WO2004043924A1 - 2-pyridone derivatives as inhibitors of neutrophile elastase - Google Patents

2-pyridone derivatives as inhibitors of neutrophile elastase Download PDF

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Publication number
WO2004043924A1
WO2004043924A1 PCT/SE2003/001739 SE0301739W WO2004043924A1 WO 2004043924 A1 WO2004043924 A1 WO 2004043924A1 SE 0301739 W SE0301739 W SE 0301739W WO 2004043924 A1 WO2004043924 A1 WO 2004043924A1
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WIPO (PCT)
Prior art keywords
carboxamide
methyl
oxo
phenyl
dihydropyridine
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PCT/SE2003/001739
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French (fr)
Inventor
Håkan BLADH
Tomas Klingstedt
Joakim Larsson
Karolina Lawitz
Matti Lepistö
Hans LÖNN
Grigorios Nikitidis
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Astrazeneca Ab
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Publication date
Priority claimed from SE0203348A external-priority patent/SE0203348D0/en
Priority claimed from SE0300388A external-priority patent/SE0300388D0/en
Priority claimed from SE0302120A external-priority patent/SE0302120D0/en
Priority to MXPA05004818A priority Critical patent/MXPA05004818A/en
Priority to UAA200504328A priority patent/UA81271C2/en
Priority to US10/534,720 priority patent/US20060035938A1/en
Priority to SI200330314T priority patent/SI1562902T1/en
Priority to JP2005506687A priority patent/JP2006513261A/en
Priority to BR0316081-5A priority patent/BR0316081A/en
Priority to AU2003276802A priority patent/AU2003276802B2/en
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to NZ539787A priority patent/NZ539787A/en
Priority to CA002504766A priority patent/CA2504766A1/en
Priority to DE60305061T priority patent/DE60305061T2/en
Priority to EP03811170A priority patent/EP1562902B1/en
Publication of WO2004043924A1 publication Critical patent/WO2004043924A1/en
Priority to IS7867A priority patent/IS2478B/en
Priority to NO20052818A priority patent/NO20052818L/en
Priority to HK05111156A priority patent/HK1079200A1/en
Priority to CY20061101039T priority patent/CY1106130T1/en

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Definitions

  • This invention relates to novel 2-pyridone derivatives, processes for their preparation, pharmaceutical compositions comprising them, and their use in therapy.
  • 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.
  • NE 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.
  • 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 coUagens 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 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.
  • neutrophil recruitment into the lungs which is associated with increased lung elastase burden and emphysema in ⁇ rproteinase inhibitor-deficient mice (Cavarra et al., 1996, Lab. Invest. 75, 273-280).
  • Individuals with higher levels of the NE- ⁇ i protease inhibitor complex in bronchoalveolar lavage fluid show significantly accelerated decline in lung functions compared to those with lower levels (Betsuyaku et al.
  • Neutrophil-predominant airway inflammation and mucus obstruction of the airways are major pathologic features of COPD, including cystic fibrosis and chronic bronchitis. NE impairs mucin production, leading to mucus obstruction of the airways. NE is reported to increase the expression of major respiratory mucin gene, MUC5AC (Fischer, B.M & Noynow, 2002, Am. I. Respir. Cell Biol., 26, 447-452). Aerosol administration of ⁇ E 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).
  • ⁇ E 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 ⁇ E 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 ⁇ E is also implicated in mucus hypersecretion in asthma.
  • 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 ⁇ _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).
  • a NE inhibitor reduced bleomycin-induced pulmonary fibrosis (Taooka et al., 1997, Am. J. Resp. Crit. Care Med., 156, 260-265).
  • 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.
  • the antiproteases and NE complexed with antiprotease are increased in lung cancer area (Marchandise et al., 1989, Eur. Resp. I. 2, 623-629).
  • polymorphism in the promoter region of the NE gene are associated with lung cancer development (Taniguchi et al., 2002, Clin. Cancer Res., 8, 1115-1120.
  • Acute lung injury caused by endotoxin in experimental animals is associated with elevated levels of NE ( Kawabata, et al., 1999, Am. J. Resp. Crit. Care, 161, 2013-2018).
  • Acute lung inflammation caused by intratracheal injection of lipopolysaccharide in mice has been shown to elevate the NE activity in bronchoalveolar lavage fluid which is significantly inhibited by a NE inhibitor (Fujie et al., 1999, Eur. J. Pharmacol., 374, 117-125; Yasui, et al., 1995, Eur. Resp. J., 8, 1293-1299).
  • NE also plays an important role in the neutrophil- induced increase of pulmonary microvascular permeability observed in a model of acute lung injury caused by tumor necrosis factor (TNF ⁇ ) and phorbol myristate acetate (PMA) in isolated perfused rabbit lungs (Miyazaki et al., 1998, Am. J. Respir. Crit. Care Med., 157, 89-94).
  • TNF ⁇ tumor necrosis factor
  • PMA phorbol myristate acetate
  • NE 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).
  • 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. I. Respir. Crit. Care Med., 166, 954-960).
  • NE plays a key role in experimental cerebral ischemic damage (Shimakura et al., 2000, Brain Research, 858, 55-60), ischemia-reperfusion lung injury (Kishima et al., 1998, Ann. Thorac. Surg. 65, 913-918) and myocardial ischemia in rat heart (Tiefenbacher et al., 1997, Eur. J. PhysioL, 433, 563-570).
  • Human NE levels in plasma are significantly increased above normal in inflammatory bowel diseases, for example, Crohn's disease and ulcerative colitis (Adeyemi et al., 1985, Gut, 26, 1306-1311).
  • NE has also been assumed to be involved in the pathogenesis of rheumatoid arthritis (Adeyemi et al., 1986, Rheumatol. Int., 6, 57). The development of collegen induced arthritis in mice is suppressed by a NE inhibitor (Kakimoto et al., 1995, Cellular Immunol. 165, 26-32).
  • human NE is known as one of the most destructive serine proteases and has been implicated in a variety of inflammatory diseases.
  • the important endogenous inhibitor of human NE is ⁇ rantitrypsin.
  • 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 i-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.
  • diseases such as pulmonary emphysema, pulmonary fibrosis, adult respiratory distress syndrome (ARDS), ischemia reperfusion injury, rheumatoid arthritis and pulmonary hypertension.
  • WO 02/053543 discloses pyridone derivatives having affinity for cannabinoid 2-type receptor.
  • the present invention discloses novel 2-pyridone derivatives that are inhibitors of human neutrophil elastase and homologous serine proteases such as proteinase 3 and pancreatic elastase, and are thereby useful in therapy.
  • the present invention provides a compound of formula (I)
  • X represents O or S
  • Y represents N or CR ; and when R represents OH, Y may also, in the tautomeric form, represent NR ;
  • Y represents CR ; and when Y represents CR , then Y may also represent N;
  • R represents H or Cl to 6 alkyl; said alkyl being optionally substituted by one or more
  • R represents H, Cl to 6 alkyl or phenyl; said phenyl being optionally further substituted by halogen, Cl to 6 alkyl and Cl to 6 alkoxy;
  • R represents H, halogen or Cl to 6 alkyl
  • 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; or G represents a five- or six- membered saturated or partially unsaturated cycloalkyl ring; or G represents a five- or six-membered saturated or partially unsaturated heterocyclic ring containing one
  • R 5 represents H, halogen, Cl to 6 alkyl, CN, Cl to 6 alkoxy, NO 2 , NR 14 R 15 , 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 an integer 1, 2 or 3 and when n represents 2 or 3, each R group is selected independently;
  • R and R independently represent H or Cl to 6 alkyl; said alkyl being optionally further substituted by OH or Cl to 6 alkoxy; 4 4 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 NR 16 ;
  • 29 L represents a bond, O, NR or Cl to 6 alkyl; said alkyl optionally incorporating a heteroatom selected from O, S and NR ; and said alkyl being optionally further substituted by OH or OMe;
  • 2 G represents a monocyclic ring system selected from:
  • phenyl or phenoxy 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
  • each of the two rings is independently selected from:
  • 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
  • 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,
  • G may also represent H
  • n, p, q, s and t independently represent an integer 0, 1 or 2;
  • R and R independently represent H, Cl to 6 alkyl, formyl or C2 to 6 alkanoyl; said alkyl being optionally further substituted by phenyl optionally substituted by halogen, Cl to 6
  • R and R independently represent H, Cl to 6 alkyl, formyl, C2 to 6 alkanoyl, S(O) t R
  • alkyl group being optionally further substituted by halogen, CN, Cl
  • 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,
  • R and R independently represent H, Cl to 6 alkyl, formyl or C2 to 6 alkanoyl;
  • R represents H, Cl to 6 alkyl or C3 to 6 cycloalkyl
  • R represents H, Cl to 6 alkyl or phenyl; said phenyl being optionally further substituted by halogen, Cl to 6 alkyl or Cl to 6 alkoxy;
  • R W , R" R 12 , R W , R 17 , R 20 , R 21 , R 32 , R M , R 24 , R 28 , R 29 , R 30 , R 31 , R 33 , R 34 , R 35 ,
  • 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.
  • Cl to 3 alkyl and Cl to 4 alkyl are to be interpreted analogously.
  • Cl to 3 alkyl substituted by one or more F atoms examples include fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, pentafluoroethyl and 3,3,3-trifluoropropyl.
  • Cl to 6 alkoxy referred to herein denotes an oxygen substituent bonded to a straight or branched chain alkyl group having from 1 to 6 carbon atoms. Examples of such groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy and s-butoxy.
  • the terms "Cl to 3 alkoxy” and “Cl to 4 alkoxy” are to be interpreted analogously.
  • Cl to 3 alkoxy substituted by one or more F atoms include fluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy and 3,3,3-trifluoropropoxy.
  • C2 to 6 alkanoyl 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.
  • halogen referred to herein denotes fluorine, chlorine, bromine and iodine.
  • Examples of a five or six membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N include furan, thiophene, pyrrole, oxazole, oxadiazole, isoxazole, imidazole, thiazole, triazole, thiadiazole, pyridine, pyrimidine and pyrazine.
  • C3 to 6 saturated or partially unsaturated cycloalkyl referred to herein denotes a 3 to 6 membered non-aromatic carbocyclic ring optionally incorporating one or more double bonds. Examples include cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl.
  • the term "five- or six-membered saturated or partially unsaturated cycloalkyl ring” is to be interpreted analogously.
  • a carbonyl group denotes a 4 to 7 membered non-aromatic heterocyclic ring optionally incorporating one or more double bonds and optionally incorporating a carbonyl group.
  • Examples include tetrahydrofuran, thiolane 1,1-dioxide, tetrahydropyran, 4-oxo-4H-pyran, pyrrolidine, pyrroline, imidazolidine, 1,3-dioxolane, piperidine, piperazine, morpholine, perhydroazepine, pyrrolidone and piperidone.
  • 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.
  • Cl to 6 alkyl; said alkyl optionally incorporating a heteroatom selected from O, S and NR embraces a straight or branched chain arrangement of 1 to 6 carbon atoms in which any two carbon atoms are optionally separated by O, S or NR .
  • the definition thus includes, for example, methylene, ethylene, propylene, hexamethylene, ethylethylene, -CH 2 CH 2 O-CH 2 -, -CH 2 CH 2 O-CH 2 -CH 2 - -CH 2 CH 2 S- and
  • 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 CH 2 include biphenyl, thienylphenyl, pyrazolylphenyl, phenoxyphenyl, naphthyl, indanyl, quinolyl, tetrahydroquinolyl, benzofuranyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, isoquinolyl, chromanyl, indenyl, quinazolyl, quinoxalyl, chromanyl, isocromanyl, 3H-indolyl, lH-indazolyl, quinuclidyl, tetrahydronaphthyl, dihydrobenz
  • S(O)q include 4-(piperazin-l-ylsulfonyl)phenyl, 4-(morpholin-4-ylsulfonyl)phenyl,
  • R represents H, halogen, Cl to 6 alkyl, CN, Cl to 6 alkoxy, Cl to 3 alkyl substituted by one or more F atoms or Cl to 3 alkoxy substituted by one or more F atoms.
  • R represents halogen, Cl to 6 alkyl, CN, Cl to 6 alkoxy or Cl to 3 alkyl substituted by one or more F atoms.
  • R represents halogen, CH 3 , CN, OCH 3 or CF 3 .
  • n represents an integer 1 or 2. In another embodiment, n represents the integer 1.
  • R represents halogen, CN or CF 3 ; n represents the integer 1; and G represents phenyl.
  • the invention provides compounds of formula (I) wherein X represents O;
  • G represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3
  • R represents H
  • L represents Cl
  • G represents an optionally substituted monocyclic ring system selected from:
  • 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
  • G represents an optionally substituted monocyclic ring system selected from:
  • 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
  • Y represents N or NR and R represents OH or a tautomer thereof; Y represents
  • G represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to
  • G represents an optionally substituted monocyclic ring system selected from:
  • 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
  • G represents phenyl or pyridyl
  • R represents H
  • L represents Cl to 6 alkyl
  • G represents optionally substituted phenyl.
  • G represents phenyl or pyridyl
  • R represents H
  • L represents methylene
  • 2 G represents optionally substituted phenyl.
  • X in formula (I) represents O.
  • the invention discloses compounds of formula (I) in which Y
  • Y represents N.
  • R represents OH in the tautomeric form and Y represents NR .
  • R represents optionally substituted Cl to 6 alkyl. In another embodiment, R represents Cl to 6 alkyl, particularly methyl. 1 In one embodiment, G represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N. In another
  • G in formula (I) represents phenyl or pyridyl. In another embodiment, G in formula (I) represents phenyl. In another embodiment, G in formula (I) represents phenyl and (R ) n represents a CF 3 group in the 3-position.
  • R represents H.
  • L represents Cl to 6 alkyl. In another embodiment, L represents
  • L represents NR and R represents H.
  • G represents an optionally substituted monocyclic ring system selected from:
  • 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
  • G represents optionally substituted phenyl.
  • G represents phenyl substituted by OSO2R , S(O) s R , SO2NR R ,
  • the invention specifically provides one or more compounds as described in the Examples herein, or the non-salt form thereof or a pharmaceutically acceptable salt thereof.
  • Particular compounds include:
  • N-(4-chlorobenzyl)-l-(3,5-dimethylphenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide N-[4-(aminosulfonyl)benzyl]-l-(3,5-dimethylphenyl)-6-methyl-2-oxo-l,2- dihydropyridine-3-carboxamide l-(3,5-dimethylphenyl)-N-(4-methoxybenzyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide N-benzyl- 1 -(3 ,5-dimethylphenyl)-6-methyl-2-oxo- 1 ,2-dihydropyridine-3-carboxamide
  • 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.
  • preferred salts include those formed from hydrochloric, hydrobromic, sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids.
  • the invention provides a process for the preparation of a compound of formula (I) which comprises: reacting a compound of formula (II)
  • R , R , Y , Y , X, G and n are as defined in formula (I) and L represents a leaving group, with an amine of formula (L ⁇ ) or a salt thereof
  • the process is carried out at a suitable temperature, generally between 0 °C and the boiling point of the solvent, in a suitable solvent such as dichloromethane or N-methylpyrrolidinone.
  • a suitable solvent such as dichloromethane or N-methylpyrrolidinone.
  • the process is optionally carried out in the presence of a base and/or a coupling reagent such as HATU, HO AT, HOBT or DIEA.
  • Suitable leaving groups L include OH and halogen, particularly OH.
  • 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.
  • a suitable base such as sodium methoxide
  • a suitable solvent such as ethanol
  • compounds of formulae (IN) and (N) are either known or may be prepared using methods that will be readily apparent to the man skilled in the art.
  • compounds of formula (IV) can be prepared according to the methods of S.M Brombridge et al., Synthetic Communications, 1993, 23, 487-494.
  • compounds of formula (V) can be prepared according to the methods of Igor N. Ukrainets et al., Tetrahedron, 1994, 50, 10331-10338.
  • 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.
  • a suitable base such as l,4-diazabicyclo[2.2.2]octane
  • a suitable base such as sodium ethoxide
  • a suitable solvent such as ethanol
  • a compound of formula (LX) can be prepared from the corresponding isocyanate derivative by treatment with ammonia in acetonitrile.
  • Salts of compounds of formula (I) may be formed by reacting the free base or a salt, enantiomer, tautomer or protected derivative thereof, with one or more equivalents of the appropriate acid.
  • the reaction may be carried out in a solvent or medium in which the salt is insoluble, or in a solvent in which the salt is soluble followed by subsequent removal of the solvent in vacuo or by freeze drying.
  • Suitable solvents include, for example, water, dioxane, ethanol, 2-propanol, tetrahydrofuran or diethyl ether, or mixtures thereof.
  • the reaction may be a metathetical process or it may be carried out on an ion exchange resin.
  • the compounds of the invention and intermediates may be isolated from their reaction mixtures, and if necessary further purified, by using standard techniques.
  • the compounds of formula (I) may exist in enantiomeric or diastereoisomeric forms or mixtures thereof, all of which are included within the scope of the invention.
  • the various optical isomers may be isolated by separation of a racemic mixture of the compounds using conventional techniques, for example, fractional crystallisation or HPLC.
  • 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.
  • the compounds of formula (I), and their pharmaceutically acceptable salts, are useful because they possess pharmacological activity in animals.
  • the compounds of formula (I) have activity as pharmaceuticals, in particular as modulators of human neutrophil elastase and homologous serine proteases such as proteinase 3 and pancreatic elastase, and as such are predicted to be useful in therapy.
  • the compounds of formula (I) are particularly useful as inhibitors of human neutrophil elastase. They may thus be used in the treatment or prophylaxis of inflammatory diseases and conditions.
  • ARDS adult respiratory distress syndrome
  • cystic fibrosis cystic fibrosis
  • pulmonary emphysema chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • 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 tract (especially inflammatory bowel disease, ulcerative colitis, pancreatitis and gastritis); inflammation of the skin (especially psoriasis, eczema,
  • another aspect of the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of diseases or conditions in which inhibition of neutrophil elastase activity is beneficial; and a method of treating, or reducing the risk of, diseases or conditions in which inhibition of neutrophil elastase activity is beneficial which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of inflammatory diseases or conditions; and a method of treating, or reducing the risk of, inflammatory diseases or conditions which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the compounds of this invention may be used in the treatment of adult respiratory distress syndrome (ARDS), cystic fibrosis, pulmonary emphysema, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, asthma, rhinitis, ischemia-reperfusion injury, rheumatoid arthritis, osteoarthritis, cancer, atherosclerosis and gastric mucosal injury.
  • ARDS adult respiratory distress syndrome
  • cystic fibrosis pulmonary emphysema
  • COPD chronic obstructive pulmonary disease
  • pulmonary hypertension asthma
  • rhinitis ischemia-reperfusion injury
  • rheumatoid arthritis rheumatoid arthritis
  • osteoarthritis cancer
  • atherosclerosis atherosclerosis
  • gastric mucosal injury 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. .
  • the dose of the compound to be administered will depend on the compound employed, the disease being treated, the mode of administration, the age, weight and sex of the patient. Such factors may be determined by the attending physician. However, in general, satisfactory results are obtained when the compounds are administered to a human at a daily dosage of between 0.1 mg/kg to 100 mg/kg (measured as the active ingredient).
  • the compounds of formula (I) may be used on their own, or in the form of appropriate pharmaceutical formulations comprising the compound of the invention in combination with a pharmaceutically acceptable diluent, adjuvant or carrier.
  • Particularly preferred are compositions not containing material capable of causing an adverse reaction, for example, an allergic reaction.
  • Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
  • 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.
  • 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.
  • the compound is desirably finely divided.
  • the finely divided compound preferably has a mass median diameter of less than 10 ⁇ m, and may be suspended in a propellant mixture with the assistance of a dispersant, such as a C 8 -C 20 fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
  • a dispersant such as a C 8 -C 20 fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated 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.
  • 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.
  • 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.
  • This spheronized powder may be filled into the drug reservoir of a multidose inhaler, for example, that known as the Turbuhaler ® in which a dosing unit meters the desired dose which is then inhaled by the patient.
  • a multidose inhaler for example, that known as the Turbuhaler ® in which a dosing unit meters the desired dose which is then inhaled by the patient.
  • the active compound with or without a carrier substance, is delivered to the patient.
  • the active compound may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets.
  • an adjuvant or a carrier for example, lactose, saccharose, sorbitol, mannitol
  • a starch for example, potato starch, corn starch or amylopectin
  • a cellulose derivative for example, gelatine or polyvinylpyrrolidone
  • a lubricant for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, par
  • the cores may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum, titanium dioxide, and the like.
  • the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
  • 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.
  • 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.
  • 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.
  • reaction mixture was stirred for 2.5 h at room temperature, then acidified to pH 2 using 5M hydrochloric acid, and then extracted with dichloromethane. The combined organic phases were washed with water, dried, filtered and evaporated to give the title compound (268 mg, 100%).
  • Diethyl malonate (160 g, 1.0 mole) was added dropwise to a stirred, refluxing solution of 1,1,3,3-tetraethoxypropane (330 g, 1.5 mol), acetic anhydride (306 g, 2.0 moles) and zinc chloride (10 g, 0.073 mole) over a period of 30 minutes.
  • the mixture was heated for 1 h, and after that a Dean-Stark apparatus was connected and the lower boiling components were distilled off. Additional acetic anhydride (150 ml) was added and refluxing was continued for 1 h.
  • the reaction mixture was distilled to give the title compound as a yellow oil (182 g, 75%), b.p. 139-143 °C at 0.8 mm Hg.
  • Example 4.5 1 -(2-Fluoro-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo- 1 ,2- . dihvdropyridine-3-carboxamide 1H NMR (CDCI 3 ): ⁇ 9.86 (IH, brt); 8.69 (IH, dd); 7.49 (IH, dd); 7.30-7.25 (3H, m); 7.20- 7.14 (2H, m); 6.84 (2H, d); 6.54 (IH, t); 4.56 (2H, brd); 3.79 (3H, s); 2.39 (3H, s).

Abstract

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

Description

2-pyridone derivatives as inhibitors of neutrophile elastase
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 coUagens 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 αrantitrypsin (Laurell and Eriksson, 1963, Scand. J. Clin. Invest. 15, 132-140). Subsequently it was determined that j-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 αrproteinase inhibitor-deficient mice (Cavarra et al., 1996, Lab. Invest. 75, 273-280). Individuals with higher levels of the NE-αi protease inhibitor complex in bronchoalveolar lavage fluid show significantly accelerated decline in lung functions compared to those with lower levels (Betsuyaku et al. 2000, Respiration, 67, 261-267). Instillation of human NE via the trachea in rats causes lung haemorrhage, neutrophil accumulation during acute phase and emphysematous changes during chronic phase (Karaki et al., 2002, Am. J. Resp. Crit. Care Med., 166, 496-500). Studies have shown that the acute phase of pulmonary emphysema and pulmonary haemorrhage caused by NE in hamsters can be inhibited by pre-treatment with inhibitors of NE ( Fujie et al.,1999, Infiamm. Res. 48, 160-167).
Neutrophil-predominant airway inflammation and mucus obstruction of the airways are major pathologic features of COPD, including cystic fibrosis and chronic bronchitis. NE impairs mucin production, leading to mucus obstruction of the airways. NE is reported to increase the expression of major respiratory mucin gene, MUC5AC (Fischer, B.M & Noynow, 2002, Am. I. Respir. Cell Biol., 26, 447-452). Aerosol administration of ΝE 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 ΝE 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 ΝE 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 ΝE 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: αι_protenase inhibitor complex is increased in serum of patients with pulmonary fibrosis, which correlates with the clinical parameters in these patients (Yamanouchi et al., 1998, Eur. Resp. J. 11, 120-125). In a murine model of human pulmonary fibrosis, a NE inhibitor reduced bleomycin-induced pulmonary fibrosis (Taooka et al., 1997, Am. J. Resp. Crit. Care Med., 156, 260-265). Furthermore investigators have shown that NE deficient mice are resistant to bleomycin-induced pulmonary fibrosis (Dunsmore et al., 2001, Chest, 120, 35S-36S). Plasma NE level was found to be elevated in patients who progressed to ARDS implicating the importance of NE in early ARDS disease pathogenesis. (Donnelly et al., 1995, Am. J. Res. Crit. Care Med., 151, 428-1433). The antiproteases and NE complexed with antiprotease are increased in lung cancer area (Marchandise et al., 1989, Eur. Resp. I. 2, 623-629). Recent studies have shown that polymorphism in the promoter region of the NE gene are associated with lung cancer development (Taniguchi et al., 2002, Clin. Cancer Res., 8, 1115-1120.
Acute lung injury caused by endotoxin in experimental animals is associated with elevated levels of NE ( Kawabata, et al., 1999, Am. J. Resp. Crit. Care, 161, 2013-2018). Acute lung inflammation caused by intratracheal injection of lipopolysaccharide in mice has been shown to elevate the NE activity in bronchoalveolar lavage fluid which is significantly inhibited by a NE inhibitor (Fujie et al., 1999, Eur. J. Pharmacol., 374, 117-125; Yasui, et al., 1995, Eur. Resp. J., 8, 1293-1299). NE also plays an important role in the neutrophil- induced increase of pulmonary microvascular permeability observed in a model of acute lung injury caused by tumor necrosis factor (TNFα) 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. I. Respir. Crit. Care Med., 166, 954-960).
NE plays a key role in experimental cerebral ischemic damage (Shimakura et al., 2000, Brain Research, 858, 55-60), ischemia-reperfusion lung injury (Kishima et al., 1998, Ann. Thorac. Surg. 65, 913-918) and myocardial ischemia in rat heart (Tiefenbacher et al., 1997, Eur. J. PhysioL, 433, 563-570). Human NE levels in plasma are significantly increased above normal in inflammatory bowel diseases, for example, Crohn's disease and ulcerative colitis (Adeyemi et al., 1985, Gut, 26, 1306-1311). In addition NE has also been assumed to be involved in the pathogenesis of rheumatoid arthritis (Adeyemi et al., 1986, Rheumatol. Int., 6, 57). The development of collegen induced arthritis in mice is suppressed by a NE inhibitor (Kakimoto et al., 1995, Cellular Immunol. 165, 26-32).
Thus, human NE is known as one of the most destructive serine proteases and has been implicated in a variety of inflammatory diseases. The important endogenous inhibitor of human NE is αrantitrypsin. 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 i-antitrypsin either through inactivation by oxidants such as cigarette smoke, or as a result of genetic inability to produce sufficient serum levels. Human NE has been implicated in the promotion or exacerbation of a number of diseases such as pulmonary emphysema, pulmonary fibrosis, adult respiratory distress syndrome (ARDS), ischemia reperfusion injury, rheumatoid arthritis and pulmonary hypertension.
WO 02/053543 discloses pyridone derivatives having affinity for cannabinoid 2-type receptor. The present invention discloses novel 2-pyridone derivatives that are inhibitors of human neutrophil elastase and homologous serine proteases such as proteinase 3 and pancreatic elastase, and are thereby useful in therapy.
Disclosure of the Invention
The present invention provides a compound of formula (I)
Figure imgf000006_0001
(I)
wherein
X represents O or S;
1 2 1 1 Y represents N or CR ; and when R represents OH, Y may also, in the tautomeric form, represent NR ;
2 3 1 2 2
Y represents CR ; and when Y represents CR , then Y may also represent N;
R represents H or Cl to 6 alkyl; said alkyl being optionally substituted by one or more
7 8 9 10 substituents selected independently from halogen, CN, CHO, OR , NR R , S(O)mR and
11 12 SO2NR R ; and, when Y represents N, R may also represent OH;
7 R represents H, Cl to 6 alkyl or phenyl; said phenyl being optionally further substituted by halogen, Cl to 6 alkyl and Cl to 6 alkoxy;
2 R represents H, halogen or Cl to 6 alkyl;
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; or G represents a five- or six- membered saturated or partially unsaturated cycloalkyl ring; or G represents a five- or six-membered saturated or partially unsaturated heterocyclic ring containing one
13 13 heteroatom selected from O, S and NR where R represents H or Cl to 6 alkyl;
R5 represents H, halogen, Cl to 6 alkyl, CN, Cl to 6 alkoxy, NO2, NR14R15, Cl to 3 alkyl substituted by one or more F atoms or Cl to 3 alkoxy substituted by one or more F atoms;
14 15
R and R independently represent H or Cl to 3 alkyl; said alkyl being optionally further substituted by one or more F atoms;
n represents an integer 1, 2 or 3 and when n represents 2 or 3, each R group is selected independently;
4 6 R and R independently represent H or Cl to 6 alkyl; said alkyl being optionally further substituted by OH or Cl to 6 alkoxy; 4 4 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;
29 L represents a bond, O, NR or Cl to 6 alkyl; said alkyl optionally incorporating a heteroatom selected from O, S and NR ; and said alkyl being optionally further substituted by OH or OMe;
2 G represents a monocyclic ring system selected from:
i) phenyl or phenoxy, ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S and N, iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two
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 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,
1 R 19 8 90 91 99 9 94
NR R , NO2, OSO2R , CO2R , C(=NH)NH2, C(O)NR R , C(S)NR R ,
SC(=NH)NH2, NR31C(=NH)NH2, S(O)sR25, SO2NR26R27, Cl to 3 alkoxy substituted by
39 one or more F atoms and Cl to 3 alkyl substituted by SO R or by one or more F atoms; or
2 when L does not represent a bond, G may also represent H;
m, p, q, s and t independently represent an integer 0, 1 or 2;
8 9 R and R independently represent H, Cl to 6 alkyl, formyl or C2 to 6 alkanoyl; said alkyl being optionally further substituted by phenyl optionally substituted by halogen, Cl to 6
30 alkyl, Cl to 6 alkoxy or SO2R ;
8 9 or the group NR R together represents a 5 to 7 membered azacyclic ring optionally
28 incorporating one further heteroatom selected from O, S and NR ;
18 19 39
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
41 42 to 4 alkoxy or CONR R ;
25 R represents H, Cl to 6 alkyl or C3 to 6 cycloalkyl; said alkyl group being optionally further substituted by one or more substituents selected independently from OH, CN,
CONR R , CO2R 7, OCOR4 , 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 ring being optionally further substituted by one or more substituents selected independently from halogen, CN, Cl to 4
44 45 46 47 alkyl, Cl to 4 alkoxy, OH, CONR R , CO2R , S(O)sR and NHCOCH ;
26 27
R and R independently represent H, Cl to 6 alkyl, formyl or C2 to 6 alkanoyl;
32 R represents H, Cl to 6 alkyl or C3 to 6 cycloalkyl;
38
R represents H, Cl to 6 alkyl or phenyl; said phenyl being optionally further substituted by halogen, Cl to 6 alkyl or Cl to 6 alkoxy;
RW, R", R12, RW, R17, R20, R21, R32, RM, R24, R28, R29, R30, R31, R33, R34, R35,
„36 ,-37 _39 „40 „41 „42 „43 „44 „45 _,46 , „47 . , , Al R , R , R , R , R , R ., R , R , R , R and R independently represent H or
Cl to 6 alkyl;
and pharmaceutically acceptable salts thereof, with the proviso that the following compounds are disclaimed: N-benzyl-5 ,6-dimethyl-2-oxo- 1 -phenyl- 1 ,2-dihydropyridine-3 -carboxamide ;
N-(2-phenethyl)-5 ,6-dimethyl-2-oxo- 1 -phenyl- 1 ,2-dihydropyridine-3-carboxamide;
N-(2-hydroxyethyl)-2,4-dioxo-3-phenyl-l,2,3,4-tetrahydropyrimidine-5-carboxamide;
N-[2-(dimethylamino)ethyl]-2,4-dioxo-3-phenyl-l,2,3,4-tetrahydropyrimidine-5- carboxamide; 4- [2- [[[ 1 ,2-dihydro- 1 -(4-methylcyclohexyi)-2-oxo-3 -pyridinyljcarbonyl] amino] ethyl] - benzoic acid; and
4-[2-[[(l-cyclohexyl-l,2-dihydro-2-oxo-3-pyridinyl]carbonyl]amino]ethyl]-benzoic acid. The compounds of formula (I) may exist in enantiomeric forms. It is to be understood that all enantiomers, diastereomers, racemates and mixtures thereof are included within the scope of the invention.
Compounds of formula (I) may also exist in various tautomeric forms. Thus, for example,
1 1 compounds of formula (I) wherein R represents OH and Y represents N, are tautomers of compounds of formula (la) wherein R represents H.
Figure imgf000011_0001
(la)
All possible tautomeric forms and mixtures thereof are included within the scope of the invention. Compounds of formula (la) wherein R represents H or optionally substituted Cl to 6 alkyl are thus specifically 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 alkyl group having from 1 to 6 carbon atoms. Examples of such groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy and s-butoxy. The terms "Cl to 3 alkoxy" and "Cl to 4 alkoxy" are to be interpreted analogously.
Examples of "Cl to 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 3 heteroatoms independently selected from O, S and N include furan, thiophene, pyrrole, oxazole, oxadiazole, isoxazole, imidazole, thiazole, triazole, thiadiazole, pyridine, pyrimidine and pyrazine.
Unless otherwise indicated, the term "C3 to 6 saturated or partially unsaturated cycloalkyl" referred to herein denotes a 3 to 6 membered non-aromatic carbocyclic ring optionally incorporating one or more double bonds. Examples include cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl. The term "five- or six-membered saturated or partially unsaturated cycloalkyl ring" is to be interpreted analogously.
Unless otherwise indicated, the term "C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms independently selected from O, S(O)p
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, tetrahydropyran, 4-oxo-4H-pyran, pyrrolidine, pyrroline, imidazolidine, 1,3-dioxolane, piperidine, piperazine, morpholine, perhydroazepine, pyrrolidone and piperidone. The term "five- or six-membered saturated or partially unsaturated heterocyclic ring containing one heteroatom selected from O, S and
13 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; said alkyl optionally incorporating a heteroatom selected from O, S and NR " embraces a straight or branched chain arrangement of 1 to 6 carbon atoms in which any two carbon atoms are optionally separated by O, S or NR . The definition thus includes, for example, methylene, ethylene, propylene, hexamethylene, ethylethylene, -CH2CH2O-CH2-, -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, naphthyl, indanyl, quinolyl, tetrahydroquinolyl, benzofuranyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, isoquinolyl, chromanyl, indenyl, quinazolyl, quinoxalyl, chromanyl, isocromanyl, 3H-indolyl, lH-indazolyl, quinuclidyl, tetrahydronaphthyl, dihydrobenzofuranyl, morpholine-4-ylphenyl, 1,3- benzodioxolyl, l,l-dioxido-2,3-dihydro-l-benzothienyl, 2,3-dihydro-l,4-benzodioxinyl and 3,4-dihydro-isochromenyl . Examples of bicyclic ring systems in which the two rings are separated by a linker group
S(O)q include 4-(piperazin-l-ylsulfonyl)phenyl, 4-(morpholin-4-ylsulfonyl)phenyl,
4-(piperidin-l-ylsulfonyl)phenyl, 4-(pyrrolidin-l-ylsulfonyl)phenyl, 4-(4-pyridinylsulfonyl)phenyl, 4-(phenylsulfonyl)phenyl, 4-(thiazolylsulfonyl)phenyl, 4-(pyrimidin-2-ylsulfonyl)phenyl, 4-(imidazolylsulfonyl)phenyl, 4-(triazolylsulfonyl)phenyl and 4-(oxazolylsulfonyl)phenyl.
In one embodiment, R represents H, halogen, Cl to 6 alkyl, CN, Cl to 6 alkoxy, Cl to 3 alkyl substituted by one or more F atoms or Cl to 3 alkoxy substituted by one or more F atoms. In another embodiment, R represents halogen, Cl to 6 alkyl, CN, Cl to 6 alkoxy or Cl to 3 alkyl substituted by one or more F atoms. In another embodiment, R represents halogen, CH3, CN, OCH3 or CF3.
In one embodiment, n represents an integer 1 or 2. In another embodiment, n represents the integer 1.
In one embodiment, R represents halogen, CN or CF3; n represents the integer 1; and G represents phenyl.
In one aspect, the invention provides compounds of formula (I) wherein X represents O;
1 2 2 3 1
Y represents CR ; Y represents CR ; R represents optionally substituted Cl to 6 alkyl;
G represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3
4 heteroatoms independently selected from O, S and N; R represents H; L represents Cl to
2 6 alkyl; and G represents an optionally substituted monocyclic ring system selected from:
i) phenyl, ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from 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 another aspect the invention provides compounds of formula (I) wherein X represents
1 2 2 3 1 2 3
O; Y represents CR ; Y represents CR ; R represents Cl to 6 alkyl; R and R each represent H; G represents phenyl or a five- or six-membered heteroaromatic ring
4 containing 1 to 3 heteroatoms independently selected from O, S and N; R represents H; L
2 represents Cl to 6 alkyl; and G represents an optionally substituted monocyclic ring system selected from:
i) phenyl, ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from 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 another aspect the invention provides compounds of formula (I) wherein X represents
1 1
O; Y represents N or NR and R represents OH or a tautomer thereof; Y represents
3 1 CR ; G represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to
4 3 heteroatoms independently selected from O, S and N; R represents H; L represents Cl
2 to 6 alkyl; and G represents an optionally substituted monocyclic ring system selected from:
i) phenyl, ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from 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 another aspect the invention provides compounds of formula (I) wherein X represents
1 2 2 3 1 2 3
O; Y represents CR ; Y represents CR ; R represents Cl to 6 alkyl; R and R each
1 4 represent H; G represents phenyl or pyridyl; R represents H; L represents Cl to 6 alkyl;
2 and G represents optionally substituted phenyl.
In another aspect the invention provides compounds of formula (I) wherein X represents
1 2 2 3 1 2 3
O; Y represents CR ; Y represents CR ; R represents Cl to 6 alkyl; R and R each
1 4 represent H; G represents phenyl or pyridyl; R represents H; L represents methylene; and
2 G represents optionally substituted phenyl.
In one embodiment, X in formula (I) represents O.
1 In one embodiment, the invention discloses compounds of formula (I) in which Y
2 2 3 represents CR and Y represents CR . In another embodiment, the invention discloses
1 2 2 3 2 compounds of formula (I) in which Y represents CR and Y represents CR and R and
3 R each represent H.
1 1
In another embodiment, Y represents N. In another embodiment, R represents OH in the tautomeric form and Y represents NR .
In one embodiment, R represents optionally substituted Cl to 6 alkyl. In another embodiment, R represents Cl to 6 alkyl, particularly methyl. 1 In one embodiment, G represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N. In another
1 1 embodiment, G in formula (I) represents phenyl or pyridyl. In another embodiment, G in formula (I) represents phenyl. In another embodiment, G in formula (I) represents phenyl and (R )n represents a CF3 group in the 3-position.
4 In one embodiment, R represents H.
In one embodiment, L represents Cl to 6 alkyl. In another embodiment, L represents
29 29
-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 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.
2 In another embodiment, G represents optionally substituted phenyl. In another iδ 1 Λ ? embodiment, G represents phenyl substituted by OSO2R , S(O)sR , SO2NR R ,
I O 1 Q I O 1 Q 00
NR R (wherein at least one of R and R represents S(O)tR or SO2NR R ) or
39 Cl to 3 alkyl substituted by SO2R . In another aspect, the invention specifically provides one or more compounds as described in the Examples herein, or the non-salt form thereof or a pharmaceutically acceptable salt thereof.
Particular compounds include:
N-(4-chlorobenzyl)-l-(4-chlorophenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide
6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide 6-methyl-N-(4-morpholin-4-yIbenzyl)-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
6-methyl-N- [4-(methylsulf onyl)phenyl] -2-oxo- 1 - [3 -(trifluoromethyl)ρhenyl] -1,2- dihydropyridine-3-carboxamide
N- [4-(dimethylamino)benzyl] -6-methyl-2-oxo- 1 - [3-(trifluoromethyl)phenyl]- 1 ,2- dihydropyridine-3-carboxamide
N-[4-(aminosulfonyl)benzyl]-6-methyl~2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N-(4-methoxybenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-
3-carboxamide N-benzyl-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxamide
N-(4-chlorobenzyl)-l-(2-fluoro-5-methylphenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide
N-(3-chlorobenzyl)-l-(2-fluoro-5-methylphenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide l-(2-fluoro-5-methylphenyl)-N-(4-methoxybenzyl)-6-methyl-2-oxo-l,2-dihydropyridine-
3 -carboxamide
N-(4-methoxybenzyl)-l-(3-methoxyphenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide N-(3-chlorobenzyl)-l-(3-methoxyphenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide N-(4-chlorobenzyl)-l-(3-methoxyphenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide
N- [4-(aminosulf onyl)benzyl] - 1 -(3 -chlorophenyl)-6-methyl-2-oxo- 1 ,2-dihydropyridine-3 - carboxamide N-(4-chlorobenzyl)-l-(3-chloro-4-methylphenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-chloro-4-methylphenyl)-N-(4-methoxybenzyl)-6-methyl-2-oxo-l,2-dihydropyridine-
3-carboxamide
N-(4-chlorobenzyl)-l-(2,3-dimethylphenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide
N-(4-chlorobenzyl)-l-(3-chloro-4-fluoroρhenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-chloro-4-fluorophenyl)-N-(4-methoxybenzyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide N-(4-chlorobenzyl)- 1 -(3-ethylphenyl)-6-methyl-2-oxo- 1 ,2-dihydropyridine-3-carboxamide l-(3-bromophenyl)-N-(4-chlorobenzyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-bromophenyl)-N-(4-methoxybenzyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide N-(2,3-dihydro-l-benzofuran-5-ylmethyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]- l,2-dihydropyridine-3-carboxamide
6-methyl-2-oxo-N-[3-(2-oxopyrrolidin-l-yl)propyl]-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N-(4-bromobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxamide
N-(4-chlorophenyl)-6-methyl-2-oxo- 1 - [3 -(trifluoromethyl)phenyl] - 1 ,2-dihydropyridine-3 - carboxamide
6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide
N-(4-methoxybenzyl)-6-methyl-2-oxo-l-phenyl-l,2-dihydropyridine-3-carboxamide N-(4-chlorobenzyl)-6-methyl-2-oxo-l-phenyl-l,2-dihydropyridine-3-carboxamide
N-(4-chlorobenzyl)-l-(3,5-dimethylphenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide N-[4-(aminosulfonyl)benzyl]-l-(3,5-dimethylphenyl)-6-methyl-2-oxo-l,2- dihydropyridine-3-carboxamide l-(3,5-dimethylphenyl)-N-(4-methoxybenzyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide N-benzyl- 1 -(3 ,5-dimethylphenyl)-6-methyl-2-oxo- 1 ,2-dihydropyridine-3-carboxamide
N-(4-chlorobenzyl)-6-methyl-l-(3-methylphenyl)-2-oxo-l,2-dihydropyridine-3- carboxamide
N-(4-methoxybenzyl)-6-methyl-l-(3-methylphenyl)-2-oxo-l,2-dihydropyridine-3- carboxamide N-(3-chlorobenzyl)-6-methyl-l-(3-methylphenyl)-2-oxo-l,2-dihydropyridine-3- carboxamide
N-(4-chlorobenzyl)-l-(3-chlorophenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide
N-(3-chlorobenzyl)-l-(3-chlorophenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-chlorophenyl)-N-(4-methoxybenzyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide methyl 4- [( { [ 1 -(3 -chloroρhenyl)-6-methyl-2-oxo- 1 ,2-dihydropyridin-3- yl]carbonyl } amino)methyl]benzoate 4-[({ [l-(3-chlorophenyl)-6-methyI-2-oxo-l,2-dihydropyridin-3- yljcarbonyl } amino)methyl]benzoic acid l-(3-cyanophenyl)-N-(cyclohexylmethyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-N-(2-furylmethyl)-6-methyl-2-oxo-l,2-dihydropyridine-3-carboxamide l-(3-cyanophenyl)-6-methyl-2-oxo-N-(pyridin-3-ylmethyl)-l,2-dihydropyridine-3- carboxamide
N-benzyl- 1 -(3-cyanophenyl)-6-methyl-2-oxo- 1 ,2-dihydropyridine-3-carboxamide l-(3-cyanophenyl)-N-2,3-dihydro-lH-inden-l-yl-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-N-(2-methoxybenzyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide 1 -(3-cyanophenyl)-6-methyl-2-oxo-N-(3 ,4,5-trimethoxybenzyl)- 1 ,2-dihydropyridine-3- carboxamide
1 -(3-cyanophenyl)-N-(2,5-dimethoxybenzyl)-6-methyl-2-oxo- 1 ,2-dihydropyridine-3- carboxamide
1 -(3-cyanophenyl)-N-(3 ,4-dimethoxybenzyl)-6-methyl-2-oxo- 1 ,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-N-[(l-ethylpyrrolidin-2-yl)methyl]-6-methyl-2-oxo-l,2- dihydropyridine-3-carboxamide
N-(4-chlorobenzyl)-l-(3-cyanophenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-N-(4-methoxybenzyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide
N-(3-chlorobenzyl)-l-(3-cyanophenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-6-methyl-2-oxo-N-(thien-2-ylmethyl)-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-N-(cyclopropylmethyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-N-(3-methoxybenzyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-6-methyl-2-oxo-N-(pyridin-4-ylmethyl)-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]-6-methyl-2-oxo-l,2- dihydropyridine-3-carboxamide
1 -(3-cyanophenyl)-6-methyl-N- [2-(l -methylpyrrolidin-2-yl)ethyl]-2-oxo- 1 ,2- dihydropyridine-3-carboxamide
N-[2-(3-chlorophenyl)ethyl]-l-(3-cyanophenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-6-methyl-2-oxo-N-(2-pyridin-2-ylethyl)-l,2-dihydropyridine-3- carboxamide
N- [2-(4-chlorophenyl)ethyl] - 1 -(3 -cy anophenyl)-6-methyl-2-oxo- 1 ,2-dihydropyridine-3 - carboxamide l-(3-cyanophenyl)-N-[2-(2-methoxyphenyl)ethyl]-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide
N-[2-(2-chlorophenyl)ethyl]-l-(3-cyanophenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-N-[2-(3-methoxyphenyl)ethyl]-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-N-[2-(4-fluorophenyl)ethyl]-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-N-[2-(2,4-dichlorophenyl)ethyl]-6-methyl-2-oxo-l,2-dihydropyridine-
3-carboxamide l-(3-cyanophenyl)-N-[2-(3-fluorophenyl)ethyl]-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-N-[2-(2-fluorophenyl)ethyl]-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-N-(2-cyclohex-l-en-l-ylethyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide
N-[2-(4-bromophenyl)ethyl]-l-(3-cyanophenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide
N-(3-bromobenzyl)-l-(3-cyanophenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide N-(4-bromobenzyl)-l-(3-cyanophenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide
N-(2-bromobenzyl)-l-(3-cyanophenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-N-(3,4-dihydro-2H-pyran-2-ylmethyl)-6-methyl-2-oxo-l,2- dihydropyridine-3-carboxamide l-(3-cyanophenyl)-6-methyl-N-(4-methylbenzyl)-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-6-methyl-N-(l-naphthylmethyl)-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-N-(2-ethoxybenzyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-6-methyl-N-(3-methylbenzyl)-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-N-(4-fluorobenzyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide
N-(l,3-benzodioxol-5-ylmethyl)-l-(3-cyanophenyl)-6-methyl-2-oxo-l,2-dihydropyridine-
3-carboxamide l-(3-cyanophenyl)-N-(2,4-dichlorobenzyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-6-methyl-N-(2-methylbenzyl)-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-N-(3,4-difluorobenzyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-cyanoρhenyl)-N-(3,4-dichlorobenzyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-6-methyl-N-[(5-methyl-2-furyl)methyl]-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-cyanoρhenyl)-6-methyl-2-oxo-N-l,2,3,4-tetrahydronaphthalen-l-yl-l,2- dihydropyridine-3-carboxamide l-(3-cyanophenyl)-N-(2,3-dimethoxybenzyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-N-(3,5-dimethoxybenzyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-N-[l-(4-fluorophenyl)ethyl]-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide
N- [ 1 -(4-chlorophenyl)ethyl] - 1 -(3 -cyanophenyl)-6-methyl-2-oxo- 1 ,2-dihydropyridine-3 - carboxamide 1 -(3-cyanoρhenyl)-N-(2,5-difluorobenzyl)-6-methyl-2-oxo- 1 ,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-N-(2,3-dihydro-l-benzofuran-5-ylmethyl)-6-methyl-2-oxo-l,2- dihydropyridine-3-carboxamide methyl 4-[({ [l-(3-cyanophenyl)-6-methyl-2-oxo-l ,2-dihydropyridin-3- yl]carbonyl}amino)methyi]benzoate l-(3-cyanophenyl)-6-methyl-2-oxo-N-(4-phenoxybenzyl)-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-N-[(lS)-2,3-dihydro-lH-inden-l-yl]-6-methyl-2-oxo-l,2- dihydropyridine-3-carboxamide l-(3-cyanophenyl)-6-methyl-2-oxo-N-(thien-3-ylmethyl)-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-6-methyl-N-[(5-methylisoxazol-3-yl)methyl]-2-oxo-l,2- dihydropyridine-3-carboxamide l-(3-cyanophenyl)-N-[(2,5-dimethyl-3-furyl)methyl]-6-methyl-2-oxo-l,2-dihydropyridine-
3-carboxamide l-(3-cyanophenyl)-N-(3-furylmethyl)-6-methyl-2-oxo-l,2-dihydropyridine-3-carboxamide l-(3-cyanophenyl)-6-methyl-2-oxo-N-[4-(lH-pyrazol-l-yl)benzyl]-l,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-6-methyl-2-oxo-N-(4-thien-2-ylbenzyl)-l,2-dihydropyridine-3- carboxamide
N-[4-(aminosulfonyl)benzyl]-l-(3-cyanophenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3- carboxamide
N-[2-(l,3-benzodioxol-5-yl)ethyl]-l-(3-cyanophenyl)-6-methyl-2-oxo-l,2- dihydropyridine-3-carboxamide
1 -(3-cyanophenyl)-6-methyl-2-oxo-N-(2-thien-2-ylethyl)- 1 ,2-dihydropyridine-3- carboxamide l-(3-cyanophenyl)-N-[2-(2,4-dimethylphenyl)ethyl]-6-methyl-2-oxo-l,2-dihydropyridine-
3-carboxamide l-(3-cyanophenyl)-6-methyl-N-[2-(4-methylρhenyl)ethyl]-2-oxo-l,2-dihydropyridine-3- carboxamide N-{2-[4-(aminosulfonyl)phenyl]ethyl}-l-(3-cyanophenyl)-6-methyl-2-oxo-l,2- dihydropyridine-3-carboxamide
1 -(3-cyanophenyl)-6-methyl-2-oxo-N- [( 1 S)- 1 -phenylethyl] - 1 ,2-dihydropyridine-3 - carboxamide N-(cyclohexylmethyl)-6-methyl-2-oxo- 1 - [3 -(trifluoromethyl)phenyl] - 1 ,2-dihydropyridine-
3-carboxamide
N-(2-furylmethyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-αihydropyridine-3- carboxamide
6-methyl-2-oxo-N-(pyridin-3-ylmethyl)-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N-2,3-dihydro- lH-inden- l-yl-6-methyl-2-oxo- 1 -[3-(trifluoromethyl)phenyl]- 1 ,2- dihydropyridine-3-carboxamide
N-(2-methoxybenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-
3-carboxamide 6-methyl-2-oxo-N-(tetrahydrofuran-2-ylmethyl)-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-N-(3,4,5-trimethoxybenzyl)-l,2- dihydropyridine-3 -carboxamide
N-(3-fluorobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)ρhenyl]-l,2-dihydropyridine-3- carboxamide
N-(2,5-dimethoxybenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N- [( 1 -ethylpyrrolidin-2-yl)methyl] -6-methyl-2-oxo- 1 - [3 -(trifluoromethyl)phenyl] -1,2- dihydropyridine-3-carboxamide N-(2-chlorobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxamide
N-(4-chlorobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxamide
N-(3-chlorobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxamide
6-methyl-2-oxo-N-(thien-2-ylmethyl)-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-
3-carboxamide N-(cyclopropylmethyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N-(3-methoxybenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-
3-carboxamide 6-methyl-2-oxo-N-(pyridin-4-ylmethyl)-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N- [2-(3 ,4-dimethoxyphenyl)ethyl] -6-methyl-2-oxo- 1 - [3 -(trifluoromethyl)phenyl] -1,2- dihydropyridine-3-carboxamide
N-[2-(4-methoxyphenyl)ethyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
6-methyl-2-oxo-N-(2-phenylethyl)-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxamide
6-methyl-N-[2-(l-methylpyrrolidin-2-yl)ethyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide N-[2-(3-chlorophenyl)ethyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
6-methyl-2-oxo-N-(2-pyridin-2-ylethyl)-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N- [2-(2-methoxyphenyl)ethyl] -6-methyl-2-oxo- 1 - [3 -(trifluoromethyl)phenyl] -1,2- dihydropyridine-3 -carboxamide
N-[2-(2-chlorophenyl)ethyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridme-3-carboxamide
N-[2-(3-methoxyphenyl)ethyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide N-[2-(4-fluorophenyl)ethyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N-[2-(2,4-dichlorophenyl)ethyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N-[2-(3-fluorophenyl)ethyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N-[2-(2-fluorophenyl)ethyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide N-(2-cyclohex-l-en-l-ylethyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N-[2-(4-bromophenyl)ethyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide 6-methyl-2-oxo-N-[(lS)-l-phenylethyl]-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N-(3-bromobenzyl)-6-methyl-2-oxo- 1 - [3-(trifluoromethyl)phenyl]- 1 ,2-dihydropyridine-3- carboxamide
N-(4-bromobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxamide
N-(2-bromobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxamide
N-(3 ,4-dihydro-2H-pyran-2-ylmethyl)-6-methyl-2-oxo- 1 - [3-(trifluoromethyl)phenyl]- 1 ,2- dihydropyridine-3-carboxamide 6-methyl-N-(4-methylbenzyl)-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxamide
6-methyl-N-(l-naphthylmethyl)-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-
3-carboxamide
N-(2-ethoxybenzyl)-6-methyl-2-oxo- 1 - [3 -(trifluoromethyl)phenyl] - 1 ,2-dihydropyridine-3 - carboxamide
6-methyl-N-(3-methylbenzyl)-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxamide
N-(4-fluorobenzyl)-6-methyl-2-oxo- 1 - [3 -(trifluoromethyl)phenyl] - 1 ,2-dihydropyridine-3 - carboxamide N-(l ,3-benzodioxol-5-ylmethyl)-6-methyl-2-oxo- 1 -[3-(trifluoromethyl)phenyl] - 1 ,2- dihydropyridine-3-carboxamide
N-(2,4-dichlorobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
6-methyl-N-(2-methylbenzyl)-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxamide
N-(3,4-difluorobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide N-(2-fluorobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxamide
N-(2-chloro-4-fluorobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide N-(3,4-dichlorobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
6-methyl-N-[(5 -methyl-2-f uryl)methyl] -2-oxo- 1 - [3-(trifluoromethyl)phenyl] -1,2- dihydropyridine-3-carboxamide
6-methyl-2-oxo-N- 1,2,3 ,4-tetrahydronaphthalen- 1 -yl- 1 - [3-(trifluoromethyl)phenyl] -1,2- dihydropyridine-3-carboxamide
N-(2,3-dimethoxybenzyl)-6-methyl-2-oxo- 1 - [3-(trifluoromethyl)phenyl]- 1 ,2- dihydropyridine-3-carboxamide
N- [ 1 -(4-chlorophenyl)ethyl] -6-methyl-2-oxo- 1 -[3-(trifluoromethyl)phenyl] -1,2- dihydropyridine-3-carboxamide N-(2,5-difluorobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide methyl 4-{[({6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridin-3- yl } carbonyl)amino]methyl jbenzoate
6-methyl-2-oxo-N-(4-phenoxybenzyl)-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine- 3-carboxamide
N-[(2,2-dimethyl-l,3-dioxolan-4-yl)methyl]-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide
6-methyl-N-[(5-methylisoxazol-3-yl)methyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide N-[(2,5-dimethyl-3-furyl)methyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N-(3-furylmethyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxamide
6-methyl-2-oxo-N-[4-(lH-pyrazol-l-yl)benzyl]-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
6-methyl-2-oxo-N-(4-thien-2-ylbenzyl)-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide N-[2-(l,3-benzodioxol-5-yl)ethyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
6-methyl-2-oxo-N-(2-thien-2-ylethyl)-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-
3-carboxamide N-[2-(4-tert-butylphenyl)ethyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydroρyridine-3-carboxamide
6-methyl-N-[2-(4-methylphenyl)ethyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N-{2-[4-(aminosulfonyl)phenyl]ethyl}-6-methyl-2-oxo-l-[3-(trifluoromethyl)ρhenyl]-l,2- dihydropyridine-3-carboxamide
6-methyl-2-oxo-N- [( IR)- 1 -phenylethyl] - 1 -[3-(trifluoromethyl)phenyl] -1,2- dihydropyridine-3-carboxamide
3-{[4-(2-methoxyphenyl)piperazin-l-yl]carbonyl}~6-methyl-l-[3-
(trifluoromethyl)phenyl]pyridin-2(lH)-one N-[(4-cyanocyclohexyl)methyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3 -carboxamide
3- { [4-(4-fluorophenyl)piperazin- 1 -yl] carbonyl } -6-methyl- 1 - [3 -
(trifluoromethyl)phenyl]pyridin-2(lH)-one
N-[2-(4'-fluoro-l,r-biphenyl-4-yl)ethyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]- l,2-dihydropyridine-3-carboxamide
N-(2-hydroxy-l-phenylethyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
6-methyl-2-oxo-N-[(2R)-2-phenylcyclopropyl]-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide N-[l-(4-chlorobenzyl)piperidin-4-yl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
6-methyl-N-(2-morpholin-4-ylethyl)-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N-[2-(4-chlorophenyl)ethyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)ρhenyl]-l,2- dihydropyridine-3-carboxamide
N-(2-hydroxy-2-phenylethyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide N-cyclopentyl-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxamide
N-[2-(lH-imidazol-4-yl)ethyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide N-(3,5-dimethoxybenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N-(4-hydroxycyclohexyl)-6-methyl-2-oxo- 1 - [3 -(trifluoromethyl)phenyl] -1,2- dihydropyridine-3-carboxamide
6-methyl-2-oxo-N-(2-pyridin-2-ylethyl)-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3 -carboxamide
6-methyl-2-oxo-N-lH-l,2,4-triazol-3-yl-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N-[l-(hydroxymethyl)-2-methylpropyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide 3- { [3-(3 ,4-dichlorophenoxy)pyrrolidin- l-yl]carbonyl } -6-methyl- 1 -[3-
(trifluoromethyl)phenyl]pyridin-2(lH)-one
6-methyl-2-oxo-N-(pyridin-3 -ylmethyl)- 1 - [3 -(trifluoromethyl)phenyl] -1,2- dihydropyridine-3-carboxamide
N-(2-methoxyethyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxamide
N-(2-hydroxypropyl)-6-methyl-2-oxo- 1 - [3 -(trifluoromethyl)phenyl] - 1 ,2-dihydropyridine-
3 -carboxamide ethyl 4- [( { 6-methyl-2-oxo- 1 - [3 -(trifluoromethyl)phenyl] - 1 ,2-dihydropyri din-3 - yl}carbonyl)amino]piperidine-l-carboxylate N-[3-(lH-imidazol-l-yl)propyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N-(4-chlorobenzyl)-l-(3-methylphenyl)-2-oxo-l,2-dihydropyridine-3-carboxamide
N-(4-chlorobenzyl)-6 '-methyl-2-oxo-2H- 1 ,2'-bipyridine-3 -carboxamide
N-(4-methoxybenzyl)-l-(3-methylphenyl)-2-oxo-l,2-dihydropyridine-3-carboxamide methyl 4-[({ [l-(3-methylphenyl)-2-oxo-l ,2-dihydropyridin-3- yl]carbonyl } amino)methyl]benzoate 4-[({[l-(3-methylphenyl)-2-oxo-l,2-dihydropyridin-3-yl]carbonyl}amino)methyl] benzoic acid
N-(4-chlorobenzyl)-l-(2-fluoro-5-methylphenyl)-2-oxo-l,2-dihydropyridine-3- carboxamide l-(2-fluoro-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-l,2-dihydropyridine-3- carboxamide
N- [4-(dimethylamino)benzyl] - 1 -(2-fluoro-5 -methylphenyl)-2-oxo- 1 ,2-dihydropyridine-3- carboxamide
N-[4-(aminosulfonyl)benzyl]-l-(2-fluoro-5-methylphenyl)-2-oxo-l,2-dihydropyridine-3- carboxamide
N-(4-chlorobenzyl)-4'-methyl-2-oxo-2H-l,2'-bipyridine-3-carboxamide
N-(4-chlorobenzyl)-l-(2,5-dimethylphenyl)-2-oxo-l,2-dihydropyridine-3-carboxamide
1 -(2,5-dimethylphenyl)-N-(4-methoxybenzyl)-2-oxo- 1 ,2-dihydropyridine-3-carboxamide
N-[4-(dimethylamino)benzyl]-l-(2,5-dimethylphenyl)-2-oxo-l,2-dihydropyridine-3- carboxamide
N-(4-chlorobenzyl)- 1 - [2-methyl-5-(trifluoromethyl)phenyl] -2-oxo- 1 ,2-dihydropyridine-3 - carboxamide
N-(4-methoxybenzyl)-l-[2-methyl-5-(trifluoromethyl)phenyl]-2-oxo-l,2-dihydropyridine-
3 -carboxamide N-[4-(dimethylamino)benzyl]-l-[2-methyl-5-(trifluoromethyl)phenyl]-2-oxo-l,2- dihydropyridine-3-carboxamide
N-benzyl-5 -methyl-2-oxo- 1 - [3-(trifluoromethyl)phenyl] - 1 ,2-dihydropyridine-3 - carboxamide
N-(2-chlorobenzyl)-5-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxamide
5 -methyl-2-oxo-N-(2-phenylethyl)- 1 - [3 -(trifluoromethyl)phenyl] - 1 ,2-dihydropyridine-3- carboxamide
N-(4-chlorophenyl)-5 -methyl-2-oxo- 1 - [3-(trifluoromethyl)phenyl] - 1 ,2-dihydropyridine-3 - carboxamide 6-ethyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide N-[4-(methylsulfonyl)benzyl]-2-oxo-6-propyl-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
6-butyl-N-[4-(methylsulfonyl)benzyl]-2-oxo- 1 - [3-(trifluoromethyl)phenyl]- 1 ,2- dihydropyridine-3-carboxamide 6-(methoxymethyl)-N- [4-(methylsulf onyl)benzyl] -2-oxo- 1 - [3 -(trifluoromethyl)phenyl] -
1 ,2-dihydropyridine-3-carboxamide
6-(hydroxymethyl)-N- [4-(methylsulf onyl)benzyl] -2-oxo- 1 - [3 -(trifluoromethyl)phenyl] -
1 ,2-dihydropyridine-3-carboxamide
N-[4-(aminosulfonyl)benzyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]- 1 ,2,3,4- tetrahydropyrinτidine-5-carboxamide
N-[4-(dimethylamino)benzyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4- tetrahydropyrimidine-5-carboxamide
N-(4-chlorobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4-tetrahydropyrimidine-
5-carboxamide N-(2,3-dihydro-l-benzofuran-5-ylmethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4- tefrahydropyrimidine-5-carboxamide
N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4- tetrahydropyrimidine-5-carboxamide
N-(4-bromobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4-tetrahydropyrimidine- 5-carboxamide
N-(4-methoxybenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4- tetrahycjj:opyrimidine-5-carboxamide
N-(l,3-benzodioxol-5-ylmethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4- teteahydropyrimidine-5-carboxamide N-(3-chlorobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4-tetrahydropyrimidine-
5-carboxamide l-butyl-N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4- tetrahydropyrimidine-5-carboxamide l-(2-methoxyethyl)-N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-3-[3- (trifluoromethyl)phenyl]-l,2,3,4-tetrahy<lropyrimidine-5-carboxamide l-methyl-N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4- tetrahydropyrimidine-5-carboxamide l-ethyl-N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4- tetrahydropyrimidine-5-carboxamide
N-(4-chlorobenzyl)-l-(2-methoxyethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4- tetrahydropyrimidine-5-carboxamide 5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N-(4-chlorobenzyl)-l-(2-methoxyethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4- tetrahydropyrimidine-5-carboxamide
N-(4-methoxybenzyl)-l-(2-methoxyethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]- l,2,3,4-tefrahyαι-opyrirnidine-5-carboxamide l-(2-methoxyethyl)-2,4-dioxo-N-(pyridin-4-ylmethyl)-3-[3-(trifluoromethyl)phenyl]-
1 ,2,3 ,4-tetrahydropyrimidine-5-carboxamide
N-[2-(3,4-dimethoxyphenyl)ethyl]-l-(2-methoxyethyl)-2,4-dioxo-3-[3-.
(trifluoromethyl)phenyl]-l ,2,3,4-tefrahydropyrimidine-5-carboxamide l-(2-methoxyethyl)-N-[2-(3-methoxyphenyl)ethyl]-2,4-dioxo-3-[3-
(trifluoromethyl)phenyl]-l,2,3,4-tetrahydroρyrimidine-5-carboxamide l-(2-methoxyethyl)-N-(4-methylbenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4- tetrahydropyrimidine-5-carboxamide l-(2-methoxyethyl)-N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-3-[3- (trifluoromethyl)phenyl]-l ,2,3,4-tetrahydroρyrimidine-5-carboxamide
N-(4-fluorobenzyl)- 1 -(2-methoxyethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]- 1 ,2,3 ,4- tefrahydropyrimidine-5-carboxamide
N-(l,3-benzodioxol-5-ylmethyl)-l-(2-methoxyethyl)-2,4-dioxo-3-[3-
(trifluoromethyl)phenyl] -1,2,3 ,4-tetrahydropyrimidine-5-c arboxamide N-(2-chloro-4-fluorobenzyl)- 1 -(2-methoxyethyl)-2,4-dioxo-3- [3-(trifluoromethyl)phenyl]-
1 ,2,3 ,4-tetrahydropyrimidine-5-carboxamide
N-(3,4-dichlorobenzyl)-l-(2-methoxyethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-
1 ,2,3 ,4-tetrahydropyrimidine-5-carboxamide methyl 4-{ [({ l-(2-methoxyethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4- tetrahydropyrimidin-5-yl } carbonyl)amino]methyl }benzoate l-(2-methoxyethyl)-N-[(5-methylisoxazol-3-yl)methyl]-2,4-dioxo-3-[3-
(trifluoromethyl)phenyl]-l,2,3,4-tefrahyά -opyrinιidine-5-carboxamide l-(2-methoxyethyl)-2,4-dioxo-N-[4-(lH-ρyrazol-l-yl)benzyl]-3-[3-
(trifluoromethyl)phenyl]-l,2,3,4-tefrahydropyrimidine-5-carboxamide
N-(4-chlorobenzyl)-3-(3-chloroρhenyl)- 1 -(2-methoxyethyl)-2,4-dioxo- 1 ,2,3 ,4- tefrahydropyrimidine-5-carboxamide 3-(3-chlorophenyl)-N-(4-methoxybenzyl)-l-(2-methoxyethyl)-2,4-dioxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide
3-(3-chlorophenyl)-l-(2-methoxyethyl)-2,4-dioxo-N-(ρyridin-4-ylmethyl)-l,2,3,4- tetrahydropyrimidine-5 -c arboxamide
3-(3-chlorophenyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]-l-(2-methoxyethyl)-2,4-dioxo- l,2,3,4-tefrahydropyrirnidine-5-carboxamide
3-(3-chlorophenyl)-l-(2-methoxyethyl)-N-[2-(3-methoxyphenyl)ethyl]-2,4-dioxo-l,2,3,4- tetrahydropyrirnidine-5-carboxamide
N-(3-bromobenzyl)-3-(3-chlorophenyl)-l-(2-methoxyethyl)-2,4-dioxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide 3-(3-chlorophenyl)-l-(2-methoxyethyl)-N-(4-methylbenzyl)-2,4-dioxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide
3-(3-chloroρhenyl)-l-(2-methoxyethyl)-N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide
3-(3-chlorophenyl)-N-(4-fluorobenzyl)-l-(2-methoxyethyl)-2,4-dioxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide
N-(l,3-benzodioxol-5-ylmethyl)-3-(3-chlorophenyl)-l-(2-methoxyethyl)-2,4-dioxo- l,2,3,4-tefrahydropyrimidine-5-carboxamide
3-(3-chloroρhenyl)-N-(3,4-difluorobenzyl)-l-(2-methoxyethyl)-2,4-dioxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide N-(2-chloro-4-fluorobenzyl)-3-(3-chlorophenyl)-l-(2-methoxyethyl)-2,4-dioxo-l,2,3,4- tetrahydropyrimidine-5-carboxarnide
3-(3-chlorophenyl)-N-(3 ,4-dichlorobenzyl)- 1 -(2-methoxyethyl)-2,4-dioxo- 1 ,2,3 ,4- tetrahydropyrimidine-5-carboxamide methyl 4-[({[3-(3-chlorophenyl)-l-(2-methoxyethyl)-2,4-dioxo-l,2,3,4- tetrahydropyrimidin-5-yl]carbonyl } amino)methyl]benzoate
3-(3-chlorophenyl)-l-(2-methoxyefhyl)-N-[(5-methylisoxazol-3-yl)methyl]-2,4-dioxo- l,2,3,4-tetrahydropyrimidine-5-carboxamide 3-(3-chlorophenyl)-l-(2-methoxyethyl)-2,4-dioxo-N-[4-(lH-ρyrazol-l-yl)benzyl]-l,2,3,4- tetrahydropyrimidine-5-carboxamide l-butyl-N-(4-chlorobenzyl)-3-(3-methoxyphenyl)-2,4-dioxo-l,2,3,4-tefrahydropyrimidine-
5-carboxamide l-butyl-3-(3-methoxyphenyl)-N-[2-(3-methoxyphenyl)ethyl]-2,4-dioxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide
N-(3-bromobenzyl)-l-butyl-3-(3-methoxyphenyl)-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-
5-carboxamide l-butyl-N-(4-fluorobenzyl)-3-(3-methoxyphenyl)-2,4-dioxo-l,2,3,4-tetrahydropyrimidine- 5-carboxamide
N-(l,3-benzodioxol-5-ylmethyl)-l-butyl-3-(3-methoxyphenyl)-2,4-dioxo-l,2,3,4- tetrahy<lropyrimidine-5-carboxamide
1 -butyl-N-(2,4-dichlorobenzyl)-3-(3-methoxyphenyl)-2,4-dioxo- 1 ,2,3 ,4- tefrahydropyrimidine-5-carboxamide l-butyl-N-(3,4-difluorobenzyl)-3-(3-methoxyρhenyl)-2,4-dioxo-l, 2,3,4- tetrahydropyrimidine-5-carboxamide l-butyl-N-(2-chloro-4-fluorobenzyl)-3-(3-methoxyphenyl)-2,4-dioxo-l,2,3,4- tettahydropyrimidine-5-carboxamide
1 -butyl-N-(2,3-dihydro- 1 -benzofuran-5-ylmethyl)-3-(3-methoxyphenyl)-2,4-dioxo- 1 ,2,3 ,4- tefrahydι:opyrimidine-5-carboxamide l-butyl-N-(4-chlorobenzyl)-3-(3-chlorophenyl)-2,4-dioxo-l,2,3,4-tefrahyα^opyrimidine-5- carboxamide l-butyl-3-(3-chlorophenyl)-N-(4-methoxybenzyl)-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-
5-carboxamide l-butyl-3-(3-chlorophenyl)-2,4-dioxo-N-(pyridin-4-ylmethyl)-l,2,3,4- tetrahydropyrimidine-5-carboxamide l-butyl-3-(3-chloroρhenyl)-N-[2-(3,4-dimethoxyρhenyl)ethyl]-2,4-dioxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide l-butyl-3-(3-chlorophenyl)-N-[2-(3-methoxyphenyl)ethyl]-2,4-dioxo-l,2,3,4- tefrahydropyrinτidine-5-carboxamide
N-(3-bromobenzyl)-l-butyl-3-(3-chlorophenyl)-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5- carboxamide N-(4-bromobenzyl)- 1 -butyl-3-(3-chlorophenyl)-2,4-dioxo- 1 ,2,3 ,4-tetrahydropyrimidine-5- carboxamide l-butyl-3-(3-chlorophenyl)-N-(4-methylbenzyl)-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5- carboxamide l-butyl-3-(3-chlorophenyl)-N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-l,2,3,4- tetrahydropyrimidine-5 -carboxamide l-butyl-3-(3-chlorophenyl)-N-(4-fluorobenzyl)-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5- carboxamide
N-(l,3-benzodioxol-5-ylmethyl)-l-butyl-3-(3-chlorophenyl)-2,4-dioxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide l-butyl-3-(3-chlorophenyl)-N-(2,4-dichlorobenzyl)-2,4-dioxo-l,2,3,4- tefrahydropyrimidine-5-carboxamide l-butyl-3-(3-chlorophenyl)-N-(3,4-difluorobenzyl)-2,4-dioxo-l,2,3,4- tefrahydropyrir dine-5-carboxamide 1 -butyl-N-(2-chloro-4-fluorobenzyl)-3-(3-chlorophenyl)-2,4-dioxo- 1 ,2,3 ,4- tetrahydropyrimidine-5-carboxamide l-butyl-3-(3-chlorophenyl)-N-(3,4-dichlorobenzyl)-2,4-dioxo-l,2,3,4- tefrahydropyrimidine-5-carboxamide l-butyl-3-(3-chlorophenyl)-N-(2,3-dihydro-l-benzofuran-5-ylmethyl)-2,4-dioxo-l,2,3,4- tetrahydropyrirmdine-5-carboxamide l-butyl-3-(3-chlorophenyl)-N-[(4-cyanocyclohexyl)methyl]-2,4-dioxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide l-butyl-3-(3-chlorophenyl)-N-[(5-methylisoxazol-3-yl)methyl]-2,4-dioxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide l-butyl-3-(3-chlorophenyl)-2,4-dioxo-N-[4-(lH-pyrazol-l-yl)benzyl]-l,2,3,4- tetrahydropyrimidine-5-carboxamide l-butyl-3-(3-chlorophenyl)-2,4-dioxo-N-[3-(2-oxopyrrolidin-l-yl)proρyl]-l,2,3,4- tetrahydropyrimidine-5-carboxamide l-butyl-N-(4-chlorobenzyl)-3-(3-cyanophenyl)-2,4-dioxo-l,2,3,4-tefrahydropyrimidine-5- carboxamide l-butyl-3-(3-cyanophenyl)-N-(4-methoxybenzyl)-2,4-dioxo-l,2,3,4-tefrahydropyrimidine-
5-carboxamide l-butyl-3-(3-cyanoρhenyl)-2,4-dioxo-N-(pyridin-4-ylmethyl)-l,2,3,4- tetrahydropyrimidine-5-carboxamide l-butyl-3-(3-cyanoρhenyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]-2,4-dioxo-l,2,3,4- tetrahyαiOpyrinιidme-5-carboxamide l-butyl-3-(3-cyanophenyl)-N-[2-(3-methoxyρhenyl)ethyl]-2,4-dioxo-l,2,3,4- tetrahydropyrimidine-5-carboxarnide
N-(3-bromobenzyl)-l-butyl-3-(3-cyanophenyl)-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5- carboxamide
N-(4-bromobenzyl)-l-butyl-3-(3-cyanophenyl)-2,4-dioxo-l,2,3,4-tefrahydropyrimidine-5- carboxamide l-butyl-3-(3-cyanophenyl)-N-(4-methylbenzyl)-2,4-dioxo-l,2,3,4-tefrahydropyrimidine-5- carboxamide l-butyl-3-(3-cyanophenyl)-N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide l-butyl-3-(3-cyanophenyl)-N-(4-fluorobenzyl)-2,4-dioxo-l,2,3,4-tefrahydropyrimidine-5- carboxamide
N-(l,3-benzodioxol-5-ylmethyl)-l-butyl-3-(3-cyanophenyl)-2,4-dioxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide l-butyl-3-(3-cyanophenyl)-N-(2,4-dichlorobenzyl)-2,4-dioxo-l,2,3,4- tetrahydropyrimichne-5-carboxarnide l-butyl-3-(3-cyanophenyl)-N-(3,4-difluorobenzyl)-2,4-dioxo-l,2,3,4- tetrahydropyrimichne-5-carboxamide l-butyl-N-(2-chloro-4-fluorobenzyl)-3-(3-cyanophenyl)-2,4-dioxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide l-butyl-3-(3-cyanoρhenyl)-N-(3,4-dichlorobenzyl)-2,4-dioxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide
1 -butyl-N-[(4-cyanocyclohexyl)methyl]-3-(3-cyanophenyl)-2,4-dioxo- 1 ,2,3 ,4- tetrahydropyrimidine-5-carboxamide l-butyl-3-(3-cyanophenyl)-N-[(5-methylisoxazol-3-yl)methyl]-2,4-dioxo-l,2,3,4- tetrahydjropyrimidine-5-carboxamide
1 -butyl-3-(3-cyanoρhenyl)-2,4-dioxo-N-[4-(lH-pyrazol- 1 -yl)benzyl] - 1 ,2,3 ,4- tefrahydropyrimidine-5-carboxamide l-butyl-3-(3-cyanophenyl)-2,4-dioxo-N-[3-(2-oxopyrrolidin-l-yl)propyl]-l,2,3,4- tefrahydropyrimidine-5-carboxamide l-butyl-N-(4-chlorobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4- tetrahydropyrimidine-5-carboxamide l-butyl-N-(4-methoxybenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)ρhenyl]-l,2,3,4- tetrahydropyrimidine-5-carboxamide l-butyl-2,4-dioxo-N-(pyridin-4-ylmethyl)-3-[3-(trifluoromethyl)phenyl]-l,2,3,4- tetrahydropyrimidine-5-carboxamide l-butyl-N-[2-(3,4-dimethoxyphenyl)ethyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]- 1 ,2,3 ,4-tetrahydropyrimidine-5-carboxamide l-butyl-N-[2-(3-methoxyphenyl)ethyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4- tetrahydropyrimidine-5-carboxamide
N-(3-bromobenzyl)-l-butyl-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4- tetrahydroρyrimidine-5-carboxamide N-(4-bromobenzyl)-l-butyl-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4- tetrahydropyrimidine-5-carboxamide l-butyl-N-(4-methylbenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)ρhenyl]-l,2,3,4- tetrahydropyrimidine-5-carboxamide l-butyl-N-[4-(methylsulfonyl)benzyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4- tetrahydroρyrimidine-5-carboxamide l-butyl-N-(4-fluorobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4- tetrahydropyrimidine-5-carboxamide
N-(l,3-benzodioxol-5-ylmethyl)-l-butyl-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4- tetrahydropyrimidine-5-carboxamide l-butyl-N-(2,4-dichlorobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4- tetrahydropyrirmdine-5-carboxamide l-butyl-N-(3,4-difluorobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4- tetrahydropyrimidine-5-carboxamide l-butyl-N-(2-chloro-4-fluorobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)ρhenyl]-l,2,3,4- tetrahydropyrimidine-5-carboxamide
1 -butyl-N-(3 ,4-dichlorobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl] - 1 ,2,3 ,4- tetrahydropyriιrjidine-5-carboxamide 1 -butyl-N-(2,3-dihydro- 1 -benzofuran-5-ylmethyl)-2,4-dioxo-3- [3-
(trifluoromethyl)phenyl]-l,2,3,4-tetrahydropyrimidine-5-carboxamide l-butyl-N-[(4-cyanocyclohexyl)methyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4- tetrahydropyrirmdine-5-carboxamide l-butyl-N-[(5-methylisoxazol-3-yl)methyl]-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-
1 ,2,3 ,4-tetrahydropyrimidine-5-carboxamide l-butyl-2,4-dioxo-N-[4-(lH-ρyrazol-l-yl)benzyl]-3-[3-(trifluoromethyl)ρhenyl]-l,2,3,4- tetrahydropyrimidine-5-carboxamide
1 -butyl-2,4-dioxo-N- [3-(2-oxopyrrolidin- 1 -yl)propyl] -3- [3-(trifluoromethyl)phenyl] - l,2,3,4-tetrahydropyrimidine-5-carboxarnide
6-(chloromethyl)-N-[4-(methylsulfonyl)benzyl] -2-oxo- 1- [3-(trifluoromethyl)phenyl] - 1 ,2- dihydropyridine-3-carboxamide
N- [4-(methylsulf onyl)benzyl] -6- [(methylthio)methyl] -2-oxo- 1 - [3-
(trifluoromethyl)phenyl]- 1 ,2-dihydropyridine-3-carboxamide N- [4-(methylsulf onyl)benzyl] -6-( { [4-(methylsulf onyl)benzyl] amino } methyl)-2-oxo- 1 - [3^-
(trifluoromethyl)phenyl] - 1 ,2-dihydropyridine-3 -carboxamide
N-[4-(methylsulfonyl)benzyl]-6-(morpholin-4-ylmethyl)-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide
6-(cyanomethyl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
6-isopropyl-N- [4-(methylsulf onyl)benzyl] -2-oxo- 1 - [3-(trifluoromethyl)phenyl] -1,2- dihydropyridine-3-carboxamide
N- [4-(ethylsulf onyl)benzyl] -6-methyl-2-oxo- 1 - [3-(trifluoromethyl)phenyl] -1,2- dihydropyridine-3-carboxamide N-[3-chloro-4-(methylsulfonyl)benzyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-
1 ,2-dihydropyridine-3-carboxamide
6-methyl-2-oxo-l-(3-trifIuoromethyl-phenyl)-l ,2-dihydro-pyridine-3-carboxylic acid 4- cyclopropanesulfonyl-benzylamide
N- [3 -methoxy-4-(methylsulf onyl)benzyl] -6-methyl-2-oxo- 1 - [3-(trifluoromethyl)phenyl] - l,2-dihydropyridine-3-carboxamide
N-[3-bromo-4-(methylsulfonyl)benzyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-
1 ,2-dihydropyridine-3-carboxamide N-[3-cyano-4-(methylsulfonyl)benzyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)-phenyl]-
1 ,2-dihydropyridine-3-carboxamide
6-methyl-N- [3-methyl-4-(methylsulf onyl)benzyl] -2-oxo- 1 - [3 -(trifluoromethyl)-phenyl] -
1 ,2-dihydropyridine-3 -carboxamide 6-methyl-N-[4-(methylthio)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
6-methyl-N-[4-(methylsulfinyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N- [4-(benzylsulf onyl)benzyl] -6-methyl-2-oxo- 1 - [3-(trifluoromethyl)phenyl] -1,2- dihydropyridine-3-carboxamide
6-methyl-2-oxo-N-[4-(propylsulfonyl)benzyl]-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N- [4-(butylsulf onyl)benzyl] -6-methyl-2-oxo- 1 - [3 -(trifluoromethyl)phenyl] -1,2- dihydropyridine-3-carboxamide N- [4-(isobutylsulf onyl)benzyl] -6-methyl-2-oxo- 1 - [3-(trifluoromethyl)phenyl] -1,2- dihydropyridine-3-carboxamide
N-[4-(-?ec-butylsulfonyl)benzyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N-[4-(isopropylsulfonyl)benzyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
6-methyl-N-{4-[(3-methylbutyl)sulfonyl]benzyl}-2-oxo-l-[3-(trifluoromethyl)phenyl]- l,2-dihydropyridine-3-carboxamide
N-{4-[(cyclopropylmethyl)sulfonyl]benzyl}-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide 6-methyl-2-oxo-N- { 4- [(tetrahydrofuran-2-ylmethyl)sulf onyl] -benzyl } - 1 - [3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide
N-{4-[(2-hydroxyethyl)sulfonyl]benzyl}-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-
1 ,2-dihydropyridine-3 -carboxamide
N-{4-[(cyanomethyl)sulfonyl]benzyl}-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N-{4-[(2-amino-2-oxoethyl)sulfonyl]benzyl}-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl]- 1 ,2-dihydropyridine-3-carboxamide N-{4-[(4-cyanobenzyl)sulfonyl]benzyl}-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-
1 ,2-dihydropyridine-3 -carboxamide
N-{4-[(2-cyanoethyl)sulfonyl]benzyl}-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide N-{4-[(3-hydroxypropyl)sulfonyl]benzyl}-6-methyl-2-oxo-l-[3-(triiluoromethyl)phenyl]-
1 ,2-dihydropyridine-3 -carboxamide
N-(4- { [2-(dimethylamino)-2-oxoethyl] sulf onyl } benzyl)-6-methyl-2-oxo- 1 - [3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide ethyl 3-[(4-{[({6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridin-3- yl }carbonyl)amino]methyl }phenyl)sulfonyl]propanoate
2- [(4- { [({ 6-methyl-2-oxo- 1 - [3 -(trifluoromethyl)phenyl] - 1 ,2-dihydropyridin-3 - yl }carbonyl)amino]methyl }phenyl)sulfonyl]ethyl acetate
N-{4-[(3-cyanobenzyl)sulfonyl]benzyl}-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-
1 ,2-dihydropyridine-3-carboxamide methyl 3-[(4-{ [({6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridin-3- yl }carbonyl)amino]methyl }phenyl)sulfonyl]propanoate
6-methyl-N-(4-{[(2-methyl-l,3-thiazol-4-yl)methyl]sulfonyl}benzyl)-2-oxo-l-[3-'
(trifluoromethyl)phenyl]- 1 ,2-dihydropyridine-3-carboxamide
6-methyl-2-oxo-N- { 4- [(pyridin-4-ylmethyl)sulf onyljbenzyl } - 1 - [3 - (trifluoromethyl)phenyl] - 1 ,2-dihydropyridine-3-carbpxamide
N- { 4-[(3-cyanopropyl)sulf onyljbenzyl } -6-methyl-2-oxo-l -[3-(trifluoromethyl)phenyl] -
1 ,2-dihydropyridine-3-carboxamide
N-(4-{[(3,5-dimethylisoxazol-4-yl)methyl]sulfonyl}benzyl)-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide N-(4-{ [4-(acetylamino)benzyl]sulfonyl}benzyl)-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide
6-methyl-N-[4-({2-[(5-methyl-l,3,4-thiadiazol-2-yl)amino]-2-oxoethyl}sulfonyl)benzyl]-
2-oxo-l-[3-(Mfluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide
6-methyl-N-[4-(methylsulfonyl)phenoxy]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
6-methyl-2-oxo-l-(3-trifluoromethyl-phenyl)-l,2-dihydro-pyridine-3-carboxylic acid (4- bromo-phenoxy)-amide 6-methyl-2-oxo-N-phenoxy-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxamide
N-(4-aminobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydroproline-3- carboxamide 6-methyl-N-{4-[(methylsulfonyl)amino]benzyl}-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N-{4-[bis(methylsulfonyl)amino]benzyl}-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-
1 ,2-dihydropyridine-3 -carboxamide
N-[[4-[[(dimethylamino)sulfonyl]amino]phenyl]methyl]-l,2-dihydro-6-methyl-2-oxo-l- [3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide
6-methyl-N- { 4- [methyl(methylsulf onyl)amino]benzyl } -2-oxo- 1 - [3 -
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide
N-[[4-[butyl(methylsulfonyl)amino]phenyl]methyl]-l,2-dihydro-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl]-3-pyridinecarboxamide l,2-dihydro-6-methyl-N-[[4-[(l-methylethyl)(methylsulfonyl)-amino]phenyl]methyl]-2- oxo- 1 - [3 -(trifluoromethyl)phenyl] -3 -pyridinecarboxamide
N- { 4-[(2-methoxyethyl)(methylsulfonyl)amino]benzyl } -6-methyl-2-oxo- 1 -[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide
N- { 4- [(2-cyanoethyl)(methylsulf onyl)amino]benzyl } -6-methyl-2-oxo- 1 - [3- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide •
N- { 4- [ethyl (methylsulfonyl)amino]benzyl } -6-methyl-2-oxo- 1-[3-
(trifluoromethyl)ρhenyl]-l,2-dihydropyridine-3-carboxamide
1 ,2-dihydro-6-methyl-N- [ [4-[(methylsulf onyl)propylamino] -phenyl]methyl] -2-oxo- 1 - [3 -
(trifluoromethyl)phenyl]-3-pyridinecarboxamide N-[[4-[(3-amino-3-oxopropyl)(methylsulfonyl)amino]phenyl]-methyl]-l,2-dihydro-6- methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide l,2-dihydro-6-methyl-N-[[4-[(methylsulfonyl)oxy]phenyl]methyl]-2-oxo-l-[3-
(trifluoromethyl)phenyl]-3-pyridinecarboxamide
2-propanesulfonic acid, 4-[[[[l ,2-dihydro-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]- 3-pyridinyl]carbonyl]amino]methyl]phenyl ester
N-[(l,l-dioxido-2,3-dihydro-l-benzothien-5-yl)methyl]-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide N-[(l,l-dioxido-2,3-dihydro-l-benzothien-5-yl)methyl]-5-iodo-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl] - 1 ,2-dihydropyridine-3-carboxamide
5-iodo-N- { 4-[isopropyl(methylsulf onyl)amino]benzyl } -6-methyl-2-oxo- 1 - [3-
(trifluoromethyl)phenyl] - 1 ,2-dihydropyridine-3 -carboxamide l,2-dihydro-6-methyl-N-[[4-[(methylsulfonyl)methyl]phenyl]-methyl]-2-oxo-l-[3-
(trifluoromethyl)phenyl]-3-pyridinecarboxamide
6-chloro-5-methyl-4-(3-methylphenyl-N-[4-(methylsulfonyl)benzyl]-3-oxo-3,4- dihydropyrazine-2-carboxamide
5-bromo-6-(difluoromethyl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3- (trifluoromethyl)phenyl]-l ,2-dihydropyridine-3-carboxamide
6-(difluoromethyl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-
1 ,2-dihydropyridine-3 -carboxamide
N-(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide 6-methyl-N- [3 -(methylsulf onyl)benzyl] -2-oxo-l-[3- (trifluoromethyl)phenyl] -1,2- dihydropyridine-3-carboxamide
6-methyl-N'- [4-(methylsulf onyl)phenyl] -2-oxo- 1 - [3-(trifluoromethyl)phenyl] -1,2 dihydropyridine-3-carbohydrazide
N'-(4-bromophenyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine- 3-carbohydrazide
N-[(5-methoxy-4-oxo-4H-pyran-2-yl)methyl]-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl]- 1 ,2-dihydropyridine-3-carboxamide
N-(4-cyanobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxamide N-{[3-(4-methoxyphenyl)isoxazol-5-yl]methyl}-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl] - 1 ,2-dihydropyridine-3 -carboxamide
N'-(4-cyanophenyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carbohydrazide
6-methyl-2-oxo-N- [( 1 -phenyl- 1 H-pyrazol-4-yl)methyl] - 1 - [3 -(trifluoromethyl)phenyl] - l,2-dihydropyridine-3-carboxamide
N-(2,3-dihydro-l,4-benzodioxin-2-ylmethyl)-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide 6-methyl-N-{[l-(3-methylphenyl)-lH-pyrazol-4-yl]methyl}-2-oxo-l-[3-
(trifluoromethyl)phenyl] - 1 ,2-dihydropyridine-3 -carboxamide
N'-(4-chlorophenyl)-6-methyl-2-oxo- 1 - [3 -(trifluoromethyl)phenyl] - 1 ,2-dihydropyridine-
3-carbohydrazide 6-methyl-2-oxo-N-[2-(tetrahydro-2H-ρyran-4-yl)ethyl]-l-[3-(trifluoromethyl)ρhenyl]-l,2- dihydropyridine-3-carboxamide
N- [( 1 -ethyl- lH-pyrazol-4-yl)methyl] -6-methyl-2-oxo- 1 - [3-(trifluoromethyl)phenyl] -1,2- dihydropyridine-3-carboxamide
N- [(4-benzylmorpholin-2-yl)methyl] -6-methyl-2-oxo- 1 - [3-(trifluoromethyl)phenyl] -1,2- dihydropyridine-3-carboxamide
6-methyl-N-[3-(2-methylpiperidin-l-yl)propyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide methyl 2-{[({6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridin-3- yl}carbonyl)amino]methyl}-3-furoate 6-methyl-N- [( 1 -methyl- 1 H-pyrazol-4-yl)methyl] -2-oxo- 1 - [3 -(trifluoromethyl)phenyl] -
1 ,2-dihydropyridine-3-carboxamide
N-(3-azeρan-l-ylpropyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
6-methyl-N-(3-morpholin-4-ylpropyl)-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
6-methyl-2-oxo-N-(3-piperidin- 1 -ylpropyl)- 1 - [3-(trifluoromethyl)phenyl] -1,2- dihydropyridine-3-carboxamide
N-[3-(3,5-dimethyl-lH-ρyrazol-l-yl)proρyl]-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl] - 1 ,2-dihydropyridine-3 -carboxamide N-[3-(2-ethylpiperidin-l-yl)propyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
6-methyl-N-[2-(l-methyl-lH-imidazol-5-yl)ethyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-
1 ,2-dihydropyridine-3-carboxamide
N-[(l-ethyl-3-methyl-lH-pyrazol-4-yl)methyl]-6-methyl-2-oxo-l-[3- (trifluoromethyl)phenyl]-l ,2-dihydropyridine-3-carboxamide
N-[4-(acetylamino)benzyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide 6-methyl-2-oxo-N-[3-( lH-pyrazol- 1 -yl)propyl]- 1 -[3-(trifluoromethyl)phenyl]- 1 ,2- dihydropyridine-3-carboxamide
6-methyl-2-oxo-N-(pyridin-2-ylmethyl)-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3 -carboxamide 6-methyl-N-{[l-(4-methylphenyl)-lH-pyrazol-4-yl]methyl}-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide
6-methyl-N'-(4-methylphenyl)-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-
3-carbohydrazide
6-methyl-N- [3 -(4-methylpiperidin- 1 -yl)propyl] -2-oxo- 1 - [3-(trifluoromethyl)phenyl] -1,2- dihydropyridine-3-carboxamide
6-methyl-2-oxo-N-[3-(5-oxo-4,5-dihydro-lH-pyrazol-4-yl)propyl]-l-[3-
(trifluoromethyl)phenyl]- 1 ,2-dihydropyridine-3-carboxamide ethyl 5-methyl-4-{[({6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridin-
3-yl } carbonyl)amino]methyl } -2-furoate N-[(6-fluoro-4H-l,3-benzodioxin-8-yl)methyl]-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl] - 1 ,2-dihydropyridine-3 -carboxamide
6-methyl-2-oxo-N-(2-pyridin-3-ylethyl)-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N-[(l ,3-dimethyl-lH-pyrazol-4-yl)methyl]-6-methyl-2-oxo-l -[3- (trifluoromethyl)phenyl] - 1 ,2-dihydropyridine-3-carboxamide
6-methyl-2-oxo-N-(2-pyridin-4-ylethyl)-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N'-(4-fluorophenyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-
3-carbohydrazide 6-methyl-N-[(l-methyl-lH-ρyrrol-2-yl)methyl]-2-oxo-l-[3-(trifluoromethyl)ρhenyl]-l,2- dihydropyridine-3-carboxamide
6-methyl-2-oxo-N'-phenyl- 1 - [3 -(trifluoromethyl)phenyl] - 1 ,2-dihydropyridine-3 - carbohydrazide
N-[(l-ethyl-5-methyl-lH-pyrazol-4-yl)methyl]-6-methyl-2-oxo-l-[3- (trifluoromethyl)phenyl]- 1 ,2-dihydropyridine-3-carboxamide
6-methyl-N-[2-(l-methyl-lH-imidazol-4-yl)ethyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-
1 ,2-dihydropyridine-3-carboxamide N-[2-(l,3-dioxolan-2-yl)ethyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
N-(l-benzothien-3-ylmethyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide N-[(l,5-dimethyl-lH-pyrazol-4-yl)methyl]-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl] - 1 ,2-dihydropyridine-3-carboxamide
N-[2-(3,5-dimethyl-lH-pyrazoI-4-yl)ethyl]-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide
N-[2-(3,5-dimethylisoxazol-4-yl)ethyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]- 1 ,2-dihydropyridine-3-carboxamide
N-(3 ,4-dihydro- lH-isochromen- l-ylmethyl)-6-methyl-2-oxo- 1-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide
N-{[(2R)-l-ethylpyrrolidin-2-yl]methyl}-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-
1 ,2-dihydropyridine-3-carboxamide 6-methyl-2-oxo-N-[(2R)-tetrahydrofuran-2-ylmethyl]-l-[3-(trifluoromethyl)ρhenyl]-l,2- dihydropyridine-3-carboxamide
5-chloro-N- { 4- [(dimethylamino)sulf onyl]benzyl } -6-methyl-2-oxo- 1 - [3-
(trifluoromethyl)phenyl] - 1 ,2-dihydropyridine-3 -carboxamide
N-{4-[(dimethylamino)sulfonyl]benzyl}-6-methyl-2-oxo-l-[3-(trifluoromethyl)-phenyl]- l,2-dihydropyridine-3-carboxamide
5 -chloro-6-methyl-2-oxo-N- [4-(piperazin- 1 -ylsulf onyl)benzyl] - 1 - [3 -(trifluoro- methyl)phenyl] - 1 ,2-dihydropyridine-3 -carboxamide
6-methyl-2-oxo-N- [4-(piperazin- 1 -ylsulf onyl)benzyl] - 1 - [3-(trifluoromethyl)-phenyl] -1,2- dihydropyridine-3-carboxamide 6-methyl-N- [4-(morpholin-4-ylsulf onyl)benzyl] -2-oxo- 1 - [3-(trifluoromethyl)phenyl] -1,2- dihydropyridine-3-carboxamide
6-methyl-2-oxo-N-[4-(piperidin-l-ylsulfonyl)benzyl]-l~[3-(trifluoromethyl)-phenyl]-l,2- dihydropyridine-3-carboxamide
6-methyl-N- { 4-[(methylamino)sulf onyl]benzyl } -2-oxo- 1 - [3-(trifluoromethyl)-phenyl] -1,2- dihydropyridine-3-carboxamide
6-methyl-2-oxo-N-[4-(pyrrolidin-l-ylsulfonyl)benzyl]-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide 5-chloro-6-methyl-2-oxo-N-[4-(pyrrolidin-l-ylsulfonyl)benzyl]-l-[3-
(trifluoromethyl)phenyl] - 1 ,2-dihydropyridine-3 -carboxamide
5-chloro-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)-phenyl]-
1 ,2-dihydropyridine-3-carboxamide N- { 4- [(acetyl amino)sulfonyl]benzyl } -6-methyl-2-oxo- 1 - [3-(trifluoromethyl)-phenyl] -1,2- dihydropyridine-3-carboxamide
N- [4-(isopropylsulf onyl)benzyl] -5-iodo-6-methyl-2-oxo- 1 - [3 -(trifluoromethyl)phenyl] -1,2- dihydropyridine-3-carboxamide
N-[4-(cyclopropylsulfonyl)benzyl]-5-iodo-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]- l,2-dihydropyridine-3 -carboxamide
1 ,2-dihydro-6-methyl-N- [ [4- [(methylsulf onyl)oxy]phenyl]methyl] -2-oxo- 1 - [3 -
(trifluoromethyl)phenyl]-3-pyridinecarboxarnide
N-[4-(l,l-dioxidoisothiazolidin-2-yl)benzyl]-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl] - 1 ,2-dihydropyridine-3 -carboxamide 6-methyl-2-oxo-N-[[4-(4-pyridinylsulfonyl)phenyl]methyl]-l-[3-(trifluoromethyl)phenyl]-
1 ,2-dihydropyridine-3-carboxamide
6-methyl-2-oxo-N- [4-(phenylsulf onyl)benzyl]- 1 - [3 -(trifluoromethyl)phenyl] -1,2- dihydropyridine-3-carboxamide
6-methyl-2-oxo-N-[4-(l,3-thiazol-2-ylsulfonyl)benzyl]-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
6-methyl-2-oxo-N- [4-(pyrimidin-2-ylsulf onyl)benzyl] - 1 - [3-(trifluoromethyl)phenyl] - 1 ,2- dihydropyridine-3-carboxamide
N-[4-(lH-imidazol-2-ylsulfonyl)benzyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-
1 ,2-dihydropyridine-3-carboxamide 6-methyl-N-{4-[(l-methyl-lH-l,2,4-triazol-5-yl)sulfonyl]benzyl}-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyrichne-3-carboxamide
6-methyl-N-{4-[(5-methyl-l,3-oxazol-4-yl)sulfonyl]benzyl}-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide
6-methyl-N-{[6-(methylsulfonyl)pyridin-3-yl]methyl}-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide
5 -fluoro-6-methyl-N- [4-(methylsulf onyl)benzyl] -2-oxo- 1 - [3 -(trifluoromethyl)phenyl] -1,2- dihydropyridine-3-carboxamide N-[4-(methylsulfonyl)benzyl]-2-oxo-6-(2-oxoethyl)-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
5-ethyl-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide and pharmaceutically 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: reacting a compound of formula (II)
Figure imgf000048_0001
G
1 5 1 2 1 1 wherein R , R , Y , Y , X, G and n are as defined in formula (I) and L represents a leaving group, with an amine of formula (Lπ) or a salt thereof
Figure imgf000049_0001
(III)
4 2 wherein R , G and L are as defined in formula (I),
and where desired or necessary converting the resultant compound of formula (I), or another salt thereof, into a pharmaceutically acceptable salt thereof; or converting one compound of formula (I) into another compound of formula (I); and where desired converting the resultant compound of formula (I) into an optical isomer thereof.
The process is carried out at a suitable temperature, generally between 0 °C and the boiling point of the solvent, in a suitable solvent such as dichloromethane or N-methylpyrrolidinone. The process is optionally carried out in the presence of a base and/or a coupling reagent such as HATU, HO AT, HOBT or DIEA. Suitable leaving groups L include OH and halogen, particularly OH.
1 2 2 3 1 2 3
Compounds of formula (II) wherein Y is CR , Y is CR , L is OH and R and R are both hydrogen can be prepared by condensing a compound of formula (IN)
Figure imgf000049_0002
(IV) wherein R is as defined in formulaa ((II)),, with a compound of formula (N)
Figure imgf000050_0001
(V)
1 5 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 (IN) and (N) 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 (IV) can be prepared according to the methods of S.M Brombridge et al., Synthetic Communications, 1993, 23, 487-494. And compounds of formula (V) can be prepared according to the methods of Igor N. Ukrainets et al., Tetrahedron, 1994, 50, 10331-10338.
1 2 2 3 1 1
Compounds of formula (LT) wherein Y is CR , Y is CR , L is OH and R is hydrogen can be prepared by reacting a compound of formula (NI)
Figure imgf000050_0002
(VI)
1 5 wherein G , R and n are as defined in formula (I), with a compound of formula (VLT)
Figure imgf000051_0001
(VII)
2 3 wherein R or R are as defined in formula (I), at a suitable temperature, such as 160 °C, followed by base promoted cyclisation and acid hydrolysis. Compounds of formula (Nil) can be prepared according to US 3,838,155.
1 2 2 3 1 1 2
Compounds of formula (II) wherein Y is CR , Y is CR , L is OH, R is methyl and R
3 and R are both hydrogen can be prepared by condensing a compound of formula (NIL!)
(R5)n H
(VIII)
1 5 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.
1 1 2 3
Compounds of formula (LI) wherein R is OH, Y is nitrogen and Y is CR can be prepared by condensing a compound of formula (LX)
Figure imgf000052_0001
(IX)
1 5 wherein G , R and n are as defined in formula (I), with a compound of formula (X)
Figure imgf000052_0002
(X)
in the presence of a suitable base, such as sodium ethoxide, at a suitable temperature in a suitable solvent such as ethanol.
A compound of formula (LX) can be prepared from the corresponding isocyanate derivative by treatment with ammonia in acetonitrile.
Salts of compounds of formula (I) may be formed by reacting the free base or a salt, enantiomer, tautomer or protected derivative thereof, with one or more equivalents of the appropriate acid. The reaction may be carried out in a solvent or medium in which the salt is insoluble, or in a solvent in which the salt is soluble followed by subsequent removal of the solvent in vacuo or by freeze drying. Suitable solvents include, for example, water, dioxane, ethanol, 2-propanol, tetrahydrofuran or diethyl ether, or mixtures thereof. The reaction may be a metathetical process or it may be carried out on an ion exchange resin.
Compounds of formula (I) and intermediate compounds thereto may be prepared as such or in protected form. The protection and deprotection of functional groups is, for example, described in 'Protective Groups in Organic Chemistry', edited by J. W. F. McOmie, Plenum Press (1973), and 'Protective Groups in Organic Synthesis', 3rd edition, T. W. Greene & P. G. M. Wuts, Wiley-Interscience (1999).
The compounds of the invention and intermediates may be isolated from their reaction mixtures, and if necessary further purified, by using standard techniques.
The compounds of formula (I) may exist in enantiomeric or diastereoisomeric forms or mixtures thereof, all of which are included within the scope of the invention. The various optical isomers may be isolated by separation of a racemic mixture of the compounds using conventional techniques, for example, fractional crystallisation or HPLC. Alternatively, the individual enantiomers may be made by reaction of the appropriate optically active starting materials under reaction conditions that will not cause racemisation.
Intermediate compounds may also exist in enantiomeric forms and may be used as purified enantiomers, diastereomers, racemates or mixtures thereof.
According to a further aspect of the invention we provide a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a medicament.
The compounds of formula (I), and their pharmaceutically acceptable salts, are useful because they possess pharmacological activity in animals. The compounds of formula (I) have activity as pharmaceuticals, in particular as modulators of human neutrophil elastase and homologous serine proteases such as proteinase 3 and pancreatic elastase, and as such are predicted to be useful in therapy. The compounds of formula (I) are particularly useful as inhibitors of human neutrophil elastase. They may thus be used in the treatment or prophylaxis of inflammatory diseases and conditions.
Examples of these conditions are: adult respiratory distress syndrome (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 tract (especially inflammatory bowel disease, ulcerative colitis, pancreatitis and gastritis); inflammation of the skin (especially psoriasis, eczema, dermatitis); in tumour metastasis or invasion; in disease associated with uncontrolled degradation of the extracellular matrix such as osteoarthritis; in bone resorptive disease (such as osteoporosis and Paget's disease); diseases associated with aberrant angiogenesis; the enhanced collagen remodelling associated with diabetes, periodontal disease (such as gingivitis), corneal 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; HIN 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 neutrophil elastase activity is beneficial which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of inflammatory diseases or conditions; and a method of treating, or reducing the risk of, inflammatory diseases or conditions which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In particular, the compounds of this invention may be used in the treatment of adult respiratory distress syndrome (ARDS), cystic fibrosis, pulmonary emphysema, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, asthma, rhinitis, ischemia-reperfusion injury, rheumatoid arthritis, osteoarthritis, cancer, atherosclerosis and gastric mucosal injury.
Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition. .
For the above mentioned therapeutic indications, the dose of the compound to be administered will depend on the compound employed, the disease being treated, the mode of administration, the age, weight and sex of the patient. Such factors may be determined by the attending physician. However, in general, satisfactory results are obtained when the compounds are administered to a human at a daily dosage of between 0.1 mg/kg to 100 mg/kg (measured as the active ingredient).
The compounds of formula (I) may be used on their own, or in the form of appropriate pharmaceutical formulations comprising the compound of the invention in combination with a pharmaceutically acceptable diluent, adjuvant or carrier. Particularly preferred are compositions not containing material capable of causing an adverse reaction, for example, an allergic reaction. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
According to the invention, there is provided a pharmaceutical formulation comprising preferably less than 95% by weight and more preferably less than 50% by weight of a compound of formula (I) 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 μm, and may be suspended in a propellant mixture with the assistance of a dispersant, such as a C8-C20 fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated 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 known as the Turbuhaler® in which a dosing unit meters the desired dose which is then inhaled by the patient. With this system the active compound, with or without a carrier substance, is delivered to the patient.
For oral administration the active compound may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum, titanium dioxide, and the like. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
For the preparation of soft gelatine capsules, the compound may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above mentioned excipients for tablets. Also liquid or semisolid formulations of the drug may be filled into hard gelatine capsules. Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, 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 procedures
1H NMR and 13C NMR were recorded on a Varian Inova 400 MHz or a Varian ercwry- VX 300 MHz instrument. The central peaks of chloroform-ti (6H 7.27 ppm), dimethylsulfoxide-dtf (δπ 2.50 ppm), acetonitrile-d3 (δπ 1.95 ppm) or methanol--^ (δπ 3.31 ppm) where used as internal references. Low-resolution mass spectra were obtained on an Agilent 100 LC-MS system equipped with an APCI ionisation chamber. 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. Unless otherwise stated, organic solutions were dried using anhydrous Na2SO_j,.
Unless otherwise stated, the following methods were used for HPLC and LC/MS analysis: LC/MS-MethodA
Instrument Agilent 1100; Column Waters Symmetry 2.1 x 30 mm; Mass APCI; Flow rate 0.7 ml/min; Wavelength 254 nm; Solvent A: Water + 0.1% TFA; B: Acetonitrile + 0.1% TFA ; Gradient 15-95%/B 8 min, 95% B 1 min. LC-MethodB Instrument Agilent 1100; Column KR100-5C18 150 x 4.6 mm; Flow rate 1.0 ml/min; Wavelength 220 nm; Solvent A: Water + 0.1% TFA; B: Acetonitrile + 0.1% TFA; Gradient 20-100%/B 8 min, 100% B 2 min.
The following abbreviations are used:
HBTU O-(Benzotriazol-l-yl)-N)N,N ,N -tetramethyluronium hexafluorophosphate
HATU O-(7- Azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
HOBT 1-Hydroxybenzotriazole
HOAT l-Hydroxy-7-azabenzotriazole DLEA N,N-Diisopropylethylamine
NMP l-N-Methyl-2-pyrrolidinone
THF Tetrahydrofuran
TFA Trifluoroacetic acid
Example 1 N-(4-Chlorobenzyl)-l-(4-chlorophenyl')-6-methyl-2-oxo-l,2- dihydropyridine-3-carboxamide
a Ethyl 3-r(4-chlorophenyl)aminol-3-oxopropanoate
The title compound was prepared essentially as described by I. V. Ukrainets et al., Tetrahedron, 1994, 50, 10331-10338. b) Ethyl 1 -(4-chlorophenv -6-methyl-2-oxo-l .2-dihvdropyridine-3-carboxylate
A mixture of ethyl 3-[(4-chlorophenyl)amino]-3-oxopropanoate (1 g, 4 mmol), 4-methoxy- 3-buten-2-one (0.42 g, 4.2 mmol) and sodium methoxide (0.22 g, 4.1 mmol) in ethanol (10 ml) was heated to reflux for 5 h. After cooling, the solvent was evaporated off. The residue was chromatographed on silica using heptane/ethyl acetate (1:1 to 1:5) as eluent, affording the title compound (297 mg, 25%).
1H NMR (CDC13): δ 8.17 (IH, d); 7.49 (2H, d); 7.13 (2H, d); 6.21 (IH, d); 4.34 (2H, q); 2.03 (3H, s); 1.35 (3H, t). c) l-(4-Chlorophenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3-carboxylic acid Ethyl l-(4-chlorophenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3-carboxylate (297 mg, 1.0 mmol) was dissolved in a mixture of IM sodium hydroxide solution (6 ml) and THF (5 ml). The reaction mixture was stirred for 2.5 h at room temperature, then acidified to pH 2 using 5M hydrochloric acid, and then extracted with dichloromethane. The combined organic phases were washed with water, dried, filtered and evaporated to give the title compound (268 mg, 100%).
1H NMR (CDCI3): δ 8.51 (IH, d); 7.59 (2H, d); 7.18 (2H, d); 6.53 (IH, d); 2.15 (3H, s). d) N-(4-Chlorobenzyl)-l-(4-chlorophenylV6-methyl-2-oxo-1.2-dihvdropyridine-3- carboxamide
A mixture of l-(4-chlorophenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3-carboxylic acid (100 mg, 0.38 mmol), HBTU (59 mg, 0.42 mmol), HOBT (64 mg, 0.42 mmol) and DIEA (195 μl, 1.14 mmol) in NMP (1 ml) was added to 4-chlorobenzylamine (108 mg, 0.76 mmol) in NMP (0.5 ml). The reaction mixture was stirred for 18 h. The solvent was evaporated off and the residue was purified using preparative HPLC to give the title compound (60 mg, 41%). 1H NMR (CDC13): δ 9.91 (IH, brs); 8.54 (IH, d); 7.53 (2H, d); 7.24 (4H, s); 7.13 (2H, d); 6.42 (IH, d); 4.53 (2H, d); 2.07 (3H, s).
Using the general method described in Example 1, the compounds of Examples 1.1 to 1.27 were prepared:
Example 1.1 6-Methyl-N-[4-(methylsulfonyllbenzyll-2-oxo-l-[3-
(trifluoromethyllphenyll-l,2-dihydropyridine-3-carboxamide
1H NMR (CDC13): δ 9.96 (IH, t); 8.57 (IH, d); 7.85 (2H, d); 7.80 (IH, d); 7.73 (IH, t);
7.50 (3H, brd); 7.42 (IH, d); 6.46 (IH, d); 4.65 (2H, d); 3.00 (3H, s); 2.07 (3H, s).
Example 1.2 6-Methyl-N-(4-morpholin-4-ylbenzyl)-2-oxo- 1-T3-
(trifluoromethvDphenyll-1.2-dihydropyridine-3-carboxamide
1H NMR (DMSO-d6): δ 9.69 (IH, brt); 8.38 (IH, d); 7.89-7.87 (2H, m); 7.79 (IH, t); 7.70 (IH, d); 7.15 (2H, d); 6.87 (2H, d); 6.62 (IH, d); 4.36 (2H, d); 3.72-3.69 (4H, m) 3.05- 3.03; (4H, m); 2.00 (3H, s). APCI-MS m/z: 472 [MH+].
Example 1.3 6-Methyl-N-[4-(methylsulfonyl)phenyll-2-oxo-l-r3-
(trifluoromethyDphenyl1-l,2-dihvdropyridine-3-carboxamide 1H NMR (CDC13): δ 12.00 (IH, s); 8.66 (IH, d); 7.92-7.85 (5H, m); 7.79 (IH, t); 7.56 (IH, s); 7.49 (IH, d); 6.55 (IH, d); 3.04 (3H, s); 2.13 (3H, s). APCI-MS m/z: 451[MH+].
Example 1.4 N-[4-(Dimethylamino)benzyl1-6-methyl-2-oxo-l-[3- (trifluoromethyπphenyll-l.Σ-dihydropyridine-S-carboxamide
1HNMR (CDCI3): δ 9.67 (IH, brs); 8.57 (IH, d); 7.78 (IH, d); 7.71 (IH, t); 7.49 (IH, s);
7.41 (IH, d); 7.21 (2H, brd); 6.72 (2H, brs); 6.43 (IH, d); 4.50 (2H, d); 2.91 (6H, s); 2.05 (3H, s).
Example 1.5 N- [4-( Aminosulf onvDbenzyl] -6-methyl-2-oxo- 1 - [3 -
(trifluoromethyl)phenyl1-l,2-dihvdJopyri(]ine-3-carboxamide
1H NMR (DMSO-ds): δ 9.89 (IH, brs); 8.37 (IH, d); 7.91 (IH, s); 7.89 (IH, d); 7.80 (IH, t); 7.75 (2H, d); 7.72 (IH, d); 7.45 (2H, d); 7.27 (2H, s); 6.62 (IH, d); 4.54 (2H, s); 2.02
(3H, s).
Example 1.6 N-(4-MethoxybenzylV6-methyl-2-oxo-l-[3-
(trifluoromethvDphenyl1-l,2-dihvdropyridine-3-carboxamide
1HNMR (CDCI3): δ 9.72 (IH, brs); 8.59 (IH, d); 7.79 (IH, d); 7.72 (IH, t); 7.49 (IH, s);
7.42 (IH, d); 7.24 (2H, d); 6.82 (2H, d); 6.44 (IH, d); 4.52 (2H, d); 3.76 (3H, s); 2.05 (3H, S).
Example 1.7 N-Benzyl-6-methyl-2-oxo-l-[3-(trifluoromethvDphenyll-1.2- dihvdropyridine-3-carboxamide
1H NMR (CDCI3): δ 9.85 (IH, brs); 8.62 (IH, d); 7.81 (IH, d); 7.74 (IH, t); 7.52 (IH, s); 7.44 (IH, d); 7.36-7.21 (5H, m); 6.47 (IH, d); 4.61 (2H, d); 2.08 (3H, s). Example 1.8 N-(4-Chlorobenzyl)-l-(2-fluoro-5-methylphenyl)-6-methyl-2-oxo-
1.2-dihvdropyridine-3 -carboxamide
1H NMR (CD3OD): δ 8.48 (IH, d); 7.40-7.36 (IH, m); 7.30 (4H, s); 7.25 (IH, t); 7.19 (IH, dd); 6.62 (IH, d); 4.56 (2H, q); 2.39 (3H, s); 2.13 (3H, s).
Example 1.9 N-(3-Chlorobenzyl)-l-(2-fluoro-5-methylphenylV6-methyl-2-oxo-
1.2-dihydropyridine-3-carboxamide
1H NMR (CD3OD): δ 8.48 (IH, d); 7.40-7.36 (IH, m); 7.33-7.32 (IH, m); 7.29-7.22 (4H, m); 7.20 (IH, dd); 6.62 (IH, d); 4.57 (2H, q); 2.39 (3H, s); 2.13 (3H, s).
Example 1.10 l-(2-Fluoro-5-methylphenyl)-N-(4-methoxybenzyl)-6-methyl-2-oxo-
1 ,2-dihvdropyridine-3-carboxamide
1H NMR (CD3OD): δ 8.48 (IH, d); 7.40-7.36 (IH, m); 7.27-7.21 (3H, m); 7.02 (IH, dd); 6.86 (2H, d); 6.62 (IH, d); 4.50 (2H, q); 3.75 (3H, s); 2.39 (3H, s); 2.12 (3H, s). APCI-MS m z: 381 [MH+].
Example 1.11 N-(4-MethoxybenzylH-(3-methoxyphenyl)-6-methyl-2-oxo-l,2- dihvdropyridine-3-carboxamide 1H NMR (CDC13): δ 9.86 (IH, brs); 8.54 (IH, d); 7.45 (IH, t); 7.23 (2H, d); 7.04-7.01 (IH, m); 6.80 (2H, d); 6.78-6.75 (IH, m); 6.70 (IH, t); 6.39 (IH, d); 4.51 (2H, d); 3.82 (3H, s); 3.76 (3H, s); 2.09 (3H, s). APCI-MS m/z: 379 [MH+].
Example 1.12 N-(3-Chlorobenzyl)-l-(3-methoxyphenyl)-6-methyl-2-oxo-l,2- dihvdropyridine-3-carboxamide
1H NMR (CDC13): δ 10.00 (IH, brs); 8.55 (IH, d); 7.47 (IH, t); 7.30 (IH, brs); 7.19 (3H, brs); 7.05-7.01 (IH, m); 6.80-6.75 (IH, m); 6.72 (IH, t); 6.41 (IH, d); 4.55 (2H, d); 3.83 (3H, s); 2.11 (3H, s). Example 1.13 N-(4-Chlorobenzyl)- 1 -(3-methoxyphenyl)-6-methyl-2-oxo- 1 ,2- dihvdropyridine-3-carboxamide
1H NMR (CDCI3): δ 10.00 (IH, brs); 8.56 (IH, d); 7.48 (IH, t); 7.28 (4H, s); 7.07-7.03 (IH, m); 6.81-6.77 (IH, m); 6.73 (IH, t); 6.41 (IH, d); 4.56 (2H, d); 3.85 (3H, s); 2.12 (3H, s).
Example 1.14 N- [4-( Aminosulf ony benz yll - 1 -(3 -chlorophenyl V6-methyl-2-oxo-
1 ,2-dihydropyridine-3-carboxamide
1H NMR (CDC13): δ 9.99 (IH, t); 8.55 (IH, d); 7.84 (2H, d); 7.53-7.49 (2H, m); 7.46 (IH, d); 7.25-7.24 (IH, m); 7.14-7.10 (IH, m); 6.44 (IH, d); 4.72 (2H, brs); 4.64 (2H, d); 2.10 (3H, s).
Example 1.15 N-(4-Chlorobenzyl)-l-(3-chloro-4-methylphenyl')-6-methyl-2-oxo-
1 ,2-dihydropyridine-3-carboxamide 1H NMR (CDC13): δ 9.93 (IH, brs); 8.56 (IH, d); 7.44 (IH, d); 7.28 (4H, s); 7.24 (IH, d); 7.03 (IH, dd); 6.43 (IH, d); 4.56 (2H, d); 2.46 (3H, s); 2.12 (3H, s).
Example 1.16 l-(3-Chloro-4-methylphenyl)-N-(4-methoxybenzyl')-6-methyl-2- oxo- 1 ,2-dihvdropyridine-3-carboxamide 1H NMR (CDC13): δ 9.80 (IH, brs); 8.54 (IH, d); 7.40 (IH, d); 7.23 (2H, d); 7.20 (IH, d); 7.00 (IH, dd); 6.81 (2H, d); 6.39 (IH, d); 4.51 (2H, d); 3.76 (3H, s); 2.43 (3H, s); 2.09 (3H, s).
Example 1.17 N-(4-Chlorobenzyl -l-(2.3-dimethylρhenylV6-methyl-2-oxo-1.2- dihydropyridine-3-carboxamide
1H NMR (CDC13): δ 10.04 (IH, brs); 8.58 (IH, d); 7.31-7.24 (6H, m); 6.96-6.94 (IH, m); 6.45 (IH, d); 4.63-4.50 (2H, m); 2.38 (3H, s); 2.03 (3H, s); 1.95 (3H, s).
Example 1.18 N-(4-Chlorobenzy -l-(3-chloro-4-fluorophenyl')-6-methyl-2-oxo- 1 ,2-dihvdropyridine-3-carboxamide 1H NMR (CDC13): δ 9.83 (IH, brs); 8.57 (IH, d); 7.38-7.32 (2H, m); 7.27 (4H, s); 7.15- 7.11 (IH, m); 6.45 (IH, d); 4.57 (2H, d); 2.12 (3H, s). APCI-MS m/z: 405.1, 407 [MH+].
Example 1.19 l-(3-Chloro-4-fluorophenyl)-N-(4-methoxybenzyl)-6-methyl-2-oxo-
1.2-dihvdropyri(une-3-carboxamide
1H NMR (CDC13): δ 9.72 (IH, brs); 8.58 (IH, d); 7.39-7.31 (2H, m); 7.26 (2H, d); 7.14- 7.10 (IH, m); 6.84 (2H, d); 6.43 (IH, d); 4.54 (2H, d); 3.79 (3H, s); 2.11 (3H, s).
Example 1.20 N-(4-ChlorobenzylVl-(3-ethylphenylV6-methyl-2-oxo-1.2- dihydropyridine-3-carboxamide
1H NMR (CDC13): δ 10.03 (IH, brs); 8.56 (IH, d); 7.49 (IH, t); 7.36 (IH, d); 7.28 (4H, s); 7.02 (2H, d); 6.42 (IH, d); 4.61-4.50 (2H, m); 2.75 (2H, q); 2.09 (3H, s); 1.29 (3H, t).
Example 1.21 l-(3-Bromophenyl)-N-(4-chlorobenzyl)-6-methyl-2-oxo-1.2- dihvdropyridine-3-carboxamide
1H NMR (CDC13): δ 9.86 (IH, brs); 8.55 (IH, d); 7.67-7.64 (IH, m); 7.45 (IH, t); 7.39 (IH, t); 7.25 (4H, s); 7.17-7.15 (IH, m); 6.42 (IH, d); 4.54 (2H, d); 2.09 (3H, s). APCI-MS m/z: 431.1, 433 [MH+].
Example 1.22 l-(3-Bromophenyl -N-(4-methoxybenzyl)-6-methyl-2-oxo-l,2- dihvdropyridine-3-carboxamide
1H NMR (CDC13): δ 9.74 (IH, brs); 8.55 (IH, d); 7.65-7.63 (IH, m); 7.44 (IH, t); 7.38 (IH, t); 7.23 (2H, d); 7.16-7.14 (IH, m); 6.81 (2H, d); 6.40 (IH, d); 4.52 (2H, d); 3.76 (3H, s); 2.07 (3H, s).
Example 1.23 N-(2.3-Dihvdro-l-benzofuran-5-ylmethylV6-methyl-2-oxo-l-[3-
(trifluoromethyl phenyl1-l,2-αihydropyridine-3-carboxamide 1H NMR (CDCI3): δ 9.70 (IH, brs); 8.59 (IH, d); 7.79 (IH, d); 7.73 (IH, t); 7.50 (IH, s);
7.43 (IH, d); 7.17 (IH, s); 7.05 (IH, d); 6.69 (IH, d); 6.44 (IH, d); 4.56-4.50 (4H, m); 3.16
(2H, t); 2.06 (3H, s).
APCI-MS m/z: 429 [MH+].
Example 1.24 6-Methyl-2-oxo-N-[3-('2-oxopyrrolidin-l-yl')propyll-l-[3-
(trifluoromethyl)phenyll - 1 ,2-dihydropyridine-3 -carboxamide
1H NMR (CDCI3): δ 9.55 (IH, brs); 8.55 (IH, d); 7.82 (IH, d); 7.75 (IH, t); 7.52 (IH, s);
7.45 (IH, d); 6.45 (IH, d); 3.44-3.33 (6H, m); 2.38 (2H, t); 2.05-1.98 (2H, m); 2.08 (3H, s); 1.86-1.79 (2H, m).
APCI-MS m/z: 422 [MH+].
Example 1.25 N-(4-Bromobenzyl')-6-methyl-2-oxo-l-[3-(trifluoromethyl')phenyn-
1.2-dιhydropyridine-3-carboxamide 1H NMR (CDCI3): δ 9.84 (IH, brs); 8.58 (IH, d); 7.81 (IH, d); 7.73 (IH, t); 7.51 (IH, s); 7.43 (IH, d); 7.41 (2H, d); 7.20 (2H, d); 6.46 (IH, d); 4.59-4.49 (2H, m); 2.08 (3H, s). APCI-MS m/z: 465.1, 467 [MH+].
Example 1.26 N-(4-Chlorophenyl)-6-methyl-2-oxo-l-[3-(trifluoromethy phenyll- 1.2-dihvdropyridine-3 -carboxamide APCI-MS m/z: 407 [MH+].
Example 1.27 6-Methyl-2-oxo-l-[3-(trifluoromethyl)phenyn-l,2-dihvdropyridine-
3-carboxamide APCI-MS m/z: 297 [MH+].
Example 2 N-(4-Methoxybenzyl)-6-methyl-2-oxo-l-phenyl- 2- dihydropyridine-3-carboxamide
a) 6-Methyl-2-oxo-l -phenyl- 1 ,2-dihydropyridine-3-carbonitrile A mixture of cyanoacetanilide (0.80 g, 5 mmol), 4-methoxy-3-buten-2-one (1 g, 10 mmol) and l,4-diazabicyclo[2,2,2]octane (0.55 g, 5 mmol) in diethyleneglycol monomethylether was heated to 125 °C for 5 h. The reaction mixture was partitioned between dichloromethane (100 ml) and 2M hydrochloric acid (100 ml). The organic layer was separated, washed with water, dried, filtered and evaporated. The residue was chromatographed on silica using heptane/ethyl acetate (1:1) as eluent, affording the title compound (660 mg, 63%).
1H NMR (CDC13): δ 7.78 (IH, d); 7.52 (3H, m); 7.17 (2H, dd); 6.22 (IH, d); 2.06 (3H, s). b 6-Methyl-2-oxo-l-phenyl-1.2-dihydropyridine-3-carboxylic acid 6-Methyl-2-oxo-l-phenyl-l,2-dihydropyridine-3-carbonitrile (300 mg, 1.4 mmol) was dissolved in 2.5M sulphuric acid (10 ml). The mixture was heated to 100 °C for 16 h. After cooling, the solution was poured into water and made alkaline with 5M sodium hydroxide solution. The water phase was washed with dichloromethane, then acidified to pH 2-3 using 2M hydrochloric acid. The acidified water phase was extracted with dichloromethane, dried, filtered and evaporated to give the title compound (300 mg, 92%).
1H NMR (CDC13): δ 13.96 (IH, s); 8.50 (IH, d); 7.59 (3H, m); 7.23 (2H, dd); 6.53 (IH, d); 2.13 (3H, s). c) N-(4-Methoxybenzyl)-6-methyl-2-oxo-l-phenyl-1.2-dihvdropyridine-3-carboxamide The title compound was prepared from 6-methyl-2-oxo-l -phenyl- 1,2-dihy dropyridine-3- carboxylic acid and 4-methoxybenzylamine by a method analogous to that described in Example 1 step (d).
1H NMR (CDCI3): δ 9.87 (IH, brs); 8.56 (IH, brd); 7.52 (3H, m); 7.23 (2H, d); 7.18 (2H, d); 6.79 (2H, d); 6.40 (IH, d); 4.51 (2H, d); 3.75 (3H, s); 2.04 (3H, s).
The compounds of Examples 2.1 to 2.174 were prepared by a method analogous to that described in Example 1 or 2.
Example 2.1 N-(4-ChlorobenzylV6-methyl-2-oxo-l-phenyl-l,2-dihydropyridine- 3-carboxamide 1H NMR (CDCI3): δ 9.96 (IH, s); 8.54 (IH, d); 7.54 (3H, m); 7.23 (4H, s); 7.18 (2H, d); 6.41 (IH, d); 4.54 (2H, d); 2.06 (3H, s).
Example 2.2 N-(4-ChlorobenzylV 1 -(3.5-dimethylphenyl)-6-methyl-2-oxo-l .2- dihvdropyridine-3-carboxamide
1HNMR (CDCI3): δ 10.01 (IH, brs); 8.52 (IH, d); 7.23 (4H, s); 7.11 (IH, s); 6.78 (2H, s); 6.38 (IH, d); 4.53 (2H, d); 2.36 (6H, s); 2.07 (3H, s).
Example 2.3 N-[4-(AminosulfonyDbenzvn-l-(3,5-dimethylphenyl)-6-methyl-2- oxo- 1.2-dihydropyridine-3-carboxamide
1H NMR (CDCI3): δ 10.14 (IH, brs); 8.51 (IH, d); 7.82 (2H, d); 7.45 (2H, d); 7.12 (IH, s); 6.79 (2H, s); 6.41 (IH, d); 4.72 (2H, s); 4.62 (2H, d); 2.36 (6H, s); 2.09 (3H, s).
Example 2.4 l-(3,5-Dimethylphenyl)-N-(4-methoxybenzyl)-6-methyl-2-oxo-1.2- dihydropyridine-3-carboxamide
1H NMR (C CI3): δ 9.90 (IH, brs); 8.54 (IH, d); 7.24 (2H, s); 7.11 (IH, s); 6.81 (2H, d); 6.79 (2H, s); 6.38 (IH, d); 4.52 (2H, d); 3.77 (3H, s); 2.37 (6H, s); 2.07 (3H, s).
Example 2.5 N-Benzyl-l-(3,5-dimethylρhenyl)-6-methyl-2-oxo-l,2- dihydropyridine-3-carboxamide
1H NMR (CDCI3): δ 9.98 (IH, brs); 8.57 (IH, d); 7.36-7.19 (5H, m); 7.13 (IH, s); 6.82 (2H, s); 6.41 (IH, d); 4.61 (2H, d); 2.39 (6H, s); 2.10 (3H, s).
Example 2.6 N-(4-Chlorobenzyl)-6-methyl- 1 -(3 -methylphen yl)-2-oxo- 1 ,2- dihvdropyridine-3-carboxamide
1H NMR (CD3OD): δ 8.46 (IH, d); 7.47 (IH, t); 7.36 (IH, d); 7.30 (4H, s); 7.10 (IH, s); 7.06 (IH, d); 6.60 (IH, d); 4.56 (2H, s); 2.42 (3H, s); 2.09 (3H, s). APCI-MS m/z: 367 [MH+]. Example 2.7 N-(4-Methoxybenzyl')-6-methyl-l-(3-methylphenyl')-2-oχo-1.2- dihvdropyridine-3-carboxamide
1H NMR (CD3OD): δ 8.45 (IH, d); 7.44 (IH, t); 7.33 (IH, d); 7.22 (2H, d); 7.07 (IH, s);
7.03 (IH, d); 6.84 (2H, d); 6.58 (IH, d); 4.49 (2H, s); 3.74 (3H, s); 2.41 (3H, s); 2.07 (3H, S).
APCI-MS m/z: 363 [MH+].
Example 2.8 N-f 3-Chlorobenzyl V6-methyl- 1 -(3-methylphenyl)-2-oxo- 1.2- dihvcfropyrichne-3-c-ιrboxamide 1H NMR (CD3OD): δ 8.46 (IH, d); 7.46 (IH, t); 7.35 (IH, d); 7.32-7.21 (4H, m); 7.10 (IH, s); 7.06 (IH, d); 6.60 (IH, d); 4.56 (2H, s); 2.42 (3H, s); 2.09 (3H, s).
Example 2.9 N-(4-ChlorobenzylVl-(3-chlorophenylV6-methyl-2-oxo-l,2- dihydropyridine-3-carboxamide 1H NMR (DMSO-d6): δ 9.86 (IH, t); 8.35 (IH, d); 7.59-7.58 (3H, m); 7.39-7.29 (5H, m); 6.60 (IH, d); 4.46 (2H, d); 2.04 (3H, s). APCI-MS m/z: 387.1, 389 [MH+].
Example 2.10 N-(3-Chlorobenzyl -l-(3-chlorophenylV6-methyl-2-oxo-1.2- dihy(iropyridine-3-carboxamide
1H NMR (DMSO-d6): δ 9.88 (IH, t); 8.36 (IH, d); 7.59-7.58 (3H, m); 7.39-7.32 (4H, m); 7.25 (IH, d); 6.60 (IH, d); 4.48 (2H, d); 2.04 (3H, s). APCI-MS m/z: 387.1, 389 [MH+].
Example 2.11 1 -(3-Chlorophenyl)-N-(4-methoχybenzyl)-6-methyl-2-oxo- 1 ,2- dihydropyridine-3-carboxamide
1H NMR (DMSO-d6): δ 9.73 (IH, t); 8.34 (IH, d); 7.56 (2H, d); 7.34-7.31 (IH, m); 7.19 (2H, d); 6.85 (2H, d); 6.58 (IH, d); 6.60 (IH, d); 4.38 (2H, d); 3.69 (3H, s); 2.01 (3H, s). APCI-MS m/z: 383 [MH+]. Example 2.12 Methyl 4-rfl [l-(3-chlorophenyl -6-methyl-2-oxo-l,2- dihvdropyridin-3-yncarbonyl I amino)methvnbenzoate
1H NMR (DMSO-d6): δ 9.92 (IH, t); 8.36 (IH, d); 7.91 (2H, d); 7.60-7.58 (3H, m); 7.41 (2H, d); 7.38-7.35 (IH, m); 6.60 (IH, d); 4.56 (2H, d); 3.83 (3H, s); 2.04 (3H, s). APCI-MS m/z: 411 [MH+] .
Example 2.13 4-[({[l-G-ChlorophenylV6-methyl-2-oxo-1.2-dihvdropyridin-3- vncarbonyl I amino methyl]benzoic acid
1H NMR (DMSO-d6): δ 12.82 (IH, brs); 9.91 (IH, t); 8.36 (IH, d); 7.88 (2H, d); 7.59-7.58 (3H, m); 7.39 (2H, d); 7.38-7.35 (IH, m); 6.60 (IH, d); 4.55 (2H, d); 2.04 (3H, s). APCI-MS m/z: 397 [MH+].
Example 2.14 1 -(3-Cyanophenyl)-N-(cvclohexylmethylV 6-methyl-2-oxo- 1.2- dihydropyridine-3-carboxamide APCI-MS m/z: 350 [MH+].
Example 2.15 l-(3-CvanophenylVN-(2-furylmethyl')-6-methyl-2-oxo-1.2- dihydropyridine-3-carboxamide
APCI-MS m/z: 334 [MH+].
Example 2.16 1 -(3-Cvanophenyl)-6-methyl-2-oxo-N-(pyridin-3- ylmethylV 1.2- dihvdropyridine-3-carboxamide
APCI-MS m/z: 345 [MH+].
Example 2.17 N-Benzyl-l-(3-cyanophenyl)-6-methyl-2-oxo-1.2-dihvdropyridine-
3-carboxamide APCI-MS m/z: 344 fMH+l Example 2.18 l-(3-CvanophenylVN-2.3-dihvdro-lH-inden-l-yl-6-methyl-2-oxo-
1 ,2-dihydropyridine-3-carboxamide APCI-MS m/z: 370 [MH+].
Example 2.19 l-(3-CvanophenylVN-(2-methoxybenzyl)-6-methyl-2-oxo-l,2- dihydropyridine-3-carboxamide
APCI-MS m/z: 374 [MH+].
Example 2.20 l-(3-CvanophenylV6-methyl-2-oxo-N-(3.4.5-trimethoxybenzvD-1.2- dihydropyridine-3-carboxamide APCI-MS m/z: 434 [MH+].
Example 2.21 l-(3-CyanophenylVN-(2,5-dimethoxybenzyl)-6-methyl-2-oxo-l,2- dihydropyridine-3-carboxamide APCI-MS m/z: 404 [MH+] .
Example 2.22 l-(3-CyanophenylVN-(3.4-cUmethoxybenzyll-6-methyl-2-oxo-l,2- dihydropyridine-3-carboxamide
APCI-MS m/z: 404 [MH+].
Example 2.23 l-(3-CvanophenvD-N-[(l-ethylpyrrolidin-2-vnmethvn-6-methyl-2- oxo-1.2-dihvdropyridine-3-carboxamide
APCI-MS m/z: 365 [MH+].
Example 2.24 N-(4-ChlorobenzylVl-(3-cyanophenylV6-methyl-2-oxo-l,2- dihvdropyridine-3-carboxamide APCI-MS m/z: 378 [MH+].
Example 2.25 1 -('3-CvanophenylVN-(4-methoxybenzyl')-6-methyl-2-oxo- 1.2- dihydropyridine-3-carboxamide APCI-MS m/z: 374 [MH+].
Example 2.26 N-(3-Chlorobenzviy 1 -(3-cyanophenyl)-6-methyl-2-oxo- 1 ,2- dihvdropyridine-3-carboxamide APCI-MS m/z: 378 [MH+].
Example 2.27 1 -(3-Cvanophenyl V6-methyl-2-oxo-N-(thien-2-ylmethylV 12- dihydropyridine-3-carboxamide
APCI-MS m/z: 350 [MH+].
Example 2.28 1 -(3-Cyanophenyl)-N-(cvclopropylmethyl >-6-methyl-2-oxo- 12- dihvdropyridme-3-carboxamide
APCI-MS m/z: 308 [MH+].
Example 2.29 1 -(3-Cyanophenyl)-N-(3-methoxybenzyl)-6-methyl-2-oxo- 12- dihydropyridine-3-carboxamide APCI-MS m/z: 374 [MH+].
Example 2.30 1 -(3-Cyanophenyl)-6-methyl-2-oxo-N-(pyridin-4-ylmethyl')- 12- dihvdropyridine-3-carboxamide APCI-MS m/z: 345 [MH+].
Example 2.31 l-(3-Cyanophenyl)-N-[2-(3.4-dimethoxyphenyl)ethyl]-6-methyl-2- oxo-l,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 417 [MH+].
Example 2.32 l-(3-CvanophenylV6-methyl-N-r2-(l-methylpyrrolidin-2-yl)ethyn-
2-oxo-l,2-dihvdropyridine-3-carboxamide
APCI-MS m/z: 365 [MH+]. Example 2.33 N-r2-(3-Chlorophenvnethyll-lA3-cyanoρhenylV6-methyl-2-oxo-
1 ,2-dihydropyridine-3-carboxamide APCI-MS m/z: 392 [MH+].
Example 2.34 l-(3-CvanophenylV6-methyl-2-oxo-N-(2-pyridin-2-ylethyl -1.2- dihvdropyridine-3-carboxamide APCI-MS m/z: 359 [MH+].
Example 2.35 N-[2-('4-Chloroρhenyl')ethyll-l-(3-cvanophenylV6-methyl-2-oxo- 1.2-dihvdropyridine-3-carboxamide APCI-MS m/z: 392 [MH+].
Example 2.36 1 -(3 -C yanophenylVN- [2-(2-methoxyphenyl)ethyl] -6-methyl-2-oxo-
1 ,2-dihydropyridine-3-carboxamide APCI-MS m/z: 388 [MH+].
Example 2.37 N-r2-(2-Chlorophenyl')ethvn-l-(3-cyanophenyl')-6-methyl-2-oxo-
1 ,2-dihvdropyridine-3 -carboxamide APCI-MS m/z: 392 [MH+].
Example 2.38 l-(3-Cyanophenyl')-N-[2-(3-methoxyphenyl)ethyll-6-methyl-2-oxo-
1.2-dihvdropyridine-3-carboxamide APCI-MS m/z: 388 [MH+].
Example 2.39 l-(3-Cvanoρhenyl)-N-r2-(4-fluoroρhenvDethyll-6-methyl-2-oxo-1.2- dihvdropyridine-3-carboxamide APCI-MS m/z: 376 [MH+].
Example 2.40 l-(3-CvanophenylVN-r2-(2.4-dichlorophenvDethyll-6-methyl-2- oxo- 1.2-dihvdropyridine-3-carboxamide APCI-MS m/z: 426 [MH+].
Example 2.41 l-(3-CvanoρhenylVN-r2- 3-f1uorophenyltethyll-6-methyl-2-oxo-1.2- dihvdropyridine-3-carboxamide APCI-MS m/z: 376 [MH+].
Example 2.42 l-(3-CvanophenylVN-r2-r2-fluorophenvnethyll-6-methyl-2-oxo-1.2- dihvdropyridine-3-carboxamide
APCI-MS m/z: 376 [MH+].
Example 2.43 1 -(3-Cyanophenyl)-N-(2-cyclohex- 1 -en- 1 - ylethyl)-6-methyl-2-oxo-
1 ,2-dihydropyridine-3-carboxamide APCI-MS m/z: 362 [MH+].
Example 2.44 N-r2-(4-Bromophenyl)ethyl]-l-(3-cyanophenylV6-methyl-2-oxo-
1.2-dihydropyridine-3-carboxamide APCI-MS m/z: 438 [MH+].
Example 2.45 N-(3-Bromobenzyl)- 1 -(3-cyanophenyl)-6-methyl-2-oxo- 1.2- dihvdropyridine-3-carboxamide APCI-MS m/z: 424 [MH+].
Example 2.46 N-(4-Bromobenzyl)-l-(3-cyanophenyl)-6-methyl-2-oxo-1.2- dihydropyridine-3-carboxamide APCI-MS m/z: 424 [MH+].
Example 2.47 N-(2-Bromobenz yl)- 1 -(3 -c yanophen ylV6-methyl-2-oxo- 1.2- dihydropyridine-3-carboxamide
APCI-MS m/z: 424 [MH+]. Example 2.48 l-(3-Cvanophenv -N-(3.4-dihvdro-2H-pyran-2-ylmethylV6-methyl-
2-oxo- 1 ,2-dihydropyridine-3-carboxamide APCI-MS m/z: 350 [MH+].
Example 2.49 l-(3-Cvanophenyl -6-methyl-N-(4-methylbenzylV2-oxo-1.2- dihydropyridine-3-carboxamide
APCI-MS m/z: 358 [MH+].
Example 2.50 l-(3-CvanoρhenylV6-methyl-N-(l-naphthylmethvn-2-oxo-l,2- dihydropyridine-3-carboxamide APCI-MS m/z: 394 [MH+].
Example 2.51 l-("3-Cvanophenyl -N-(2-ethoxybenzyl)-6-methyl-2-oxo-1.2- dihydropyridine-3-carboxamide APCI-MS m/z: 388 [MH+].
Example 2.52 l-(3-Cyanophenyl -6-methyl-N-[4-(methylsulfonyl)benzyl1-2-oxo-
1 ,2-dihydropyridine-3 -carboxamide APCI-MS m/z: 422 [MH+].
Example 2.53 l-(3-Cyanophenyl)-6-methyl-N-(3-methylbenzyl')-2-oxo-1.2- dihydropyridine-3-carboxamide APCI-MS m/z: 358 [MH+].
Example 2.54 l-(3-Cvanophenyl)-N-(4-fluorobenzyl)-6-methyl-2-oxo-l,2- dihydropyridine-3-carboxamide APCI-MS m/z: 362 [MH+].
Example 2.55 N-(1.3-Benzodioxol-5-ylmethyl)-l-(3-cyanophenyl)-6-methyl-2- oxo-l,2-dihydropyridine-3-carboxamide APCI-MS m/z: 388 [MH+].
Example 2.56 l-(3-CvanophenylVN-(2.4-dichlorobenzylV6-methyl-2-oxo-1.2- dihydropyridine-3-carboxamide
.+,
APCI-MS m/z: 412 [MH ]
Example 2.57 l-("3-CvanoρhenylV6-methyl-N-(2-methylbenzyl -2-oxo-1.2- dihvdropyridine-3-carboxamide
APCI-MS m/z: 358 [MH+].
Example 2.58 l-(3-CvanophenylVN-(3.4-difluorobenzyl)-6-methyl-2-oxo-1.2- dihydropyridine-3-carboxamide
APCI-MS m/z: 380 [MH+].
Example 2.59 l-(3-Cyanophenyl)-N-(3,4-dichlorobenzyiy6-methyl-2-oxo-1.2- dihydropyridine-3-carboxamide APCI-MS m/z: 412 [MH+].
Example 2.60 l-G-Cvanophenyl)-6-methyl-N-[(5-methyl-2-furvDmethyll-2-oxo- 1.2-dihydropyridine-3-carboxamide APCI-MS m/z: 348 [MH+].
Example 2.61 l-(3-CvanophenylV6-methyl-2-oxo-N-1.2.3.4-tetrahydronaphthalen- l-yl-1.2-dihydropyridine-3-carboxamide APCI-MS m/z: 384 [MH+].
Example 2.62 l-(3-CyanophenylVN-(2.3-dimethoxybenzylV6-methyl-2-oxo-l,2- dihydropyridine-3-carboxamide
APCI-MS m/z: 404 [MH+]. Example 2.63 1 -(3-Cyanophenyl)-N-C3 ,5-dimethoxybenzyl)-6-methyl-2-oxo- 12- dihydropyridine-3-carboxamide
APCI-MS m/z: 404 [MH+].
Example 2.64 l-(3-CyanophenylVN-ri-(4-fluorophenyl')ethyl1-6-methyl-2-oxo-l,2- dihvdropyridine-3-carboxamide
APCI-MS m/z: 376 [MH+].
Example 2.65 N- [ 1 -(4-Chloropheny ethyll - 1 -(3-c vanophenyl)-6-methyl-2-oxo- 1.2-dihydropyridme-3-carboxamide APCI-MS m/z: 392 [MH+].
Example 2.66 l-f3-Cvanophenyl)-N-(2,5-difluorobenzyl)-6-methyl-2-oxo-l,2- dihvdropyridine-3-carboxamide APCI-MS m/z: 380 [MH+].
Example 2.67 l-(3-Cvanophenyl)-N-(2,3-dihydro-l-benzofuran-5-ylmethyl')-6- methyl-2-oxo- 1 ,2-dihydropyridine-3-carboxamide APCI-MS m z: 386 [MH+].
Example 2.68 Methyl 4-[(| [l-(3-cvanophenyl)-6-methyl-2-oxo-1.2-dihydropyridin-
3-yllcarbonyl } amino^methyllbenzoate APCI-MS m/z: 402 [MH+].
Example 2.69 1 -(3-Cvanophenyl)-6-methyl-2-oxo-N-(4-phenoxybenzylV 12- dihydropyridine-3-carboxamide APCI-MS m/z: 436 [MH+].
Example 2.70 l-(3-CvanophenylVN-r(lS -2.3-dihvdro-lH-inden-l-yll-6-methyl-2- oxo-1.2-dihydropyridine-3-carboxamide APCI-MS m/z: 370 [MH+].
Example 2.71 l-(3-Cvanophenv -6-methyl-2-oxo-N-(thien-3-ylmethylV1.2- dihvdropyridine-3-carboxamide APCI-MS m/z: 350 [MH+].
Example 2.72 l-(3-Cvanophenyl)-6-methyl-N-r(5-methylisoxazol-3-yllmethyll-2- oxo-l,2-dihvdropyridine-3-carboxamide
APCI-MS m/z: 349 [MH+].
Example 2.73 l-(3-CvanoρhenylVN-[(2.5-dimethyl-3-furvDmethvn-6-methyl-2- oxo-1.2-dihvdropyridine-3-carboxamide
APCI-MS m/z: 362 [MH+].
Example 2.74 1 -(3-Cyanoρhenyl )-N-(3-furylmethylV6-methyl-2-oxo- 1.2- dihvdropyridine-3-carboxamide APCI-MS m/z: 334 [MH+].
Example 2.75 1 -(3-Cvanophenyl)-6-methyl-2-oxo-N- \4-( IH-pyrazol- 1 -vDbenzyll- 1.2-dihvdropyridine-3-carboxamide APCI-MS m/z: 410 [MH+].
Example 2.76 l-(3-CvanoρhenylV6-methyl-2-oxo-N-(4-thien-2-ylbenzyl 1.2- dihvdropyridine-3-carboxamide APCI-MS m z: 426 [MH+].
Example 2.77 N-r4-(Aminosulfonyl;benzyll-l-(3-cyanophenviy6-methyl-2-oxo-
1.2-dihvdropyridine-3-carboxamide APCI-MS m/z: 423 [MH+]. Example 2.78 N-[2-ri.3-Benzodioxol-5-vnethyl1-l-(3-cvanophenyl')-6-methyl-2- oxo- 1 ,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 402 [MH+].
Example 2.79 l-(3-Cvanophenyl)-6-methyl-2-oxo-N-(2-thien-2-ylethylV 2- dihvdropyridine-3-carboxamide
APCI-MS m/z: 364 [MH+].
Example 2.80 l-(3-CvanophenylVN-r2-r2.4-dimethylphenyl,)ethyll-6-methyl-2- oxo- 1.2-dihydropyridine-3 -carboxamide APCI-MS m/z: 386 [MH+].
Example 2.81 l-(3-CvanophenylV6-methyl-N-r2-(4-methylρhenyl>ethyll-2-oxo-
1 ,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 372 [MH+].
Example 2.82 N- { 2- F4-(Aminosulf onvDphenyll ethyl ) - 1 A3 -c vanophenylV6- methyl-2-oxo- 1 ,2-dihydropyridine-3-carboxamide APCI-MS m/z: 437 [MH+].
Example 2.83 l-(3-CvanophenylV6-methyl-2-oxo-N-[(lSVl-ρhenylethyll-1.2- dihvdropyridine-3-carboxamide
APCI-MS m z: 358 [MH+].
Example 2.84 N-(Cvclohexylmethyl -6-methyl-2-oxo-l-[3-
(trifluoromethy phenyll-l,2-dihydropyridine-3-carboxamide APCI-MS m/z: 393 [MH+].
Example 2.85 N-(2-FurylmethylV6-methyl-2-oxo- 1 -[3-(trifluoromethyl)phenyl1 - 1 ,2-dihydropyridine-3-carboxamide APCI-MS m/z: 377 [MH+].
Example 2.86 6-Methyl-2-oxo-N-(ρyridin-3-ylmethyl')-l-r3-
(trifluoromethyl)phen yll - 1 ,2-dihydrop yridine-3 -carboxamide APCI-MS m/z: 388 [MH+],
Example 2.87 N-2.3-Dihvdro-lH-inden-l-yl-6-methyl-2-oxo-l-r3-
(trifluoromethyπphenyll-l^-dihydropyridine-S-carboxamide APCI-MS m/z: 413 [MH+].
Example 2.88 N-(2-MethoxybenzylV 6-methyl-2-oxo- 1-T3-
(trifluoromethyl)phenyll - 1.2-dihydrop yridine-3 -carboxamide APCI-MS m/z: 417 [MH+].
Example 2.89 6-Methyl-2-oxo-N-(tetrahydrofuran-2-ylmethyl)-l-[3-
(trifluoromethyl)phenyl]-l,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 381 [MH+].
Example 2.90 6-Methyl-2-oxo- 1 -F3-(trifluoromethyl )phenyll -NA3.4.5- trimethoxybenzyl)-l,2-dihydropyriαine-3-carboxamide APCI-MS m/z: 477 [MH+].
Example 2.91 N-(3-Fluorobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl ρhenyl1-
1 ,2-dihydropyridine-3-carboxamide APCI-MS m z: 405 [MH+].
Example 2.92 N-(2.5-DimethoxybenzylV6-methyl-2-oxo-l-r3-
(trifluoromethyl)phenyll - 1 ,2-dihydropyridine-3 -carboxamide APCI-MS m/z: 447 [MH+]. Example 2.93 N-[(l-Ethylpyrrolidin-2-vDmethyll-6-methyl-2-oxo-l-r3-
(trifluoromethv phenyll - 1 ,2-dihydropyridine-3 -carboxamide APCI-MS m/z: 408 [MH+].
Example 2.94 N-(2-ChlorobenzylV6-methyl-2-oxo-l-[3-(trifluoromethyl phenyll-
1 ,2-dihydropyridine-3-carboxamide APCI-MS m/z: 421 [MH+].
Example 2.95 N-(4-ChlorobenzylV6-methyl-2-oxo-l-[3-(trifluoromethvDphenyl1- 1 ,2-dihydropyridine-3-carboxarnide APCI-MS m/z: 421 [MH+].
Example 2.96 N-(3 -Chlorobenzyl V6-methyl-2-oxo- 1 - f3 -(trifluoromethyl)phenyl] -
1 ,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 421 [MH+].
Example 2.97 6-Methyl-2-oxo-N-(thien-2-ylmethyl)-l-[3-('trifluoromethyl phenyll-
1 ,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 393 [MH+].
Example 2.98 N-(Cvclopropylmethyl)-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyll-1.2-dihvdropyridine-3-carboxamide APCI-MS m/z: 351 [MH+].
Example 2.99 N-(3-MethoxybenzylV6-methyl-2-oxo-l-r3-
(trifluorometh VOphenyl] - 1 ,2-dihydropyridine-3 -carboxamide APCI-MS m/z: 417 [MH+].
Example 2.100 6-Methyl-2-oxo-N-(pyridin-4-ylmethylVl-r3- (trifluoromethyl)phenyll-l,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 388 [MH+].
Example 2.101 N-r2-(3.4-DimethoxyphenvDethyll-6-methyl-2-oxo-l-[3-
(trifluoromethvDphenyll - 1 ,2-dihydropyridine-3-carboxamide APCI-MS m/z: 461 [MH+].
Example 2.102 N-[2-(4-Methoxyphenyl')ethyll-6-methyl-2-oxo-l-r3-
(trifluoromethyl phenyl]-l,2-dihydropyridine-3-carboxamide APCI-MS m/z: 431 [MH+].
Example 2.103 6-Methyl-2-oxo-N-(2-ρhenylethvD-l-[3-(trifluoromethyl)phenvn-
1 ,2-dihydropyridine-3-carboxamide APCI-MS m/z: 401 [MH+].
Example 2.104 6-Methyl-N-[2-(l-methylpyrrolidin-2-yl)ethvn-2-oxo-l-[3-
(trifluoromethyljphenyl]-l,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 408 [MH+].
Example 2.105 N-r2-(3-ChlorophenvDethyll-6-methyl-2-oxo-l-[3- (trifluoromethyl)phenyl1- 2-dihvdropyridine-3-carboxamide APCI-MS m/z: 435 [MH+].
Example 2.106 6-Methyl-2-oxo-N-(2-pyridin-2-ylethylVl-[3-
(trifluoromethyl)phenyll - 1 ,2-dihydropyridine-3-carboxamide APCI-MS m z: 402 [MH+].
Example 2.107 N-r2A2-MethoxyphenvDethyl1-6-methyl-2-oxo-l-r3-
(trifluoromethyl phenyl]-l,2-dihy(j opyridine-3-carboxamide APCI-MS m/z: 431 [MH+]. Example 2.108 N-F2-(2-Chlorophenvnethyll-6-methyl-2-oxo-l-r3-
(trifluoromethyl)phenyll-l,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 435 [MH+].
Example 2.109 N-[2-('3-Methoxyphenyl ethyll-6-methyl-2-oxo-l-r3-
(trifluoromethyl)phenyll - 1.2-dihydropyridine-3 -carboxamide APCI-MS m/z: 431 [MH+].
Example 2.110 N-[2-(4-FluorophenvDethyll-6-methyl-2-oxo-l-r3- (trifluoromethyl)phenvn-l,2-dihydropyridine-3-carboxamide APCI-MS m z: 419 [MH+].
Example 2.111 N-[2-(2.4-Dichlorophenyl')ethyll-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyn-1.2-dihvdropyridine-3-carboxamide APCI-MS m/z: 469 [MH+].
Example 2.112 N-[2-(3-FluorophenvDethyll-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyll - 1 ,2-dihydrop yridine-3 -carboxamide APCI-MS m/z:419 [MH+].
Example 2.113 N-[2-(2-FluorophenvDethyll-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl1-l,2-dihydropyridine-3-carboxarnide APCI-MS m/z: 418 [MH+].
Example 2.114 N-(2-Cvclohex-l-en-l-ylethylV6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyll-l,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 405 [MH+].
Example 2.115 N-r2-f4-BromophenvDethyll-6-methyl-2-oxo-l-r3- (trifluoromethyliphenyll-l^-dihvdropyridine-S-carboxamide APCI-MS m/z: 481 [MH ].
Example 2.116 6-Methyl-2-oxo-N-[riS -l-phenylethyl]-l-r3-
(trifluoromethy phenyll-l^-dihyiJropyridine-S-carboxamide APCI-MS m/z: 401 [MH+].
Example 2.117 N-(3-Bromobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl phenyll-
1 ,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 467 [MH+].
Example 2.118 N-(4-Bromobenzyl)-6-methyI-2-oxo- 1 -[3-(trifluoromethyl iphenyll -
1 ,2-dihydropyridine-3 -carboxamide APCI-MS m/z: 467 [MH+].
Example 2.119 N-(2-Bromobenz yl)-6-methyl-2-oxo- 1 - r3-(trifluoromethyl)phenyl1-
1 ,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 467 [MH+].
Example 2.120 N-(3,4-Dihvdro-2H-pyran-2-ylmethylV6-methyl-2-oxo-l-r3- (trifluoromethyl)phenyll-1.2-dihydropyridine-3-carboxarnide APCI-MS m/z: 393 [MH+].
Example 2.121 6-Methyl-N-(4-methylbenzyl)-2-oxo-l-[3-(trifluoromethvnphenyll-
1 ,2-dihydropyridine-3-carboxamide APCI-MS m/z: 401 [MH+].
Example 2.122 6-Methyl-N-fl-naphthylmethylV2-oxo-l-r3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide APCI-MS m/z: 437 [MH+]. Example 2.123 N-(2-Ethoxybenzyl)-6-methyl-2-oxo-1-r3-(trifluoromethyl')phenvn-
1 ,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 431 [MH+].
Example 2.124 6-Methyl-N-(3-methylbenzylV2-oxo-l-[3-(trifluoromethv phenyll-
1.2-dihvdropyridine-3-carboxamide APCI-MS m/z: 401 [MH+].
Example 2.125 N-(4-Fluorobenzyl)-6-methyl-2-oxo-l-r3-(trifluoromethyl phenyl]- 1 ,2-dihydropyridine-3-carboxamide APCI-MS m/z: 405 [MH+].
Example 2.126 N-(1.3-Benzodioxol-5-ylmethylV6-methyl-2-oxo-l-r3-
(trifluoromethyl phenyl]-1.2-dihydropyridine-3-carboxaπ ide APCI-MS m/z: 431 [MH+].
Example 2.127 N-(2.4-Dichlorobenzyl V6-methyl-2-oxo- 1 - [3-
(trifluoromethvDphenyl]-l,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 456 [MH+].
Example 2.128 6-Methyl-N-(2-methylbenzylV2-oxo-l-[3-(trifluoromethyl')phenyll-
1 ,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 401 [MH+].
Example 2.129 N-(3.4-Difluorobenzyl -6-methyl-2-oxo-l-[3-
(trifluoromethyDphenyl]-l,2-dihvdropyridine-3-carboxamide APCI-MS m z: 423 [MH+].
Example 2.130 N-(2-Fluorobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethvDphenyll- 1 ,2-dihydropyridine-3-carboxamide APCI-MS m/z: 405 [MH+].
Example 2.131 N-(2-Chloro-4-fluorobenzylV6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl1-l,2-dihydropyridine-3-carboxamide APCI-MS m/z: 439 [MH+] .
Example 2.132 N-(3.4-DichlorobenzylV6-methyl-2-oxo-l-[3-
(trifluoromethyDphenyl]- 1 ,2-dihydiOpyridine-3-carboxamide APCI-MS m/z: 456 [MH+].
Example 2.133 6-Methyl-N-rf5-methyl-2-furyl methyll-2-oxo-l-r3-
(trifluoromethvQphenyl] - 1 ,2-αihydropyridine-3-carboxamide APCI-MS m/z: 391 [MH+].
Example 2.134 6-Methyl-2-oxo-N- 1 ,2.3.4-tetrahvdronaphthalen- 1 -yl- 1 -[3-
(trifluoromethyl phenyl]-l,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 427 [MH+].
Example 2.135 N-(2.3-DimethoxybenzylV6-methyl-2-oxo-l-[3- (trifluoromethyl)phenyl1-l,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 447 [MH+].
Example 2.136 N-ri-(4-Chlorophenyl)ethyl]-6-methyl-2-oxo-l-F3-
(trifluoromethyl)phenyl1-1.2-dihvdropyridine-3-carboxamide APCI-MS m/z: 434 [MH+].
Example 2.137 N-(2.5-DifluorobenzylV6-methyl-2-oxo-l-[3-
(trifluoromethyDphenyll-l^-dihydropyridine-S-carboxamide APCI-MS m/z: 423 [MH+]. Example 2.138 Methyl 4-1 rd6-methyl-2-oxo-l-r3-(trifluoromethyl phenyll-1.2- dihydropyridin-3-yl lcarbonyllaminolmethyl Ibenzoate APCI-MS m/z: 445 [MH+].
Example 2.139 6-Methyl-2-oxo-N-(4-phenoxybenzvD-l-r3-
(trifluoromethyl)phenyll-l,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 479 [MH+] .
Example 2.140 N-[(2.2-Dimethyl-1.3-dioxolan-4-vnmethvn-6-methyl-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 411 [MH+].
Example 2.141 e-Methyl-N-FCS-methv so azol-S-vnmethvn-Σ-o o-l-rS-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide APCI-MS m/z: 392 [MH+].
Example 2.142 N-[(2.5-Dimethyl-3-furvDmethyl]-6-methyl-2-oxo-l-r3-
(trifluoromethyl)phenyl]-l,2-dihvdropyridine-3-carboxamide
APCI-MS m/z: 405 [MH+].
Example 2.143 N-(3-Furylmethyl -6-methyl-2-oxo-l-[3-(trifluoromethyl)phenvn-
1 ,2-dihydropyridine-3-carboxamide APCI-MS m/z: 377 [MH+].
Example 2.144 6-Methyl-2-oxo-N-[4-(lH-pyrazol-l-yl)benzyll-l-[3-
(trifluoromethyl)phenvn- 1.2-dihvdropyridine-3-carboxamide APCI-MS m/z: 453 [MH+].
Example 2.145 6-Methyl-2-oxo-N-(4-thien-2-ylbenzylV 1 - 3- (trifluoromethyl)phenvn-l,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 469 [MH+].
Example 2.146 N-[2-(1.3-Benzodioxol-5-vnethvn-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl1-1.2-dihvdropyridine-3-carboxamide APCI-MS m/z: 445 [MH+].
Example 2.147 6-Methyl-2-oxo-N-(2-thien-2-ylethylVl-r3-(trifluoromethvDphenyll-
1 ,2-dihydropyridine-3-carboxamide APCI-MS m/z: 407 [MH+].
Example 2.148 N-[2-.4-Tert-butylphenyl ethyll-6-methyl-2-oxo-l-r3-
(trifluoromethyl)phenyl] - 1 ,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 457 [MH+].
Example 2.149 6-Methyl-N-r2-(4-methylphenvDethyl1-2-oxo-l-[3-
(trifluoromethyDphenyl]-l,2-dihydropyridine-3-carboxamide APCI-MS m/z: 415 [MH+].
Example 2.150 N-(2-r4-(Aminosulfonyl;phenyl]ethyl}-6-methyl-2-oxo-l-r3- (trifluoromethyl)phenyl]-l,2-oihvdropyridine-3-carboxamide APCI-MS m/z: 480 [MH+].
Example 2.151 6-Methyl-2-oxo-N-r(lRVl-phenylethyll-l-[3-
(trifluoromethyl)phenyl]-1.2-dihvdropyridine-3-carboxamide APCI-MS m/z: 401 [MH+].
Example 2.152 3-1 [4-(2-Methoxyphenyl)piperazin- 1 -yl] carbonyl ) -6-methyl- 1 - [3 -
(trifluoromethyl)phenyl1pyridin-2(lH)-one
APCI-MS m/z: 472 [MH+]. Example 2.153 N- [(4-Cvanocvclohexynmethyll -6-methyl-2-oxo- 1-T3-
(trifluoromethyl)phen yl] - 1.2-dihydrop yridine-3 -carboxamide APCI-MS m/z: 418 [MH+].
Example 2.154 3- { [4-(4-Fluorophenyl')ρiperazin- 1 -yllcarbonyl } -6-methyl- 1 - [3-
(trifluoromethyl)phenyl1pyridin-2(lH)-one
APCI-MS m z: 460 [MH+].
Example 2.155 N- r2-(4'-Fluoro- 1.1 '-biphenyl-4- ylteth yll -6-methyl-2-oxo- 1 - [3 - (trifluoromethyl phenyl1-l,2-dihydropyridine-3-carboxamide APCI-MS m/z: 495 [MH+].
Example 2.156 N-(2-Hvdrox v- 1 -phenylethyl V6-methyl-2-oxo- 1-T3-
(trifluoromethyl phenyl] - 1 ,2-dihydrop yridine-3 -carboxamide APCI-MS m/z: 417 [MH+].
Example 2.157 6-Methyl-2-oxo-N-[(2R)-2-phenylcvclopropyn-l-[3-
(trifluoromethyl)phenyll-l,2-dihydropyridine-3-carboxamide APCI-MS m/z: 413 [MH+].
Example 2.158 N-[l-(4-ChlorobenzvDρiperidin-4-yll-6-methyl-2-oxo-l-[3-
(trifluoromethyDphenyl]-l,2-dihydropyridine-3-carboxamide
APCI-MS m/z: 504 [MH+].
Example 2.159 6-Methyl-N-(2-morpholin-4-ylethylV2-oxo-l-r3-
(trifluoromethvDphenyll-l,2-αihvdropyridine-3-carboxamide APCI-MS m/z: 410 [MH+].
Example 2.160 N-r2-(4-ChlorophenvDethyll-6-methyl-2-oxo-l-r3- (trifluoromethvDphenyl1-l,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 435 [MH+].
Example 2.161 N-(2-Hvdroxy-2-phenylethylV6-methyl-2-oxo- 1-13-
(trifluoromethyl)phenyll-1.2-dihvdropyridine-3-carboxamide APCI-MS m/z: 417 [MH+].
Example 2.162 N-Cyclopentyl-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl1-l,2- dihydropyridine-3-carboxamide
APCI-MS m/z: 365 [MH+].
Example 2.163 N-[2-(lH-Imidazol-4-vDethyll-6-methyl-2-oxo-l-r3-
(trifluoromethy phenyl]-1.2-αihvdropyridine-3-carboxamide APCI-MS m/z: 391 [MH+].
Example 2.164 N-(3.5-Dimethoxybenzyl)-6-methyl-2-oxo-l-[3-
(MfluoromethvDphenyl]-l,2-dihydropyridine-3-carboxamide APCI-MS m/z: 447 [MH+].
Example 2.165 N-(4-Hydroxycyclohexyl')-6-methyl-2-oxo-l-[3- (MfluoromethvDphenyll-l,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 395 [MH+].
Example 2.166 6-Methyl-2-oxo-N-(2-pyridin-2-ylethylVl-r3-
(trifluoromethyl)phenvn-1.2-dihvdropyridine-3-carboxamide APCI-MS m/z: 402 [MH+].
Example 2.167 6-Methyl-2-oxo-N-lH-1.2.4-triazol-3-yl-l-r3-
(trifluoromethyl)phenyll-1.2-dihvdropyridine-3-carboxamide APCI-MS m/z: 364 [MH+]. Example 2.168 N- f 1 -(Hvdroxymethyl V 2-methylprop yll -6-methyl-2-oxo- 1 - [3 -
(trifluoromethyl)phenyl1-1.2-dihvdropyridine-3-carboxamide
APCI-MS m/z: 383 [MH+].
Example 2.169 3-j[3-(3,4-Dichlorophenoxy)pyrrolidin-l-yl1carbonyll-6-methyl-l-
[3-(trifluoromethyl)phenyllpyridin-2(lED-one
APCI-MS m/z: 512 [MH+].
Example 2.170 6-Methyl-2-oxo-N-(pyridin-3-ylmethylVl-[3- (trifluoromethyl)phenyll - 1.2-dihvdropyridine-3-carboxamide APCI-MS m/z: 388 [MH+].
Example 2.171 N-(2-MethoxyethylV6-methyl-2-oxo-l-[3-(trifluoromethv phenyll-
1.2-dihvdropyridine-3-carboxamide APCI-MS m/z: 355 [MH+].
Example 2.172 N-(2-HvdroxyproρylV6-methyl-2-oxo-l-r3-
(trifluoromethyl phenyl]-l,2-dihydropyridine-3-carboxamide APCI-MS m/z: 355 [MH+].
Example 2.173 Ethyl 4-r({6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl1-1.2- dihydropyridin-3-yl } carbon vDaminolpiperidine- 1 -carboxylate APCI-MS m/z: 452 [MH+].
Example 2.174 N-r3-(lH-Jjnidazol-l-yl)propyl]-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 405 [MH+].
Example 3 N-(4-Chlorobenzyl)-l-(3-methylphenyl)-2-oxo-l,2-dihvdropyridine- 3-carboxamide a) Diethyl [3-ethoxyprop-2-enylidenelmalonate
Diethyl malonate (160 g, 1.0 mole) was added dropwise to a stirred, refluxing solution of 1,1,3,3-tetraethoxypropane (330 g, 1.5 mol), acetic anhydride (306 g, 2.0 moles) and zinc chloride (10 g, 0.073 mole) over a period of 30 minutes. The mixture was heated for 1 h, and after that a Dean-Stark apparatus was connected and the lower boiling components were distilled off. Additional acetic anhydride (150 ml) was added and refluxing was continued for 1 h. The reaction mixture was distilled to give the title compound as a yellow oil (182 g, 75%), b.p. 139-143 °C at 0.8 mm Hg. 1H NMR (CDC13): δ 7.38 (IH, d, =12.1 Hz); 7.04 (IH, d, =12.2 Hz); 6.19 (IH, t, J=12.1 Hz); 4.27 (2H, q); 4.21 (2H, q); 3.96 (2H, q); 1.36-1.24 (9H, m). b) Diethyl {3-[(3-methylpheny aminolprop-2-enylidene}malonate
Diethyl [3-ethoxyprop-2-enylidene]malonate (9.7 g, 40 mmol) and m-toluidine (4.3 g, 40, mmol) were dissolved in ethanol (150 ml) and stirred at room temperature for three days, The solvents were evaporated off. Column chromatography on silica using heptane/ethyl acetate (4: 1) as eluent afforded the title compound as an oil, which solidified after standing for a couple of days (10 g, 83%).
1H NMR (CDC13): δ 7.65 (IH, d, J=12.4 Hz); 7.39 (2H, brd, =7.7 Hz); 7.19 (IH, t, J=7.7
Hz); 6.85 (IH, d, 1=7.7 Hz); 6.75 (IH, s); 6.73 (IH, d, 1=6.5 Hz); 6.46 (IH, m, =12.4, 6.5 Hz); 4.32 (2H, q); 4.25 (2H, q); 2.35 (3H, s); 1.36 (3H, t) 1.33 (3H, t).
APCI-MS m z: 304 [MH+]. c) l-(3-Methylphenyl')-2-oxo-1.2-dihvdropyridine-3-carboxylic acid
Diethyl {3-[(3-methylphenyl)amino]prop-2-enylidene}malonate (10 g, 33 mmol) was mixed with 2M sodium hydroxide solution (100 ml) and stirred at room temperature for 30 minutes. The reaction mixture was extracted (washed) with ethyl acetate and 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 to afford the title compound (7.3 g, 97%). 1H NMR (CDCI3): δ 14.08 (IH, s); 8.64 (IH, dd, J=7.2, 2.2 Hz); 7.72 (IH, dd, =6.7, 2.2 Hz); 7.47 (IH, t, J=7.7 Hz); 7.37 (IH, d, =7.7 Hz); 7.23 (IH, s); 7.21 (IH, brd); 6.67 (IH, t, J=7.2, 6.7 Hz); 2.47 (3H, s). APCI-MS m/z: 230 [MH+]. d) N-(4-Chlorobenzyl)-l-(3-methylphenyl -2-oxo-l,2-dihydropyridine-3-carboxamide To a mixture of l-(3-methylphenyl)-2-oxo-l,2-dihydropyridine-3-carboxylic acid (115 mg, 0.5 mmol), HATU (209 mg, 0.55 mmol), HO AT (75 mg, 0.55 mmol) and DIEA (275 μl, 1.6 mmol) in dichloromethane (2.5 ml) was added 4-chlorobenzylamine (71 mg, 0.5 mmol) in dichloromethane (1 ml). The reaction was stirred for 1 h at room temperature. More dichloromethane was added and the crude product was washed twice with aqueous sodium hydrogencarbonate, 0.5M aqueous citric acid and water. The solvent was removed in vacuo and the residue was purified by column chromatography on silica using dichloromethane/ethyl acetate (4: 1) as eluent to afford the title compound in almost quantitative yield. 1H NMR (CDC13): δ 10.10 (IH, brt); 8.68 (IH, dd); 7.58 (IH, dd); 7.43 (IH, t); 7.33-7.25 (5H, m); 7.20-7.14 (2H, m); 6.53 (IH, t); 4.59 (2H, d); 2.45 (3H, s). APCI-MS m/z: 353 [MH+].
Example 4 N-(4-ChlorobenzylV6'-methyl-2-oxo-2H-1.2'-bipyridine-3- carboxamide
a) Diethyl 13-[(6-methylpyridin-2-yl)amino1prop-2-enylidene I malonate Diethyl [3-ethoxyprop-2-enylidene]malonate (1.7 g, 7 mmol) and 2-amino-6- methylpyridine (1.08 g, 10 mmol) were heated (without solvent) at 140 °C for 6 h. The reaction mixture was worked-up as described in Example 3 (b) to afford the title compound. APCI-MS m/z: 305 [MH+]. b) 6'-Methyl-2-oxo-2H-1.2'-bipyridine-3-carboxylic acid
The title compound was prepared from diethyl {3-[(6-methylpyridin-2-yl)amino]prop-2- enylidene}malonate using the method described in Example 3 (c). 1H NMR (CDC13): δ 14.02 (IH, brs); 8.65 (IH, dd); 8.20 (IH, dd); 7.84 (IH, t); 7.68 (IH, d); 7.33 (IH, d); 6.72 (IH, t); 2.64 (3H, s).
APCI-MS m z: 231 [MH+]. c) N-(4-Chlorobenzviy 6'-methyl-2-oxo-2H- 1 ,2'-bipyridine-3-carboxamide
The title compound was prepared from 6'-methyl-2-oxo-2H-l,2'-bipyridine-3-carboxylic acid and 4-chlorobenzylamine using the method described in Example 3 (d).
1H NMR (CDCI3): δ 10.04 (IH, brt); 8.68 (IH, dd); 7.95 (IH, dd); 7.79 (IH, t); 7.55 (2H, d); 7.29 (5H, brd); 6.58 (IH, t); 4.61 (2H, d); 2.62 (3H, s).
APCI-MS m/z: 354 [MH+].
The compounds of Examples 4.1 to 4.18 were prepared by a method analogous to that described for Example 4.
Example 4.1 N-(4-Methoxybenzyl')- 1 - (3 -methylphenyl -2-oxo- 1,2- dihvdropyridine-3-carboxamide
1H NMR (CDCI3): δ 9.98 (IH, brt); 8.68 (IH, dd); 7.56 (IH, dd); 7.42 (IH, t); 7.32-7.25
(3H, m); 7.18-7.13 (2H, m); 6.84 (2H, d); 6.52 (IH, t); 4.56 (2H, d); 3.79 (3H, s); 2.43 (3H, s).
APCI-MS m/z: 349 [MH+].
Example 4.2 Methyl 44(1 ri-(3-methylphenvD-2-oxo-1.2-dihvdroρyridin-3- yllcarbonyl I amino)methvnbenzoate
1H NMR (CDCI3): δ 10.17 (IH, brt); 8.69 (IH, dd); 7.98 (2H, d); 7.59 (IH, dd); 7.46-7.40
(3H, m); 7.32 (IH, d); 7.20-7.16 (2H, m); 6.54 (IH, t); 4.69 (2H, d); 3.92 (3H, s); 2.45 (3H, S).
APCI-MS m/z: 377 [MH+].
Example 4.3 4-IT ( \ 1 -(3-Methylρhenyl V2-oxo- 1 ,2-dihvdropyridin-3- yl1carbonv amino)methyl] benzoic acid A suspension of methyl 4-[({[l-(3-methylphenyl)-2-oxo-l,2-dihydropyridin-3- yl]carbonyl}amino)methyl] benzoate (120 mg, 0.32 mmol) and 2M sodium hydroxide solution (0.5 ml) in methanol (20 ml) and water (10 ml) was stirred at 40 °C overnight. The methanol was evaporated off and the aqueous solution was acidified with IM hydrochloric acid (1 ml). A beige coloured precipitate appeared which was filtered off, washed twice with water and dried to afford the title compound (110 mg, 95%). 1H NMR (DMSO-de): δ 12.84 (IH, s); 10.05 (IH, t); 8.45 (IH, dd); 7.99 (IH, dd); 7.88 (2H, d); 7.43-7.38 (3H, m); 7.30 (IH, d); 7.27 (IH, s); 7.24 (IH, d); 6.61 (IH, t); 4.57 (2H, d); 2.35 (3H, s). APCI-MS m/z: 363 [MH+].
Example 4.4 N-(4-Chlorobenzyl)-l-(2-fluoro-5-methylphenyl)-2-oxo-l,2- dihvdropyridine-3-carboxamide
1H NMR (CDCI3): δ 9.97 (IH, brt); 8.69 (IH, dd); 7.51 (IH, dd); 7.31-7.26 (5H, m); 7.21- 7.15 (2H, m); 6.56 (IH, t); 4.59 (2H, brs); 2.40 (3H, s). APCI-MS m/z: 371 [MH+].
Example 4.5 1 -(2-Fluoro-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo- 1 ,2- . dihvdropyridine-3-carboxamide 1H NMR (CDCI3): δ 9.86 (IH, brt); 8.69 (IH, dd); 7.49 (IH, dd); 7.30-7.25 (3H, m); 7.20- 7.14 (2H, m); 6.84 (2H, d); 6.54 (IH, t); 4.56 (2H, brd); 3.79 (3H, s); 2.39 (3H, s). APCI-MS m/z: 367 [MH+].
Example 4.6 N-[4-(Dimethylamino)benzyl1-l-(2-fluoro-5-methylphenyl)-2-oxo- 1.2-dihvdropyridine-3-carboxamide
1H NMR (CDCI3): δ 9.78 (IH, brt); 8.69 (IH, dd); 7.47 (IH, dd); 7.27 (IH, dd); 7.22 (2H, d); 7.19-7.13 (2H, m); 6.68 (2H, d); 6.53 (IH, t); 4.53 (2H, brd); 2.92 (6H, s); 2.39 (3H, s). APCI-MS m/z: 380 [MH+]. Example 4.7 N-[4-(Aminosulfonyl)benzyll-l-r2-fluoro-5-methylphenyl)-2-oxo-
1 ,2-dihydropyridine-3-carboxamide
1H NMR (CDCI3): δ 10.11 (IH, brt); 8.69 (IH, dd); 7.86 (2H, d); 7.54 (IH, dd); 7.48 (2H, d); 7.30 (IH, dd); 7.20 (2H, d); 7.17 (2H, brd); 6.58 (IH, t); 4.68 (2H, brd); 2.41 (3H, s). APCI-MS m/z: 416 [MH+].
Example 4.8 N-(4-ChlorobenzylV4'-methyl-2-oxo-2H- 1 ,2'-bip yridine-3 - carboxamide
1H NMR (CDCI3): δ 10.02 (IH, brt); 8.68 (IH, dd); 8.48 (IH, d); 7.94 (IH, dd); 7.58 (IH, s); 7.30-7.28 (4H, m); 7.23 (IH, d); 6.58 (IH, t); 4.61 (2H, d); 2.48 (3H, s). APCI-MS m/z: 354 [MH+].
Example 4.9 N-(4-Chlorobenzyl)-l-(2,5-dimethylphenyl)-2-oxo-l,2- dihvdropyridine-3-carboxamide 1H NMR (CDC13): δ 10.11 (IH, brt); 8.69 (IH, dd); 7.47 (IH, dd); 7.29-7.20 (6H, m); 7.02 (IH, s); 6.54 (IH, t); 4.59 (2H, m); 2.38 (3H, s); 2.09 (3H, s). APCI-MS m/z: 367 [MH+].
Example 4.10 l-(2,5-Dimethylphenyl)-N-(4-methoxybenzyl)-2-oxo-l,2- dihydropyridine-3-carboxamide
1H NMR (CDC13): δ 9.97 (IH, brt); 8.67 (IH, dd); 7.43 (IH, dd); 7.27-7.16 (4H, m); 6.99 (IH, s); 6.81 (2H, d); 6.50 (IH, t); 4.53 (2H, m); 3.77 (3H, s); 2.35 (3H, s); 2.07 (3H, s). APCI-MS m/z: 363 [MH+].
Example 4.11 N-[4-(T>imethylamino)benzyl1-l-(2,5-dimethylphenyl)-2-oxo-l,2- dihvdropyridine-3-carboxamide
1H NMR (CDCI3): δ 9.91 (IH, brt); 8.69 (IH, dd); 7.43 (IH, dd); 7.26-7.19 (4H, m); 7.01 (IH, s); 6.68 (2H, d); 6.52 (IH, t); 4.52 (2H, m); 2.92 (6H, s); 2.37 (3H, s); 2.08 (3H, s). APCI-MS m/z: 376 [MH+]. Example 4.12 N-(4-Chlorobenzyl)-l-[2-methyl-5-(trifluoromethyl)phenyll-2-oxo-
1 ,2-dihydropyridine-3-carboxamide
1H NMR (CDC13): δ 9.94 (IH, brt); 8.72 (IH, dd); 7.69 (IH, dd); 7.53 (IH, d); 7.50 (IH, s); 7.46 (IH, dd); 7.28 (4H, s); 6.60 (IH, t); 4.59 (2H, m); 2.23 (3H, s). APCI-MS m/z: 421 [MH+].
Example 4.13 N-(4-MethoxybenzvD- 1 - [2-methyl-5-(trifluoromethyl)phenyll-2- oxo-l,2-dihydropyridine-3-carboxamide
1H NMR (CDCI3): δ 9.80 (IH, brt); 8.71 (IH, dd); 7.65 (IH, dd); 7.50 (IH, d); 7.47 (IH, s); 7.42 (IH, dd); 7.27-7.24 (4H, m); 6.82 (2H, d); 6.56 (IH, t); 4.54 (2H, m); 3.76 (3H, s);
2.19 (3H, s).
APCI-MS m/z: 417 [MH+].
Example 4.14 N-[4-(Dimethylamino)benzyl1-l-[2-methyl-5- (trifluoromethyl)phenyl]-2-oxo-l,2-dihvdropyridine-3-carboxamide
1H NMR (CDC13): δ 9.75 (IH, brt); 8.73 (IH, dd); 7.67 (IH, dd); 7.52 (IH, d); 7.49 (IH, s); 7.42 (IH, dd); 7.23 (2H, d); 6.69 (2H, d); 6.57 (IH, t); 4.53 (2H, m); 2.92 (6H, s); 2.21
(3H, s).
APCI-MS m/z: 430 [MH+].
Example 4.15 N-Benzyl-5-methyl-2-oxo-l-[3-(trifluoromethyl)phenyll-l,2- dihydropyridine-3-carboxamide
APCI-MS m/z: 387 [MH+].
Example 4.16 N-(2-Chlorobenzyl)-5-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl1-
1 ,2-dihydropyridine-3-carboxamide APCI-MS m/z: 421 [MH+].
Example 4.17 5-Methyl-2-oxo-N-(2-phenylethyl -l-r3-(trifluoromethv phenyn- 1 ,2-dihydropyridine-3-carboxamide APCI-MS m/z: 401 [MH+].
Example 4.18 N-(4-Chlorophenyl)-5-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl1-
1 ,2-dihydropyridine-3-carboxarnide APCI-MS m/z: 407 [MH+].
Example 5 6-Ethyl-N-[4-fmethylsulfonvnbenzyll-2-oxo-l-r3-
(trifluoromethyDphenyl]-l,2-dihvdropyridine-3-carboxamide
a) 6-Ethyl-2-oxo-l-[3-(trifluoromethyl')phenyl1-l,2-dihvdropyridine-3-carboxylic acid
The title compound was prepared from ethyl 3-oxo-3-{ [3-(trifluoromethyl)phenyl] amino }propanoate and l-methoxypent-l-en-3-one using the method described in Example
1 steps (a) and (b).
1H NMR (CDCI3): δ 13.75 (IH, brs); 8.59 (IH, d); 7.87 (IH, d); 7.79 (IH, t); 7.55 (IH, s); 7.49 (IH, d); 6.61 (IH, d); 2.37 (2H, q); 1.20 (3H, t).
APCI-MS m/z: 312 [MH+]. b) 6-Ethyl-N-[4-(methylsulfonyl benzvn-2-oxo-l-[3-(trifluoromethvnphenvn-l,2- dihydropyridine-3-carboxarnide
The title compound was prepared from 6-ethyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxylic acid and 4-(methylsulfonyl) benzylamine hydrochloride using the method described in Example 3 (d).
1H NMR (CDCI3): δ 10.00 (IH, brt); 8.64 (IH, d); 7.88 (2H, d); 7.82 (IH, d); 7.75 (IH, t);
7.53 (2H, d); 7.52 (IH, s); 7.45 (IH, d); 6.51 (IH, d); 4.68 (2H, m); 3.02 (3H, s); 2.31 (2H, q); 1.17 (3H, t). APCI-MS m/z: 479 [MH+].
The compounds of Examples 5.1 and 5.2 were prepared by a method analogous to that described for Example 5. Example 5.1 N-[4-(Methylsulfony benzyll-2-oxo-6-propyl-l-[3-
(trifluoromethyl)phenyl1-l,2-dihvdropyridine-3-carboxamide
1H NMR (CDC13): δ 10.00 (IH, brt); 8.62 (IH, d); 7.88 (2H, d); 7.83 (IH, d); 7.75 (IH, t);
7.53 (2H, d); 7.52 (IH, s); 7.45 (IH, d); 6.49 (IH, d); 4.68 (2H, m); 3.02 (3H, s); 2.26 (2H, t); 1.55 (2H, sxt); 0.87 (3H, t).
APCI-MS m/z: 493 [MH+].
Example 5.2 6-Butyl-N-[4-(methylsulfonv benzyll-2-oxo-l-[3-
(trifluoromethyPphenyll - 1 ,2-dihydropyridine-3-carboxamide 1H NMR (CDCI3): δ 10.00 (IH, brt); 8.62 (IH, d); 7.88 (2H, d); 7.83 (IH, d); 7.75 (IH, t); 7.54 (2H, d); 7.52 (IH, s); 7.45 (IH, d); 6.49 (IH, d); 4.68 (2H, m); 3.03 (3H, s); 2.29 (2H, t); 1.49 (2H, qv); 1.24 (2H, sxt); 0.80 (3H, t). APCI-MS m/z: 507 [MH+].
Example 6 6-(Methoxymethyl)-N-r4-(methylsulfonyl)benzyl1-2-oxo-l-[3-
(trifluoromethy phenyl] - 1 ,2-dihydropyridine-3-carboxamide
a) 6-(Bromomethyl)-2-oxo-l-[3-(trifluoromethyl)phenyl1-l,2-dihvdropyridine-3- carboxylic acid The title compound was prepared by refluxing 6-methyl-2-oxo-l-[3-(trifluoromethyl) phenyl]-l,2-dihydropyridine-3-carboxylic acid (297 mg, 1 mmol), N-bromosuccinimide (240 mg, 1.3 mmol) and 2,2'-azobis-2-methylpropionitrile (AIBN) (15 mg) in carbon tetrachloride/chloroform (2:1, 5 ml) overnight. The solvent was evaporated to give the title compound. APCI-MS m/z: 376/378 [MH+]. b 6-(Methoxymethyl)-2-oxo-l-[3-(trifluoromethyl)phenyll-l,2-dihvdropyridine-3- carboxylic acid
The title compound was prepared by heating crude 6-(bromomethyl)-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxylic acid with an excess of sodium methoxide in methanol at 40 °C for 15 minutes. The organic solvents were removed, water was added and the reaction mixture was washed with ethyl acetate. The water phases were acidified with hydrochloric acid to pH 3-4. A yellowish precipitate appeared which was filtered off, washed (water and water/methanol, 1:1) and dried to give the title compound.
1H NMR (CDC13): δ 13.66 (IH, brs); 8.63 (IH, d); 7.87 (IH, d); 7.77 (IH, t); 7.58 (IH, s); 7.50 (IH, d); 6.84 (IH, d); 3.96 (2H, d); 3.27 (3H, s).
APCI-MS m/z: 328 [MH+]. c) 6-(Methoxymethv -N-[4-(methylsulfonyDbenzyn-2-oxo-l-[3-
(trifluoromethvπphenyl1-l,2-dihydropyridine-3-carboxamide
The title compound was prepared from 6-(methoxymethyl)-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxylic acid and 4-(methylsulfonyl) benzylamine hydrochloride using the method described in Example 3 (d).
1H NMR (CDC13): δ 9.98 (IH, brt); 8.67 (IH, d); 7.87 (2H, d); 7.82 (IH, d); 7.73 (IH, t);
7.53 (3H, m); 7.47 (IH, d); 6.72 (IH, d); 4.67 (2H, m); 3.92 (2H, d); 3.23 (3H, s); 3.01
(3H, s). APCI-MS m/z: 495 [MH+].
Example 7 6-(HydroxymefhylVN- [4-(methylsulf onvDbenzyll -2-oxo- 1 - [3 -
(trifluoromethvDphenyl1-l,2-dihy(kopyridine-3-carboxamide
a) 6-(Hydroxymethyl -2-oxo-l-[3-(trifluoromethyl)phenvn-l,2-dihydropyridine-3- carboxylic acid
The title compound was prepared by heating 6-(bromomethyl)-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxylic acid and dilute sodium hydroxide in methanol for a few minutes. The reaction mixture was washed with ethyl acetate. The water phases were acidified with hydrochloric acid. A precipitate appeared which was recrystallised several times from ethyl acetate/methanol to give the title compound.
1H NMR (DMSO-d6): δ 13.99 (IH, brs); 8.53 (IH, d); 8.00 (IH, s); 7.94 (IH, d); 7.83 (IH, t); 7.81 (IH, d); 6.94 (IH, d); 5.85 (IH, t); 3.99 (2H, d). APCI-MS m/z: 314 [MH+] . b) 6-(Hydroxymethyl)-N-[4-(methylsulfonyl)benzyll-2-oxo-l-[3-
(trifluoromethyljphenyll - 1 ,2-dihvdropyridine-3 -carboxamide
The title compound was prepared from 6-(hydroxymethyl)-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3 -carboxylic acid and 4-(methylsulfonyl) benzylamine hydrochloride using the method described in Example 3 (d).
1HNMR (DMSO-de): δ 9.92 (IH, brt); 8.49 (IH, d); 7.92-7.81 (4H, m); 7.78 (IH, t); 7.71
(IH, d); 7.53 (2H, d); 6.78 (IH, d); 5.71 (IH, t); 4.57 (2H, brd); 3.95 (2H, brd); 3.16 (3H, s).
APCI-MS m/z: 481 [MH+].
Example 8 N-F4-(Aminosulfonyl)benzyll-2,4-dioxo-3-[3-
(trifluoromethyl)phenyl1-l,2,3.4-tetrahydropyrimidine-5-carboxamide
a) 2,4-Dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4-tefrahv(jropyrimidine-5-carboxylic acid
3-(Trifluoromethyl)phenyl isocyanate (3.52 g, 22 mmol) was added quickly to a vigorously stirred ice-cooled solution of aqueous ammonia (10 ml, 33%) in acetonitrile (40 ml). The mixture was heated at 40 °C for 10 minutes and then the solvent was evaporated. The resulting urea was redissolved in dry ethanol (15 ml) and diethyl ethoxymethylene- malonate (5 ml, 24.7 mmol) and finally sodium ethoxide solution (50 mmol in ethanol) was added, and the mixture was refluxed for 2 h. Water (10 ml) was added and the mixture was allowed to cool, then washed with ethyl acetate, acidified to pH~3 with cone, hydrochloric acid and extracted with ethyl acetate. The organic extracts were dried and evaporated to give a solid material. Recrystallisation from heptane/ethyl acetate afforded the title compound (0.5 g, 7%).
1H NMR (CDC13): δ 12.41 (IH, brd, J=6.4Hz); 8.15 (IH, d, I=6.4Hz); 7.46 (IH, d, J=7.6Hz); 7.40 (IH, t, I=7.6Hz); 7.30 (brs, IH); 7.22 (IH, d, J=7.6Hz). APCI-MS m/z: 300 [MH+]. b) N-r4-(Aminosulfonyl')benzyl1-2,4-dioxo-3-r3-(trifluoromethvDphenvn-l,2,3.4- tefrahydropyrimidine-5-carboxamide The title compound was prepared from 2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4- tetrahydropyrimidine-5-carboxylic acid and N-[4-(aminosulfonyl)-benzylamine hydrochloride using the method described in Example 1 (d).
1H NMR (DMSO-d6): δ 12.21 (IH, brd); 9.11 (IH, t); 8.29 (IH, s); 7.81 (2H, d); 7.77-7.70 (3H, m); 7.65 (IH, d); 7.44 (IH, d); 7.28 (2H, s); 4.46 (2H, d).
The compounds of Examples 8.1 to 8.8 were prepared using the general method described for Example 8.
Example 8.1 N-[4-(Dimethylamino)benzyl1-2,4-dioxo-3-[3-
(trifluoromethyl)phenyl1-l,2,3,4-tetrahvdropyrimidine-5-carboxamide trifluoroacetate 1H NMR (CD3CN): δ 9.73 (IH, brd); 8.96 (IH, brt); 8.35 (IH, d); 7.79 (IH, d); 7.72 (IH, t); 7.63 (IH, s); 7.55 (IH, d); 7.36 (2H, d); 7.23 (2H, d); 4.49 (2H, d); 3.04 (6H, s).
Example 8.2 N-(4-Chlorobenzyl)-2,4-dioxo-3-[3-(trifluoromethyl')phenyll- l,2,3,4-tetrahvdropyrinιidine-5-carboxamide
1H NMR (CD3CN): δ 9.65 (IH, brd); 8.96 (IH, brt); 8.39 (IH, d); 7.80 (IH, d); 7.72 (IH, t); 7.63 (IH, s); 7.56 (IH, d); 7.33 (2H, d); 7.25 (2H, d); 4.49 (2H, d).
Example 8.3 N-('2,3-Dihvdro-l-benzofuran-5-ylmethyl')-2.4-dioxo-3-r3-
(trifluoromethyl phenyl1 - 1 ,2,3 ,4-tetrahvdropyrimidine-5-carboxamide 1H NMR (CDC13): δ 8.53 (IH, d); 7.76 (IH, m); 7.67 (IH, m); 7.53 (IH, m); 7.44 (IH, m), 7.13 (IH, m); 7.04 (IH, m); 6.68 (IH, d); 5.28 (2H, d); 4.57 (2H, t); 3.19 (2H, t). APCI-MS m/z: 432 [MH+].
Example 8.4 N-[4-(Methylsulfonyl)benzvn-2.4-dioxo-3-[3-
(trifluoromethvPphenyll - 1 ,2,3 ,4-tetrahvdropyrimidine-5-carboxamide 1H NMR (CDCI3): δ 9.05 (IH, m); 8.52 (IH, d); 8.40 (IH, m); 7.88 (2H, d); 7.75 (IH, d); 7.66 (IH, t); 7.53 (IH, m); 7.49 (2H, d); 7.44 (IH, d); 4.65 (2H, d); 3.01 (3H, s). APCI-MS m/z: 468 [MH+]. Example 8.5 N-(4-Bromobenzyl")-2.4-dioxo-3-[3-(trifluoromethyl)phenyll- l,2,3,4-tetrahydropyrimidine-5-carboxamide
1H NMR (CDC13): δ 8.90 (IH, m); 8.50 (IH, d); 8.32 (IH, m); 7.74 (IH, d); 7.65 (IH, m); 7.52 (IH, m); 7.42 (3H, m); 7.16 (2H, d); 4.50 (2H, d). APCI-MS m/z: 467[MH+].
Example 8.6 N-(4-Methoxybenzyl>2,4-dioxo-3 - [3- ( trifluorometh vDphenyll -
1 ,2,3 ,4-tefrahvdropyrimidine-5-carboxamide 1H NMR (CDCI3): δ 8.86 (IH, m); 8.62- 8.53 (2H, m); 7.77 (IH, m); 7.69 (IH, m); 7.55 (IH, m), 7.47 (IH, m), 7.24 (2H, m); 6.86 (IH, m); 4.52 (2H, d); 3.80 (3H, s). APCI-MS m/z: 420 [MH+].
Example 8.7 N-Q.3-Benzodioxol-5-ylmethylV2.4-dioxo-3-r3- (trifluoromethyl)phenyl]-l,2,3,4-tefrahyαι:opyrimidine-5-carboxamide
1H NMR (CDCI3): δ 8.93 (IH, m); 8.71 (IH, m); 8.54 (IH, t); 7.76 (IH, d); 7.68 (IH, t);
7.54 (IH, m); 7.46 (IH, d); 7.27 (IH, s); 6.85 (IH, d); 6.76 (IH, d); 5.95 (2H, d); 4.56 (IH, d); 4.48 (IH, d).
APCI-MS m/z: 434 [MH+].
Example 8.8 N-O-Chlorobenzyiy∑^-dioxo-S-rSAtrifluoromethvDphenyll-
1.2,3,4-tetrahydropyrimidine-5-carboxamide
1H NMR (CDCI3): δ 10.07 (IH, d); 9.11 (IH, t); 8.54 (IH, d); 7.78 (IH, d); 7.69 (IH, t);
7.55 (IH, m); 7.47 (IH, d); 7.29 (IH, m); 7.26 (2H, m); 7.19 (IH, m); 4.58 (2H, d). APCI-MS m z: 424 [MH+].
Example 9 1 -Butyl-N- r4-(methylsulf onvDbenzyll-2,4-dioxo-3- r3-
(trifluoromethyl)phenyl1-l,2,3,4-tetrahvdropyrimidine-5-carboxamide
a) N-Butyl-N'-[3-(trifluoromethyl)phenvnurea l-Isocyanato-3-(trifluoromethyl)benzene (0.74 ml, 5.34 mmol) was added to an ice cooled solution of n-butylamine (1.06 ml, 10.68 mmol) in acetonitrile (10 ml). The mixture was stirred for 10 minutes and then the solvent was evaporated to give the title compound as a white solid (1.37 g, 99%). APCI-MS m/z: 261 [MH+]. b) Ethyl l-butyl-Σ^-dioxo-S-lS-ftrifluoromethy phenyll-l^^^-tetrahydropyrimidine-S- carboxylate
To a solution of N-butyl-N'-[3-(trifluoromethyl)phenyl]urea (1.37 g, 5.26 mmol) and diethyl (ethoxymethylene)malonate (2.13 ml, 10.68 mmol) in NMP (6 ml) at 100 °C was added potassium tert-butoxide (0.10 g, 0.89 mmol) and the mixture was stirred for 1 h.
Ethyl acetate was added and the mixture was washed with IM hydrochloric acid, brine and water. The solvent was evaporated and the resulting oil was purified by HPLC to give the title compound (667 mg, 33%).
1H NMR (CDC13): δ 8.33 (IH, s); 7.70 (IH, d); 7.62 (IH, t); 7.51 (IH, s); 7.41 (IH, d); 4.35 (2H, q); 3.89 (2H, t); 1.81-1.74 (2H, m); 1.45-1.33 (5H, m); 0.99 (3H, t).
APCI-MS m/z: 385 [MH+]. c) 1 -Butyl-2,4-dioxo-3-[3-(trifluoromethyl)phenyll - 1 ,2,3 ,4-tetrahydropyrimidine-5- carboxylic acid
A solution of ethyl l-butyl-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4- tetrahydropyrimidine-5-carboxylate (101 mg, 0.26 mmol) and 0.5M sodium hydroxide solution (700 μl, 0.35 mmol) in THF was stirred for 2 h. Water was added and the mixture was washed with ethyl acetate. Acidification of the aqueous phase, extraction with ethyl acetate and removal of the solvent yielded the title compound (65 mg, 70%). 1HNMR (CDC13): δ 8.57 (IH, s); 7.79 (IH, d); 7.70 (IH, t); 7.55 (IH, s); 7.46 (IH, d); 3.96 (2H, t); 1.85-1.75 (2H, m); 1.50-1.37 (2H, m); 1.00 (3H, t). APCI-MS m/z: 357 [MH+]. d l-Butyl-N-[4-(methylsulfonvnbenzyll-2,4-dioxo-3-[3-(trifluoromethvnphenvn- l,2,3.4-tetrahydropyrimidine-5-carboxamide
A solution of 4-methylsulphonylbenzylamine hydrochloride (30 mg, 0.14 mmol) and DIEA (24 μl, 0.14 mmol) in dichloromethane (1 ml) was added to a stirred mixture of l-butyl-2,4-dioxo-3-[3-(1rifluoromethyl)phenyl]-l,2,3,4-tetrahydropyrimidine-5-carboxylic acid (44 mg, 0.12 mmol), HATU (52 mg, 0.14 mmol), HO AT (19 mg, 0.14 mmol) and DIEA (63 μl, 0.37 mmol) in dichloromethane (1 ml). The resulting mixture was stirred for 2 h. The solvent was evaporated and the product was purified by HPLC and by flash chromatography to give the title compound (22 mg, 35%).
1H NMR (CDC13): δ 9.14 (IH, t); 8.55 (IH, s); 7.89 (2H, d); 7.75 (IH, d); 7.67 (IH, t);
7.53 (IH, s); 7.50 (2H, d); 7.44 (IH, d); 4.66 (2H, d); 3.93 (2H, t); 3.03 (3H, s); 1.83-1.75 (2H, m); 1.47-1.38 (2H, m); 0.99 (3H, t).
APCI-MS m/z: 524 [MH+].
The compounds of Examples 9.1 to 9.4 were prepared using the general method described for Example 9:
Example 9.1 l-(2-MethoxyethylVN-r4-(methylsulfonyl benzyll-2,4-dioxo-3-r3- (trifluoromethyl)phenyl]-l,2,3,4-tetrahydropyrirmdine-5-carboxamide
1H NMR (CDCI3): δ 9.13 (IH, t); 8.61 (IH, s); 7.90 (2H, d); 7.75 (IH, d); 7.67 (IH, t);
7.54 (IH, s); 7.51 (2H, d); 7.45 (IH, d); 4.66 (2H, d); 4.12 (2H, t); 3.68 (2H, t); 3.40 (3H, s); 3.03 (3H, s).
APCI-MS m/z: 526 [MH+].
Example 9.2 l-Memyl-N-r4-fmemylsutfonyl)benzyl1-2.4-dioxo-3-r3-
(trifluoromethyl phenyl1-l,2,3,4-tetrahydropyrimidine-5-carboxamide
1H NMR (CDCI3): δ 9.10 (IH, t); 8.57 (IH, s); 7.90 (2H, d); 7.76 (IH, d); 7.67 (IH, t);
7.52 (IH, s); 7.50 (2H, d); 7.43 (IH, d); 4.66 (2H, d); 3.61 (3H, s); 3.03 (3H, s). APCI-MS m/z: 482 [MH+].
Example 9.3 l-Ethyl-N-[4-(,methylsulfonyl)benzyll-2.4-dioxo-3-[3-
(trifluoromethyl)phenyll-l,2,3,4-tetrahydropyrimidine-5-carboxamide 1H NMR (CDCI3): δ 9.13 (IH, t); 8.58 (IH, s); 7.90 (2H, d); 7.75 (IH, d); 7.67 (IH, t); 7.53 (IH, s); 7.50 (2H, d); 7.44 (IH, d); 4.66 (2H, d); 4.01 (2H, q); 3.03 (3H, s); 1.45 (3H, t).
APCI-MS m/z: 496 [MH+].
Example 9.4 N-(4-ChlorobenzylVl-(2-methoxyethylV2.4-dioxo-3-[3-
(trifluoromethyl phenyl1-l,2,3,4-tefrahvdropyrimidine-5-carboxamide
1H NMR (CDC13): δ 8.99 (IH, t); 8.60 (IH, s); 7.74 (IH, d); 7.66 (IH, t); 7.53 (IH, s); 7.44
(IH, d); 7.30-7.22 (4H, m); 4.54 (2H, d); 4.11 (2H, t); 3.67 (2H, t); 3.40 (3H, s). APCI-MS m/z: 482 [MH+].
Example 10 5-Iodo-6-methyl-N- [4-(methylsulf onyDbenzyll -2-oxo- 1 - [3 -
(trifluoromethyl)phenvn - 1 ,2-dihydrop yridine-3 -carboxamide
N-Iodosuccinimide (9.7mg, 0.043 mmol) was added to a stirred solution of 6-methyl-N- [4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxamide (20 mg, 0.043 mmol) in trifluoromethanesulfonic acid (0.5 ml). The mixture . was stirred for 10 minutes. Dichloromethane (10 ml) was added and the organic phase was washed with aqueous sodium hydrogencarbonate, aqueous sodium thiosulfate and water.
The extracts were dried and evaporated to give the title compound (100%). 1H NMR (CDCI3): δ 9.81 (IH, brt); 8.86 (IH, s,); 7.88 (2H, d); 7.82-7.69 (3H, m); 7.48
(2H, d); 7.40 (IH, d); 4.65 (2H, m); 3.01 (3H, s); 2.28 (3H, s).
The following Intermediates were prepared using the procedure described in Example 9(c):
1 -(2-Methoxyethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyll - 1 ,2,3 ,4-tetrahvdropyrimidine- 5-carboxyιic acid APCI-MS m/z: 359 [MH+].
3-(3-Chlorophenyl)- 1 -(2-methoxyethyl)-2,4-dioxo- 1 ,2,3 ,4-tetrahydropyrimidine-5- carboxylic acid APCI-MS m/z: 325 [MH+].
l-Butyl-3-(3-methoxyphenyl)-2,4-dioxo-l,2,3,4-tetrahydjoρyrimidine-5-carboxylic acid 1H NMR (DMSO-d6): δ 12.09 (IH, br s); 8.79 (IH, s); 7.39 (IH, t); 7.01 (IH, dd); 9.91 (IH, t); 6.85(lH,d); 3.89 (2H, t); 3.74 (3H, s); 1.61 (2H, pentet); 1.30 (2H, hextet); 0.89 (3H, t).
l-Butyl-3-(3-(trifluoromethyl)phenyl)-2,4-dioxo-l,2,3,4-tetrahvdropyrimidine-5- carboxylic acid 1H NMR (DMSO-d6): δ 12.55 (IH, br s); 8.76 (IH, s); 7.84-7.60 (4H, m); 3.89 (2H, t); 1.63 (2H, pentet); 1.30 (2H, hextet); 0.89 (3H, t).
l-Butyl-3-(3-chlorophenyl)-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5-carboxylic acid APCI-MS m/z 323 [MH+].
l-Butyl-3-(3-cyanophenyl)-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5-carboxylic acid 1H NMR (DMSO-d6): δ 12.30 (IH, br s); 8.74 (IH, s); 7.94-7.85 (2H, m); 7.75-7.69 (2H, m); 3.89 (2H, t); 1.63 (2H, pentet); 1.30 (2H, hextet); 0.89 (3H, t).
Example 11 N-(4-ChlorobenzvD-l-(2-methoxyethylV2.4-dioxo-3-r3-
(trifluoromethyl)phenyl1-l,2,3,4-tetrahydropyrimidine-5-carboxamide l-(2-Methoxyethyl)-2,4-dioxo-3-[3-(trifluoromethyl)phenyl]-l,2,3,4-tetrahydropyrimidine- 5-carboxylic acid (0.016 mmol, 0.2M in NMP) was added to PS-Carbodiimide resin (60 mg), HOBT (0.032 mmol, 0.3M in NMP) and NMP (200 μl). The mixture was stirred for 15 minutes and 4-chlorobenzylamine (0.019 mmol, 0.3M in NMP) was added. After shaking overnight the excess HOBT was scavenged using PS-Trisamine resin (45 mg), shaking for 2 h before the resin reagents were filtered off. The title compound was obtained after purification using preparative HPLC. APCI-MS m/z: 482.4 [MH+]. Examples 11.1 to 11.13 were prepared from l-(2-methoxyethyl)-2,4-dioxo-3-[3- (trifluoromethyl)phenyl]-l,2,3,4-tetrahydropyrimidine-5-carboxylic acid and the appropriate amine using the general procedure described in Example 11:
Example 11.1 N-(,4-Methoxybenzyl -l-C2-methoxyethyl')-2,4-dioxo-3-r3-
(trifluoromethyl)phenyl]-l,2,3,4-tefrahydropyrirmdine-5-carboxamide APCI-MS m/z: 478.5 [MH+].
Example 11.2 l-(2-MethoxyethylV2,4-dioxo-N-(ρyridin-4-ylmethyl)-3-r3- (trifluoromethyl)phenyl] - 1 ,2,3 ,4-tetrahydropyrirmdine-5-carboxamide APCI-MS m/z: 449.4 [MH+].
Example 11.3 N-r2-(3,4-Dimethoxyphenyl)ethyll-l-(2-methoxyethyl -2,4-dioxo-3-
[3-(trifluoromethyl)phenyl]-l,2,3,4-tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 522.5 [MH+].
Example 11.4 l-(2-MethoxyethylVN-[2-(3-methoxyphenvnethyll-2,4-dioxo-3-r3-
(trifluoromethvDphenyll-l,2,3,4-tetrahydropyrimidine-5-carboxamide
APCI-MS m/z: 492.5 [MH ]
Example 11.5 l-(2-MethoxyethvD-N-(4-methylbenzylV2,4-dioxo-3-[3-
(trifluoromethyl)phenyl1-l,2,3,4-tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 462.5 [MH+].
Example 11.6 l-(2-MethoxyethylVN-[4-(methylsulfonyl')benzyll-2.4-dioxo-3-[3-
(trifluoromethyl)phenyl1-l,2,3,4-tetrahvoj,opyrirmdine-5-carboxamide APCI-MS m/z: 526.5 [MH+].
Example 11.7 N-(4-FluorobenzylVl-(2-methoxyethylV2,4-dioxo-3-r3- (trifluoromethyl phenyl]-l,2,3,4-tetrahvdropyrimidine-5-carboxamide APCI-MS m/z: 466.4 [MH+].
Example 11.8 N-(l,3-Benzodioxol-5-ylmethylAl-(2-methoxyethylV2,4-dioxo-3-
[3-(trifluoromethvDphenyl]-l,2,3,4-tetrahvdropyrimidine-5-carboxamide APCI-MS m/z: 492.5 [MH+].
Example 11.9 N-(2-Chloro-4-fluorobenzylVl-f2-methoxyethvD-2.4-dioxo-3-r3-
(trifluoromethyl)phenyll - 1 ,2,3 ,4-tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 500.4 [MH+].
Example 11.10 N-(3 ,4-Dichlorobenzyl)- 1 -(2-methoxyethylV2.4-dioxo-3- β-
(trifluoromethyl)phenyl1-l,2,3,4-tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 516.4, 518.4 [MH+].
Example 11.11 Methyl 4-{\({ l-(2-methoxyethylV2,4-dioxo-3-r3-
(trifluoromethyl)phenyl]-l,2,3,4-tetrahydropyrimidin-5- yl I carbon vDaminolmethyl Ibenzoate APCI-MS m/z: 506.5 [MH+].
Example 11.12 l-(2-Methoχyethyl)-N-[(5-methylisoxazol-3-vDmethyl1-2,4-dioxo-3-
[3-(trifluoromethyl phenyl1-l,2,3,4-tetrahvdropyrimidine-5-carboxamide APCI-MS m/z: 453.4 [MH+].
Example 11.13 l-(2-MethoxyethvD-2,4-dioxo-N-[4-(lH-pyrazol-l-yl)benzyl1-3-r3- (trifluoromethyl)phenyll-l,2,3,4-tefrahydropyrimidine-5-carboxamide APCI-MS m/z: 514.5 [MH+].
Examples 11.14 to 11.29 were prepared from 3-(3-chlorophenyl)-l-(2-methoxyethyl)-2,4- dioxo-l,2,3,4-tetrahydropyrimidine-5-carboxylic acid and the appropriate amine using the general procedure described in Example 11 : Example 11.14 N-(4-ChlorobenzylV3-(3-chlorophenylVl-(2-methoxyethvD-2.4- dioxo- 1 ,2,3 ,4-tetrahvdropyrimidine-5-carboxamide APCI-MS m/z: 448.4, 450.4 [MH+].
Example 11.15 3-r3-ChloroρhenylVN-(4-methoxybenzylVl-(2-methoxyethylV2.4- dioxo-l,2,3,4-tetrahydropyrirmdine-5-carboxamide
APCI-MS m/z: 444.4 [MH+].
Example 11.16 3-(3-ChlorophenylVl-(2-methoxyethyl)-2,4-dioxo-N-(pyridin-4- ylmethyl)-l,2,3,4-tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 415.4 [MH+].
Example 11.17 3-(3-Chloroρhenyl)-N-[2-(3,4-dimethoxyphenyl')ethyll-l-(2- methoxyethyl -2,4-dioxo-l,2,3,4-tefrahydjopyrimidine-5-carboxamide APCI-MS m/z: 488.5 [MH+].
Example 11.18 3-(3-ChloroρhenylVl-(2-methoxyethylVN-F2-(3- methoxyphenyl)ethyl1-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 458.5 [MH+].
Example 11.19 N-(3-BromobenzylV3-(3-chloroρhenylVl-(2-methoxyethylV2.4- dioxo-l,2,3,4-tetrahvdropyrimidine-5-carboxamide
APCI-MS m/z: 492.4, 494.3 [MH+].
Example 11.20 3-(3-ChlorophenylV 1 -(2-methoxyethyl )-N-(4-methylbenzylV2.4- dioxo- 1 ,2,3 ,4-tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 428.4 [MH+]. Example 11.21 3-(3-Chlorophenyl -l-(2-methoxyethylVN-[4-
(methylsulfonyl)benzyl1-2,4-dioxo-1.2,3,4-tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 492.4 [MH+].
Example 11.22 3-(3-ChloroρhenylVN-(4-fluorobenzylVl-(2-methoxyethylV2,4- dioxo- 1 ,2,3 ,4-tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 432.4 [MH+].
Example 11.23 N-(l,3-Benzodioxol-5-ylmethylV3-(3-chlorophenyl)-l-(2- methoxyethyl)-2,4-dioxo- 1 ,2,3 ,4-tetrahvdropyrimidine-5-carboxamide APCI-MS m/z: 458.4 [MH+].
Example 11.24 3-(3-ChlorophenylVN-(3.4-difluorobenzyl')-l-(2-methoxyethylV2.4- dioxo- 1 ,2,3 ,4-tefrahydropyrimidine-5-carboxamide APCI-MS m/z: 450.3 [MH+].
Example 11.25 N-(2-Chloro-4-fιuorobenzylV3-(3-chlorophenylVl-f2- methoxyethyl)-2,4-dioxo- 1 ,2,3 ,4-tetrahvdropyrimidine-5-carboxamide APCI-MS m/z: 466.4, 468.4 [MH+].
Example 11.26 3-r3-ChlorophenylVN-('3.4-dichlorobenzylVl-r2-methoxyethyl)-2,4- dioxo-l,2,3,4-tefrahydropyrimidine-5-carboxamide
APCI-MS m/z: 482.3, 484.3 [MH+].
Example 11.27 Methyl 4-[(l r3-(3-chlorophenylVl-(2-methoxyethylV2.4-dioxo-
1 ,2,3 ,4-tetrahydropyrimidin-5-yl1carbonyl ) amino')methyl1benzoate APCI-MS m/z: 472.4 [MH+].
Example 11.28 3-r3-ChlorophenylVl-(2-methoxyethylVN-[(5-methylisoxazol-3- yl)methyll-2,4-dioxo-1.2.3,4-tetrahy( ropyrimidine-5-carboxamide APCI-MS m/z: 419.4 [MH+].
Example 11.29 3-(3-ChlorophenylVl-(2-methoxyethvD-2,4-dioxo-N-[4-(lH- pyrazol- 1 -vDbenzyll - 1 ,2,3 ,4-tetrahydropyrimidine-5-carboxamide APCI-MS m z: 480.5 [MH+].
Examples 11.30 to 11.38 were prepared from l-butyl-3-(3-methoxyphenyl)-2,4-dioxo- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid and the appropriate amine using the general procedure described in Example 11:
Example 11.30 l-Butyl-N-(4-chlorobenzylV3-(3-methoxyphenylV2,4-dioxo-1.2.3.4- tetrahvdropyrimidine-5-carboxamide
APCI-MS m z: 442.4 [MH+].
Example 11.31 l-Butyl-3-(3-methoxyphenylVN-r2-(3-methoxyphenyl)ethyl1-2.4- dioxo-l,2,3,4-tetrahvdropyrimidine-5-carboxamide APCI-MS m/z: 452.3 [MH+].
Example 11.32 N-(3-Bromobenzyl)-l-butyl-3-(3-methoxyρhenylV2,4-dioxo-1.2.3,4- tefrahyqj:opyrimidine-5-carboxamide APCI-MS m/z: 486.4, 488.4 [MH+].
Example 11.33 1 -Butyl-N-(4-fluorobenzyl)-3 -(3-methoxyphenyl >-2.4-dioxo- 1 ,2,3 ,4- tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 426.3 [MH+].
Example 11.34 N-(l,3-Benzodioxol-5-ylmethyl')-l-butyl-3-(3-methoxyphenvn-2.4- dioxo- 1 ,2,3 ,4-tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 452.4 [MH+]. Example 11.35 l-Butyl-N-(2,4-dichlorobenzv -3-(3-methoxyphenyl)-2,4-dioxo-
1 ,2,3 ,4-tetrahydropyrimidine-5-carboxarnide APCI-MS m/z: 476.4, 478.4 [MH+].
Example 11.36 l-Butyl-N-(3,4-difluorobenzyl -3-(3-methoxyphenyl)-2,4-dioxo- l,2,3,4-tefrahydropyrimidine-5-carboxamide APCI-MS m/z: 444.3 [MH+].
Example 11.37 l-Butyl-N-(2-chloro-4-fluorobenzylV3-(3-methoxyphenyl)-2,4- dioxo- 1 ,2,3 ,4-tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 460.3 [MH+].
Example 11.38 l-Butyl-N-(2,3-dihvdro-l-benzofuran-5-ylmethvD-3-(3- methoxyphenyl)-2,4-αioxo-l,2,3,4-tetrahydxopyrimidine-5-carboxarnide APCI-MS m/z: 450.5 [MH+].
Examples 11.39 to 11.58 were prepared from l-butyl-3-(3-chlorophenyl)-2,4-dioxo- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid and the appropriate amine using the general procedure described in Example 11:
Example 11.39 l-Butyl-N-(4-chlorobenzylV343-chlorophenylV2.4-dioxo-l,2.3.4- tetrahvdropyrimidine-5-carboxamide
APCI-MS m/z: 446.4, 448.4 [MH+].
Example 11.40 1 -Butyl-3-(3-chlorophenyl VN-(4-methoxybenzyl')-2.4-dioxo- 1.2,3.4- tefrahvdropyrimidine-5-carboxamide APCI-MS m/z: 442.4 [MH+].
Example 11.41 l-Butyl-3-(3-chlorophenylV2.4-dioxo-N-(pyridin-4-ylmethvIV l,2,3,4-tetrahydropyrimidine-5-carboxarnide APCI-MS m/z: 413.3 [MH+].
Example 11.42 l-Butyl-3-(3-chlorophenylVN-r2-(3,4-dimethoxyphenvDethyll-2,4- dioxo-l,2,3,4-tetrahyάj-opyrimidine-5-carboxamide APCI-MS m/z: 486.4 [MH+].
Example 11.43 l-Butyl-3-(3-chlorophenylVN-r2-(3-methoxyphenvDethyll-2,4- dioxo- 1 ,2,3 ,4-tetrahvdropyrimidine-5-carboxamide APCI-MS m/z: 456.4 [MH+].
Example 11.44 N-(3-BromobenzylVl-butyl-3-(3-chlorophenylV2.4-dioxo-1.2,3,4- tetrahvdropyrimidine-5-carboxamide
APCI-MS m/z: 490.3, 492.3 [MH+].
Example 11.45 N-(4-Bromobenzyl -l-butyl-3-(3-chlorophenylV2,4-dioxo-l,2,3,4- tetrahyckopyrimidine-5-carboxamide APCI-MS m/z: 490.3, 492.3 [MH+].
Example 11.46 l-Butyl-3-(3-chlorophenylVN-(4-methylbenzylV2,4-dioxo-l,2,3,4- tetrahvdropyrimidine-5-carboxamide APCI-MS m/z: 426.4 [MH+].
Example 11.47 l-Butyl-3-(3-chlorophenviyN-r4-(methylsulfonvnbenzyl]-2,4- dioxo-l,2,3,4-tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 490.4 [MH+].
Example 11.48 l-Butyl-3-(3-chlorophenvn-N-(4-fluorobenzyl')-2,4-dioxo-1.2,3.4- tetrahydropyrimidine-5-carboxamide
APCI-MS m/z: 430.4 [MH+]. Example 11.49 N-Q.3-Benzodioxol-5-ylmethyl -butyl-3-(3-chlorophenyl;-2,4- dioxo-l,2,3,4-tetrahvdropyrimidine-5-carboxamide
+-
APCI-MS m/z: 456.4 [MH ]
Example 11.50 l-Butyl-3-(3-chlorophenylVN-(2,4-dichlorobenzyl -2.4-dioxo- l,2,3,4-tetrahvdropyrimidine-5-carboxamide
APCI-MS m/z: 480.3, 482.3 [MH+].
Example 11.51 l-Butyl-3-(3-chlorophenylVN-(3,4-difluorobenzylV2.4-dioxo- l,2,3,4-tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 448.4 [MH+].
Example 11.52 1 -Butyl-N-(2-chloro-4-fluorobenz yl)-3 -(3 -chlorophenyl)-2 ,4-dioxo-
1 ,2,3 ,4-tefrahydropyrimidine-5-carboxamide APCI-MS m/z: 464.4, 466.4 [MH+].
Example 11.53 l-Butyl-3-(3-chlorophenylVN-(3,4-dichlorobenzyl)-2,4-dioxo-
1 ,2,3 ,4-tetrahydropyrinιidine-5-carboxamide APCI-MS m/z: 480.3, 482.4 [MH+].
Example 11.54 1 -Butyl-3-(3-chlorophenyl)-N-(2,3-dihydro- 1 -benzofuran-5- ylmethyl)-2,4-dioxo- 1 ,2,3 ,4-tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 452.4 [MH+].
Example 11.55 l-Butyl-3-(3-chlorophenyl)-N-r(4-cyanocvclohexyDmethyll-2,4- dioxo-l,2,3,4-tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 443.3 [MH+].
Example 11.56 l-Butyl-3-(3-chloroρhenylVN-r(5-methylisoxazol-3-vDmethyll-2.4- dioxo- 1 ,2,3 ,4-tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 417.3 [MH+].
Example 11.57 1 -Butyl-3-(3-chlorophenyl >2,4-dioxo-N-[4-( IH-pyrazol- 1 - yl)benzyl]-l,2,3,4-tetrahvdropyrirmdine-5-carboxamide APCI-MS m/z: 478.4 [MH+].
Example 11.58 l-Butyl-3-(3-chloroρhenyl)-2,4-dioxo-N-F3-(2-oxopyrrolidin-l- yDpropyl]-l,2,3,4-tetrahydropyrimidine-5-carboxamide
APCI-MS m/z: 447.3 [MH+].
Examples 11.59 to 11.77 were prepared from l-butyl-3-(3-cyanoρhenyl)-2,4-dioxo- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid and the appropriate amine using the general procedure described in Example 11:
Example 11.59 1 -Butyl-N-(4-chlorobenzyl)-3-(3-cvanophenylV2.4-dioxo- 1.2.3.4- tetrahvdropyrimidine-5-carboxamide APCI-MS m/z: 437.4 [MH+].
Example 11.60 l-Butyl-3-(3-cvanophenyl')-N-(4-methoxybenzyl)-2.4-dioxo-1.2.3.4- tefrahydropyrimidine-5-carboxamide APCI-MS m/z: 433.5 [MH+].
Example 11.61 l-Butyl-3-(3-cvanophenyl)-2,4-dioxo-N-(pyridin-4-ylmethylV
1.2,3 ,4-tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 404.3 [MH+].
Example 11.62 l-Butyl-3-(3-cvanophenviyN-r2-(3,4-dimethoχyphenvnethyll-2.4- dioxo- 1 ,2,3 ,4-tetrahvdropyrimidine-5-carboxamide APCI-MS m/z: 477.4 [MH+]. Example 11.63 l-Butyl-3-(3-cvanophenylVN-[2-(3-methoxyphenyl)ethyll-2,4- dioxo-1.2.3.4-tetrahvdropyrimidine-5-carboxamide
APCI-MS m/z: 447.3 [MH+].
Example 11.64 N-(3-Bromobenzyl)-l-butyl-3-(3-cvanophenyl)-2,4-dioxo-1.2.3.4- tetrahydropyrimidine-5-carboxamide
APCI-MS m/z: 481.4, 483.4 [MH+].
Example 11.65 N-(4-Bromobenzyl)-l-butyl-3-(3-cvanophenvD-2,4-dioxo-l,2,3,4- tetrahvdropyrimidine-5-carboxamide APCI-MS m/z: 481.4, 483.4 [MH+].
Example 11.66 l-Butyl-3-(3-cvanoρhenylVN-(4-methylbenzyl)-2,4-dioxo-1.2.3.4- tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 417.4 [MH+].
Example 11.67 l-Butyl-3-(3-cvanophenyl)-N-[4-(methylsulfonv benzyl]-2,4-dioxo- l,2,3,4-tefrahvdropyrimidine-5-carboxamide
APCI-MS m/z: 481.4 [MH+].
Example 11.68 l-Butyl-3-(3-cvanophenylVN-(4-fluorobenzylV2,4-dioxo-1.2.3.4- tetrahydropyrirnidine-5-carboxamide
APCI-MS m/z: 421.3 [MH+].
Example 11.69 N-Q,3-Benzodioxol-5-ylmethylVl-butyl-3-(3-cyanophenylV2.4- dioxo-l,2,3,4-tefrahvdropyrimidine-5-carboxamide APCI-MS m/z: 447.4 [MH+].
Example 11.70 l-Butyl-3-(3-cvanophenyl')-N-(2.4-dichlorobenzylV2.4-dioxo- 1 ,2,3 ,4-tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 471.4, 473.4 [MH ].
Example 11.71 l-Butyl-3-(3-cvanophenylVN-(3,4-difluorobenzylV2.4-dioxo-
1 ,2,3 ,4-tetrahvdropyrimidine-5-carboxamide APCI-MS m/z: 439.4 [MH+] .
Example 11.72 l-Butyl-N-(2-chloro-4-fluorobenzyl)-3-(3-cvanophenyl)-2,4-dioxo- l,2,3,4-tetrahydropyrimidine-5-carboxamide
APCI-MS m/z: 455.4 [MH+].
Example 11.73 l-Butyl-3-(3-cvanophenyl -N-(3,4-dichlorobenzyl')-2.4-dioxo- l,2,3,4-tetrahvdropyrimidine-5-carboxamide
APCI-MS m/z: 471.4, 473.5 [MH+].
Example 11.74 l-Butyl-N-[(4-cyanocvclohexyl)methyl1-3-(3-cyanophenyl)-2,4^ dioxo- 1 ,2,3 ,4-tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 434.5 [MH+].
Example 11.75 l-Butyl-3-(3-cyanophenyl)-N-[(5-methylisoxazol-3-yl)methyl1-2,4- dioxo-l,2,3,4-tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 408.4 [MH+].
Example 11.76 l-Butyl-3-(3-cvanophenylV2,4-dioxo-N-[4-(lH-pyrazol-l- yDbenzyll-l,2,3,4-tefrahvdropyrimidine-5-carboxamide APCI-MS m/z: 469.5 [MH+].
Example 11.77 l-Butyl-3-(3-cvanophenyl -2,4-dioxo-N-[3-(2-oxopyrrolidin-l- yl)propyl]-l,2,3,4-tetrahvdropyrimimιιe-5-carboxamide
APCI-MS m/z: 438.4 [MH+]. Examples 11.78 to 11.97 were prepared from l-butyl-3-(3-(trifluoromethyl)phenyl)-2,4- dioxo-l,2,3,4-tetrahydropyrimidine-5-carboxylic acid and the appropriate amine using the general procedure described in Example 11:
Example 11.78 l-Butyl-N-(4-chlorobenzylV2,4-dioxo-3-[3-
(trifluoromethyl)phenyll - 1 ,2,3 ,4-tetrahvdropyrimidine-5-carboxamide APCI-MS m/z: 480.4, 482.4 [MH+].
Example 11.79 l-Butyl-N-(4-methoxybenzylV2.4-dioxo-3-[3- (trifluoromethyl)phenyl1-l,2,3,4-tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 476.5 [MH+].
Example 11.80 l-Butyl-2.4-dioxo-N-('pyridin-4-ylmethylV3-r3-
(trifluoromethyl)phenyl]-l,2,3,4-tetrahydropyriirudine-5-carboxamide APCI-MS m/z: 447.4 [MH+].
Example 11.81 1 -Butyl-N- [2-(3 ,4-dimethoxyρhenvDethyll -2,4-dioxo-3-r3-
(trifluoromethyl)phenyl]-l,2,3,4-tetrahydropyrin idine-5-carboxamide APCI-MS m/z: 520.4 [MH+].
Example 11.82 l-Butyl-N-[2-(3-methoxyphenvDethyll-2,4-dioxo-3-F3-
(trifluoromethyl)phenyl]-l,2,3,4-tefrahyαι,opyrimidine-5-carboxamide APCI-MS m/z: 490.4 [MH+].
Example 11.83 N-(3-BromobenzylVl-butyl-2,4-dioxo-3-[3-
(trifluoromethyl)phenyll - 1 ,2,3 ,4-tefrahyclropyrimidine-5-carboxamide APCI-MS m/z: 524.4, 526.5 [MH+].
Example 11.84 N-f4-Bromobenzviyi-butyl-2,4-dioxo-3-[3- (trifluoromethv phenyl1-l,2,3,4-tetrahvdropyrimidine-5-carboxamide APCI-MS m/z: 524.4, 526.5 [MH+].
Example 11.85 l-Butyl-N-(4-methylbenzylV2,4-dioxo-3-[3-
(trifluoromethyl phenyl]-l,2,3,4-tetrahvdropyrimidine-5-carboxamide APCI-MS m/z: 460.4 [MH+].
Example 11.86 l-Butyl-N-[4-('methylsulfonv benzyll-2,4-dioxo-3-r3- f trifluoromethv phenyll- 1 ,2,3 ,4-tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 524.5 [MH+].
Example 11.87 l-Butyl-N-(-4-fluorobenzyl)-2,4-dioxo-3-[3-(trifluoromethvDphenyll- l,2,3,4-tetrahydropyriii]idine-5-carboxamide
APCI-MS m/z: 464.4 [MH+].
Example 11.88 N-(1.3-Benzodioxol-5-ylmethvD-l-butyl-2,4-dioxo-3-r3-
(trifluoromethyl phenyl1-l,2,3,4-tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 490.5 [MH+].
Example 11.89 l-Butyl-N-(2.4-dichlorobenzylV2,4-dioxo-3-[3- ( fluoromethv phenyll-l,2,3,4-tetrahydropyrir dine-5-carboxamide APCI-MS m/z: 514.4, 516.4 [MH+].
Example 11.90 l-Butyl-N-(3,4-difluorobenzylV2,4-dioxo-3-[3-
(1rifluoromethv phenyl1-l,2,3,4-tetrahvdropyrimidine-5-carboxamide APCI-MS m/z: 482.5 [MH+].
Example 11.91 l-Butyl-N-(2-chloro-4-fluorobenzylV2.4-dioxo-3-[3- ftrifluoromethyl)phenyl]-l,2,3,4-tetrahvdropyrimidine-5-carboxamide APCI-MS m/z: 498.4, 500.4 [MH+]. Example 11.92 l-Butyl-N-(3,4-dichlorobenzylV2.4-dioxo-3-r3-
(trifluoromethyl)phenyl1-l,2,3,4-tetrahvdropyrimidine-5-carboxamide APCI-MS m/z: 514.4, 516.4 [MH+].
Example 11.93 l-Butyl-N-(2,3-dihvdro-l-benzofuran-5-ylmethyl)-2.4-dioxo-3-r3-
(trifluoromethyl)phenyl]-l,2,3,4-tetrahvdropyrimidine-5-carboxamide APCI-MS m z: 486.5 [MH+].
Example 11.94 l-Butyl-N-[(4-cvanocvclohexyl)methyll-2,4-dioxo-3-r3- (trifluoromethyl)phenyl1-l,2,3,4-tetrahvdropyrimidine-5-carboxamide APCI-MS m/z: 477.5 [MH+].
Example 11.95 l-Butyl-N-[(5-methylisoxazol-3-vnmethyll-2,4-dioxo-3-r3-
(trifluoromethyl)phenyl]-l,2,3,4-tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 451.3 [MH+].
Example 11.96 l-Butyl-2,4-dioxo-N-f4-αH-ρyrazol-l-yr)benzyl1-3-r3-
(trifluoromethyl)phenyl1-1.2,3,4-tetrahydropyrimidine-5-carboxamide APCI-MS m/z: 512.5 [MH+].
Example 11.97 l-Butyl-2,4-dioxo-N-[3-(2-oxopyrrolidin-l-yl')proρyll-3-r3-
(trifluoromethyl)phenyll-l,2,3,4-tetrahydropyrirmdine-5-carboxamide APCI-MS m z: 481.4 [MH+].
Example 12 6-(Chloromethyl)-N-[4-(methylsulfonv benzvn-2-oxo-l-[3-
(trifluoromethyl)phenyl1-1.2-dihydropyridine-3-carboxamide The title compound was prepared by heating 6-(hydroxymethyl)-N-[4- (methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxamide (48 mg, 0.1 mmol) and an excess of thionyl chloride (1 ml) in CH2C12 (10 ml) for 1 h. Removal of the solvents afforded the product (50 mg, 100%) as a white solid after trituration from diethyl ether.
1H-NMR (DMSO-d6): δ 9.93 (IH, brt); 8.67 (IH, d); 7.88 (2H, d); 7.86 (IH, d); 7.76 (IH, t); 7.61 (IH, s); 7.54 (IH, d); 7.52 (2H, d); 6.75 (IH, d); 4.68 (2H, m); 4.12 (2H, s); 3.02 (3H, s).
APCI-MS m/z: 499 [MH+].
Example 13 N-[4-(Methylsulfonyl')benzyll-6-[(methylthio)methyl1-2-oxo-l-[3-
(trifluoromethyl phenyl1-l,2-dihvdropyridine-3-carboxamide The title compound was prepared by stirring 6-(chloromethyl)-N-[4-
(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxamide (40 mg, 0.08 mmol) with an excess of sodium methylthiolate (28 mg, 0.4 mmol) in NMP (10 ml) at room temperature overnight. Water was added and the reaction mixture was extracted with EtOAc. The crude product was purified by column chromatography on silica using EtO Ac/heptane (4: 1) as eluent to afford 15 mg (37%) of the title compound.
-1H-NMR (CDC13): δ 9.97 (IH, brt); 8.63 (IH, d); 7.88 (2H, d); 7.81 (IH, d) 7.73 (IH, t);
7.62 (IH, s); 7.53 (3H, m); 6.51 (IH, d); 4.67 (2H, m); 3.26 (2H, d); 3.02 (3H, s); 2.03
(3H, s). APCI-MS m/z: 511 [MH+] .
Example 14 N-[4-(Methylsulfonyl benzyll-6-({[4-
(methylsulf ony benzyl] amino ) methyl)-2-oxo- 1 - [S-drifluoromethy phenyll -1,2- dihvdropyridine-3-carboxamide The title compound was prepared by stirring 6-(chloromethyl)-N-[4-
(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxamide with an excess of 4-(methylsulfonyl) benzylamine hydrochloride and DIEA in NMP at room temperature overnight. The crude product was purified by preparative HPLC. APCI-MS m/z: 648 [MH+]. Example 15 N-[4-(Methylsulfonyl)benzyl1-6-(morpholin-4-ylmethyl)-2-oxo-l-
[3-(trifluoromethyl)phenyl1-l,2-dihvdropyridine-3-carboxamide The title compound was prepared by stirring 6-(chloromethyl)-N-[4- (methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxamide with an excess of morpholine in THF at 50 °C overnight. The crude product was purified by preparative HPLC. APCI-MS m/z: 550 [MH+].
Example 16 6-(Cvanomethyl)-N- [4-(methylsulf onyDbenzyll -2-oxo- 143-
(trifluoromethyl)phenyll-l,2-dihvdropyridine-3-carboxamide The title compound was prepared by stirring 6-(chloromethyl)-N-[4- (methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxamide with an excess of sodium cyanide in THF at 50 °C overnight. The crude product was purified by preparative HPLC. APCI-MS m/z: 490 [MH+].
Example 17 6-Isopropyl-N- [4-(methylsulf onyDbenzyll -2-oxo- 1 - [3 -
(trifluoromethyDphenyll- 1 ,2-dihydropyridine-3-carboxamide
a) 6-Isopropyl-2-oxo-l-r3-(trifluoromethyl)phenyl1-l,2-dihydropyridine-3-carboxylic acid
A mixture of ethyl 3-oxo-3-{[3-(trifluoromethyl)phenyl]amino}propanoate (5.5 g, 20 mmol), l-methoxy-4-methylpent-l-en-3-one (prepared using the method of S.M. Bromidge et al, Synth. Commun., 23(4), 487-494 (1993) (2.7 g, 21 mmol) and sodium methoxide (2 g, 40 mmol) in ethanol (50 ml) was heated to reflux for 5 h and then cooled. Water (50 ml) and 2M NaOH were added and the mixture stirred at room temperature overnight. The organic solvents were removed and the reaction mixture extracted with EtOAc. The aqueous phases were acidified with 0.5M citric acid to pH 3-4, the precipitate formed was filtered off, washed with water and dried to afford 0.4 g (6%) of the title compound as a brownish powder.
1H-NMR (CDC13): δ 13.74 (IH, s); 8.59 (IH, d); 7.87 (IH, d); 7.78 (IH, t); 7.54 (IH, brs); 7.48 (IH, d); 6.64 (IH, d); 2.54 (IH, m); 1.20 (6H, t). APCI-MS m/z: 326 [MH+]. b) 6-Isopropyl-N-[4-(methylsulfonyl')benzvn-2-oxo-l-r3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide
To a mixture of 6-isopropyl-2-oxorl-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxylic acid (98 mg, 0.3 mmol), HATU (126 mg, 0,33 mmol), HOAT (45 mg, 0,33 mmol) and DIEA (162 μl, 0.95 mmol) in NMP (3 ml) was added 4-(methylsulfonyl) benzylamine hydrochloride (69 mg, 0.31 mmol), the pH was adjusted to approx. pH 8-9 with DIEA.
The mixture was stirred for 1 h at room temperature. EtOAc was added and the organic phase washed twice with aqueous sodium hydrogen carbonate, 0.5M citric acid and water. The solvent was removed in vacuo and the residue was purified by column chromatography on silica using CH2Cl2/EtOAc (4:1) as eluent to afford the title compound in quantitative yield.
1H-NMR (CDC13): δ 9.99 (IH, brt); 8.65 (IH, d); 7.87 (2H, d); 7.82 (IH, d); 7.74 (IH, t);
7.51 (3H, m); 7.44 (IH, d); 6.54 (IH, d); 4.67 (2H, m); 3.01 (3H, s); 2.49 (IH, m); 1.17 (6H, t).
APCI-MS m/z: 493 [MH+].
Example 18 N-[4-(EthylsulfonvDbenzyl]-6-methyl-2-oxo-l-r3-
(trifluoromethyl)phenyll-l,2-dihv(3Jopyridine-3-carboxamide
a) tert-Butyl [4-(methylsulfonyl)benzyl]carbamate
To a solution of [4-(methylsulfonyl)benzyl]amine (600 mg, 2.7 mmol) in THF (9 ml), di-tert-butyldicarbonate (590 mg, 2.7 mmol) and DLEA (926 μl, 5.4 mmol) were added and the mixture was stirred overnight. After removal of the solvent the crude product was purified by flash chromatography to give the subtitle compound (650 mg, 84 %). 1H-NMR (CDCI3): δ 7.91 (2H, d); 7.49 (2H, d); 5.00 (IH, bs); 4.42 (2H, d); 3.05 (3H, s);
1.48 (9H, s).
APCI-MS m/z: 169.1, 186.1 [MH+]. b) tert-Butyl r4-(ethylsulfonyDbenzyl1carbamate To a solution of tert-butyl [4-(methylsulfonyl)benzyl]carbamate (400 mg, 1.4 mmol) in
THF (5 ml) at -72 °C, n-butyl lithium (1750 μl, 2.8 mmol) was added dropwise while maintaining the temperature at -70 °C. After addition the temperature was allowed to rise to -40 °C and methyl iodide (105 μl, 1.7 mmol) added. The mixture was stirred for 1 h, an aqueous solution of NH4CI was added and then the mixture was extracted with EtOAc. The organic layer was washed with NE^Cl solution and evaporated. The crude product was purified by preparative HPLC to give the subtitle compound (148 mg, 35%).
1H-NMR (CDCI3): δ 7.88 (2H, d); 7.49 (2H, d); 4.98 (IH, bs); 4.43 (2H, bs); 3.11 (2H, q);
1.48 (9H, s); 1.28 (3H, t).
APCI-MS m/z: 183.2, 200.2 [MH+]. c [4-(Ethylsulfonyl)benzyl1 amine trifiuoroacetate
Tert-butyl [4-(ethylsulfonyl)benzyl]carbamate (148 mg, 0.5 mmol) was stirred in 10%
TFA in CH2C12 for 3 h. The solvent was evaporated leaving the title compound (191 mg).
APCI-MS m/z: 200.1 [MH+]. d) N-[4-(Ethylsulfonyl')benzyll-6-methyl-2-oxo-l-[3-(trifluoromethynphenvn-1.2- dihydropyridine-3-carboxamide
The title compound was obtained from 4-(ethylsulfonyl)benzylamine trifiuoroacetate and l-(3-methylphenyl)-2-oxo-l,2-dihydropyridine-3-carboxylic acid using a procedure analogous to that described in Example 17.
1H-NMR (CDCI3): δ 9.98 (IH, t); 8.59 (IH, d); 7.84-7.81 (3H, m); 7.74 (IH, t); 7.52-7.50 (3H, m); 7.45 (IH, d); 6.48 (IH, d); 4.74-4.63 (2H, m); 3.08 (2H, q); 2.09 (3H, t); 1.26
(3H, t).
APCI-MS m/z: 479.3 [MH+].
Example 19 N43-Chloro-44methylsuIfonvnbenzyl]-6-methyl-2-oxo-143- (trifluoromethyl phenyll-l,2-dihvdropyridine-3-carboxamide a) 3-Chloro-4-(methylthio)benz aldehyde
To a stirred solution of 2-chlorothioanisole (1.25 ml, 9.5 mmol) in CH2C12 at -5 °C, titanium(IV) chloride (2076 μl, 18.9 mmol) was added dropwise over 10 min, while maintaining the temperature below 0 °C . After addition the mixture was stirred for 10 min before ,α-dichloromethyl methyl ether (0.94 ml, 10.4 mmol) was added dropwise maintaining the temperature below 0 °C. After addition, the mixture was allowed to reach ambient temperature and poured onto a saturated aqueous solution of sodium bicarbonate (70 ml). The mixture was filtered through a plug of celite, washing with CH2C12. The phases were separated and the aqueous phase was extracted with CH2C12. The combined organic phases were washed with brine and the solvent removed in vacuo. The crude product was purified by flash chromatography to yield the subtitle product (535 mg, 30%). 1H-NMR (CDC13): δ 9.91 (IH, s); 7.84 (IH, d); 7.75 (IH, dd); 7.27 (IH, d); 2.56 (3H, s). APCI-MS m/z: 187.1 [MH+]. b) r3-Chloro-4-(methylthio1phenvHmethanol
To a solution of 3-chloro-4-(methylthio)benzaldehyde (332 mg, 1.8 mmol) in THF (6 ml) and water (0.6 ml), NaBH-j. (269 mg, 7.1 mmol) was added . The mixture was stirred for 2 h. The reaction was quenched with IM aqueous HCI and EtOAc was added. After separating the phases, the organic layer was washed with water, dried and evaporated to afford the subtitle compound (350 mg, 91%).
1H-NMR (CDCI3): δ 7.39 (IH, d); 7.26 (IH, dd); 7.17 (IH, d); 4.66 (2H, s); 2.49 (3H, s). APCI-MS m/z: 170.9 [MH+]. c [3-Chloro-4-(methylsulfonyl)phenyl1methanol [3-Chloro-4-(methylthio)phenyl]methanol (350 mg, 1.9 mmol) was dissolved in aqueous sodium hydroxide (0.5M, 4.44 ml) and stirred for 20 min, sodium bicarbonate (1.23 g) and acetone (1.5 ml) were added followed by addition of Oxone (1.85 g, 3.0 mmol) in EDTA (6.5 ml, 0.4 mM). After stirring for 2 h the reaction was quenched by addition of sodium bisulphite (0.9 g) in water. EtOAc was added and the solution was acidified with aqueous 2M HCI. Sodium chloride was added to the aqueous which was then extracted with EtOAc. The organic layers were combined and washed with water, brine and dried. Evaporation afforded the subtitle compound as a white solid (359 mg, 88%). 1H-NMR (CDC13): δ 8.12 (IH, d); 7.60 (IH, d); 7.44 (IH, dd); 4.81 (2H, s); 3.27 (3H, s). d) 4-(BromomethylV2-chloro-l-(methylsulfonyl)benzene [3-Chloro-4-(methylsulfonyl)phenyl]methanol (239 mg, 1.1 mmol) was added to dioxane. The slurry was stirred and heated to 40 °C before addition of PB^ (71 μl, 0.8 mmol). The reaction was heated to 100 °C for 1 h and then allowed to cool. Water was added and the mixture extracted with EtOAc. The organic layer was washed with water followed by brine and dried. Evaporation afforded the subtitle compound (310 mg, 100%). 1H-NMR (CDCI3): δ 8.14 (IH, d); 7.61 (IH, d); 7.49 (IH, dd); 4.46 (2H, s); 3.28 (3H, s). e) [3-Chloro-4-(methylsulf onyDbenzyll amine
4-(Bromomethyl)-2-chloro-l-(methylsulfonyl)benzene (160 mg, 0.56 mmol) was dissolved in methanol (3 ml) and added to an equal mixture of ammonia (28%) and methanol (10 ml). The reaction was stirred at 40 °C for 1 h and evaporated. The crude product was dissolved in EtOAc and aqueous 6M sulphuric acid. The aqueous phase was separated, adjusted to pH 14 using sodium hydroxide and extracted with CH2C12. The CH2C12 phase was dried and evaporated to afford the title compound (65 mg, 53%). APCI-MS m/z: 219.9 [MH+]. f) N- [3 -Chloro-4-(methylsulf onyDbenzyll -6-methyl-2-oxo- 1 - [3-(trifluoromethyl)phenyn - 1 ,2-dihydropyridine-3-carboxamide
The title compound was prepared as described in Example 17.
1H-NMR (CDCI3): δ 10.03 (IH, t); 8.58 (IH, d); 8.07 (IH, d); 7.82 (IH, d); 7.75 (IH, t); 7.52 (2H, d); 7.45 (IH, d); 7.41 (IH, d); 6.49 (IH, d); 4.69-4.57 (2H, m); 3.23 (3H, s); 2.10 (3H, s). APCI-MS m/z: 499.0 [MH+].
Example 20 6-Methyl-2-oxo-l-(3-trifluoromethyl-phenyD-l,2-dihydro-pyridine-
3-carboxylic acid 4-cyclopropanesulfonyl-benzylamide
a) 4-Cvclopropanesulfonyl-benzylamine l-Cyclopropanesulfonyl-4-methyl-benzene, prepared by the method of W. E. Truce, et al, J. Org. Chem., 1961, 26, 1463-1467, (190 mg, 0.969 mmol), N-bromosuccinimide (190 mg, 1.07 mmol) and benzoyl peroxide (12 mg) in carbon tetrachloride (4 ml) were heated under reflux for 24 h, cooled, filtered and concentrated. The residue in methanol (1 ml) was added in portions during 10 min to a solution of ammonium hydroxide (28 %, 2 ml) in methanol (2 ml). After 2 h the solution was partitioned between EtOAc (10 ml) and sulphuric acid (0.4M, 10 ml), the pH of the aqueous layer was adjusted to 14 using 2M aqueous KOH and then extracted three times with dichloromethane. The organic phase was dried and concentrated to give the subtitle compound (83 mg). 1H-NMR (CDCI3): δ 7.78 (2H, bd); 7.35 (2H, bd); 2.46 (3H, s); 2.46 (IH, m); 1.34 (2H, m); 1.02 (2H, m). APCI-MS m/z: 212 [MH+].
The corresponding dibenzyl amine (12%) is also present. b) 6-Methyl-2-oxo-l-(3-trifluoromethyl-phenyl)-l ,2-dihvdro-pyridine-3-carboxylic acid 4-cyclopropanesulfonyl-benzylamide
The title compound was obtained from 4-cyclopropanesulfonyl-benzylamine and l-(3- methylphenyl)-2-oxo-l,2-dihydropyridine-3-carboxylic acid by a method analogous to that described in Example 17. 1H-NMR (CDCI3): δ 9.93 (IH, brt); 8.38 (IH, d); 7.89 (2H, bd); 7.84-7.80 (3H, m); 7.73 (IH, bd); 7.53 (2H, d); 6.26 (IH, d); 4.58 (2H, d); 2.80 (IH, m); 2.02 (3H, s); 1.08 (2H, m); 1.01 (2H, m). APCI-MS m/z: 491.1 [MH+].
Example 21 N-[3-Methoxy-4-(methylsulfonvDbenzvn-6-methyl-2-oxo-l-[3- (trifluoromethyl)phenyll - 1 ,2-dihydropyridine-3-carboxamide
a) [3-Methoxy-4-(methylsulfonyl)phenyl1methanol
[3-Methoxy-4-(methylthio)phenyl]methanol, prepared as described by Garcia et al. Supramolecular Chemistry, 1992, 1, 31-45, (75 mg, 0.4 mmol) was dissolved in aqueous sodium hydroxide (0.5M, 1.22 ml) and stirred for 30 min. Further reaction as in Example 19 (c) gave, after trituation with toluene, the subtitle compound as white crystals (47 mg,
54%).
1H-NMR (CDC13): δ 7.97 (d, / 8.0 Hz, IH); 7.15 (s, IH); 7.08 (d, J 8.0 Hz, IH); 4.81 (d, J
5.4 Hz, 2H); 4.04 (s, 3H); 3.32 (s, 3H). APCI-MS m/z: 217 [MH+]. b) 4-(BromomethvD-2-methoxy- 1 -(methylsulf ony benzene
To a slurry of [3-methoxy-4-(methylsulfonyl)phenyl]methanol (69 mg, 0.32 mmol) and toluene at 40 °C was added PBr3 (30 μl, 0.32 mmol). The reaction was heated to 100 °C for 1 h, cooled and water added. The reaction mixture was diluted with EtOAc, washed with water and brine and dried. Evaporation afforded the subtitle compound as a pale yellow oil (62 mg, 69%).
1H-NMR (CDC13): δ 7.97 (d, J 8.0 Hz, IH); 7.14 (dd, / 8.0, 1.4 Hz, IH); 7.10 (d, J 1.2
Hz, IH); 4.50 (s, 2H); 4.05 (s, 3H); 3.24 (s, 3H).
APCI-MS m/z: 280 [MH+]. c 3-Methoxy-4-(methylsulfonyl)benzylamine
4-(Bromomethyl)-2-methoxy-l-(methylsulfonyl)benzene (62 mg, 0.22 mmol) in methanol was slowly added to an equal mixture of ammonia (28%) and methanol. The reaction was stirred at room temperature for 2 h and evaporated. The reaction mixture was partitioned was between EtOAc and aqueous 6M sulphuric acid. The aqueous phase was made alkaline with sodium hydroxide and extracted with CH2C12. The CH2C12 phase was dried and evaporated to afford the title compound (36 mg, 76%).
APCI-MS m/z: 216 [MH+]. d^ N-[3-Methoxy-4-(methylsulfonyl)benzyl1-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide The title compound was obtained from 3-methoxy-4-(methylsulfonyl)benzylamine and l-(3-methylphenyl)-2-oxo-l,2-dihydropyridine-3-carboxylic acid by a method analogous to that described in Example 17.
1H-NMR (CDC13): δ 10.03 (s, IH); 8.60 (d, J7.5 Hz, IH); 7.91 (d, J 8.1 Hz, IH); 7.83 (d,
78.3 Hz, IH); 7.76 (t, J7.8 Hz, IH); 7.54 (d, J4.7 Hz, IH); 7.46 (d, J7.2 Hz, IH); 6.50 (d, J 7.2 Hz, IH); 7.05 (td, J 7.9, 5.3 Hz, 2H); 4.64 (t, J 6.3 Hz, 2H); 3.98 (s, 3H); 3.19 (s,
3H); 2.11 (s, 3H).
APCI-MS m/z: 495 [MH+].
Example 22 N- [3 -Bromo-4-(meth ylsulf onvPbenzyl] -6-methyl-2-oxo- 1 - [3 -
(trifluoromethyl jphenyll - 1 ,2-dihydropyridine-3-carboxamide
a 3-Bromo-4-(methylthio)benzaldehyde
To a solution of 3-bromo-4-fluorobenzaldehyde (0.5 g, 2.5 mmol) in NMP (10 ml), potassium carbonate (0.68 g, 4.92 mmol) and sodium metanethiolate (0.26 g, 3.69 mmol) were added. The mixture was heated to 70 °C for 7 h, cooled, and partitioned between EtOAc and water. The organic phase was dried, filtered, evaporated and purified by column chromatography on silica using heptane/EtOAc (4:1) as eluent to afford the title compound (0.25 g, 44%). 1H-NMR (CDC13): δ 9.89 (IH, s); 8.00 (IH, d); 7.79 (IH, dd); 7.23 (IH, d); 2.54 (3H, s). APCI-MS m/z: 465.3 [MH+]. b) [3-Bromo-4-(methylthio phenynmethanol
To a solution of 3-bromo-4-(methylthio)benzaldehyde (0.25 g, 1.08 mmol) in methanol (15 ml) was added sodium borohydride (0.2 g, 5.4 mmol). The solution was stirred at room temperature for 4 h, water was added, and the mixture was extracted with CH2C12. The organic layer was dried, filtered and evaporated to give 0.24 g (95%) of the title compound. 1H-NMR (CDC13): δ 7.55 (IH, d); 7.29 (IH, dd); 7.12 (IH, d); 4.64 (2H, s); 2.48 (3H, s). c) r3-Bromo-4-(methylsulfonyl)phenyllmethanol A suspension of sodium hydroxide (2.5 ml, 1.25 mmol) and [3-bromo-4-
(methylthio)phenyl]methanol (0.24 g, 1.03 mmol) was stirred at ambient temperature for 20 min, then sodium bicarbonate (0.69 g, 8.2 mmol) and acetone (1 ml) were added, followed by a Oxone solution (1.6 g in 6 ml of 0.4 mM EDTA) added over 10 min. The suspension was stirred overnight at room temperature. EtOAc was added and the solution was acidified with 5M HCI. The organic phase was washed several times with water and then dried, filtered and evaporated to give the title compound 0.19 g (70%). APCI-MS m/z: 249.1, 251 [MH+]. d) 2-Bromo-4-(bromomethyl)- 1 -(methylsulf onvDbenzene [3-Bromo-4-(methylsulfonyl)phenyl]methanol (0.19 g, 0.72 mmol) was mixed with toluene (5 ml) and phosphorus tribromide (30 μl, 0.32 mmol) at 40 °C, and the mixture was stirred at 100 °C for 20 min. EtOAc (100 ml) was added to the cooled solution and then washed with water. The organic phase was dried, filtered and evaporated to give 0.23 g (97%) of the title compound. 1H-NMR (DMSO-de): δ 8.06 (IH, d); 8.02 (IH, d); 7.73 (IH, dd); 4.76 (2H, s); 3.38 (3H, s). e [3-Bromo-4-(methylsulfonvDbenzyl1amine
A solution of 2-bromo-4-(bromomethyl)-l-(methylsulfonyl)benzene (230 mg, 0.70 mmol) in methanol (3 ml) and THF (1 ml) was added to HtOH (7 ml, 28%) during 30 min. After 4 h the solution was acidified with 0.5M HCI, washed twice with CH2C12 and then basified to pH 14 with 5M sodium hydroxide. The water phase was extracted with
CH2C12, and the organic layer was dried, filtered and evaporated to give 80 mg (43%) of the title compound.
1H-NMR (DMSO-d6): δ 7.99 (IH, d); 7.89 (IH, d); 7.58 (IH, dd); 3.79 (2H, s); 3.31 (3H, s)- APCI-MS m/z: 264, 266 [MH+]. f) N-[3-Bromo-4-(methylsulfonyDbenzyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyll-
1 ,2-dihvdropyridine-3-carboxamide
The title compound was obtained from [3-bromo-4-(methylsulfonyl)benzyl]amine and l-(3-methylphenyl)-2-oxo-l,2-dihydropyridine-3-carboxylic acid by a method analogous to that described in Example 17.
1H-NMR (DMSO-d6): δ 9.94 (IH, t); 8.37 (IH, d); 8.02 (IH, d); 7.93-7.68 (5H, m); 7.54
(IH, d); 6.61 (IH, d); 4.55 (2H, d); 3.33 (3H, s).
APCI-MS m/z: 543.2, 545.2 [MH+]. Example 23 N-[3-Cyano-4-(methylsulfonvDbenzyll-6-methyl-2-oxo-l-[3-
(trifluoromethylVphenyl]-l,2-dihydropyridine-3-carboxamide
a) 5-Formyl-2-(methylthio)benzonitrile The subtitle compound was prepared analogously to Example 22a but at room temperature for 1 h instead of heating the reaction mixture.
1H-NMR (400 MHz, CDC13): δ 9.94 (IH, s); 8.07 (IH, d, J 1.7 Hz); 8.01 (IH, dd, / 8.3,
1.8 Hz); 7.40 (IH, d, J 8.3 Hz); 2.64 (3H, s).
GC-MS m/z: 177 [M+]. b) 5-(Hydroxymethyl)-2-(methylthio)benzonitrile
The subtitle compound was prepared analogously to Example 22b.
1H-NMR (400 MHz, CDC13): δ 7.62 (IH, s); 7.53 (IH, d, J 8.3 Hz); 7.32 (IH, d, J 8.3
Hz); 4.70 (2H, s); 2.57 (3H, s). c) 5-(Hydroxymethyl)-2-(methylsulfonyl)benzonitrile The subtitle compound was prepared analogously to Example 22c.
1H-NMR (400 MHz, CDC13): δ 8.17 (IH, d, / 8.1 Hz); 7.93 (IH, s); 7.79 (IH, d, J 8.2
Hz); 4.88 (2H, s); 3.27 (3H, s). dl 5-(Bromomethyl)-2-(methylsulfonvDbenzonitrile
The subtitle compound was prepared analogously to Example 22d. 1H-NMR (400 MHz, CDC13): δ 8.18 (IH, d, J 8.1 Hz); 7.93 (IH, d, J 1.7 Hz); 7.82 (IH, dd, / 8.2, 1.6 Hz); 4.51 (2H, s); 3.29 (3H, s). e) 5-(Aminomethyl)-2-(methylsulfonyl)benzonitrile
The subtitle compound was prepared analogously to Example 22e.
1H-NMR (400 MHz, CD3OD): δ 8.14 (IH, d, J 8.2 Hz); 8.04 (IH, s); 7.88 (IH, d, J 8.1 Hz); 3.97 (2H, s); 3.29 (3H, s)
APCI-MS m/z: 211 [MH+]. f) N-F3-Cyano-4-(methylsulfonyl)benzyll-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyn-
1.2-dihvdropyridine-3-carboxamide
The title compound was prepared analogously to Example 17. 1H-NMR (400 MHz, CDC13): δ 10.19 (IH, t, J 5.7 Hz); 8.56 (IH, d, J7.4 Hz); 8.11 (IH, d, / 8.1 Hz); 7.85 - 7.71 (4H, m); 7.53 (IH, s); 7.46 (IH, d, J 8.0Hz); 6.51 (IH, d, J7.5 Hz); 4.71 (IH, dd, J 15.9, 6.2 Hz); 4.65 (IH, dd, J 15.9, 6.0 Hz); 3.23 (3H, s); 2.11 (3H, s). APCI-MS m/z: 490 [MH+].
Example 24 6-Methyl-N-r3-methyl-4-(methylsulfonyl)benzyll-2-oxo-l-[3-
(trifluoromethyl)-phenyl]-l,2-dihydropyridine-3-carboxamide
a) 3-Methyl-4-(methylthio benzaldehyde
The subtitle compound was prepared analogously to Example 22a. GC-MS m/z: 166 [M+]. b) F3-Methyl-4-(methylthio phenyl1methanol
The subtitle compound was prepared analogously to Example 22b. 1H-NMR (300 MHz, CDC13): δ 7.18 - 7.09 (3H, m); 4.57 (2H, s); 2.44 (3H, s); 2.32 (3H, s). c [3-Methyl-4-(methylsulfonyl phenyl]methanol
The subtitle compound was prepared analogously to Example 22c.
1H-NMR (300 MHz, CDC13): δ 7.92 (IH, d, J 18.7 Hz); 7.35 - 7.29 (2H, m); 4.73 (2H, s); 3.05 (3H, s); 2.66 (3H, s). d) 4-(Bromomethyl')-2-methyl-l-(methylsulfonyl')benzene
The subtitle compound was prepared analogously to Example 22d.
1H-NMR (300 MHz, CDC13): δ 8.00 (IH, d, J 8.1 Hz); 7.42 - 7.28 (2H, m); 4.46 (2H, s);
3.07 (3H, s); 2.70 (3H, s). e) [3 -Methyl-4-(meth ylsulf onvDbenzyll amine
The subtitle compound was prepared analogously to Example 22e.
1H-NMR (400 MHz, CDC13): δ 7.98 (IH, d, J 8.2 Hz); 7.35 - 7.29 (2H, m); 3.93 (2H, s);
3.06 (3H, s); 2.70 (3H, s).
APCI-MS m/z: 200 [MH+]. f) 6-Methyl-N-[3-methyl-4-(methylsulfonvDbenzyl1-2-oxo-l-[3-(trifluoromethyl')- phenyl1-l,2-dihydropyridine-3-carboxamide The title compound was prepared analogously to Example 17.
1H-NMR (300 MHz, CDC13): δ 9.91 (IH, bt, 75.7Hz); 8.58 (IH, d, 77.5 Hz); 7.95 (IH, d, 78.1Hz); 7.83 - 7.27 (6H, m); 6.47 (IH, dd, 77.5, 0.5 Hz); 4.68 - 4.53 (2H, m); 3.03 (3H, s); 2.66 (3H, s); 2.08 (3H, s). APCI-MS m/z: 479 [MH+].
Example 25 6-Methyl-N44-(methylthio>benzyl]-2-oxo-143- (trifluoromethyDphenyl1-l,2-dihydropyridine-3-c-u:boxamide
6-Methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxylic acid (1.29 g, 4.35 mmol) and [4-(methylthio)benzyl]amine (0.66 g, 4.35 mmol) were dissolved in NMP (18 ml). HBTU (1.81 g, 4.79 mmol) and DIEA (1.86 ml, 10.9 mmol) were added neat at room temperature and the mixture was stirred overnight. The reaction mixture was poured into EtOAc. The organic phase was washed with 2.5% aqueous sodium carbonate, then three times with water and dried. Purification by flash-chromatography (EtOAc: cyclohexane 9:1) gave the title compound (1.3 g, 69%).
1H-NMR (400 MHz, DMSO-d6) δ 9.78 (IH, t, 75.8 Hz); 8.38 (IH, d, 77.4 Hz); 7.91 - 7.69 (4H, m,); 7.22 (4H, m); 6.62 (IH, d, 77.6 Hz); 4.42 (2H, d, 75.9 Hz); 2.43 (3H, s,); 2.01 (3H, s).
APCI-MS m/z: 433.1 [MH+].
Example 26 6-Methyl-N44-(methylsulfinyl)benzyl]-2-oxo-143-
(trifluoromethyl)phenyl1-l,2-dihydropyridine-3-carboxamide 6-Methyl-N-[4-(methylthio)benzyl]-2-oxo-l-[3-(trifluoromethyl)ρhenyl]-l,2- dihydropyridine-3-carboxamide (1.26 g, 2.93 mmol) was dissolved in CH2C12 (12 ml). The solution was cooled to -15 °C. To the stirred solution 3-chloroperoxybenzoic acid (672 mg, 2.93 mmol) was added portion wise. The reaction was stirred for 1 h. The cooling bath was removed and the reaction was allowed to reach room temperature. After 2 h, CH C12 and diluted sodium thiosulphate solution were added. The mixture was shaken and the water phase was separated. The organic layer was washed twice with saturated NaHCO3, once with brine and finally dried. Purification by flash- chromatography (EtOAc: MeOH 9:1) gave the title compound (1.1 g, 80%). 1H-NMR (400 MHz, DMSO-d6) δ 9.88 (IH, t, 75.9 Hz); 8.38 (IH, d, 77.5 Hz); 7.93 - 7.69 (4H, m,); 7.62 (2H, d, 78.2 Hz); 7.47 (2H, d, 78.2 Hz); 6.62 (IH, d, 77.7 Hz); 4.54 (2H, d, 76.0 Hz); 2.70 (3H, s,); 2.02 (3H, s,). APCI-MS m/z: 449.1 [MH+].
Example 27 N-[4-(Benzylsulfonyl)benzyll-6-methyl-2-oxo-l-[3- (trifluoromethyl)phenyll - 1 ,2-dihvdropyridine-3-carboxamide
a) N-(4-Mercaptobenzyl V6-methyl-2-oxo- 143-(trifluoromethyl)phenyl1 -1,2- dihvdropyridine-3-carboxamide 6-Methyl-N-[4-(methylsulfinyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide (0.30 g, 0.67 mmol) was dissolved in dry acetonitrile (3 ml) and 2,6-lutidine (0.24 ml, 2.08 mmol) was added. The solution was cooled to -20 °C and trifluoroacetic anhydride (0.28 ml, 2.0 mmol) was added . The reaction was kept between -10 °C and 0 °C for 1 h, and then allowed to reach room temperature. All volatile materials were evaporated at 30 °C. The crude residue was cooled to 0 °C. A degassed, dry 1:1 mixture of triethylamine (1.1 ml) and methanol (1.1 ml), cooled to 0 °C, was added. The reaction was stirred at room temperature for 30 min and then evaporated. The residue was dissolved in a 1:1 mixture of methanol and 6M hydrochloric acid and stirred at 50 °C for 20 min. The major part of the solvent was evaporated. Ethyl acetate and water were added. The water phase was separated and washed again with ethyl acetate. The combined organic phase was washed with brine, dried, evaporated and used as crude product in the next step. LC-MS; method B RT: 8.19 min, APCI-MS m/z: 419.3 [MH+].
b) N- F4-(B enzylsulf on vDbenzyll -6-meth yl-2-oxo- 1 - \3 -(trifluorometh vPphenyll -1.2- dihydropyridine-3-carboxamide In an argon filled vial N-(4-mercaptobenzyl)-6-methyl-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-dihy(kopyri(iine-3-carboxarnide (29 mg, 0.07 mmol) was dissolved in dried, degassed ethanol (0.1 ml) and cooled to 0 °C. A solution of potassium tert-butoxide (7.8 mg, 0.7 mmol) in ethanol (0.2 ml) was added. The reaction was stirred for 45 min. (Bromomethyl)benzene (12 μl, 0.105 mmol) in ethanol (0.1 ml) was added. The ice bath was removed and the reaction was stirred overnight. A mixture of ethyl acetate and IM aqueous NΗ CI was added. The organic layer was separated, dried and evaporated. The residue was dissolved in CH2C12 (240 μl) and cooled with stirring to - 15 °C. 3-Chloroρeroxybenzoic acid (35 mg, 0.154 mmol) in CH2C12 (200 μl) was added. The cooling bath was removed and the reaction was stirred overnight. EtOAc and 5% aqueous sodium thiosulfate were added. The organic layer was separated, washed with 5% aqueous sodium carbonate, brine and dried. Purification by preparative HPLC gave the title compound (11 mg, 30%). 1H-NMR (400 MHz, DMSO-d6) δ 9.91 (IH, t, 76.1 Hz); 8.38 (IH, d, 77.5 Hz); 7.81 (4H, m); 7.66 (2H, d, 78.4 Hz); 7.46 (2H, d, 78.2 Hz); 7.31 - 7.11 (5H, m,); 6.63 (IH, d, 77.6
Hz); 4.62 (2H, s,); 4.57 (2H, d, 76.1 Hz); 2.03 (3H, s,). APCI-MS m/z: 541.4 [MH+].
Following the general method of Example 27 (b), the compounds of Examples 28 to 33 were prepared:
Example 28 6-Methyl-2-oxo-N-[4-(propylsulfonyl)benzyl]-l-[3-
(trifluoromethyl phenyll-l,2-dihydropyridine-3-carboxamide
From N-(4-mercaptobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and 1-bromopropane (10 μl, 0.105 mmol). Yield: 12 mg (35%).
1H-NMR (400 MHz, DMSO-d6) δ 9.93 (IH, t, 76.1 Hz); 8.38 (IH, d, 77.5 Hz); 7.94 - 7.70 (6H, m); 7.53 (2H, d, 78.2 Hz); 6.63 (IH, d, 77.6 Hz); 4.58 (2H, d, 76.1 Hz); 3.22 (2H, m); 2.02 (3H, s,); 1.52 (2H, q, 77.6 Hz); 0.89 (3H, t, 77.4 Hz). APCI-MS m/z: 493.3 [MH+]. Example 29 N44-(ButylsulfonvDbenzyl1-6-methyl-2-oxo-143-
(trifluoromethyl)phenyl1-l,2-dihvdropyridine-3-carboxamide
From N-(4-mercaptobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l ,2- , dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and 1-bromobutane (11 μl, 0.105 mmol). Yield: 14 mg, 0.028 mmol (39%).
1H-NMR (400 MHz, DMSO-de) δ 9.93 (IH, t, 76.1 Hz); 8.38 (IH, d, 77.4 Hz); 7.93 - 7.70 (6H, m); 7.53 (2H, d, 78.3 Hz); 6.63 (IH, d, 77.7 Hz); 4.59 (2H, d, 76.1 Hz); 3.24 (2H, m); 2.02 (3H, s,); 1.48 (2H, m); 1.31 (2H, m); 0.81 (3H, t, 77.3 Hz). APCI-MS m/z: 507.3 [MH+].
Example 30 N-[4-(Isobutylsulfonyl)benzyll-6-methyl-2-oxo-l-[3-
( fluoromethyl phenyl1-l,2-dihydropyridine-3-carboxamide
From N-(4-mercaptobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and l-bromo-2-methylpropane (11 μl, 0.105 mmol). Yield: 10 mg, 0.020 mmol (28%).
1H-NMR (400 MHz, DMSO-dδ) δ 9.93 (IH, t, 76.0 Hz); 8.38 (IH, d, 77.5 Hz); 7.94 - 7.69 (6H, m,); 7.53 (2H, d, 78.3 Hz); 6.63 (IH, d, 77.7 Hz); 4.58 (2H, d, 76.2 Hz); 3.16 (2H, d, 76.5 Hz); 2.02 (3H, s,); 1.96 (IH, quintet, 76.6 Hz); 0.95 (6H, d, 76.7 Hz). APCI-MS m/z: 507.3 [MET].
Example 31 N-[4-(^ec-Butylsulfonyl)benzyn-6-methyl-2-oxo-l-r3-
(trifluoromethyDphenyl1-l,2-dihvdropyridine-3-carboxamide
From N-(4-mercaptobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and 2-brombutane (11 μl, 0.105 mmol). Yield: 12 mg, 0.024 mmol (35%).
1H-NMR (400 MHz, DMSO-d^) δ 9.94 (IH, t, 76.0 Hz); 8.38 (IH, d, 77.5 Hz); 7.93 - 7.69 (6H, m,); 7.53 (2H, d, 78.2 Hz); 6.63 (IH, d, 77.8 Hz); 4.59 (2H, d, 76.1 Hz); 3.17 (IH, dq, 713.4, 6.7 Hz); 2.02 (3H, s,); 1.77 (IH, m); 1.29 (IH, m); 1.11 (3H, d, 76.9 Hz); 0.89 (3H, t, 77.5 Hz). APCI-MS m/z: 507.4 [MH+].
Example 32 N- [4-(Isopropylsulf onyDbenzyl] -6-methyl-2-oxo- 1 - [3 -
(trifluoromethyl)phenyl]-l,2-dihvdropyridine-3-carboxamide From N-(4-mercaρtobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and 2-bromopropane (10 μl, 0.105 mmol). Yield: 11 mg, 0.022 mmol (33%).
1H-NMR (400 MHz, DMSO-d6) δ 9.94 (IH, t, 76.1 Hz); 8.38 (IH, d, 77.4 Hz); 7.94 -
7.69 (6H, m,); 7.54 (2H, d, 78.3 Hz); 6.63 (IH, d, 77.7 Hz); 4.60 (2H, d, 76.1 Hz); 3.36 (IH, septet, 76.2 Hz); 2.03 (3H, s,); 1.13 (6H, d, 76.8 Hz).
APCI-MS m/z: 493.3 [MH+].
Example 33 6-Methyl-N- 14-[(3-methylbutyl)sulf onyllbenzyl } -2-oxo- 143-
(trifluoromethyl)phenyll - 1 ,2-dihydropyridine-3-carboxamide From N-(4-mercaptobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and l-bromo-3-methylbutane (13 μl,
0.105 mmol). Yield:ll mg, 0.021 mmol (31 %).
1H-NMR (400 MHz, DMSO-d6) δ 9.93 (IH, t, 76.1 Hz); 8.38 (IH, d, 77.4 Hz); 7.94 -
7.69 (6H, m,); 7.53 (2H, d, 78.3 Hz); 6.63 (IH, d, 77.5 Hz); 4.59 (2H, d, 76.1 Hz); 3.23 (2H, m); 2.02 (3H, s,); 1.57 (IH, septet, 76.8 Hz); 1.39 (2H, m); 0.80 (6H, d, 76.6 Hz).
APCI-MS m/z: 521.4 [MH+].
Following the general method of Example 27, the compounds of Examples 34 to 52 were prepared:
Example 34 N- { 4-[(Cyclopropylmethyl)sulfonyllbenzyl ) -6-methyl-2-oxo- 1 - [3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide From N-(4-mercaptobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and (bromomethyl)cyclopropane (10 μl, 0.105 mmol). Yield: 13 mg, 0.027 mmol (38%). 1H-NMR (400 MHz, DMSO-dg) δ 9.93 (IH, t, 76.2 Hz); 8.38 (IH, d, 77.5 Hz); 7.93 - 7.70 (6H, m,); 7.53 (2H, d, 78.3 Hz); 6.63 (IH, d, 77.6 Hz); 4.59 (2H, d, 76.1 Hz); 3.21 (2H, d, 77.2 Hz); 2.02 (3H, s,); 0.80 (IH, m); 0.43 (2H, m); 0.09 (2H, m). APCI-MS m/z: 505.3 [MH+].
Example 35 6-Methyl-2-oxo-N- { 4- [(tetrahydrof uran-2-ylmethyl)sulf onyll - benzyl } - 1 - [3 -(trifluoromethyl)phenyll - 1 ,2-dihvdropyridine-3 -carboxamide From N-(4-mercaptobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and 2-(bromomethyl)tetrahydrofuran (12 μl, 0.105 mmol). Yield: 8 mg, 0.015 mmol (22%).
1H-NMR (400 MHz, DMSO-de) δ 9.93 (IH, t, 76.0 Hz); 8.38 (IH, d, 77.5 Hz); 7.93 - 7.70 (6H, m,); 7.51 (2H, d, 78.2 Hz); 6.63 (IH, d, 77.6 Hz); 4.58 (2H, d, 76.1 Hz); 4.05 (IH, quintet, 76.5 Hz); 3.59 (IH, q, 77.4 Hz); 3.50 (3H, m); 2.02 (3H, s,); 1.94 (IH, m); 1.75 (2H, m); 1.54 (lH, m). APCI-MS m/z: 535.4 [MH+].
Example 36 N-(4-r(2-HvdroxyethvDsulfonyllbenzyll-6-methyl-2-oxo-l-r3-
(trifluoromethyl)phenyll - 1 ,2-dihvdropyridine-3 -carboxamide
From N-(4-mercaptobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and 2-bromoethanol (7 μl, 0.105 mmol). Yield: 12 mg, 0.025 mmol (36%).
1H-NMR (400 MHz, DMSO-ds) δ 9.93 (IH, t, 76.1 Hz); 8.38 (IH, d, 77.4 Hz); 7.93 -
7.70 (6H, m,); 7.52 (2H, d, 78.3 Hz); 6.63 (IH, d, 77.6 Hz); 4.58 (2H, d, 76.1 Hz); 3.65
(2H, t, 76.4 Hz); 3.40 (2H, t, 76.5 Hz); 2.02 (3H, s,). APCI-MS m/z: 495.3 [MH+].
Example 37 N- ( 4- [(Cyanomethyl)sulf onyllbenz yl I -6-methyl-2-oxo- 143-
(trifluoromethyl)phenyl1-l,2-dihvdropyridine-3-carboxamide From N-(4-mercaptobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and chloroacetonitrile (7 μl, 0.105 mmol). Yield: 8 mg, 0.017 mmol (24%).
1H-NMR (400 MHz, DMSO-de) δ 9.96 (IH, t, 76.1 Hz); 8.37 (IH, d, 77.5 Hz); 7.95 - 7.69 (6H, m,); 7.62 (2H, d, 78.3 Hz); 6.63 (IH, d, 77.6 Hz); 5.20 (2H, s,); 4.61 (2H, d, 7 6.2 Hz); 2.03 (3H, s,). APCI-MS m/z: 490.3 [MH+].
Example 38 N- { 4-1(2- Amino-2-oxoethyl)sulf onyllbenzyl I -6-methyl-2-oxo-l - [3 -(trifluoromethyl)phenyll - 1 ,2-dihydropyridine-3-carboxamide
From N-(4-mercaptobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and 2-bromoacetamide (14 mg,
0.105 mmol). Yield: 15 mg, 0.029 mmol (41%).
1H-NMR (400 MHz, DMSO-d6) δ 9.94 (IH, t, 76.1 Hz); 8.38 (IH, d, 77.4 Hz); 7.95 - 7.46 (10H, m,); 6.62 (IH, d, 77.6 Hz); 4.58 (2H, d, 76.0 Hz); 4.18 (2H, s,); 2.02 (3H, s,).
APCI-MS m/z: 508.3 [MH+].
Example 39 N- ( 4- [(4-Cvanobenzyl)sulf onyllbenzyl } -6-methyl-2-oxo- 143-
(trifluoromethyl)ρhenyn-l,2-dihvdropyridine-3-carboxamide From N-(4-mercaptobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l ,2- dihydropyridine-3-carboxarnide (29 mg, 0.07 mmol) and 4-(bromomethyl)benzonitrile (21 mg, 0.105 mmol). Yield: 3 mg, 0.004 mmol (6%). LC-MS; method B RT: 7.80 min, APCI-MS m/z: 566.4 [MH+].
Example 40 N- { 4- [(2-Cyanoethyl)sulf onyllbenzyl I -6-methyl-2-oxo- 1 - [3-
(trifluoromethyl)phenyll-l,2-αihydropyridine-3-carboxamide From N-(4-mercaptobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and 3-chloropropanenitrile (8 μl, 0.105 mmol). Yield: 1 mg, 0.002 mmol (3%). LC-MS; method B RT: 7.16 min, APCI-MS m/z: 504.3 [MH+]. Example 41 N-l44(3-Hvdroxypropyl)sulfonyl1benzyl)-6-methyl-2-oxo-143-
(trifluorometh vDphen yll - 1 ,2-dihydrop yridine-3 -carboxamide From N-(4-mercaptobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3 -carboxamide (29 mg, 0.07 mmol) and 3-bromopropan-l-ol (9 μl, 0.105 mmol). Yield: 6 mg, 0.012 mmol (18%). LC-MS; method B RT: 6.40 min, APCI-MS m/z: 509.3 [MH+].
Example 42 N-(4-{ [2-(Dimethylamino)-2-oxoethyl]sulfonyl }benzylV6-methyl- 2-oxo-l-r3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide
From N-(4-mercaptobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and 2-chloro-N,N- dimethylacetamide (11 μl, 0.105 mmol). Yield: 10 mg, 0.019 mmol (27%). LC-MS; method B RT: 6.61 min, APCI-MS m/z: 536.4 [MH+].
Example 43 Ethyl 34(4-1 Td 6-methyl-2-oxo-143-(trifluoromethvnphenyl]-l .2- dihvdropyridin-3-yl|carbonyl)amino]methyl}phenyl)sulfonyllpropanoate From N-(4-mercaptobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and ethyl 3-bromopropanoate (13 μl, 0.105 mmol). Yield: 5 mg, 0.009 mmol (13%).
LC-MS; method B RT: 7.64 min, APCI-MS m/z: 551.4 [MH+].
Example 44 2-[(4-| [({6-Methyl-2-oxo-l-r3-(trifluoromethvnphenyll-1.2- dihydro yridin-3-yl ) carbon yl)amino]methyl IphenvDsulfonyl] ethyl acetate From N-(4-mercaptobenzyl)-6-methyl-2-oxo- 1 - [3-(trifluoromethyl)phenyl] -1,2- dihydropyridine-3 -carboxamide (29 mg, 0.07 mmol) and 2-bromoethyl acetate (12 μl,
0.105 mmol). Yield: 7 mg, 0.014 mmol (20%).
LC-MS; method B RT: 7.19 min, APCI-MS m/z: 537.3 [MH+]. Example 45 N- { 4-[(3-Cyanobenzyl)sulf onyllbenzyl I -6-methyl-2-oxo- 143-
(trifluoromethyl)phenvn - 1 ,2-dihydrop yridine-3 -carboxamide From N-(4-mercaptobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and 3-(bromomethyl)benzonitrile (21 mg, 0.105 mmol). Yield: 2 mg, 0.004 mmol (6%). LC-MS; method B RT: 7.77 min, APCI-MS m/z: 566.3 [MH+].
Example 46 Methyl 34(4-1 r((6-methyl-2-oxo-l-[3-(trifluoromethvDρhenyll- l^-dihvdropyridin-S-yllcarbonvParninolmethyllphenvDsulfonyllpropanoate From N-(4-mercaptobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l ,2- dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and methyl 3-bromopropanoate (11 μl, 0.105 mmol). Yield: 2 mg, 0.005 mmol (7%).
LC-MS; method B RT: 7.28 min, APCI-MS m/z: 537.3 [MH+].
Example 47 6-Methyl-N-(4-( r(2-methyl-l .3-thiazol-4- yl)methyl1sulfonyl}benzyl)-2-oxo-l-[3-(trifluoromethyl')phenyll-l,2-dihvdropyridine-3- carboxamide trifiuoroacetate
From N-(4-mercaptobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and 4-(chloromethyl)-2-methyl-l,3- thiazole hydrochloride (19 mg, 0.105 mmol). Yield: 11 mg, 0.017 mmol (24%).
LC-MS; method B RT: 7.21 min, APCI-MS m/z: 562.3 [MH+].
Example 48 6-Methyl-2-oxo-N-(4-[(ρyridin-4-ylmethyl')sulfonyl1benzyll-l-[3-
(trifluoromethvPphenyll-l,2-dihvdropyridine-3-carboxamide trifiuoroacetate From N-(4-mercaptobenzyl)-6-methyl-2-oxo- 1 - [3-(trifluoromethyl)phenyl]- 1 ,2- dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and 4-(chloromethyl)pyridine hydrochloride (17 mg, 0.105 mmol). Yield: 5 mg, 0.008 mmol (11%). LC-MS; method B RT: 5.79 min, APCI-MS m/z: 542.3 [MH+]. Example 49 N- ( 4- r(3-Cyanopropyl)sulf onyllbenzyl I -6-methyl-2-oxo- 143-
(trifluoromethyl)phenyl1-1.2-dihvdropyridine-3-carboxamide From N-(4-mercaptobenzyl)-6-methyl-2-oxo- 1 - [3 -(trifluoromethyl)phenyl] -1,2- dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and 4-bromobutanenitrile (10 μl, 0.105 mmol). Yield: 11 mg, 0.022 mmol (31%).
LC-MS; method B RT: 7.19 min, APCI-MS m/z: 518.3 [MH+].
Example 50 N-(4-{ [(3,5-Dimethylisoxazol-4-yl)methyllsulfonyl IbenzylVό- methyl-2-oxo- l-[3-(trifluoromethyl phenyll- 1 ,2-dihydropyridine-3-carboxamide trifiuoroacetate
From N-(4-mercaptobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and 4-(chloromethyl)-3,5- dimethylisoxazole (13 μl, 0.105 mmol). Yield: 9 mg, 0.013 mmol (19%). LC-MS; method B RT: 7.50 min, APCI-MS m/z: 560.4 [MH+].
Example 51 N-(4-|[4-(Acetylamino')benzvnsulfonyl}benzyl')-6-methyl-2-oxo-l-
[3-(trifluoromethyDphenyl]-l,2-dihvdropyridine-3-carboxamide From N-(4-mercaptobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and N-[4-(chloromethyl)phenyl]- acetamide (19 mg, 0.105 mmol). Yield: 7 mg, 0.013 mmol (18%). LC-MS; method B RT: 6.98 min, APCI-MS m/z: 598.4 [MH+].
Example 52 6-Methyl-N-[4-(l2-[(5-methyl-1.3,4-thiadiazol-2-vPamino1-2- oxoethyl I sulf onvDbenzyl] -2-oxo- 1 - [3 -(trifluoromethyl)phenyll - 1 ,2-dihy drop yridine-3 - carboxamide
From N-(4-mercaptobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide (29 mg, 0.07 mmol) and 2-bromo-N-(5-methyl-l,3,4- thiadiazol-2-yl)acetamide (25 mg, 0.105 mmol). Yield: 4 mg, 0.006 mmol (9%). LC-MS; method B RT: 6.62 min, APCI-MS m/z: 606.2 [MH+]. Example 53 6-Methyl-N44-(methylsulfonyl)phenoxy1-2-oxo-l-[3-
(trifluoromethyl)phen yl] - 1 ,2-dihvdrop yridine-3 -carboxamide
To a mixture of 6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxylic acid (67 mg, 0.22 mmol), HATU (93.7 mg, 0.25 mmol), HO AT (34 mg, 0.25 mmol), DIEA (150 μl, .87 mmol) and NMP (2 ml) was added
O-[4-(methylsulfonyl)phenyl]hydroxylamine, prepared according to the procedure in 7 Med. Chem., 1967, 512 (41 mg, 0.22 mmol). After stirring at room temperature for 3 h the mixture was partitioned between EtOAc and water. The organic extract was washed with brine, dried, filtered and evaporated to dryness. The crude product was further purified by preparative HPLC to give the title compound as a white solid (41 mg, 40%).
1H-NMR (CDC13): δ 12.19 (IH, s); 8.58 (IH, d, 77.4 Hz); 7.92 - 7.86 (3H, m); 7.80 (IH, t, 77.9 Hz); 7.57 (IH, s); 7.50 (IH, d, 77.9 Hz); 7.30 - 7.26 (5H, m); 6.56 (IH, d, 77.5 Hz); 3.03 (3H, s); 2.16 (3H, s). APCI-MS m/z: 567 [MH+].
Example 54 6-Methyl-2-oxo-l-(3-trifluoromethyl-phenyl)-l,2-dihydro-pyridine-
3-carboxylic acid (4-bromo-phenoxy)-amide
A solution of 6-methyl-2-oxo-l-(3-trifluoromethyl-phenyl)-l,2-dihydro-pyridine-3- carboxylic acid (0.060 g, 0.20 mmol) in CH2C12 (5 ml) and SOCl2 (5 ml) was stirred for 3 h at room temperature and then concentrated to give the crude intermediate acid chloride as a solid. The solid was dissolved in 1,4-dioxane and O-(4-bromo-phenyl)- hydroxylamine, prepared according to the procedure in 7. Med. Chem., 1967, 512, (0.10 g, 0.53 mmol) was added and the mixture was stirred at room temperature for 10 min. The volatiles were removed and the residue was purified on preparative HPLC, giving 0.055 g (58%) of the title compound as an off-white solid.
1H-NMR (CDC13): δ 12.08 (IH, s); 8.57 (IH, d, 77.42 Hz); 7.84 (IH, d, 78.01 Hz); 7.77 (IH, t, 78.01 Hz); 7.55 (IH, s); 7.47 (IH, d, 78.01 Hz); 7.38 (2H, d, 78.87 Hz); 7.00 (2H, 8.90 Hz); 6.52 (IH, d, 77.48 Hz); 2.13 (3H, s) APCI-MS m/z: 467.1 and 469.0 [MH+]. Example 55 6-Methyl-2-oxo-N-phenoxy-l-[3-(trifluoromethvPphenvn-l,2- dihvdropyridine-3-carboxamide
The title compound was prepared as described in Example 53 starting form O-phenyl hydroxylamine. 1H-NMR (CDC13): δ 12.04 (lH,s); 8.58 (lH,d); 7.85-7.74 (2H,m); 7.55 (lH,brs); 7.48 (lH,d); 7.32-7.26 (2H,m); 7.12 (2H,d); 7.02 (lH,t); 6.51 (lH,d); 2.12 (3H,s). APCI-MS m/z: 389[MH+].
Example 56 N-(4- Aminobenz yl)-6-methyl-2-oxo- 1 - [3 -(trifluoromethyl)phenyll - 1 ,2-dihvdroproline-3-carboxamide
To a mixture of l-(3-methylphenyl)-2-oxo-l,2-dihydropyridine-3-carboxylic acid (212 mg, 0.7 mmol), HATU (272 mg, 0.7 mmol), HO AT (97 mg, 0.7 mmol) and DIEA (275 mg, 2.13 mmol) in NMP (3 ml) was added (4-aminobenzyl)amine (87 mg, 0.7 mmol) in NMP (1 ml). The reaction was stirred for 12 h at room temperature. The reaction mixture was diluted with water (1.0 ml) and purified on a Xterra@Prep MS C8 column (19 x 50 mm) using a gradient of CH3CN/water at a flow rate of 20 ml/min. Freeze drying of the mixture afforded the title compound (140 mg, 49%).
1H-NMR (400 MHz, CDC13), δ 9.74 (IH, t, 75.4 Hz ), 8.56 (IH, d, 77.5 Hz ), 7.78 (IH, m ), 7.50 (IH, s ), 7.43 (IH, d, 77.8 Hz ), 7.27 (IH, s ), 7.15 (2H, d, 78.1 Hz ), 6.81 (2H, d, 78.2 Hz ), 6.43 (IH, d, 77.4 Hz), 4.49 (2H, m), 2.06 (3H, s, 79.1 Hz) APCI-MS m/z: 402.2 [MH+].
Example 57 6-Methyl-N- ( 4- [(methylsulf onyPaminolbenzyl I -2-oxo- 143 -
(trifluoromethyl)phenyll - 1 ,2-dihydropyridine-3 -carboxamide To a mixture of N-(4-aminobenzyl)-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydroproline-3-carboxamide (80 mg, 0.2 mmol) in CH2C12, methanesulfonyl chloride (23 mg, 0.2 mmol) and DLEA (26 mg, 0.2 mmol) were added . The reaction mixture was stirred for 0.5 h at room temperature. The CH2C12 was evaporated off and the residue dissolved in CH3CN/water and purified on a Xterra@Prep MS C8 column (19 x 50 mm) using a gradient of CH3CN/water at a flow rate of 20 ml/min. Freeze drying of the mixture afforded the title compound (67 mg, 70%).
1H-NMR (400 MHz, CDC13) δ 9.83 (IH, s ), 8.59 (IH, d, 77.4 Hz ), 7.80 (IH, d, 77.9 Hz), 7.73 (IH, t, 77.8 Hz), 7.51 (IH, s), 7.43 (IH, d, 77.9 Hz), 7.31 (2H, d, 78.4 Hz), 7.14 (2H, d, 78.4 Hz), 6.46 (IH, d, 77.4 Hz), 6.38 (IH, s), 4.57 (m, IH), 2.97 (3H, s, 7 3.9 Hz), 2.08 (3H, s, 74.3 Hz ). APCI-MS m/z: 480.1 [MH+].
Example 58 N- 14- [Bis(methylsulf onyPaminolbenzyl ) -6-methyl-2-oxo- 1- F3- (trifluoromethyl phenyl1-l,2-dihydropyridine-3-carboxamide
The title compound was isolated as a by-product using the method described in Example
57.
1H-NMR (400 MHz, CDC13): δ 9.94 (t, 75.6 Hz, IH), 8.59 (d, 77.4 Hz, IH), 7.82 (d, 7
7.9 Hz, IH), 7.75 (t, 77.8 Hz, 2H), 7.53 (s, IH), 7.45 (t, 75.6 Hz, 3H), 7.29 (d, 79.7 Hz, 2H), 6.47 (d, 77.5 Hz, IH), 4.64 (t, 75.1 Hz, 2H), 3.39 (s, 6H), 2.09 (s, 3H).
APCI-MS m/z: 558.4 [MH+].
Example 59 N- [ [4- [ [(Dimethylamino)sulf onyl] aminolphenyllmethyl] -1,2- dihvdro-6-methyl-2-oxo-l-r3-(trifluoromethyl)phenyl1-3-pyridinecarboxamide The title compound was prepared from N-(4-aminobenzyl)-6-methyl-2-oxo-l-[3- (1rifluoromethyl)phenyl]-l,2-dihydroproline-3-carboxamide and dimethylsulfamoyl chloride (2 mg, 10%) following the method outlined in Example 57. 1H-NMR (400 MHz, CD3OD) δ 8.48 (IH, d, 77.5 Hz); 7.86 (IH, d, 77.4 Hz); 7.79 (2H, t, 77.9 Hz); 7.73 (IH, s, ); 7.59 (IH, d, 78.5 Hz); 7.25 (2H, d, 78.6 Hz); 7.17 (2H, d, 7 8.5 Hz); 6.63 (IH, d, 77.6 Hz); 4.52 (2H, s, ); 2.74 (6H, s, ); 2.09 (3H, s). APCI-MS m z: 509.3 [MH+].
Example 60 6-Methyl-N- { 4- [methyl (methylsulf onypaminolbenz yl } -2-oxo- 143-
(trifluoromethvPphenyl1-l,2-dihydropyridine-3-carboxamide To a mixture of 6-methyl-N-{4-[(methylsulfonyl)amino]benzyl}-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (10 mg, 0.02 mmol) in dichloromethane, iodomethane (4 mg, 0.03 mmol) and DIEA (3.9 mg, 0.03 mmol) were added . The reaction was stirred for 10 min at 60 °C in a microwave oven. After evaporation of the solvent, the residue was dissolved in CH CN/water and purified on a Xterra@Prep MS C8 column (19 x 50 mm) using a gradient of CH3CN/water at a flow rate of 20 ml/min. Freeze drying of the mixture afforded the title compound (6 mg, 60%). 1H-NMR (400 MHz, DMSO-de) δ 9.83 (IH, t, 75.9 Hz), 8.38 (IH, d, 77.5 Hz), 7.89 (2H, d, 78.7 Hz), 7.80 (IH, t, 77.7 Hz), 7.71 (IH, d, 78.0 Hz), 7.32 (4H, m), 6.62 (IH, d, 77.5 Hz), 4.48 (2H, d, 75.9 Hz), 3.20 (3H, s), 2.91 (3H, s), 2.01 (3H, s) APCI-MS m/z: 494.1 [MH+].
Following the general method of Example 60, the compounds of Examples 60.1 to 60.7 were prepared:
Example 60.1
N- [ [4- [ButvKmethylsulf onyPaminolphenyllmethyll - 1 ,2-dihydro-6-methyl-2-oxo- 143- (trifluoromethyPphenyll-3-pyridinecarboxamide Using 1-iodobutane. Yield (7 mg, 43%). 1H-NMR (400 MHz, DMSO-d6) δ 9.86 (IH, s, ); 8.38 (IH, d, 77.3 Hz); 7.89 (2H, d, 79.5 Hz); 7.80 (IH, t, 77.4 Hz); 7.72 (IH, d, 78.2 Hz); 7.32 (4H, s, ); 6.63 (IH, d, 77.2 Hz); 4.49 (2H, d, 75.8 Hz); 3.58 (2H, s, ); 2.91 (3H, s, ); 2.02 (3H, s, ); 1.27 (4H, s, ); 0.81 (3H, t, 76.2 Hz). APCI-MS m/z: 536.4 [MH+].
Example 60.2 l,2-Dihvdro-6-methyl-N-[[4-[(l-methylethvP(methylsulfonvP- amino1phenyl]methyl]-2-oxo-l-[3-(trifluoromethvPphenyll-3-pyricu-necarboxamide Using 2-iodopropane. Yield (10 mg, 38%).
1H-NMR (400 MHz, DMSO-d6) δ 9.88 (2H, t, 76.0 Hz); 8.39 (2H, d, 77.4 Hz); 7.89 (4H, d, 711.6 Hz); 7.80 (3H, t, 77.8 Hz); 7.72 (2H, d, 78.1 Hz); 7.33 (4H, d, 78.3 Hz); 7.22 (4H, d, 78.3 Hz); 6.63 (2H, d, 77.6 Hz); 4.52 (4H, d, 76.1 Hz); 4.30 (2H, quintet, 76.7 Hz); 3.02 (7H, s, ); 2.02 (6H, s, ); 1.04 (12H, d, 76.8 Hz). APCI-MS m/z: 522.4 [MH+].
Example 60.3 N- { 4-[(2-MethoxyethyP(methylsulfonyl)amino1benzyl } -6-methyl-
2-oxo- 1 - [3 -(trifluoromethyPphenyll - 1 ,2-dihvdropyridine-3-carboxamide Using 2-bromoethyl methyl ether. Yield (15 mg, 33%).
1H-NMR (400 MHz, DMSO-d6) δ 9.86 (IH, t, 75.9 Hz); 8.38 (IH, d, 77.4 Hz); 7.89 (2H, d, 79.3 Hz); 7.80 (IH, t, 77.8 Hz); 7.72 (IH, d, 77.9 Hz); 7.32 (4H, d, ); 6.62 (IH, d, 7 7.5 Hz); 4.49 (2H, d, 76.0 Hz); 3.73 (2H, t, 75.8 Hz); 3.29 (2H, t, 75.7 Hz); 3.17 (3H, s, ); 2.98 (3H, s, ); 2.02 (3H, s). APCI-MS m/z: 538.4 [MH+].
Example 60.4 N- ( 4-[(2-CyanoethyP(methylsulf onyPaminolbenzyl } -6-methyl-2- oxo-l-[3-(trifluoromethvPphenyl]-l,2-dihvdropyridine-3-carboxamide
Using 3-bromopropionitrile. Yield (3 mg, 19%).
1H-NMR (400 MHz, DMSO-d6) δ 9.86 (IH, t, ); 8.39 (IH, d, 77.4 Hz); 7.89 (2H, d, 79.3
Hz); 7.80 (IH, t, 70.0 Hz); 7.72 (IH, d, 77.5 Hz); 7.36 (4H, s, ); 6.63 (IH, d, 77.5 Hz);
4.50 (2H, d, 76.2 Hz); 3.86 (2H, t, 76.4 Hz); 3.00 (3H, s, ); 2.60 (2H, t, 76.3 Hz); 2.02 (3H, s).
APCI-MS m/z: 533.1 [MH+].
Example 60.5 N- { 4- [Ethyl (methylsulf onyPaminolbenzyl ) -6-methyl-2-oxo- 143-
(trifluoromethyPphenyll-l,2-dihvdropyridine-3-carboxamide Using iodoethane. Yield: (6 mg, 59%).
1H-NMR (400 MHz, DMSO-dδ) δ 9.86 (IH, t, 75.9 Hz); 8.38 (IH, d, 77.4 Hz); 7.89 (2H, d, 79.3 Hz); 7.80 (IH, t, 77.8 Hz); 7.72 (IH, d, 78.1 Hz); 7.32 (4H, dd, 7 11.6, 8.7 Hz);
6.62 (IH, d, 77.5 Hz); 4.49 (2H, d, 76.0 Hz); 3.62 (2H, q, 77.1 Hz); 2.93 (3H, s, ); 2.02
(3H, s, ); 0.96 (3H, t, 77.1 Hz); APCI-MS m/z: 508.4 [MH+]. Example 60.6 1 ,2-Dihydro-6-methyl-N- [ [4- [(methylsulf onvPpropylaminol - phenvnmethyll-2-oxo-l-[3-(trifluoromethvPphenyll-3-pyridinecarboxamide
Using 1-iodopropane. Yield (6 mg, 57%).
1H-NMR (400 MHz, DMSO-d6) δ 9.86 (IH, t, 76.0 Hz); 8.38 (IH, d, 77.5 Hz); 7.89 (2H, d, 78.8 Hz); 7.80 (IH, t, 77.8 Hz); 7.72 (IH, d, 78.2 Hz); 7.32 (4H, s, ); 6.62 (IH, d, 7
7.7 Hz); 4.49 (2H, d, 76.0 Hz); 3.54 (2H, t, 77.1 Hz); 2.92 (3H, s, ); 2.01 (3H, s, ); 1.31
(2H, q, 77.2 Hz); 0.80 (3H, t, 77.3 Hz).
APCI-MS m/z: 522.4 [MH+].
Example 60.7 N- [ [4- [(3- Amino-3 -oxopropyP (methylsulf on vPaminolphenyll - methyl]-l,2-dihvdro-6-methyl-2-oxo-l-[3-(trifluoromethvPphenyl]-3- pyridinecarboxamide
Using 3-bromopropionamide. Yield (7 mg, 30%). 1H-NMR (400 MHz, DMSO-de) δ 9.86 (IH, t, 76.0 Hz); 8.39 (IH, d, 77.5 Hz); 37.89 ' (2H, d, 7 10.5 Hz); 7.80 (IH, t, 77.7 Hz); 7.72 (IH, d, 77.8 Hz); 7.32 (5H, dd, 7 11.0, 8.8 Hz); 6.81 (IH, s, ); 6.63 (IH, d, 77.6 Hz); 4.50 (2H, d, 76.0 Hz); 3.80 (2H, t, 77.5 Hz); 2.96 (3H, s, ); 2.17 (2H, t, 77.6 Hz); 2.02 (3H, s). APCI-MS m/z: 551.4 [MH+].
Example 61 l,2-Dihvdro-6-methyl-N-[[4-[(methylsulfonyl)oxy]phenyllmethyn-
2-oxo- 1 - F3-(trifluoromethyPphenyl]-3-pyrictoecarboxamide
a) N-(4-HydroxybenzvP-6-methyl-2-oxo- 1 - [3 -(trifluoromethypphen yl] -1,2- dihvdropyridine-3-carboxamide
To a mixture of l-(3-methylphenyl)-2-oxo-l,2-dihydropyridine-3-carboxylic acid (1 g, 3.36 mmol), HATU (1.28 g, 3.36 mmol), HOAT (457 mg, 3.36 mmol) and DLEA (1.7 g, 13.36 mmol) in NMP (10 ml) was added (4-hydroxybenzyl)amine hydrobromide (686 mg, 3.36 mmol) in NMP (5 ml). The reaction was stirred for 12 h at room temperature. The reaction mixture was diluted with water (75.0 ml) and extracted with EtOAc. The organic phase was dried (MgSO4), filtered and evaporated affording the title compound (1.2 g, 89%).
1H-NMR (400 MHz, DMSO-d6) δ 9.66 (IH, t, 75.7 Hz); 9.27 (IH, s, ); 8.36 (IH, d, 77.4 Hz); 7.86 (2H, d, 74.5 Hz); 7.78 (IH, t, 78.0 Hz); 7.68 (IH, d, 77.9 Hz); 7.06 (2H, d, 7 8.3 Hz); 6.67 (2H, d, 78.5 Hz); 6.60 (IH, d, 77.4 Hz); 4.33 (2H, d, 75.8 Hz); 1.99 (3H, s).
APCI-MS m/z: 403.3 [MH+]. b) l,2-Dihydro-6-methyl-N-[r4-[(methylsulfonyPoxy]phenyl]methyll-2-oxo-l-[3-
(trifluoromethyPphenyl1-3-pyridinecarboxamide The title compound was prepared from N-(4-hydroxybenzyl)-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide and methansulfonyl chloride as in Example 57 (200 mg, 84%).
1H-NMR (400 MHz, DMSO-ds) δ 9.87 (IH, t, 76.0 Hz); 8.38 (IH, d, 77.5 Hz); 7.89 (2H, d, 78.9 Hz); 7.80 (IH, t, 77.8 Hz); 7.72 (IH, d, 77.9 Hz); 7.39 (2H, d, 78.6 Hz); 7.29 (2H, d, 78.6 Hz); 6.62 (IH, d, 77.5 Hz); 4.50 (2H, d, 76.0 Hz); 3.35 (3H, s); 2.02 (3H, s).
APCI-MS m z: 481.3 [MH+].
Example 62 2-Propanesulfonic acid, 4-[[[n,2-dihydro-6-methyl-2-oxo-l-[3- (trifluoromethyPphenyn-3-pyridinyllcarbonyllamino1methyl]phenyl ester
The title compound was prepared from N-(4-hydroxybenzyl)-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-chhyckopyridine-3-carboxamide and isopropylsulfonyl chloride as in Example 57.
1H-NMR (400 MHz, DMSO-d6) δ 9.83 (IH, t, ); 8.35 (IH, d, 77.5 Hz); 7.86 (2H, d, 78.7 Hz); 7.78 (IH, t, 77.7 Hz); 7.69 (IH, d, 77.3 Hz); 7.35 (2H, d, 78.5 Hz); 7.22 (2H, d, 7
8.6 Hz); 6.60 (IH, d, 77.3 Hz); 4.46 (2H, d, 76.2 Hz); 3.66 (IH, m); 1.99 (3H, s); 1.38
(6H, d, 76.9 Hz).
APCI-MS m/z 509.4 [MH+]. Example 63 N- [( 1 , 1 -Dioxido-2,3-dihvdro- 1 -benzothien-5-yl)methyll-6-methyl-
2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-(h-hydropyridine-3-carboxamide
a) 2,3-Dihydro-l-benzothiophene-5-carbaldehyde and 2,3-Dihydro-l-benzothiophene-7- carbaldehyde
The subtitle compounds were prepared according to the procedure described in WO 01/12602. b) 2,3-Dihvdro-l-benzothien-5-ylmethanol and 2,3-Dihydro-l-benzothien-7-ylmethanol The title compounds were prepared by stirring a mixture of 2,3-dihydro-l- benzothiophene-5-carbaldehyde and 2,3-dihydro-l-benzothiophene-7-carbaldehyde (4.3 g, 26 mmol) with sodium borohydride (3.78 g, 100 mmol) in THF (100 ml) and water (10 ml) at room temperature overnight. IM Hydrochloric acid was added slowly to quench the excess of borohydride. The mixture was extracted with EtOAc and washed with water. The solvents were removed in vacuo and the residue purified by column chromatography on silica using heptane/EtOAc (4: 1) as eluent to afford 2,3-dihydro-l- benzothien-5-ylmethanol (1.84 g):
1H-NMR (CDC13): δ 7.22 (IH, brs); 7.20 (IH, d, 78.3 Hz); 7.11 (IH, brd, 78.3 Hz); 4.61 (2H, s); 3.41-3.25 (4H, m); and 2,3-dihydro-l-benzothien-7-ylmethanol (1.18 g) (total yield 70%): 1H-NMR (CDC13): δ 7.18 (IH, d, 77.5 Hz); 7.15 (IH, d, 77.5 Hz); 7.05 (IH, t, 77.5 Hz); 4.63 (2H, s); 3.41-3.28 (4H, m). c l,l-Dioxido-2,3-dihvdro-l-benzothien-5-yl)methanol
The title compound was prepared by stirring 2,3-dihydro-l -benzothien-5-ylmethanol (1.08 g, 6.38 mmol), oxone (5.8 g, 9.4 mmol), aqueous EDTA (22 ml, 0.4 mM), and sodium hydrogen carbonate (4.8 g) in a mixture of acetone and water at pH 7.5 at room temperature overnight. The reaction mixture was extracted with EtOAc and washed with water. The solvents were removed in vacuo and the residue purified by column chromatography on silica using heptane/EtOAc (4:1) as eluent to afford the subtitle compound (1.0 g, 79%). 1H-NMR (CDCI3): δ 7.70 (IH, d, 77.9 Hz); 7.43 (IH, d, 77.9 Hz); 7.42 (IH, s); 4.79
(2H, s); 3.53-3.36 (4H, m). d) 5-(Bromomethyl)-2,3-dihydro-l-benzothiophene 1,1 -dioxide
The title compound was prepared by refluxing (l,l-dioxido-2,3-dihydro-l-benzothien-5- yl)methanol (1.0 g, 5 mmol) with phosphorus tribromide (0.524 g, 0.188 ml, 2 mmol) in dry toluene (20 ml) for 1 h. Water was added and the crude mixture was extracted with > EtOAc, washed with water and brine and dried. The solvents were removed in vacuo to afford the subtitle compound (1.15 g, 88%). 1H-NMR (CDCI3): δ 7.73 (IH, d, 78.0 Hz); 7.51 (IH, d, 78.0 Hz); 7.43 (IH, s); 4.51 (2H, s); 3.53 (2H, t, 6.8 Hz); 3.43 (2H, t, 76.8 Hz). e) (l,l-Dioxido-2,3-dihydro-l-benzothien-5-yPmethylamine The title compound was prepared by stirring 5-(bromomethyl)-2,3-dihydro-l- benzothiophene 1,1 -dioxide (1.14 g, 4.36 mmol) with aqueous ammonia (43 ml) in methanol/THF 1:1 (30 ml) overnight. The solvents were removed in vacuo to afford the subtitle compound (700 mg, 81%).
1H-NMR (CDCI3): δ 8.05 (2H, brs); 7.82 (IH, d, 78.3 Hz); 7.63 (IH, s); 7.61 (IH, d, 7
8.3 Hz); 4.15 (2H, s); 3.62 (2H, t, 76.9 Hz); 3.36 (2H, t, 76.9 Hz).
APCI-MS m/z: 198 [MH+]. f) N4(l , l-Dioxido-2,3-dihydro- l-benzothien-5-yPmethyl]-6-methyl-2-oxo-l-[3- (trifluoromethyPphenyll-l,2-dihydropyridine-3-carboxamide
Starting from 6-methyl-2-oxo- 1 -[3 -(trifluoromethyDphenyl] - 1 ,2-dihydropyridine-3 - carboxylic acid (743 mg, 2.5 mmol) and (l,l-dioxido-2,3-dihydro-l-benzothien-5- yl)methylamine (500 mg, 2.5 mmol) using the method described in Example 17, the title compound (1.05 g, 88%) was obtained. 1H-NMR (CDCI3): δ 9.94 (IH, brt, 76.0 Hz); 8.39 (IH, d, 77.5 Hz); 7.93 (IH, s); 7.91(1H, d, 77.7 Hz); 7.83 (IH, t, 77.7 Hz); 7.74 (IH, d, 77.7 Hz); 7.70 (IH, d, 78.0 Hz); 7.45(1H, d, 78.0 Hz); 7.43 (IH, s); 6.64 (IH, d, 77.5 Hz); 4.58 (2H, d, 76.0 Hz); 3.57 (2H, t, 76.9 Hz); 3.34 (2H, t, 76.9 Hz); 2.04 (3H, s). APCI-MS m/z: 477 [MH+]. Example 64 N-F(l,l-Dioxido-2,3-dihydro-l-benzothien-5-yl)methyl1-5-iodo-6- methyl-2-oxo- 143-(trifluoromethyl)phen yll - 1 ,2-dihvdropyridine-3-carboxamide To a solution of N-[(l,l-dioxido-2,3-dihydro-l-benzothien-5-yl)methyl]-6-methyl-2-oxo- l-[3-(trifluoromethyl)phenyl]-l,2-oιhydropyridine-3-carboxamide (102 mg, 0.21 mmol), dichloromethane (1.8 ml) and TFA (0.9 ml) was added N-iodosuccinimide (47 mg, 0.21 mmol). The mixture was stirred at room temperature for 4 h and the solvent was then removed in vacuo. The residue was partitioned between EtOAc and aqueous NaHCO3 and the organic extract was washed with water, dried, filtered and evaporated. The crude product was purified by preparative HPLC to give the title compound as a white solid (87 mg, 69%).
1H-NMR (CDC13): δ 9.85 (IH, t, 75.7 Hz); 8.91 (IH, s); 7.83 (IH, d, 78.1 Hz); 7.76 (IH, t, 78.0 Hz); 7.68 (IH, d, 78.0 Hz); 7.49 (IH, s); 7.41 (2H, d, 78.0 Hz); 7.34 (IH, s); 4.64 (2H, t, 76.5 Hz); 3.48 (2H, t, 76.9 Hz); 3.35 (2H, t, 77.0 Hz); 2.32 (3H, s). APCI-MS m/z: 603 [MH+].
Example 65 5-Iodo-N- { 4-[isopropyl (methylsulf onyPaminolbenzyl } -6-methyl-
2-oxo-l-[3-(trifluoromethyl)phenyll-l,2-dihydropyridine-3-carboxamide
The title product was prepared as described for Example 64 but starting from N-{4-
[isopropyl(methylsulfonyl)-amino]benzyl}-6-methyI-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide. White powder (4 mg, 68%).
1H-NMR (400 MHz, DMSO-d6) d 9.77 (IH, t, 76.1 Hz); 8.61 (IH, s); 7.90 (2H, t, 78.2 Hz); 7.81 (IH, t, 77.9 Hz); 7.72 (IH, d, 77.9 Hz); 7.33 (2H, d, 78.2 Hz); 7.21 (2H, d, 7 8.3 Hz); 4.51 (2H, d, 76.0 Hz); 4.30 (IH, quintet, 76.7 Hz); 3.02 (3H, s); 2.20 (3H, s); 1.04 (6H, d, 6.7 Hz).
APCI-MS mz: 648 [MH+].
Example 66 l,2-Dihvdro-6-methyl-N-f[4-[(methylsulfonvPmethyllphenyll- methyll -2-oxo- 1 - [3-(trifluoromethyPphenvn -3 -pyridinecarboxamide a) 6-Methyl-N-(4-[(methylthio)methyl1benzyl)-2-oxo-l-[3-(trifluoromethvPphenvn-lT2- dihydropyridine-3-carboxamide
To a mixture of l-(3-methylphenyl)-2-oxo-l,2-dihydropyridine-3-carboxylic acid (412 mg, 1.39 mmol), TBTU (527 mg, 1.39 mmol) and DIEA (719 mg, 5.56 mmol) in NMP was added [(methylthio)methyl]benzene (232 mg, 1.39 mmol) in NMP (1 ml). The reaction was stirred for 1 h at room temperature, then diluted with water (15 ml) and extracted with EtOAc. The organic phase was dried (M SO4), filtered and evaporated affording the crude title compound (620 mg), which was used directly in the next step. bι 1.2-Dihvdro-6-methyl-N-[[4-[(methylsulfonyl)methyllphenyllmethyl1-2-oxo-l-[3- (trifluoromethyl)phenyl]-3-pyridinecarboxamide.
To crude 6-methyl-N- { 4- [(methylthio)methyl]benzyl} -2-oxo- 1- [3- ( fluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide (620 mg 1.39 mmol ) in CH2C12 (10 ml) cooled to -150 °C was added m-chloroperoxybenzoic acid (483 mg, 2.8 mmol). The mixture was stirred for 30 min and then overnight at room temperature. The reaction mixture was diluted with more CH2C12 and water, washed with sodium thiosulfate, sodium bicarbonate and brine. The solvent was removed in vacuum and 25 mg of the residue was dissolved in CHsCN/water (2.0 ml) and purified on a Xterra@Prep MS C8 column (19 x 50 mm) using a gradient of CHsCN/water at a flow rate of 20 ml/min. Freeze drying of the mixture afforded the title compound (15 mg). 1H-NMR (400 MHz, DMSO-dβ) δ 9.66 (IH, t, 75.7 Hz); 9.27 (IH, s, ); 8.36 (IH, d, 77.4 Hz); 7.86 (2H, d, J4.5 Hz); 7.78 (IH, t, 78.0 Hz); 7.68 (IH, d, 77.9 Hz); 7.06 (2H, d, 7 8.3 Hz); 6.67 (2H, d, 78.5 Hz); 6.60 (IH, d, 77.4 Hz); 4.33 (2H, d, 75.8 Hz); 1.99 (3H, s).
APCI-MS m/z: 479.3 [MH+].
Example 67 6-Chloro-5-methyl-4-(3-methylphenyl-N44-
(methylsuIfonyl)benzyl]-3-oxo-3,4-dihvdropyrazine-2-carboxamide
a) 6-Chloro-5-methyl-4-(3-methylphenyl)-3-oxo-3,4-dihydropyrazine-2-carbonitrile The title compound was prepared essentially as described by Gibson, et al.7. Org. Chem.
1994, 59, 1072-1077 andHoornaert et al. Tetrahedron, 1990, 46, 5715-5732. b) 6-Chloro-5-methyl-4-(3-methylphenyl)-3-oxo-3,4-dihvdropyrazine-2-carboxylic acid
A solution of 6-chloro-5-methyl-4-(3-methylphenyl)-3-oxo-3,4-dihydropyrazine-2- carbonitrile (100 mg, 0.38 mmol) in 1 IM sulphuric acid (10 ml) was heated at 90 °C for 16 h. Water (200 ml) was added. The water phase was extracted with dichloromethane.
The organic layer was dried, filtered and evaporated to give the subtitle compound (20 mg,
19%).
APCI-MS m/z: 279.2 [MH+], HPLC Chromolith speedROD RP 18e 50-4.6 mm, flow 2.5 ml/min, wavelength 254 nm, time 1.93 min. c) 6-Chloro-5-methyl-4-(3-methylphenyl-N-r4-(methylsulfonyl)benzyπ-3-oxo-3,4- dihvdropyrazine-2-carboxamide
The title compound was prepared starting from 6-chloro-5-methyl-4-(3-methylphenyl)-3- oxo-3,4-dihydropyrazine-2-carboxylic acid and (4-mefhylsulfonyl)benzyl amine as described in Example 17.
1H-NMR (DMSO-d6)-. δ 9.68 (IH, t); 7.87 (2H, d); 7.57 (2H, d); 7.49 (IH, t); 7.36 (IH, d); 7.19 (2H, d); 4.59 (2H, d); 3.18 (3H, s); 2.36 (3H, s); 2.11 (3H, s).
APCI-MS m/z: 446.3 [MH+].
Example 68 5-Bromo-6-(difluoromethyl)-N-[4-(methylsulfonyl)benzvn-2-oxo- l-[3-(trifluoromethyPphenyll-l,2-α^hydropyridine-3-carboxarnide
a) Ethyl 6-methyl-2-oxo-l-r3-(trifluoromethyPphenyl1-l,2-dihydropyridine-3-carboxylate The title compound was prepared by stirring a mixture of 6-methyl-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxylic acid (20.8 g, 70 mmol) with sodium carbonate (8.16 g, 77 mmol) in NMP (150 ml). Ethyl iodide (15.6 g, 100 mmol) was added slowly (about 10-15 minutes) and the mixture stirred at room temperature for 4 h. Water was added and the crude product was extracted with EtOAc, washed with water and dried and filtered. The solvent was removed in vacuo and the residue triturated with diethyl ether (100 ml), filtered, washed with diethyl ether and dried to afford the subtitle compound (18 g, 79%) as a white solid.
1H-NMR (CDC13): δ 8.21 (IH, d, 77.4 Hz); 7.75 (IH, d, 77.9 Hz); 7.68 (IH, t, 77.9 Hz);
7.49 (IH, s); 7.42 (IH, d, 77.9 Hz); 6.25 (IH, d, 77.4 Hz); 4.36 (2H, q, 77.2 Hz); 2.03 (3H, s); 1.37 (3H, t, 77.2 Hz).
APCI-MS m/z: 326 [MH+]. b j Ethyl 5-bromo-6-(bromomethvP-2-oxo-l 43-(trifluoromethyl)phenyll- 1.2- dihydropyridiήe-3-carboxylate
The subtitle compound (3.25 g, 98%) was prepared by stirring ethyl 6-methyl-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxylate (2.25 g, 6.9 mmol) with
N-bromosuccinimide (2.45 g, 13.8 mmol) and benzoyl peroxide (35 mg, 0.14 mmol) in carbon tetrachloride (40 ml) at 70 °C for 4 h.
1H-NMR (CDC13): δ 8.33 (IH, s); 7.82 (IH, d, 77.9 Hz); 7.72 (IH, t, 77.9 Hz); 7.62 (IH, s); 7.56 (IH, d, 77.9 Hz); 4.38 (2H, q, 77.1 Hz); 4.16-4.08 (2H, m); 1.37 (3H, t, 77.1 Hz).
APCI-MS m z: 482/484/486 [MH+]. c) Ethyl 5 -bromo-6-(hvdroxymethvP-2-oxo- 1 - [3 -(trifluoromethyPphen yil -1,2- dihydropyridine-3-carboχylate
The subtitle compound was prepared in quantitative yield by stirring ethyl 5-bromo-6- (bromomethyl)-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxylate with aqueous sodium bicarbonate in aqueous THF at 60 °C overnight.
1H-NMR (CDCI3): δ 8.35 (IH, s); 7.78 (IH, d, 77.9 Hz); 7.68 (IH, t, 77.9 Hz); 7.57 (IH, s); 7.50 (IH, d, 77.9 Hz); 4.45-4.33 (4H, m); 1.37 (3H, t, 77.1 Hz).
APCI-MS m/z: 420/422 [MH+]. d) Ethyl 5-bromo-6-formyl-2-oxo-l-r3-(trifIuoromethvPphenyl]-l ,2-dihydropyridine-3- carboxylate
Dimethyl sulphoxide (1.14 g, 1.036 ml, 14.6 mmol) was added dropwise to a solution of oxalyl chloride (0.93 g, 0.64 ml, 7.3 mmol) in dry CH2C12 (40 ml) at -70 °C under an argon atmosphere. After 10 minutes stirring, ethyl 5-bromo-6-(hydroxymethyl)-2~oxo-l- [3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxylate (2.8 g, 6.66 mmol) in CH2C12 (10 ml) was added and stirring was continued for 20 minutes followed by the addition of triethylamine (3.34 g, 4.6 ml, 33 mmol). After a further 15 minutes at low temperature, the reaction mixture was allowed to reach -15 °C and water (20 ml) was added. Stirring was continued until the reaction mixture reached room temperature. It was then extracted with water and CH2CI2, washed with brine, dried and filtered. The solvents were removed in vacuo and the residue purified by column chromatography on silica using CH2C12 as eluent to afford the title compound (1.46 g, 52%). 1H-NMR (CDCI3): δ 9.74 (IH, s); 8.31 (IH, s); 7.75 (IH, d, 77.9 Hz); 7.65 (IH, t, 77.9 Hz); 7.46 (IH, s); 7.41 (IH, d, 77.9 Hz); 4.41 (2H, q, 77.1 Hz); 1.39 (3H, t, 77.1 Hz). APCI-MS m z: 418/420 [MH+]. e) Ethyl 5-bromo-6-(difluoromethyP-2-oxo-l-r3-(trifluoromethyPphenyl]-l,2- dihydropyridine-3-carboxylate.
The subtitle compound was prepared by stirring ethyl 5-bromo-6-formyl-2-oxo-l-[3-
(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxylate (0.98 g, 2.34 mmol) with (diethylamino)sulfur trifluoride (DAST) (378 mg, 2.34 mmol) in dry CH2C12 (20 ml) overnight. Water was added and the reaction mixture was extracted with CH2C12. The solvents were removed in vacuo to afford 1.06 g (100%) of the subtitle compound. 1H-NMR (CDCI3): δ 8.29 (IH, brt, 71.1 Hz); 7.77 (IH, d, 78.1 Hz); 7.65 (IH, t, 78.1 Hz); 7.53 (IH, s); 7.46 (IH, t, 78.1 Hz); 6.82 (IH, t, 755.1 Hz); 4.39 (2H, q, 77.1 Hz); 1.38 (2H, q, 77.1 Hz).
APCI-MS m/z: 440/442 [MH+]. f) 5-Bromo-6-(difluoromethvP-N-r4-(methylsulfonyPbenzyll-2-oxo-l-r3-
(trifluoromethvPphenyπ-l,2-αιhydropyridine-3-carboxamide
The title compound was prepared from 5-bromo-6-(difluoromethyl)-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxylic acid [obtained from ethyl 5- bromo-6-(difluoromethyl)-2-oxo-l-[3-(trifluoromethyl)phenyl3-l,2-dihydropyridine-3- carboxylate by alkaline hydrolysis] and 4-(rnethylsulfonyl) benzylamine hydrochloride using the method described in Example 17. 1H-NMR (CDCI3): δ 9.79 (IH, brt, 75.2 Hz); 8.78 (IH, s); 7.89 (2H, d, 78.4 Hz); 7.82
(IH, d, 77.8 Hz); 7.70 (IH, t, 77.8 Hz); 7.55 (IH, s); 7.50 (2H, d, 78.4 Hz); 7.47 (IH, d,
77.8 Hz); 6.92 (IH, t, 751.9 Hz); 4.67 (2H, m); 3.02 (3H, s).
APCI-MS m z: 579/581 [MH+].
Example 69 6-(DifluoromethvP-N44-(methylsulfonyl)benzyl] -2-oxo- 143-
(trifluoromethyl)phenyll-1.2-dihvdropyridine-3-carboxamide
The title compound was prepared by hydrogenation of 5-bromo-6-(difluoromethyl)-N-[4-
(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydroρyridme-3- carboxamide with palladium on charcoal (Pd/C) and ammonium formate in methanol.
1H-NMR (CDCI3): δ 10.00 (IH, brt, 75.8 Hz); 8.76 (IH, d, 77.5 Hz); 7.89 (2H, d, 78.2
Hz); 7.87 (IH, d, 77.9 Hz); 7.77 (IH, t, 77.9 Hz); 7.58 (IH, s); 7.52 (IH, d, 77.9 Hz);
7.51 (2H, d, 78.2 Hz); 6.98 (IH, d, 77.5 Hz); 6.10 (IH, t, 753.0 Hz); 4.70 (2H, m); 3.03
(3H, s). APCI-MS m z: 501 [MH+].
The compounds described in Examples 70.1 to 70.50 were prepared by a method analogous to that described in Examples 1 and 2:
Example 70.1 N-(2,3-Dihydro-l,4-benzodioxin-6-ylmethyl)-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyll-l,2-dihydropyridine-3-carboxamide
1H NMR (DMSO-dδ): δ 9.93 (IH, t); 8.38 (IH, d); 7.88 (2H, d); 7.80 (IH, t); 7.70 (IH, d); 6.79-6.70 (3H, m); 6.62 (IH, d); 4.34 (2H, d); 4.18 (4H, s). APCI-MS m/z: 466.3 [MH+].
Example 70.2 6-Methyl-N43-(methylsulfonvPbenzyl'l-2-oxo-143-
(trifluoromethyPphenyl]- 1 ,2-dihydropyridine-3-carboxamide
1H NMR (DMSO-dβ): δ 9.93 (IH, t); 8.38 (IH, d); 7.95-7.45 (8H, m); 6.62 (IH, d); 4.58 (2H, d); 3.18 (3H, s). Example 70.3 6-Methyl-N'44-(methylsulfonvPρhenyl]-2-oxo-143-
(trifluoromethvPphenyll-l,2 dihydropyridine-3-carbohvdrazide
1H NMR (DMSO-dg): δ 10.80 (IH, s); 9.62 (IH, d); 7.99-7.74 (4H, m); 7.65 (2H, d);
6.80 (2H, d); 6.67 (IH, d); 3.07 (3H, s).
Example 70.4 N'-(4-BromophenvP~6-methyl-2-oxo-143-
(trifluoromethvPphenyll-l,2-dihydropyridine-3-carbohvdrazide
1HNMR (DMSO-de): δ 10.69 (IH, s); 8.35 (IH, d); 7.99-7.73 (4H, m); 7.29 (2H, d);
6.66 (3H, dd).
Example 70.5 N-[(5-Methoxy-4-oxo-4H-pyran-2-yl)methyl1-6-methyl-2-oxo-l-
[3-(trifluoromethyPphenyl1-l,2-dihvdropyridine-3-carboxamide
APCI-MS m/z: 435.2 [MH+].
Example 70.6 N-(4-CyanobenzyP-6-methyl-2-oxo-143-(trifluoromethypphenyll-
1 ,2-dihydropyridine-3-carboxamide APCI-MS m/z: 412.3 [MH+].
Example 70.7 N-{[3-(4-MethoχyphenyPisoxazol-5-yllmethvU-6-methyl-2-oxo-l- [3-(trifluoromethyPρhenyll-l,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 484.4 [MH+].
Example 70.8 N'-(4-CyanophenvP-6-methyl-2-oxo-l-[3-(trifluoromethvPphenyll- l,2-dihydropyridine-3-carbohydrazide APCI-MS m/z: 413.3 [MH+J.
Example 70.9 6-Methyl-2-oxo-N4(l-phenyl-lH-pyrazol-4-yl)methyl1-143-
(trifluoromethypphenyll- 1 ,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 467.3 [MH+]. Example 70.10 N-(2,3-Dihvdro-l,4-benzodioxin-2-ylmethvP-6-methyl-2-oxo-l-r3-
(trifluoromethyl)phenyl1-l,2-dihvdropyridine-3-carboxamide
APCI-MS m/z: 445.2 [MH+].
Example 70.11 6-Methyl-N- l-(3-methylρhenvP-lH-pyrazol-4-yllmethylA2-oxo- l-r3-(trifluoromethyl)phenyl1-1.2-dihvdropyridine-3-carboxamide APCI-MS m/z: 467.3 [MH+].
Example 70.12 N'-(4-ChlorophenvP-6-methyl-2-oxo-l-r3- rtrifluoromethyl)phenyll-l,2-dihydropyridine-3-carbohvdrazide APCI-MS m/z: 422.2 [MH+].
Example 70.13 6-Methyl-2-oxo-N-[2-(tetrahvdro-2H-pyran-4-yl)ethyl1-l-[3-
(trifluoromethyPphenyl1-l,2-dihy<jj;opyridine-3-carboxamide APCI-MS m/z: 409.4 [MH+].
Example 70.14 N-rri-Ethyl-lH-pyrazol-4-vPmethyl1-6-methyl-2-oxo-l-[3-
(trifluoromethyPphenyl1-l,2-dihydropyridine-3-carboxamide
APCI-MS m z: 405.2 [MH+].
Example 70.15 N-[(,4-Benzylmorpholin-2-vPmethyll-6-methyl-2-oxo-l-r3-
(trifluoromethyl)phenyll-l,2-oιhydropyridine-3-carboxamide
APCI-MS m/z: 486.3 [MH+].
Example 70.16 6-Methyl-N-r3-(2-meth ylpiperidin- 1 - vPρropyl]-2-oxo-l 43-
(trifluoromethyPphenyl1-1.2-dihvdropyridine-3-carboxamide APCI-MS m/z: 436.3 [MH+].
Example 70.17 Methyl 24 r((6-methyl-2-oxo-l-F3-(trifluoromethvPphenylM.2- dihydropyridin-3-yl } carbon vPaminolmethyl )-3-furoate APCI-MS m/z: 558.3 [MH+].
Example 70.18 6-Methyl-N-rri-methyl-lH-pyrazol-4-yPmethyll-2-oxo-l-r3-
(trifluoromethyPphenyll- 1 ,2-dihydrop yridine-3-carboxamide APCI-MS m/z: 391.2 [MH+].
Example 70.19 N-(3-Azeρan-l-ylproρvD-6-methyl-2-oxo-143-
(trifluoromethyPphenyll- 1 ,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 436.3 [MH+].
Example 70.20 6-Methyl-N-(3-morpholin-4~ylpropyl)-2-oxo-143-
(trifluoromethvPphenyll- 1 ,2-dihydropyridine-3-carboxamide APCI-MS m/z: 424.3 [MH+].
Example 70.21 6-Methyl-2-oxo-N-(3-ρiperidin- 1- ylprop vP- 143-
(trifluoromethvPphenyl]- 1 ,2-dihydrop yridine-3-carboxamide APCI-MS m/z: 422.3 [MH+].
Example 70.22 N-r3-(3.5-Dimethyl-lH-ρyrazoI-l-vPproρvn-6-methyl-2-oxo-l-F3- (trifluoromethyPphenyl]-l,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 433.3 [MH+].
Example 70.23 N-r3-(2-Ethylpiperidin-l-vPρropyn-6-methyl-2-oxo-l-r3-
(trifluoromethvPphenyll-l,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 450.4 [MH+].
Example 70.24 6-Methyl-N-r2-(l-methyl-lH-imidazol-5-vPethyll-2-oxo-l-[3-
(trifluoromethyPphenyl]-l,2-dihydropyridine-3-carboxamide
APCI-MS m/z: 405.2 [MH+]. Example 70.25 N-r(l-Ethyl-3-methyl-lH-pyrazol-4-yl)methyl1-6-methyl-2-oxo-l-
[3-(trifluoromethvPphenyl1-l,2-dihydropyridine-3-carboxamide
APCI-MS m z: 419.2 [MH+].
Example 70.26 N-[4-(Acetylamino)benzyl1-6-methyl-2-oxo-l-[3-
(trifluoromethyPphenyl]-l,2-dihydropyridine-3-carboxamide APCI-MS m/z: 444.2 [MH+].
Example 70.27 6-Methyl-2-oxo-N-[3-(lH-Pyrazol-l-vPpropyl1-l-r3- (trifluoromethyPphenyll-l^-Q-Jhydropyridine-S-carboxamide APCI-MS m/z: 405.2 [MH+].
Example 70.28 6-Methyl-2-oxo-N-(pyridin-2-ylmethvP-143-
(trifluoromethyPphenyll - 1 ,2-dihydropyridine-3 -carboxamide APCI-MS m/z: 388.3 [MH+].
Example 70.29 6-Methyl-N-{ri-(4-methylphenvP-lH-pyrazol-4-yl1methyll-2-oxo-
1 - [3 -(trifluoromethyPphenyll - 1 ,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 467.3 [MH+].
Example 70.30 6-Methyl~N'-(4-methylphenvP-2-oxo-143-
(trifluoromethyPphenyn-l,2-dihydropyridine-3-carbohydrazide APCI-MS m/z: 402.2 [MH+].
Example 70.31 6-Methyl-N-r3-(4-methylρiρeridin-l-vPpropyll-2-oxo-l-r3-
(trifluoromethyPphenyll-l,2-dihydropyridine-3-carboxamide APCI-MS m z: 436.3 [MH+].
Example 70.32 6-Methyl-2-oxo-N43-(5-oxo-4.5-αihydro-lH-ρyrazol-4-yPpropyIl- l-[3-(trifluoromethvPphenyn-l,2-dihvdropyridine-3-carboχamide APCI-MS m/z: 421.3 [MH+].
Example 70.33 Ethyl 5-methyl-4-{ [(l6-methyl-2-oxo-l-r3-
(trifluoromethyPphenyll-l,2-Q^hydropyridin-3-yl}carbonyl)aminolmethyl}-2-furoate APCI-MS m/z: 463.3 [MH+].
Example 70.34 N4f6-Fluoro-4H-l,3-benzodioxin-8-yl)methyl1-6-methyl-2-oxo-l- r3-(trifluoromethvPphenyll- 1 ,2-dihydropyridine-3-carboxamide APCI-MS m/z: 463.3 [MH+].
Example 70.35 6-Methyl-2-oxo-N-(2-pyridin-3-ylethvP-l-[3-
( fluoromethyl)phenyl]-1.2-dihydropyridine-3-carboxamide APCI-MS m/z: 402.2 [MH+].
Example 70.36 N-r(l,3-Dimethyl-lH-pyrazol-4-vPmethvn-6-methyl-2-oxo-l-r3-
(trifluoromethyPphenyl1-l,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 405.2 [MH+].
Example 70.37 6-Methyl-2-oxo-N-(2-pyridin-4-ylethyl)-l-r3- (trifluoromethyPphenyll-l,2-dihvdropyridine-3-carboxamide APCI-MS m z: 402.2 [MH+].
Example 70.38 N'-(4-FluorophenyP-6-methyl-2-oxo-l-r3-(trifIuoromethyPphenyI1- l,2-dihvdropyridine-3-carbohydrazide APCI-MS m/z: 406.2 [MH+].
Example 70.39 6-Methyl-N4(l-methyl-m-ρyrtol-2-vPmethyl1-2-oxo-143-
("trifluoromethyPphenyl1-1.2-dihvdropyridine-3-carboxamide
APCI-MS m/z: 390.3 [MH+]. Example 70.40 6-Methyl-2-oxo-N'-ρhenyl-l-r3- rifluoromethvPρhenvn-1.2- dihydropyridine-3-carbohydrazide
APCI-MS m/z: 388.3 [MH+].
Example 70.41 N-[(l-Ethyl-5-methyl-lH-ρyrazol-4-vPmethvn-6-methyl-2-oxo-l-
[3-(trifluoromethvPphenyl1-l,2-άjhydropyridine-3-carboxamide
APCI-MS m/z: 419.2 [MH+].
Example 70.42 6-Methyl-N42-(l-methyl-lH-imidazol-4-vPethyll-2-oxo-143- (trifluoromethyPphenyll-l,2-dihydropyridine-3-carboxamide APCI-MS m/z: 405.2 [MH+].
Example 70.43 N42-(1.3-Dioxolan-2-vPethyl1-6-methyl-2-oxo-143-
(trifluoromethyPphenyll-l,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 397.3 [MH+].
Example 70.44 N-(l-Benzothien-3-ylmethvP-6-methyl-2-oxo-l-[3-
(trifluoromethyPphenyl1-l,2-dihvdropyrioιne-3-carboxamide APCI-MS m/z: 443.3 [MH+].
Example 70.45 N-r(l,5-Dimethyl-lH-ρyrazol-4-vPmethyll-6-methyl-2-oxo-l-[3-
, trifluorometh yPphen yll - 1 ,2-dihydrop yridine-3 -carboxamide APCI-MS m/z: 405.2 [MH+J.
Example 70.46 N42-(3,5-Dimethyl-lH-pyrazol-4-vPethyl1-6-methyl-2-oxo-143-
(trifluoromethyl)phenyll-l,2-dihvdropyridine-3-carboxamide APCI-MS m z: 419.2 [MH+].
Example 70.47 N-[2-(3,5-Dimethylisoxazol-4-yPethyl]-6-methyl-2-oxo-l-[3- (trifluoromethyl)phenyn- 1 ,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 420.3 [MH+].
Example 70.48 N-(3,4-Dihvdro-lH-isochromen-l-ylmethyl)-6-methyl-2-oxo-l-r3-
(trifluoromethyl)phenyn- 1 ,2-dihvdropyridine-3-carboxamide APCI-MS m/z: 443.2 [MH+].
Example 70.49 N-{[(2RVl-Ethylpyrrolidin-2-ynmethyl)-6-methyl-2-oxo-l-r3-
(trifluoromethyl)phenyl]-l,2-dihvciropyridine-3-carboχamide
APCI-MS m/z: 408.3 [MH+].
Example 70.50 6-Methyl-2-oxo-N-[r2RVtetrahvdrofuran-2-ylmethyll-l-r3-
(trifluoromethyPphenyl1-l,2-dihvdropyridine-3-carboxamide
APCI-MS m/z: 381.2 [MH+].
Example 71 5-Chloro-N- (4-r(dimethylamino)sulfonyl]benzyl I -6-methyl-2-oxo- l-r3-(lrifluoromethvPphenyl1-l,2-dihydropyridine-3-carboxamide
a) N-r4-(Benzylthio)benzyl]-6-methyl-2-oxo-l-r3-(trifluoromethyPphenyll-l,2- dihvdropyridine-3-carboxamide The subtitle compound was prepared as described for N-[4-(benzylsulfonyl)benzyl]-6- methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide [Example 27 (b)] but excluding the oxidation step. The sub title product was purified by preparative HPLC (x-terra column, 0.2% ammonia, acetonitrile) to afford the title compound. 1H NMR (DMSO): δ 9.78 (IH, t, J 6.0 Hz); 8.37 (IH, d, J 7.5 Hz); 7.91 - 7.68 (4H, m); 7.35 - 7.16 (9H, m); 6.62 (IH, d, J 7.6 Hz); 4.47 - 4.37 (2H, m); 4.20 (2H, s); 2.01 (3H, s). APCI-MS m/z: 509 [MH+].
b) 5-Chloro-N-l4-r(dimethylamino')sulfonyllbenzyl}-6-methyl-2-oxo-l-[3- (trifluoromethyPphenyll-l,2-dihydropyridine-3-carboxamide To N-[4-(benzylthio)benzyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide (92 mg, 0.18 mmol) was added 50% formic acid/water (18 ml) and CH2C12 (9 ml). The reaction mixture was cooled to -20 °C and chlorine gas was bubbled through for 1 min. After evaporation of the excess chlorine the reaction mixture was partitioned between CH2C12 and water. The organic phase was washed with 0.5M aqueous NaHCO3 and brine, and then dried. After filtration, the solvent was removed in vacuo and the residue was dissolved in ethanol (10 ml). 5.6M Dimethylamine in ethanol (250 μl) was added and the mixture was stirred at room temperature overnight. After removal of the solvent the residue was purified by preparative HPLC (x-terra, 0.2% ammonia, acetonitrile) to afford the title compound (41 mg, 43%).
1H NMR (CDC13): δ 9.88-9.81 (IH, m); 8.65 (IH, s); 7.85 - 7.67 (4H, m); 7.51 - 7.39 (4H, m); 4.73 - 4.59 (2H, m); 2.68 (6H, s); 2.19 (3H, s). APCI-MS m/z: 528 [MH+].
Example 72 N-l4-[φimethylamino sulfonyllbenzyl)-6-methyl-2-oxo-l-r3-
(trifluoromethyP-phenyll - 1 ,2-dihydrop yridine-3 -carboxamide 5-Chloro-N-{4-[(dimethylamino)sulfonyl]benzyl}-6-methyl-2-oxo-l-[3- ( fluoromethyPphenyn-l^-dihydropyridine-S-carboxamide (15 mg, 0.028 mmol) was dissolved in hot methanol (1 ml). After cooling to room temperature, ammonium formate (6 mg, 0.1 mmol) and 10% palladium on carbon (3 mg) were added. The reaction mixture was stirred in a sealed vial at room temperature for 4 h. After filtration through Celite, the solvent was evaporated and the residue was purified by column chromatography on silica using CH2Cl2/methanol (98:2) as eluent to afford the title compound (6 mg, 43%). 1H NMR (CDC13): δ 10.01-9.92 (IH, m); 8.59 (IH, d, J 7.5 Hz); 7.85 - 7.66 (4H, m); 7.55 - 7.41 (4H, ); 6.48 (IH, d, J 7.5 Hz); 4.75 - 4.59 (2H, m); 2.68 (6H, s); 2.09 (3H, s). APCI-MS m/z: 494 [MH+].
Example 73 5-Chloro-6-methyl-2-oχo-N-[4-(piρerazin-l-ylsulfonvPbenzyll-l-[3-
(trifluoro-methvPphenyl1-l,2-dihvdropyridine-3-carboxarnide The title compound was prepared using the general method of Example 71. 1H NMR (CDCI3): δ 9.99 - 9.82 (2H, m); 8.64 (IH, d, 8.2 Hz); 7.86 - 7.62 (4H, m); 7.53 7.39 (4H, m); 4.76 - 4.55 (2H, m); 3.86 - 2.92 (8H, m); 2.19 (3H, s). APCI-MS m/z: 569 [MH+].
Using the general method of Example 72, the compounds of Examples 74 to 78 were prepared:
Example 74 6-Methyl-2-oxo-N44-(piρerazin- 1 -ylsulf onyPbenzyll- 143-
(trifluoromethyP-phenyll - 1 ,2-dihydropyridine-3-carboxamide
1H NMR (CDC13): δ 10.11 - 9.79 (2H, m); 8.67 - 8.50 (IH, m); 7.89 - 7.38 (8H, m); 6.52 6.43 (IH, m); 4.78 - 4.52 (2H, m); 3.89 - 3.62 (2H, m); 3.49 - 2.94 (6H, m); 2.09 (3H, s). APCI-MS m/z: 535 [MH+].
Example 75 6-Methyl-N-[4-(morpholin-4-ylsulfonvPbenzvn-2-oxo-l-[3- (trifluoromethypphenyll- 1 ,2-dihydropyridine-3-carboxamide
1H NMR (CDC13): δ 10.05-9.95 (IH, m); 8.58 (IH, d, 7.5 Hz); 7.84 - 7.64 (4H, m); 7.54
7.41 (4H, m); 6.48 (IH, dd, 17.4, 0.8 Hz); 4.75 - 4.59 (2H, m); 3.76 - 3.69 (4H, ); 3.01 -
2.94 (4H, m); 2.09 (3H, s).
APCI-MS m z: 536 [MH+].
Example 76 6-Methyl-2-oxo-N- r4-(ρiperidin- 1 -ylsulf onyPbenzyll - 1 - [3-
(trifluorornethyP-phen yl] - 1 ,2-dihvdropyridine-3 -carboxamide lBNMR (COCl3): δ 10.02-9.92 (IH, m); 8.60 (IH, d, J 7.3 Hz); 7.84 - 7.64 (4H, m); 7.54 •
7.41 (4H, m); 6.48 (IH, dd, J 7.5, 0.5 Hz); 4.74 - 4.59 (2H, m); 2.99 - 2.91 (4H, m); 2.09 (3H, s); 1.68 - 1.35 (6H, m).
APCI-MS m z: 534 [MH+].
Example 77 6-Methyl-N- { 4- [(methylamino')sulf onyllbenzyl I -2-oxo- 1-T3-
(trifluoromethylVphenyl]-l,2-dihvdropyridine-3-carboxamide 1H NMR (CDCI3): δ 10.02-9.92 (IH, m); 8.59 (1H, d, J 7.3 Hz); 7.86 - 7.70 (4H, m); 7.54 -
7.41 (4H, m); 6.48 (IH, d, 17.3 Hz); 4.73 - 4.58 (2H, m); 4.29 (IH, s); 2.63 (3H, s); 2.09
(3H, s).
APCI-MS m z: 480 [MH+].
Example 78 6-Methyl-2-oxo-N-[4-(pyrrolidin-l-ylsulfonyPbenzyll-l-[3-
(trifluoromethyl)phenyl1-l,2-dihydropyridme-3-carboxamide
1H NMR (CDCI3): δ 10.00 - 9.91 (IH, m); 8.60 (IH, d, 7.5 Hz); 7.85 - 7.68 (4H, m); 7.53
- 7.40 (4H, m); 6.48 (IH, dd, J 7.5, 0.7 Hz); 4.76 - 4.58 (2H, m); 3.26 - 3.16 (4H, m); 2.09 (3H, s); 1.80 - 1.70 (4H, m).
APCI-MS m z: 520 [MH+].
Example 79 5-Chloro-6-methyl-2-oxo-N-[4-(pyrrolidin-l-ylsulfonvPbenzyπ-l-
[3-(trifluoromethvPphenyl]-l,2-dihydropyridine-3-carboxamide The title compound was prepared using the general method of Example 71.
1H NMR (CDC13): δ 9.89 - 9.79 (IH, m); 8.66 (IH, s); 7.86 - 7.72 (4H, m); 7.52 - 7.40 (4H, m); 4.74 - 4.59 (2H, m); 3.25 - 3.17 (4H, m); 2.19 (3H, s); 1.78 - 1.72 (4H, m). APCI-MS m/z: 554 [MH+].
Example 80 5-Chloro-6-methyl-N44-(methylsulfonyl)benzyll-2-oxo-143-
(trifluoromethyl)-phenyl1-l,2-dihvdropyridine-3-carboxamide 6-Methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide [Example 1.1] (50 mg, 0.108 mmol) was dissolved in acetonitrile (1 ml) and cooled to 0 °C. KNO3 (16 mg, 0.16 mmol) and sulfuryl chloride (13 μl, 0.16 mmol) were added. The reaction mixture was stirred for 1 h at 0 °C, followed by the addition of saturated aqueous Na2CO3 and diethyl ether . The aqueous phase was extracted with diethyl ether and the combined organic phase was washed with brine and dried. After filtration, the solvent was removed in vacuo, the residue was dissolved in methanol, a white precipitate appeared and was filtered off and dried to afford the title compound (22 mg, 41%). 1H NMR (CDCI3): δ 9.93 - 9.80 (IH, ); 8.64 (IH, s); 7.94 - 7.69 (4H, m); 7.57 - 7.37 (4H, m); 4.75 - 4.57 (2H, m); 3.01 (3H, s); 2.19 (3H, s). APCI-MS m/z: 499 [MH+].
Example 81 N-{4-r(Acetylamino)sulfonyllbenzyll-6-methyl-2-oxo-l-r3-
(trifluoromethyP-phenyl1-l,2-dihydropyridine-3-carboxamide N-[4-(Aminosulfonyl)benzyl]-6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide [Example 1.5] (16 mg, 0.034 mmol) was dissolved in CH2C12 (1 ml). Powdered KOH (6 mg, 0.11 mmol) and 10% acetyl chloride in CH2C12 (25 μl, 0.035 mmol) were added and the mixture was stirred at room temperature for 1.5 h. Water and IM aqueous HCI were added. The reaction mixture was extracted with CH2CI2. The organic phase was washed with water, brine and dried. The solvent was removed in vacuo and the residue was purified by preparative HPLC (x-terra, 0.2% ammonia, acetonitrile) to afford the title compound (7 mg, 41%). 1HNMR (CDCI3): δ 10.03-9.96 (IH, m); 8.58 (IH, d, J 7.4 Hz); 8.16 (IH, s); 7.98 - 7.93 (2H, m); 7.83 - 7.71 (2H, m); 7.53 - 7.42 (4H, m); 6.47 (IH, d, 7.4 Hz); 4.72 - 4.59 (2H, m); 2.08 (3H, s); 2.02 (3H, s). APCI-MS m/z: 508 [MH+].
Using the general method of Example 10, the compounds of Examples 82 and 83 were prepared:
Example 82 N-f4-(IsopropylsulfonyPbenzvI]-5-iodo-6-methyl-2-oxo-l-[3-
(trifluoromethyPphenyl1-l,2-dihvdropyridine-3-carboxamide 1H NMR (CDC13): δ 9.90 (IH, t, J 5.7 Hz); 8.91 (IH, s); 7.83-7.80 (3H, m); 7.76 (IH, t, I 7.9 Hz); 7.50-7.48 (3H, m); 7.41 (IH, d, J 7.8 Hz); 4.68 (2H, t, J 6.2 Hz); 3.15 (IH, m); 2.31 (3H, s); 1.28 (6H, d, 6.89 Hz). APCI-MS m/z: 619 [MH+]. Example 83 N44-(CvclopropylsulfonyPbenzyll-5-iodo-6-methyl-2-oxo-l43-
(trifluoromethyPphenyl1-l,2-dihydropyridine-3-carboxamide
1HNMR (CDC13): δ 9.86 (IH, t, I 5.8 Hz); 8.90 (IH, s); 7.83-7.80 (3H, m); 7.75 (IH, t, I 7.8 Hz); 7.49-7.47 (3H, m); 7.40 (IH, d, J 7.8 Hz); 4.66 (2H, t, J 5.7 Hz); 2.42 (IH, m); 2.31 (3H, s); 1.32 (2H, m); 1.01 (2H, m). APCI-MS m/z: 617 [MH+].
Example 84 l,2-Dihvdro-6-methyl-N-r[4-[(methylsulfonyPoxylphenvnmethvn-
2-oxo-l-[3-(trifluoromethyPphenyl1-3-pyridinecarboxamide The title compound (31 mg, 46%) was prepared from N-(4-hydroxybenzyl)-6-methyl-2- oxo-l-[3-(trifluoromethyl)phenyl]-l ,2-dihydropyridine-3-carboxamide and benzensulfonyl chloride using the general method of Example 61.
1H NMR (DMSO-d6) δ 9.87 (IH, t, J 6.0 Hz); 8.38 (IH, d, 1 7.5 Hz); 7.89 (2H, d, J 8.9
Hz); 7.80 (IH, t, 1 7.8 Hz); 7.72 (IH, d, J 7.9 Hz); 7.39 (2H, d, I 8.6 Hz); 7.29 (2H, d, J 8.6 Hz); 6.62 (IH, d, J 7.5 Hz); 4.50 (2H, d, J 6.0 Hz); 3.35 (3H, s,); 2.02 (3H, s).
APCI-MS m z: 543.3 [MH+].
Example 85 N44-(l,l-Dioxidoisothiazolidin-2-yPbenzyl1-6-methyl-2-oxo-143-
(trifluoromethyPphenyn- 1 ,2-dihvdropyridine-3-carboxamide The title compound (12 mg, 9.5%) was prepared from N-(4-aminobenzyl)-6-methyl-2-oxo- l-[3-(1rifluoromethyl)phenyl]-l,2-dihydroproline-3-carboxamide and 3- chloropropanesulfonyl chloride using the general method of Example 56.
1H NMR (DMSO-d6) δ 9.78 (IH, t, J 5.8 Hz); 8.37 (IH, d, J 7.4 Hz); 7.88 (2H, d, 17.6
Hz); 7.79 (IH, t, J 7.8 Hz); 7.70 (IH, d, I 8.2 Hz); 7.28 (2H, d, I 8.6 Hz); 7.14 (2H, d, I 8.5 Hz); 6.61 (IH, d, J 7.5 Hz); 4.43 (2H, d, J 5.8 Hz); 3.69 (2H, t, J 6.5 Hz); 3.47 (2H, t, J 7.4
Hz); 2.38 (2H, quintet, J 7.0 Hz); 2.01 (3H, s).
APCI-MS m/z 506.3 [MH+].
Example 86 6-Methyl-2-oxo-N-rr4-(4-pyridmylsulfonyPphenyl]methyl1-l-r3- (trifluoromethyPphen yll- 1 ,2-dihydrop yridine-3-carboxamide a) l-r4-(Pyridin-4-ylsulfonvPphenyl1methanamine
To a mixture of 4-mercaptopyridine (0.8 g, 7.2 mmol) and K2CO3 (2.0 g, 14.4 mmol) in
NMP, 4-fluorobenzaldehyde (0.99 g, 8.0 mmol) was added. The mixture was then stirred at 70 °C for 3 h. After cooling, the reaction mixture was diluted with water (5.0 ml) and extracted with EtOAc. The organic solvent was evaporated and the residue dissolved in methanol. Sodium borohydride (0.57 g, 15 mmol) was added and the mixture stirred for 3 h at room temperature. After addition of water, the methanol was removed in vacuo and the residue extracted with CH2C12. The organic phase was dried over MgSO4, filtered, and evaporated and the residue was dissolved in toluene (10 ml). The toluene solution was heated to 40 °C, phosphorus tribromide (0.25 g, 0.92 mol) was added and the temperature increased to 100 °C for 30 minutes. After cooling, water (50 ml) was added and the mixture extracted with EtOAc. The organic phase was evaporated, the residue dissolved in methanol and slowly added to a mixture of 25% ammonia (15 ml) in methanol (10 ml). After stirring for 3 h at room temperature the subtitle compound was obtained. (0.30 g, 37%) as a white solid. APCI-MS m z: 217.2 [MH ].
b) 6-Methyl-2-oxo-N-[r4-(4-pyridinylsuIfonyPphenyl]methyl]-l-r3- (trifluoromethyPphenyll-l,2-dihvdropyridine-3-carboxamide
To a mixture of 6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxylic acid (0.28 g, 0.92 mmol), HBTU (0.35 g, 0.92 mmol) and DIEA (0.24 g, 1.84 mmol) in NMP was added l-[4-(pyridin-4-ylsuIfonyI)phenyI]methanamine (0.20 g, 0.92 mmol) in NMP (1 ml). The reaction mixture was stirred for 1 h at room temperature, then diluted with water (15 ml) and extracted with EtOAc. The organic phase was dried
(MgSO ), filtered and evaporated. To the residue dissolved in CH2CI2 (10 ml) cooled to - 15 °C was added m-chloroperoxybenzoic acid (0.48 g, 2.76 mmol). The mixture was stirred for 30 min and then overnight at room temperature. The reaction mixture was diluted with more CH2CI2 and water, washed with Na2S2O3, NaHCO3 and brine. The solvent was removed in vacuo and 25 mg of the residue was dissolved in acetonitrile/water (2.0 ml) and purified on a Xterra@Prep MS C8 column (19 x 50 mm) using a gradient of acetonitrile/water at a flow rate of 20 rruVmin. Freeze drying of the mixture afforded the title compound (12 mg, 49%).
1H NMR (DMSO-dg) δ 9.92 (IH, t, J 6.0 Hz); 8.85 (2H, dd, J 4.4, 1.6 Hz); 8.34 (IH, d, J 7.5 Hz); 7.96 (2H, dd, 1 6.7, 1.7 Hz); 7.90 (4H, m,); 7.87 (IH, t, J 4.4, 1.6 Hz); 7.71 (IH, d,
17.9 Hz); 7.54 (2H, d, J 8.4 Hz); 6.61 (2H, d, J 8.2 Hz); 4.55 (2H, d, 6.0 Hz); 2.01 (3H, s).
APCI-MS m/z: 528.4 [MH+].
Starting from 6-methyl-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2-dihydropyridine-3- carboxylic acid and the appropriate methanamine derivative and using the general method of Example 86, the compounds of Examples 87 to 91, 92(b) and 93(b) were prepared:
Example 87 6-Methyl-2-oxo-N444phenylsulfonvPbenzyll-143- (trifluoromethyPphenyl1-l,2-dihvdropyridine-3-carboxamide
The title compound (34 mg, 21%) was prepared using l-[4-(phenylthio)phenyl]methanamine (from thiophenol and 4-fluorobenzaldehyde).
1H NMR (CDC13) δ 9.90 (IH, t, J 6.0 Hz); 8.34 (IH, d, J 7.5 Hz); 7.90 (6H, m); 7.80 (IH, t, J 8.1 Hz); 7.78 (2H, m); 7.59 (2H, t, 17.5 Hz); 7.49 (2H, d, J 8.4 Hz); 6.60 (IH, d, J 7.7 Hz); 4.53 (2H, d, 6.2 Hz); 2.01 (3H, s).
APCI-MS m/z: 527.4 [MH+].
Example 88 6-Methyl-2-oxo-N44-α,3-thiazol-2-ylsulfonvPbenzyl1-143-
(trifluoromethyPphenyll - 1 ,2-dihvdropyridine-3 -carboxamide The title compound (50 m , 21%) was prepared using l-[4-(l,3-thiazol-2- ylsulfonyl)phenyl]methanamine (from 2-mercaptothiazole and 4-fluorobenzaldehyde). 1H NMR (400 MHz, DMSO-d6) δ 9.91 (IH, t, J 6.1 Hz); 8.32 (IH, d, J 11.8 Hz); 8.23 (IH, d, 7.9 Hz); 8.06 (IH, d, 1 3.1 Hz); 7.95 (2H, d, 8.4 Hz); 7.87 (2H, d, 7.2 Hz); 7.78 (IH, t, J 7.9 Hz); 7.68 (IH, t, 7.5 Hz); 7.54 (2H, d, I 8.4 Hz); 6.59 (IH, d, 17.7 Hz); 4.54 (2H, d, J 6.4 Hz); 1.99 (3H, s). APCI-MS m/z: 534.3 [MH+].
Example 89 6-Methyl-2-oxo-N44-(pyrimidin-2-ylsulfonvPbenzyl1-143-
(trifluoromethyPphenyl1-l,2-dihydropyridine-3-carboxamide The title compound (10 mg, 23%) was prepared using l-[4-(pyrimidin-2- ylsulfonyl)phenyl]methanamine (from 2-mercaptopyrimidine and 4-fluorobenzaldehyde).
1H NMR (DMSO-de): δ 9.63 (IH, t, 1 6.1 Hz); 8.69 (IH, d, J 4.9 Hz); 8.05 (IH, d, 7.5
Hz); 7.60 (4H, q, J 8.6 Hz); 7.45 (3H, m); 7.23 (2H, d, J 8.3 Hz); 6.30 (IH, d, 7.4 Hz);
4.27 (2H, d, J 6.6 Hz); 1.70 (3H, s). APCI-MS m z: 529.3 [MH+],
Example 90 N-[4-(lH-Imidazol-2-ylsulfonyPbenzyll-6-methyl-2-oxo-l-[3-
(trifluoromethyl)phenyll-l,2-dihydropyridine-3-carboxamide The title compound (8 mg, 16%) was prepared using l-[4-(lH-imidazol-2- ylsulfonyl)phenyl]methanamine (from 2-mercaptoimidazole and 4-fluorobenzaldehyde). 1H NMR (DMSO-de) δ 9.91 (1Η, t, J 6.2 Ηz); 8.35 (2Η, d, J 7.4 Hz); 7.88 (4H, t, J 8.4 Hz); 7.80 (IH, t, J 7.7 Hz); 7.72 (IH, d, J 7.9 Hz); 7.52 (2H, d, I 8.3 Hz); 7.27 (IH, s); 6.61 (IH,. d, J 7.5 Hz); 5.75 (IH, s); 4.54 (2H, d, J 6.0 Hz); 2.02 (3H, s). APCI-MS m/z: 517.3 [MH+].
Example 91 6-Methyl-N- { 4-1(1 -methyl- IH- 1 ,2,4-triazol-5- vPsulfonyllbenzyl I -2- oxo-l-[3-(trifluoromethyl)phenyn-l,2-dihvdropyridine-3-carboxamide The title compound (6 mg, 15%) was prepared using l-{4-[(l-methyl-lH-l,2,4-triazol-5- yl)sulfonyl]phenyl} methanamine (from 3-mercapto-4-methyl-4Η-l,2,4-triazole and 4- fluorobenzaldehyde).
1H NMR (DMSO-d6) δ 9.95 (IH, t, J 6.0 Hz); 8.74 (IH, s); 8.36 (IH, d, J 7.5 Hz); 7.99 (2H, d, J 8.4 Hz); 7.89 (2H, d, J 8.5 Hz); 7.80 (2H, t, J 7.8 Hz); 7.72 (IH, d, J 7.8 Hz); 7.59 (2H, d, I 8.4 Hz); 6.62 (IH, d, 17.3 Hz); 4.59 (2H, d, J 6.3 Hz); 3.86 (3H, s); 2.02 (3H, s). APCI-MS m/z: 532.3 [MH+]. Example 92 6-Methyl-N- 14- [(5-methyl-l ,3-oxazol-4-vPsulf onyllbenzyl I -2-oxo- l-[3-(trifluoromethyl)phenyl1-l,2-dihydropyridine-3-c-urboxamide
a) 1 - { 44(5-Methyl- 1 ,3-oxazol-4-yPsulfonyl1phenyl ) methanamine To 5-methyl-4-[(4-methylphenyl)sulfonyl]-l,3-oxazole (prepared according to J. Chem. Soc, Perkin Trans. 1, 2000, 527-531) (3.7 g, 15.6 mmol) dissolved in chlorobenzene, N-bromosuccinimide (3.5 g, 19.6 mmol) and 2,2'-azobis(2-methylpropinitrile) (0.27 g, 1.6 mmol) were added. The reaction mixture was then stirred and heated to 60 °C. Bromine (0.104 g, 0.65 mmol) was added and the mixture heated to 90 °C for an additional 2 h. After cooling, 2 % aqueous NaHSO (10 ml) and water (40 ml) were added and the mixture extracted with EtOAc. The organic phase was evaporated, the residue dissolved in methanol and slowly added to a mixture of 25% ammonia (150 ml) in methanol (100 ml). After stirring for 3 h at room temperature the ammonia was removed in vacuo and the water phase extracted with EtOAc. The organic phase was dried (MgSO4), filtered and evaporated affording the subtitle compound (2 g, 51 ).
b 6-Methyl-N-{4-r(5-methyl-l,3-oxazol-4-vPsulfonvπbenzv -2-oxo-l-[3- (trifluoromethyl)ρhenyl1-1.2-dihvdropyridine-3-carboxamide The title compound (7 mg, 21%) was prepared using l-{4-[(5-methyl-l,3-oxazol-4- yl)sulfonyl]phenyl}methanamine.
1H NMR (DMSO-de) δ 9.92 (IH, t, J 6.0 Hz); 8.39 (IH, s); 8.35 (IH, d, J 7.4 Hz); 7.88 (4H, t, J 5.4 Hz); 7.80 (IH, t, J 8.2 Hz); 7.71 (IH, d, J 8.2 Hz); 7.52 (2H, d, J 8.1 Hz); 6.61 (IH, d, J 7.5 Hz); 4.55 (2H, d, J 6.1 Hz); 2.64 (3H, s); 2.02 (3H, s); 1.91 (2H, s). APCI-MS m/z: 532.3 [MH+].
Example 93 6-Methyl-N-{ [6-(methylsulfonyl)pyridin-3-vnmethyl }-2-oxo-143-
(trifluoromethyPphenvn - 1 ,2-dihydropyridine-3 -carboxamide
a) l-[6-(Methylsulfonyl)pyridin-3-yl1methanamine To 2-chloropyridine-5-carboxyaldehyde (0.50 g, 3.5 mol) in THF (5 ml), sodium methanethiolate (0.50 g, 7.0 mmol) was added. The mixture was then stirred at 70 °C overnight. After cooling, the reaction mixture was diluted with water (15 ml) and extracted with EtOAc. The organic phase was evaporated and the residue dissolved in methanol. Sodium borohydride (0.26 g, 7.0 mmol) was added and the mixture stirred for 3 h at room temperature. After addition of water, the methanol was removed in vacuo and the residue extracted with CH2C12. The organic phase was dried (MgSO ), filtered, evaporated and treated with CH2C12 (50 ml). To the CH2C12 mixture, phosphorus tribromide (0.25 g, 0.92 mmol) was added and the mixture stirred overnight at room temperature. Water (50 ml) was then added and the mixture extracted with EtOAc. Finally, the organic phase was evaporated, the residue dissolved in methanol and slowly added to a mixture of 25% ammonia (20 ml) in methanol (20 ml). After stirring for 3 h at room temperature the subtitle compound was obtained.
b) 6-Methyl-N-{ [6-(methylsulfonyl)pyridin-3-yllmethyl }-2-oxo-143-
(trifluoromethvPphenyll- 1 ,2-dihydropyridine-3-carboxamide
The title compound (12 mg, 24%) was prepared using [6-(methylsulfonyl)pyridin-3- yl]methylamine l-[6-(methylsulfonyl)pyridin-3-yl]methanamine.
1H-NMR (DMSO-d6) δ 9.98 (IH, t, J 6.1 Hz); 8.71 (IH, s); 8.36 (IH, d, J 7.5 Hz); 8.01 (2H, s); 7.90 (2H, d, J 8.3 Hz); 7.81 (IH, t, 7.7 Hz); 7.72 (IH, d, 17.9 Hz); 6.62 (IH, d, J
7.5 Hz); 4.61 (2H, d, 6.1 Hz); 3.25 (3H, s); 2.03 (3H, s).
APCI-MS m/z: 466.3 [MH+].
Example 94 5-Fluoro-6-methyl-N-[4-(methylsulfonyl)benzyl1-2-oxo-l-r3- (trifluoromethyPphenyll-l,2-dihydropyridine-3-carboxamide
To 6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl)phenyl]-l,2- dihydropyridine-3-carboxamide [Example 1.1] (0.25 g, 0.54 mmol) in acetonitrile (4.5 ml) under argon, l-chloromethyl-4-fluoro-l ,4-diazoniabicyclo[2.2.2]octane- bis(tetrafluoroborate) (0.45 g, 1.27 mmol) was added. The reaction mixture was heated at 80 °C for 2 h. Water was then added and the product purified on a Xterra@Prep MS C8 column (19 x 50 mm) using a gradient of acetonitrile/water at a flow rate of 20 ml/min. Freeze drying of the mixture afforded the title compound (75 mg, 29%). 1H NMR (CDC13) δ 10.02 (IH, t, I 5.4 Hz); 8.57 (IH, d, 19.0 Hz); 7.88 (2H, d, J 8.4 Hz); 7.84 (IH, d, J 8.1 Hz); 7.76 (IH, t, J 7.9 Hz); 7.51 (4H, d, J 8.4 Hz); 7.44 (IH, d, J 8.0 Hz); 4.67 (2H, t, J 5.7 Hz); 3.05 (3H, s); 2.08 (3H, d, J 3.3 Hz). APCI-MS m/z: 483.3 [MH+].
Example 95 N- r4-(methylsulfonvPbenzyll-2-oxo-6-(2-oxoethvP- 143- .
(trifluoromethvPphenyll - 1 ,2-dihy droρyridine-3 -carboxamide Phosphorus oxychloride (1.8 ml, 19.7 mmol) was added dropwise under argon to a stirred ice-cooled solution of dry N,N-dimethylformamide (2.8 ml). After the addition, the cooling was stopped and the mixture was stirred at room temperature for 30 min. Dry dichloromethane (10 ml) was added and the solution was cooled to -20 °C. 6-Methyl-N-[4- (methylsulf onyl)benzyl] -2-oxo- 1 - [3 -(trifluoromethyl) phenyl] - 1 ,2-dihydropyridine-3- carboxamide (1.1 g, 2.4 mmol) was added in small portions at such a rate that the temperature did not rise above 1 °C. After 15 min. at 0 °C, potassium carbonate (3.4 g, 24.6 mmol) was added and the mixture was heated to reflux for 20 min. The reaction mixture was cooled and poured into a cooled solution of 50% aqueous sodium carbonate (200 ml) and stirred at room temperature for 5 h. The mixture was extracted with ethyl acetate. The organic layers were washed with water, brine, dried, filtered and concentrated at reduced pressure to give a dark oil. A part of the oil was purified by preparative HPLC to give the title compound as a yellow solid.
^NMR (CDC13): δ 10.06 (IH, t, J 5.3 Hz); 9.47 (IH, s); 8.66 (IH, d, J 7.4 Hz); 7.89 (2H, d, I 8.2 Hz); 7.82 (IH, d, J 8.1 Hz); 7.71 (IH, t, J 7.9 Hz); 7.53 - 7.49 (3H, m); 7.41 (IH, d, J 8.2 Hz); 6.50 (IH, d, J 7.4 Hz); 4.69 (2H, t, J 5.6 Hz); 3.60 (2H, s); 3.02 (3H, s). APCI-MS m/z: 493 [MH+].
Example 96 5-Ethyl-6-methyl-N-[4-(methylsulfonvPbenzyl1-2-oxo-l-[3-
(trifluoromethvPphenyll-l,2-dihv(jj:opyridine-3-carboxamide A mixture of 6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3-(trifluoromethyl) phenyl]-5-vinyl-l,2-dihyckopyridine-3~carboxamide (patent application SE 0302487-4) (58 mg, 0.12 mmol), 5% palladium on carbon (11 mg) in ethanol (15 ml) and EtOAc (15 ml) was stirred vigorously under a hydrogen atmosphere for 16 h. The mixture was filtered through Celite, the filtrate was evaporated to dryness and the residue was purified by preparative HPLC to give the title compound as a white solid (33 mg, 56%). 1H-NMR (CDC13): δ 10.09 (IH, t, 75.7 Hz); 8.55 (IH, s); 7.87 (2H, d, 78.3 Hz); 7.80 (IH, d, 77.8 Hz); 7.74 (IH, t, 77.9 Hz); 7.52 (2H, d, 78.4 Hz); 7.50 (IH, s); 7.43 (IH, d, 77.6 Hz); 4.67 (2H, t, 76.4 Hz); 3.01 (3H, s); 2.59 (2H, q, 77.5 Hz); 2.04 (3H, s); 1.23 (3H, t, 77.5 Hz).
APCI-MS m/z: 493 [MH+].
Screen
Human Neutrophil Elastase Quenched-FRET Assay
The assay uses Human Neutrophil Elastase (HNE) purified from serum (Calbiochem art. 324681; Ref. Baugh, R.J. et al, 1976, Biochemistry. 15, 836-841). HNE was stored in 50 mM NaOAc, 200 mM NaCI, pH 5.5 with added 30% glycerol at -20 °C. The protease substrate used was Elastase Substrate V Fluorogenic, MeOSuc-AAPV-AMC (Calbiochem art. 324740; Ref. Castillo, M.I. et al., 1979, Anal. Biochem. 99, 53-64). The substrate was stored in DMSO at -20 °C. The assay additions were as follows: Test compounds and controls were added to black 96-well flat-bottom plates (Greiner 655076), 1 μL in 100% DMSO, followed by 30 μL HNE in assay buffer with 0.01% TritonX-100. The assay buffer constitution was: 100 mM Tris (pH 7.5) and 500 mM NaCI. The enzyme and the compounds were incubated at room temperature for 15 minutes. Then 30 μl substrate in assay buffer was added. The assay was stopped after 30 minutes incubation at room temperature by adding 60 μl 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: Exitation 380 nm, Emission 460 nm. IC50 values were determined using Xlfit curve fitting using model 205.
When tested in the above screen, the compounds of the Examples gave IC50 values for inhibition of human neutrophil elastase activity of less than 30 μM, indicating that the compounds of the invention are expected to possess useful therapeutic properties. Specimen results are shown in the following Table:
Figure imgf000177_0001

Claims

Claims
1. A compound of formula (I)
Figure imgf000178_0001
(I)
wherein:
X represents O or S;
1 2 1 1
Y represents N or CR ; and when R represents OH, Y may also, in the tautomeric form, represent NR ;
2 3 1 2 2
Y represents CR ; and when Y represents CR , then Y may also represent N;
R represents H or Cl to 6 alkyl; said alkyl being optionally substituted by one or more
7 8 9 10 substituents selected independently from halogen, CN, CHO, OR , NR R , S(O)mR and
SO2NRUR12; and, when Y represents N, R may also represent OH; 7 R represents H, Cl to 6 alkyl or phenyl; said phenyl being optionally further substituted by halogen, Cl to 6 alkyl and Cl to 6 alkoxy;
2 R represents H, halogen or Cl to 6 alkyl;
3 R represents H or F;
1
G represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3
1 heteroatoms independently selected from O, S and N; or G represents a five- or six- membered saturated or partially unsaturated cycloalkyl ring; or G represents a five- or six-membered saturated or partially unsaturated heterocyclic ring containing one
13 13 heteroatom selected from O, S and NR where R represents H or Cl to 6 alkyl;
R5 represents H, halogen, Cl to 6 alkyl, CN, Cl to 6 alkoxy, NO2, NR14R15, Cl to 3 alkyl substituted by one or more F atoms or Cl to 3 alkoxy substituted by one or more F atoms;
14 15
R and R independently represent H or Cl to 3 alkyl; said alkyl being optionally further substituted by one or more F atoms;
n represents an integer 1, 2 or 3 and when n represents 2 or 3, each R group is selected independently;
4 6
R and R independently represent H or Cl to 6 alkyl; said alkyl being optionally further substituted by OH or Cl to 6 alkoxy;
4 4 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; 29 L represents a bond, O, NR or Cl to 6 alkyl; said alkyl optionally incorporating a
Figure imgf000180_0001
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
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 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,
NR18R19, NO2, OSO2R38, CO2R20, C(=NH)NH2, C(O)NR21R22, C(S)NR23R24,
SC(=NH)NH2, NR31C(=NH)NH2, S(O)sR25, SO2NR26R27, Cl to 3 alkoxy substituted by
39 one or more F atoms and Cl to 3 alkyl substituted by SO2R or by one or more F atoms; or
2 when L does not represent a bond, G may also represent H;
m, p, q, s and t independently represent an integer 0, 1 or 2;
8 9
R and R independently represent H, Cl to 6 alkyl, formyl or C2 to 6 alkanoyl; said alkyl being optionally further substituted by phenyl optionally substituted by halogen, Cl to 6
30 alkyl, Cl to 6 alkoxy or SO2 ;
8 9 or the group NR R together represents a 5 to 7 membered azacyclic ring optionally
28 incorporating one further heteroatom selected from O, S and NR ;
18 19 32
R and R independently represent H, Cl to 6 alkyl, formyl, C2 to 6 alkanoyl, S(O)tR
33 34 or SO2NR R ; said alkyl group being optionally further substituted by halogen, CN, Cl
41 42 to 4 alkoxy or CONR R ;
25 R represents H, Cl to 6 alkyl or C3 to 6 cycloalkyl; said alkyl group being optionally further substituted by one or more substituents selected independently from OH, CN,
CONR R , CO2R , OCOR , C3 to 6 cycloalkyl, a C4 to 7 saturated heterocyclic ring
43 containing one or two heteroatoms independently selected from O, S(0)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
44 45 46 47 alkyl, Cl to 4 alkoxy, OH, CONR R , CQ 2R , S(O)sR and NHCOCH3;
.26 . „27
R and R independently represent H, Cl to 6 alkyl, formyl or C2 to 6 alkanoyl;
32 R represents H, Cl to 6 alkyl or C3 to 6 cycloalkyl;
38
R represents H, Cl to 6 alkyl or phenyl; said phenyl being optionally further substituted by halogen, Cl to 6 alkyl or Cl to 6 alkoxy;
10 11 12 16 17 20 21 22 23 24 28 29 30 31 33 34 35 J , Jv , JK. , Jtv , JK. , Jv , Jtv , XV , iv , JK. , JK. , XV , XV , JK , JK. , Jv , XV ,
_-36 „37 _39 D40 .-,41 w 2 „43 .-,44 w45 _46 _-,47 .
R , R , R , R , R , R , R , R , R , R and R independently represent H or
Cl to 6 alkyl;
and pharmaceutically acceptable salts thereof, with the proviso that the following compounds are disclaimed:
N-benzyl-5 ,6-dimethyl-2-oxb- 1-phenyl- 1 ,2-dihydropyridine-3-carboxamide;
N-(2-phenethyl)-5,6-dimethyl-2-oxo-l-phenyl-l,2-dihydropyridine-3-carboxamide;
N-(2-hydroxyethyl)-2,4-dioxo-3-phenyl-l,2,3,4-tetrahydropyrimidine-5-carboxamide; N-[2-(dimethylamino)emyl]-2,4-dioxo-3-phenyl-l,2,3,4-tetrahydropyrimidine-5- carboxamide;
4-[2-[[[l,2-dihydro-l-(4-methylcyclohexyl)-2-oxo-3-pyridinyl]carbonyl]amino]ethyl]- benzoic acid; and
4-[2-[[(l-cyclohexyl-l,2-dihydro-2-oxo-3-pyridinyl]carbonyl]amino]ethyl]-benzoic acid.
2. A compound according to Claim 1 wherein X represents O.
2 3
3. A compound according to Claim 1 or Claim 2 wherein R and R each represent H. 1
4. A compound of formula (I), according to any one of Claims 1 to 3, wherein G represents phenyl or pyridyl.
5. A compound of formula (I), according to Claim 1, or a pharmaceutically acceptable salt thereof, for use as a medicament.
6. A pharmaceutical formulation comprising a compound of formula (I), as defined in any one of Claims 1 to 4, or a pharmaceutically acceptable salt thereof, optionally in admixture with a pharmaceutically acceptable diluent or carrier.
7. A method of treating, or reducing the risk of, a human disease or condition in which inhibition of neutrophil elastase activity is beneficial which comprises administering to a person suffering from or susceptible to such a disease or condition, a therapeutically effective amount of a compound of formula (I), as defined in any one of Claims 1 to 4, or a pharmaceutically acceptable salt thereof.
8. The use of a compound of formula (I) as defined in any one of Claims 1 to 4, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of human diseases or conditions in which inhibition of neutrophil elastase activity is beneficial.
9. The use of a compound of formula (I) as defined in any one of Claims 1 to 4, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of inflammatory diseases or conditions.
10. 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)
Figure imgf000184_0001
wherein R , R , Y , Y , X, G and n are as defined in Claim 1 and L represents a leaving group, with an amine of formula (III) or a salt thereof
Figure imgf000184_0002
(III)
.4 Jl wherein R , G and L are as defined in Claim 1,
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.
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