-oxo-5-phenyl-l -[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylate (0.85 g, 2.12 mmol) in THF (5 ml), methanol (3 ml) and water (1 ml). The reaction mixture was stirred at room temperature for 2 h and then concentrated in vacuo. Acetonitrile (3 ml) was added to the residue and the solution was acidified using TFA. The

resulting solid was collected by filtration, washed with water and acetone and air dried to give the title compound as white solid (0.62 g, 78 %).
2H NMR (CDC13): δ13.75 (1H, s); 8.59 (1H, s); 7.87 (1H, d, J 8.1 Hz); 7.80 (1H, t, J 7.9 Hz); 7.61 (1H, s); 7.54 (1H, d, J 7.6 Hz); 7.51 - 7.40 (3H, m); 7.31 (2H, m); 2.08 (3H, s). APCI-MS m/z: 374.2 [MH+].
e) A^-(CvclohexvlmethvlV6-methvI-2-oxo-5-phenvl-l-r3-ftrifluoromethvl>phenvn-1.2-
dihydropvridine-3-carboxamide
(Cyclohexylmethyl)amine in NMP (135 1*1,0.3M, 0.04 mmol) was added to a mixture of
6-methyl-2-oxo-5-phenyl-l-[3-(trifluoromethyl)-phenyl]-l^-dihydro-pyridine-3-
carboxylic acid (12 mg, 0.03 mmol), HATU (15 mg, 0.04 mmol), HOAT (7 mg, 0.04
mmol) and DIEA (13 mg, 0.1 mmol) in NMP (160 jil). The reaction mixture was stirred
for 17 h at room temperature. The solvent was removed in vacuo, and the residue was
dissolved hi acetonitriis/water, 50/50, to a total volume of 1.6 ml, and purified using
preparative HPLC to give the title compound (7 mg, 50%).
RT (Ci8, UV220 nm): 7.0 min.
APCI-MS m/z: 469.1 [MS*].
Using the general procedure described in Example 63 and the appropriate amine, the compounds of Examples 64 to 90 were prepared.
Example 64 6-Methyl-N-(2-morpholin-4-ylethyn-2-QXo-5-phenvl-l-f3-
(trifluororaethvlVphenvl1-L2-dihvdropyrJdine-3-carboxaniide
RT (Cig, UV 220 nm): 4.6 min.
APCI-MS m/z: 486.2 [MH+].
Example 65 6-Methvl-2-oxo-5-phenvl-N-flH-1.2.4-triazol-3-vl')-l-r3-
(ftifluQrom&lhyDphenyl1-l^-dihvdropyridine-3~carboxarnide
RT (da, UV 220 nm): 52 min.
APCI-MS m/z: 440.2 [MH*].

Example 66 N-r2-(lH-Indol-3-vnethvl1-6-methvl-2-oxo-5-phenvl-l-r3-
(trifluoromethvl')-phenyn-1.2-dihvdropyridine-3-carboxaniide
RT (C,8, UV 220 ran): 6.5 min.
APCI-MS ro/z: 516.2 [ME4].
Example 67 6-Methvl-2-oxo-5-phenvI-N-('l-phenvlethvlVl-r3-(trifluoromethvDphenvll-1.2-dihydropvridine-3-carboxamide RT (Cis, UV 220 nm): 6.8 min.
APCI-MS m/z: 477.2 [MR*].
Example 68 6-Methvl-2-oxo-5-phenvl-N-(2-phcnvlethv]Vl-r3-(trifluoromethvl>phenvn-1.2-dihvdropyridine-3-carboxamide RT (Ci8, UV 220 ran): 6.7 min. APCI-MS m/z: 477.2 [MH*].
Example 69 6-Methvl-2-oxo-5-phenvl-N-rf2RV2-phenvlcyclopropvn-l-r3-
{liifluoromethvlVphenvn-L2-dihvdtopyridine-3-carboxaroide
RT (C18, UV 220 ran): 6.9 min.
APa-MS m/z: 489.2 [MR*].
Example 70 N-(2.3-Dihvdro-lH-inden-2-vlV6-methvl-2-oxo-5-phenvl-l-r3-
(trifluoromethvlVph&nyl1-l,2-dihvdropvridine-3-carboxamide
RT (Ct8, UV 220 nm): 6.8 min.
APCI-MS m/z: 489.2 [MM*].
Example 71 N-rfl-Ethvlpvrrolidin^-vDmethvn-e-methvl^-oxo-S-phenvl-l-rS-
(trifluoro-methvDphenvn-1.2-dihvdropvridine-3-carboxamide
RT (Cis, UV 220 nm): 4.7 min.
APCI-MS m/z: 484.2 [MH*].
Example 72 6-Met|ivl-N-(l-naphthv]methvlV2-oxo-5-phenvl-l-f3-ftrifluoyomethyDphenyn-l^-dihydropvridine-S-caiboxamide RT (C18, UV 220 nra): 7.0 min.
APCI-MS m/z: 513.2 [MH*].
Example 73 N-(l .3-Benzodioxol-5-vImethvlV6-meth vl-2-oxo-5-phenvI-l -13-
ftrifluoromethv])-phenyn-1.2-dihvdropvridine-3-carboxamide
RT (Ci8, UV 220 nra): 6.5 min.
APCI-MS m/z: 507.2 [MR*].
Example 74 N-f2-ChIoro-4-fluofobenzviV6-methvl-2-oxo-5-phenvl-l-r3-(trifluoromethvl VphsgyH-l .2-ditjydropvridine-3 -carboxamide RT (Cw, UV 220 nm): 7.0 min.
APCI-MS m/z: 515.2 [MH*].
Example 75 6-Methvl-2-oxo-5-plienvl-N-(2-thienvlmethvI)-l-r3-ftrifluoromethv})phenyn-1.2-dihydropyridine-3-carboxamide • RT (Cjg, UV 220 nm): 6.5 min. APCI-MS m/z: 469.1 [MH+J.
Example 76 N--Cvclohex-l-en-l-ylethvlve-methvl^-oxo-S-phenvl-l-rS-ftrifluoromethvlVphenyn-1.2-jihydropvridine'3-carboxamide RT (Cig, UV 220 nm): 7.2 min. APCI-MS m/z: 481.3 [MH*].
Example 77 6-MethyI-2-oxo-N-(4-phenoxybenzvn-5-phenVl-l-r3-{trifluoroi^5thvnphenvll-l^-diftydropyridine-3-carbpxamide RT (C,8, UV 220 nm): 7.3 min. APCI-MS m/z: 555.2 [MH*].
Example 78 N-r(2.5-Dimethvl-3-furvl)methvl1-6-methvl-2-oxo-5-phenvl-l-r3-(trifluoro-methyl)phenvn-lJ2-dihvdropvridine-3-carboxaniide
APCI-MS m/z: 481.4
Example 79 N-f2-r4-fAminosulfonvnphenvnethvn-6-metfavl-2-oxo-5-Dhenvl-l-r3-
(trifluoromethvl^phenyn-l^-dihvdropvridine-S-carboxainide
RT (Ci8, UV 220 nm): 5.8 min.
APCI-MS m/z: 556.1 [MR*].
Example 80 6-Methvl-2-oxo-5-phenvl-N-r4-flH-pvrazol-l-vnbehzvIT-l-r3- -(trifluoromethylV-phenvn-1 .2-dihvdropvridine-3-carboxamide RT (Cis, UV 220 nm): 6.4 min.
APCI-MS m/z: 529.1 [MB*].
Example 81 6-Methvl-2-oxo-N-phenoxv-5-phenvM-r3-(triflubromethvl')pherivn-l^-
dihydro-pvridme-3-carboxamide RT (Ci8> UV 220 nm): 6.6 min.
APCI-MS m/z: 465.1 [MH+J.
Example 82 N-^-Fluoro^H-LS-benzodioxin-S-yDmethyn^-methvl^-oxo-S-phenvl-1 -f 3-(trifluoromethvnphenyI1-l .2-dihvdropvridme-3-carboxamide RT (Cia, UV 220 nm): 6.6 min.
APCI-MS m/z: 539.2 [MH+j.
Example 83 6-Methvl-2-oxo-5-phenvl-N-[2-(tetrahvdro-2H-pvran-4-vnethvl1-l-r3-
(trifluoro-methynphenvll-1.2-dihydrppyridine-3-carboxamide
RT (Cis, UV 220 nm): 6.0 min.
APCI-MS m/z: 485.2 [MH+].
Example 84 6-Methvl-2"Qxo-5-phenvl-N-r3-(lH-pvrazQl-l-v]^propvn-l-f3-
(trifluoromethvlVphenvn-l^-dihvdiopvridine-S-caiboxamide
RT (C18, UV 220 nm): 5.7 rain.
APCI-MS m/z: 481.1 [MR*].
Example 85 6-Meth vI-N-ff 1 -methvI-lH-pvrazoI-4-vnmethvn-2-oxo-5-phenyl-l -r
RT (C18, UV 220 nm): 5.4 min. APa-MS m/z: 467.2 [MB*].
Example 86 6-MeflivI-2-oxo-5-phenvl-N-ffl-phe]iivl-lH-pvra2ol-4-vnmethvn-l-r3-
(trifluoro-methyBphen\11-L2-dlhydrcpyridine-3-carboxamide
RT (Cis, UV 220 nm): 6.5 min.
APCI-MS m/z: 529.1 [MH1].
Example 87 N-rf5-Methoxv-4-oxo-4H-pvran-2-vr)methvn-6-methyl-2-oxo-5-pheavl-l-
r3-(trifluoromethynphenvl1-1.2-di^yc|ropyridinc-3 RT (Gig, UV 220 nm): 5.4 min.
APCI-MS m/z: 511.1 [MH+].
Example 88 N-(3-Azepan-l-ylpropyn-6-metljyI-^-oxo-5-phenyI-l-f3-
ftrifluoromethvDphenyn-l^-dihydropyridine-S-carboxamiije
RT (Gig, UV 220 nm): 5.0 min.
APCI-MS m/z: 512.3 [MH+].
Example 89 N-r4-CvanobenzvlV6-methvl-2-oxo-5-phenvI-l-f3-(tiifluoromethynphenyJ1-12-djhydropyridine-3-carboxamide RT (Gig, UV 220 nm): 6.4 min.
APCI-MS m/z: 488.2 [MH+].
Example 90 6-Methvl-2-oxo-N-r3-('5-oxo-4.5-dihvdro-lH-pvrazol-4-vl')propvn-5-
phenvl-l-r3-(trifluoromethvnphenyn-L2-dihydropvridine-3-carboxamide
RT (C,8, UV 220 nm): 5.0 min.
APCI-MS m/z: 497.2 [MH+].
Example 91 e-Methvl-S^-methvl^H-pvrazol-S-vD^-oxo-l-G-trifluoromethvl-phenvlV1.2-dihydro-pvridme-3-carboxvlicacid(3-methvl-isoxazoI-5-ylmethyjVaniide
a") 6-Methyl-2-oxo-l -(3-trifluoromefliyl-phenylVl .2-dihydro-pvridrne-3-carboxylic acid prop-2-ynyIamide
SOCb (10 ml) was added in one portion to a solution of 6-methyl-2-oxo-l-(3-tiifluoromethyl-phenyl)-l,2-dihydro-pyridine-3-carboxylic add (Example 1 (b), 1.0 g, 336 mmol) in DCM (10 ml). The solution was stirred magnetically for 1 h at which time LC-MS showed complete conversion. The crude mixture was evaporated in vacuo, giving the intermediate acid chloride as a yellow solid. This solid was dissolved in 1,4-dioxane (10 ml, dried over molecular sieves) and propargylamine (0.23 g, 4.17 mmol) and . triethylamine (1 ml) were added. The mixture was stirred for 10 minutes, and LQMS showed complete formation of the product. The mixture was concentrated in vacuo and the residue was purified on silica giving the subtitle compound (0.93 g, 83%) as a yellowish solid after evaporating the pure fractions.
*H NMR (DMSO-de): δ 9.82 (1H, t, /7.4 Hz); 8.36 (1H, d, J 7.7 Hz); 7.91 (1H, s); 7.90 (1H, d); 7.82 (1H, t, / 8.1 Hz); 7.73 (1H, d, J 8.1 Hz); 6.63 (1H, d, J 7.5 Hz); 4.KM.04 (2H, m); 3.11 (1H, t, J2A Hz); 2.02 (3H, s). APCI-MS rn/z: 335.1 [MH+].
b) 6-MethyI-2-oxo-l-(3-trifluoromethvlphenylVl,2-dihydro-pvridine-3-carboxvlic acid
(3-methvl-isoxazoI-5-vlmethylVamide
The compound obtained in step (a) (0.050 g, 0.15 rnmol) was dissolved in EtOAc (15 ml)
under magnetic stirring. To this solution was added N-hydroxyacetimidoyl chloride (0.15
g, 1.6 mmol), water (0.3 ml) and KHCOs (0.16 g, 1.6 mmol). The mixture was stirred for 2
days at which time LC-MS showed 90% conversion. The reaction was stopped and the mixture was partitioned between EtOAc (25 ml) and water (25 ml). The organic phase was washed (water, brine) and dried. Filtration and evaporation gave a crude mixture which was purified by chromatography on silica. Freeze-drying the pure fractions afforded the . subtitle compound (0.031 g, 53%) as a white powder.
*HNMR (DMSO-d6): δ 9.86 (1H, t, 75.9 Hz); 8.37 (1H, d, J 7.6 Hz); 7.91 (IH, s); 7.90
(IH, d); 7.81 (1H, t, 31$ Hz); 7.72 (IH, d, J7.7 Hz); 6.63 (1H, d, J7.6 Hz); 6.15 (1H, s); 4.58 (2H, d, 5.9 Hz); 2.17 (3H, s); 2.03 (3H, s).
APCI-MS m/z: 392.2.2 [MR*].
c) 6-Methyl-5-f2-methvl-2H~pvra2ol-3-ylV2-oxo-l-(3-trifluoroniethyl-phenyl)-jJZ-dihvdro-pvridine-3-carboxylic acid f3-methvl-isoxazol-5-vlmethvIVamide The compound obtained in step (b) (0.019 g, 0.048 mmol) was dissolved in DCM (1.5 ml) and TFA (1J5 ml). A magnetic stirrer bar and N-iodosuccinimide (0.011 g, 0.048 mmd) were added and the vial was sealed and stirred for 90 minutes at room temperature. LC-MS showed complete conversion of the starting material. The volatiles were removed in vacuo and the crude material was purified on silica, giving the 5-iodinated intermediate (0.014 g). This intermediate was dissolved in DME (2.5 ml) to a vial, and 5-trimethylstannyl-l -methyl-lH-pyrazole (0.02 g, 0.082 mmol) and Pd(PPh3)4 (0.010 g, 8.7 pmol) were added. The vial was sealed and the mixture was heated (130 °C) with stirring for 1 h. LC-MS now showed complete conversion of the iodide to a product with the expected MW. Evaporation and purification by preparative HPLC afforded the title compound (0.008 g, 35%, two steps) as a white solid after freeze-drying the pure fractions. 'HNMR (DMSO-dtf): δ 9.82 (IH, t, J=6.0 Hz); 8.21 (IH, s); 8.02 (IH, s); 7.92 (IH, d, 7 7.6 Hz); 7.88-7.78 (2H, m); 7.53(1H, d, J 1.9 Hz); 633 (IH, d, J 1.9 Hz); 6.16 (IH, s); 4.60 (2H, d, J 6.1 Hz); 3.72 (3H, s); 2.17 (3H, s); 1.82 (3H, s).
APCI-MS m/z: 472.1 [MH*].
Example 92 6-MethvI-5-f2-methvl-2H-pvrazol-3-vlV2-oxo-l-f3-trifluoromethvl-phenvD-1.2-dihvdro-pyridine-3-carboxvlic acid (5-methanesulfonvlrnethyl-fl.2.41oxadiazol-3-y]methvlVamide
a) 6-Methvl-5-(2-methvI-2H-pvrazoI-3-vlV2-oxo-l-(3-trifluoromethvl-phenvn-1.2-
dihydro-pyridine-3-carboxvlic acid
Ethyl 5-iodo-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxylate (Example 63 (b), 0.77 g, 1.7 mmol), DME (25 ml), 5-trimethylstannyl-l-methyl-lH-pyrazole (0.49 g, 2 mmol), Pd(PPh3)4 (0.10 g, 0.087 mmol) 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 product. The mixture was allowed to cool, and was then diluted with EtOAc (50 ml), -washed with water and brine, and further dried with NajjSO^ Filtration and evaporation and subsequent purification on silica gave the intermediate ester. This material was dissolved in THF (10 ml) and water (5 ml) and NaOH (2M, 1 ml, 2 mmol) was added. The mixture was stirred at 50 °C for 1 h. The THF was evaporated off and the aqueous solution was acidified whereupon the product precipitated. The product was extracted with EtOAc. The extracts were dried (Na2$O4) and evaporated to give the carboxylic acid (0.3 g, 47%) as yellowish solid.
*HNMR (DMSO-dtf): δ 13.80 (1H, s); 8.25 (1H, s); 8.07 (1H, s); 7.99-7.93 (1H, in); 7.90-7.85 (2H, m); 7.54 (1H, d, J 1.8 Hz); 6.36 (1H, d, /1.8 Hz); 3.73 (3H, s); 1.86 (3H, s). APCI-MS m/z: 363.3 [MR*].
b) 6-Methvl-5-(2-methyl-2H-pvrazoI-3-vIV2-oxo-l -(3-trifluoromethvl-phenvD-1.2-
• dihydro-pvridine-3-carboxvlic acid cvanomethvl amide
The compound obtained in step (a) (0.2 g, 0.53 mmol) was dissolved in 1,4-dioxane (5 ml), HBTU (0.19 g, 0.5 mmol) and DIEA (0.32 g, 2.5 mmol). The mixture was stirred for 10 minutes and aminoacetonitrile hydrochloride (0.55 g, 0.6 mmol) was added. After 1 h the mixture was evaporated and the residue purified by chromatography on silica to give the amide (0.15 g, 72%) as a white solid.
JH NMR (DMSO-dtf): δ 9.75 (1H, t, J 5.9 Hz); 8.22 (1H, s); 8.03 (1H, s); 7.93 (1H, d, J
7.25 Hz); 7.88-7.81 (2H, m); 7.54 (1H, d, J 1.8 Hz); 6.34 (1H, d, J 1.8 Hz); 4.31 (2H, d, 5.9 Hz); 3.72 (3H, s); 1.83 (3H, s).
APCI-MS m/z: 416.2 [MH+]. Retention time 22 minutes.
c> 6-Methvl-5-f2-methvl-2H-pvrazoI-3-vlV2-oxo-l-f3-trifluoromethvlphenvlVl.2-dihydro-pvndine-3-carboxylic acid (N-hydroxvcaibaniimidovlmetfyvIVamide The compound obtained in step (b) (0.21 g, 0.5 mmol), hydroxylamine hydrochloride (0.070 g, 1 ramol), NaOAc (0.080 g, 1 mmol), EtOH (2 ml) and a magnetic stiirer bar were placed in a vial. The vial was sealed and the mixture was heated (90 °C) with stirring for 3 h. LC-MS showed complete conversion of the nitrile into a mixture of two compounds
with the masses 449 and 465 ([MH J). Evaporation and purification on preparative HPLC
gave a mixture of the two products containing 90% of the desired compound. This material was used without further purification.
APCI-MS m/z: 4492 [MH*].
d) 6^Methvl-5-(2-methyl-2H-pvrazol-3-vl)-2-oxo-l-(3-trifltioroinethvIphenvlV-1.2-dihydro-pyridine-3-carboxyIicacid(5-methanesulfonvlroetfiyl-r:t.2.41oxadia20l-3-ylmethvlVamide
The compound obtained in step (c) (0.019 g, 0.042 mmol) was dissolved in 1,4-dioxane (dry, 1 ml) and CHsCN (dry, 1 ml) in a vial. 2-MethanesuIfonylacetylchloride (prepared according to literature procedures, 0.015 g, 0.095 mmol) was added, the vial was sealed and the mixture was stirred at room temperature for 1 h. Isolation of this material and purification by preparative HPLC gave, after freeze-drying, the required intermediate
(0.011 g). This solid was dissolved in 1,4-dioxane (2 ml) in a vial and acetic acid (5 drops) was added. The vial was sealed and the mixture was heated (90 °C) with stirring for 5 h (monitoring the reaction by LC-MS). When reaction was complete, the mixture was allowed to cool and the volatiles were removed in vacuo. The crude mixture was purified by preparative HPLC to give the title compound (0.008 g, 35%, 2 steps) as a white solid after freeze-drying the pure fractions.
NMR (DMSO-dd): δ 9.93 (1H, t, J 6.0 Hz); 8.21 (1H, s); 8.04 (1H, s); 7.93 (1H, d, /
7.93 Hz); 7.88-7.82 (2H, m); 7.53 (1H, d, J 1.9 Hz); 6.33 (1H, d, J 1.9 Hz); 5.18 (2H, s); 4.70 (2H, d, / 6.0 Hz); 3.72 (3H, s); 3.19 (3H, s); 1.83 (3H, s).
APCI-MS m/z: 551.2 [MH+].
Example 93 6-MethvI-S-(2-methvl-2H-pvrazol-3-vlV2-oxo-l-(3-trifluoromethvI> phenvD-1.2-dihvdro-pyridine-3-carboxvlicacid(ri.2.41oxadiazol-3-vlmethylVamidc 6-Me%l-5-(2-memyl-2H-pyrazol-3-yl)-2-oxo-l-(3-trifluoromemyl-phenyl>l,2-dihydro-pyridine-3-carboxylic acid (N-hydroxycarbamimidoylmethyl)-amide (Example 92 (c), 0.017 g, 0.038 mmol), triethyl-orthoformate (1 ml) and a magnetic stirrer bar were placed in a vial. The vial was sealed and the mixture was heated (130 °C) with stirring for 3 h. LC-MS showed complete conversion of the starting material to a product with the expected MW. The volatiles were, removed in vacuo and the residue was purified by preparative HPLC. Pure fractions were freeze-dried to give the title compound (0.009 g, 53%) as a white solid.
1H NMR (DMSO-dtf): δ 9.92 (1H, t, / 5.9 Hz); 9.54 (1H, s); 8.21 (1H, s); 8.03 (1H, s);
7.93 (lH,d,/ 7.0 Hz); 7.88-7.82 (2H, m); 7.53 (1H, d, J 1.8 Hz); 6.33 (1H, d, J 1.8 Hz); 4.69 (2H, d, J 5.9 Hz); 3.72 (3H, s); 1.83 (3H, s).
APCI-MS m/z: 459.1 [MH+].
Example 94 6-Methvl-5-fl-methvl-lH-pvrazol-5-vn-N-fr5-fmethvlsulfonvnpvridin-2-yJlmethyn^-oxo-l-fS-drifluoromethynphenyn-l^-dihydropyridine-S-carpoxamide
a) 5-fMethylthio)pyridine-2-carbonitrile
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%).
1H NMR (CD3OD): 8 8.54 (1H, d, J 2.3 Hz); 7.83 - 7.71 (2H, m); 2.60 (3H, s).
b") 5-(Methvlsulfonvl)pyridine-2-carbonitrile
5-(Methylthio)pvridine-2-carbomtrile (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 ramol) 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%).
!HNMR (CDaOD): δ 9.22 (1H, d, J 2.3 Hz); 8.54 (1H, dd, J 8.1,2.3 Hz); 8.13 (1H, d, J 8.3 Hz); 3.27 (3H, s).
c) (I5-(MethvlsulfQnynpyridin-2-ynmethyI I atnine hvdrochloride
5-(Methylsulfonyl)pyridine-2-carbonitrile (2.15 g, 11.8 mmol) was dissolved in methanol
(230 ml). 6M HC1 (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,
89%).
*H NMR (CD3OD): δ 9.10 (1H, d, J 2.2 Hz); 8.36 (1H, dd, J 8,2,2.4 Hz); 7.68 (1H, d) 6-MethvI-5-n-methvl-lH-pvrazol-5-ylVN-( r5-fmethvlsulfonvnpvridin-2-vl1methvl I-
2-oxp-l-f3-ftrifl^o^omethyDphenyl1-1.2-dihyd^opv^idine-3-carboxamide
HBTU (30 mg, 0.079 mmol) was added to {[5-(methylsulfonyl)pyridin-2-yI]methyl}amine hydrochloride (20 mg, 0.090 mmol), 6-methyl-5-(2-methyl-2H-pyrazol-3-yl)-2-oxo-l-(3-trifIuoromethyl-phenyl)-l,2-dihydro-pyridine-3-carboxylic acid (Example 92 (a), 27 mg, 0.072 mmol) and DIEA (23 ujf 0.31 mmol) in NMP (0.25 ml) and the mixture was stirred in a sealed vial overnight. The product was purified by preparative HPLC and freeze-dried to give the title compound as a white solid (8 mg, 20%).
*HNMR (CD3OD): δ 9.01 (1H, d, J 2.2 Hz); 8.37 (1H, s); 8.28 (1H, dd, J 8.4,2.3 Hz);
7.93 - 7.80 (3H, m); 7.73 - 7.60 (2H, m); 7.57 (1H, d, J 2.0 Hz); 6,38 (1H, d, J 2.0 Hz); 4.83 (2H, s); 3.79 (3H, s); 3.18 (3H, s); 1.94 (3H, s).
APCI-MS m/z: 546.1 [M4].
Example 95 5-f3.S-Dimefevlisoxazol-4-vlV6--methvl-N-U5-finetfavl8ulfoiivl')pvridin-2-vllmethvl) -2-oxol-f 3-ftrifluorometh vnphenvl1-L2-dihvdropvridine-3-carboxaniide
a) 5-f3.5-Dimethvlisoxazol-4-vn-6-methvI-2-oxo-l-r3-ftrifluoromethvl)phenvn-1.2-dihydropvridine-3-carboxylic acid
ETjiyl54odo-6-methyl-2-oxcHl-[3-(trifiuoromethyl)phariyl]-l^-dihydropyridine-3-carboxylate (Example 63 (b), 0.72 g, 1.6 mmol), DME (20 ml), 3,5-dimethylisoxazolyI-4-boronic acid (0.28 g, 2 mmol), Pd2(dba)3 (0.036 g, 0.039 mmol), PPhs (0.062 g, 0.23 mmol), 2M Na2CO3 (10 ml) and a magnetic stirrer bar were placed in a pressure safe glass vessel. The vessel was sealed and heated (120 °C) with stirring overnight. LC-MS showed complete formatiojn of the required product (including hydrolysis of the ester). The mixture was allowed to cool, the aqueous phase was acidified, and the organic phase was diluted with EtOAo (50 ml) and the phases were allowed to separate. The organic phase was washed with water and brine, and further dried with NazSO* Filtration and evaporation gave a crude mixture which was purified by preparative HPLC giving the carboxylic acid (0.27 g, 43%) as yellowish solid.
H1NMR (DMSO-dtf): δ 13.93 (1H, s); 8.25 (1H, s); 8.07 (1H, s); 7.99-7.93 (1H, m); 7.89-7.85 (2H, m); 2.35 (3H, m); 2.15-2.10 (3H, m); 1.85 (3H, s). APCI-MS m/z: 393.1 [MH*].
bA 5-f3.5-DimethyUsoxazol-4-vlV6-memvl-N-fr5-(rnethylsulfpnyl^pyridiT>-2-vl1methyll-
g-oxo-l-fS-ftrifluoroniethyDphenyll-l^-dihydropvridine-S-carboxamide
The title compound was prepared from 5-(3,5-dimethylisoxazol-4-yl)-6-methyl-2-oxo-l-
[3-(trifluoromethyl)phenyl]-l^-dihydropyridine-3-carboxylic acid using a method
analogous to that described in Example 94.
LH NMR (GD3OD): δ 9.01 (1H, d, J 1.8 Hz); 8.31 (IH, s); 8.28 (IH, dd, J 8.2,2.4 Hz);
7.92 - 7.80 (3H, m); 7.70 (IH, d, J 7.9 Hz); 7.62 (IH, d, J 8.2 Hz); 4.82 (2H, s); 3.18 (3H, s); 2.34 (3H, d, J 2.2 Hz); 2.18 (3H, d, J 2.0 Hz); 1.93 (3H, s).
APCI-MS m/z: 561.1 [MH+],
Screen Human Neutrophil Elastase Quenched-FRET Assay
The assay uses Human Neutrophil Elastase (HNE) purified from serum (Calbiochem art. 324681; Ref. Baugh, RJ. et al., 1976, Biochemistry. 15,836-841). HNE was stored in 50 mM NaOAc, 200 mM Nad, pH 5.5 with added 30% glycerol at -20 aC. The protease substrate used was Elastase Substrate V Huorogenic, 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 End controls were added to blade 96-well flat-bottom plates (Greiner 655076), 1 /tL in 100% DMSO, followed by 30 fiL HNE in assay buffer with 0.01% TritonX-lOQ, 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 jtl substrate hi assay buffer was added. The assay was stopped after 30 minutes incubation at room temperature by adding 60 /til 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 run, Emission 460 nra. ICso 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 nM, indicating that the
compounds of the invention are expected to possess useful therapeutic properties. pecimen results are shown in the following Table:
(Table Removed)






We Claim
1. A 2-pyridone compound of formula (1)

(Formula Removed)

wherein:
3 Y represents CR orN;
R1 represents H or C1 to 6 alkyl;
2 R represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to 4
heteroatoms independently selected from O, S and N; said aromatic ring being optionally substituted by 1 to 3 substituents selected independently from OH, halogen, C1 to 6 alkyl,
C1to 6 alkoxy, NR58COR5°, COOR51, COR52, CONR53R54 and NR47R48; said alkyl
49 being optionally further substituted by OH, C1 to 6 alkoxy, CN or CO2R ;
R and R independently represent H, C1 to 6 alkyl or C2 to 6 alkanoyl;
3 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;
R5 represents H, halogen, C1to 6 alkyl, CN, C1 to 6 alkoxy, N02, NR14R15, C1 to 3 alkyl
substituted by one or more F atoms or C1 to 3 alkoxy substituted by one or more F atoms;
14 15
R and R independently represent H or C1 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 C1 to 6 alkyl; said alkyl being optionally further substituted by OH or
C1 to 6 alkoxy;
. .
or R4 and L are joined together such that the group -NR4 L represents a 5 to 7 membered
azacyclic ring optionally incorporating one further heteroatom selected from O, S and
NR16;
L represents a bond, O, S(0)p, NR29 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
17 two heteroatoms independently selected from O, S(O)p and NR and 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 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 NR 17 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 CH2,
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, NRI8R19, N02, OSO2R38, CO2R20, C(=NH)NH2, C(O)NR2lR22, C(S)NR23R21, SC(=NH)NH2, NR31C(=NH)NH2, S(O)sR25, S02NR26R27, Cl to 3 alkoxy substituted by

one or more F atoms and C1 to 3 alkyl substituted by SO2R , NR3 R3 or by one or more F
atoms;
or
when L does not represent a bond, G may also represent II;
At each occurrence, p, q, s and t independently represent an integer 0, 1 or 2;
R18 and R19 independently represent H, CI to 6 alkyl, formyl, C2 to 6 alkanoyl, S(O)tR32 or
SO2NR33R34; said alkyl group being optionally further substituted by halogen. CN, C1to 4
alkoxyor CONR4lR42;
R ' represents H, C1 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, C02R37, OCOR40, C3 to 6 cycloalkyl, a C4 to 7 saturated heterocyclic ring
containing one or two heteroatoms independently selected from O, S(0)p and NR4j 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, C1 to 4
alkyl, C1 to 4 alkoxy, OH, CONR44R45, CO2R46, S(0)sR55 and NHCOCH3;
R32 represents H, C1 to 6 alkyl or C3 to 6 cycloalkyl;
R16, R17, R20, R21 R22, R23, R24, R26, R27, R29, R31, R33, R34, R35, R36, R37, R38, R39, R40,
R41, R42, R43, R44, R45R46, R49, R50, R51, R52, R53, R54, RS5, R56, R57 and R58
independently represent H or C1 to 6 alkyl;
and pharmaceutically acceptable salts thereof.
2. A 2-pyridone compound of formula (I), as claimed in Claim 1, wherein Y
3 represents CR .
3. A 2-pyridone compound of formula (I), as claimed in claim 1 or Claim 2, wherein G represents phenyl.
4. A 2-pyridone compound of formula (I), as claimed in any one of Claims 1 to 3, wherein R represents CI, CF13, CN or CF3.
5. A 2-pyridone compound as claimed in claim 1 is 6-methyl-5-(l-methyl -111-
pyrazol-5-yl)-N-{[5-(methylsulfonyl) pyridin-2-yl} methyl}-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide or a pharmaceutically
acceptable salt thereof.

6. A pharmaceutical formulation comprising preferably less than 95% by weight and
more preferably less than 50% by weight of a compound of formula (I) in admixture with a
pharmaceutically acceptable diluent or carrier., as claimed in any one of Claim 1, or a
pharmaceutically acceptable salt thereof; optionally alongwith a pharmaceutically
acceptable diluent or carrier.
7. A process for the preparation of a compound of formula (I), as defined in any one of
Claims 1 to 4, and optical isomers, racemates and tautomers thereof and pharmaceutically
acceptable salts thereof, which comprises:
reacting a compound of formula (II) at a temperature between 50°C to 150°C



(Formula Removed)

wherein R1,R4,R5,Y, G1,G2,L and n are as defined in formula (I) and Hal represents a
halogen atom, preferably bromo or iodo;
with a nucleophile R2 -M wherein R2 is as defined in formula (1) and M represents an
organo-tin or organo boronic acid group;

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 (I); and where desired converting the resultant compound of formula (I) into an optical isomer thereof.

Documents:

2107-DELNP-2006-Abstract-(02-04-2009).pdf

2107-DELNP-2006-Abstract-(24-11-2008).pdf

2107-DELNP-2006-Abstract.pdf

2107-DELNP-2006-Claims-(02-04-2009).pdf

2107-DELNP-2006-Claims-(24-11-2008).pdf

2107-delnp-2006-claims.pdf

2107-DELNP-2006-Correspondence-Others-(02-04-2009).pdf

2107-DELNP-2006-Correspondence-Others-(24-11-2008).pdf

2107-DELNP-2006-Correspondence-Others.pdf

2107-DELNP-2006-Description (Complete)-(02-04-2009).pdf

2107-DELNP-2006-Description (Complete)-(24-11-2008).pdf

2107-delnp-2006-description (complete).pdf

2107-DELNP-2006-Form-1-(02-04-2009).pdf

2107-DELNP-2006-Form-1-(24-11-2008).pdf

2107-delnp-2006-form-1.pdf

2107-DELNP-2006-Form-2-(02-04-2009).pdf

2107-DELNP-2006-Form-2-(24-11-2008).pdf

2107-delnp-2006-form-2.pdf

2107-DELNP-2006-Form-26-(24-11-2008).pdf

2107-DELNP-2006-Form-3-(24-11-2008).pdf

2107-delnp-2006-form-3.pdf

2107-DELNP-2006-Form-5-(24-11-2008).pdf

2107-delnp-2006-form-5.pdf

2107-DELNP-2006-PCT-210-(02-04-2009).pdf

2107-delnp-2006-pct-210.pdf

2107-delnp-2006-pct-304.pdf

2107-DELNP-2006-Petition-137-(24-11-2008).pdf

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Patent Number 234227
Indian Patent Application Number 2107/DELNP/2006
PG Journal Number 23/2009
Publication Date 05-Jun-2009
Grant Date 12-May-2009
Date of Filing 18-Apr-2006
Name of Patentee ASTRAZENECA AB
Applicant Address S-151 85 SODERTALJE,SWEDEN.
Inventors:
# Inventor's Name Inventor's Address
1 MARJANA ANDERSSON ASTRAZENECA R&D LUND, SE-221 87 LUND,SWEDEN.
2 PETER HANSEN ASTRAZENECA R&D LUND, SE-221 87 LUND,SWEDEN.
3 HANS LONN ASTRAZENECA R&D LUND, SE-221 87 LUND,SWEDEN.
4 ANTONIOS NIKITIDIS ASTRAZENECA R&D LUND, SE-221 87 LUND,SWEDEN.
5 PETTER SJOLIN ASTRAZENECA R&D LUND, SE-221 87 LUND,SWEDEN.
PCT International Classification Number C07D 211/86
PCT International Application Number PCT/SE2004/001335
PCT International Filing date 2004-09-15
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 0302486-6 2003-09-18 Sweden