WO2016046782A1 - Composés imidazole biaryle en tant qu'inhibiteurs de la s-nitrosoglutathion réductase - Google Patents

Composés imidazole biaryle en tant qu'inhibiteurs de la s-nitrosoglutathion réductase Download PDF

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WO2016046782A1
WO2016046782A1 PCT/IB2015/057356 IB2015057356W WO2016046782A1 WO 2016046782 A1 WO2016046782 A1 WO 2016046782A1 IB 2015057356 W IB2015057356 W IB 2015057356W WO 2016046782 A1 WO2016046782 A1 WO 2016046782A1
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imidazol
methyl
alkyl
ethyl
biphenyl
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PCT/IB2015/057356
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English (en)
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Laxmikant Atmaram Gharat
Nagarajan Muthukaman
Shital TONDLEKAR
Neelima Khairatkar-Joshi
Daisy Manish Shah
Sheetal R KADAM
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Glenmark Pharmaceuticals S.A.
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Publication of WO2016046782A1 publication Critical patent/WO2016046782A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present patent application is directed to imidazole biaryl compounds which act as inhibitors of 5-Nitrosoglutathione reductase (GSNOR).
  • GSNOR 5-Nitrosoglutathione reductase
  • the present patent application further provides processes for their preparation, pharmaceutical compositions comprising the compounds, and the use of the compounds or the compositions in the treatment or prevention of various diseases, conditions and/or disorders mediated by GSNOR.
  • GSNO 5-Nitrosoglutathione
  • SNO 5-nitrosothiol
  • NO nitric oxide
  • Increases in bioavailable NO are associated with anti-inflammatory and smooth muscle relaxant effects, especially in organ systems characterized by smooth muscle and endothelial/epithelial layers such as the respiratory, cardiovascular, and gastrointestinal systems (Whalen et al., Cell, 2007, 129, 511-522; Foster et al., Trends Mol. Med., 2009, 15, 391-404; Pacher et al., Physiol. Rev., 2007, 87, 315-424).
  • GSNOR 5-nitrosoglutathione reductase
  • HMGSH hydroxymethylglutathione
  • ADH alcohol dehydrogenase superfamily
  • GSNOR catalyses the oxidation of HMGSH to 5-formylglutathione using a catalytic zinc and NAD+ as a coenzyme.
  • the enzyme also catalyses the NADH-dependent reduction of S- nitrosoglutathione (GSNO) (Kubienova et al., Biochimie, 2013, 95(4), 889-902). It is a primary ADH that is ubiquitously expressed in plant and animals.
  • GSNOR reduces 5-nitrosoglutathione (GSNO) to the unstable intermediate, S- hydroxylaminoglutathione, which then rearranges to form glutathione sulfinamide, or in the presence of GSH, forms oxidized glutathione (GSSG) and hydroxyl amine (Jensen et al., Biochem. J., 1998, 331(2), 659-68; Hedberg et al., Eur. J. Biochem., 2003, 270, 1249-1256; Staab et al., Chem. Biol. Interact., 2009, 178(1-3), 29-35).
  • GSNOR regulates the cellular concentrations of GSNO and plays a central role in regulating the levels of endogenous 5-nitrosothiols and controlling protein S- nitrosylation-based signaling.
  • GSNOR is also involved in regulating NO levels and signaling, pleiotropic effects are observed in GSNOR knockout models.
  • Deleting the GSNOR gene from both yeast and mice increased the cellular levels of GSNO and nitrosylated proteins, and the yeast cells showed increased susceptibility to nitrosative stress (Liu et al., Nature, 2001, 410(6827), 490-494), Null mice show increased levels of 5-nitrosated proteins, increased beta adrenergic receptor numbers in lung and heart (Whalen et al., Cell, 2007, 129(3), 511-522), diminished tachyphylaxis to p2-adrenergic receptor agonists, hypo-responsiveness to methacholine and allergen challenge and reduced infarct size after occlusion of the coronary artery (Que et al., Science, 2005, 308(5728), 1618-1621; Lima et al., Proc.
  • GSNO depletion associates with various diseases including asthma ⁇ Chem. Biol. Interact, 2009, 178(1-3), 29-35).
  • GSNOR expression has been inversely correlated with 5-nitrosothiol (SNO) levels in the alveolar lining fluid in the lung and with responsiveness to methacholine challenge in patients with mild asthma (Que et al., Am. J. Respir. Crit. Care Med., 2009, 180(3), 226-231).
  • SNO and NO concentrations regulate respiratory function by modulating airway tone and pro- and antiinflammatory responses in the respiratory tract (Snyder et al., Am. J. Respir. Crit.
  • GSNO in concentrations present in the airways relaxes airway smooth muscle (Gaston et al., Proc Natl Acad Sci., 1993, 90, 10957-10961), improves airway ciliary motility (Li et al., Am J Respir Cell Mol Biol., 2000, 23, 175— 181), inhibits airway epithelial amiloride-sensitive sodium transport while activating calcium-dependent epithelial chloride transport (Jain et al., Am J Physiol., 1998; 274, 475-484, Kamosinska et al., Am J Physiol., 1997, 272, 1098-1104), promotes neutrophilic apoptosis (Fortenberry et al., Am J Physiol., 1999, 276, L435-L442), and has anti
  • GSNO cystic fibrosis transmembrane regulation protein
  • CFTR cystic fibrosis transmembrane regulation protein
  • AF508 cystic fibrosis transmembrane regulation protein
  • levels of GSNO tend to be low in the cystic fibrosis (CF) airway (Grasemann et al., J Pediatr., 1999, 135, 770-772).
  • aerosolized GSNO is well tolerated by cystic fibrosis patients (Snyder et al., Am. J. Respir. Crit. Care Med., 2002, 165(7), 922-926).
  • GSNO also plays an important role in inflammatory bowel disease (IBD). NO and GSNO maintain normal intestinal physiology via anti-inflammatory actions and maintenance of the intestinal epithelial cell barrier. In IBD, reduced levels of GSNO and NO are evident and may also occur via up-regulation of GSNOR activity (Savidge et al., Gastroenterology, 2007, 132, 1344-1358). In human asthma, there are lowered SNO concentrations in the lungs, likely attributable to up-regulated GSNOR activity (Que et al., Am. J. Respir. Crit. Care Med., 2009, 180, 226-231).
  • mice with genetic deletion of GSNOR exhibit increases in lung SNOs and are protected from airway hyper-responsivity (Que et al., Science, 2005, 308, 1618-1621).
  • GSNOR has been shown to have an important influence on NO containing species, regulation of smooth muscle tone in the airways, and function of adrenergic receptors in lungs and heart (Whalen et al., Cell, 2007, 129, 511-522; Que et al., Am. J. Respir. Crit. Care Med., 2009, 180, 226-231; Liu et al., Cell, 2004, 116, 617-628).
  • GSNOR inhibitors have been demonstrated in animal models of chronic obstructive pulmonary disease (COPD) (Blonder et al., Am. J. Respir. Crit. Care Med., 2011, 22727) and high salt induced hypertension (Chen et al., Appl Physiol, 2013, 114(6), 752-760).
  • COPD chronic obstructive pulmonary disease
  • International patent publications viz., WO2012170371, WO2012083171,
  • WO2012083165, WO2012048181, WO2012009227, WO2011100433, WO2011099978, WO2011075478, WO2011038204, WO2010019910, WO2010019909, WO2010019905 and WO2010019903 disclose compounds which are inhibitors of GSNOR.
  • GSNOR has been recognized as a potential therapeutic target for the treatment of a broad range of diseases due to the important role that GSNO plays in the biological systems.
  • the present application is directed to compounds that are inhibitors of the S- nitrosoglutathione reductase (GSNOR).
  • the present invention relates to compound of formula (I)
  • A is selected from
  • R a is selected from hydrogen, Ci_ 8 alkyl, Ci_ 8 alkoxyCi_ 8 alkyl and - (CR b R c ) x OC(0)R b ;
  • R d is selected from hydrogen and Ci_ 8 alkyl; at each occurrence, R 1 is independently selected from halogen, hydroxyl, nitro,
  • Xi, X 2 , X3 and X 4 are independently selected from CR 4 and N; at each occurrence, R 4 is independently selected from hydrogen, halogen, hydroxyl, nitro, Ci_ 8 alkyl, Ci_ 8 alkoxy, Ci_ 8 alkoxyCi_ 8 alkyl, hydroxyCi_ 8 alkyl, haloCi_ 8 alkyl, haloCi_ 8 alkoxy, C 3 -i 2 cycloalkyl, C 3 _i 2 cycloalkylCi_ 8 alkyl, -(CR b R c ) y OR b , - 0(CR b R c ) y R b , -(CH 2 ) y C(0)NR b R c , -(CH 2 ) y NR b C(0)R c , -(CH 2 ) y NR b S0 2 R c , (CH 2 ) y NR b R
  • the compounds of formula (I) may involve one or more embodiments.
  • Embodiments of formula (I) include compounds of formula (Ie), (II) and (III) as described hereinafter. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments.
  • the invention provides compounds of formula (I) as defined above wherein R is hydrogen or Ci_ 8 alkyl (e.g. methyl) (according to one embodiment defined below), m is 0 (according to another embodiment defined below), n is 0 (according to yet another embodiment defined below) and p is 0 (according to yet another embodiment defined below).
  • R a is selected from hydrogen and Ci_ 8 alkyl (e.g. methyl or ethyl).
  • R a is selected from hydrogen and Ci_ 8 alkyl (e.g. methyl or ethyl).
  • R a is selected from hydrogen, methyl and ethyl.
  • R is hydrogen or Ci-galkyl (e.g. methyl) and p is 0.
  • B is selected from
  • R is hydrogen or methyl and p is 0.
  • R 4 is independently selected from hydrogen, halogen (e.g. CI or F), Ci_ 8 alkyl (e.g. methyl or ethyl), haloCi_ 8 alkyl (e.g. trifluoromethyl, 2-fluoroethyl or 3-fluoropropyl), hydroxyCi_ 8 alkyl (e.g. 2- hydroxyethyl, hydroxymethyl or 3-hydroxypropyl), Ci_ 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g.
  • C 3 _i 2 cycloalkyl e.g. cyclopropyl
  • 5 to 14 membered heteroarylCi_ 8 alkyl e.g. 3-(2-methyl- lH-imidazol-l- yl)propyl, 3-ethylpyridyl or 4-ethylpyridyl
  • -(CR b R c ) y OR b e.g. 2-methyl pyridyl-5- oxopropyl or pyridyl-3-methoxy
  • -0(CR b R c ) y R b e.g.
  • R 4 is independently selected from hydrogen, halogen (e.g. CI or F), Ci_ 8 alkyl (e.g. methyl or ethyl), haloCi_ 8 alkyl (e.g. trifluoromethyl, 2-fluoroethyl or 3-fluoropropyl), hydroxyCi_ 8 alkyl (e.g. 2- hydroxyethyl, hydroxymethyl or 3-hydroxypropyl), Ci_ 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g.
  • C 3 _i 2 cycloalkyl e.g. cyclopropyl
  • 5 to 14 membered heteroarylCi_ 8 alkyl e.g. 3-(2-methyl-lH-imidazol-l- yl)propyl, pyridyl-3-ethyl or pyridyl-4-ethyl
  • -(CR b R c ) y OR b e.g. 2-methyl-5- propoxypyridine or pyridyl-3 -methoxy
  • -0(CR b R c ) y R b e.g.
  • R b and R c are independently selected from hydrogen, 5 to 14 membered heteroaryl (e.g. 2- methylpyridin-5-yl, pyridin-3-yl or pyridin-2-yl) and Ci_ 8 alkyl (e.g. isopropyl); and y is 1 to 3.
  • heteroaryl e.g. 2- methylpyridin-5-yl, pyridin-3-yl or pyridin-2-yl
  • Ci_ 8 alkyl e.g. isopropyl
  • R 4 is independently selected from hydrogen, halogen (e.g. CI or F), Ci_ 8 alkyl (e.g. methyl or ethyl), haloCi_ 8 alkyl (e.g. trifluoromethyl, 2-fluoroethyl or 3-fluoropropyl), hydroxyCi_ 8 alkyl (e.g. 2- hydroxyethyl, hydroxymethyl or 3-hydroxypropyl), Ci_ 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g.
  • C 3 _i 2 cycloalkyl e.g. cyclopropyl
  • 5 to 14 membered heteroarylCi_ 8 alkyl e.g. 3-(2-methyl-lH-imidazol-l- yl)propyl, pyridyl-3-ethyl or pyridyl-4-ethyl
  • -(CR b R c ) y OR b e.g. 2-methyl-5- propoxypyridine or pyridyl-3 -methoxy
  • -0(CR b R c ) y R b e.g.
  • R b and R c are independently selected from hydrogen, 2-methylpyridin-5-yl, pyridin-3-yl, pyridin-2-yl and isopropyl; and y is 1 to 3.
  • R 4 is independently selected from hydrogen, CI, F, methyl, ethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 2-hydroxyethyl, hydroxymethyl, 3-hydroxypropyl, methoxy, 3-ethoxypropyl, 4-ethoxybutyl, cyclopropyl, 3-(2-methyl-lH-imidazol-l-yl)propyl, pyridyl-3 -ethyl, pyridyl-4-ethyl, 2-methyl-5-propoxypyridine, pyridyl-3-methoxy, pyridin-3-methyloxy, pyridin-2- methyloxy, acetamide, propanamide, 2-methyl-N-propylpropanamide, N-ethyl-2- methylpropanamide, N-propylpropane-2- sulfonamide and piperidin-
  • R 4 is selected from hydrogen, halogen (e.g. CI or F), hydroxyCi_ 8 alkyl (e.g. 2-hydroxyethyl or hydroxymethyl), haloCi_ 8 alkyl (e.g. trifluoromethyl, 2-fluoroethyl or 3-fluoropropyl), Ci-galkyl (e.g. methyl or ethyl), C 3 _i 2 cycloalkyl (e.g. cyclopropyl) and - (CH 2 ) y C(0)NR b R c (e.g. acetamide).
  • halogen e.g. CI or F
  • hydroxyCi_ 8 alkyl e.g. 2-hydroxyethyl or hydroxymethyl
  • haloCi_ 8 alkyl e.g. trifluoromethyl, 2-fluoroethyl or 3-fluoropropyl
  • Ci-galkyl e.g. methyl or ethyl
  • R 4 is selected from hydrogen, CI, F, 2-hydroxyethyl, hydroxymethyl, trifluoromethyl, 2-fluoroethyl, 3- fluoropropyl, methyl, ethyl, cyclopropyl and acetamide.
  • Xi is N, CH, -C(halogen) (e.g. -C(C1) or -C(F)), -C(hydroxyCi_ salkyl) (e.g. -C(C 2 H 4 OH) or -C(CH 2 OH)), -C(haloCi_ 8 alkyl) (e.g. -C(CF 3 ), -C(C 2 H 4 F) or -C(C 3 H 6 F)), -Cid-galkyl) (e.g.
  • compounds of formula (I) in which X 2 is CR 4 or N.
  • R 4 is selected from hydrogen, halogen (e.g. CI or F), haloCi_ 8 alkyl (e.g. trifluoromethyl or 3-fluoropropyl), Ci_ 8 alkyl (e.g. methyl or ethyl) or -(CR b R c ) y OR b (e.g. 2-methylpyridyl-5-oxypropyl).
  • halogen e.g. CI or F
  • haloCi_ 8 alkyl e.g. trifluoromethyl or 3-fluoropropyl
  • Ci_ 8 alkyl e.g. methyl or ethyl
  • OR b e.g. 2-methylpyridyl-5-oxypropyl
  • X 2 is CR 4 or N.
  • R 4 is selected from hydrogen, CI, F, trifluoromethyl, 3-fluoropropyl, methyl, ethyl and 2-methylpyridyl-5-oxypropyl.
  • X 2 is N, -C(H), -C(halogen) (e.g. -C(C1) or -C(F),), -C(haloCi_ galkyl) (e.g. -C(CF 3 ) or -C(C 3 H 6 F)), -C(Ci_ 8 alkyl) (e.g. -C(C 2 H 5 ), -C(CH 3 )) or C(- (CR b R c ) y OR b ) (e.g. -C(2-methylpyridyl-5-oxypropyl)).
  • X 2 is N, -C(H), -C(halogen) (e.g. -C(C1) or -C(F),), -C(haloCi_ galkyl) (e.g. -C(CF 3 ) or -C(C 3 H 6 F)), -C(Ci_ 8 alkyl) (e.g. -C
  • X 3 is CR 4 or N.
  • R 4 is hydrogen, halogen (e.g. CI or F), Ci_ 8 alkyl (e.g. methyl or ethyl) or 5 to 14 membered heteroarylCi_ 8 alkyl (e.g. 3 -(2-methyl- lH-imidazol- 1 -yl)propyl) .
  • R 4 is hydrogen, CI, F, methyl, ethyl or 3-(2-methyl- lH-imidazol- l-yl)propyl.
  • R 4 is hydrogen, halogen (e.g. CI or F), Ci-galkyl (e.g. methyl or ethyl) or 5 to 14 membered heteroarylCi_ 8 alkyl (e.g. 3- (2-methyl-lH-imidazol- l-yl)propyl).
  • R 4 is hydrogen, CI, F, methyl, ethyl or 3-(2-methyl-lH-imidazol-l-yl)propyl.
  • X 3 is N, CH, -C(halogen) (e.g -C(C1) or -C(F)), -C(Ci_ 8 alkyl) (e.g. -C(CH 3 ) or -C(C 2 H 5 )) or -C(5 to 14 membered heteroarylCi_ 8 alkyl) (e.g. -C(3- (2-methyl-lH-imidazol- l-yl)propyl).
  • halogen e.g -C(C1) or -C(F)
  • -C(Ci_ 8 alkyl) e.g. -C(CH 3 ) or -C(C 2 H 5 )
  • -C(5 to 14 membered heteroarylCi_ 8 alkyl) e.g. -C(3- (2-methyl-lH-imidazol- l-yl)propyl.
  • X 3 is N, CH, -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ) or -C(3-(2- methyl- lH-imidazol- l-yl)propyl).
  • X 3 is CH, -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ) or -C(3-(2-methyl- lH-imidazol-l-yl)propyl).
  • R 4 is selected from hydrogen, halogen (e.g. CI or F), hydroxyCi_ 8 alkyl (e.g. 3-hydroxypropyl), Ci_ 8 alkyl (e.g. methyl or ethyl), Ci_ 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. 3-ethoxypropyl or 4- ethoxybutyl), -(CH 2 ) y NR b C(0)R c (e.g.
  • pyridyl-3-methoxy 0(CR b R c ) y R b (e.g. pyridin-3-methyloxy or pyridin-2-methyloxy) and 3 to 15 membered heterocyclyl (e.g. piperidin- l-ethanone).
  • R 4 is selected from hydrogen, CI, F, 3-hydroxypropyl, methyl, ethyl, methoxy, 3-ethoxypropyl, 4-ethoxybutyl, 2- methyl-N-propylpropanamide, N-ethyl-2-methylpropanamide, N-propylpropane-2- sulfonamide, pyridyl-3 -ethyl, pyridyl-4-ethyl, propanamide, pyridyl-3-methoxy, pyridin-3-methyloxy, pyridin-2-methyloxy and piperidin- l-ethanone.
  • X 4 is N, CH, halogen (e.g. -C(C1) or -C(F)), hydroxyCi_ 8 alkyl (e.g. -C(C 3 H 6 OH)), Ci_ 8 alkyl (e.g. -C(CH 3 ), -C(C 2 H 5 )), Ci_ 8 alkoxy (e.g. -C(OCH 3 )), Ci_ 8 alkoxyCi_ 8 alkyl (e.g.
  • X 4 is N, CH, -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ), -C(OCH 3 ), - C(C 3 H 6 OH), -C(C 3 H 6 OC 2 H 5 ), -C(C 4 H 8 OC 2 H 5 ), -C(2-methyl-N-propylpropanamide), - C(N-ethyl-2-methylpropanamide), -C(N-propylpropane-2-sulfonamide), -C(pyridyl-3- ethyl), -C(pyridyl-4-ethyl), -C(C 2 H 4 CONH 2 ), -C(pyridyl-3-methoxy), -C(pyridin-3- methyloxy), -C(pyridin-2-methyloxy) or -C(piperidin-l
  • Xi is N, CH, -C(halogen) (e.g. C(C1) or -C(F)), -C(hydroxyCi_ 8 alkyl) (e.g. -C(C 2 H 4 OH) or -C(CH 2 OH)), -C(haloCi_ 8 alkyl) (e.g. -C(CF 3 ), -C(C 2 H 4 F) or -C(C 3 H 6 F)), -C(Ci_ 8 alkyl) (e.g.
  • -C(C 3 _i 2 cycloalkyl) e.g. - C(cyclopropyl) or -C(-(CH 2 ) y C(0)NR b R c ) (e.g. -C(CH 2 CONH 2 )
  • X 2 is N, -C(H), - C(halogen) (e.g. -C(C1) or -C(F),), -C(haloCi_ 8 alkyl) (e.g. -C(CF 3 ) or -C(C 3 H 6 F)), - C(Ci_ 8 alkyl) (e.g.
  • X 3 is N, CH, -C(halogen) (e.g -C(C1) or -C(F)), -C(Ci_ 8 alkyl) (e.g. - C(CH 3 ) or -C(C 2 H 5 )) or -C(5 to 14 membered heteroarylCi_ 8 alkyl) (e.g.
  • X 4 is N, CH, halogen (e.g. -C(C1) or -C(F)), hydroxyCi_ 8 alkyl (e.g. -C(C 3 H 6 OH)), Ci_ 8 alkyl (e.g. -C(CH 3 ), -C(C 2 H 5 )), Ci_ 8 alkoxy (e.g. -C(OCH 3 )), d-galkoxyd-galkyl (e.g.
  • Xi is N, -C(H), -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ), -C(C 2 H 4 OH), -C(CH 2 OH), -C(CF 3 ), -C(C 2 H 4 F), -C(C 3 H 6 F), -C(CH 2 CONH 2 ) or -C(cyclopropyl);
  • X 2 is N, -C(H), -C(C1), -C(F), -C(C 2 H 5 ), -C(CH 3 ), -C(CF 3 ) or -C(C 3 H 6 F) or -C(2- methylpyridyl-5-oxypropyl);
  • X 3 is N, CH, -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ) or -C
  • R a is hydrogen or Ci_ 8 alkyl (e.g. methyl or ethyl).
  • Xi, X 2, X 3 and X 4 are independently selected from CR 4 and N; R is hydrogen or Ci_ 8 alkyl (e.g. methyl);
  • R 4 is hydrogen, halogen (e.g. CI or F), Ci_ 8 alkyl (e.g. methyl or ethyl), haloCi
  • alkyl e.g. trifluoromethyl, 2-fluoroethyl or 3-fluoropropyl
  • hydroxyCi_ 8 alkyl e.g. 2- hydroxyethyl, hydroxymethyl or 3-hydroxypropyl
  • Ci_ 8 alkoxy e.g. methoxy
  • Ci_ 8 alkoxyCi_ 8 alkyl e.g. 3-ethoxypropyl or 4-ethoxybutyl
  • C 3 _i 2 cyclo alkyl e.g. cyclopropyl
  • 5 to 14 membered heteroarylCi_ 8 alkyl e.g.
  • R b and R c are independently selected from hydrogen, 5 to 14 membered heteroaryl (e.g. 2-methylpyridin-5-yl, pyridin-3-yl or pyridin-2-yl) and Ci_ 8 alkyl (e.g. isopropyl); m is 0; n is 0; y is 0 to 3 and p is 0.
  • heteroaryl e.g. 2-methylpyridin-5-yl, pyridin-3-yl or pyridin-2-yl
  • Ci_ 8 alkyl e.g. isopropyl
  • Xi is N, -C(H), -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ), -C(C 2 H 4 OH), -C(CH 2 OH), - C(CF 3 ), -C(C 2 H 4 F), -C(C 3 H 6 F), -C(CH 2 CONH 2 ) or -C(cyclopropyl);
  • X 2 is N, -C(H), - C(C1), -C(F), -C(C 2 H 5 ), -C(CH 3 ), -C(CF 3 ) or -C(C 3 H 6 F) or -C(2-methylpyridyl-5- oxypropyl);
  • X 3 is N, CH, -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ) or -C(3-(2-methyl-lH- imid
  • R 4 is hydrogen, CI, F, methyl, ethyl, trifluoromethyl, 2-fluoroethyl, 3- fluoropropyl, 2-hydroxyethyl, hydroxymethyl, 3-hydroxypropyl, methoxy, 3- ethoxypropyl, 4-ethoxybutyl, cyclopropyl, 3-(2-methyl- lH-imidazol-l-yl)propyl, pyridyl-3 -ethyl, pyridyl-4-ethyl, 2-methyl-5-propoxypyridine, pyridyl-3 -methoxy, pyridin-3-methyloxy, pyridin-2-methyloxy, acetamide, propanamide, 2-methyl-N- propylpropanamide, N-ethyl-2-methylpropanamide, N-propylpropane-2- sulfonamide or piperidin- 1-ethanone;
  • R is hydrogen or methyl
  • R b and R c are independently selected from hydrogen, 2-methylpyridin-5-yl, pyridin-3-yl and pyridin-2-yl and isopropyl; m is 0; n is 0; y is 0 to 3 and p is 0. According to another embodiment, specifically provided are compounds of formula (I), in which A is
  • Xi is N, -C(H), -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ), -C(C 2 H 4 OH), -C(CH 2 OH), - C(CF 3 ), -C(C 2 H 4 F), -C(C 3 H 6 F), -C(CH 2 CONH 2 ) or -C(cyclopropyl);
  • X 2 is N, -C(H), - C(C1), -C(F), -C(C 2 H 5 ), -C(CH 3 ), -C(CF 3 ) or -C(C 3 H 6 F) or -C(2-methylpyridyl-5- oxypropyl);
  • X 3 is N, CH, -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ) or -C(3-(2-methyl-lH- imid
  • R 4 is independently selected from hydrogen, CI, F, methyl, ethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 2-hydroxyethyl, hydroxymethyl, 3- hydroxypropyl, methoxy, 3-ethoxypropyl, 4-ethoxybutyl, cyclopropyl, 3-(2-methyl- lH-imidazol-l-yl)propyl, pyridyl-3-ethyl, pyridyl-4-ethyl, 2-methyl-5- propoxypyridine, pyridyl-3-methoxy, pyridin-3-methyloxy, pyridin-2-methyloxy, acetamide, propanamide, 2-methyl-N-propylpropanamide, N-ethyl-2- methylpropanamide, N-propylpropane-2-sulfonamide and piperidin- l-ethanone;
  • R is hydrogen or methyl
  • R b and R c are independently selected from hydrogen, 2-methylpyridin-5-yl, pyridin-3-yl or pyridin-2-yl and isopropyl; m is 0; n is 0; y is 0 to 3 and p is 0. According to another embodiment, specifically provided are compounds of formula (I), in which A is
  • Xi is N, -C(H), -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ), -C(C 2 H 4 OH), -C(CH 2 OH), - C(CF 3 ), -C(C 2 H 4 F), -C(C 3 H 6 F), -C(CH 2 CONH 2 ) or -C(cyclopropyl);
  • X 2 is N, -C(H), - C(C1), -C(F), -C(C 2 H 5 ), -C(CH 3 ), -C(CF 3 ) or -C(C 3 H 6 F) or -C(2-methylpyridyl-5- oxypropyl);
  • X 3 is N, CH, -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ) or -C(3-(2-methyl-lH- imid
  • R 4 is independently selected from hydrogen, CI, F, methyl, ethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 2-hydroxyethyl, hydroxymethyl, 3- hydroxypropyl, methoxy, 3-ethoxypropyl, 4-ethoxybutyl, cyclopropyl, 3-(2-methyl- lH-imidazol-l-yl)propyl, pyridyl-3-ethyl, pyridyl-4-ethyl, 2-methyl-5- propoxypyridine, pyridyl-3-methoxy, pyridin-3-methyloxy, pyridin-2-methyloxy, acetamide, propanamide, 2-methyl-N-propylpropanamide, N-ethyl-2- methylpropanamide, N-propylpropane-2-sulfonamide and piperidin- l-ethanone;
  • R is hydrogen or methyl
  • R b and R c are independently selected from hydrogen, 2-methylpyridin-5-yl, pyridin-3-yl or pyridin-2-yl and isopropyl; m is 0; n is 0; y is 0 to 3 and p is 0. According to one embodiment, specifically provided are compounds of formula (I) with an IC 50 value of less than 1000 nM, preferably, less than 500 nM, more preferably, less than 100 nM, still more preferably, less than 50 nM, with respect to GSNOR inhibitory activity.
  • the invention also provides a compound of formula (Ie), which is an embodiment of a compound of formula (I).
  • A is selected from
  • R is selected from hydrogen and Ci_ 8 alkyl
  • Xi, X 2 , X 3 and X 4 are independently selected from CR 4 and N; at each occurrence, R 4 is independently selected from hydrogen, halogen, hydroxyl, nitro, Ci_ 8 alkyl, Ci_ 8 alkoxy, Ci_ 8 alkoxyCi_ 8 alkyl, hydroxyCi_ 8 alkyl, haloCi_ galkyl, haloCi_ 8 alkoxy, C 3 _i 2 cycloalkyl, C 3 _i 2 cycloalkylCi_ 8 alkyl, -(CR b R c ) y OR b , - 0(CR b R c ) y R b , -(CH 2 ) y C(0)NR b R c , -(CH 2 ) y NR b C(0)R c , -(CH 2 ) y NR b S0 2 R c , (CH 2 ) y NR b R c
  • the compounds of formula (Ie) may involve one or more embodiments.
  • Embodiments of formula (Ie) include compounds of formula (II) and (III) as described hereinafter. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments.
  • the invention provides compounds of formula (Ie) as defined above wherein R is hydrogen or Ci_ 8 alkyl (e.g. methyl) (according to one embodiment defined below) and p is 0 (according to another embodiment defined below).
  • R is hydrogen or Ci_ 8 alkyl (e.g. methyl)
  • p is 0 (according to another embodiment defined below).
  • specifically provided are compounds formula (Ie), in which A is selected from
  • R is hydrogen or methyl and p is 0.
  • R 4 is independently selected from hydrogen, halogen (e.g. CI or F), Ci_ 8 alkyl (e.g. methyl or ethyl), haloCi_ 8 alkyl (e.g. trifluoromethyl, 2-fluoroethyl or 3-fluoropropyl), hydroxyCi_ 8 alkyl (e.g. 2- hydroxyethyl, hydroxymethyl or 3-hydroxypropyl), Ci_ 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g.
  • C 3 _i 2 cycloalkyl e.g. cyclopropyl
  • 5 to 14 membered heteroarylCi_ 8 alkyl e.g. 3-(2-methyl-lH-imidazol-l- yl)propyl, 3-ethylpyridyl or 4-ethylpyridyl
  • -(CR b R c ) y OR b e.g. 2-methyl pyridyl-5- oxopropyl or pyridyl-3-methoxy
  • -0(CR b R c ) y R b e.g.
  • R 4 is independently selected from hydrogen, halogen (e.g. CI or F), Ci_ 8 alkyl (e.g. methyl or ethyl), haloCi_ 8 alkyl (e.g. trifluoromethyl, 2-fluoroethyl or 3-fluoropropyl), hydroxyCi_ 8 alkyl (e.g. 2- hydroxyethyl, hydroxymethyl or 3-hydroxypropyl), Ci_ 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g.
  • C 3 _i 2 cycloalkyl e.g. cyclopropyl
  • 5 to 14 membered heteroarylCi_ 8 alkyl e.g. 3-(2-methyl-lH-imidazol-l- yl)propyl, pyridyl-3-ethyl or pyridyl-4-ethyl
  • -(CR b R c ) y OR b e.g. 2-methyl-5- propoxypyridine or pyridyl-3 -methoxy
  • -0(CR b R c ) y R b e.g.
  • R b and R c are independently selected from hydrogen, 5 to 14 membered heteroaryl (e.g. 2- methylpyridin-5-yl, pyridin-3-yl or pyridin-2-yl) and Ci_ 8 alkyl (e.g. isopropyl); and y is 1 to 3.
  • heteroaryl e.g. 2- methylpyridin-5-yl, pyridin-3-yl or pyridin-2-yl
  • Ci_ 8 alkyl e.g. isopropyl
  • R 4 is independently selected from hydrogen, halogen (e.g. CI or F), Ci_ 8 alkyl (e.g. methyl or ethyl), haloCi_ 8 alkyl (e.g. trifluoromethyl, 2-fluoroethyl or 3-fluoropropyl), hydroxyCi_ 8 alkyl (e.g. 2- hydroxyethyl, hydroxymethyl or 3-hydroxypropyl), Ci_ 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g.
  • C 3 _i 2 cycloalkyl e.g. cyclopropyl
  • 5 to 14 membered heteroarylCi_ 8 alkyl e.g. 3-(2-methyl-lH-imidazol-l- yl)propyl, pyridyl-3-ethyl or pyridyl-4-ethyl
  • -(CR b R c ) y OR b e.g. 2-methyl-5- propoxypyridine or pyridyl-3 -methoxy
  • -0(CR b R c ) y R b e.g.
  • R b and R c are independently selected from hydrogen, 2-methylpyridin-5-yl, pyridin-3-yl, pyridin-2-yl and isopropyl; and y is 1 to 3.
  • R 4 is independently selected from hydrogen, CI, F, methyl, ethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 2-hydroxyethyl, hydroxymethyl, 3-hydroxypropyl, methoxy, 3-ethoxypropyl, 4-ethoxybutyl, cyclopropyl, 3-(2-methyl-lH-imidazol-l-yl)propyl, pyridyl-3 -ethyl, pyridyl-4-ethyl, 2-methyl-5-propoxypyridine, pyridyl-3-methoxy, pyridin-3-methyloxy, pyridin-2- methyl
  • R 4 is selected from hydrogen, halogen (e.g. CI or F), hydroxyCi_ 8 alkyl (e.g. 2-hydroxyethyl or hydroxymethyl), haloCi_ 8 alkyl (e.g. trifluoromethyl, 2-fluoroethyl or 3-fluoropropyl), Ci- 8 alkyl (e.g. methyl or ethyl), C 3 _i 2 cycloalkyl (e.g. cyclopropyl) and - (CH 2 ) y C(0)NR b R c (e.g. acetamide).
  • halogen e.g. CI or F
  • hydroxyCi_ 8 alkyl e.g. 2-hydroxyethyl or hydroxymethyl
  • haloCi_ 8 alkyl e.g. trifluoromethyl, 2-fluoroethyl or 3-fluoropropyl
  • Ci- 8 alkyl e.g. methyl or ethy
  • R 4 is selected from hydrogen, CI, F, 2-hydroxyethyl, hydroxymethyl, trifluoromethyl, 2-fluoroethyl, 3- fluoropropyl, methyl, ethyl, cyclopropyl and acetamide.
  • Xi is N, CH, -C(halogen) (e.g. -C(C1) or -C(F)), -C(hydroxyCi_ 8 alkyl) (e.g. -C(C 2 H 4 OH) or -C(CH 2 OH)), -C(haloCi_ 8 alkyl) (e.g. -C(CF 3 ), -C(C 2 H 4 F) or -C(C 3 H 6 F)), -Cid-galkyl) (e.g.
  • Xi is N, -C(H), -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ), -C(C 2 H 4 OH), -C(CH 2 OH), -C(CF 3 ), -C(C 2 H 4 F), -C(C 3 H 6 F), -C(CH 2 CONH 2 ) or -C(cyclopropyl).
  • R 4 is selected from hydrogen, halogen (e.g. CI or F), haloCi_ 8 alkyl (e.g. trifluoromethyl or 3-fluoropropyl), Ci_ 8 alkyl (e.g. methyl or ethyl) or -(CR b R c ) y OR b (e.g. 2-methylpyridyl-5-oxypropyl).
  • halogen e.g. CI or F
  • haloCi_ 8 alkyl e.g. trifluoromethyl or 3-fluoropropyl
  • Ci_ 8 alkyl e.g. methyl or ethyl
  • OR b e.g. 2-methylpyridyl-5-oxypropyl
  • R 4 is selected from hydrogen, CI, F, trifluoromethyl, 3-fluoropropyl, methyl, ethyl and 2-methylpyridyl- 5-oxypropyl.
  • X 2 is N, -C(H), -C(halogen), -C(haloCi_ 8 alkyl), -C(Ci_ 8 alkyl) or C(-(CR b R c ) y OR b ).
  • compounds of formula (le) in which X 2 is N, -C(H), -C(halogen) (e.g. -C(C1) or -C(F),), -C(haloCi_ galkyl) (e.g. -C(CF 3 ) or -C(C 3 H 6 F)), -Cid-galkyl) (e.g. -C(C 2 H 5 ), -C(CH 3 )) or C(- (CR b R c ) y OR b ) (e.g. -C(2-methylpyridyl-5-oxypropyl)).
  • X 2 is N, -C(H), -C(C1), -C(F), -C(C 2 H 5 ), -C(CH 3 ), -C(CF 3 ) or - C(C 3 H 6 F) or -C(2-methylpyridyl-5-oxypropyl).
  • R 4 is hydrogen, halogen (e.g. CI or F), Ci_ 8 alkyl (e.g. methyl or ethyl) or 5 to 14 membered heteroarylCi_ 8 alkyl (e.g. 3-(2-methyl-lH-imidazol- l-yl)propyl).
  • R 4 is hydrogen, CI, F, methyl, ethyl or 3-(2-methyl- lH-imidazol- l-yl)propyl.
  • R 4 is hydrogen, halogen (e.g. CI or F), Ci- 8 alkyl (e.g. methyl or ethyl) or 5 to 14 membered heteroarylCi_ 8 alkyl (e.g. 3- (2-methyl-lH-imidazol- l-yl)propyl).
  • compounds of formula (Ie) in which X 3 is CR 4 .
  • R 4 is hydrogen, CI, F, methyl, ethyl or 3-(2-methyl-lH-imidazol-l-yl)propyl.
  • X 3 is N, CH, -C(halogen) (e.g -C(C1) or -C(F)), -C(Ci_ 8 alkyl) (e.g. -C(CH 3 ) or -C(C 2 H 5 )) or -C(5 to 14 membered heteroarylCi_ 8 alkyl) (e.g. -C(3- (2-methyl-lH-imidazol-l-yl)propyl).
  • halogen e.g -C(C1) or -C(F)
  • -C(Ci_ 8 alkyl) e.g. -C(CH 3 ) or -C(C 2 H 5 )
  • -C(5 to 14 membered heteroarylCi_ 8 alkyl) e.g. -C(3- (2-methyl-lH-imidazol-l-yl)propyl.
  • X 3 is N, CH, -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ) or -C(3-(2- methyl- lH-imidazol- l-yl)propyl).
  • X 3 is CH, -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ) or -C(3-(2-methyl- lH-imidazol-l-yl)propyl).
  • R 4 is selected from hydrogen, halogen (e.g. CI or F), hydroxyCi_ 8 alkyl (e.g. 3-hydroxypropyl), Ci_ 8 alkyl (e.g. methyl or ethyl), Ci_ 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. 3- ethoxypropyl or 4-ethoxybutyl), -(CH 2 ) y NR b C(0)R c (e.g.
  • pyridyl-3 -methoxy 0(CR b R c ) y R b (e.g. pyridin-3-methyloxy or pyridin-2-methyloxy) and 3 to 15 membered heterocyclyl (e.g. piperidin-l-ethanone).
  • R 4 is selected from hydrogen, CI, F, 3-hydroxypropyl, methyl, ethyl, methoxy, 3-ethoxypropyl, 4- ethoxybutyl, 2-methyl-N-propylpropanamide, N-ethyl-2-methylpropanamide, N- propylpropane-2-sulfonamide, pyridyl-3 -ethyl, pyridyl-4-ethyl, propanamide, pyridyl- 3-methoxy, pyridin-3-methyloxy, pyridin-2-methyloxy and piperidin-l-ethanone.
  • X 4 is N, CH, halogen (e.g. -C(C1) or -C(F)), hydroxyCi_ 8 alkyl (e.g. -C(C 3 H 6 OH)), Ci_ 8 alkyl (e.g. -C(CH 3 ), -C(C 2 H 5 )), Ci_ 8 alkoxy (e.g. -C(OCH 3 )), Ci_ 8 alkoxyCi_ 8 alkyl (e.g.
  • X 4 is N, CH, -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ), -C(OCH 3 ), - C(C 3 H 6 OH), -C(C 3 H 6 OC 2 H 5 ), -C(C 4 H 8 OC 2 H 5 ), -C(2-methyl-N-propylpropanamide), - C(N-ethyl-2-methylpropanamide), -C(N-propylpropane-2-sulfonamide), -C(pyridyl-3- ethyl), -C(pyridyl-4-ethyl), -C(C 2 H 4 CONH 2 ), -C(pyridyl-3-methoxy), -C(pyridin-3- methyloxy), -C(pyridin-2-methyloxy) or -C(piperidin-
  • Xi is N, CH, -C(halogen) (e.g. C(C1) or -C(F)), -C(hydroxyCi_ 8 alkyl) (e.g. -C(C 2 H 4 OH) or -C(CH 2 OH)), -C(haloCi_ 8 alkyl) (e.g. -C(CF 3 ), -C(C 2 H 4 F) or -C(C 3 H 6 F)), -C(Ci_ 8 alkyl) (e.g.
  • -C(C 3 _i 2 cycloalkyl) e.g. - C(cyclopropyl) or -C(-(CH 2 ) y C(0)NR b R c ) (e.g. -C(CH 2 CONH 2 )
  • X 2 is N, -C(H), - C(halogen) (e.g. -C(C1) or -C(F),), -C(halod_ 8 alkyl) (e.g. -C(CF 3 ) or -C(C 3 H 6 F)), - C(Ci_ 8 alkyl) (e.g.
  • X 3 is N, CH, -C(halogen) (e.g -C(C1) or -C(F)), -C(Ci_ 8 alkyl) (e.g. - C(CH 3 ) or -C(C 2 H 5 )) or -C(5 to 14 membered heteroarylCi_ 8 alkyl) (e.g.
  • X 4 is N, CH, halogen (e.g. -C(C1) or -C(F)), hydroxyd-galkyl (e.g. -C(C 3 H 6 OH)), d_ 8 alkyl (e.g. -C(CH 3 ), -C(C 2 H 5 )), d_ 8 alkoxy (e.g. -C(OCH 3 )), d-galkoxyd-galkyl (e.g.
  • Xi is N, -C(H), -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ), -C(C 2 H 4 OH), -C(CH 2 OH), -C(CF 3 ), -C(C 2 H 4 F), -C(C 3 H 6 F), -C(CH 2 CONH 2 ) or -C(cyclopropyl);
  • X 2 is N, -C(H), -C(C1), -C(F), -C(C 2 H 5 ), -C(CH 3 ), -C(CF 3 ) or -C(C 3 H 6 F) or -C(2- methylpyridyl-5-oxypropyl);
  • X 3 is N, CH, -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ) or -
  • Xi, X 2, X 3 and X 4 are independently selected from CR 4 and N; R is hydrogen or Ci_ 8 alkyl (e.g. methyl);
  • R 4 is hydrogen, halogen (e.g. CI or F), Ci_ 8 alkyl (e.g. methyl or ethyl), haloCi_ 8 alkyl (e.g. trifluoromethyl, 2-fluoroethyl or 3-fluoropropyl), hydroxyCi_ 8 alkyl (e.g. 2- hydroxyethyl, hydroxymethyl or 3-hydroxypropyl), Ci_ 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. 3-ethoxypropyl or 4-ethoxybutyl), C3_i 2 cycloalkyl (e.g.
  • halogen e.g. CI or F
  • Ci_ 8 alkyl e.g. methyl or ethyl
  • haloCi_ 8 alkyl e.g. trifluoromethyl, 2-fluoroethyl or 3-fluoropropyl
  • heteroarylCi_ 8 alkyl e.g. 3-(2-methyl-lH-imidazol-l- yl)propyl, 3-ethylpyridyl or 4-ethylpyridyl
  • -(CR b R c ) y OR b e.g. 2-methyl pyridyl-5- oxopropyl or pyridyl-3-methoxy
  • -0(CR b R c ) y R b e.g. pyridin-3-methyloxy or pyridin- 2-methyloxy
  • -(CH 2 ) y C(0)NR b R c e.g.
  • R b and R c are independently selected from hydrogen, 5 to 14 membered heteroaryl (e.g. 2-methylpyridin-5-yl, pyridin-3-yl or pyridin-2-yl) and Ci_ 8 alkyl (e.g. isopropyl); y is 0 to 3 and
  • Xi is N, -C(H), -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ), -C(C 2 H 4 OH), -C(CH 2 OH), - C(CF 3 ), -C(C 2 H 4 F), -C(C 3 H 6 F), -C(CH 2 CONH 2 ) or -C(cyclopropyl);
  • X 2 is N, -C(H), - C(C1), -C(F), -C(C 2 H 5 ), -C(CH 3 ), -C(CF 3 ) or -C(C 3 H 6 F) or -C(2-methylpyridyl-5- oxypropyl);
  • X 3 is N, CH, -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ) or -C (3- (2-methyl- 1H- imida
  • R 4 is independently selected from hydrogen, CI, F, methyl, ethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 2-hydroxyethyl, hydroxymethyl, 3- hydroxypropyl, methoxy, 3-ethoxypropyl, 4-ethoxybutyl, cyclopropyl, 3-(2-methyl- lH-imidazol-l-yl)propyl, pyridyl-3-ethyl, pyridyl-4-ethyl, 2-methyl-5- propoxypyridine, pyridyl-3-methoxy, pyridin-3-methyloxy, pyridin-2-methyloxy, acetamide, propanamide, 2-methyl-N-propylpropanamide, N-ethyl-2- methylpropanamide, N-propylpropane-2- sulfonamide and piperidin-l-ethanone;
  • R is hydrogen or methyl
  • R b and R c are independently selected from hydrogen, 2-methylpyridin-5-yl, pyridin-3-yl, pyridin-2-yl and isopropyl; y is 0 to 3 and p is 0.
  • Xi is N, -C(H), -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ), -C(C 2 H 4 OH), -C(CH 2 OH), - C(CF 3 ), -C(C 2 H 4 F), -C(C 3 H 6 F), -C(CH 2 CONH 2 ) or -C(cyclopropyl);
  • X 2 is N, -C(H), - C(C1), -C(F), -C(C 2 H 5 ), -C(CH 3 ), -C(CF 3 ) or -C(C 3 H 6 F) or -C(2-methylpyridyl-5- oxypropyl);
  • X 3 is N, CH, -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ) or -C(3-(2-methyl-lH- imid
  • R is hydrogen or methyl
  • R b and R c are independently selected from hydrogen, 2-methylpyridin-5-yl, pyridin-3-yl, pyridin-2-yl and isopropyl; y is 0 to 3 and p is 0.
  • Xi is N, -C(H), -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ), -C(C 2 H 4 OH), -C(CH 2 OH), - C(CF 3 ), -C(C 2 H 4 F), -C(C 3 H 6 F), -C(CH 2 CONH 2 ) or -C(cyclopropyl);
  • X 2 is N, -C(H), - C(C1), -C(F), -C(C 2 H 5 ), -C(CH 3 ), -C(CF 3 ) or -C(C 3 H 6 F) or -C(2-methylpyridyl-5- oxypropyl);
  • X 3 is N, CH, -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ) or -C(3-(2-methyl-lH- imid
  • R 4 is independently selected from hydrogen, CI, F, methyl, ethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 2-hydroxyethyl, hydroxymethyl, 3- hydroxypropyl, methoxy, 3-ethoxypropyl, 4-ethoxybutyl, cyclopropyl, 3-(2-methyl- lH-imidazol-l-yl)propyl, pyridyl-3-ethyl, pyridyl-4-ethyl, 2-methyl-5- propoxypyridine, pyridyl-3-methoxy, pyridin-3-methyloxy, pyridin-2-methyloxy, acetamide, propanamide, 2-methyl-N-propylpropanamide, N-ethyl-2- methylpropanamide, N-propylpropane-2-sulfonamide and piperidin-l-ethanone; R is hydrogen or methyl;
  • R b and R c are independently selected from hydrogen, 2-methylpyridin-5-yl, pyridin-3-yl, pyridin-2-yl and isopropyl; y is 0 to 3 and p is 0. According to one embodiment, specifically provided are compounds of formula (Ie) with an IC 50 value of less than 1000 nM, preferably, less than 500 nM, more preferably, less than 100 nM, still more preferably, less than 50 nM, with respect to GSNOR inhibitory activity.
  • the invention also provides a compound of formula (II), which is an embodiment of a compound of formula (I).
  • A is selected from
  • R is selected from hydrogen and Ci_ 8 alkyl
  • Xi, X 2 , X 3 and X 4 are independently selected from CR 4 and N; at each occurrence, R 4 is independently selected from hydrogen, halogen, hydroxyl, nitro, Ci_ 8 alkyl, Ci_ 8 alkoxy, Ci_ 8 alkoxyCi_ 8 alkyl, hydroxyCi_ 8 alkyl, haloCi_ galkyl, haloCi_ 8 alkoxy, C 3 _i 2 cycloalkyl, C 3 _i 2 cycloalkylCi_ 8 alkyl, -(CR b R c ) y OR b , - 0(CR b R c ) y R b , -(CH 2 ) y C(0)NR b R c , -(CH 2 ) y NR b C(0)R c , -(CH 2 ) y NR b S0 2 R c , (CH 2 ) y NR b R c
  • the compounds of formula (II) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments.
  • the invention provides compounds of formula (II) as defined above wherein R is hydrogen or Ci_ 8 alkyl (e.g. methyl) (according to one embodiment defined below), and p is 0 (according to another embodiment defined below).
  • R is hydrogen or Ci_ 8 alkyl (e.g. methyl)
  • p is 0 (according to another embodiment defined below).
  • specifically provided are compounds formula (II), in which A is selected from
  • R is hydrogen or Ci_ 8 alkyl (e.g. methyl).
  • R 4 is independently selected from hydrogen, halogen (e.g. CI or F), Ci_ 8 alkyl (e.g. methyl or ethyl), haloCi_ 8 alkyl (e.g. trifluoromethyl, 2-fluoroethyl or 3-fluoropropyl), hydroxyCi_ 8 alkyl (e.g. 2- hydroxyethyl, hydroxymethyl or 3-hydroxypropyl), Ci_ 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g.
  • C 3 _i 2 cycloalkyl e.g. cyclopropyl
  • 5 to 14 membered heteroarylCi_ 8 alkyl e.g. 3-(2-methyl- lH-imidazol-l- yl)propyl, 3-ethylpyridyl or 4-ethylpyridyl
  • -(CR b R c ) y OR b e.g. 2-methyl pyridyl-5- oxopropyl or pyridyl-3-methoxy
  • -0(CR b R c ) y R b e.g.
  • R 4 is independently selected from hydrogen, halogen (e.g. CI or F), Ci_ 8 alkyl (e.g. methyl or ethyl), haloCi_ 8 alkyl (e.g. trifluoromethyl, 2-fluoroethyl or 3-fluoropropyl), hydroxyCi_ 8 alkyl (e.g. 2- hydroxyethyl, hydroxymethyl or 3-hydroxypropyl), Ci_ 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g.
  • C 3 _i 2 cycloalkyl e.g. cyclopropyl
  • 5 to 14 membered heteroarylCi_ 8 alkyl e.g. 3-(2-methyl-lH-imidazol-l- yl)propyl, pyridyl-3-ethyl or pyridyl-4-ethyl
  • -(CR b R c ) y OR b e.g. 2-methyl-5- propoxypyridine or pyridyl-3 -methoxy
  • -0(CR b R c ) y R b e.g.
  • R b and R c are independently selected from hydrogen, 5 to 14 membered heteroaryl (e.g. 2- methylpyridin-5-yl, pyridin-3-yl or pyridin-2-yl) and Ci_ 8 alkyl (e.g. isopropyl); and y is 1 to 3.
  • heteroaryl e.g. 2- methylpyridin-5-yl, pyridin-3-yl or pyridin-2-yl
  • Ci_ 8 alkyl e.g. isopropyl
  • R 4 is independently selected from hydrogen, halogen (e.g. CI or F), Ci_ 8 alkyl (e.g. methyl or ethyl), haloCi_ 8 alkyl (e.g. trifluoromethyl, 2-fluoroethyl or 3-fluoropropyl), hydroxyCi_ 8 alkyl (e.g. 2- hydroxyethyl, hydroxymethyl or 3-hydroxypropyl), Ci_ 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g.
  • C 3 _i 2 cycloalkyl e.g. cyclopropyl
  • 5 to 14 membered heteroarylCi_ 8 alkyl e.g. 3-(2-methyl-lH-imidazol-l- yl)propyl, pyridyl-3-ethyl or pyridyl-4-ethyl
  • -(CR b R c ) y OR b e.g. 2-methyl-5- propoxypyridine or pyridyl-3 -methoxy
  • -0(CR b R c ) y R b e.g.
  • R b and R c are independently selected from hydrogen, 2-methylpyridin-5-yl, pyridin-3-yl, pyridin-2-yl and isopropyl; and y is 1 to 3.
  • R 4 is independently selected from hydrogen, CI, F, methyl, ethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 2-hydroxyethyl, hydroxymethyl, 3-hydroxypropyl, methoxy, 3-ethoxypropyl, 4-ethoxybutyl, cyclopropyl, 3-(2-methyl-lH-imidazol-l-yl)propyl, pyridyl-3 -ethyl, pyridyl-4-ethyl, 2-methyl-5-propoxypyridine, pyridyl-3-methoxy, pyridin-3-methyloxy, pyridin-2- methyloxy, acetamide, propanamide, 2-methyl-N-propylpropanamide, N-ethyl-2- methylpropanamide, N-propylpropane-2- sulfonamide and piperidin
  • R 4 is selected from hydrogen, halogen (e.g. CI or F), hydroxyCi_ 8 alkyl (e.g. 2-hydroxyethyl or hydroxymethyl), haloCi_ 8 alkyl (e.g. trifluoromethyl, 2-fluoroethyl or 3-fluoropropyl), Ci- 8 alkyl (e.g. methyl or ethyl), C3_i 2 cycloalkyl (e.g. cyclopropyl) and - (CH 2 ) y C(0)NR b R c (e.g. acetamide).
  • halogen e.g. CI or F
  • hydroxyCi_ 8 alkyl e.g. 2-hydroxyethyl or hydroxymethyl
  • haloCi_ 8 alkyl e.g. trifluoromethyl, 2-fluoroethyl or 3-fluoropropyl
  • Ci- 8 alkyl e.g. methyl or ethyl
  • R 4 is selected from hydrogen, CI, F, 2-hydroxyethyl, hydroxymethyl, trifluoromethyl, 2-fluoroethyl, 3- fluoropropyl, methyl, ethyl, cyclopropyl and acetamide.
  • Xi is N, CH, -C(halogen) (e.g. C(C1) or -C(F)), -C(hydroxyCi_ galkyl) (e.g. -C(C 2 H 4 OH) or -C(CH 2 OH)), -C(haloCi_ 8 alkyl) (e.g. -C(CF 3 ), -C(C 2 H 4 F) or -C(C 3 H 6 F)), -Cid-galkyl) (e.g.
  • compounds of formula (II) in which X 2 is CR 4 or N.
  • R 4 is selected from hydrogen, halogen (e.g. CI or F), haloCi_ 8 alkyl (e.g. trifluoromethyl or 3-fluoropropyl), Ci-galkyl (e.g. methyl or ethyl) or -(CR b R c ) y OR b (e.g. 2-methylpyridyl-5-oxypropyl).
  • R 4 is selected from hydrogen, CI, F, trifluoromethyl, 3-fluoropropyl, methyl, ethyl and 2-methylpyridyl- 5-oxypropyl.
  • X 2 is N, -C(H), -C(halogen), -C(haloCi_ 8 alkyl), -C(Ci_ 8 alkyl) or C(-(CR b R c ) y OR b ).
  • X 2 is N, -C(H), -C(halogen) (e.g. -C(C1) or -C(F),), -C(haloCi_ salkyl) (e.g. -C(CF 3 ) or -C(C 3 H 6 F)), -C(Ci_ 8 alkyl) (e.g. -C(C 2 H 5 ), -C(CH 3 )) or C(- (CR b R c ) y OR b ) (e.g. -C(2-methylpyridyl-5-oxypropyl)).
  • X 2 is N, -C(H), -C(halogen) (e.g. -C(C1) or -C(F),), -C(haloCi_ salkyl) (e.g. -C(CF 3 ) or -C(C 3 H 6 F)), -C(Ci_ 8 alkyl) (e.g. -C
  • X 2 is N, -C(H), -C(C1), -C(F), -C(C 2 H 5 ), -C(CH 3 ), -C(CF 3 ) or - C(C H 6 F) or -C(2-methylpyridyl-5-oxypropyl).
  • R 4 is hydrogen, halogen (e.g. CI or F), Ci_ 8 alkyl (e.g. methyl or ethyl) or 5 to 14 membered heteroarylCi_ 8 alkyl (e.g. 3-(2-methyl-lH-imidazol- l-yl)propyl).
  • R 4 is hydrogen, CI, F, methyl, ethyl or 3-(2-methyl- lH-imidazol- l-yl)propyl.
  • R 4 is hydrogen, halogen (e.g. CI or F), Ci-galkyl (e.g. methyl or ethyl) or 5 to 14 membered heteroarylCi_ 8 alkyl (e.g. 3- (2-methyl-lH-imidazol- l-yl)propyl).
  • R 4 is hydrogen, CI, F, methyl, ethyl or 3-(2-methyl-lH-imidazol-l-yl)propyl.
  • X 3 is N, CH, -C(halogen) (e.g -C(C1) or -C(F)), -C(Ci_ 8 alkyl) (e.g. -C(CH 3 ) or -C(C 2 H 5 )) or -C(5 to 14 membered heteroarylCi_ 8 alkyl) (e.g. -C(3- (2-methyl-lH-imidazol- l-yl)propyl).
  • halogen e.g -C(C1) or -C(F)
  • -C(Ci_ 8 alkyl) e.g. -C(CH 3 ) or -C(C 2 H 5 )
  • -C(5 to 14 membered heteroarylCi_ 8 alkyl) e.g. -C(3- (2-methyl-lH-imidazol- l-yl)propyl.
  • X 3 is N, CH, -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ) or -C(3-(2- methyl- lH-imidazol- l-yl)propyl).
  • X 3 is CH, -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ) or -C(3-(2-methyl- lH-imidazol-l-yl)propyl).
  • R 4 is selected from hydrogen, halogen (e.g. CI or F), hydroxyCi_ 8 alkyl (e.g. 3-hydroxypropyl), Ci_ 8 alkyl (e.g. methyl or ethyl), Ci_ 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. 3- ethoxypropyl or 4-ethoxybutyl), -(CH 2 ) y NR b C(0)R c (e.g.
  • pyridyl-3 -methoxy 0(CR b R c ) y R b (e.g. pyridin-3-methyloxy and pyridin-2-methyloxy) or 3 to 15 membered heterocyclyl (e.g. piperidin- l-ethanone).
  • R 4 is selected from hydrogen, CI, F, 3-hydroxypropyl, methyl, ethyl, methoxy, 3-ethoxypropyl, 4- ethoxybutyl, 2-methyl-N-propylpropanamide, N-ethyl-2-methylpropanamide, N- propylpropane-2-sulfonamide, pyridyl-3 -ethyl, pyridyl-4-ethyl, propanamide, pyridyl- 3-methoxy, pyridin-3-methyloxy, pyridin-2-methyloxy and piperidin-l-ethanone.
  • X 4 is N, CH, halogen (e.g. -C(C1) or -C(F)), hydroxyCi_ 8 alkyl (e.g. -C(C 3 H 6 OH)), Ci_ 8 alkyl (e.g. -C(CH 3 ), -C(C 2 H 5 )), Ci_ 8 alkoxy (e.g. -C(OCH 3 )), Ci_ 8 alkoxyCi_ 8 alkyl (e.g.
  • X 4 is N, CH, -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ), -C(OCH 3 ), - C(C 3 H 6 OH), -C(C 3 H 6 OC 2 H 5 ), -C(C 4 H 8 OC 2 H 5 ), -C(2-methyl-N-propylpropanamide), - C(N-ethyl-2-methylpropanamide), -C(N-propylpropane-2-sulfonamide), -C(pyridyl-3- ethyl), -C(pyridyl-4-ethyl), -C(C 2 H 4 CONH 2 ), -C(pyridyl-3-methoxy), -C(pyridin-3- methyloxy), -C(pyridin-2-methyloxy) or -C(piperidin-
  • Xi is N, CH, -C(halogen) (e.g. C(C1) or -C(F)), -C(hydroxyCi_ 8 alkyl) (e.g. -C(C 2 H 4 OH) or -C(CH 2 OH)), -C(haloCi_ 8 alkyl) (e.g. -C(CF 3 ), -C(C 2 H 4 F) or -C(C 3 H 6 F)), -C(Ci_ 8 alkyl) (e.g.
  • -C(C 3 _i 2 cycloalkyl) e.g. - C(cyclopropyl) or -C(-(CH 2 ) y C(0)NR b R c ) (e.g. -C(CH 2 CONH 2 )
  • X 2 is N, -C(H), - C(halogen) (e.g. -C(C1) or -C(F),), -C(haloCi_ 8 alkyl) (e.g. -C(CF 3 ) or -C(C 3 H 6 F)), - C(Ci_ 8 alkyl) (e.g.
  • X 3 is N, CH, -C(halogen) (e.g -C(C1) or -C(F)), -C(Ci_ 8 alkyl) (e.g. - C(CH 3 ) or -C(C 2 H 5 )) or -C(5 to 14 membered heteroarylCi_ 8 alkyl) (e.g.
  • X 4 is N, CH, halogen (e.g. -C(C1) or -C(F)), hydroxyCi_ 8 alkyl (e.g. -C(C 3 H 6 OH)), Ci_ 8 alkyl (e.g. -C(CH 3 ), -C(C 2 H 5 )), Ci_ 8 alkoxy (e.g. -C(OCH 3 )), Q-galkoxyQ-galkyl (e.g.
  • Xi is N, -C(H), -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ), -C(C 2 H 4 OH), -C(CH 2 OH), -C(CF 3 ), -C(C 2 H 4 F), -C(C 3 H 6 F), -C(CH 2 CONH 2 ) or -C(cyclopropyl);
  • X 2 is N, -C(H), -C(C1), -C(F), -C(C 2 H 5 ), -C(CH 3 ), -C(CF 3 ) or -C(C 3 H 6 F) or -C(2- methylpyridyl-5-oxypropyl);
  • X 3 is N, CH, -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ) or -
  • Xi, X 2i X 3 and X 4 are independently selected from CR 4 and N;
  • R is hydrogen or Ci_ 8 alkyl (e.g. methyl);
  • R 4 is hydrogen, halogen (e.g. CI or F), Ci_ 8 alkyl (e.g. methyl or ethyl), haloCi_ 8 alkyl (e.g. trifluoromethyl, 2-fluoroethyl or 3-fluoropropyl), hydroxyCi_ 8 alkyl (e.g. 2- hydroxyethyl, hydroxymethyl or 3-hydroxypropyl), Ci_ 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. 3-ethoxypropyl or 4-ethoxybutyl), C 3 _i 2 cycloalkyl (e.g.
  • halogen e.g. CI or F
  • Ci_ 8 alkyl e.g. methyl or ethyl
  • haloCi_ 8 alkyl e.g. trifluoromethyl, 2-fluoroethyl or 3-fluoropropyl
  • heteroarylCi_ 8 alkyl e.g. 3-(2-methyl- lH-imidazol-l- yl)propyl, 3-ethylpyridyl or 4-ethylpyridyl
  • -(CR b R c ) y OR b e.g. 2-methyl pyridyl-5- oxopropyl or pyridyl-3-methoxy
  • -0(CR b R c ) y R b e.g. pyridin-3-methyloxy or pyridin- 2-methyloxy
  • -(CH 2 ) y C(0)NR b R c e.g.
  • R b and R c are independently selected from hydrogen, 5 to 14 membered heteroaryl (e.g. 2-methylpyridin-5-yl, pyridin-3-yl or pyridin-2-yl) and Ci_ 8 alkyl (e.g. isopropyl); y is 0 to 3 and p is 0.
  • heteroaryl e.g. 2-methylpyridin-5-yl, pyridin-3-yl or pyridin-2-yl
  • Ci_ 8 alkyl e.g. isopropyl
  • Xi is N, -C(H), -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ), -C(C 2 H 4 OH), -C(CH 2 OH), - C(CF 3 ), -C(C 2 H 4 F), -C(C 3 H 6 F), -C(CH 2 CONH 2 ) or -C(cyclopropyl);
  • X 2 is N, -C(H), - C(C1), -C(F), -C(C 2 H 5 ), -C(CH 3 ), -C(CF 3 ) or -C(C 3 H 6 F) or -C(2-methylpyridyl-5- oxypropyl);
  • X 3 is N, CH, -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ) or -C(3-(2-methyl-lH- imid
  • R 4 is independently selected from hydrogen, CI, F, methyl, ethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 2-hydroxyethyl, hydroxymethyl, 3- hydroxypropyl, methoxy, 3-ethoxypropyl, 4-ethoxybutyl, cyclopropyl, 3-(2-methyl- lH-imidazol-l-yl)propyl, pyridyl-3-ethyl, pyridyl-4-ethyl, 2-methyl-5- propoxypyridine, pyridyl-3-methoxy, pyridin-3-methyloxy, pyridin-2-methyloxy, acetamide, propanamide, 2-methyl-N-propylpropanamide, N-ethyl-2- methylpropanamide, N-propylpropane-2-sulfonamide and piperidin- l-ethanone;
  • R is hydrogen or methyl
  • R b and R c are independently selected from hydrogen, 2-methylpyridin-5-yl, pyridin-3-yl, pyridin-2-yl and isopropyl
  • y is 0 to 3 and p is 0.
  • Xi is N, -C(H), -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ), -C(C 2 H 4 OH), -C(CH 2 OH), - C(CF 3 ), -C(C 2 H 4 F), -C(C 3 H 6 F), -C(CH 2 CONH 2 ) or -C(cyclopropyl);
  • X 2 is N, -C(H), - C(C1), -C(F), -C(C 2 H 5 ), -C(CH 3 ), -C(CF 3 ) or -C(C 3 H 6 F) or -C(2-methylpyridyl-5- oxypropyl);
  • X 3 is N, CH, -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ) or -C(3-(2-methyl-lH- imid
  • R 4 is independently selected from hydrogen, CI, F, methyl, ethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 2-hydroxyethyl, hydroxymethyl, 3- hydroxypropyl, methoxy, 3-ethoxypropyl, 4-ethoxybutyl, cyclopropyl, 3-(2-methyl- lH-imidazol-l-yl)propyl, pyridyl-3-ethyl, pyridyl-4-ethyl, 2-methyl-5- propoxypyridine, pyridyl-3-methoxy, pyridin-3-methyloxy, pyridin-2-methyloxy, acetamide, propanamide, 2-methyl-N-propylpropanamide, N-ethyl-2- methylpropanamide, N-propylpropane-2-sulfonamide and piperidin- l-ethanone;
  • R is hydrogen or methyl
  • R b and R c are independently selected from hydrogen, 2-methylpyridin-5-yl, pyridin-3-yl, pyridin-2-yl and isopropyl; y is 0 to 3 and p is 0. According to another embodiment, specifically provided are compounds of formula (II), in which A is
  • Xi is N, -C(H), -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ), -C(C 2 H 4 OH), -C(CH 2 OH), - C(CF 3 ), -C(C 2 H 4 F), -C(C 3 H 6 F), -C(CH 2 CONH 2 ) or -C(cyclopropyl);
  • X 2 is N, -C(H), - C(C1), -C(F), -C(C 2 H 5 ), -C(CH 3 ), -C(CF 3 ) or -C(C 3 H 6 F) or -C(2-methylpyridyl-5- oxypropyl);
  • X 3 is N, CH, -C(C1), -C(F), -C(CH 3 ), -C(C 2 H 5 ) or -C(3-(2-methyl-lH- imid
  • R 4 is independently selected from hydrogen, CI, F, methyl, ethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 2-hydroxyethyl, hydroxymethyl, 3- hydroxypropyl, methoxy, 3-ethoxypropyl, 4-ethoxybutyl, cyclopropyl, 3-(2-methyl- lH-imidazol-l-yl)propyl, pyridyl-3-ethyl, pyridyl-4-ethyl, 2-methyl-5- propoxypyridine, pyridyl-3-methoxy, pyridin-3-methyloxy, pyridin-2-methyloxy, acetamide, propanamide, 2-methyl-N-propylpropanamide, N-ethyl-2- methylpropanamide, N-propylpropane-2-sulfonamide and piperidin- l-ethanone;
  • R is hydrogen or methyl
  • R b and R c are independently selected from hydrogen, 2-methylpyridin-5-yl, pyridin-3-yl, pyridin-2-yl and isopropyl; y is 0 to 3 and p is 0.
  • compounds of formula (II) with an IC 50 value of less than 1000 nM, preferably, less than 500 nM, more preferably, less than 100 nM, still more preferably, less than 50 nM, with respect to GSNOR inhibitory activity.
  • the invention also provides a compound of formula (III), which embodiment of a compound of formula (I) or (II).
  • R is selected from hydrogen and Ci_ 8 alkyl; at each occurrence, R 4 is independently selected from hydrogen, halogen, hydroxyl, nitro, Ci_ 8 alkyl, Ci_ 8 alkoxy, Ci_ 8 alkoxyCi_ 8 alkyl, hydroxyCi_ 8 alkyl, haloCi- 8 alkyl, haloCi_ 8 alkoxy, C 3 -i 2 cycloalkyl, C 3 _i 2 cycloalkylCi_ 8 alkyl, -(CR b R c ) y OR b , - 0(CR b R c ) y R b , -(CH 2 ) y C(0)NR b R c , -(CH 2 ) y NR b C(0)R c , -(CH 2 ) y NR b S0 2 R c , (CH 2 ) y NR b R c , 3 to 15 membered heterocyclyl
  • the compounds of formula (III) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments.
  • the invention provides compounds of formula (III) as defined above wherein R is hydrogen or Ci_ 8 alkyl (e.g. methyl).
  • R 4 is independently selected from hydrogen, halogen (e.g. CI or F), Ci_ 8 alkyl (e.g. methyl or ethyl), haloCi_ 8 alkyl (e.g. trifluoromethyl, 2-iluoroethyl or 3-iluoropropyl), hydroxyCi_ 8 alkyl (e.g. 2- hydroxyethyl, hydroxymethyl or 3-hydroxypropyl), Ci_ 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g.
  • C 3 _i 2 cycloalkyl e.g. cyclopropyl
  • 5 to 14 membered heteroarylCi_ 8 alkyl e.g. 3-(2-methyl-lH-imidazol-l- yl)propyl, 3-ethylpyridyl or 4-ethylpyridyl
  • -(CR b R c ) y OR b e.g. 2-methyl pyridyl-5- oxopropyl or pyridyl-3-methoxy
  • -0(CR b R c ) y R b e.g.
  • R 4 is independently selected from hydrogen, halogen (e.g. CI or F), Ci_ 8 alkyl (e.g. methyl or ethyl), haloCi_ 8 alkyl (e.g. trifluoromethyl, 2-fluoroethyl or 3-fluoropropyl), hydroxyCi_ 8 alkyl (e.g. 2- hydroxyethyl, hydroxymethyl or 3-hydroxypropyl), Ci_ 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g.
  • C 3 _i 2 cycloalkyl e.g. cyclopropyl
  • 5 to 14 membered heteroarylCi_ 8 alkyl e.g. 3-(2-methyl-lH-imidazol-l- yl)propyl, pyridyl-3-ethyl or pyridyl-4-ethyl
  • -(CR b R c ) y OR b e.g. 2-methyl-5- propoxypyridine or pyridyl-3 -methoxy
  • -0(CR b R c ) y R b e.g.
  • R b and R c are independently selected from hydrogen, 5 to 14 membered heteroaryl (e.g. 2- methylpyridin-5-yl, pyridin-3-yl or pyridin-2-yl) and Ci_ 8 alkyl (e.g. isopropyl); and y is 1 to 3.
  • heteroaryl e.g. 2- methylpyridin-5-yl, pyridin-3-yl or pyridin-2-yl
  • Ci_ 8 alkyl e.g. isopropyl
  • R 4 is independently selected from hydrogen, halogen (e.g. CI or F), Ci_ 8 alkyl (e.g. methyl or ethyl), haloCi_ 8 alkyl (e.g. trifluoromethyl, 2-fluoroethyl or 3-fluoropropyl), hydroxyCi_ 8 alkyl (e.g. 2- hydroxyethyl, hydroxymethyl or 3-hydroxypropyl), Ci_ 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g.
  • C 3 _i 2 cycloalkyl e.g. cyclopropyl
  • 5 to 14 membered heteroarylCi_ 8 alkyl e.g. 3-(2-methyl-lH-imidazol-l- yl)propyl, pyridyl-3-ethyl or pyridyl-4-ethyl
  • -(CR b R c ) y OR b e.g. 2-methyl-5- propoxypyridine or pyridyl-3-methoxy
  • -0(CR b R c ) y R b e.g.
  • R b and R c are independently selected from hydrogen, 2-methylpyridin-5-yl, pyridin-3-yl, pyridin-2-yl and isopropyl; and y is 1 to 3.
  • R 4 is independently selected from hydrogen, CI, F, methyl, ethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 2-hydroxyethyl, hydroxymethyl, 3-hydroxypropyl, methoxy, 3-ethoxypropyl, 4-ethoxybutyl, cyclopropyl, 3-(2-methyl-lH-imidazol-l-yl)propyl, pyridyl-3 -ethyl, pyridyl-4-ethyl, 2-methyl-5-propoxypyridine, pyridyl-3-methoxy, pyridin-3-methyloxy, pyridin-2- methyloxy, acetamide, propanamide, 2-methyl-N-propylpropanamide, N-ethyl-2- methylpropanamide, N-propylpropane-2-sulfonamide and piperidin-l
  • R is hydrogen or Ci_ 8 alkyl (e.g. methyl).
  • R is hydrogen or Ci_ 8 alkyl (e.g. methyl);
  • R 4 is hydrogen, halogen (e.g. CI or F), Ci_ 8 alkyl (e.g. methyl or ethyl), haloCi- 8 alkyl (e.g. trifluoromethyl, 2-fluoroethyl or 3-fluoropropyl), hydroxyCi_ 8 alkyl (e.g. 2- hydroxyethyl, hydroxymethyl or 3-hydroxypropyl), Ci_ 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. 3-ethoxypropyl or 4-ethoxybutyl), C3_i 2 cycloalkyl (e.g.
  • halogen e.g. CI or F
  • Ci_ 8 alkyl e.g. methyl or ethyl
  • haloCi- 8 alkyl e.g. trifluoromethyl, 2-fluoroethyl or 3-fluoropropyl
  • heteroarylCi_ 8 alkyl e.g. 3-(2-methyl-lH-imidazol-l- yl)propyl, 3-ethylpyridyl or 4-ethylpyridyl
  • -(CR b R c ) y OR b e.g. 2-methyl pyridyl-5- oxopropyl or pyridyl-3-methoxy
  • -0(CR b R c ) y R b e.g. pyridin-3-methyloxy or pyridin- 2-methyloxy
  • -(CH 2 ) y C(0)NR b R c e.g.
  • R b and R c are independently selected from hydrogen, 5 to 14 membered heteroaryl (e.g. 2-methylpyridin-5-yl, pyridin-3-yl or pyridin-2-yl) and Ci-galkyl (e.g. isopropyl); y is 0 to 3.
  • heteroaryl e.g. 2-methylpyridin-5-yl, pyridin-3-yl or pyridin-2-yl
  • Ci-galkyl e.g. isopropyl
  • R is hydrogen or methyl
  • R 4 is independently selected from hydrogen, CI, F, methyl, ethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 2-hydroxyethyl, hydroxymethyl, 3- hydroxypropyl, methoxy, 3-ethoxypropyl, 4-ethoxybutyl, cyclopropyl, 3-(2-methyl- lH-imidazol-l-yl)propyl, pyridyl-3-ethyl, pyridyl-4-ethyl, 2-methyl-5- propoxypyridine, pyridyl-3-methoxy, pyridin-3-methyloxy, pyridin-2-methyloxy, acetamide, propanamide, 2-methyl-N-propylpropanamide, N-ethyl-2- methylpropanamide, N-propylpropane-2- sulfonamide and piperidin-l-ethanone;
  • R b and R c are independently selected from hydrogen, 2-methylpyridin-5-yl, pyridin-3-yl, pyridin-2-yl and isopropyl; y is 0 to 3.
  • Compounds of the present invention include the compounds in Examples 1-73.
  • esters of compounds of the present invention refer to a modified version or a precursor of a parent compound, designed to enhance the delivery properties and be converted to the parent compound in the body.
  • Esters of compounds of the present invention are entities structurally related to parent acidic drug compound, which, after administration, release the parent drug in vivo as the result of some metabolic process, such as enzymatic or chemical hydrolysis of a susceptible functionality.
  • the advantage of ester form may lie in its physical properties such as enhanced water permeability compared to parental drug or it may enhance the drug stability for long term storage.
  • the present application also provides a pharmaceutical composition that includes at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein.
  • the compounds described herein may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a tablet, capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient such as a carrier or a diluent
  • a carrier or enclosed within a carrier which can be in the form of a tablet, capsule, sachet, paper or other container.
  • the compounds and pharmaceutical compositions described herein are useful for inhibiting GSNOR activity.
  • the invention is further directed towards processes for the preparation of the compounds of the invention.
  • the invention is still further directed to methods of inhibiting GSNOR activity and treatment of disorders associated therewith using compounds of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compounds of the present invention or a pharmaceutically acceptable salt thereof.
  • the present patent application further provides a method for treating, controlling, delaying or preventing in a mammalian patient in need of treatment of one or more diseases, conditions and/or disorders selected from the group consisting of pulmonary disorders, cardiovascular and heart disease, diseases characterized by angiogenesis, inflammatory diseases, functional bowel disorders, diseases where there is risk of occurring apoptosis, thrombosis and restenosis, degenerative neurologic disorders, arthritis, liver injury, impotence, sleep apnea, diabetic wound healing, cutaneous infections, psoriasis, obesity, stroke, reperfusion injury, CNS disorders, disorders where preconditioning of heart or brain for NO protection against subsequent ischemic events is beneficial, bacterial infections and other diseases/disorders associated with GSNOR activation, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound according to the present invention or a pharmaceutically acceptable salt thereof.
  • the present patent application provides a method for treating, controlling, delaying or preventing in a mammalian patient in need of treatment of one or more diseases, conditions and/or disorders selected from pulmonary disorders associated with hypoxemia and/or smooth muscle constriction in the lungs and airways and/or lung infection and/or lung inflammation and/or lung injury (e.g., pulmonary hypertension, Acute respiratory distress syndrome (ARDS), asthma, bronchospasm, cough, pneumonia, pulmonary fibrosis/interstitial lung diseases, cystic fibrosis, Chronic obstructive pulmonary disease (COPD)); cardiovascular disease and heart disease (e.g., hypertension, ischemic coronary syndromes, atherosclerosis, heart disease, glaucoma); diseases characterized by angiogenesis (e.g., coronary artery disease), disorders where there is risk of thrombosis and restenosis occurring; inflammatory diseases (e.g., AIDS related dementia, inflammatory bowel disease (IBD), Crohn's disease, co
  • the present patent application provides a method for treating, controlling, delaying or preventing in a mammalian patient in need of treatment of one or more diseases, conditions and/or disorders selected from pulmonary hypertension, ARDS, asthma, bronchospasm, cough, pneumonia, pulmonary fibrosis/interstitial lung diseases, cystic fibrosis, Chronic obstructive pulmonary disease (COPD), hypertension, ischemic coronary syndromes, atherosclerosis, heart disease, glaucoma, coronary artery disease, AIDS related dementia, inflammatory bowel disease (IBD), Crohn's disease, colitis, psoriasis, heart failure, atherosclerosis, degenerative neurologic disorders, arthritis, drug induced liver injury, ischemic liver injury, alcoholic liver injury, impotence, sleep apnea, diabetic wound healing, cutaneous infections, psoriasis, obesity, thyroid disease, stroke, traumatic muscle injury in heart or lung, crush injury, anxiety, depression, psychosis, schizophrenia
  • the present patent application provides a method for treating, controlling, delaying or preventing in a mammalian patient in need of treatment of one or more diseases, conditions and/or disorders selected from pulmonary hypertension, ARDS, asthma, bronchospasm, cough, pneumonia, pulmonary fibrosis/interstitial lung diseases, cystic fibrosis and Chronic obstructive pulmonary disease (COPD).
  • one or more diseases, conditions and/or disorders selected from pulmonary hypertension, ARDS, asthma, bronchospasm, cough, pneumonia, pulmonary fibrosis/interstitial lung diseases, cystic fibrosis and Chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the present patent application provides a method for treating, controlling, delaying or preventing in a mammalian patient in need of treatment of one or more diseases, conditions and/or disorders selected from asthma, cystic fibrosis and Chronic obstructive pulmonary disease (COPD).
  • one or more diseases, conditions and/or disorders selected from asthma, cystic fibrosis and Chronic obstructive pulmonary disease (COPD).
  • COPD Chronic obstructive pulmonary disease
  • the present patent application provides a method for treating, controlling, delaying or preventing in a mammalian patient in need of treatment of asthma. In yet another aspect, the present patent application provides a method for treating, controlling, delaying or preventing in a mammalian patient in need of treatment of cystic fibrosis.
  • the present patent application provides a method for treating, controlling, delaying or preventing in a mammalian patient in need of treatment of Chronic obstructive pulmonary disease (COPD).
  • COPD Chronic obstructive pulmonary disease
  • the present patent application provides use of a compound of the present invention for treating, controlling, delaying or preventing in a mammalian patient in need of treatment of one or more diseases, conditions and/or disorders selected from pulmonary hypertension, ARDS, asthma, bronchospasm, cough, pneumonia, pulmonary fibrosis/interstitial lung diseases, cystic fibrosis, Chronic obstructive pulmonary disease (COPD), hypertension, ischemic coronary syndromes, atherosclerosis, heart disease, glaucoma, coronary artery disease, AIDS related dementia, inflammatory bowel disease (IBD), Crohn's disease, colitis, psoriasis, heart failure, atherosclerosis, degenerative neurologic disorders, arthritis, drug induced liver injury, ischemic liver injury,
  • the present patent application provides use of a compound of the present invention for treating, controlling, delaying or preventing in a mammalian patient in need of treatment of one or more diseases, conditions and/or disorders selected from pulmonary hypertension, ARDS, asthma, bronchospasm, cough, pneumonia, pulmonary fibrosis/interstitial lung diseases, cystic fibrosis and COPD.
  • diseases, conditions and/or disorders selected from pulmonary hypertension, ARDS, asthma, bronchospasm, cough, pneumonia, pulmonary fibrosis/interstitial lung diseases, cystic fibrosis and COPD.
  • halogen or halo means fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo).
  • alkyl refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e. Ci_ 8 alkyl), and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n- butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).
  • C 1-6 alkyl refers to an alkyl chain having 1 to 6 carbon atoms.
  • Ci_ 4 alkyl refers to an alkyl chain having 1 to 4 carbon atoms. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched.
  • alkoxy denotes an alkyl group attached via an oxygen linkage to the rest of the molecule (i.e. Ci_ 8 alkoxy). Representative examples of such groups are -OCH 3 and -OC 2 H 5 . Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched.
  • alkoxyalkyl or "alky loxy alkyl” refers to an alkoxy or alkyloxy group as defined above directly bonded to an alkyl group as defined above (i.e. Ci_ 8 alkoxyCi_ 8 alkyl or Ci_ 8 alkyloxyCi_ 8 alkyl).
  • alkoxyalkyl moiety includes, but are not limited to, -CH 2 OCH 3 and -CH 2 OC 2 H 5 . Unless set forth or recited to the contrary, all alkoxyalkyl groups described herein may be straight chain or branched.
  • haloalkyl refers to at least one halo group (selected from F, CI, Br or I), linked to an alkyl group as defined above (i.e. haloCi_ 8 alkyl).
  • haloalkyl moiety include, but are not limited to, trifluoromethyl, difluoromethyl and fluoromethyl groups. Unless set forth or recited to the contrary, all haloalkyl groups described herein may be straight chain or branched.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms (i.e. haloCi_ 8 alkoxy).
  • haloalkoxy include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1-bromoethoxy.
  • all haloalkoxy groups described herein may be straight chain or branched.
  • hydroxyalkyl refers to an alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyCi_ 8 alkyl).
  • hydroxyalkyl moieties include, but are not limited to -CH 2 OH, -C 2 FL 4 OH and -CH(OH)C 2 H 4 OH.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, (i.e.C 3 _i 2 cycloalkyl).
  • monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapthyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl.
  • C 3 _ 6 cycloalkyl refers to the cyclic ring having 3 to 6 carbon atoms.
  • cycloalkylalkyl refers to a cyclic ring-containing radical having 3 to about 6 carbon atoms directly attached to an alkyl group (i.e. C3_ 6 cycloalkylCi_ 8 alkyl).
  • the cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
  • aryl refers to an aromatic radical having 6 to 14 carbon atoms (i.e.
  • C6-i 4 aryl including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
  • heterocyclic ring or “heterocyclyl” unless otherwise specified refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical (i.e. 3 to 15 membered heterocyclyl) which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s).
  • heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolidinyl, 2-oxoazepinyl, octahydroin
  • heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group (i.e. 3 to 15 membered heterocyclylCi_ 8 alkyl).
  • the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • heteroaryl refers to substituted or unsubstituted 5 to 14 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S (i.e. 5 to 14 membered heteroaryl).
  • the heteroaryl may be a mono-, bi- or tricyclic ring system.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, iso
  • heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group (i.e. 5 to 14 membered heterarylCi-galkyl).
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulf
  • treating or “treatment” of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • subject includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non- domestic animals (such as wildlife).
  • domestic animals e.g., household pets including cats and dogs
  • non- domestic animals such as wildlife.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
  • the compounds of the invention are typically administered in the form of a pharmaceutical composition.
  • Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the invention.
  • the pharmaceutical compositions described herein comprise one or more compounds described herein and one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use.
  • the pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, solvents and the like.
  • suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters, and polyoxyethylene.
  • compositions described herein may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, suspending agents, preserving agents, buffers, sweetening agents, flavouring agents, colorants or any combination of the foregoing.
  • compositions may be in conventional forms, for example, capsules, tablets, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present invention may be formulated so as to provide desired release profile.
  • Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition can be carried out using any of the accepted routes of administration of such compounds or pharmaceutical compositions.
  • the route of administration may be any route which effectively transports the active compound of the patent application to the appropriate or desired site of action.
  • Suitable routes of administration include, but are not limited to, oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular, and topical.
  • Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges.
  • Liquid formulations include, but are not limited to, syrups, emulsions, and sterile injectable liquids, such as suspensions or solutions.
  • Topical dosage forms of the compounds include, but are not limited to, ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, impregnated dressings, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration.
  • compositions described herein may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of
  • Suitable doses of the compounds for use in treating the diseases and disorders described herein can be determined by those skilled in the relevant art.
  • Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects. Mode of administration, dosage forms, and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the present patent application.
  • the present invention provides compounds and pharmaceutical compositions which inhibit GSNOR activity and are thus useful in the treatment or prevention of disorders associated with GSNOR activation.
  • Compounds and pharmaceutical compositions of the present invention inhibit GSNOR and are thus useful in the treatment or prevention of a range of disorders associated with the activation of GSNOR which includes, but are not limited to pulmonary disorders, cardiovascular and heart disease, diseases characterized by angiogenesis, inflammatory diseases, functional bowel disorders, diseases where there is risk of occurring apoptosis, thrombosis and restenosis, degenerative neurologic disorders, arthritis, liver injury, impotence, sleep apnea, diabetic wound healing, cutaneous infections, psoriasis, obesity, stroke, reperfusion injury, CNS disorders, disorders where preconditioning of heart or brain for NO protection against subsequent ischemic events is beneficial, bacterial infections and other diseases/disorders associated with GSNOR activation.
  • the compounds of the present invention may be used to prevent or treat one or more diseases, conditions and/or disorders selected from pulmonary disorders associated with hypoxemia and/or smooth muscle constriction in the lungs and airways and/or lung infection and/or lung inflammation and/or lung injury (e.g., pulmonary hypertension, Acute respiratory distress syndrome (ARDS), asthma, bronchospasm, cough, pneumonia, pulmonary fibrosis/interstitial lung diseases, cystic fibrosis, chronic obstructive pulmonary disease (COPD)); cardiovascular disease and heart disease (e.g., hypertension, ischemic coronary syndromes, atherosclerosis, heart disease, glaucoma); diseases characterized by angiogenesis (e.g., coronary artery disease), disorders where there is risk of thrombosis and restenosis occurring; inflammatory diseases (e.g., AIDS related dementia, inflammatory bowel disease (IBD), Crohn's disease, colitis, and psoriasis); diseases where there is risk of apop,
  • the compounds of the present invention may be used for treatment of pulmonary disorders associated with hypoxemia and/or smooth muscle constriction in the lungs and airways and/or lung infection and/or lung inflammation and/or lung injury (e.g., pulmonary hypertension, Acute respiratory distress syndrome (ARDS), asthma, bronchospasm, cough, pneumonia, pulmonary fibrosis/interstitial lung diseases, cystic fibrosis, chronic obstructive pulmonary disease (COPD)).
  • pulmonary disorders associated with hypoxemia and/or smooth muscle constriction in the lungs and airways and/or lung infection and/or lung inflammation and/or lung injury e.g., pulmonary hypertension, Acute respiratory distress syndrome (ARDS), asthma, bronchospasm, cough, pneumonia, pulmonary fibrosis/interstitial lung diseases, cystic fibrosis, chronic obstructive pulmonary disease (COPD)).
  • the compounds of the present invention may be used for treatment of respiratory disorders including, but are not limited to, chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, cystic fibrosis, and cough.
  • COPD chronic obstructive pulmonary disease
  • asthma asthma
  • bronchospasm cystic fibrosis
  • cough cough
  • the compounds of the present invention may be used for treatment of respiratory disorders including, chronic obstructive pulmonary disease (COPD), cyctic fibrosis and asthma.
  • COPD chronic obstructive pulmonary disease
  • cyctic fibrosis chronic obstructive pulmonary disease
  • asthma chronic obstructive pulmonary disease
  • the compounds of the present invention may be used for treatment of chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the compounds of the present invention may be used for treatment of asthma.
  • the compounds of the present invention may be used for treatment of cyctic fibrosis.
  • the compounds of the present invention may be used for treatment of asthma.
  • Other respiratory disorders include, but are not limited to, bronchitis, bronchiolitis, bronchiectasis, acute nasoparyngitis, acute and chronic sinusitis, maxillary sinusitis, pharyngitis, tonsillitis, laryngitis, tracheitis, epiglottitis, croup, chronic disease of tonsils and adenoids, hypertrophy of tonsils and adenoids, peritonsillar abscess, rhinitis, abscess or ulcer and nose, pneumonia, viral and bacterial pneumonia, bronchopneumonia, influenza, extrinsic allergic alveolitis, coal workers' pneumoconiosis, asbestosis, pneumoconiosis, pneumonopathy, respiratory conditions due to chemical fumes, vapors and other external agents, emphysema, pleurisy, pneumothorax, abscess of lung
  • the present inventions further relates to the use of the compounds described herein in the preparation of a medicament for the treatment of diseases mediated by GSNOR.
  • the compounds of the invention are effective both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions.
  • the dosage administered may vary with the compound employed, the mode of administration, the treatment desired and the disorder.
  • the daily dosage of the compound of the invention administered may be in the range from about 0.05 mg/kg to about 100 mg/kg.
  • the compound of general formula (1) was reacted with a boronic acid derivative of formula (2) (wherein X is a halogen) to obtain the compound of formula (3) (wherein X is a halogen).
  • the reaction may be carried out in presence of a suitable palladium catalyst.
  • the palladium catalyst may be tetrakis(triphenylphosphine)Pd(0).
  • the reaction may be carried out in the presence of a base.
  • the base may be aq. Na 2 C0 3 .
  • the reaction may be carried out in a suitable solvent system.
  • the solvent system may be selected from MeOH, toluene or mixture thereof.
  • the compound of formula (3) is reacted with compound of formula (4) to obtain the compound of formula (5).
  • the reaction may be carried out in presence of suitable coupling agent and 1,10- phenanthroline.
  • the coupling agent may be Cul.
  • the reaction may be carried out in presence of an inorganic base.
  • the inorganic base may be K 2 C0 3 .
  • the compound of formula (5) was reacted with sodium azide to obtain compound of formula (I).
  • the reaction may be carried out in presence of a suitable base.
  • the base may be selected from triethyl ammonium chloride and ammonium chloride.
  • the reaction may be carried out in a suitable sovent.
  • the solvent may be DMF.
  • the reaction temperature may be 0-150°C.
  • the compounds of general formula (Ila), (lib) and (lie) can be prepared as described in scheme 2.
  • the compound of formula (3) was reacted with imidazole derivative of formula (6) to obtain compound of formula (7).
  • the reaction may be carried out in presence of a suitable coupling reagent.
  • the coupling agent may be Cul.
  • the reaction may be carried out in presence of a suitable base and 1,10 phenanthroline.
  • the base may be K 2 CO 3 .
  • the compound of formula (7) is reacted with an azide to obtain the compound of formula (Ila).
  • the azide may be sodium azide.
  • the reaction may be carried out in presence of a base.
  • the base may be ammonium chloride or triethyl ammonium chloride.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be DMF.
  • the reaction may be carried out at 0- 150°C.
  • the compound of formula (7) was reacted with a suitable base to obtain the compound of formula (lib).
  • the reaction may be carried out in presence of a suitable base.
  • the base may be aq. NaOH.
  • the reaction may be carried out in the presence of suitable solvent.
  • the solvent may be ethanol.
  • the compound of formula (7) is reacted with hydroxylamine hydrochloride to obtain compound of formula (8).
  • the reaction may be carried out in presence of a suitable base.
  • the base may be triethyl amine.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be ethanol.
  • the compound of formula (8) may be further reacted with a suitable coupling reagent to obtain compound of formula (lie).
  • the reaction may be carried out in presence of a suitable coupling reagent such as ⁇ , ⁇ -carbonyldiimidazole (CDI).
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be DMF.
  • Imidazole biaryl compounds of the general formula (lib) can also be prepared by using a general approach as depicted in scheme 3 and scheme 4, wherein R 1 , R 2 ,
  • the compound of general formula (9) (wherein X is a halogen) was reacted with a boronic acid derivative of formula (2) (wherein X is a halogen) to obtain compound of formula (10).
  • the reaction may be carried out in presence of a suitable palladium catalyst.
  • the palladium catalyst may be tetrakis(triphenylphosphine)Pd(0).
  • the reaction may be carried out in presence of a suitable base.
  • the base may be aq. Na 2 C0 3 .
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be MeOH, toluene or mixture thereof.
  • the compound of formula (10) is further reacted with imidazole derivative of formula (6) to obtain compound of formula (11).
  • the reaction may be carried out in presence of a suitable coupling reagent.
  • the coupling reagent may be Cul.
  • the reaction may be carried out in presence of a base and 1,10 phenanthroline.
  • the base may be K2CO3.
  • the compound of formula (11) on hydrolysis gives compound of formula (lib).
  • the hydrolysis reaction was carried out by using a suitable base.
  • the base may be aq. NaOH.
  • the reaction may be carried out in presence of a suitable solvent.
  • the solvent may be methanol.
  • the compounds of general formula (lib) can also be prepared as described in scheme 4.
  • compound of formula (12) was reacted with a suitable metal halide to obtain compound of formula (13) (wherein X and X' are halogen).
  • the metal halide may be a potassium halide such as KI.
  • the reaction may be carried out in presence of an oxidizing agent.
  • the oxidizing agent may be NaN0 2 .
  • the reaction may be carried out in presence of an acid.
  • the acid may be /?-Toluenesulfonic acid.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be acetonitrile.
  • the compound of formula (13) is further reacted with boronobenzoic acid of formula (14) to obtain compound of formula (15).
  • the reaction may be carried out in presence of a suitable palladium catalyst.
  • the palladium catalyst may be tetrakis(triphenylphosphine)Pd(0).
  • the reaction may be carried out in presence of a base.
  • the base may be K 2 C0 3 .
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be DMF.
  • the compound of formula (15) was then reacted with imidazole of formula (6) to obtain compound of formula (lib).
  • the reaction may be carried out in presence of a suitable coupling reagent and 1,10 phenanthroline.
  • the coupling agent may be Cul.
  • the reaction may be carried out in presence of a base.
  • the base may be K 2 CO 3 .
  • the compound of formula (12) was reacted with cyano boronobenzoic acid of formula (16) to obtain compound of formula (17).
  • the reaction may be carried out in presence of a suitable palladium catalyst.
  • the palladium catalyst may be tetra s(triphenylphosphine)Pd(0).
  • the reaction may be carried out in presence of a base.
  • the base may be K 2 CO 3 .
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be DMF.
  • the compound of formula (17) was further reacted with phenyl chloroformate to obtain compound of formula (18).
  • the reaction may be carried out in presence of a base.
  • the base may be pyridine.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be ethyl acetate.
  • the reaction may be carried out at a temperature range 0°-RT.
  • the compound of formula (18) was then reacted with dimethoxy ethanmine to obtain compound of formula (19).
  • the compound of formula (19) was further reacted with an acid.
  • the acid may be HC1.
  • the reaction is carried out in a suiable solvent to obtain compound of formula (20).
  • the solvent may be methanol.
  • the compound of formula (20) was reacted with azide to form compound of formula (la).
  • the azide may be sodium azide.
  • the reaction may be carried out in presence of a suitable base.
  • the base may be triethyl ammonium chloride or ammonium chloride.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be DMF.
  • the reaction temperature may be 0-150°C.
  • the compound of formula (17) was reacted with with chloroacetyl isocynate to obtain compound of formula (21).
  • the reaction may be carried out in presence of a base.
  • the base may be di-isopropyl ethyl amine.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be DCM.
  • the compound of formula (21) is reacted with azide to form compound of formula (lb).
  • the azide may be sodium azide.
  • the reaction may be carried out in presence of a suitable base.
  • the base may be triethyl ammonium chloride or ammonium chloride.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be DMF.
  • the reaction temperature may be 0-150°C.
  • the compound of formula (17) was reacted with phosgene to obtain compound of formula (22).
  • the reaction may be carried out in presence of a base.
  • the base may be di-isopropyl ethyl amine.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be DCM.
  • the compound of formula (22) was further reacted with methyl amino acetate to obtain compound of formula (23).
  • the reaction may be carried out in presence of a suitable solvent.
  • Th solvent may be DCM.
  • the compound of formula (23) was reacted with sodium azide to form compound of formula (Ic).
  • the reaction may be carried out in presence of a suitable base.
  • the base may be triethyl ammonium chloride or ammonium chloride.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be DMF.
  • the reaction temperature may be 0-150°C.
  • the compound of formula (20) was reacted with a suitable hydrolyzing agent to obtain compound of formula (la').
  • the hydrolyzing agent may be selected from NaOH and KOH.
  • the reaction was carried out in presence of a suitable solvent.
  • the solvent may be methanol or ethanol.
  • the reaction temperature may be 0-100°C.
  • the compound of formula (21) was reacted with a suitable hydrolyzing agent to obtain compound of formula (lb').
  • the hydrolyzing agent may be selected from NaOH and KOH.
  • the reaction was carried out in presence of a suitable solvent.
  • the solvent may be methanol or ethanol.
  • the reaction temperature may be 0-100°C.
  • the compound of formula (23) was reacted with a suitable hydrolyzing agent to obtain compound of formula (Ic').
  • the hydrolyzing agent may be selected from NaOH and KOH.
  • the reaction was carried out in presence of a suitable solvent.
  • the solvent may be methanol or ethanol.
  • the reaction temperature may be 0-100°C.
  • the compound of formula (24) can be prepared from aminoacetonitrile by treating with triethyl ortho formate at a suitable temperature.
  • the temperature may be 0-150°C.
  • the compound of formula (3) was reacted with a suitable borate to obtain compound of formula (25).
  • the borate may be tri-isopropyl borate.
  • the reaction may be carried out in presence of n-butyl lithium.
  • the reaction may be carried out in a suitable solvent such as THF, toluene.
  • the compound of formula (25) was reacted with the compound of formula (24) to give the compound of formula (26).
  • the reaction may be carried out in presence of copper acetate and molecular sieves.
  • the reaction may be carried out in a suitable solvent such as DCM.
  • the compound of formula (26) is further reacted with sodium azide to obtain compound of formula (Id).
  • the reaction may be carried out in presence of a suitable base.
  • the base may be triethyl ammonium chloride or ammonium chloride.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be DMF.
  • the reaction temperature may be 0- 150°C.
  • the compound of formula (26) was reacted with a suitable hydrolyzing agent to obtain compound of formula (Id').
  • the hyrolysing agent may be selected from NaOH or KOH.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be an alcoholic solvent.
  • the alcoholic solvent may be selected from methanol and ethanol.
  • the reaction temperature may be 0-100°C.
  • the compounds of general formula (III), can be prepared as described in scheme 7.
  • the compound of formula (27) was reacted with imidazole derivative of formula (28) to obtain compound of formula (29).
  • the reaction may be carried out in presence of a suitable coupling reagent.
  • the coupling agent may be Cul.
  • the reaction may be carried out in presence of a suitable base and 1,10 phenanthroline.
  • the base may be K 2 CO 3 .
  • the compound of formula (29) was further reacted with an azide to obtain the compound of formula (III).
  • the azide may be sodium azide.
  • the reaction may be carried out in presence of a base.
  • the base may be ammonium chloride or triethyl ammonium chloride.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be DMF.
  • Imidazole biaryl compounds of the general formula (Ie) can also be prepared by using a general approach as depicted in scheme 8, wherein A, B, R 3 , R 4 , R 5 , Xi, X 2i X 3i X4 and p are as defined in formula (Ie).
  • the compound of general formula (30) was reacted with a boronic acid derivative of formula (31) (wherein X is a halogen) to obtain the compound of formula (32) (wherein X is a halogen).
  • the reaction may be carried out in presence of a suitable palladium catalyst.
  • the palladium catalyst may be tetrakis(triphenylphosphine)Pd(0).
  • the reaction may be carried out in the presence of a base.
  • the base may be as aq. Na 2 C0 3 .
  • the reaction may be carried out in a suitable solvent system.
  • the solvent system may be selected from MeOH, toluene or mixture thereof.
  • the compound of formula (32) is reacted with compound of formula (4) to obtain the compound of formula (33).
  • the reaction may be carried out in presence of suitable coupling agent and 1,10-phenanthroline.
  • the coupling agent may be Cul.
  • the reaction may be carried out in presence of an inorganic base.
  • the inorganic base may be K 2 C0 3 .
  • the compound of formula (33) is reacted with sodium azide to obtain compound of formula (Ie).
  • the reaction may be carried out in presence of a suitable base.
  • the base may be selected from triethyl ammonium chloride and ammonium chloride.
  • the reaction may be carried out in a suitable sovent.
  • the solvent may be DMF.
  • the reaction temperature may be 0-150°C.
  • work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over anhydrous sodium sulfate, filtration and evaporation of the solvent.
  • Purification includes purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase. Use of a different eluent system is indicated within parentheses.
  • Step-1 - Preparation of 4'-bromo-[ 1,1 '-biphenyl] -4-carbonitrile
  • Step-2 - Preparation of 4'-(lH-imidazol- l-yl)-[l, -biphenyl]-4-carbonitrile
  • DMSO dimethyl sulfoxide
  • imidazole 0.527 g, 7.75 mmol
  • Cul 72 mg, 0.38 mmol
  • K 2 C0 3 0.534 g, 3.875 mmol
  • 1, 10 phenanthroline 68 mg, 0.38 mmol.
  • the reaction mixture was heated to 100°C in sealed tube for 16 h.
  • Step-1 Preparation of 3-chloro-4-iodobenzonitrile
  • Step-2 - Preparation of 4'-bromo-2-chloro-[l, -biphenyl]-4-carbonitrile
  • the title compound was prepared according to the procedure described in Step-1 of Intermediate- 1 using 3-chloro-4-iodobenzonitrile (Step- 1, intermediate-4, 0.500 g, 1.90 mmol) and (4-bromophenyl)-boronic acid (0.380 g, 1.90 mmol), tetrakis(triphenylphosphine)Pd(0) (0.043 g, 0.038 mmol) and aq. Na 2 C0 3 (0.399 g, 3.8 mmol) to afford 0.350 g of desired product.
  • Step-1 Preparation of 2-chloro-l-iodo-4-nitrobenzene
  • the title compound was prepared following the procedure described in step-1 of Intermediate-4 by using 2-chloro-4-nitroaniline (4.0 g, 23.25 mmol), p- toluenesulfonic acid (13.20 g, 69.56 mmol), acetonitrile (50 mL), aq.NaN0 2 (2.39 g, 34.87 mmol in 7 mL water) and KI (5.77 g, 34.87 mmol) to afford 5.0 g of title product.
  • Step-2 Preparation of 2'-chloro-4'-nitro-[l, -biphenyl]-4-carbonitrile
  • the title compound was prepared according to the procedure described in Step-1 of Intermediate - 1 using 2-chloro-l-iodo-4-nitrobenzene (1.3 g, 4.59 mmol) and (4- cyanophenyl)boronic acid (1.01 g, 6.8 mmol), Pd(OAC) 2 (0.150 g), triphenylphosphine (0.180 g, 0.68 mmol) and aq. K 3 (PO) 4 (3.89 g, 18.36 mmol) to afford 0.550 g of desired product.
  • Step-3 - Preparation of 4'-amino-2'-chloro-[l, -biphenyl]-4-carbonitrile
  • Step-4 - Preparation of 2'-chloro-4'-iodo-[l, -biphenyl]-4-carbonitrile
  • Step-5 - 2'-chloro-4'-( lH-imidazol- 1 -yl)- [ 1 , 1 '-biphenyl] -4-carbonitrile
  • the title compound was prepared according to the procedure described in step-2 of Intermediate -1 using 2'-chloro-4'-iodo-[l, -biphenyl]-4-carbonitrile (0.430 g, 1.26 mmol), imidazole (0.860 g, 3.78 mmol), Cul (0.144 g, 0.75 mmol), K 2 C0 3 (0.349 g, 2.52 mmol) and 1, 10 -phenanthroline (0.068 g , 0.378 mmol) to afford 0.150 g of the desired product.
  • Step-1 Preparation of 4-bromo-2-ethyl-l-iodobenzene
  • Step-2 - Preparation of 4'-bromo-2'-ethyl-[l,r-biphenyl]-4-carbonitrile
  • Step-3 - Preparation of 2'-ethyl-4'-(lH-imidazol-l-yl)-[l, -biphenyl]-4-carbonitrile
  • Step-1 Preparation of methyl 4'-bromo-2-methoxy-[l,l'-biphenyl] -4-carboxylate
  • Step-2 Preparation of methyl 4'-(lH-imidazol-l-yl)-2-methoxy-[l,l'-biphenyl]-4- carboxylate
  • Step-1 Preparation of 3-fluoro-4-iodobenzonitrile
  • Step-2 - Preparation of 4'-bromo-2-fluoro-[l, -biphenyl]-4-carbonitrile
  • Step-3 - Preparation of 2-fluoro-4'-(lH-imidazol- l-yl)-[l, -biphenyl]-4-carbonitrile
  • Step-1 Preparation of 3-chloro-4-iodobenzonitrile
  • Step-2 - Preparation of 4'-bromo-2-chloro-[l, -biphenyl]-4-carbonitrile
  • the title compound was prepared according to the procedure described in step-1 of Intermediate- 1 using 3-chloro-4-iodobenzonitrile (0.500 g, 1.90 mmol) and (4- bromophenyl)boronic acid (0.380 g, 1.90 mmol), tetrakis(triphenylphosphine)Pd(0) (0.043 g, 0.038 mmol) and aq. Na 2 C0 3 (0.399 g, 3.8 mmol) to afford 0.350 g of the desired product.
  • Step-3 - Preparation of 2-chloro-4'-(lH-imidazol-l-yl)-[l, -biphenyl]-4-carbonitrile
  • Step-1 - Preparation of 4'-bromo-2-methyl-[ 1,1 '-biphenyl] -4-carbonitrile
  • Step-2 - Preparation of 4'-(lH-imidazol- l-yl)-2-methyl-[l, -biphenyl]-4-carbonitrile
  • Step- 1 using 4'-bromo-2-methyl-[l, -biphenyl]-4-carbonitrile (Step- 1, intermediate- 10, 1.00 g, 3.86 mmol), imidazole (0.787 g, 11.58 mmol), Cul (0.073 g, 0.386 mmol), K 2 C0 3 (0.694 g, 3.86 mmol) and 1,10-phenanthroline (0.053 g, 0.386 mmol) to afford 0.600 g of the desired product.
  • Step-2 - Preparation of 4'-iodo-2'-(trifluoromethyl)-[l, -biphenyl]-4-carbonitrile
  • Step-3 - Preparation of 4'-(lH-imidazol-l-yl)-2'-(trifluoromethyl)-[l, -biphenyl]-4- carbonitrile
  • the title compound was prepared according to the procedure described in step-2 of Intermediate- 1 using 4'-iodo-2'-(trifluoromethyl)-[l, -biphenyl]-4-carbonitrile (0.200 g, 0.53 mmol), imidazole ( 0.109 g, 1.60 mmol), Cul (0.010 g, 0.053 mmol), K 2 C0 3 (0.095 g, 0.53 mmol) and 1,10- phenanthroline (0.007 g, 0.053 mmol) to afford 0.100 g of the desired product.
  • Step-1 Preparation of 4-(5-bromopyridin-2-yl)benzonitrile
  • Step-2 - Preparation of 4-(5-(lH-imidazol- l-yl)pyridin-2-yl)benzonitrile
  • Step-1 Preparation of 4-bromo-l-iodo-2-methylbenzene
  • Step-2 - Preparation of 4'-bromo-2'-methyl-[l, -biphenyl]-4-carboxylic acid
  • Step-2 - Preparation of 4-(5-(lH-imidazol- l-yl)-3-methylpyridin-2-yl)benzonitrile
  • Step-1 - Preparation of 4'-bromo-2'-methyl-[l, -biphenyl]-4-carbonitrile
  • step- 1 of Intermediate- 13 4-bromo- l-iodo-2-methylbenzene (step- 1 of Intermediate- 13, 2.00 g, 6.7 mmol) and 4-(cyanophenyl)boronic acid (0.791 g, 5.3 mmol), tetrakis(triphenylphosphine)Pd(0) (0.194 g, 0.168 mmol) and aq. Na 2 C0 3 (1.42 g, 13.4 mmol) to afford 0.700 g of the desired product.
  • Step-2 - Preparation of 4'-(lH-imidazol- l-yl)-2'-methyl-[l, -biphenyl]-4-carbonitrile
  • the title compound was prepared according to the procedure described in step-2 of Intermediate- 1 using 4'-bromo-2'-methyl-[l, -biphenyl]-4-carbonitrile (0.722 g, 2.67 mmol), imidazole (0.545 g, 8.02 mmol), Cul (0.504 g, 2.67 mmol), K 2 C0 3 (0.736 g, 5.3 mmol) and 1, 10-phenanthroline (0.240 g, 1.3 mmol) to afford 0.350g of the desired product.
  • MS [M+H] + 260.31.
  • Step-1 - Preparation of 4-(3-chloro-5-nitropyridin-2-yl)benzonitrile
  • Step-4 - Preparation of 4-(3-chloro-5-(lH-imidazol-l-yl)pyridin-2-yl)benzonitrile
  • Step-1 Preparation of 6-(4-bromophenyl)nicotinonitrile
  • Step-2 - Preparation of 6-(4-(lH-imidazol- l-yl)phenyl)nicotinonitrile
  • the title compound was prepared according to the procedure described in step-2 of Intermediate- 1 using 6-(4-bromophenyl)nicotinonitrile (0.600 g, 2.3 mmol), imidazole (0.472 g, 6.9 mmol), Cul ( 0.219 g, 1.15 mmol), K 2 C0 3 (0.637 g, 4.62 mmol), and 1,10-phenanthroline (0.207 g, 0.115 mmol) to afford 0.350 g of the desired product.
  • Step-1 Preparation of 4-(5-bromopyrimidin-2-yl)benzonitrile
  • Step-2 - Preparation of 4-(5-(lH-imidazol- l-yl)pyrimidin-2-yl)benzonitrile
  • the title compound was prepared according to the procedure described in step-2 of Intermediate- 1 using 4-(5-bromopyrimidin-2-yl)benzonitrile (0.250 g, 0.96 mmol), imidazole (0.196 g, 2.8 mmol), Cul (0.096 g, 0.48 mmol), K 2 C0 3 (0.266 g, 1.9 mmol) and 1,10-phenanthroline (0.207 g, 0.48 mmol) to afford 0.050 g of the desired product.
  • 1H NMR 300 MHz, DMSO-d 6 ): ⁇ 9.39 (s, 2H), 8.54 (m, 3H), 8.02 (m, 3H), 7.23 (s,lH).
  • Step-2 - Preparation of 4-(5-(lH-imidazol-l-yl)-3-methylpyridin-2-yl)-3- fluorobenzonitrile
  • Step-2 - Preparation of 4'-amino-2-chloro-[l, -biphenyl]-4-carbonitrile
  • Step-1 - Preparation of phenyl (2'-chloro-4'-cyano-[l, -biphenyl]-4-yl)carbamate
  • Step-2 Preparation of l-(2'-chloro-4'-cyano-[l,l'-biphenyl]-4-yl)-3-(2,2- dimethoxyethyl)urea
  • the title compound was prepared according to the procedure described in step-1 using phenyl (2'-chloro-4'-cyano-[l, -biphenyl]-4-yl)carbamate (180 mg, 0.516 mmol), pyridine (48.9 mg, 0.619 mmol), dimethoxy ethyl amine (65.0 mg, 0.619 mmol) in EtOAc (5.0 mL) to afford 200 mg of the title product.
  • Step-3 - Preparation of 2-chloro-4'-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-[l,l'- biphenyl] -4-carbonitrile
  • MeOH 5.0 mL
  • 0.5 N HC1 5.0 mL
  • the reaction mixture was stirred at rt for 16 h.
  • the reaction mixture was concentrated under reduced pressure to afford 300 mg of the title compound.
  • Step-1 - Preperation of 2-chloro-4'-isocyanato-[l, -biphenyl]-4-carbonitrile
  • Step- 1 -Preperation of 4-(5-bromo-3-nitropyridin-2-yl)benzonitrile
  • Step-2 -Preperation of 4-(5-(lH-imidazol-l-yl)-3-nitropyridin-2-yl)benzonitrile
  • Step-3 -Preperation of 4-(3-amino-5-(lH-imidazol- l-yl)pyridin-2-yl)benzonitrile
  • the title compound was prepared following the procedure described in step-3 of Intermediate- 5 by using 4-(5-(lH-imidazol- l-yl)-3-nitropyridin-2-yl)benzonitrile (0.400 g), cone. HC1 (0.5 mL) and Fe powder (0.200 g) in methanol (5.0 mL) to afford 0.300 g of title product.
  • Step-4 -Preperation of 4-(5-(lH-imidazol-l-yl)-3-iodopyridin-2-yl)benzonitrile
  • Step-5 -Preperation of 4-(3-cyclopropyl-5-(lH-imidazol- l-yl)pyridin-2- yl)benzonitrile
  • Step- 1 -Preperation of 4-(3-chloro-5-nitropyridin-2-yl)-3-fluorobenzaldehyde
  • Step-2 -Preperation of (E)-4-(3-chloro-5-nitropyridin-2-yl)-3-fluorobenzaldehyde oxime
  • Step-3 -Preperation of 4-(3-chloro-5-nitropyridin-2-yl)-3-fluorobenzonitrile
  • Step-6 -Preperation of 4-(3-chloro-5-(lH-imidazol-l-yl)pyridin-2-yl)-3- fluorobenzonitrile
  • Step- 1 -Preperation of 4-(3-chloro-5-nitropyridin-2-yl)-3-methylbenzonitrile
  • Step-2 -Preperation of 4-(5-amino-3-chloropyridin-2-yl)-3-methylbenzonitrile
  • Step-4 -Preperation of 4-(3-chloro-5-(lH-imidazol-l-yl)pyridin-2-yl)-3- methylbenzonitrile
  • Step 1 - Preperation of (E)-methyl 3-(2-amino-5-cyanophenyl)acrylate
  • Step 3 Preperation of methyl 3-(5-cyano-2-iodophenyl)propanoate
  • Step-6 -Preperation of 4'-bromo-2-(3-ethoxypropyl)-[l, -biphenyl]-4-carbonitrile
  • Step-1 - Preperation of 4'-bromo-2'-ethyl-2-fluoro-[l, -biphenyl]-4-carbonitrile
  • Step-1 - Preperation of 4-(5-bromopyridin-2-yl)-3-methylbenzonitrile
  • the title compound was prepared according to the procedure described in step-2 of Intermediate- 1 using 2,5-dibromopyridine (853 mg, 3.60 mmol), (4-cyano-2- methylphenyl)boronic acid (580 mg, 3.60 mmol), tetrakis(triphenylphosphine)Pd(0) (0.104 g, 0.025 mmol), aq. Na 2 C0 3 (576 mg, 7.20 mmol in 2 mL water) in THF (10 mL) to afford 200 mg of desired product.
  • Step-2 - Preperation of 4-(5-(lH-imidazol- l-yl)pyridin-2-yl)-3-methylbenzonitrile
  • Step-1 - Preperation of 4-(5-bromopyridin-2-yl)-3-fluorobenzonitrile
  • Step-2 - Preperation of 4-(5-(lH-imidazol-l-yl)pyridin-2-yl)-3-fluorobenzonitrile
  • Step-2 - Preperation of 4-amino-3-(4-ethoxybut-l-yn-l-yl)benzonitrile
  • Step-1 - Preperation of 4'-bromo-2-chloro-[l, -biphenyl]-4-carbonitrile
  • Step-2 - Preperation of (2'-chloro-4'-cyano-[l, l'-biphenyl]-4-yl)boronic acid
  • Toluene (1 :2; 50 mL) was added tri-isopropyl borate (1.5 g, 8.20 mmol) at - 70°C followed by addition on n-BuLi (0.525 g, 8.2 mmol) at same temperature.
  • the reaction mixture was stirred at -70°C for 2 h.
  • Step-3 - Preperation of 2-chloro-4'-(5-oxo-4,5-dihydro- lH-imidazol- l-yl)-[l, l' biphenyl] -4-carbonitrile
  • (2'-chloro-4'-cyano-[l, -biphenyl]-4-yl)boronic acid 1.0 g, 3.88 mmol
  • lH-imidazol-5(4H)-one Intermediate-33, 0.326 g, 3.88 mmol
  • DCM 50 mL
  • molecular sieves Cu(OAc) 2 (1.54 g, 7.76 mmol), Et 3 N (0.979 g, 9.69 mmol).
  • step- 1 The title compound was prepared according to the procedure described in step-2 of Intermediate- 1 using 4'-bromo-2-chloro-[l, -biphenyl]-4-carbonitrile (step- 1, Intermediate-34, 500 mg, 1.71 mmol), 2-methyl- lH- imidazole (140 mg, 1.70 mmol), Cul (161 mg, 0.847 mmol), K 2 C0 3 (468 mg, 3.39 mmol), 1,10-phenanthroline (153 mg, 0.847 mmol) in DMSO (5.0 mL) to afford 100 mg of the desired product.
  • Step-1 - Preperation of 3-chloro-4-(6-chloropyridin-3-yl)benzonitrile
  • the title compound was prepared according to the procedure described in step-2 of Intermediate- 1 using 3-chloro-4-iodobenzonitrile (667 mg, 2.53 mmol), (6- chloropyridin-3-yl)boronic acid (330 mg, 2.09 mmol), tetrakis(triphenylphosphine)Pd(0) (60 mg, 0.051 mmol) and aq. Na 2 C0 3 (443 mg, 4.17 mmol) to afford 200 mg of the title product.
  • Step-2 - Preperation of 4-(5-(lH-imidazol- l-yl)pyridin-2-yl)-3-chlorobenzonitrile
  • Step-1 - Preperation of 5-(lH-imidazol- l-yl)-2-nitroaniline
  • Step-2 - Preperation of l-(3-iodo-4-nitrophenyl)-lH-imidazole
  • Step-3 - Preperation of 3-(5-(lH-imidazol- l-yl)-2-nitrophenyl)prop-2-yn- l-ol
  • Step-4 - Preperation of 3-(2-amino-5-(lH-imidazol- l-yl)phenyl)propan- l-ol
  • Step-5 - Preperation of 3-(5-(lH-imidazol-l-yl)-2-iodophenyl)propan- l-ol
  • Step-6 - Preperation of 2'-(3-hydroxypropyl)-4'-(lH-imidazol- l-yl)-[l,l'-biphenyl]-4- carbonitrile
  • Step-7 - Preperation of 2'-(3-fluoropropyl)-4'-(lH-imidazol-l-yl)-[l, -biphenyl]-4- carbonitrile
  • Step 4 Preparation of 2'-(2-hydroxyethyl)-4'-nitro-[l, -biphenyl]-4-carbonitrile
  • Step 7 Preparation of 2'-(2-hydroxyethyl)-4'-(lH-imidazol-l-yl)-[l, l'-biphenyl]-4- carbonitrile
  • Step 1 Preparation of 2'-(3-hydroxypropyl)-4'-(2-methyl- lH-imidazol- l-yl)-[l, - biphenyl] -4-carbonitrile
  • Step 2 Preparation of 2'-(3-fluoropropyl)-4'-(2-methyl-lH-imidazol- l-yl)-[l,r- biphenyl] -4-carbonitrile
  • the title compound was prepared following the procedure described in step-7 of Intermediate- 37 by using 2'-(3-hydroxypropyl)-4'-(2-methyl- lH-imidazol-l-yl)-[l, - biphenyl] -4-carbonitrile (65 mg, 0.20 mmol), DCM (5 mL), DAST (49.5 mg,0.030 mmol) at -60°C to afford 40 mg of title product.
  • Step 1 - Preparation of 3-(5-cyano-2-iodophenyl)propyl methanesulfonate
  • step-4 To a solution of 3-(3-hydroxypropyl)-4-iodobenzonitrile (step-4, Intermediate-27, 1.2 g, 4.18 mmol) in DCM (30 mL) was added Et 3 N (0.63 mL, 4.39 mmol), mesyl chloride (0.35 mL, 4.39 mmol) at 0°C. The reaction mass was stirred at rt for 24 h. The reaction mass was quenched with water, extracted with DCM. The organic layers were dried over Na 2 S0 4 and concentrated to afford 1.0 g of title compound. .
  • Step 2 - Preparation of 4-Iodo-3-(3-(2-methyl- lH-imidazol-l-yl)propyl)benzonitrile
  • Step 3 - Preparation of 4'-bromo-2-(3-(2-methyl- lH-imidazol- l-yl)propyl)-[l, l'- biphenyl] -4-carbonitrile
  • Step 4 - Preparation of 4'-(lH-imidazol-l-yl)-2-(3-(2-methyl- lH-imidazol-l- yl)propyl)- [1,1 '-biphenyl] -4-carbonitrile
  • Step 1 - Preparation of 3-(4'-cyano-4-(lH-imidazol-l-yl)-[l,l'-biphenyl]-2-yl)propyl methanesulfonate
  • step-6 Intermediate-37, 200 mg, 0.66 mmol
  • Et 3 N 1.0 mL
  • DCM 5.0 mL
  • methansulfonyl chloride 0.5 ml
  • Step 2 - Preparation of 4'-(lH-imidazol-l-yl)-2'-(3-((6-methylpyridin-3- yl)oxy)propyl)- [ 1 , 1 '-biphenyl] -4-carbonitrile
  • Step 2 - Preparation of 2,3-dibromo-5-nitropyridine
  • PBr 3 5.52 g, 0.020 mol
  • DCM 20 mL
  • Br 2 2.18 g, 0.013 mol
  • 3- bromo-5-nitropyridin-2-ol 3.0 g, 0.013 mol
  • the reaction mass was filtered to afford 2.2 g of title compound.
  • Step 3 - Preparation of 4-(3-bromo-5-nitropyridin-2-yl)benzonitrile
  • Step 4 - Preparation of 4-(3-(3-hydroxyprop-l-yn-l-yl)-5-nitropyridin-2- yl)benzonitrile
  • Step 8 - Preparation of 4-(3-(3-fluoropropyl)-5-(lH-imidazol- l-yl)pyridin-2- yl)benzonitrile
  • Step 1 - Preparation of 4'-bromo-2'-ethyl-[l, -biphenyl]-4-carbonitrile
  • Step 2 - Preparation of 2'-ethyl-4'-(2-methyl-lH-imidazol-l-yl)-[l,r-biphenyl]-4- carbonitrile
  • the title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using 4'-bromo-2'-ethyl-[l, -biphenyl]-4-carbonitrile (500 mg, 1.74 mmol), DMSO (3 mL), 2-methyl-lH-imidazole (430 mg, 5.20 mmol), Cul (165 mg, 0.870 mmol), K 2 CO 3 (360 mg, 2.6 mmol) and 1,10 phenanthroline (156 mg, 0.870 mmol) to afford 50 mg of title product.
  • Step 2 - Preparation of 4'-bromo-2-chloro-6-methyl-[l, l'-biphenyl]-4-carbonitrile
  • Step 3 Preparation of 2-chloro-6-methyl-4'-(2-methyl- lH-imidazol-l-yl)-[ l,l'- biphenyl] -4-carbonitrile
  • the title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using 4'-bromo-2-chloro-6-methyl-[l, -biphenyl]-4-carbonitrile (150 mg, 0.480 mmol), DMSO (3 mL), 2-methyl-lH-imidazole (120 mg, 1.46 mmol), Cul (46 mg, 0.240 mmol), K 2 C0 3 (99 mg, 0.71 mmol) and 1, 10-phenanthroline (43 mg, 0.24 mmol) to afford 40 mg of title product.
  • Step 1 - Preparation of 2'-(2-hydroxyethyl)-4'-(2-methyl- lH-imidazol- l-yl)-[l,r- biphenyl] -4-carbonitrile
  • Step 2 - Preparation of 2'-(2-fluoroethyl)-4'-(2-methyl-lH-imidazol- l-yl)-[l,r- biphenyl] -4-carbonitrile
  • Step 5 - Preparation of 2'-(hydroxymethyl)-4'-iodo-[l, -biphenyl]-4-carbonitrile
  • Step 1 - Preparation of 4'-bromo-2-chloro-2'-methyl-[ 1, 1 '-biphenyl] -4-carbonitrile
  • Step 2 - Preparation 2-chloro-4'-(lH-imidazol- l-yl)-2'-methyl-[l, -biphenyl]-4- carbonitrile
  • Step 1 - Preparation of 2-(4'-cyano-4-(lH-imidazol-l-yl)-[l, -biphenyl]-2-yl)acetic acid
  • Step 5 - Preparation of 4-(3-ethyl-5-(lH-imidazol- l-yl)pyridin-2-yl)benzonitrile
  • Step 1 - Preparation of 4'-bromo-2-(3-hydroxypropyl)-[l, -biphenyl]-4-carbonitrile
  • step-4 Intermediate- 27, 200 mg, 0.68 mmol
  • (4-bromophenyl)boronic acid 138 g, 0.69 mol
  • Pd(dppf)Cl 2 27 mg, 0.03 mmol
  • aq. K 2 C0 3 187 mg, 1.36 mmol
  • 1,4-dioxane 10 mL
  • Step 3 - Preparation of 4'-amino-2',6'-dichloro-[l, -biphenyl]-4-carbonitrile
  • Step 4 - Preparation of 2',6'-dichloro-4'-iodo-[l, -biphenyl]-4-carbonitrile
  • Step 5 - Preparation of 2',6'-dichloro-4'-(lH-imidazol-l-yl)-[l, -biphenyl]-4- carbonitrile
  • Step 2 Preparation of ie/ -butyl (3-(2-amino-5-cyanophenyl)prop-2-yn-l- yl)carbamate
  • Step 2 Preparation of ie/ -butyl (3-(2-amino-5-cyanophenyl)propyl)carbamate

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Abstract

La présente invention concerne des composés de formule (Ie) et les sels pharmaceutiquement acceptables de ceux-ci, dans lesquels A, B, R1, R2, m, n, X1, X2, X3 et X4 sont tels que définis dans la description, qui sont actifs en tant qu'inhibiteurs de la S-nitrosoglutathion réductase (GSNOR). Ces composés préviennent, inhibent ou suppriment l'action de la GSNOR et sont par conséquent utiles dans le traitement des maladies, des troubles, des syndromes ou des états médiés par la GSNOR tels que, par exemple, l'hypertension pulmonaire, le syndrome de détresse respiratoire aiguë (ARDS), l'asthme, le bronchospasme, la toux, la pneumonie, la fibrose pulmonaire, les maladies pulmonaires interstitielles, la fibrose kystique et la broncho-pneumopathie chronique obstructive (BPCO).
PCT/IB2015/057356 2014-09-26 2015-09-24 Composés imidazole biaryle en tant qu'inhibiteurs de la s-nitrosoglutathion réductase WO2016046782A1 (fr)

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WO2018018091A1 (fr) 2016-07-28 2018-02-01 Vectus Biosystems Limited Compositions pour le traitement d'une fibrose pulmonaire

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011017350A2 (fr) * 2009-08-04 2011-02-10 Amira Pharmaceuticals, Inc. Composés en tant qu'antagonistes du récepteur de l'acide lysophosphatidique
WO2012078593A2 (fr) * 2010-12-07 2012-06-14 Amira Pharmaceuticals, Inc. Antagonistes des récepteurs de l'acide lysophosphatidique et utilisations de ceux-ci
WO2012170371A1 (fr) * 2011-06-10 2012-12-13 N30 Pharmaceuticals, Llc Composés en tant qu'inhibiteurs de la s-nitrosoglutathion réductase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011017350A2 (fr) * 2009-08-04 2011-02-10 Amira Pharmaceuticals, Inc. Composés en tant qu'antagonistes du récepteur de l'acide lysophosphatidique
WO2012078593A2 (fr) * 2010-12-07 2012-06-14 Amira Pharmaceuticals, Inc. Antagonistes des récepteurs de l'acide lysophosphatidique et utilisations de ceux-ci
WO2012170371A1 (fr) * 2011-06-10 2012-12-13 N30 Pharmaceuticals, Llc Composés en tant qu'inhibiteurs de la s-nitrosoglutathion réductase

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018018091A1 (fr) 2016-07-28 2018-02-01 Vectus Biosystems Limited Compositions pour le traitement d'une fibrose pulmonaire
KR20190036550A (ko) * 2016-07-28 2019-04-04 벡투스 바이오시스템즈 리미티드 폐 섬유증 치료용 조성물
CN109661387A (zh) * 2016-07-28 2019-04-19 维克图斯生物系统有限公司 用于治疗肺纤维化的组合物
AU2017301113B2 (en) * 2016-07-28 2019-08-08 Vectus Biosystems Limited Compositions for the treatment of pulmonary fibrosis
EP3490970A4 (fr) * 2016-07-28 2020-07-22 Vectus Biosystems Limited Compositions pour le traitement d'une fibrose pulmonaire
US10919863B2 (en) 2016-07-28 2021-02-16 Vectus Biosystems Limited Compositions for the treatment of pulmonary fibrosis
RU2747801C2 (ru) * 2016-07-28 2021-05-14 Вектус Байосистемс Лимитед Композиции для лечения легочного фиброза
KR102377981B1 (ko) * 2016-07-28 2022-03-23 벡투스 바이오시스템즈 리미티드 폐 섬유증 치료용 조성물
US11401245B2 (en) 2016-07-28 2022-08-02 Vectus Biosystems Limited Compositions for the treatment of pulmonary fibrosis

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