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WO2016128905A1 - Thienopyrrole compounds as s-nitrosoglutathione reductase inhibitors - Google Patents

Thienopyrrole compounds as s-nitrosoglutathione reductase inhibitors Download PDF

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Publication number
WO2016128905A1
WO2016128905A1 PCT/IB2016/050695 IB2016050695W WO2016128905A1 WO 2016128905 A1 WO2016128905 A1 WO 2016128905A1 IB 2016050695 W IB2016050695 W IB 2016050695W WO 2016128905 A1 WO2016128905 A1 WO 2016128905A1
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WIPO (PCT)
Prior art keywords
thieno
pyrrole
carboxylic acid
imidazol
methyl
Prior art date
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PCT/IB2016/050695
Other languages
French (fr)
Inventor
Abhisek Banerjee
Laxmikant Atmaram Gharat
Neelima Khairatkar-Joshi
Daisy Manish Shah
Sheetal R KADAM
Original Assignee
Glenmark Pharmaceuticals S.A.
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Publication of WO2016128905A1 publication Critical patent/WO2016128905A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present patent application is directed to Thienopyrrole 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 5-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 5-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 S- 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 anti-inflammatory responses in the respiratory tract (Snyder et al., Am. J. Respir. Crit.
  • 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., J Appl Physiol., 2013, 114(6), 752-760).
  • COPD chronic obstructive pulmonary disease
  • 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). SUMMARY OF THE INVENTION
  • the present invention relates to compound of formula (I)
  • P is selected from phenyl and 5 or 6 membered heteroaryl
  • A is selected from
  • one of X is S and the other is CR 4 ; the dotted line indicates a bond that commences at CR 4 ;
  • R a is selected from hydrogen, Ci_ 8 alkyl, Ci_ 8 alkoxyCi_ 8 alkyl, -(CR c R d ) y OC(0)R c and - (CH 2 ) y C(0)OR c ;
  • R b and R b are independently selected from hydrogen, cyano, Ci_ 8 alkyl and C 6-14 aryl; at each occurrence, R 1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, Ci_ 8 alkyl, C 2 _ioalkenyl, C 2 _ioalkynyl, 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, C 3 _ 8 cycloalkenyl, C 3 _ 8cycloalkenylCi_ 8 alkyl, C 6 -i 4 aryl, C 6 -i 4 aryloxy, C 6 -i 4 arylCi_ 8 alkyl, 3 to 15 membered heterocycly
  • R is selected from Ci_ 8 alkyl, Ci_ 8 alkoxy, Ci_ 8 alkoxyCi_ 8 alkyl, hydroxyCi_ 8 alkyl, haloCi-salkyl, -(CH 2 ) y C(0)R c , -C(0)(CH 2 ) y R c , -(CH 2 ) y C(0)NR c R d , -(CH 2 ) y C(0)OR c , - (CH 2 ) y CHR c R d , -(CH 2 ) y NR c R d , -(CH 2 ) y NR c C(0)R d , -(CR c R d ) y OR c , -(CH 2 ) y S(0) z R c , - (CR c R d ) y O(CR c R d ) y SiR c R c R c , C 3 -i
  • R 6 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carbamoyl, Ci_ 8 alkyl, C 2 -ioalkenyl, C 2 -ioalkynyl, 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, C 3 _ scycloalkenyl, C 3 _ 8 cycloalkenylCi_ 8 alkyl, C 6 -i 4 aryl, C 6 -i 4 aryloxy, C 6 -i 4 arylCi_ 8 alkyl, 3 to 15 membered heterocyclyl, 3 to 15 membered heterocyclylCi_ 8 alkyl, 5 to 15 membere
  • R 4 is selected from hydrogen, halogen, Ci_ 8 alkyl, Ci_ 8 alkoxy, Ci_ 8 alkoxyCi_ 8 alkyl, hydroxyCi_ 8 alkyl, haloCi_ 8 alkyl, haloCi_ 8 alkoxy and C 3 _i 2 cycloalkyl;
  • R 5 is selected from hydrogen, halogen, amino, Ci_ 8 alkyl, C 2 -ioalkenyl, C 2 -ioalkynyl, 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, C 3 _ 8 cycloalkenyl, C 3 _ 8 cycloalkenylCi_ 8 alkyl, -(CH 2 ) y C(0)R c , - (CH 2 ) y C(0)NR c R d , -(CH 2 ) y C(0)OR c , -(CH 2 ) y CHR c R d , -(CH 2 ) y NR c R d , -(CH 2
  • R c and R d are independently selected from hydrogen, halogen, hydroxyl, nitro, amino, cyano, Ci_ 8 alkyl, C 2 -ioalkenyl, C 2 -ioalkynyl, Ci_ 8 alkoxy, Ci_ 8 alkoxyCi_ galkyl, hydroxyCi_ 8 alkyl, haloCi_ 8 alkyl, haloCi_ 8 alkoxy, C 3 _i 2 cycloalkyl, C 3 -i 2 cycloalkylCi- galkyl, C 3 _ 8 cycloalkenyl, C 3 _ 8 cycloalkenylCi_ 8 alkyl, C 6 -i 4 aryl, C 6 -i 4 aryloxy, C 6 -i 4 arylCi_ 8 alkyl, 3 to 15 membered heterocyclyl, 3 to 15 membered heterocyclylCi_ 8 alkyl, 5 to 15 membered
  • n is selected from '0' to '3', both inclusive;
  • y is selected from '0' to '6', both inclusive;
  • z is selected from '0' to '2', both inclusive.
  • the invention also provides a compound of formula (la)
  • W is independently selected from N, CR 1 and CH;
  • A is selected from
  • one of X is S and the other is CR 4 ; the dotted line indicates a bond that commences at
  • R a is selected from hydrogen, Ci_ 8 alkyl, -(CR c R d ) y OC(0)R c and -(CH 2 ) y C(0)OR c ;
  • R b and R b are independently selected from hydrogen, cyano, Ci_ 8 alkyl and C 6-14 aryl; at each occurrence, R 1 is independently selected from halogen, hydroxyl, Ci_ 8 alkyl, Ci_ 8alkoxy and haloCi_ 8 alkyl;
  • R is Ci_ 8 alkyl
  • R is selected from Ci_ 8 alkyl, Ci_ 8 alkoxyCi_ 8 alkyl, hydroxyCi_ 8 alkyl, (CH 2 ) y C(0)NR c R d , -(CH 2 )yNR c R d , -(CR c R d ) y OR c , -(CR c R d ) y O(CR c R d ) y SiR c R c R c , C 3 _ i 2 cycloalkylCi_ 8 alkyl, C 6 -i 4 aryl, C 6 -i 4 arylCi_ 8 alkyl, 3 to 15 membered heterocyclylCi_ 8 alkyl, 5 to 15 membered heteroaryl and 5 to 15 membered heteroarylCi_ 8 alkyl each of which being optionally substituted by one or more R 6 ;
  • R 6 is independently selected from halogen, hydroxyl, cyano, carbamoyl, Ci_ 8 alkyl, Ci_ 8 alkoxy, hydroxyCi_ 8 alkyl, haloCi_ 8 alkyl, 5 to 15 membered heteroaryl, -(CH 2 ) y C(0)NR e R f , -(CH 2 ) y NR e C(0)R f , -0(CR e R f ) y R e and -S(0) z R e ; or two R 6 together with the 'C atom to which they are attached, form a C 3 _i 2 cycloalkyl ring or a 3 to 15 membered heterocyclyl ring;
  • R 4 is selected from hydrogen, and Ci_ 8 alkyl
  • R 5 is selected from hydrogen, Ci_ 8 alkyl and C 3 _i 2 cycloalkyl
  • R c and R d are independently selected from hydrogen, Ci_ 8 alkyl and 5 to 15 membered heteroaryl;
  • R e and R f are independently selected from hydrogen, hydroxyl, Ci_ 8 alkyl and C 6 -i 4 aryl; wherein C 6 -i 4 aryl is optionally substituted by hydroxyl;
  • n is selected from '0' to '4', both inclusive;
  • n is selected from '0' to '3', both inclusive;
  • y is selected from '0' to '6', both inclusive;
  • z is selected from '0' to '2', both inclusive.
  • the invention also provides a compound of formula (lb)
  • A is selected from
  • R a is selected from hydrogen, Ci_ 8 alkyl, -(CR c R d ) y OC(0)R c and -(CH 2 ) y C(0)OR c ; at each occurrence, R 1 is independently selected from halogen, hydroxyl, Ci_ 8 alkyl, Ci_
  • R is Ci_ 8 alkyl
  • R is selected from Ci_ 8 alkyl, Ci_ 8 alkoxyCi_ 8 alkyl, hydroxyCi_ 8 alkyl, (CH 2 ) y C(0)NR c R d , -(CH 2 ) y NR c R d , -(CR c R d ) y OR c , -(CR c R d ) y O(CR c R d ) y SiR c R c R c , C 3 _ i 2 cycloalkylCi_ 8 alkyl, C 6 -i 4 aryl, C 6 -i 4 arylCi_ 8 alkyl, 3 to 15 membered heterocyclylCi_ 8 alkyl, 5 to 15 membered heteroaryl and 5 to 15 membered heteroarylCi- 8 alkyl each of which being optionally substituted by one or more R 6 ;
  • R 6 is independently selected from halogen, hydroxyl, cyano, carbamoyl, Ci_ 8 alkyl, Ci_ 8 alkoxy, hydroxyCi_ 8 alkyl, haloCi_ 8 alkyl, 5 to 15 membered heteroaryl, -(CH 2 ) y C(0)NR e R f , -(CH 2 ) y NR e C(0)R f , -0(CR e R f ) y R e and -S(0) z R e ; or two R 6 together with the 'C atom to which they are attached, form a C 3 _i 2 cycloalkyl ring or a 3 to 15 membered heterocyclyl ring;
  • R 5 is selected from hydrogen, Ci_ 8 alkyl and C 3 _i 2 cycloalkyl;
  • R c and R d are independently selected from hydrogen, Ci_ 8 alkyl and 5 to 15 membered heteroaryl;
  • R e and R f are independently selected from hydrogen, hydroxyl, Ci_ 8 alkyl and C 6-14 aryl; wherein C6 i 4 aryl is optionally substituted by hydroxyl;
  • n is selected from '0' to '4', both inclusive;
  • n is selected from '0' to '3', both inclusive;
  • y is selected from '0' to '6', both inclusive;
  • z is selected from '0' to '2', both inclusive.
  • the compounds of formula (lb) 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. For example, the invention provides compounds of formula (lb) as defined
  • R is Ci-galkyl (e.g. methyl) and n is 0 or 1.
  • R 2 is methyl and n is 0 or 1.
  • R a is selected from hydrogen, Ci_ 8 alkyl (e.g. methyl or ethyl), -(CR c R d ) y OC(0)R c (e.g. (Pivaloyloxy)methyl) and -(CH 2 ) y C(0)OR c (e.g. 2- Ethoxy-2-oxoethyl).
  • R a is selected from hydrogen, Ci_ 8 alkyl (e.g. methyl or ethyl), -(CR c R d ) y OC(0)R c (e.g. (Pivaloyloxy)methyl) and -(CH 2 ) y C(0)OR c (e.g. 2- Ethoxy-2-oxoethyl), R c is hydrogen or Ci_ 8 alkyl (e.g. ethyl or tert-butyl), R d is hydrogen and y is 1.
  • R a is selected from hydrogen, methyl, ethyl, (Pivaloyloxy)methyl and 2-Ethoxy-2-oxoethyl.
  • R a is selected from hydrogen, Ci_ 8 alkyl (e.g. methyl or ethyl), - (CR c R d ) y OC(0)R c (e.g. (Pivaloyloxy)methyl) and -(CH 2 ) y C(0)OR c (e.g. 2-Ethoxy-2- oxoethyl).
  • R a is selected from hydrogen, Ci_ 8 alkyl (e.g. methyl or ethyl), - (CR c R d ) y OC(0)R c (e.g. (Pivaloyloxy)methyl) and -(CH 2 ) y C(0)OR c (e.g. 2-Ethoxy-2- oxoethyl).
  • R c is hydrogen or Ci_ 8 alkyl (e.g. ethyl or tert-butyl)
  • R d is hydrogen and y is 1.
  • R a is selected from hydrogen, methyl, ethyl, (Pivaloyloxy)methyl and 2-Ethoxy-2-oxoethyl.
  • R 1 is independently selected from hydroxyl, Ci-galkyl (e.g. methyl or ethyl), Ci-galkoxy (e.g. methoxy), halogen (e.g. chloro, bromo or fluoro) and haloCi-galkyl (e.g. trifluoromethyl).
  • R 1 is independently selected from hydroxyl, methyl, ethyl, methoxy, chloro, bromo, fluoro and trifluoromethyl.
  • R is selected from Ci_ 8 alkyl (e.g. methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl or heptyl), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. methyoxyethyl, or 3-methoxypropyl), hydroxyCi_ 8 alkyl (e.g.
  • Ci_ 8 alkyl e.g. methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl or heptyl
  • Ci_ 8 alkoxyCi_ 8 alkyl e.g. methyoxyethyl, or 3-methoxypropyl
  • hydroxyCi_ 8 alkyl e.g.
  • heterocyclylCi_ 8 alkyl e.g 4- morpholinobutyl, 4-(piperazin-l-yl)butyl, 4-(azetidin-l-yl)butyl, 3-(azetidin-l-yl)propyl or azetidin-l-ylethyl
  • heteroaryl e.g 4-oxo-3,4-dihydro-2H- benzo[e][l,3]oxazin-7-yl or 4-oxo-3,4-dihydroquinazolin-7-yl
  • heteroarylCi-galkyl e.g.
  • R is selected from Ci_ 8 alkyl (e.g. methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl or heptyl), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. methyoxyethyl, or 3-methoxypropyl), hydroxyCi_ 8 alkyl (e.g.
  • Ci_ 8 alkyl e.g. methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl or heptyl
  • Ci_ 8 alkoxyCi_ 8 alkyl e.g. methyoxyethyl, or 3-methoxypropyl
  • hydroxyCi_ 8 alkyl e.g.
  • heterocyclylCi_ 8 alkyl e.g 4- morpholinobutyl, 4-(piperazin-l-yl)butyl, 4-(azetidin-l-yl)butyl, 3-(azetidin-l-yl)propyl or azetidin-l-ylethyl
  • heteroaryl e.g 4-oxo-3,4-dihydro-2H- benzo[e][l,3]oxazin-7-yl or 4-oxo-3,4-dihydroquinazolin-7-yl
  • heteroarylCi_ 8 alkyl e.g.
  • R is selected from Ci_ 8 alkyl (e.g. methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl or heptyl), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. methyoxyethyl, or 3-methoxypropyl), hydroxyCi_ 8 alkyl (e.g.
  • Ci_ 8 alkyl e.g. methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl or heptyl
  • Ci_ 8 alkoxyCi_ 8 alkyl e.g. methyoxyethyl, or 3-methoxypropyl
  • hydroxyCi_ 8 alkyl e.g.
  • heterocyclylCi_ 8 alkyl e.g 4- morpholinobutyl, 4-(piperazin-l-yl)butyl, 4-(azetidin-l-yl)butyl, 3-(azetidin-l-yl)propyl or azetidin-l-ylethyl
  • heteroaryl e.g 4-oxo-3,4-dihydro-2H- benzo[e][l,3]oxazin-7-yl or 4-oxo-3,4-dihydroquinazolin-7-yl
  • heteroarylCi-galkyl e.g.
  • R c and R d are independently selected from hydrogen, Ci_ 4 alkyl (e.g. methyl or ethyl), 5 to 15 membered heteroaryl (e.g. 3- pyridyl or 4-pyridyl) and 'y' is 0, 1, 2, 3 or 4.
  • R is selected from C 1-8 alkyl (e.g. methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl or heptyl), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. methyoxyethyl, or 3-methoxypropyl), hydroxyCi_ 8 alkyl (e.g.
  • C 1-8 alkyl e.g. methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl or heptyl
  • Ci_ 8 alkoxyCi_ 8 alkyl e.g. methyoxyethyl, or 3-methoxypropyl
  • hydroxyCi_ 8 alkyl e.g.
  • heterocyclylCi_ 8 alkyl e.g 4- morpholinobutyl, 4-(piperazin-l-yl)butyl, 4-(azetidin-l-yl)butyl, 3-(azetidin-l-yl)propyl or azetidin-l-ylethyl
  • heteroaryl e.g 4-oxo-3,4-dihydro-2H- benzo[e][l,3]oxazin-7-yl or 4-oxo-3,4-dihydroquinazolin-7-yl
  • heteroarylCi- 8 alkyl e.g.
  • R c and R d are independently selected from hydrogen, methyl, ethyl, 3-pyridyl, 4-pyridyl and 'y' is 0, 1, 2, 3 or 4.
  • R is methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4- methylpentyl, hexyl, heptyl, methyoxyethyl, 3-methoxypropyl, 2-hydroxyethyl, 4- hydroxybutyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, 4- amino-4-oxobutyl, 2-(dimethylamino)ethyl, phenyl, cyclopropylmethyl, cyclohexylmethyl, benzyl, phenethyl, 4-morpholinobutyl, 4-(piperazin-l-yl)butyl, 4-(azetidin-l-yl)butyl, 3- (azetidin-l-yl)propyl, azetidin-l
  • R 6 is selected from cyano, hydroxyl, carbamoyl, halogen (e.g. chloro or fluoro), haloCi-galkyl (e.g. trifluoromethyl), Ci_ 8 alkyl (e.g. methyl or ethyl), Ci_ 8 alkoxy (e.g. methoxy, ethoxy or 3-isobutoxy), hydroxyCi_ 8 alkyl (e.g. 3-hydroxypropyl), 5 to 15 membered heteroaryl (e.g.
  • cyclohexyl or two R 6 together with the 'C atom to which they are attached, form a C 3 _ i 2 cycloalkyl ring (e.g. cyclohexyl) or a 3 to 15 membered heterocyclyl ring (e.g. tetrahydropyran) .
  • R 6 is selected from cyano, hydroxyl, carbamoyl, halogen (e.g. chloro or fluoro), haloCi_ 8 alkyl (e.g. trifluoromethyl), Ci_ 8 alkyl (e.g. methyl or ethyl), Ci_ 8 alkoxy (e.g. methoxy, ethoxy or 3-isobutoxy), hydroxyCi_ 8 alkyl (e.g. 3-hydroxypropyl), 5 to 15 membered heteroaryl (e.g.
  • R e and R f are independently selected from hydrogen, hydroxyl, Ci_ 4 alkyl (e.g. methyl, ethyl or isopropyl), C6 i 4 aryl optionally substituted by hydroxyl (e.g. 4-hydroxyphenyl), 5 to 15 membered heteroaryl (e.g. 3-pyridyl or 4-pyridyl), 'y' is 0, 1, 2, 3 or 4 and 'z' is 2.
  • R 6 is selected from cyano, hydroxyl, carbamoyl, halogen (e.g. chloro or fluoro), haloCi-galkyl (e.g. trifluoromethyl), Ci_ 8 alkyl (e.g. methyl or ethyl), Ci_ 8 alkoxy (e.g. methoxy, ethoxy or 3-isobutoxy), hydroxyCi_ 8 alkyl (e.g. 3-hydroxypropyl), 5 to 15 membered heteroaryl (e.g.
  • R e and R f are independently selected from hydrogen, hydroxyl, methyl, ethyl, isopropyl, 4-hydroxyphenyl, 3-pyridyl and 4-pyridyl), 'y' is 0, 1, 2, 3 or 4 and 'z' is 2.
  • R 6 is selected from cyano, hydroxyl, carbamoyl, chloro, fluoro, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, 3-isobutoxy, 3-hydroxypropyl, tetrazolyl, 5- oxo-2,5-dihydro- l,2,4-oxadiazol-3-yl, 4-hydroxybenzamido, acetamidomethyl, acetamido, isobutyramidomethyl, 2-hydroxyethoxy, methylsulfonyl and cyclohexyl or two R 6 together with the 'C atom to which they are attached, form cyclohexyl ring or a tetrahydropyran ring.
  • R is selected from Ci_ 8 alkyl (e.g. methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl or heptyl), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. methyoxyethyl or 3-methoxypropyl), hydroxyCi_ 8 alkyl (e.g.
  • Ci_ 8 alkyl e.g. methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl or heptyl
  • Ci_ 8 alkoxyCi_ 8 alkyl e.g. methyoxyethyl or 3-methoxypropyl
  • hydroxyCi_ 8 alkyl e.g.
  • C6-i 4 arylCi_ 8 alkyl e.g. benzyl, 3-carbamoylbenzyl, 4-carbamoylbenzyl, 4-(acetamidomethyl)benzyl, 3- (acetamidomethyl)benzyl, 4-carbamoyl-3-methoxybenzyl, 3-cyanobenzyl, 4-cyanobenzyl, 4- hydroxyphenethyl, 4-acetamidophenethyl or 4-(methylsulfonyl)phenethyl), 3 to 15 membered heterocyclylCi_ 8 alkyl (e.g 4-morpholinobutyl, 4-(4-methylpiperazin- l-yl)butyl, 2-(3- carbamoylazetidin- l-yl)ethyl, 4-(3-hydroxyazetidin- l-yl)butyl, 3-(3-
  • R is selected from Ci_ 8 alkyl (e.g. methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl or heptyl), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. methyoxyethyl or 3-methoxypropyl), hydroxyCi_ 8 alkyl (e.g.
  • Ci_ 8 alkyl e.g. methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl or heptyl
  • Ci_ 8 alkoxyCi_ 8 alkyl e.g. methyoxyethyl or 3-methoxypropyl
  • hydroxyCi_ 8 alkyl e.g.
  • C6-i 4 arylCi_ 8 alkyl e.g. benzyl, 3-carbamoylbenzyl, 4-carbamoylbenzyl, 4-(acetamidomethyl)benzyl, 3- (acetamidomethyl)benzyl, 4-carbamoyl-3-methoxybenzyl, 3-cyanobenzyl, 4-cyanobenzyl, 4- hydroxyphenethyl, 4-acetamidophenethyl or 4-(methylsulfonyl)phenethyl), 3 to 15 membered heterocyclylCi_ 8 alkyl (e.g 4-morpholinobutyl, 4-(4-methylpiperazin- l-yl)butyl, 2-(3- carbamoylazetidin- l-yl)ethyl, 4-(3-hydroxyazetidin- l-yl)butyl, 3-(3-
  • R c and R d are independently selected from hydrogen, Ci_ 4 alkyl (e.g. methyl or ethyl), 5 to 15 membered heteroaryl (e.g. 3-pyridyl or 4-pyridyl) and 'y' is 0, 1, 2, 3 or 4.
  • R is selected from Ci_ 8 alkyl (e.g. methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl or heptyl), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. methyoxyethyl or 3-methoxypropyl), hydroxyCi_ 8 alkyl (e.g.
  • Ci_ 8 alkyl e.g. methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl or heptyl
  • Ci_ 8 alkoxyCi_ 8 alkyl e.g. methyoxyethyl or 3-methoxypropyl
  • hydroxyCi_ 8 alkyl e.g.
  • R c and R d are independently selected from hydrogen, methyl, ethyl, 3-pyridyl, 4-pyridyl and 'y' is 0, 1, 2, 3 or 4.
  • R is selected from methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl, heptyl, methyoxyethyl, 3-methoxypropyl, 2-hydroxyethyl, 4- hydroxybutyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, 4- amino-4-oxobutyl, 2-(dimethylamino)ethyl, 4-carbamoyl-3-isobutoxyphenyl, 4-(5H- tetrazolyl-5-yl)phenyl, 4-(lH-tetrazol-5-yl)phenyl, 4-cyanophenyl, 4-carbamoylphenyl, 4- carbamoyl-3-chlorophenyl, 4-acetamido-2-methyl
  • R 5 is selected from hydrogen, Ci-galkyl (e.g. methyl or butyl) and C 3 _ i 2 cycloalkyl (e.g. cyclohexyl).
  • R 5 is selected from hydrogen, butyl and cyclohexyl.
  • R a is hydrogen, Ci_ 8 alkyl (e.g. methyl or ethyl), -(CR c R d ) y OC(0)R c (e.g. (Pivaloyloxy)methyl) or -(CH 2 ) y C(0)OR c (e.g. 2-Ethoxy-2-oxoethyl),
  • R 1 is hydroxyl, Ci_ 8 alkyl (e.g. methyl or ethyl), Ci_ 8 alkoxy (e.g. methoxy), halogen (e.g. chloro, bromo or fluoro) or haloCi_ 8 alkyl (e.g. trifluoromethyl),
  • Ci_ 8 alkyl e.g. methyl or ethyl
  • Ci_ 8 alkoxy e.g. methoxy
  • halogen e.g. chloro, bromo or fluoro
  • haloCi_ 8 alkyl e.g. trifluoromethyl
  • R is Ci_ 8 alkyl (e.g. methyl),
  • R is Ci- 8 alkyl (e.g. methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4- methylpentyl, hexyl or heptyl), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. methyoxyethyl, or 3-methoxypropyl), hydroxyCi_ 8 alkyl (e.g. 2-hydroxyethyl, 4-hydroxybutyl, 3-hydroxypropyl, 4-hydroxybutyl, 5- hydroxypentyl or 6-hydroxyhexyl), -(CH 2 ) y C(0)NR c R d (e.g.
  • heterocyclylCi_ 8 alkyl e.g 4-morpholinobutyl, 4-(piperazin-l-yl)butyl, 4- (azetidin-l-yl)butyl, 3-(azetidin-l-yl)propyl or azetidin-l-ylethyl
  • heteroaryl e.g 4-oxo-3,4-dihydro-2H-benzo[e][l,3]oxazin-7-yl or 4-oxo-3,4- dihydroquinazolin-7-yl
  • heteroarylCi_ 8 alkyl e.g.
  • R 6 is cyano, hydroxyl, carbamoyl, halogen (e.g. chloro or fluoro), haloCi_ 8 alkyl (e.g. trifluoromethyl), Ci_ 8 alkyl (e.g. methyl or ethyl), Ci_ 8 alkoxy (e.g. methoxy, ethoxy or 3- isobutoxy), hydroxyCi_ 8 alkyl (e.g. 3-hydroxypropyl), 5 to 15 membered heteroaryl (e.g. tetrazolyl or 5-oxo-2,5-dihydro-l,2,4-oxadiazol-3-yl), -(CH 2 ) y NR e C(0)R f (e.g.
  • R 5 is hydrogen, Ci-galkyl (e.g. methyl or butyl) or C 3 _i 2 cycloalkyl (e.g. cyclohexyl), R e and R f are hydrogen, hydroxyl, Ci_ 4 alkyl (e.g. methyl, ethyl or isopropyl), C6-i 4 aryl optionally substituted by hydroxyl (e.g. 4-hydroxyphenyl) or 5 to 15 membered heteroaryl
  • 'y' is 0, 1, 2, 3 or 4
  • 'z' is 2
  • m is 0 or 1
  • n is 0 or 1.
  • R is hydroxyl, methyl, ethyl, methoxy, chloro, bromo, fluoro or trifluoromethyl
  • R is methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl, heptyl, methyoxyethyl, 3-methoxypropyl, 2-hydroxyethyl, 4-hydroxybutyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, 4-amino-4-oxobutyl, 2-
  • R 5 is hydrogen, butyl or cyclohexyl
  • n 0 or 1.
  • the invention also provides a compound of formula (Ic)
  • A is selected from
  • R a is selected from hydrogen, Ci_ 8 alkyl, -(CR c R d ) y OC(0)R c and -(CH 2 ) y C(0)OR c ; at each occurrence, R 1 is independently selected from halogen, hydroxyl, Ci_ 8 alkyl, Ci_ 8 alkoxy and haloCi_ 8 alkyl; 2
  • R is Ci_ 8 alkyl
  • U is Ci-galkyl
  • V is -CR 6 , -CH or N;
  • R 6 is independently selected from halogen, hydroxyl, cyano, carbamoyl, Ci_ 8 alkyl, Ci_ 8 alkoxy, hydroxyCi_ 8 alkyl, haloCi_ 8 alkyl, 5 to 15 membered heteroaryl, -(CH 2 ) y C(0)NR e R f , -(CH 2 ) y NR e C(0)R f , -0(CR e R f ) y R e and -S(0) z R e ; or two R 6 together with the 'C atom to which they are attached, form a C3_i 2 cycloalkyl ring or a 3 to 15 membered heterocyclyl ring;
  • R c and R d are independently selected from hydrogen, Ci_ 8 alkyl and 5 to 15 membered heteroaryl;
  • R e and R f are independently selected from hydrogen, hydroxyl, Ci_ 8 alkyl and C 6-14 aryl; wherein C6 i 4 aryl is optionally substituted by hydroxyl;
  • n is selected from '0' to '4', both inclusive;
  • n is selected from '0' to '3', both inclusive;
  • y is selected from '0' to '6', both inclusive;
  • z is selected from '0' to '2', both inclusive.
  • p is selected from '0' to '5', both inclusive.
  • the compounds of formula (Ic) 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. For example, the invention provides compounds of formula (Ic) as defined
  • R is Ci_ 8 alkyl (e.g. methyl) and n is 0 or 1.
  • R 2 is methyl and n is 0 or 1.
  • R a is selected from hydrogen, Ci_ 8 alkyl (e.g. methyl or ethyl), -(CR c R d ) y OC(0)R c (e.g. (Pivaloyloxy)methyl) and -(CH 2 ) y C(0)OR c (e.g. 2- Ethoxy-2-oxoethyl).
  • R a is selected from hydrogen, Ci_ 8 alkyl (e.g. methyl or ethyl), -(CR c R d ) y OC(0)R c (e.g. (Pivaloyloxy)methyl) and -(CH 2 ) y C(0)OR c (e.g. 2- Ethoxy-2-oxoethyl), R c is hydrogen or Ci_ 8 alkyl (e.g. ethyl or tert-butyl), R d is hydrogen and y is 1.
  • R a is selected from hydrogen, methyl, ethyl, (Pivaloyloxy)methyl and 2-Ethoxy-2-oxoethyl.
  • R a is selected from hydrogen, Ci_ 8 alkyl (e.g. methyl or ethyl), - (CR c R d ) y OC(0)R c (e.g. (Pivaloyloxy)methyl) and -(CH 2 ) y C(0)OR c (e.g. 2-Ethoxy-2- oxoethyl).
  • R a is selected from hydrogen, Ci_ 8 alkyl (e.g. methyl or ethyl), - (CR c R d ) y OC(0)R c (e.g. (Pivaloyloxy)methyl) and -(CH 2 ) y C(0)OR c (e.g. 2-Ethoxy-2- oxoethyl).
  • R c is hydrogen or Ci_ 8 alkyl (e.g. ethyl or tert-butyl)
  • R d is hydrogen and y is 1.
  • R a is selected from hydrogen, methyl, ethyl, (Pivaloyloxy)methyl and 2-Ethoxy-2-oxoethyl.
  • R 1 is independently selected from hydroxyl, Ci-galkyl (e.g. methyl or ethyl), Ci-galkoxy (e.g. methoxy), halogen (e.g. chloro, bromo or fluoro) and haloCi-galkyl (e.g. trifluoromethyl).
  • R 1 is independently selected from hydroxyl, methyl, ethyl, methoxy, chloro, bromo, fluoro and trifluoromethyl.
  • R 6 is selected from cyano, hydroxyl, carbamoyl, halogen (e.g. chloro or fluoro), haloCi_ 8 alkyl (e.g. trifluoromethyl), Ci_ 8 alkyl (e.g. methyl or ethyl), Ci_ 8 alkoxy (e.g. methoxy, ethoxy or 3-isobutoxy), hydroxyCi_ 8 alkyl (e.g. 3-hydroxypropyl), 5 to 15 membered heteroaryl (e.g.
  • R 6 is selected from cyano, hydroxyl, carbamoyl, halogen (e.g. chloro or fluoro), haloCi_ 8 alkyl (e.g. trifluoromethyl), Ci_ 8 alkyl (e.g. methyl or ethyl), Ci_ 8 alkoxy (e.g. methoxy, ethoxy or 3-isobutoxy), hydroxyCi_ 8 alkyl (e.g. 3-hydroxypropyl), 5 to 15 membered heteroaryl (e.g.
  • R e and R f are independently selected from hydrogen, hydroxyl, Ci_ 4 alkyl (e.g. methyl, ethyl or isopropyl) and C6-i 4 aryl optionally substituted by hydroxyl (e.g. 4-hydroxyphenyl), 'y' is 0, 1, 2, 3 or 4 and 'z' is 2.
  • R 6 is selected from cyano, hydroxyl, carbamoyl, halogen (e.g. chloro or fluoro), haloCi_ 8 alkyl (e.g. trifluoromethyl), Ci_ 8 alkyl (e.g. methyl or ethyl), Ci_ 8 alkoxy (e.g. methoxy, ethoxy or 3-isobutoxy), hydroxyCi_ 8 alkyl (e.g. 3-hydroxypropyl), 5 to 15 membered heteroaryl (e.g.
  • R e and R f are independently selected from hydrogen, hydroxyl, methyl, ethyl, isopropyl, and 4-hydroxyphenyl, 'y' is 0, 1, 2, 3 or 4 and 'z' is 2.
  • R 6 is selected from cyano, hydroxyl, carbamoyl, chloro, fluoro, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, 3-isobutoxy, 3-hydroxypropyl, tetrazolyl, 5- oxo-2,5-dihydro- 1 ,2,4-oxadiazol-3-yl, 4-hydroxybenzamido, acetamidomethyl, isobutyramidomethyl, acetamido, 2-hydroxyethoxy and methylsulfonyl.
  • U is Ci_ 8 alkyl (e.g. methyl, ethyl, propyl or butyl).
  • V is -C(cyano), -C(hydroxyl), -C(carbamoyl), -C(halogen) (e.g. -C(C1) or -C(F)), -C(haloCi_ 8 alkyl) (e.g. -C(CF 3 )),-C(Ci_ 8 alkyl) (e.g. -C(CH 3 ) or -C(C 2 H 5 )), -C(d- 8 alkoxy) (e.g.
  • V is -C(cyano), -C(hydroxyl), -C(carbamoyl), -C(halogen) (e.g. -C(C1) or -C(F)), -C(halod_ 8 alkyl) (e.g. -C(CF 3 )),-C(d_ 8 alkyl) (e.g. -C(CH 3 ) or -C(C 2 H 5 )), -C(d_ 8 alkoxy) (e.g.
  • R e and R f are independently selected from hydrogen, hydroxyl, Ci_ 4 alkyl (e.g. methyl, ethyl or isopropyl) and C6-i 4 aryl optionally substituted by hydroxyl (e.g. 4- hydroxyphenyl), 'y' is 0, 1, 2, 3 or 4 and 'z' is 2.
  • V is -C(cyano), -C(hydroxyl), -C(carbamoyl), -C(halogen) (e.g. -C(C1) or -C(F)), -C(halod_ 8 alkyl) (e.g. -C(CF 3 )),-C(d_ 8 alkyl) (e.g. -C(CH 3 ) or -C(C 2 H 5 )), -C(d_ 8 alkoxy) (e.g.
  • R e and R f are independently selected from hydrogen, hydroxyl, methyl, ethyl, isopropyl, and 4-hydroxyphenyl, 'y' is 0, 1, 2, 3 or 4 and 'z' is 2.
  • V is -C(cyano), -C(hydroxyl), -C(carbamoyl), -C(C1), -C(F)), -C(CF 3 )), -C(CH 3 ), -C(C 2 H 5 ), -C(methoxy), -C(ethoxy) or -C(3-isobutoxy)), -C(3-hydroxypropyl)), - C(tetrazolyl), -C(5-oxo-2,5-dihydro-l,2,4-oxadiazol-3-yl), -C(4-hydroxybenzamido), C(acetamidomethyl), -C(isobutyramidomethyl) or -C(acetamido)), -C(2-hydroxyethoxy), - C(methylsulfonyl)), CH or N.
  • V is -C(cyano), -C(hydroxyl), -C(carbamoyl
  • R a is hydrogen, Ci_ 8 alkyl (e.g. methyl or ethyl), -(CR c R d ) y OC(0)R c (e.g. (Pivaloyloxy)methyl) or -(CH 2 ) y C(0)OR c (e.g. 2-Ethoxy-2-oxoethyl),
  • R 1 is hydroxyl, Ci_ 8 alkyl (e.g. methyl or ethyl), Ci_ 8 alkoxy (e.g. methoxy), halogen (e.g. chloro, bromo or fluoro) or haloCi_ 8 alkyl (e.g. trifluoromethyl),
  • Ci_ 8 alkyl e.g. methyl or ethyl
  • Ci_ 8 alkoxy e.g. methoxy
  • halogen e.g. chloro, bromo or fluoro
  • haloCi_ 8 alkyl e.g. trifluoromethyl
  • R is Ci- 8 alkyl (e.g. methyl),
  • R 6 is cyano, hydroxyl, carbamoyl, halogen (e.g. chloro or fluoro), haloCi_ 8 alkyl (e.g. trifluoromethyl), Ci_ 8 alkyl (e.g. methyl or ethyl), Ci_ 8 alkoxy (e.g. methoxy, ethoxy or 3- isobutoxy), hydroxyCi_ 8 alkyl (e.g. 3-hydroxypropyl), 5 to 15 membered heteroaryl (e.g. tetrazolyl or 5-oxo-2,5-dihydro-l,2,4-oxadiazol-3-yl), -(CH 2 ) y NR e C(0)R f (e.g.
  • R 5 is hydrogen, Ci_ 8 alkyl (e.g. methyl or butyl) or C3_i 2 cycloalkyl (e.g. cyclohexyl),
  • Ci_ 8 alkyl e.g. methyl, ethyl, propyl or butyl
  • V is -CR 6 , CH or N
  • R e and R f are hydrogen, hydroxyl, Ci_ 4 alkyl (e.g. methyl, ethyl or isopropyl) or C 6 - i 4 aryl optionally substituted by hydroxyl (e.g. 4-hydroxyphenyl),
  • R is hydroxyl, methyl, ethyl, methoxy, chloro, bromo, fluoro or trifluoromethyl.
  • R 6 is cyano, hydroxyl, carbamoyl, chloro, fluoro, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, 3-isobutoxy, 3-hydroxypropyl, tetrazolyl, 5-oxo-2,5-dihydro- 1,2,4- oxadiazol-3-yl, 4-hydroxybenzamido, acetamidomethyl, isobutyramidomethyl, acetamido, 2- hydroxyethoxy or methylsulfonyl,
  • R 5 is hydrogen, butyl or cyclohexyl
  • U is methyl, ethyl, propyl or butyl
  • V is -C(cyano), -C(hydroxyl), -C(carbamoyl), -C(C1), -C(F)), -C(CF 3 )), -C(CH 3 ), - C(C 2 H5), -C(methoxy), -C(ethoxy) or -C(3-isobutoxy)), -C (3-hydroxypropyl)), -C (tetrazolyl), -C(5-oxo-2,5-dihydro-l,2,4-oxadiazol-3-yl), -C(4-hydroxybenzamido), -C (acetamidomethyl), -C(isobutyramidomethyl) or -C(acetamido)), -C(2-hydroxyethoxy), -C(methylsulfonyl)), CH or N,
  • P is 0, 1 or 2
  • m is 0 or 1
  • n is 0 or 1.
  • Compounds of the present invention include the compounds in Examples 1-184.
  • 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.
  • 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).
  • 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.
  • 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 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, 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
  • 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 Chronic obstructive pulmonary disease (COPD).
  • 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 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 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
  • halogen or halo means fluorine (fluoro), chlorine (chloro), bromine
  • 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).
  • Ci_ 8 alkyl alkyl 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
  • 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.
  • alkoxy alkyl 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.
  • alkenyl refers to a hydrocarbon chain containing from 2 to 10 carbon atoms (i.e. C 2 - 10 alkenyl) and including at least one carbon-carbon double bond.
  • alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), z ' so-propenyl, 2- methyl-l-propenyl, 1-butenyl, and 2-butenyl.
  • alkynyl refers to a hydrocarbyl radical having at least one carbon-carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred i.e. C 2 - 10 alkynyl).
  • alkynyl groups include ethynyl, propynyl, and butynyl.
  • 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.
  • hydroxy alkyl 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 H 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. C 3 _ 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.
  • cycloalkenyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, for example C 3 _ 8 cycloalkenyl, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl.
  • cycloalkenylalkyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, directly attached to an alkyl group, for example C3_ 8 cycloalkenylCi_ 8 alkyl.
  • the cycloalkenylalkyl 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.
  • aryl refers to an aromatic radical having 6 to 14 carbon atoms (i.e. C 6- i 4 aryl), including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
  • aryloxy refers to an aryl group as defined above attached via an oxygen linkage to the rest of the molecule (i.e. C 6 i 4 aryloxy).
  • aryloxy moiety include, but are not limited to phenoxy and naphthoxy.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, i.e. C 6 -i 4 arylCi_ 8 alkyl, such as -CH 2 C 6 H 5 and -C 2 H 4 C 6 H5.
  • heterocyclic ring or “heterocyclyl” unless otherwise specified refers to 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 unless otherwise specified refers to 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, naphth
  • heteroaryl refers to 5 to 6 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S.
  • the heteroaryl is a monocyclic ring system.
  • heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and thiadiazolyl.
  • 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 Pharmacy, 20 th Ed., 2003 (Lippincott Williams & Wilkins).
  • 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.
  • 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 and mediastinum, pulmonary congestion and hypostasis, postinflammatory
  • any of the methods of treatment described herein comprise administering an effective amount of a compound according to Formula (I), (la), (lb) or (Ic), or a pharmaceutically- acceptable salt thereof, to a subject (particularly a human) in need thereof.
  • 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 synthesis of compound of formula (I) can be performed as described in Synthetic scheme 1.
  • the compound of formula (1) (wherein Z is an ester or any group which can be subsequently converted to A following the methods known to one skilled in the art) is reacted with the compound of formula (2) (wherein LG is an appropriate leaving group) to give compound of formula (I).
  • the reaction may be carried out in presence of a suitable base.
  • the base may be sodium hydride or potassium carbonate.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be selected from N,N-dimethyl formamide and dimethyl sulfoxide.
  • the reaction may be carried out at a suitable temperature. In an embodiment the reaction may be carried out in the temperature range of 25-250°C.
  • Z can be converted to A to obtain compound of formula (I) following the methods known to one skilled in the art.
  • Z when Z is an ester group, it is hydrolyzed to a carboxylic acid.
  • the hydrolysis reaction may be carried out in presence of a suitable base.
  • the base may be selected from lithium hydroxide and sodium hydroxide.
  • the reaction may be carried out in a suitable solvent or combinations of solvents.
  • the solvent may be tetrahydrofuran, methanol, water or combination thereof.
  • the reaction may be carried out at a suitable temperature. In an embodiment the reaction may be carried out in the temperature range of 25-250°C.
  • the reaction may be carried out in presence of a suitable reagent to obtain compound of formula (I).
  • the reagents may be sodium azide, ammonium chloride or combination thereof.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be N,N-dimethyl formamide or dimethyl sulfoxide.
  • the reaction may be carried out at a suitable temperature range. The reaction may be carried out in a temperature range of 25-
  • Thienopyrrole compound of the formula (lb) can be prepared by using a general approach as depicted in scheme 2, wherein A, Q, R 1 , R3 , R 5 and m are as defined in formula (I).
  • the synthesis of the compound of formula (lb) is performed as described in synthetic scheme 2.
  • the substituted thiophene compound of formula (3) may be treated with an appropriate aldehyde compound of formula (4) to obtain the compound of formula (5).
  • the reaction may be carried out in the presence of an appropriate base.
  • the base may be pyrrolidine.
  • the reaction may be carried out in the presence of a suitable solvent or mixture of solvents.
  • the reaction may be carried out in methanol.
  • the reaction may be carried out at a suitable temperature.
  • the reaction may be carried out at a temperature range of 25-250°C.
  • the compound of formula (5) may be converted to the compound of formula (6).
  • the conversion of compound of formula (5) to compound of formula (6) may be accomplished in presence of an appropriate organophosphorous reagent.
  • the organophosphorous reagent may be triphenyl phosphine.
  • the reaction may be carried out in the presence of suitable solvent or mixture of solvents.
  • the reaction may be carried out in the presence of 1,2-dichlorobenzene.
  • the reaction may be carried out at a suitable temperature.
  • the reaction may be carried out at a temperature range of 20-200°C.
  • the compound of formula (6) is converted to compound of formula (lb) in presence of a suitable reagent.
  • the hydrolysis reaction may be carried out in presence of a suitable base.
  • the base may be selected from lithium hydroxide and sodium hydroxide.
  • the reaction may be carried out in a suitable solvent or combinations of solvents.
  • the solvent may be tetrahydrofuran, methanol, water or combination thereof.
  • the reaction may be carried out at a suitable temperature. In an embodiment the reaction may be carried out at a suitable temperature range of 25-250°C.
  • reaction when Z is a nitrile group, it is converted to A which is tetrazole to obtain compound of formula (lb).
  • this reaction may be carried out in presence of suitable reagents such as sodium azide, ammonium chloride or combination thereof.
  • reaction may be carried out in a suitable solvent.
  • the solvent may be N,N-dimethyl formamide or dimethyl sulfoxide.
  • reaction may be carried out at a suitable temperature. In an embodiment the reaction may be carried out at a temperature range of 25-250°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-(lH-imidazol-l-yl)benzaldehyde
  • Step-3 Preparation of ethyl 5-methyl- -nitrothiophene-2-carboxylate
  • Step-5 Preparation of ethyl 5-(4-(lH-imidazol-l-yl)phenyl)-4H-thieno[3,2- ⁇ ]pyrrole-2- carboxylate
  • Step- 1 Preparation of methyl 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-cyano-3- isobutoxyphenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylate
  • Step-2 Preparation of methyl 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-carbamoyl-3- isobutoxyphenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylate
  • Step-3 Preparation of 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-carbamoyl-3- isobutoxyphenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid
  • Step- 1 Preparation of methyl 4-(4-cyano-3-methoxyphenyl)-5-(2-methyl-4-(2-methyl-lH- imidazol-l-yl)phenyl)-4H-thieno[ - ⁇ ]pyrrole-2-carboxylate
  • Step-2 Preparation of methyl 4-(4-carbamoyl-3-methoxyphenyl)-5-(2-methyl-4-(2-methyl- lH-imidazol- l-yl)phenyl)-4H-thi - ⁇ ]pyrrole-2-carboxylate
  • Step-3 Preparation of 4-(2-(hydroxymethyl)-5-(2-methyl-4-(2-methyl-lH-imidazol-l- yl)phenyl)-4H-thieno[3,2- ⁇ ]pyrrol-4-yl)-2-methoxybenzamide
  • Step- 1 Preparation of 4-(2-formyl-5-(2-methyl-4-(2-methyl- lH-imidazol-l-yl)phi
  • Step-2 Preparation of 4-(2-cyano-5-(2-methyl-4-(2-methyl- lH-imidazol- l-yl)phenyl)-4H- thieno[3,2- ]pyrrol-4-yl)-2-methoxybenzamide
  • Step-3 Preparation of 2-methoxy-4-(5-(2-methyl-4-(2-methyl- lH-imidazol-l-yl)phenyl)-2- (lH-tetrazol-5-yl)-4H-thieno[3,2- ]pyrrol-4-yl)benzamide
  • Example- 19 The title compound was prepared following the procedure described in Example-31 using 5- (4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-carbamoyl-3-methoxyphenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid (Example- 19, 46 mg, 0.09 mmol), Nal (36 mg, 0.24 mmol), K 2 C0 3 (26 mg, 0.19 mmol) and chloromethyl pivalate (23 mg, 0.14 mmol) in DMF (1 mL) to afford 37 mg of the title product.
  • Example-21 4- (4-carbamoyl-3-methoxyphenyl)-5-(2-methyl-4-(2-methyl- lH-imidazol- l-yl)phenyl)-4H- thieno[3,2- ]pyrrole-2-carboxylic acid (Example-21, 68 mg, 0.13 mmol), ethyl -2- chloroacetate (26 mg, 0.20 mmol), Nal (52 mg, 0.34 mmol) and K 2 C0 3 (38 mg, 0.27 mmol) in DMF (0.5 mL) rt for 16 h to afford 25 mg of the title product.
  • Step- 1 Preparation of ethyl 5-(4-(lH-imidazol-l-yl)phenyl)-4-ethyl-4H-thieno[3,2- ⁇ ]pyrrole- 2-carboxylate
  • Step-2 Preparation of 5-(4-(lH-imidazol-l-yl)phenyl)-4-ethyl-4H-thieno[3,2-3 ⁇ 4pyrrole-2- carboxylic acid
  • the title compound was prepared following the procedure described in Method- A, Step-3, by using ethyl 5-(4-(lH-imidazol- l-yl)phenyl)-4-ethyl-4H-thieno[3,2- ⁇ ]pyrrole-2-carboxylate (30 mg, 0.08 mmol), LiOH (14 mg, 0.33 mmol in 1.0 mL water) in THF (2.0 mL) to afford 10 mg of the title product.
  • Step-2 Preparation of methyl 5-(4-(lH-imidazol-l-yl)phenyl)-6-butyl-4H-thieno[3,2- ]pyrrole-2-carboxylate
  • Step-3 Preparation of 5-(4-(lH-imidazol-l-yl)phenyl)-6-butyl-4-methyl-4H-thieno[3,2- ]pyrrole-2-carboxylic acid
  • the title compound was prepared following the procedure described in Method-C, Step- 1, using methyl 5-(4-(lH-imidazol-l-yl)phenyl)-6-butyl-4H-thieno[3,2- ⁇ ]pyrrole-2-carboxylate (180 mg, 0.47 mmol), NaH (37 mg, 0.94 mmol, 60% in mineral oil) and methyliodide (199 mg, 1.42 mmol) in DMF (5 mL) at 60°C for 30-40 mins to afford 20 mg of the title product.
  • the aqueous solution was acidified with citric acid and was extracted with 10 % MeOH in CH 2 CI 2 .
  • the organic layer was washed with brine, separated, dried, filtered and concentrated.
  • the residue was purified by column chromatography to afford 15 mg of the title product.
  • Example 92 The title compound was prepared following the procedure described in Example-96 using 5- (4-(lH-imidazol-l-yl)-2-methylphenyl)-4-((2-carbamoylpyridin-4-yl)methyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid (Example-92).
  • Step- 1 Preparation of methyl 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(pyridin-4- ylmethyl)-4H-thieno[3,2- ]pyrrol -2-carboxylate
  • Step-2 Preparation of (5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(pyridin-4-ylmethyl)-4H- thieno[3,2- ]pyrrol-2-yl)methano
  • Step-3 Preparation of 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(pyridin-4-ylmethyl)-4H- thieno[3,2- ]pyrrole-2-carbaldehyde
  • Step-4 Preparation of 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(pyridin-4-ylmethyl)-4H- thieno[3,2- ]pyrrole-2-carbonitril
  • the title compound was prepared following the procedure described in Method-B, Step-2, using 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(pyridin-4-ylmethyl)-4H-thieno[3,2- ]pyrrole-2-carbaldehyde (180 mg, 0.45 mmol), aq. ammonia (1.0 mL) and iodine (700 mg, 2.75 mmol) in THF (1.0 mL) to afford 130 mg of the title product.
  • Step-5 Preparation of 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(pyridin-4-ylmethyl)-2- (lH-tetrazol-5-yl)-4H-thieno[3,2-£]pyrrole
  • the title compound was prepared following the procedure described in Method-B, Step-3, using 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(pyridin-4-ylmethyl)-4H-thieno[3,2- &]pyrrole-2-carbonitrile (130 mg, 0.3 mmol), NaN 3 (260 mg, 4.01 mmol) and NH 4 C1 (214 mg, 4.01 mmol) in DMF (1.0 mL) to afford 35 mg of the title product.
  • Step 1 Preparation of 5-(4-(lH-imidazol-l-yl)phenyl)-4-butyl-4H-thieno[3,2- ⁇ ]pyrrole-2- carbohydrazide
  • Step 2 Preparation of 5-(5-(4-(lH-imidazol- l-yl)phenyl)-4-butyl-4H-thieno[3,2- ⁇ ]pyrrol-2- yl)- 1 ,3 ,4-oxadiazol-2(3H)-one
  • Step- 1 Preparation of 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-isopentyl-4H-thieno[3,2- ]pyrrole-2-carboxamide
  • Step-2 Preparation of 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-isopentyl-2-(4H- 1,2,4- triazol-3-yl)-4H-thieno[3,2- ]pyrrole
  • Step- 1 Preparation of methyl 4-(4-cyanophenyl)-5-(4-(cyclopentyloxy)-2- (trifluoromethyl)phenyl)-4H-thien - ⁇ ]pyrrole-2-carboxylate
  • Step-2 Preparation of 4-(4-carbamoylphenyl)-5-(4-(cyclopentyloxy)-2-
  • Step-3 Preparation of 4-(4-carbamoylphenyl)-5-(4-hydroxy-2-(trifluoromethyl)phenyl)-4H- thieno[3,2- ⁇ ]pyrrole-2-carboxylic acid
  • Step- 1 Preparation of methyl 5-(2-chloro-4-(cyclopentyloxy)phenyl)-4-(4-cyano-3- nitrophenyl)-4H-thieno[3,2- ]p
  • Step-2 Preparation of methyl 4-(4-carbamoyl-3-nitrophenyl)-5-(2-chloro-4- (cyclopentyloxy)phenyl)-4H-thien - ⁇ ]pyrrole-2-carboxylate
  • Step-3 Preparation of methyl 4-(3-amino-4-carbamoylphenyl)-5-(2-chloro-4- (cyclopentyloxy)phenyl)-4H-thieno[3,2- ⁇ ]pyrrole-2-carboxylate
  • Step-4 Preparation of methyl 5-(2-chloro-4-(cyclopentyloxy)phenyl)-4-(2-methyl-4-oxo-3,4- dihydroquinazolin-7-yl)-4H-thieno[3,2- ⁇ ]pyrrole-2-carboxylate
  • Step-5 Preparation of methyl 5-(2-chloro-4-hydroxyphenyl)-4-(2-methyl-4-oxo-3,4- dihydroquinazolin-7-yl)-4H-thieno[3,2- ⁇ ]pyrrole-2-carboxylate
  • Step-6 Preparation of 5-(2-chloro-4-hydroxyphenyl)-4-(2-methyl-4-oxo-3,4- dihydroquinazolin-7-yl)-4H-thieno[3,2- ⁇ ]pyrrole-2-carboxylic acid
  • Step- 1 Preparation of methyl 5-(2-chloro-4-(cyclopentyloxy)phenyl)-4-(4-cyano-3- methylphenyl)-4H-thieno[3,2- ]p
  • Step-2 Preparation of methyl 4-(4-carbamoyl-3-methylphenyl)-5-(2-chloro-4- (cyclopentyloxy)phenyl)-4H-thien - ⁇ ]pyrrole-2-carboxylate
  • Step-3 Preparation of 4-(5-(2-chloro-4-(cyclopentyloxy)phenyl)-2-(hydroxymethyl)-4H- thieno[3,2- ]pyrrol-4-yl)-2-methylbenzamide
  • Step-4 Preparation of 4-(5-(2-chloro-4-(cyclopentyloxy)phenyl)-2-formyl-4H-thieno[3,2- ]pyrrol-4-yl)-2-methylbenzamide
  • the title compound was prepared following the procedure described in Method-B, Step-2, using 4-(5-(2-chloro-4-(cyclopentyloxy)phenyl)-2-formyl-4H-thieno[3,2-3 ⁇ 4pyrrol-4-yl)-2- methylbenzamide (120 mg, 0.25 mmol), aq. ammonia (3.0 mL) and iodine (955 mg, 3.80 mmol) in THF (3.0 mL) to afford 110 mg of the title product.
  • Step-6 Preparation of 4-(5-(2-chloro-4-hydroxyphenyl)-2-cyano-4H-thieno[3,2- ⁇ ]pyrrol-4- yl)-2-methylbenzamide
  • Step-7 Preparation of 4-(5-(2-chloro-4-hydroxyphenyl)-2-(lH-tetrazol-5-yl)-4H-thieno[3,2- ]pyrrol-4-yl)-2-methylbenzamide
  • Example- 124 The title compound was prepared following the procedure described in Example- 118 using 4- (5-(2-Chloro-4-hydroxyphenyl)-2-(lH-tetrazol-5-yl)-4H-thieno[3,2- ⁇ ]pyrrol-4-yl)-2- hydroxybenzamide (Example- 124).
  • Step- 1 Preparation of methyl 4-butyl-5-(4-(cyclopentyloxy)-2-(trifluoromethyl)phi thieno[3,2- ]pyrrole-2-carboxylate
  • Step-2 Preparation of methyl 4-butyl-5-(4-hydroxy-2-(trifluoromethyl)phenyl)-4H- thieno[3,2- ]pyrrole-2-carboxylate
  • Step-3 Preparation of 4-butyl-5-(4-hydroxy-2-(trifluoromethyl)phenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid
  • Step- 1 Preparation of methyl 6-(cyclohex- l-en- l-yl)-5-(4-(cyclopentyloxy)-2- (trifluoromethyl)phenyl)-4H-thieno[3,2- ⁇ ]pyrrole-2-carboxylate
  • Step-2 Preparation of methyl 6-cyclohexyl-5-(4-(cyclopentyloxy)-2- (trifluoromethyl)phenyl)-4H-thie - ⁇ ]pyrrole-2-carboxylate
  • Step-3 Preparation of methyl 6-cyclohexyl-5-(4-(cyclopentyloxy)-2- (trifluoromethyl)phenyl)-4-methyl-4H-thieno[3,2- ⁇ ]pyrrole-2-carboxylate
  • the title compound was prepared following the procedure described in Method-A, Step-3, using methyl 6-cyclohexyl-5-(4-hydroxy-2-(trifluoromethyl)phenyl)-4-methyl-4H-thieno[3,2- ]pyrrole-2-carboxylate (50 mg, 0.114 mmol) and LiOH (24 mg, 0.57 mmol in 1.0 mL water) in THF:MeOH (3.0 mL : 2.0 mL) to afford 15 mg of the title product.
  • Step-1 Preparation of methyl 4-isopentyl-5-(4-methoxy-2-(trifluoromethyl)phi
  • Step-2 Preparation of 4-isopentyl-5-(4-methoxy-2-(trifluoromethyl)phenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid
  • Example- 152 The title compound was prepared following the procedure described in Example-96 using 5- (4-(lH-imidazol-l-yl)-2-methylphenyl)-4-((2-carbamoylpyridin-4-yl)methyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid (Example- 152).
  • 1H NMR 300 MHz, DMSO-i3 ⁇ 4 ⁇ 7.46-7.40 (m, 3H), 7.02-6.89 (m, 4H), 6.67-6.61 (m, 1H), 6.38 (s, 1H), 5.09 (s, 2H).
  • Step-2 Preparation of 4-butyl-5-(2-chloro-4-(cyclopentyloxy)phenyl)-4H-thieno[3,2- ]pyrrole-2-carbaldehyde
  • Step-3 Preparation of 4-butyl-5-(2-chloro-4-(cyclopentyloxy)phenyl)-4H-thieno[3,2- ]pyrrole-2-carbonitrile
  • Step- 1 Preparation of 4-butyl-5-(4-(cyclopentyloxy)-2-(trifluoromethyl)phi
  • Step-4 Preparation of 4-butyl-5-(4-hydroxy-2-(trifluoromethyl)phenyl)-N-(methylsulfonyl)- 4H-thieno[3,2- ]pyrrole-2-carboxamide
  • Step- 1 Preparation of 4-butyl-5-(4-(cyclopentyloxy)-2-(trifluoromethyl)phi
  • Step-2 Preparation of 4-butyl-5-(4-hydroxy-2-(trifluoromethyl)phenyl)-N-(phenylsulfonyl)- 4H-thieno[3,2- ]pyrrole-2-carboxamide
  • Step- 1 Preparation of 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-N-cyano-4-(4- hydroxybutyl)-4H-thieno [3 ,2- ]pyrrole-2-carboxamide
  • Step-2 Preparation of 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-N-cyano-4-(4- hydroxybutyl)-4H-thieno [3 ,2- ]pyrrole-2-carboxamide
  • Step- 1 Preparation of ethyl 5-(4-chloro-2-methoxyphenyl)-4-(4-cyanophenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylate
  • Step-2 Preparation of 4-(4-carbamoylphenyl)-5-(4-chloro-2-methoxyphenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid
  • Step- 1 Preparation of ethyl 4-(4-(lH-tetrazol-5-yl)phenyl)-5-(4-chloro-2-methoxyphenyl)- 4H-thieno[3,2- ]pyrrole-2-carboxylate
  • Step-2 Preparation of 4-(4-(lH-tetrazol-5-yl)phenyl)-5-(4-chloro-2-methoxyphenyl)-4H- thieno[3,2- ⁇ ]pyrrole-2-carboxylic acid
  • Step- 1 Preparation of ethyl 4-(4-cyanophenyl)-5-(4-(methylthio)phenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylate
  • Step-2 Preparation of ethyl 4-(4-carbamoylphenyl)-5-(4-(methylthio)phenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylate
  • Step-3 Preparation of 4-(4-carbamoylphenyl)-5-(4-(methylthio)phenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid
  • the title compound was prepared following the procedure described in Method-A, Step-3, using ethyl 4-(4-carbamoylphenyl)-5-(4-(methylthio)phenyl)-4H-thieno[3,2- ⁇ ]pyrrole-2- carboxylate (70 mg, 0.160 mmol) and LiOH (27 mg, 0.64 mmol in 1.0 mL water) in THF (2 mL) to afford 15 mg of the title product.
  • Step- 1 Preparation of ethyl 4-(4-carbamoylphenyl)-5-(4-(methylsulfonyl)phi
  • Example-181, Step-1 The title compound was prepared following the procedure described in Method-A, Step-2, using ethyl 4-(4-cyanophenyl)-5-(4-(methylthio)phenyl)-4H-thieno[3,2- ⁇ ]pyrrole-2- carboxylate (Example-181, Step-1 ; 80 mg, 0.13 mmol), ⁇ 2 0 2 (1 mL, 30% in water), NaOH (30 mg, 0.38 mmol) in MeOH (3 mL) to afford 15 mg of the title product.
  • Step-2 Preparation of 4-(4-carbamoylphenyl)-5-(4-(methylsulfonyl)phenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid
  • Step- 1 Preparation of methyl 4-(4-cyanophenyl)-5-(4-(pyrimidin-5-yl)phenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylate
  • Step-2 Preparation of 4-(4-carbamoylphenyl)-5-(4-(pyrimidin-5-yl)phenyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid
  • Step- 1 Preparation of methyl 4-(4-cyanophenyl)-5-(4-(imidazo[l,2-a]pyridin-3-yl)phenyl)- 4H-thieno[3,2- ]pyrrole-2-carboxylate
  • Step-2 Preparation of 4-(4-carbamoylphenyl)-5-(4-(imidazo[l,2-(3]pyridin-3-yl)phenyl)-4H- thieno[3,2- ]pyrrole-2-carboxylic acid
  • GSNOR activity for the reduction of GSNO was determined by measuring the NADH- and GSNO-dependent decrease in absorbance at 340 nm (A340) as previously described by Jansen et al.
  • the assay utilized human recombinant GSNOR enzyme (His tagged) and was set up in 96 well UV (Ultra-violate) plate.
  • the test compounds were dissolved in 100% DMSO to prepare 10 mM stock and then further diluted in DMSO to get the desired concentration (100 x). Final concentration of DMSO in the reaction was 1% (v/v).
  • GSNO and NADH Stock concentrations of GSNO and NADH were freshly prepared in Na phosphate buffer, pH 7.4. 2.0 ⁇ of test compounds (or controls at final 1% DMSO concentration) were added to each well containing 174 ⁇ of Na phosphate buffer. This was followed by addition of 9.5 ⁇ stock GSNO solution. The reaction was initiated by adding 14.5 ⁇ of Enzyme/NADH mix. The final assay components contained 100 mM sodium phosphate buffer, pH 7.4, 0.240 mM GSNO, 0.3 mM NADH and 20 nM of GSNO reductase in 200 ⁇ volume. The plate was read in FLUOstar plate reader and change in 340 nm absorbance/min at 25°C was recorded for 3 minutes. IC 50 values were calculated from non-linear regression analysis of the initial rate data using the GraphpadPrism software.
  • IC 50 (nM) values of the compounds are set forth in Table 12 wherein “A” refers to an IC 50 value of less than 50 nM, “B” refers to IC 50 value in range of 50.01 to 100 nM, “C” refers to IC 50 value in range of 100.01 to 500 nM and “D” refers to IC 50 value greater than 500 nM.
  • Table 12 In- vitro screening results of compounds of the present invention

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Abstract

The present disclosure is directed to compounds of formula (Ib) and pharmaceutically acceptable salts thereof, wherein A, Q, R1, R3, R5 and m are as defined herein, which are active as inhibitors of S-Nitrosoglutathione reductase (GSNOR). These compounds prevent, inhibit, or suppress the action of GSNOR and are therefore useful in the treatment of GSNOR mediated diseases, disorders, syndromes or conditions such as, e.g., pulmonary hypertension, acute respiratory distress syndrome (ARDS), asthma, bronchospasm, cough, pneumonia, pulmonary fibrosis, interstitial lung diseases, cystic fibrosis and chronic obstructive pulmonary disease (COPD).

Description

THIENOPYRROLE COMPOUNDS AS
S-NITROSOGLUTATHIONE REDUCTASE INHIBITORS
RELATED APPLICATIONS
This application claims the benefit of Indian provisional application no(s). 427/MUM/2015 filed on February 10, 2015, which is hereby incorporated by reference in its entirety.
TECHNICAL FIELD
The present patent application is directed to Thienopyrrole compounds which act as inhibitors of 5-Nitrosoglutathione reductase (GSNOR). 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.
BACKGROUND OF THE INVENTION
5-Nitrosoglutathione (GSNO) is an endogenous 5-nitrosothiol (SNO) that plays a critical role in nitric oxide (NO) signaling and is a source of bioavailable NO. 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). Studies suggest that NO metabolism has a significant role in human cardiovascular and respiratory diseases as well as in immune tolerance during organ transplantation (Casey et al., Clin. Exp. Pharmacol. Physiol., 2007, 34(12), 1291-1293; Ganz et al., Circulation, 2003, 108(17), 2049-2053; Que et al., Science, 2005, 308 (5728), 1618- 1621; Snyder et al., Am. J. Respir. Crit. Care Med., 2002, 165(7), 922-926).
5-nitrosoglutathione reductase (GSNOR), also known as S- (hydroxymethyl)glutathione (HMGSH) dehydrogenase, belongs to the large alcohol dehydrogenase superfamily (ADH), namely to the class III ADHs. 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 5-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 5-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. Natl. Acad. Set, 106(15), 6297- 6302). GSNO depletion associates with various diseases including asthma {Chem. Biol. Interact, 2009, 178(1-3), 29-35). GSNOR expression has been inversely correlated with S- 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). GSNO and NO concentrations regulate respiratory function by modulating airway tone and pro- and anti-inflammatory responses in the respiratory tract (Snyder et al., Am. J. Respir. Crit. Care Med., 2002, 165(7), 922-926; Gaston et al., Proc. Natl. Acad. Sci., 1993, 90(23), 10957-61). 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 antimicrobial effects (Persichini et al., Biochem Biophys Res Commun., 1998, 250, 575-576; Saura et al., Immunity, 1999, 10, 21-26; De Groote et al., Heart, 1998, 80, 46-50). GSNO observed to increase cellular expression and maturation of the common mutant form of the cystic fibrosis transmembrane regulation protein (CFTR), AF508, in physiologically relevant concentrations (Zaman et al., Biochem Biophys Res Commun., 2001, 284, 65-70). Levels of GSNO tend to be low in the cystic fibrosis (CF) airway (Grasemann et al., J Pediatr., 1999, 135, 770-772). According to a study acute treatment with 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). In these mice, 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). The therapeutic potential of GSNOR inhibitors has 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., J Appl Physiol., 2013, 114(6), 752-760).
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.
Given such findings, 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.
In view of the above, a need exists for new therapeutic agents that inhibit the activity of GSNOR and thus will provide new methods for treating diseases or condition associated with the inhibition of GSNOR.
The present application is directed to compounds that are inhibitors of the S- nitrosoglutathione reductase (GSNOR). SUMMARY OF THE INVENTION
aspect, the present invention relates to compound of formula (I)
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof,
wherein,
P is selected from phenyl and 5 or 6 membered heteroaryl;
Q is selected from
Figure imgf000005_0002
A is selected from
Figure imgf000005_0003
one of X is S and the other is CR4; the dotted line indicates a bond that commences at CR4;
Ra is selected from hydrogen, Ci_8alkyl, Ci_8alkoxyCi_8alkyl, -(CRcRd)yOC(0)Rc and - (CH2)yC(0)ORc;
Rb and Rb are independently selected from hydrogen, cyano, Ci_8alkyl and C6-14aryl; at each occurrence, R1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, Ci_8alkyl, C2_ioalkenyl, C2_ioalkynyl, Ci_8alkoxy, Ci_8alkoxyCi_8alkyl, hydroxyCi_8alkyl, haloCi_8alkyl, haloCi_8alkoxy, C3_i2cycloalkyl, C3_i2cycloalkylCi_8alkyl, C3_8cycloalkenyl, C3_ 8cycloalkenylCi_8alkyl, C6-i4aryl, C6-i4aryloxy, C6-i4arylCi_8alkyl, 3 to 15 membered heterocyclyl, 3 to 15 membered heterocyclylCi_8alkyl, 5 to 15 membered heteroaryl, 5 to 15 membered heteroarylCi_8alkyl, -(CH2)yC(0)Rc, -C(0)(CH2)yRc, -(CH2)yC(0)NRcRd, - (CH2)yC(0)ORc, -(CH2)yCHRcRd, -(CH2)yNRcRd, -(CH2)yNRcC(0)Rd, -NRc(CRcRd)yORc, - NRc(CRcRd)yCN, -NRc(CRcRd)yCONRcRd, -(CRcRd)yORc, -0(CRcRd)yRc, -OC(0)Rc, - N(Rc)S02Rd, -OC(0)NRcRd, S02NRcRd, -(CH2)yS(0)zRc and -S(0)zRc;
at each occurrence, R is independently selected from halogen, Ci_8alkyl, haloCi_8alkyl and C3_i2cycloalkyl;
R is selected from Ci_8alkyl, Ci_8alkoxy, Ci_8alkoxyCi_8alkyl, hydroxyCi_8alkyl, haloCi-salkyl, -(CH2)yC(0)Rc, -C(0)(CH2)yRc, -(CH2)yC(0)NRcRd, -(CH2)yC(0)ORc, - (CH2)yCHRcRd, -(CH2)yNRcRd, -(CH2)yNRcC(0)Rd, -(CRcRd)yORc, -(CH2)yS(0)zRc, - (CRcRd)yO(CRcRd)ySiRcRcRc, C3-i2cycloalkyl, C3-i2cycloalkylCi_8alkyl, C6_i4aryl, C6_i4arylCi_ 8alkyl, 3 to 15 membered heterocyclyl, 3 to 15 membered heterocyclylCi_8alkyl, 5 to 15 membered heteroaryl and 5 to 15 membered heteroarylCi_8alkyl each of which being optionally substituted by one or more R6;
at each occurrence, R6 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carbamoyl, Ci_8alkyl, C2-ioalkenyl, C2-ioalkynyl, Ci_8alkoxy, Ci_8alkoxyCi_8alkyl, hydroxyCi_8alkyl, haloCi_8alkyl, haloCi_8alkoxy, C3_i2cycloalkyl, C3_i2cycloalkylCi_8alkyl, C3_ scycloalkenyl, C3_8cycloalkenylCi_8alkyl, C6-i4aryl, C6-i4aryloxy, C6-i4arylCi_8alkyl, 3 to 15 membered heterocyclyl, 3 to 15 membered heterocyclylCi_8alkyl, 5 to 15 membered heteroaryl, 5 to 15 membered heteroarylCi_8alkyl, -(CH2)yC(0)Re, -C(0)(CH2)yRe, - (CH2)yC(0)NReRf, -(CH2)yC(0)ORe, -(CH2)yCHReRf, -(CH2)yNReRf, -(CH2)yNReC(0)Rf, - NRe(CReRf)yORe, -NRe(CReRf)yCN, -NRe(CReRf)yCONReRf, -(CReRf)yORe, -0(CReRf)yRe, - OC(0)Re, -N(Re)S02Rf, -OC(0)NReRf, S02NReRf, -(CH2)yS(0)zRe and -S(0)zRe; or two R6 together with the 'C atom to which they are attached, form a C3_i2cycloalkyl ring or a 3 to 15 membered heterocyclyl ring;
R4 is selected from hydrogen, halogen, Ci_8alkyl, Ci_8alkoxy, Ci_8alkoxyCi_8alkyl, hydroxyCi_8alkyl, haloCi_8alkyl, haloCi_8alkoxy and C3_i2cycloalkyl;
R5 is selected from hydrogen, halogen, amino, Ci_8alkyl, C2-ioalkenyl, C2-ioalkynyl, Ci_ 8alkoxy, Ci_8alkoxyCi_8alkyl, hydroxyCi_8alkyl, haloCi_8alkyl, haloCi_8alkoxy, C3_i2cycloalkyl, C3-i2cycloalkylCi_8alkyl, C3_8cycloalkenyl, C3_8cycloalkenylCi_8alkyl, -(CH2)yC(0)Rc, - (CH2)yC(0)NRcRd, -(CH2)yC(0)ORc, -(CH2)yCHRcRd, -(CH2)yNRcRd, -(CH2)yNRcC(0)Rd, - NRc(CRcRd)yORc, -NRc(CRcRd)yCN, -NRc(CRcRd)yCONRcRd, -(CRcRd)yORc, -N(Rc)S02Rd, - OC(0)NRcRd and -(CH2)yS(0)zRc;
at each occurrence, Rc and Rd are independently selected from hydrogen, halogen, hydroxyl, nitro, amino, cyano, Ci_8alkyl, C2-ioalkenyl, C2-ioalkynyl, Ci_8alkoxy, Ci_8alkoxyCi_ galkyl, hydroxyCi_8alkyl, haloCi_8alkyl, haloCi_8alkoxy, C3_i2cycloalkyl, C3-i2cycloalkylCi- galkyl, C3_8cycloalkenyl, C3_8cycloalkenylCi_8alkyl, C6-i4aryl, C6-i4aryloxy, C6-i4arylCi_8alkyl, 3 to 15 membered heterocyclyl, 3 to 15 membered heterocyclylCi_8alkyl, 5 to 15 membered heteroaryl and 5 to 15 membered heteroarylCi_8alkyl each of which being optionally substituted by substituents independently selected from halogen, hydroxyl, nitro, amino, cyano, Ci_8alkyl, C2-ioalkenyl, C2-ioalkynyl, Ci_8alkoxy, Ci_8alkoxyCi_8alkyl, hydroxyCi_8alkyl, haloCi_8alkyl, haloCi_8alkoxy, C3_i2cycloalkyl, C3_i2cycloalkylCi_8alkyl, C3_8cycloalkenyl, C3- 8cycloalkenylCi_8alkyl, C6-i4aryl, C6-i4aryloxy, C6-i4arylCi_8alkyl, 3 to 15 membered heterocyclyl, 3 to 15 membered heterocyclylC i_8alkyl, 5 to 15 membered heteroaryl, 5 to 15 membered heteroarylCi_8alkyl, -(CH2)yC(0)Rc, -C(0)(CH2)yRc, -(CH2)yC(0)NRcRd, - (CH2)yC(0)ORc, -(CH2)yCHRcRd, -(CH2)yNRcRd, -(CH2)yNRcC(0)Rd, -NRc(CRcRd)yORc, - NRc(CRcRd)yCN, -NRc(CRcRd)yCONRcRd, -(CRcRd)yORc, -0(CRcRd)yRc, -OC(0)Rc, - N(Rc)S02Rd, -OC(0)NRcRd, S02NRcRd, -(CRcRd)ySiRcRcRc, -(CH2)yS(0)zRc and -S(0)zRc; at each occurrence, Re and Rf are independently selected from hydrogen, halogen, hydroxyl, nitro, amino, cyano, Ci_8alkyl, C2-ioalkenyl, C2-ioalkynyl, Ci_8alkoxy, Ci_8alkoxyCi_ 8alkyl, hydroxyCi_8alkyl, haloCi_8alkyl, haloCi_8alkoxy, C3_i2cycloalkyl, C3_i2cycloalkylCi_ 8alkyl, C3_8cycloalkenyl, C3_8cycloalkenylCi_8alkyl, C6-i4aryl, C6-i4aryloxy, C6-i4arylCi_8alkyl, 3 to 15 membered heterocyclyl, 3 to 15 membered heterocyclylCi_8alkyl, 5 to 15 membered heteroaryl and 5 to 15 membered heteroarylCi_8alkyl each of which being optionally substituted by substituents independently selected from halogen, hydroxyl, nitro, amino, cyano, Ci_8alkyl, C2-ioalkenyl, C2-ioalkynyl, Ci_8alkoxy, Ci_8alkoxyCi_8alkyl, hydroxyCi_8alkyl, haloCi_8alkyl, haloCi_8alkoxy, C3_i2cycloalkyl, C3_i2cycloalkylCi_8alkyl, C3_8cycloalkenyl, C3- 8cycloalkenylCi_8alkyl, C6-i4aryl, C6-i4aryloxy, C6-i4arylCi_8alkyl, 3 to 15 membered heterocyclyl, 3 to 15 membered heterocyclylC i_8alkyl, 5 to 15 membered heteroaryl, 5 to 15 membered heteroarylCi_8alkyl, -(CH2)yC(0)Rc, -C(0)(CH2)yRc, -(CH2)yC(0)NRcRd, - (CH2)yC(0)ORc, -(CH2)yCHRcRd, -(CH2)yNRcRd, -(CH2)yNRcC(0)Rd, -NRc(CRcRd)yORc, - NRc(CRcRd)yCN, -NRc(CRcRd)yCONRcRd, -(CRcRd)yORc, -0(CRcRd)yRc, -OC(0)Rc, - N(Rc)S02Rd, -OC(0)NRcRd, S02NRcRd, -(CRcRd)ySiRcRcRc, -(CH2)yS(0)zRc and -S(0)zRc; m is selected from '0' to '4', both inclusive;
n is selected from '0' to '3', both inclusive;
y is selected from '0' to '6', both inclusive; and
z is selected from '0' to '2', both inclusive.
The invention also provides a compound of formula (la)
Figure imgf000008_0001
(la)
or a pharmaceutically acceptable salt thereof,
wherein,
W is independently selected from N, CR1 and CH;
Q is selected from
(R2)„
N
OH and
A is selected from
Figure imgf000008_0002
one of X is S and the other is CR4; the dotted line indicates a bond that commences at
CR4;
Ra is selected from hydrogen, Ci_8alkyl, -(CRcRd)yOC(0)Rc and -(CH2)yC(0)ORc; Rb and Rb are independently selected from hydrogen, cyano, Ci_8alkyl and C6-14aryl; at each occurrence, R1 is independently selected from halogen, hydroxyl, Ci_8alkyl, Ci_ 8alkoxy and haloCi_8alkyl;
at each occurrence, R is Ci_8alkyl;
R is selected from Ci_8alkyl, Ci_8alkoxyCi_8alkyl, hydroxyCi_8alkyl, (CH2)yC(0)NRcRd, -(CH2)yNRcRd, -(CRcRd)yORc, -(CRcRd)yO(CRcRd)ySiRcRcRc, C3_ i2cycloalkylCi_8alkyl, C6-i4aryl, C6-i4arylCi_8alkyl, 3 to 15 membered heterocyclylCi_8alkyl, 5 to 15 membered heteroaryl and 5 to 15 membered heteroarylCi_8alkyl each of which being optionally substituted by one or more R6;
at each occurrence, R6 is independently selected from halogen, hydroxyl, cyano, carbamoyl, Ci_8alkyl, Ci_8alkoxy, hydroxyCi_8alkyl, haloCi_8alkyl, 5 to 15 membered heteroaryl, -(CH2)yC(0)NReRf, -(CH2)yNReC(0)Rf, -0(CReRf)yRe and -S(0)zRe; or two R6 together with the 'C atom to which they are attached, form a C3_i2cycloalkyl ring or a 3 to 15 membered heterocyclyl ring;
R4 is selected from hydrogen, and Ci_8alkyl; R5 is selected from hydrogen, Ci_8alkyl and C3_i2cycloalkyl;
at each occurrence, Rc and Rd are independently selected from hydrogen, Ci_8alkyl and 5 to 15 membered heteroaryl;
at each occurrence, Re and Rf are independently selected from hydrogen, hydroxyl, Ci_ 8alkyl and C6-i4aryl; wherein C6-i4aryl is optionally substituted by hydroxyl;
m is selected from '0' to '4', both inclusive;
n is selected from '0' to '3', both inclusive;
y is selected from '0' to '6', both inclusive; and
z is selected from '0' to '2', both inclusive.
The invention also provides a compound of formula (lb)
Figure imgf000009_0001
or a pharmaceutically acceptable salt thereof,
wherein,
A is selected from
Figure imgf000009_0002
Q is selected from
Figure imgf000009_0003
Ra is selected from hydrogen, Ci_8alkyl, -(CRcRd)yOC(0)Rc and -(CH2)yC(0)ORc; at each occurrence, R1 is independently selected from halogen, hydroxyl, Ci_8alkyl, Ci_
8alkoxy and haloCi_8alkyl;
at each occurrence, R is Ci_8alkyl;
R is selected from Ci_8alkyl, Ci_8alkoxyCi_8alkyl, hydroxyCi_8alkyl, (CH2)yC(0)NRcRd, -(CH2)yNRcRd, -(CRcRd)yORc, -(CRcRd)yO(CRcRd)ySiRcRcRc, C3_ i2cycloalkylCi_8alkyl, C6-i4aryl, C6-i4arylCi_8alkyl, 3 to 15 membered heterocyclylCi_8alkyl, 5 to 15 membered heteroaryl and 5 to 15 membered heteroarylCi-8alkyl each of which being optionally substituted by one or more R6;
at each occurrence, R6 is independently selected from halogen, hydroxyl, cyano, carbamoyl, Ci_8alkyl, Ci_8alkoxy, hydroxyCi_8alkyl, haloCi_8alkyl, 5 to 15 membered heteroaryl, -(CH2)yC(0)NReRf, -(CH2)yNReC(0)Rf, -0(CReRf)yRe and -S(0)zRe; or two R6 together with the 'C atom to which they are attached, form a C3_i2cycloalkyl ring or a 3 to 15 membered heterocyclyl ring;
R5 is selected from hydrogen, Ci_8alkyl and C3_i2cycloalkyl;
at each occurrence, Rc and Rd are independently selected from hydrogen, Ci_8alkyl and 5 to 15 membered heteroaryl;
at each occurrence, Re and Rf are independently selected from hydrogen, hydroxyl, Ci_ 8alkyl and C6-14aryl; wherein C6 i4aryl is optionally substituted by hydroxyl;
m is selected from '0' to '4', both inclusive;
n is selected from '0' to '3', both inclusive;
y is selected from '0' to '6', both inclusive; and
z is selected from '0' to '2', both inclusive.
The compounds of formula (lb) 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. For example, the invention provides compounds of formula (lb) as defined
above wher (according to one embodiment defined below), A is
COORa or
Figure imgf000010_0001
(according to another embodiment defined below), m is 0 or 1 (according to yet another embodiment defined below), n is 0 or 1 (according to yet another embodiment defined below).
According to one embodiment, specifically provided are compounds of formula (lb), in which Q is
Figure imgf000011_0001
According to another embodiment, specifically provided are compounds of formula (lb), in which Q is
OH or
Figure imgf000011_0002
. In this embodiment R is Ci-galkyl (e.g. methyl) and n is 0 or 1.
According to yet another embodiment, specifically provided are compounds formula (lb), in which Q is
OH or
Figure imgf000011_0003
. In this embodiment R2 is methyl and n is 0 or 1.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which Q is
Figure imgf000011_0004
According to yet another embodiment, specifically provided are compounds of formula (lb), in which Q is OH.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which Q is
Figure imgf000011_0005
According to yet another embodiment, specifically provided are compounds of formula (lb), in which Q is
Figure imgf000011_0006
According to yet another embodiment, specifically provided are compounds of formula (lb), in which A is selected from
O
■X and " \
N H
¾Ra N¾ . According to yet another embodiment, specifically provided are compounds of formula (lb), in which A is selected from
Figure imgf000012_0001
In this embodiment Ra is selected from hydrogen, Ci_8alkyl (e.g. methyl or ethyl), -(CRcRd)yOC(0)Rc (e.g. (Pivaloyloxy)methyl) and -(CH2)yC(0)ORc (e.g. 2- Ethoxy-2-oxoethyl).
According to yet another embodiment, specifically provided are compounds of formula (lb), in which A is selected from
Figure imgf000012_0002
and CN . In this embodiment Ra is selected from hydrogen, Ci_8alkyl (e.g. methyl or ethyl), -(CRcRd)yOC(0)Rc (e.g. (Pivaloyloxy)methyl) and -(CH2)yC(0)ORc (e.g. 2- Ethoxy-2-oxoethyl), Rc is hydrogen or Ci_8alkyl (e.g. ethyl or tert-butyl), Rdis hydrogen and y is 1.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which A is selected from
Figure imgf000012_0003
and 'X N N> . In this embodiment Ra is selected from hydrogen, methyl, ethyl, (Pivaloyloxy)methyl and 2-Ethoxy-2-oxoethyl.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which Ra is selected from hydrogen, Ci_8alkyl (e.g. methyl or ethyl), - (CRcRd)yOC(0)Rc (e.g. (Pivaloyloxy)methyl) and -(CH2)yC(0)ORc (e.g. 2-Ethoxy-2- oxoethyl).
According to yet another embodiment, specifically provided are compounds of formula (lb), in which Ra is selected from hydrogen, Ci_8alkyl (e.g. methyl or ethyl), - (CRcRd)yOC(0)Rc (e.g. (Pivaloyloxy)methyl) and -(CH2)yC(0)ORc (e.g. 2-Ethoxy-2- oxoethyl). In this embodiment Rc is hydrogen or Ci_8alkyl (e.g. ethyl or tert-butyl), Rd is hydrogen and y is 1.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which Ra is selected from hydrogen, methyl, ethyl, (Pivaloyloxy)methyl and 2-Ethoxy-2-oxoethyl.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which A is selected from
Figure imgf000013_0001
According to yet another embodiment, specifically provided are compounds formula (lb), in which A is selected from
Figure imgf000013_0002
According to yet another embodiment, specifically provided are compounds of formula (lb), in which A is selected from
Figure imgf000013_0003
According to yet another embodiment, specifically provided are compounds of formula (lb), in which A is
Figure imgf000013_0004
According to yet another embodiment, specifically provided are compounds of formula (lb), in which A is
Figure imgf000013_0005
According to yet another embodiment, specifically provided are compounds of formula (lb), in which R1 is independently selected from hydroxyl, Ci-galkyl (e.g. methyl or ethyl), Ci-galkoxy (e.g. methoxy), halogen (e.g. chloro, bromo or fluoro) and haloCi-galkyl (e.g. trifluoromethyl).
According to yet another embodiment, specifically provided are compounds of formula (lb), in which R1 is independently selected from hydroxyl, methyl, ethyl, methoxy, chloro, bromo, fluoro and trifluoromethyl.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which R is selected from Ci_8alkyl (e.g. methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl or heptyl), Ci_8alkoxyCi_8alkyl (e.g. methyoxyethyl, or 3-methoxypropyl), hydroxyCi_8alkyl (e.g. 2-hydroxyethyl, 4-hydroxybutyl, 3- hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl or 6-hydroxyhexyl), -(CH2)yC(0)NRcRd (e.g. 4-amino-4-oxobutyl), -(CH2)yNRcRd (e.g. 2-(dimethylamino)ethyl), C6-i4aryl (e.g. phenyl), C3_i2cycloalkylCi_8alkyl (e.g. cyclopropylmethyl or cyclohexylmethyl), C6-i4arylCi_ galkyl (e.g. benzyl or phenethyl), 3 to 15 membered heterocyclylCi_8alkyl (e.g 4- morpholinobutyl, 4-(piperazin-l-yl)butyl, 4-(azetidin-l-yl)butyl, 3-(azetidin-l-yl)propyl or azetidin-l-ylethyl), 5 to 15 membered heteroaryl (e.g 4-oxo-3,4-dihydro-2H- benzo[e][l,3]oxazin-7-yl or 4-oxo-3,4-dihydroquinazolin-7-yl), 5 to 15 membered heteroarylCi-galkyl (e.g. (thiazol-4-yl)methyl, (thiazol-4-yl)propyl, thiazol-4-ylethyl, pyridin- 3-ylmethyl, 3-(lH-pyrazol-4-yl)propyl, 6-oxo-l,6-dihydropyridin-3-ylmethyl, imidazo[l,2- a]pyridin-6-ylmethyl, imidazo[5,l-b]thiazol-3-ylmethyl, lH-imidazol-l-yl)ethyl, thiophen-2- yl or pyridin-4-ylmethyl), -(CRcRd)yORc (e.g 2-ethoxyethyl, 3-methoxy-3-methylbutyl, 3- (pyridin-3-yloxy)propyl, 2-(pyridin-4-yloxy)ethyl or 4-(pyridin-3-yloxy)butyl) and - (CRcRd)yO(CRcRd)ySiRcRcRc (e.g. (2-(trimethylsilyl)ethoxy)methyl).
According to yet another embodiment, specifically provided are compounds of formula (lb), in which R is selected from Ci_8alkyl (e.g. methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl or heptyl), Ci_8alkoxyCi_8alkyl (e.g. methyoxyethyl, or 3-methoxypropyl), hydroxyCi_8alkyl (e.g. 2-hydroxyethyl, 4-hydroxybutyl, 3- hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl or 6-hydroxyhexyl), -(CH2)yC(0)NRcRd (e.g. 4-amino-4-oxobutyl), -(CH2)yNRcRd (e.g. 2-(dimethylamino)ethyl), C6-i4aryl (e.g. phenyl), C3_i2cycloalkylCi_8alkyl (e.g. cyclopropylmethyl or cyclohexylmethyl), C6-i4arylCi_ 8alkyl (e.g. benzyl or phenethyl), 3 to 15 membered heterocyclylCi_8alkyl (e.g 4- morpholinobutyl, 4-(piperazin-l-yl)butyl, 4-(azetidin-l-yl)butyl, 3-(azetidin-l-yl)propyl or azetidin-l-ylethyl), 5 to 15 membered heteroaryl (e.g 4-oxo-3,4-dihydro-2H- benzo[e][l,3]oxazin-7-yl or 4-oxo-3,4-dihydroquinazolin-7-yl), 5 to 15 membered heteroarylCi_8alkyl (e.g. (thiazol-4-yl)methyl, (thiazol-4-yl)propyl, thiazol-4-ylethyl, pyridin- 3-ylmethyl, 3-(lH-pyrazol-4-yl)propyl, 6-oxo-l,6-dihydropyridin-3-ylmethyl, imidazo[l,2- a]pyridin-6-ylmethyl, imidazo[5,l-b]thiazol-3-ylmethyl, lH-imidazol-l-yl)ethyl, thiophen-2- yl or pyridin-4-ylmethyl), -(CRcRd)yORc (e.g 2-ethoxyethyl, 3-methoxy-3-methylbutyl, 3- (pyridin-3-yloxy)propyl, 2-(pyridin-4-yloxy)ethyl or 4-(pyridin-3-yloxy)butyl) and - (CRcRd)yO(CRcRd)ySiRcRcRc (e.g. (2-(trimethylsilyl)ethoxy)methyl)each of which being optionally substituted by one or more R6.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which R is selected from Ci_8alkyl (e.g. methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl or heptyl), Ci_8alkoxyCi_8alkyl (e.g. methyoxyethyl, or 3-methoxypropyl), hydroxyCi_8alkyl (e.g. 2-hydroxyethyl, 4-hydroxybutyl, 3- hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl or 6-hydroxyhexyl), -(CH2)yC(0)NRcRd (e.g. 4-amino-4-oxobutyl), -(CH2)yNRcRd (e.g. 2-(dimethylamino)ethyl), C6-i4aryl (e.g. phenyl), C3_i2cycloalkylCi_8alkyl (e.g. cyclopropylmethyl or cyclohexylmethyl), C6-i4arylCi_ galkyl (e.g. benzyl or phenethyl), 3 to 15 membered heterocyclylCi_8alkyl (e.g 4- morpholinobutyl, 4-(piperazin-l-yl)butyl, 4-(azetidin-l-yl)butyl, 3-(azetidin-l-yl)propyl or azetidin-l-ylethyl), 5 to 15 membered heteroaryl (e.g 4-oxo-3,4-dihydro-2H- benzo[e][l,3]oxazin-7-yl or 4-oxo-3,4-dihydroquinazolin-7-yl), 5 to 15 membered heteroarylCi-galkyl (e.g. (thiazol-4-yl)methyl, (thiazol-4-yl)propyl, thiazol-4-ylethyl, pyridin- 3-ylmethyl, 3-(lH-pyrazol-4-yl)propyl, 6-oxo-l,6-dihydropyridin-3-ylmethyl, imidazo[l,2- a]pyridin-6-ylmethyl, imidazo[5,l-b]thiazol-3-ylmethyl, lH-imidazol-l-yl)ethyl, thiophen-2- yl or pyridin-4-ylmethyl), -(CRcRd)yORc (e.g 2-ethoxyethyl, 3-methoxy-3-methylbutyl, 3- (pyridin-3-yloxy)propyl, 2-(pyridin-4-yloxy)ethyl or 4-(pyridin-3-yloxy)butyl) and - (CRcRd)yO(CRcRd)ySiRcRcRc (e.g. (2-(trimethylsilyl)ethoxy)methyl) each of which being optionally substituted by one or more R6. In this embodiment Rc and Rd are independently selected from hydrogen, Ci_4alkyl (e.g. methyl or ethyl), 5 to 15 membered heteroaryl (e.g. 3- pyridyl or 4-pyridyl) and 'y' is 0, 1, 2, 3 or 4.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which R is selected from C1-8alkyl (e.g. methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl or heptyl), Ci_8alkoxyCi_8alkyl (e.g. methyoxyethyl, or 3-methoxypropyl), hydroxyCi_8alkyl (e.g. 2-hydroxyethyl, 4-hydroxybutyl, 3- hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl or 6-hydroxyhexyl), -(CH2)yC(0)NRcRd (e.g. 4-amino-4-oxobutyl), -(CH2)yNRcRd (e.g. 2-(dimethylamino)ethyl), C6-i4aryl (e.g. phenyl), C3_i2cycloalkylCi_8alkyl (e.g. cyclopropylmethyl or cyclohexylmethyl), C6-i4arylCi_ 8alkyl (e.g. benzyl or phenethyl), 3 to 15 membered heterocyclylCi_8alkyl (e.g 4- morpholinobutyl, 4-(piperazin-l-yl)butyl, 4-(azetidin-l-yl)butyl, 3-(azetidin-l-yl)propyl or azetidin-l-ylethyl), 5 to 15 membered heteroaryl (e.g 4-oxo-3,4-dihydro-2H- benzo[e][l,3]oxazin-7-yl or 4-oxo-3,4-dihydroquinazolin-7-yl), 5 to 15 membered heteroarylCi-8alkyl (e.g. (thiazol-4-yl)methyl, (thiazol-4-yl)propyl, thiazol-4-ylethyl, pyridin- 3-ylmethyl, 3-(lH-pyrazol-4-yl)propyl, 6-oxo-l,6-dihydropyridin-3-ylmethyl, imidazo[l,2- a]pyridin-6-ylmethyl, imidazo[5,l-b]thiazol-3-ylmethyl, lH-imidazol-l-yl)ethyl, thiophen-2- yl or pyridin-4-ylmethyl), -(CRcRd)yORc (e.g 2-ethoxyethyl, 3-methoxy-3-methylbutyl, 3- (pyridin-3-yloxy)propyl, 2-(pyridin-4-yloxy)ethyl or 4-(pyridin-3-yloxy)butyl) and - (CRcRd)yO(CRcRd)ySiRcRcRc (e.g. (2-(trimethylsilyl)ethoxy)methyl) each of which being optionally substituted by one or more R6. In this embodiment Rc and Rd are independently selected from hydrogen, methyl, ethyl, 3-pyridyl, 4-pyridyl and 'y' is 0, 1, 2, 3 or 4.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which R is methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4- methylpentyl, hexyl, heptyl, methyoxyethyl, 3-methoxypropyl, 2-hydroxyethyl, 4- hydroxybutyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, 4- amino-4-oxobutyl, 2-(dimethylamino)ethyl, phenyl, cyclopropylmethyl, cyclohexylmethyl, benzyl, phenethyl, 4-morpholinobutyl, 4-(piperazin-l-yl)butyl, 4-(azetidin-l-yl)butyl, 3- (azetidin-l-yl)propyl, azetidin-l-ylethyl, 4-oxo-3,4-dihydro-2H-benzo[e][l,3]oxazin-7-yl, 4- oxo-3,4-dihydroquinazolin-7-yl, (thiazol-4-yl)methyl, (thiazol-4-yl)propyl, thiazol-4-ylethyl, pyridin-3-ylmethyl, 3-(lH-pyrazol-4-yl)propyl, 6-oxo-l,6-dihydropyridin-3-ylmethyl, imidazo[l,2-a]pyridin-6-ylmethyl, imidazo[5,l-b]thiazol-3-ylmethyl, lH-imidazol-l-yl)ethyl, thiophen-2-yl, pyridin-4-ylmethyl, 2-ethoxyethyl, 3-methoxy-3-methylbutyl, 3-(pyridin-3- yloxy)propyl, 2-(pyridin-4-yloxy)ethyl, 4-(pyridin-3-yloxy)butyl and (2- (trimethylsilyl)ethoxy)methyl) each of which being optionally substituted by one or more R6.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which R6 is selected from cyano, hydroxyl, carbamoyl, halogen (e.g. chloro or fluoro), haloCi-galkyl (e.g. trifluoromethyl), Ci_8alkyl (e.g. methyl or ethyl), Ci_8alkoxy (e.g. methoxy, ethoxy or 3-isobutoxy), hydroxyCi_8alkyl (e.g. 3-hydroxypropyl), 5 to 15 membered heteroaryl (e.g. tetrazolyl or 5-oxo-2,5-dihydro-l,2,4-oxadiazol-3-yl), -(CH2)yNReC(0)Rf (e.g. 4-hydroxybenzamido, acetamidomethyl, isobutyramidomethyl or acetamido), - 0(CReRf)yRe (e.g. 2-hydroxyethoxy), -S(0)zRe (e.g. methylsulfonyl) and C3-i2cycloalkyl (e.g. cyclohexyl) or two R6 together with the 'C atom to which they are attached, form a C3_ i2cycloalkyl ring (e.g. cyclohexyl) or a 3 to 15 membered heterocyclyl ring (e.g. tetrahydropyran) .
According to yet another embodiment, specifically provided are compounds of formula (lb), in which R6 is selected from cyano, hydroxyl, carbamoyl, halogen (e.g. chloro or fluoro), haloCi_8alkyl (e.g. trifluoromethyl), Ci_8alkyl (e.g. methyl or ethyl), Ci_8alkoxy (e.g. methoxy, ethoxy or 3-isobutoxy), hydroxyCi_8alkyl (e.g. 3-hydroxypropyl), 5 to 15 membered heteroaryl (e.g. tetrazolyl or 5-oxo-2,5-dihydro-l,2,4-oxadiazol-3-yl), -(CH2)yNReC(0)Rf (e.g. 4-hydroxybenzamido, acetamidomethyl, isobutyramidomethyl or acetamido), - 0(CReRf)yRe (e.g. 2-hydroxyethoxy), -S(0)zRe (e.g. methylsulfonyl) and C3_i2cycloalkyl (e.g. cyclohexyl) or two R6 together with the 'C atom to which they are attached, form a C3_ i2cycloalkyl ring (e.g. cyclohexyl) or a 3 to 15 membered heterocyclyl ring (e.g. tetrahydropyran). In this embodiment Re and Rf are independently selected from hydrogen, hydroxyl, Ci_4alkyl (e.g. methyl, ethyl or isopropyl), C6 i4aryl optionally substituted by hydroxyl (e.g. 4-hydroxyphenyl), 5 to 15 membered heteroaryl (e.g. 3-pyridyl or 4-pyridyl), 'y' is 0, 1, 2, 3 or 4 and 'z' is 2.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which R6 is selected from cyano, hydroxyl, carbamoyl, halogen (e.g. chloro or fluoro), haloCi-galkyl (e.g. trifluoromethyl), Ci_8alkyl (e.g. methyl or ethyl), Ci_8alkoxy (e.g. methoxy, ethoxy or 3-isobutoxy), hydroxyCi_8alkyl (e.g. 3-hydroxypropyl), 5 to 15 membered heteroaryl (e.g. tetrazolyl or 5-oxo-2,5-dihydro-l,2,4-oxadiazol-3-yl), -(CH2)yNReC(0)Rf (e.g. 4-hydroxybenzamido, acetamidomethyl, isobutyramidomethyl or acetamido), - 0(CReRf)yRe (e.g. 2-hydroxyethoxy), -S(0)zRe (e.g. methylsulfonyl) and C3-i2cycloalkyl (e.g. cyclohexyl) or two R6 together with the 'C atom to which they are attached, form a C3_ i2cycloalkyl ring (e.g. cyclohexyl) or a 3 to 15 membered heterocyclyl ring (e.g. tetrahydropyran). In this embodiment Re and Rf are independently selected from hydrogen, hydroxyl, methyl, ethyl, isopropyl, 4-hydroxyphenyl, 3-pyridyl and 4-pyridyl), 'y' is 0, 1, 2, 3 or 4 and 'z' is 2.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which R6 is selected from cyano, hydroxyl, carbamoyl, chloro, fluoro, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, 3-isobutoxy, 3-hydroxypropyl, tetrazolyl, 5- oxo-2,5-dihydro- l,2,4-oxadiazol-3-yl, 4-hydroxybenzamido, acetamidomethyl, acetamido, isobutyramidomethyl, 2-hydroxyethoxy, methylsulfonyl and cyclohexyl or two R6 together with the 'C atom to which they are attached, form cyclohexyl ring or a tetrahydropyran ring.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which R is selected from Ci_8alkyl (e.g. methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl or heptyl), Ci_8alkoxyCi_8alkyl (e.g. methyoxyethyl or 3-methoxypropyl), hydroxyCi_8alkyl (e.g. 2-hydroxyethyl, 4-hydroxybutyl, 3- hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl or 6-hydroxyhexyl), -(CH2)yC(0)NRcRd (e.g. 4-amino-4-oxobutyl), -(CH2)yNRcRd (e.g. 2-(dimethylamino)ethyl), C6-i4aryl (e.g. 4- carbamoyl-3-isobutoxyphenyl, 4-(5H-tetrazolyl-5-yl)phenyl, 4-(lH-tetrazol-5-yl)phenyl, 4- cyanophenyl, 4-carbamoylphenyl, 4-carbamoyl-3-chlorophenyl, 4-acetamido-2-methylphenyl, 4-carbamoyl-2-methylphenyl, 4-carbamoyl-3-methylphenyl, 4-(5-oxo-2,5-dihydro- 1,2,4- oxadiazol-3-yl)phenyl, 4-(4-hydroxybenzamido)phenyl, 4-carbamoyl-2-fluorophenyl, 4- carbamoyl-3-(trifluoromethyl)phenyl, 4-carbamoyl-3-(3-hydroxypropyl)phenyl, 4-carbamoyl- 3-ethylphenyl, 4-carbamoyl-3-methoxyphenyl, 4-carbamoyl-3-hydroxyphenyl, 4-carbamoyl- 3- ethoxyphenyl, 4-carbamoyl-3-(2-hydroxyethoxy)phenyl or 4-carbamoyl-3-hydroxyphenyl), C3-i2cycloalkylCi_8alkyl (e.g. cyclopropylmethyl or cyclohexylmethyl), C6-i4arylCi_8alkyl (e.g. benzyl, 3-carbamoylbenzyl, 4-carbamoylbenzyl, 4-(acetamidomethyl)benzyl, 3- (acetamidomethyl)benzyl, 4-carbamoyl-3-methoxybenzyl, 3-cyanobenzyl, 4-cyanobenzyl, 4- hydroxyphenethyl, 4-acetamidophenethyl or 4-(methylsulfonyl)phenethyl), 3 to 15 membered heterocyclylCi_8alkyl (e.g 4-morpholinobutyl, 4-(4-methylpiperazin- l-yl)butyl, 2-(3- carbamoylazetidin- l-yl)ethyl, 4-(3-hydroxyazetidin- l-yl)butyl, 3-(3-hydroxyazetidin-l- yl)propyl, 2-(azetidin-l-yl)ethyl, 2-(3-hydroxyazetidin-l-yl)ethyl or 3-(3-hydroxyazetidin-l- yl)propyl), 5 to 15 membered heteroaryl (e.g. 2,2-dimethyl-4-oxo-3,4-dihydro-2H- benzo[e][l,3]oxazin-7-yl, 4-oxo-3,4-dihydrospiro[benzo[e] [l,3]oxazine-2,l'-cyclohexan]-7-yl,
4- oxo-2',3,3',4,5',6'-hexahydrospiro[benzo[e] [l,3]oxazine-2,4'-pyran]-7-yl or 2-methyl-4-oxo- 3,4-dihydroquinazolin-7-yl), 5 to 15 membered heteroarylCi_8alkyl (e.g. pyridin-4-ylmethyl, pyridin-3-ylmethyl, (2-carbamoyl-5-methylthiazol-4-yl)methyl, 2-chloro-5- (isobutyramidomethyl)benzyl, 3-(2-carbamoylthiazol-4-yl)propyl, 2-carbamoylthiazol-4- yl)methyl, 2-(2-acetamidothiazol-4-yl)ethyl, 3-(lH-pyrazol-4-yl)propyl, (l-methyl-6-oxo- l,6- dihydropyridin-3-yl)methyl, imidazo[l,2-a]pyridin-6-ylmethyl, (6-methoxypyridin-3- yl)methyl, imidazo[5,l-b]thiazol-3-ylmethyl, (6-carbamoylpyridin-3-yl)methyl, (2- methoxypyridin-4-yl)methyl, 2-(lH-imidazol- l-yl)ethyl, 2-carbamoylpyridin-4-yl)methyl, (6- cyanopyridin-3-yl)methyl, 2-cyanopyridin-4-yl)methyl, 2-methylpyridin-4-yl)methyl or (5- carbamoylthiophen-2-yl)methyl), -(CRcRd)yORc (e.g 2-ethoxyethyl, 3-methoxy-3-methylbutyl,
3- (pyridin-3-yloxy)propyl, 2-(pyridin-4-yloxy)ethyl or 4-(pyridin-3-yloxy)butyl) and - (CRcRd)yO(CRcRd)ySiRcRcRc (e.g. (2-(trimethylsilyl)ethoxy)methyl).
According to yet another embodiment, specifically provided are compounds of formula (lb), in which R is selected from Ci_8alkyl (e.g. methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl or heptyl), Ci_8alkoxyCi_8alkyl (e.g. methyoxyethyl or 3-methoxypropyl), hydroxyCi_8alkyl (e.g. 2-hydroxyethyl, 4-hydroxybutyl, 3- hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl or 6-hydroxyhexyl), -(CH2)yC(0)NRcRd (e.g. 4-amino-4-oxobutyl), -(CH2)yNRcRd (e.g. 2-(dimethylamino)ethyl), C6-i4aryl (e.g. 4- carbamoyl-3-isobutoxyphenyl, 4-(5H-tetrazolyl-5-yl)phenyl, 4-(lH-tetrazol-5-yl)phenyl, 4- cyanophenyl, 4-carbamoylphenyl, 4-carbamoyl-3-chlorophenyl, 4-acetamido-2-methylphenyl,
4- carbamoyl-2-methylphenyl, 4-carbamoyl-3-methylphenyl, 4-(5-oxo-2,5-dihydro- 1,2,4- oxadiazol-3-yl)phenyl, 4-(4-hydroxybenzamido)phenyl, 4-carbamoyl-2-fluorophenyl, 4- carbamoyl-3-(trifluoromethyl)phenyl, 4-carbamoyl-3-(3-hydroxypropyl)phenyl, 4-carbamoyl- 3-ethylphenyl, 4-carbamoyl-3-methoxyphenyl, 4-carbamoyl-3-hydroxyphenyl, 4-carbamoyl- 3- ethoxyphenyl, 4-carbamoyl-3-(2-hydroxyethoxy)phenyl or 4-carbamoyl-3-hydroxyphenyl), C3-i2cycloalkylCi_8alkyl (e.g. cyclopropylmethyl or cyclohexylmethyl), C6-i4arylCi_8alkyl (e.g. benzyl, 3-carbamoylbenzyl, 4-carbamoylbenzyl, 4-(acetamidomethyl)benzyl, 3- (acetamidomethyl)benzyl, 4-carbamoyl-3-methoxybenzyl, 3-cyanobenzyl, 4-cyanobenzyl, 4- hydroxyphenethyl, 4-acetamidophenethyl or 4-(methylsulfonyl)phenethyl), 3 to 15 membered heterocyclylCi_8alkyl (e.g 4-morpholinobutyl, 4-(4-methylpiperazin- l-yl)butyl, 2-(3- carbamoylazetidin- l-yl)ethyl, 4-(3-hydroxyazetidin- l-yl)butyl, 3-(3-hydroxyazetidin-l- yl)propyl, 2-(azetidin-l-yl)ethyl, 2-(3-hydroxyazetidin-l-yl)ethyl or 3-(3-hydroxyazetidin-l- yl)propyl), 5 to 15 membered heteroaryl (e.g. 2,2-dimethyl-4-oxo-3,4-dihydro-2H- benzo[e][l,3]oxazin-7-yl, 4-oxo-3,4-dihydrospiro[benzo[e] [l,3]oxazine-2,l'-cyclohexan]-7-yl,
4- oxo-2',3,3',4,5',6'-hexahydrospiro[benzo[e] [l,3]oxazine-2,4'-pyran]-7-yl or 2-methyl-4-oxo- 3,4-dihydroquinazolin-7-yl), 5 to 15 membered heteroarylCi_8alkyl (e.g. pyridin-4-ylmethyl, pyridin-3-ylmethyl, (2-carbamoyl-5-methylthiazol-4-yl)methyl, 2-chloro-5- (isobutyramidomethyl)benzyl, 3-(2-carbamoylthiazol-4-yl)propyl, 2-carbamoylthiazol-4- yl)methyl, 2-(2-acetamidothiazol-4-yl)ethyl, 3-(lH-pyrazol-4-yl)propyl, (l-methyl-6-oxo- l,6- dihydropyridin-3-yl)methyl, imidazo[l,2-a]pyridin-6-ylmethyl, (6-methoxypyridin-3- yl)methyl, imidazo[5,l-b]thiazol-3-ylmethyl, (6-carbamoylpyridin-3-yl)methyl, (2- methoxypyridin-4-yl)methyl, 2-(lH-imidazol- l-yl)ethyl, 2-carbamoylpyridin-4-yl)methyl, (6- cyanopyridin-3-yl)methyl, 2-cyanopyridin-4-yl)methyl, 2-methylpyridin-4-yl)methyl or (5- carbamoylthiophen-2-yl)methyl), -(CRcRd)yORc (e.g 2-ethoxyethyl, 3-methoxy-3-methylbutyl,
3- (pyridin-3-yloxy)propyl, 2-(pyridin-4-yloxy)ethyl or 4-(pyridin-3-yloxy)butyl) and - (CRcRd)yO(CRcRd)ySiRcRcRc (e.g. (2-(trimethylsilyl)ethoxy)methyl). In this embodiment Rc and Rd are independently selected from hydrogen, Ci_4alkyl (e.g. methyl or ethyl), 5 to 15 membered heteroaryl (e.g. 3-pyridyl or 4-pyridyl) and 'y' is 0, 1, 2, 3 or 4.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which R is selected from Ci_8alkyl (e.g. methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl or heptyl), Ci_8alkoxyCi_8alkyl (e.g. methyoxyethyl or 3-methoxypropyl), hydroxyCi_8alkyl (e.g. 2-hydroxyethyl, 4-hydroxybutyl, 3- hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl or 6-hydroxyhexyl), -(CH2)yC(0)NRcRd (e.g. 4-amino-4-oxobutyl), -(CH2)yNRcRd (e.g. 2-(dimethylamino)ethyl), C6-i4aryl (e.g. 4- carbamoyl-3-isobutoxyphenyl, 4-(5H-tetrazolyl-5-yl)phenyl, 4-(lH-tetrazol-5-yl)phenyl, 4- cyanophenyl, 4-carbamoylphenyl, 4-carbamoyl-3-chlorophenyl, 4-acetamido-2-methylphenyl,
4- carbamoyl-2-methylphenyl, 4-carbamoyl-3-methylphenyl, 4-(5-oxo-2,5-dihydro- 1,2,4- oxadiazol-3-yl)phenyl, 4-(4-hydroxybenzamido)phenyl, 4-carbamoyl-2-fluorophenyl, 4- carbamoyl-3-(trifluoromethyl)phenyl, 4-carbamoyl-3-(3-hydroxypropyl)phenyl, 4-carbamoyl- 3-ethylphenyl, 4-carbamoyl-3-methoxyphenyl, 4-carbamoyl-3-hydroxyphenyl, 4-carbamoyl-
3- ethoxyphenyl, 4-carbamoyl-3-(2-hydroxyethoxy)phenyl or 4-carbamoyl-3-hydroxyphenyl), C3-i2cycloalkylCi_8alkyl (e.g. cyclopropylmethyl or cyclohexylmethyl), C6-i4arylCi_8alkyl (e.g. benzyl, 3-carbamoylbenzyl, 4-carbamoylbenzyl, 4-(acetamidomethyl)benzyl, 3- (acetamidomethyl)benzyl, 4-carbamoyl-3-methoxybenzyl, 3-cyanobenzyl, 4-cyanobenzyl, 4- hydroxyphenethyl, 4-acetamidophenethyl or 4-(methylsulfonyl)phenethyl), 3 to 15 membered heterocyclylCi-galkyl (e.g 4-morpholinobutyl, 4-(4-methylpiperazin- l-yl)butyl, 2-(3- carbamoylazetidin- l-yl)ethyl, 4-(3-hydroxyazetidin- l-yl)butyl, 3-(3-hydroxyazetidin-l- yl)propyl, 2-(azetidin-l-yl)ethyl, 2-(3-hydroxyazetidin-l-yl)ethyl or 3-(3-hydroxyazetidin-l- yl)propyl), 5 to 15 membered heteroaryl (e.g. 2,2-dimethyl-4-oxo-3,4-dihydro-2H- benzo[e][l,3]oxazin-7-yl, 4-oxo-3,4-dihydrospiro[benzo[e] [l,3]oxazine-2,l'-cyclohexan]-7-yl,
4- oxo-2',3,3',4,5',6'-hexahydrospiro[benzo[e] [l,3]oxazine-2,4'-pyran]-7-yl or 2-methyl-4-oxo- 3,4-dihydroquinazolin-7-yl), 5 to 15 membered heteroarylCi-galkyl (e.g. pyridin-4-ylmethyl, pyridin-3-ylmethyl, (2-carbamoyl-5-methylthiazol-4-yl)methyl, 2-chloro-5- (isobutyramidomethyl)benzyl, 3-(2-carbamoylthiazol-4-yl)propyl, 2-carbamoylthiazol-4- yl)methyl, 2-(2-acetamidothiazol-4-yl)ethyl, 3-(lH-pyrazol-4-yl)propyl, (l-methyl-6-oxo- l,6- dihydropyridin-3-yl)methyl, imidazo[l,2-a]pyridin-6-ylmethyl, (6-methoxypyridin-3- yl)methyl, imidazo[5,l-b]thiazol-3-ylmethyl, (6-carbamoylpyridin-3-yl)methyl, (2- methoxypyridin-4-yl)methyl, 2-(lH-imidazol- l-yl)ethyl, 2-carbamoylpyridin-4-yl)methyl, (6- cyanopyridin-3-yl)methyl, 2-cyanopyridin-4-yl)methyl, 2-methylpyridin-4-yl)methyl or (5- carbamoylthiophen-2-yl)methyl), -(CRcRd)yORc (e.g 2-ethoxyethyl, 3-methoxy-3-methylbutyl, 3-(pyridin-3-yloxy)propyl, 2-(pyridin-4-yloxy)ethyl or 4-(pyridin-3-yloxy)butyl) and - (CRcRd)yO(CRcRd)ySiRcRcRc (e.g. (2-(trimethylsilyl)ethoxy)methyl). In this embodiment Rc and Rd are independently selected from hydrogen, methyl, ethyl, 3-pyridyl, 4-pyridyl and 'y' is 0, 1, 2, 3 or 4.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which R is selected from methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl, heptyl, methyoxyethyl, 3-methoxypropyl, 2-hydroxyethyl, 4- hydroxybutyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, 4- amino-4-oxobutyl, 2-(dimethylamino)ethyl, 4-carbamoyl-3-isobutoxyphenyl, 4-(5H- tetrazolyl-5-yl)phenyl, 4-(lH-tetrazol-5-yl)phenyl, 4-cyanophenyl, 4-carbamoylphenyl, 4- carbamoyl-3-chlorophenyl, 4-acetamido-2-methylphenyl, 4-carbamoyl-2-methylphenyl, 4- carbamoyl-3-methylphenyl, 4-(5-oxo-2,5-dihydro- l,2,4-oxadiazol-3-yl)phenyl, 4-(4- hydroxybenzamido)phenyl, 4-carbamoyl-2-fluorophenyl, 4-carbamoyl-3-
(trifluoromethyl)phenyl, 4-carbamoyl-3-(3-hydroxypropyl)phenyl, 4-carbamoyl-3- ethylphenyl, 4-carbamoyl-3-methoxyphenyl, 4-carbamoyl-3-hydroxyphenyl, 4-carbamoyl-3- ethoxyphenyl, 4-carbamoyl-3-(2-hydroxyethoxy)phenyl, 4-carbamoyl-3-hydroxyphenyl, cyclopropylmethyl, cyclohexylmethyl, benzyl, 3-carbamoylbenzyl, 4-carbamoylbenzyl, 4- (acetamidomethyl)benzyl, 3-(acetamidomethyl)benzyl, 4-carbamoyl-3-methoxybenzyl, 3- cyanobenzyl, 4-cyanobenzyl, 4-hydroxyphenethyl, 4-acetamidophenethyl, 4- (methylsulfonyl)phenethyl, 4-morpholinobutyl, 4-(4-methylpiperazin- l-yl)butyl, 2-(3- carbamoylazetidin- l-yl)ethyl, 4-(3-hydroxyazetidin- l-yl)butyl, 3-(3-hydroxyazetidin-l- yl)propyl, 2-(azetidin- l-yl)ethyl, 2-(3-hydroxyazetidin-l-yl)ethyl, 3-(3-hydroxyazetidin-l- yl)propyl, 2,2-dimethyl-4-oxo-3,4-dihydro-2H-benzo[e] [l,3]oxazin-7-yl, 4-oxo-3,4- dihydrospiro[benzo[e] [l,3]oxazine-2, l'-cyclohexan]-7-yl, 4-oxo-2',3,3',4,5',6'- hexahydrospiro[benzo[e] [l,3]oxazine-2,4'-pyran]-7-yl, 2-methyl-4-oxo-3,4- dihydroquinazolin-7-yl, pyridin-4-ylmethyl, pyridin-3-ylmethyl, (2-carbamoyl-5- methylthiazol-4-yl)methyl, 2-chloro-5-(isobutyramidomethyl)benzyl, 3-(2-carbamoylthiazol- 4-yl)propyl, 2-carbamoylthiazol-4-yl)methyl, 2-(2-acetamidothiazol-4-yl)ethyl, 3-(lH- pyrazol-4-yl)propyl, (l-methyl-6-oxo- l,6-dihydropyridin-3-yl)methyl, imidazo[l,2-a]pyridin- 6-ylmethyl, (6-methoxypyridin-3-yl)methyl, imidazo[5, l-b]thiazol-3-ylmethyl, (6- carbamoylpyridin-3-yl)methyl, (2-methoxypyridin-4-yl)methyl, 2-(lH-imidazol- l-yl)ethyl, 2- carbamoylpyridin-4-yl)methyl, (6-cyanopyridin-3-yl)methyl, 2-cyanopyridin-4-yl)methyl, 2- methylpyridin-4-yl)methyl, (5-carbamoylthiophen-2-yl)methyl, 2-ethoxyethyl, 3-methoxy-3- methylbutyl, 3-(pyridin-3-yloxy)propyl, 2-(pyridin-4-yloxy)ethyl, 4-(pyridin-3-yloxy)butyl) and (2-(trimethylsilyl)ethoxy)methyl).
According to yet another embodiment, specifically provided are compounds of formula (lb), in which R5 is selected from hydrogen, Ci-galkyl (e.g. methyl or butyl) and C3_ i2cycloalkyl (e.g. cyclohexyl).
According to yet another embodiment, specifically provided are compounds of formula (lb), in which R5 is selected from hydrogen, butyl and cyclohexyl.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which m is 0 or 1.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which n is 0 or 1.
According to yet another embodiment, specifically provided are compounds of formula (lb), wherein,
Figure imgf000022_0001
Ra is hydrogen, Ci_8alkyl (e.g. methyl or ethyl), -(CRcRd)yOC(0)Rc (e.g. (Pivaloyloxy)methyl) or -(CH2)yC(0)ORc (e.g. 2-Ethoxy-2-oxoethyl),
R1 is hydroxyl, Ci_8alkyl (e.g. methyl or ethyl), Ci_8alkoxy (e.g. methoxy), halogen (e.g. chloro, bromo or fluoro) or haloCi_8alkyl (e.g. trifluoromethyl),
R is Ci_8alkyl (e.g. methyl),
R is Ci-8alkyl (e.g. methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4- methylpentyl, hexyl or heptyl), Ci_8alkoxyCi_8alkyl (e.g. methyoxyethyl, or 3-methoxypropyl), hydroxyCi_8alkyl (e.g. 2-hydroxyethyl, 4-hydroxybutyl, 3-hydroxypropyl, 4-hydroxybutyl, 5- hydroxypentyl or 6-hydroxyhexyl), -(CH2)yC(0)NRcRd (e.g. 4-amino-4-oxobutyl), (CH2)yNRcRd (e.g. 2-(dimethylamino)ethyl), C6-i4aryl (e.g. phenyl), C3-i2cycloalkylCi_8alkyl (e.g. cyclopropylmethyl or cyclohexylmethyl), C6-i4arylCi_8alkyl (e.g. benzyl or phenethyl), 3 to 15 membered heterocyclylCi_8alkyl (e.g 4-morpholinobutyl, 4-(piperazin-l-yl)butyl, 4- (azetidin-l-yl)butyl, 3-(azetidin-l-yl)propyl or azetidin-l-ylethyl), 5 to 15 membered heteroaryl (e.g 4-oxo-3,4-dihydro-2H-benzo[e][l,3]oxazin-7-yl or 4-oxo-3,4- dihydroquinazolin-7-yl), 5 to 15 membered heteroarylCi_8alkyl (e.g. (thiazol-4-yl)methyl, (thiazol-4-yl)propyl, thiazol-4-ylethyl, pyridin-3-ylmethyl, 3-(lH-pyrazol-4-yl)propyl, 6-oxo- 1 ,6-dihydropyridin-3-ylmethyl, imidazo[ 1 ,2-a]pyridin-6-ylmethyl, imidazo[5, l-b]thiazol-3- ylmethyl, lH-imidazol-l-yl)ethyl, thiophen-2-yl or pyridin-4-ylmethyl), -(CRcRd)yORc (e.g 2- ethoxyethyl, 3-methoxy-3-methylbutyl, 3-(pyridin-3-yloxy)propyl, 2-(pyridin-4-yloxy)ethyl or 4-(pyridin-3-yloxy)butyl) or -(CRcRd)yO(CRcRd)ySiRcRcRc (e.g. (2- (trimethylsilyl)ethoxy)methyl) each of which being optionally substituted by one or more R6,
R6 is cyano, hydroxyl, carbamoyl, halogen (e.g. chloro or fluoro), haloCi_8alkyl (e.g. trifluoromethyl), Ci_8alkyl (e.g. methyl or ethyl), Ci_8alkoxy (e.g. methoxy, ethoxy or 3- isobutoxy), hydroxyCi_8alkyl (e.g. 3-hydroxypropyl), 5 to 15 membered heteroaryl (e.g. tetrazolyl or 5-oxo-2,5-dihydro-l,2,4-oxadiazol-3-yl), -(CH2)yNReC(0)Rf (e.g. 4- hydroxybenzamido, acetamidomethyl, isobutyramidomethyl or acetamido), -0(CReRf)yRe (e.g. 2-hydroxyethoxy), -S(0)zRe (e.g. methylsulfonyl), C3_i2cycloalkyl (e.g. cyclohexyl) or two R6 together with the 'C atom to which they are attached, form a C3_i2cycloalkyl ring (e.g. cyclohexyl) or a 3 to 15 membered heterocyclyl ring (e.g. tetrahydropyran),
R5 is hydrogen, Ci-galkyl (e.g. methyl or butyl) or C3_i2cycloalkyl (e.g. cyclohexyl), Re and Rf are hydrogen, hydroxyl, Ci_4alkyl (e.g. methyl, ethyl or isopropyl), C6-i4aryl optionally substituted by hydroxyl (e.g. 4-hydroxyphenyl) or 5 to 15 membered heteroaryl
(e.g. 3-pyridyl or 4-pyridyl),
'y' is 0, 1, 2, 3 or 4, 'z' is 2, m is 0 or 1 and n is 0 or 1.
According to yet another embodiment, specifically provided are compounds of formula (lb),
wherein,
Figure imgf000023_0001
R is hydroxyl, methyl, ethyl, methoxy, chloro, bromo, fluoro or trifluoromethyl, R is methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl, heptyl, methyoxyethyl, 3-methoxypropyl, 2-hydroxyethyl, 4-hydroxybutyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, 4-amino-4-oxobutyl, 2-
(dimethylamino)ethyl, phenyl, cyclopropylmethyl, cyclohexylmethyl, benzyl, phenethyl, 4- morpholinobutyl, 4-(piperazin-l-yl)butyl, 4-(azetidin-l-yl)butyl, 3-(azetidin-l-yl)propyl, azetidin-l-ylethyl, 4-oxo-3,4-dihydro-2H-benzo[e][l,3]oxazin-7-yl, 4-oxo-3,4- dihydroquinazolin-7-yl, (thiazol-4-yl)methyl, (thiazol-4-yl)propyl, thiazol-4-ylethyl, pyridin- 3-ylmethyl, 3-(lH-pyrazol-4-yl)propyl, 6-oxo-l,6-dihydropyridin-3-ylmethyl, imidazo[l,2- a]pyridin-6-ylmethyl, imidazo[5,l-b]thiazol-3-ylmethyl, lH-imidazol-l-yl)ethyl, thiophen-2- yl, pyridin-4-ylmethyl, 2-ethoxyethyl, 3-methoxy-3-methylbutyl, 3-(pyridin-3-yloxy)propyl, 2-(pyridin-4-yloxy)ethyl, 4-(pyridin-3-yloxy)butyl or (2-(trimethylsilyl)ethoxy)methyl) each of which being optionally substituted by one or more R6, R is cyano, hydroxyl, carbamoyl, chloro, fluoro, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, 3-isobutoxy, 3-hydroxypropyl, tetrazolyl, 5-oxo-2,5-dihydro- 1,2,4- oxadiazol-3-yl, 4-hydroxybenzamido, acetamidomethyl, acetamido, isobutyramidomethyl, 2- hydroxyethoxy, methylsulfonyl, cyclohexyl or two R6 together with the 'C atom to which they are attached, form cyclohexyl ring or a tetrahydropyran ring,
R5 is hydrogen, butyl or cyclohexyl,
m is 0 or 1 and n is 0 or 1.
According to one embodiment, specifically provided are compounds of formula (lb) with an IC50 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 (Ic)
Figure imgf000024_0001
(Ic)
or a pharmaceutically acceptable salt thereof,
wherein,
A is selected from
Figure imgf000024_0002
selected from
Figure imgf000024_0003
Ra is selected from hydrogen, Ci_8alkyl, -(CRcRd)yOC(0)Rc and -(CH2)yC(0)ORc; at each occurrence, R1 is independently selected from halogen, hydroxyl, Ci_8alkyl, Ci_ 8alkoxy and haloCi_8alkyl; 2
at each occurrence, R is Ci_8alkyl;
U is Ci-galkyl;
V is -CR6, -CH or N;
at each occurrence, R6 is independently selected from halogen, hydroxyl, cyano, carbamoyl, Ci_8alkyl, Ci_8alkoxy, hydroxyCi_8alkyl, haloCi_8alkyl, 5 to 15 membered heteroaryl, -(CH2)yC(0)NReRf, -(CH2)yNReC(0)Rf, -0(CReRf)yRe and -S(0)zRe; or two R6 together with the 'C atom to which they are attached, form a C3_i2cycloalkyl ring or a 3 to 15 membered heterocyclyl ring;
at each occurrence, Rc and Rd are independently selected from hydrogen, Ci_8alkyl and 5 to 15 membered heteroaryl;
at each occurrence, Re and Rf are independently selected from hydrogen, hydroxyl, Ci_ 8alkyl and C6-14aryl; wherein C6 i4aryl is optionally substituted by hydroxyl;
m is selected from '0' to '4', both inclusive;
n is selected from '0' to '3', both inclusive;
y is selected from '0' to '6', both inclusive;
z is selected from '0' to '2', both inclusive; and
p is selected from '0' to '5', both inclusive.
The compounds of formula (Ic) 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. For example, the invention provides compounds of formula (Ic) as defined
above wher (according to one embodiment defined below), A is
COORa or
Figure imgf000025_0001
(according to another embodiment defined below), m is 0 or 1 (according to yet another embodiment defined below), n is 0 or 1 (according to yet another embodiment defined below).
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which Q is
Figure imgf000026_0001
According to yet another embodiment, specifically provided are compounds formula (Ic), in which Q is
OH or
Figure imgf000026_0002
. In this embodiment R is Ci_8alkyl (e.g. methyl) and n is 0 or 1.
According to yet another embodiment, specifically provided are compounds formula (Ic), in which Q is
OH or
Figure imgf000026_0003
. In this embodiment R2 is methyl and n is 0 or 1.
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which Q is
Figure imgf000026_0004
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which Q is OH.
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which Q is
Figure imgf000026_0005
According to yet another embodiment, specifically provided are compounds formula (Ic), in which Q is
Figure imgf000026_0006
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which A is selected from
O
■X and " \
N H
¾Ra N¾ . According to yet another embodiment, specifically provided are compounds of formula (Ic), in which A is selected from
Figure imgf000027_0001
In this embodiment Ra is selected from hydrogen, Ci_8alkyl (e.g. methyl or ethyl), -(CRcRd)yOC(0)Rc (e.g. (Pivaloyloxy)methyl) and -(CH2)yC(0)ORc (e.g. 2- Ethoxy-2-oxoethyl).
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which A is selected from
Figure imgf000027_0002
and CN . In this embodiment Ra is selected from hydrogen, Ci_8alkyl (e.g. methyl or ethyl), -(CRcRd)yOC(0)Rc (e.g. (Pivaloyloxy)methyl) and -(CH2)yC(0)ORc (e.g. 2- Ethoxy-2-oxoethyl), Rc is hydrogen or Ci_8alkyl (e.g. ethyl or tert-butyl), Rdis hydrogen and y is 1.
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which A is selected from
Figure imgf000027_0003
and 'X N N> . In this embodiment Ra is selected from hydrogen, methyl, ethyl, (Pivaloyloxy)methyl and 2-Ethoxy-2-oxoethyl.
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which Ra is selected from hydrogen, Ci_8alkyl (e.g. methyl or ethyl), - (CRcRd)yOC(0)Rc (e.g. (Pivaloyloxy)methyl) and -(CH2)yC(0)ORc (e.g. 2-Ethoxy-2- oxoethyl).
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which Ra is selected from hydrogen, Ci_8alkyl (e.g. methyl or ethyl), - (CRcRd)yOC(0)Rc (e.g. (Pivaloyloxy)methyl) and -(CH2)yC(0)ORc (e.g. 2-Ethoxy-2- oxoethyl). In this embodiment Rc is hydrogen or Ci_8alkyl (e.g. ethyl or tert-butyl), Rd is hydrogen and y is 1.
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which Ra is selected from hydrogen, methyl, ethyl, (Pivaloyloxy)methyl and 2-Ethoxy-2-oxoethyl.
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which A is selected from
Figure imgf000028_0001
According to yet another embodiment, specifically provided are compounds formula (Ic), in which A is selected from
Figure imgf000028_0002
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which A is selected from
Figure imgf000028_0003
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which A is
Figure imgf000028_0004
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which A is
Figure imgf000028_0005
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which R1 is independently selected from hydroxyl, Ci-galkyl (e.g. methyl or ethyl), Ci-galkoxy (e.g. methoxy), halogen (e.g. chloro, bromo or fluoro) and haloCi-galkyl (e.g. trifluoromethyl).
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which R1 is independently selected from hydroxyl, methyl, ethyl, methoxy, chloro, bromo, fluoro and trifluoromethyl.
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which R6 is selected from cyano, hydroxyl, carbamoyl, halogen (e.g. chloro or fluoro), haloCi_8alkyl (e.g. trifluoromethyl), Ci_8alkyl (e.g. methyl or ethyl), Ci_8alkoxy (e.g. methoxy, ethoxy or 3-isobutoxy), hydroxyCi_8alkyl (e.g. 3-hydroxypropyl), 5 to 15 membered heteroaryl (e.g. tetrazolyl or 5-oxo-2,5-dihydro-l,2,4-oxadiazol-3-yl), -(CH2)yNReC(0)Rf (e.g. 4-hydroxybenzamido, acetamidomethyl, isobutyramidomethyl or acetamido), - 0(CReRf)yRe (e.g. 2-hydroxyethoxy) and -S(0)zRe (e.g. methylsulfonyl).
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which R6 is selected from cyano, hydroxyl, carbamoyl, halogen (e.g. chloro or fluoro), haloCi_8alkyl (e.g. trifluoromethyl), Ci_8alkyl (e.g. methyl or ethyl), Ci_8alkoxy (e.g. methoxy, ethoxy or 3-isobutoxy), hydroxyCi_8alkyl (e.g. 3-hydroxypropyl), 5 to 15 membered heteroaryl (e.g. tetrazolyl or 5-oxo-2,5-dihydro-l,2,4-oxadiazol-3-yl), -(CH2)yNReC(0)Rf (e.g. 4-hydroxybenzamido, acetamidomethyl, isobutyramidomethyl or acetamido), - 0(CReRf)yRe (e.g. 2-hydroxyethoxy) and -S(0)zRe (e.g. methylsulfonyl). In this embodiment Re and Rf are independently selected from hydrogen, hydroxyl, Ci_4alkyl (e.g. methyl, ethyl or isopropyl) and C6-i4aryl optionally substituted by hydroxyl (e.g. 4-hydroxyphenyl), 'y' is 0, 1, 2, 3 or 4 and 'z' is 2.
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which R6 is selected from cyano, hydroxyl, carbamoyl, halogen (e.g. chloro or fluoro), haloCi_8alkyl (e.g. trifluoromethyl), Ci_8alkyl (e.g. methyl or ethyl), Ci_8alkoxy (e.g. methoxy, ethoxy or 3-isobutoxy), hydroxyCi_8alkyl (e.g. 3-hydroxypropyl), 5 to 15 membered heteroaryl (e.g. tetrazolyl or 5-oxo-2,5-dihydro-l,2,4-oxadiazol-3-yl), -(CH2)yNReC(0)Rf (e.g. 4-hydroxybenzamido, acetamidomethyl, isobutyramidomethyl or acetamido), - 0(CReRf)yRe (e.g. 2-hydroxyethoxy) and -S(0)zRe (e.g. methylsulfonyl). In this embodiment Re and Rf are independently selected from hydrogen, hydroxyl, methyl, ethyl, isopropyl, and 4-hydroxyphenyl, 'y' is 0, 1, 2, 3 or 4 and 'z' is 2.
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which R6 is selected from cyano, hydroxyl, carbamoyl, chloro, fluoro, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, 3-isobutoxy, 3-hydroxypropyl, tetrazolyl, 5- oxo-2,5-dihydro- 1 ,2,4-oxadiazol-3-yl, 4-hydroxybenzamido, acetamidomethyl, isobutyramidomethyl, acetamido, 2-hydroxyethoxy and methylsulfonyl.
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which U is Ci_8alkyl (e.g. methyl, ethyl, propyl or butyl).
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which U is methyl, ethyl, propyl or butyl.
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which V is -CR6, CH or N.
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which V is -C(cyano), -C(hydroxyl), -C(carbamoyl), -C(halogen) (e.g. -C(C1) or -C(F)), -C(haloCi_8alkyl) (e.g. -C(CF3)),-C(Ci_8alkyl) (e.g. -C(CH3) or -C(C2H5)), -C(d- 8alkoxy) (e.g. -C(methoxy), -C(ethoxy) or -C(3-isobutoxy)), -C(hydroxyCi_8alkyl) (e.g. -C(3- hydroxypropyl)), -C(5 to 15 membered heteroaryl) (e.g. -C(tetrazolyl) or -C(5-oxo-2,5- dihydro-l,2,4-oxadiazol-3-yl)), -C(-(CH2)yNReC(0)Rf) (e.g. -C(4-hydroxybenzamido), - C(acetamidomethyl), -C(isobutyramidomethyl) or -C(acetamido)), -C(-0(CReRf)yRe) (e.g. - C(2-hydroxyethoxy)) and -C(-S(0)zRe) (e.g. -C(methylsulfonyl)), CH or N.
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which V is -C(cyano), -C(hydroxyl), -C(carbamoyl), -C(halogen) (e.g. -C(C1) or -C(F)), -C(halod_8alkyl) (e.g. -C(CF3)),-C(d_8alkyl) (e.g. -C(CH3) or -C(C2H5)), -C(d_ 8alkoxy) (e.g. -C(methoxy), -C(ethoxy) or -C(3-isobutoxy)), -C(hydroxyCi_8alkyl) (e.g. -C(3- hydroxypropyl)), -C(5 to 15 membered heteroaryl) (e.g. -C(tetrazolyl) or -C(5-oxo-2,5- dihydro-l,2,4-oxadiazol-3-yl)), -C(-(CH2)yNReC(0)Rf) (e.g. -C(4-hydroxybenzamido), - C(acetamidomethyl), -C(isobutyramidomethyl) or -C(acetamido)), -C(-0(CReRf)yRe) (e.g. - C(2-hydroxyethoxy)) and -C(-S(0)zRe) (e.g. -C(methylsulfonyl)), CH or N. In this embodiment Re and Rf are independently selected from hydrogen, hydroxyl, Ci_4alkyl (e.g. methyl, ethyl or isopropyl) and C6-i4aryl optionally substituted by hydroxyl (e.g. 4- hydroxyphenyl), 'y' is 0, 1, 2, 3 or 4 and 'z' is 2.
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which V is -C(cyano), -C(hydroxyl), -C(carbamoyl), -C(halogen) (e.g. -C(C1) or -C(F)), -C(halod_8alkyl) (e.g. -C(CF3)),-C(d_8alkyl) (e.g. -C(CH3) or -C(C2H5)), -C(d_ 8alkoxy) (e.g. -C(methoxy), -C(ethoxy) or -C(3-isobutoxy)), -C(hydroxyCi_8alkyl) (e.g. -C(3- hydroxypropyl)), -C(5 to 15 membered heteroaryl) (e.g. -C(tetrazolyl) or -C(5-oxo-2,5- dihydro-l,2,4-oxadiazol-3-yl)), -C(-(CH2)yNReC(0)Rf) (e.g. -C(4-hydroxybenzamido), - C(acetamidomethyl), -C(isobutyramidomethyl) or -C(acetamido)), -C(-0(CReRf)yRe) (e.g. - C(2-hydroxyethoxy)) and -C(-S(0)zRe) (e.g. -C(methylsulfonyl)), CH or N. In this embodiment Re and Rf are independently selected from hydrogen, hydroxyl, methyl, ethyl, isopropyl, and 4-hydroxyphenyl, 'y' is 0, 1, 2, 3 or 4 and 'z' is 2.
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which V is -C(cyano), -C(hydroxyl), -C(carbamoyl), -C(C1), -C(F)), -C(CF3)), -C(CH3), -C(C2H5), -C(methoxy), -C(ethoxy) or -C(3-isobutoxy)), -C(3-hydroxypropyl)), - C(tetrazolyl), -C(5-oxo-2,5-dihydro-l,2,4-oxadiazol-3-yl), -C(4-hydroxybenzamido), C(acetamidomethyl), -C(isobutyramidomethyl) or -C(acetamido)), -C(2-hydroxyethoxy), - C(methylsulfonyl)), CH or N. According to yet another embodiment, specifically provided are compounds of formula (Ic), in which m is 0 or 1.
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which n is 0 or 1.
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which p is 0, 1 or 2.
According to yet another embodiment, specifically provided are compounds of formula (Ic),
wherein,
Figure imgf000031_0001
A is
Figure imgf000031_0002
Ra is hydrogen, Ci_8alkyl (e.g. methyl or ethyl), -(CRcRd)yOC(0)Rc (e.g. (Pivaloyloxy)methyl) or -(CH2)yC(0)ORc (e.g. 2-Ethoxy-2-oxoethyl),
R1 is hydroxyl, Ci_8alkyl (e.g. methyl or ethyl), Ci_8alkoxy (e.g. methoxy), halogen (e.g. chloro, bromo or fluoro) or haloCi_8alkyl (e.g. trifluoromethyl),
R is Ci-8alkyl (e.g. methyl),
R6 is cyano, hydroxyl, carbamoyl, halogen (e.g. chloro or fluoro), haloCi_8alkyl (e.g. trifluoromethyl), Ci_8alkyl (e.g. methyl or ethyl), Ci_8alkoxy (e.g. methoxy, ethoxy or 3- isobutoxy), hydroxyCi_8alkyl (e.g. 3-hydroxypropyl), 5 to 15 membered heteroaryl (e.g. tetrazolyl or 5-oxo-2,5-dihydro-l,2,4-oxadiazol-3-yl), -(CH2)yNReC(0)Rf (e.g. 4- hydroxybenzamido, acetamidomethyl, isobutyramidomethyl or acetamido), -0(CReRf)yRe (e.g. 2-hydroxyethoxy) or -S(0)zRe (e.g. methylsulfonyl),
R5 is hydrogen, Ci_8alkyl (e.g. methyl or butyl) or C3_i2cycloalkyl (e.g. cyclohexyl),
U is Ci_8alkyl (e.g. methyl, ethyl, propyl or butyl),
V is -CR6, CH or N,
Re and Rf are hydrogen, hydroxyl, Ci_4alkyl (e.g. methyl, ethyl or isopropyl) or C6- i4aryl optionally substituted by hydroxyl (e.g. 4-hydroxyphenyl),
'y' is 0, 1, 2, 3 or 4, z is 2, p is 0, 1 or 2, m is 0 or 1 and n is 0 or 1. According to yet another embodiment, specifically provided are compounds of formula (Ic),
wherein,
Figure imgf000032_0001
R is hydroxyl, methyl, ethyl, methoxy, chloro, bromo, fluoro or trifluoromethyl.
R6 is cyano, hydroxyl, carbamoyl, chloro, fluoro, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, 3-isobutoxy, 3-hydroxypropyl, tetrazolyl, 5-oxo-2,5-dihydro- 1,2,4- oxadiazol-3-yl, 4-hydroxybenzamido, acetamidomethyl, isobutyramidomethyl, acetamido, 2- hydroxyethoxy or methylsulfonyl,
R5 is hydrogen, butyl or cyclohexyl,
U is methyl, ethyl, propyl or butyl,
V is -C(cyano), -C(hydroxyl), -C(carbamoyl), -C(C1), -C(F)), -C(CF3)), -C(CH3), - C(C2H5), -C(methoxy), -C(ethoxy) or -C(3-isobutoxy)), -C (3-hydroxypropyl)), -C (tetrazolyl), -C(5-oxo-2,5-dihydro-l,2,4-oxadiazol-3-yl), -C(4-hydroxybenzamido), -C (acetamidomethyl), -C(isobutyramidomethyl) or -C(acetamido)), -C(2-hydroxyethoxy), -C(methylsulfonyl)), CH or N,
P is 0, 1 or 2, m is 0 or 1 and n is 0 or 1.
According to one embodiment, specifically provided are compounds of formula (Ic) with an IC50 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.
Compounds of the present invention include the compounds in Examples 1-184.
It should be understood that the formulas (I), (la), (lb) and (Ic) structurally encompasses all geometrical isomers, stereoisomers, enantiomers and diastereomers, N-oxides, and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the genera described herein. As disclosed herein, 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). Preferably, 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.
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.
In another aspect, 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.
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 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 apoptosis occurring (e.g., heart failure, atherosclerosis, heart failure); degenerative neurologic disorders; arthritis; liver injury (e.g., drug induced, ischemic or alcoholic)); impotence; sleep apnea; diabetic wound healing; cutaneous infections; treatment of psoriasis; obesity (e.g., eating in response to craving for food, thyroid disease); stroke, reperfusion injury (e.g., traumatic muscle injury in heart or lung or crush injury), disorders where preconditioning of heart or brain for NO protection against subsequent ischemic events is beneficial; central nervous system (CNS) disorders (e.g., anxiety, depression, psychosis, and schizophrenia); and infections caused by bacteria (e.g., tuberculosis, C. difficile infections).
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 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, tuberculosis and C. difficile infections. 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 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).
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 one or more diseases, conditions and/or disorders selected from asthma, cystic fibrosis and Chronic obstructive pulmonary disease (COPD).
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 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.
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 Chronic obstructive pulmonary disease (COPD).
In yet another aspect, 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, 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, tuberculosis and C. difficile infections.
In yet another aspect, 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 Chronic obstructive pulmonary disease (COPD).
In yet another aspect, 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 asthma, cystic fibrosis and Chronic obstructive pulmonary disease (COPD).
DETAILED DESCRIPTION OF THE INVENTION
Definitions
The terms "halogen" or "halo" means fluorine (fluoro), chlorine (chloro), bromine
(bromo), or iodine (iodo).
The term "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_8alkyl), 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). The term "Ci_6 alkyl" refers to an alkyl chain having 1 to 6 carbon atoms. The term "Ci_4alkyl" 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.
The term "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 -OCH3 and - OC2H5. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched.
The term "alkoxy alkyl" 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_8alkoxyCi_8alkyl or Ci-8alkyloxyCi_8alkyl). Example of such alkoxyalkyl moiety includes, but are not limited to, - CH2OCH3 and -CH2OC2H5. Unless set forth or recited to the contrary, all alkoxyalkyl groups described herein may be straight chain or branched.
The term "alkenyl" refers to a hydrocarbon chain containing from 2 to 10 carbon atoms (i.e. C2-10 alkenyl) and including at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), z'so-propenyl, 2- methyl-l-propenyl, 1-butenyl, and 2-butenyl.
The term "alkynyl" refers to a hydrocarbyl radical having at least one carbon-carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred i.e. C2-10 alkynyl). Non-limiting examples of alkynyl groups include ethynyl, propynyl, and butynyl.
The term "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_8alkyl). Examples of such 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.
The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms (i.e. haloCi_8alkoxy). Examples of "haloalkoxy" include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1-bromoethoxy. Unless set forth or recited to the contrary, all haloalkoxy groups described herein may be straight chain or branched.
The term "hydroxy alkyl" 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_8alkyl). Examples of hydroxyalkyl moieties include, but are not limited to - CH2OH, -C2H4OH and -CH(OH)C2H4OH.
The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, (i.e.C3_i2cycloalkyl). Examples of monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of 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. The term "C3_6cycloalkyl" refers to the cyclic ring having 3 to 6 carbon atoms.
The term "cycloalkylalkyl" refers to a cyclic ring-containing radical having 3 to about 6 carbon atoms directly attached to an alkyl group (i.e. C3_6cycloalkylCi_8alkyl). 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.
The term "cycloalkenyl" refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, for example C3_8cycloalkenyl, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl.
The term "cycloalkenylalkyl" refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, directly attached to an alkyl group, for example C3_8cycloalkenylCi_8alkyl. The cycloalkenylalkyl 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.
The term "aryl" refers to an aromatic radical having 6 to 14 carbon atoms (i.e. C6- i4aryl), including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
The term "aryloxy" refers to an aryl group as defined above attached via an oxygen linkage to the rest of the molecule (i.e. C6 i4aryloxy). Examples of aryloxy moiety include, but are not limited to phenoxy and naphthoxy.
The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, i.e. C6-i4arylCi_8alkyl, such as -CH2C6H5 and -C2H4C6H5.
The term "heterocyclic ring" or "heterocyclyl" unless otherwise specified refers to 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. In addition, the nitrogen atom may be optionally quaternized; also, unless otherwise constrained by the definition the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s). Examples of such 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, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4- piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl or tetrahydrofuranyl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide and thiamorpholinyl sulfone. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
The term "heterocyclylalkyl" refers to a heterocyclic ring radical directly bonded to an alkyl group (i.e. 3 to 15 membered heterocyclylCi_8alkyl). 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. The term "heteroaryl" unless otherwise specified refers to 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. Examples of such 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, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl and phthalazinyl.
The term "5 or 6 membered heteroaryl" unless otherwise specified refers to 5 to 6 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S. The heteroaryl is a monocyclic ring system. Examples of such heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and thiadiazolyl.
The term "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.
The term "pharmaceutically acceptable salt" includes salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids. Examples of such salts 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, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Examples of salts derived from inorganic bases include, but are not limited to, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, and zinc.
The term "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.
The term "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).
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. Pharmaceutical Compositions
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. Typically, 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.
Examples of 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.
The pharmaceutical 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.
The pharmaceutical 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.
The pharmaceutical compositions described herein may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20th Ed., 2003 (Lippincott Williams & Wilkins).
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. Methods of Treatment
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.
In particular, 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 apoptosis occurring (e.g., heart failure, atherosclerosis, heart failure); degenerative neurologic disorders; arthritis; liver injury (e.g., drug induced, ischemic or alcoholic)); impotence; sleep apnea; diabetic wound healing; cutaneous infections; treatment of psoriasis; obesity (e.g., eating in response to craving for food, thyroid disease); stroke, reperfusion injury (e.g., traumatic muscle injury in heart or lung or crush injury), disorders where preconditioning of heart or brain for NO protection against subsequent ischemic events is beneficial; central nervous system (CNS) disorders (e.g., anxiety, depression, psychosis, and schizophrenia); and infections caused by bacteria (e.g., tuberculosis, C. difficile infections, among others).
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)).
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.
The compounds of the present invention may be used for treatment of respiratory disorders including, chronic obstructive pulmonary disease (COPD), cyctic fibrosis and asthma.
The compounds of the present invention may be used for treatment of chronic obstructive pulmonary disease (COPD).
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 and mediastinum, pulmonary congestion and hypostasis, postinflammatory pulmonary fibrosis, other alveolar and parietoalveolar pneumonopathy, idiopathic fibrosing alveolitis, Hamman-Rich syndrome, atelectasis, ARDS, acute respiratory failure, mediastinitis.
Any of the methods of treatment described herein comprise administering an effective amount of a compound according to Formula (I), (la), (lb) or (Ic), or a pharmaceutically- acceptable salt thereof, to a subject (particularly a human) in need thereof. 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. For the above-mentioned therapeutic uses 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. General Methods of Preparation
The compounds described herein, including compounds of formula (I), formula (la), formula (lb) and formula (Ic) and specific examples can be prepared using techniques known to one skilled in the art through the reaction sequences depicted in schemes 1 and 2, as well as by other methods. Furthermore, in the following schemes, where specific acids, bases, reagents, coupling agents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents, solvents etc. may be used and are included within the scope of the present invention. The modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof, are envisioned as part of the present invention. The compounds obtained using the general reaction sequence may be of insufficient purity. These compounds can be purified using any of the methods for purification of organic compounds known to persons skilled in the art, for example, crystallization or silica gel or alumina column chromatography using different solvents in suitable ratios. All possible geometrical isomers and stereoisomers are envisioned within the scope of this invention.
The starting materials used herein are commercially available or were prepared by the methods known in the art to those of ordinary skill or by methods disclosed herein. In general, the intermediates and compounds of the present invention may be prepared through the reaction schemes as follows.
A general approach for the preparation of thienopyrrole compounds of the formula (I) is depicted in scheme 1, wherein P, Q, X, A, R 1 , R3 , R 5 and m are as defined in formula (I). Scheme
Figure imgf000045_0001
The synthesis of compound of formula (I) can be performed as described in Synthetic scheme 1. The compound of formula (1) (wherein Z is an ester or any group which can be subsequently converted to A following the methods known to one skilled in the art) is reacted with the compound of formula (2) (wherein LG is an appropriate leaving group) to give compound of formula (I). In an embodiment the reaction may be carried out in presence of a suitable base. In an embodiment the base may be sodium hydride or potassium carbonate. In another embodiment the reaction may be carried out in a suitable solvent. In an embodiment the solvent may be selected from N,N-dimethyl formamide and dimethyl sulfoxide. In another embodiment the reaction may be carried out at a suitable temperature. In an embodiment the reaction may be carried out in the temperature range of 25-250°C.
Subsequently, Z can be converted to A to obtain compound of formula (I) following the methods known to one skilled in the art. In an embodiment, when Z is an ester group, it is hydrolyzed to a carboxylic acid. In an embodiment the hydrolysis reaction may be carried out in presence of a suitable base. In an embodiment the base may be selected from lithium hydroxide and sodium hydroxide. In another embodiment the reaction may be carried out in a suitable solvent or combinations of solvents. In an embodiment the solvent may be tetrahydrofuran, methanol, water or combination thereof. In another embodiment the reaction may be carried out at a suitable temperature. In an embodiment the reaction may be carried out in the temperature range of 25-250°C. In an embodiment, when Z is a nitrile group, it is converted to a tetrazole group. The reaction may be carried out in presence of a suitable reagent to obtain compound of formula (I). In an emdodiment the reagents may be sodium azide, ammonium chloride or combination thereof. In another embodiment the reaction may be carried out in a suitable solvent. In an embodiment the solvent may be N,N-dimethyl formamide or dimethyl sulfoxide. In another embodiment the reaction may be carried out at a suitable temperature range. The reaction may be carried out in a temperature range of 25-
250°C. Thienopyrrole compound of the formula (lb) can be prepared by using a general approach as depicted in scheme 2, wherein A, Q, R 1 , R3 , R 5 and m are as defined in formula (I).
Scheme 2:
Figure imgf000046_0001
The synthesis of the compound of formula (lb) is performed as described in synthetic scheme 2. In an embodiment the substituted thiophene compound of formula (3) may be treated with an appropriate aldehyde compound of formula (4) to obtain the compound of formula (5). In an embodiment the reaction may be carried out in the presence of an appropriate base. In an embodiment the base may be pyrrolidine. In another embodiment the reaction may be carried out in the presence of a suitable solvent or mixture of solvents. In an embodiment the reaction may be carried out in methanol. In another embodiment the reaction may be carried out at a suitable temperature. In an embodiment the reaction may be carried out at a temperature range of 25-250°C. Subsequently, the compound of formula (5) may be converted to the compound of formula (6). In an embodiment the conversion of compound of formula (5) to compound of formula (6) may be accomplished in presence of an appropriate organophosphorous reagent. In an embodiment, the organophosphorous reagent may be triphenyl phosphine. In an embodiment the reaction may be carried out in the presence of suitable solvent or mixture of solvents. In an embodiment the reaction may be carried out in the presence of 1,2-dichlorobenzene. In another embodiment the reaction may be carried out at a suitable temperature. In an embodiment the reaction may be carried out at a temperature range of 20-200°C. In an embodiment the compound of formula (6) is converted to compound of formula (lb) in presence of a suitable reagent. In an embodiment, when Z is an ester group, it is hydrolyzed to A which is a carboxylic acid to give compound of formula (lb). In an embodiment the hydrolysis reaction may be carried out in presence of a suitable base. In an embodiment the base may be selected from lithium hydroxide and sodium hydroxide. In an embodiment the reaction may be carried out in a suitable solvent or combinations of solvents. In an embodiment the solvent may be tetrahydrofuran, methanol, water or combination thereof. In another embodiment the reaction may be carried out at a suitable temperature. In an embodiment the reaction may be carried out at a suitable temperature range of 25-250°C. In another embodiment, when Z is a nitrile group, it is converted to A which is tetrazole to obtain compound of formula (lb). In an embodiment this reaction may be carried out in presence of suitable reagents such as sodium azide, ammonium chloride or combination thereof. In another embodiment the reaction may be carried out in a suitable solvent. In an embodiment the solvent may be N,N-dimethyl formamide or dimethyl sulfoxide. In another embodiment the reaction may be carried out at a suitable temperature. In an embodiment the reaction may be carried out at a temperature range of 25-250°C.
EXPERIMENTAL
The intermediates required for the synthesis are commercially available or alternatively, these intermediates can be prepared using known literature methods. The invention is described in greater detail by way of specific examples.
Unless otherwise stated, 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, unless otherwise mentioned, 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. The following abbreviations are used in the text: CDC13: Deuterated chloroform; CH2CI2: Dichloromethane; BBr3: Boron tribromide; Br2: Bromine; CHC13: Chloroform; CH3I: Methyl iodide; (CH3)3SiCHN2: Trimethylsilyldiazomethane; CuCN: Copper(I) cyanide; Cul: Copper(I) iodide; DIBAL-H: Diisobutylaluminium hydride; DIPEA: Ν,Ν-Diisopropylethylamine; DMF: Dimethylformamide; DMSO: Dimethyl sulfoxide; DMSO-i : Hexadeuterodimethyl sulfoxide; Et3N: Triethylamine; EtOH: Ethanol; Et20: Diethyl ether; EtOAc: Ethyl acetate; HC1: Hydrochloric acid; H2S04: Sulfuric acid; H202: Hydrogen peroxide; H20: Water; K2C03: Potassium carbonate; LiOH: Lithium hydroxide; MeOH: Methanol; NaBH4: Sodium borohydride; NaH: Sodium hydride; NaHC03: Sodium bicarbonate; Nal: Sodium iodide; Na/K: Sodium/Potassium; NaN3: Sodium azide; NaOH: Sodium hydroxide; NH3: Ammonia; NH4C1: Ammonium chloride; NH4OH: Ammonium hydroxide; NMP: N-Methyl-2- pyrrolidone; LiAlH4: Lithium aluminium hydride; Mn02: Manganese dioxide; NaOAc: Sodium acetate; Pd/C: Palladium on carbon; Pd(PPh3)4:
Tetrakis(triphenylphosphine)palladium(0); Pd(OAc)2: Palladium(II) acetate; PPh3: Triphenylphosphane; THF: Tetrahydrofuran; aq.: Aqueous; cone: Concentrated; °C: Degree Celsius; g: Gram; h: Hours; M: Molarity; mg: Milligrams; mL: Milliliter; μL·^. Microliter; mmol: Millimoles; mins: Minutes; N: Normality; RT or rt: Room temperature (22-26°C); 1H NMR: Proton Nuclear Magnetic Resonance; : Coupling constant in units of Hz; MHz: Megahertz; Hz: Hertz; MS: Mass Spectrometry; br: Broad.
The following intermediates required for the synthesis of compounds of the present invention are prepared using the approaches described above in synthetic schemes.
Intermediates
Intermediate 1
Ethyl 5-(4-(lH-imidazol- l-yl)phenyl)-4H-thieno[3,2-^]pyrrole-2-carboxylate
Figure imgf000048_0001
Step- 1 : Preparation of 4-(lH-imidazol-l-yl)benzaldehyde
Figure imgf000048_0002
To a solution of 4-fluorobenzaldehyde (1.0 g, 8.06 mmol) in DMF (3 mL) were added 1H- imidazole (2.1 g, 32.2 mmol) and K2C03 (2.2 g, 16.12 mmol). The reaction mass was heated at reflux for 6 h before it was diluted with water and was extracted with EtOAc. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 1.0 g of the title product. 1H NMR (300 MHz, DMSO d6) δ 10.03 (s, 1H), 8.47 (s, 1H), 8.07-8.04 (d, = 8.4 Hz, 2H), 7.95-7.93 (m, 3H), 7.17 (s, 1H); MS (m/z): 173 (M+H)+.
Step-2: Preparation of 5-methyl-4-nitrothiophene-2-carboxylic acid
Figure imgf000048_0003
To a mixture of acetic anhydride (17.92 g, 175.4 mmol) and fuming nitric acid (4.7 mL) was added 5-methylthiophene-2-carboxylic acid (5.0 g, 35.21 mmol) at -70°C over a period of 10- 20 mins. The reaction mixture was allowed to warm to -20°C and was stirred for 30-40 mins at the same temperature. Then the reaction mixture was treated with ice-water and the precipitated solid was filtered. The solid was further dissolved in EtOAc and was extracted with a saturated aqueous solution of NaHC03. The aqueous layer was acidified with cone. HC1 and the precipitated solid was filtered and dried to afford 4.0 g of the title product. 1H NMR (300 MHz, DMSO d6) δ 13.82 (br s, 1H), 8.03 (s, 1H), 2.79 (s, 3H).
Step-3: Preparation of ethyl 5-methyl- -nitrothiophene-2-carboxylate
Figure imgf000049_0001
To a solution of 5-methyl-4-nitrothiophene-2-carboxylic acid (4.0 g, 21.4 mmol) in ethanol (30 mL) was added cone. H2S04 (1.5 mL) and the reaction mixture was heated at reflux for 16 h. Then the reaction mixture was diluted with EtOAc. The organic layer was washed with water and brine. The organic layer was separated, dried, filtered and concentrated to afford
3.6 g of the title product. 1H NMR (300 MHz, DMSO d6) δ 8.09 (s, 1H), 4.34-4.27 (q, = 6.9 Hz, 2H), 2.79 (s, 3H), 1.32-1.27 (t, = 6.9 Hz, 3H).
Step-4: Preparation of (E)-ethyl 5-(4-(lH-imidazol- l-yl)styryl)-4-nitrothiophene-2- carboxylate
Figure imgf000049_0002
A solution of 4-(lH-imidazol- l-yl)benzaldehyde (1.0 g, 5.81 mmol) and ethyl 5-methyl-4- nitrothiophene-2-carboxylate (1.5 g, 6.97 mmol) in methanol (10 mL) was heated at reflux for 15 mins. Then pyrrolidine (41 mg, 0.52 mmol) was added to the reaction mixture and it was heated at reflux for 2 h. The reaction mass was then concentrated and the residue thus obtained was purified by column chromatography to afford 2.0 g of the title product. 1H NMR (300 MHz, DMSO d6) δ 8.37 (s, 1H), 8.12 (s, 1H), 8.04-7.98 (d, = 15.9 Hz, 1H), 7.87-7.84 (m, 3H), 7.77-7.75 (d, = 7.8 Hz, 2H), 7.68-7.63 (m, 1H), 7.13 (s, 1H), 4.37-4.30 (q, = 7.8 Hz, 2H), 1.34-1.30 (t, = 6.9 Hz, 3H).
Step-5: Preparation of ethyl 5-(4-(lH-imidazol-l-yl)phenyl)-4H-thieno[3,2-^]pyrrole-2- carboxylate
A solution of (E)-ethyl 5-(4-(lH-imidazol- l-yl)styryl)-4-nitrothiophene-2-carboxylate (2.0 g, 5.42 mmol), PPh3 (3.56 g, 13.55 mmol) in 1,2-dichlorobenzene (12.0 mL) was heated at 180- 190°C for 2-4 h. The reaction mass was concentrated and residue was purified by column chromatography to afford 200 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 12.13 (s, IH), 8.35 (s, IH), 7.93-7.90 (d, = 8.7 Hz, 2H),7.83 (s, IH), 7.77-7.74 (d, = 8.1 Hz, 2H), 7.70-7.68 (d, = 6.0 Hz, IH), 7.13 (s, IH), 7.06 (s, IH), 4.30-4.27 (q, = 7.5 Hz, 2H), 1.33- 1.28 (t, = 6.9 Hz, 3H); MS (m/z): 338 (M+H)+.
Table 1 : Following Intermediates were synthesized by following the procedure described above.
Figure imgf000050_0001
b]pyrrole-2-carboxylate
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Examples
Example 1
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-carbamoyl-3-isobutoxyphenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid
Figure imgf000053_0002
Method-A Step- 1 : Preparation of methyl 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-cyano-3- isobutoxyphenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylate
Figure imgf000054_0001
To a solution of methyl 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4H-thieno[3,2-^]pyrrole-2- carboxylate (Intermediate- 3, 300 mg, 0.89 mmol) in DMF (3.0 mL) were added K2C03 (184 mg, 1.30 mmol) and 4-fluoro-2-isobutoxybenzonitrile (700 mg, 3.62 mmol) and the reaction mixture was heated at 130°C for 5-6 h. Then the reaction mixture was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated to afford 364 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 8.42 (s, 1H), 7.82-7.79 (m, 3H), 7.64 (s, 1H), 7.57 (d, 1H), 7.42-7.39 (d, = 7.8 Hz, 1H), 7.17 (t, 2H), 6.91 (s, 1H), 6.86 (s, 1H), 3.83 (s, 3H), 3.60-3.57 (d, J = 6.3 Hz, 2H), 2.12 (s, 3H), 1.80 (m, 1H), 0.79-0.76 (d, J = 6.3 Hz, 6H); MS (m z): 511 (M+H)+.
Step-2: Preparation of methyl 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-carbamoyl-3- isobutoxyphenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylate
Figure imgf000054_0002
To a solution of methyl 5-(4-(lH-imidazol- l-yl)-2-methylphenyl)-4-(4-cyano-3- isobutoxyphenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylate (364 mg, 0.71 mmol) in MeOH (1 mL) were added H202 (2.0mL, 30% in water) and NaOH (71 mg, 71.3 mmol) at 0°C. Then the reaction mass was stirred at rt for 3 h before it was quenched with an aqueous solution of NaHS03 and pH of the mixture was adjusted to 6-7 with an aqueous solution of NaHC03. Then the precipitated solid was filtered and purified by column chromatography to afford 170 mg of the title product. 1H NMR (300 MHz, CDC13) δ 8.63 (s, 1H), 8.19-8.16 (d, = 8.4 Hz, 1H), 7.77 (s, 1H), 7.66 (m, 1H), 7.42-7.39 (m, 5H), 6.88-6.85 (d, J = 9.3 Hz, 1H), 6.70 (s, 1H), 6.64 (s, 1H), 5.98 (s, 1H), 3.91 (s, 3H), 3.63-3.61 (d, = 6.3 Hz, 2H), 2.18 (s, 3H), 2.05 (m, 1H), 1.00-0.97 (d, = 6.9 Hz, 6H); MS (m/z): 529 (M+H)+. Step-3: Preparation of 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-carbamoyl-3- isobutoxyphenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid
To a solution of methyl 5-(4-(lH-imidazol- l-yl)-2-methylphenyl)-4-(4-carbamoyl-3- isobutoxyphenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylate (50 mg, 0.09 mmol) in THF (2.0 mL) was added aqueous solution of LiOH (10 mg, 0.37 mmol in 1.0 mL water). The reaction mass was stirred at rt for 15- 16 h before it was quenched with an aqueous solution of citric acid. The precipitated solid was filtered and dried to afford 25 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 13.00 (br s, IH), 8.32 (s, IH), 7.87-7.84 (d, = 8.4 Hz, IH), 7.79 (s, IH), 7.69-7.55 (m, 4H), 7.43-7.41 (m, 2H), 7.14-7.11 (m, 2H), 6.84 (s, IH), 6.72 (s, IH), 3.52-3.50 (d, = 6.3 Hz, 2H), 2.08 (s, 3H), 1.76 (m, IH), 0.77-0.75 (d, = 6.3 Hz, 6H); MS (m/z): 515 (M+H)+.
Table 2: Following Examples were synthesized by following the procedure described above (Method A).
Figure imgf000055_0001
Figure imgf000056_0001
Example Chemical Name Intermediate Analytical Data No. and Structure
Example 8 Intermediate 1 1H NMR (300 MHz, DMSO
^ \=/ N^-^y DH and d6) δ 8.30 (s, IH), 7.78 (d,
4-fluoro-2- 2H), 7.67-7.65 (d, = 7.2 methylbenzonitrile Hz, 2H), 7.45-7.37 (m, 6H),
NH2 7.10 (br s, 2H), 7.00 (s, IH),
5-(4-(lH-imidazol- l- 2.39 (s, 3H); MS (m/z): 441 yl)phenyl)-4-(4-carbamoyl-3- (M-H)".
methyrphenyl)-4H- thieno[3,2- ]pyrrole-2- carboxylic acid
Example 9 \> Intermediate 4 1H NMR (300 MHz, DMSO and d6) δ 8.35 (s, IH), 7.95 (s,
4-fluorobenzonitrile IH), 7.90-7.87 (d, = 8.4
Hz, 2H), 7.83 (s, IH), 7.43
0 NH2 (m, 2H), 7.29-7.27 (m, 2H),
7.17 (s, IH), 7.10 (s, IH),
5-(4-(lH-imidazol- l-yl)-2- 6.47 (s, IH), 3.39 (s, 3H); methoxyphenyl)-4-(4- MS (m/z): 459 (M+H)+. carbamoylphenyl)-4H- thieno[3,2- ]pyrroe-2- carboxylic acid
Example 10 Intermediate 1 1H NMR (300 MHz, DMSO and d6) δ 8.30 (s, IH), 7.91-7.88
4-fluorobenzonitrile (d, = 8.4 Hz, 2H), 7.77 (s,
IH), 7.68-7.65 (d, = 7.8 Hz, 2H), 7.57 (s, IH), 7.54- 7.51 (d, = 8.4 Hz, 2H),
5-(4-(lH-imidazol- l- 7.39-7.37 (d, = 7.8 Hz, yl)phenyl)-4-(4-(5-oxo-2,5- 2H), 7.10 (s, IH), 7.04 (s, dihydro- 1 ,2,4-oxadiazol-3- IH); MS (m/z): 470 yl)phenyl)-4H-thieno[3,2- (M+H)+.
]pyrrole-2-carboxylic acid
Example 11 Intermediate 5 1H NMR (300 MHz, DMSO and d6) δ 8.38 (s, IH), 7.98 (s,
4-fluorobenzonitrile IH), 7.86 (s, 4H), 7.69 (d,
Η2Ν— IH), 7.59-7.56 (d, = 8.7
Hz, IH), 7.38 (s, IH), 7.28
4-(4-carbamoylphenyl)-5-(2- (br s, 3H), 7.11 (s, IH), 6.75 chloro-4-( lH-imidazol- 1 - (s, IH).
yl)phenyl)-4H-thieno[3,2- &]pyrrole-2-carboxylic acid
Figure imgf000058_0001
Figure imgf000059_0001
Example Chemical Name Intermediate Analytical Data No. and Structure
methylphenyl)-4-(4- 6.52 (s, 1Η), 6.77 (m, 2Η), carbamoyl-3- 2.16 (s, 3H); MS (m/z): 459 hydroxyphenyl) -4H- (M+H)+.
thieno[3,2- ]pyrrole-2- carboxylic acid
Example 21 Intermediate 12 1H NMR (300 MHz, DMSO and d6) δ 7.85-7.83 (d, = 7.8
4-fluoro-2- Hz, IH), 7.71 (s, IH), 7.59 methoxybenzonitrile (s, 2H), 7.48-7.45 (d, = 7.8
° NH2 Hz, IH), 7.34-7.30 (m, 3H),
4-(4-Carbamoyl-3- 7.10-7.06 (d, = 9.6 Hz, methoxyphenyl)-5-(2- IH), 6.91-6.87 (m, 2H), 6.81 methyl-4-(2-methyl- 1H- (s, IH), 3.60 (s, 3H), 2.29 (s, imidazol- 1 -yl)phenyl)-4H- 3H), 2.10 (s, 3H); MS (m/z): thieno[3,2- ]pyrrole-2- 487 (M+H)+. carboxylic acid
Example 22 Intermediate 12 1H NMR (300 MHz, DMSO
\=/ N-J-^y H and d6) δ 13.22 (s, IH), 8.40 (s,
2-(cyclopentyloxy)- IH), 7.99 (s, IH), 7.87-7.84 4-fluorobenzonitrile (d, = 8.4 Hz, IH), 7.64 (s,
NH2 IH), 7.41-7.32 (m, 4H),
4-(4-Carbamoyl-3- 6.93-6.85 (m, 2H), 6.77-6.73 hydroxyphenyl) -5 - (2-methyl- (m, 2H), 2.45 (s, 3H), 2.14 4-(2-methyl- lH-imidazol- 1- (s, 3H); MS (m/z): 473 yl)phenyl)-4H-thieno[3,2- (M+H)+.
]pyrrole-2-carboxylic acid
Example 23 Intermediate 12 1H NMR (300 MHz, DMSO
^ \=/ N^ ΟΗ and d6) δ 7.88-7.85 (d, = 8.4
3-Ethoxy-4- Hz, IH), 7.69 (s, IH), 7.60 fluorobenzonitrile (s, IH), 7.52-7.45 (m, 2H),
NH2 _ 7.34-7.27 (m, 3H), 7.12-7.09
(d, = 7.8 Hz, IH), 6.91 (s,
(4-Carbamoyl-3- IH), 6.86 (s, IH), 6.78 (s, ethoxyphenyl)- 5 - (2-methyl- IH), 3.87-3.85 (q, = 6.9 4-(2-methyl- lH-imidazol- 1- Hz, 2H), 2.29 (s, 3H), 2.08 yl)phenyl)-4H-thieno[3,2- (s, 3H), 1.21- 1.17 (t, J = 6.9 ]pyrrole-2-carboxylic acid
Hz, 3H); MS (m/z): 502 (M+H)+. Example Chemical Name Intermediate Analytical Data No. and Structure
Example 24 Intermediate 12 1H NMR (300 MHz, DMSO and d6) δ 7.92-7.90 (d, = 7.8
4-fluoro-2-(2- Hz, 1H), 7.70 (s, 2H), 7.60
(tetrahydro-2H- (s, 1H), 7.47-7.44 (d, = 7.8
NH2 pyran-2- Hz, 1H), 7.34-7.29 (m, 3H),
4-(4-Carbamoyl-3-(2- yl)ethoxy)benzonitri 7.10-7.07 (d, = 9.0 Hz, hydroxyethoxy )phenyl) - 5 - (2- le 1H), 6.91-6.86 (m, 3H), methyl-4-(2-methyl- 1H- 5.08 (m, 1H), 3.85 (m, 2H), imidazol- 1 -yl)phenyl)-4H- 3.61(m, 2H), 2.29 (s, 3H), thieno[3,2- ]pyrrole-2- 2.10 (s, 3H); MS (m/z): 517 carboxylic acid (M+H)+.
Example 25 s ΟΗ Intermediate 3 1H NMR (300 MHz, DMSO and d6) δ 8.72 (s, 1H), 8.32 (s,
4-fluoro-2- 1H), 7.80 (s, 1H), 7.73-7.70
~ ~& methoxybenzonitrile (d, = 8.1 Hz, 2H), 7.61- 7.55 (m, 2H), 7.46-7.43 (d,
5-(4-(lH-imidazol- l-yl)-2- = 8.4 Hz, 1H), 7.30 (s, 1H), methylphenyl)-4-(2,2- 7.10 (s, 1H), 6.97-6.94 (d, dimethyl-4-oxo-3 ,4-dihydro- = 8.1 Hz, 1H), 6.76 (s, 1H), 2H-benzo [e] [ 1 ,3 ] oxazin-7- 2.09 (s, 3H), 1.47 (s, 6H); yl)-4H-thieno[3,2- ]pyrrole- MS (m/z): 497 (M+H)+. 2-carboxylic acid
Example 26
4-(2-(Hydroxymethyl)-5-(2-methyl-4-(2-methyl- lH-imidazol- l-yl)phenyl)-4H-thieno[3,2- ]pyrrol-4-yl)-2-methoxybenzamide
Figure imgf000061_0001
Step- 1 : Preparation of methyl 4-(4-cyano-3-methoxyphenyl)-5-(2-methyl-4-(2-methyl-lH- imidazol-l-yl)phenyl)-4H-thieno[ -^]pyrrole-2-carboxylate
Figure imgf000061_0002
The title compound was prepared following the procedure described in Method- A, Step- 1, by using methyl 5-(2-methyl-4-(2-methyl-lH-imidazol-l-yl)phenyl)-4H-thieno[3,2-^]pyrrole-2- carboxylate (Intermediate- 12, 430 mg, 1.23 mmol) , K2CO3 (255 mg, 1.85 mmol) and 4- fluoro-2-methoxybenzonitrile (557 mg, 3.7 mmol) in DMF (5.0 mL) to afford 340 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 7.86 (s, 1H), 7.81-7.79 (d, = 8.4 Hz, 1H), 7.49-7.30 (m, 4H), 7.13-7.10 (d, = 8.1 Hz, 1H), 6.96-6.91 (m, 3H), 3.83 (s, 3H), 3.67 (s, 3H), 2.29 (s, 3H), 2.11 (s, 3H); MS (m/z): 483 (M+H)+.
Step-2: Preparation of methyl 4-(4-carbamoyl-3-methoxyphenyl)-5-(2-methyl-4-(2-methyl- lH-imidazol- l-yl)phenyl)-4H-thi -^]pyrrole-2-carboxylate
Figure imgf000062_0001
The title compound was prepared following the procedure described in Method-A, Step-2, by using methyl 4-(4-cyano-3-methoxyphenyl)-5-(2-methyl-4-(2-methyl-lH-imidazol-l- yl)phenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylate ( 280 mg, 0.58 mmol), H202 (0.5 mL, 30% in water) and NaOH (116 mg, 2.90 mmol) in THF: MeOH (1 : 1, 2 mL) to afford 155 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 8.31 (s, 1Η),7.86-7.83 (d, = 8.4 Hz, 1H), 7.79 (s, 1H), 7.58 (m, 2H), 7.48-7.45 (d, = 7.8 Hz, 1H), 7.34-7.30 (m, 2H), 7.10-7.07 (d, =
7.8 Hz, 2H), 6.91-6.89 (d, = 3.9 Hz, 1H), 6.81 (s, 1H), 3.83 (s, 3H), 3.60 (s, 3H), 2.29 (s, 3H), 2.11 (s, 3H); MS (m/z): 501 (M+H)+.
Step-3: Preparation of 4-(2-(hydroxymethyl)-5-(2-methyl-4-(2-methyl-lH-imidazol-l- yl)phenyl)-4H-thieno[3,2-^]pyrrol-4-yl)-2-methoxybenzamide
To a solution of methyl 4-(4-carbamoyl-3-methoxyphenyl)-5-(2-methyl-4-(2-methyl- lH- imidazol-l-yl)phenyl)-4H-thieno[3,2-^]pyrrole-2-carboxylate (150 mg, 0.30 mmol) in THF (2.0 mL) was added L1AIH4 (46 mg, 1.2 mmol). The reaction mixture was stirred at rt for 16 h before it was quenched with an aqueous solution of NH4C1 at 0°C. Then the reaction mixture was diluted with 10% MeOH in CHCI3 and filtered through a pad of Celite. The filtrate was washed with brine, dried, filtered and concentrated to afford to afford 43 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 7.81 (d, 1H), 7.57 (m, 2H), 7.41-7.34 (m, 4H),
7.09 (s, 1H), 7.02 (m, 1H), 6.93 (m, 1H), 6.77-6.73 (m, 2H), 5.46 (m, 1H), 4.67 (d, 2H), 3.63 (s, 3H), 2.32 (s, 3H), 2.09 (s, 3H); MS (m/z): 473 (M+H)+.
Example 27 2-Methoxy-4-(5-(2-methyl-4-(2-methyl H-imidazol -yl)phenyl)-2-(lH-tetrazol-5-yl)-4H- thieno[3,2- ]pyrrol-4-yl)benzami
Figure imgf000063_0001
Method-B
Step- 1 : Preparation of 4-(2-formyl-5-(2-methyl-4-(2-methyl- lH-imidazol-l-yl)phi
thieno[3,2- ]pyrrol-4-yl)-2-methoxybenzamide
Figure imgf000063_0002
To a solution of 4-(2-(hydroxymethyl)-5-(2-methyl-4-(2-methyl-lH-imidazol- l-yl)phenyl)- 4H-thieno[3,2- ]pyrrol-4-yl)-2-methoxybenzamide (Example-26, 218 mg, 0.46 mmol) in THF : CH2C12 (3 mL : 2 mL) was added Mn02 (401 mg, 4.60 mmol) and the reaction mass was stirred at rt for 16 h. The reaction mass was diluted with 10% MeOH in CH2C12 and filtered through Celite. The filtrate was concentrated to afford to afford 173 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 9.89 (s, 1H), 8.17 (s, 1H), 7.85-7.82 (d, = 8.4 Hz, 1H), 7.61 (m, 2H), 7.49-7.46 (d, = 7.8 Hz, 1H), 7.37 (m, 3H), 7.04-7.01(d, = 6.9 Hz, 1H), 6.94 (s, 3H), 3.68 (s, 3H), 2.29 (m, 3H), 2.13 (s, 3H).
Step-2: Preparation of 4-(2-cyano-5-(2-methyl-4-(2-methyl- lH-imidazol- l-yl)phenyl)-4H- thieno[3,2- ]pyrrol-4-yl)-2-methoxybenzamide
Figure imgf000063_0003
To a solution of 4-(2-formyl-5-(2-methyl-4-(2-methyl-lH-imidazol- l-yl)phenyl)-4H- thieno[3,2- ]pyrrol-4-yl)-2-methoxybenzamide (170 mg, 0.36 mmol) in THF (1.0 mL) was added ammonia (5.0 mL) and iodine (459 mg, 1.67 mmol) portion- wise. The reaction mixture was stirred at rt for 16 h before it was quenched with an aqueous solution of sodium bisulphite. Then the reaction mixture was extracted with CHCI3 and the organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 130 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 8.12 (s, 1H), 7.80 (m, 1H), 7.60 (m, 2H), 7.43 (d, 1H), 7.35-7.30 (m, 3H), 6.93-6.91 (m, 4H), 3.69 (s, 3H), 2.28 (s, 3H), 2.10 (s, 3H).
Step-3: Preparation of 2-methoxy-4-(5-(2-methyl-4-(2-methyl- lH-imidazol-l-yl)phenyl)-2- (lH-tetrazol-5-yl)-4H-thieno[3,2- ]pyrrol-4-yl)benzamide
To a solution of 4-(2-cyano-5-(2-methyl-4-(2-methyl-lH-imidazol- l-yl)phenyl)-4H- thieno[3,2- ]pyrrol-4-yl)-2-methoxybenzamide (130 mg, 0.27 mmol) in DMF (2.0 mL) was added NaN3 (216 mg, 3.30 mmol) and NH4C1 (178 mg, 3.34 mmol). The reaction mass was stirred at 130°C for 16 h. The reaction mixture was concentrated and residue was diluted with water. The aqueous solution was acidified with citric acid. The precipitated solid was filtered and dried to afford 10 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 7.87-7.84 (d, = 8.7 Hz, 1H), 7.59-7.56 (m, 2H), 7.46-7.44 (d, = 7.8 Hz, 2H), 7.34 (m, 3H), 7.08-7.06 (d, = 7.8 Hz, 1H), 6.95 (m, 1H), 6.81-679 (d, = 6.0 Hz, 2H), 3.62 (s, 3H), 3.32 (s, 3H), 2.13 (s, 3H); MS (m/z): 509 (M-H)~.
Table 3: Following Examples were synthesized by following the procedure described above (Method B).
Figure imgf000064_0001
Example 29
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-carbamoyl-3-methoxyphenyl)-4H-thieno[3,2- b]pyrrole-2-carboxamide
Figure imgf000065_0001
To a solution of 5-(4-(lH-imidazol- l-yl)-2-methylphenyl)-4-(4-carbamoyl-3- methoxyphenyl)-4H-thieno[3,2-^]pyrrole-2-carboxylic acid (Example-19, 50 mg, 0.10 mmol) in DMSO (4 mL) were added (benzotriazol-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (93 mg, 0.21 mmol), DIPEA (53 mg, 0.42 mmol) and NH4C1 (22 mg, 0.42 mmol). The reaction mass was stirred at rt for 16 h before it was quenched with ice-water and the precipitated solid was filtered and purified by column chromatography to afford 12 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 8.28 (s, 1H), 7.92 (s, 1H), 7.84-7.82 (d, = 8.1 Hz, 1H), 7.73 (s, 1H), 7.54 (s, 1H), 7.50-7.48 (d, = 8.4 Hz, 1H), 7.43-7.40 (d, = 8.1 Hz, 1H), 7.11 (s, 1H), 6.96-6.93 (d, = 8.4 Hz, 1H), 6.84 (s, 1H), 6.76 (s, 1H), 3.65 (s, 3H), 2.09 (s, 3H); MS (m/z): 472 (M+H)+.
Example 30
Methyl 5-(4-(lH-imidazol- l-yl)phenyl)-4-(4-carbamoylphenyl)-4H-thieno[3,2-^]pyrrole-2- carboxylate
Figure imgf000065_0002
To a solution of 5-(4-(lH-imidazol- l-yl)phenyl)-4-(4-carbamoylphenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid (Example-3, 130 mg, 0.30 mmol) in CH2CI2 (5.0 mL) was added (CH3)3SiCHN2 (3.0 mL) at 0°C and the reaction mass was stirred at rt for 30 mins. The reaction mass was concentrated and triturated with Et20 to afford 90 mg of the title product.
1H NMR (300 MHz, DMSO d6) δ 8.30 (s, 1H), 8.07 (s, 1H), 7.98-7.95 (d, = 8.4 Hz, 2H), 7.78 (s, 1H), 7.67-7.61 (d, = 8.4 Hz, 2H), 7.45-7.43 (d, = 7.2 Hz, 2H), 7.38-7.36 (d, = 7.2 Hz, 2H), 7.10 (s, 1H), 7.05 (s, 1H), 3.81 (s, 3H); MS (m/z): 443 (M+H)+.
Example 31
(Pivaloyloxy)methyl 5-(4-(lH-imidazol- l-yl)phenyl)-4-(4-carbamoylphenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylate
Figure imgf000066_0001
To a solution of 5-(4-(lH-imidazol- l-yl)phenyl)-4-(4-carbamoylphenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid (Example-3, 25.0 mg, 0.05 mmol) in DMF (1 mL) were added Nal (21.7 mg, 0.14 mmol), K2C03 (16 mg, 0.11 mmol) and chloromethyl pivalate (13.7 mg, 0.08 mmol). Then the reaction mixture was stirred at rt for 3 h before it was quenched with water. The reaction mixture was extracted with EtOAc and the organic layer was washed with 10% NaHC03 and brine. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 12 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 8.30 (br s, 1H), 8.07 (s, 1H), 7.98-7.95 (d, = 8.4 Hz, 2H), 7.78 (m, 1H), 7.68-7.66 (m, 3H), 7.49 (s, 1H), 7.47-7.44 (d, = 8.1 Hz, 2H), 7.38-7.36 (d, = 8.1 Hz, 2H), 7.08 (s, 2H), 5.90 (s, 2H), 1.14 (s, 9H); MS (m/z): 543 (M+H)+.
Example 32
(Pivaloyloxy)methyl 5-(4-(lH-imidazol- l-yl)-2-methylphenyl)-4-(4-carbamoyl-3- methoxyphenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylate
Figure imgf000066_0002
The title compound was prepared following the procedure described in Example-31 using 5- (4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-carbamoyl-3-methoxyphenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid (Example- 19, 46 mg, 0.09 mmol), Nal (36 mg, 0.24 mmol), K2C03 (26 mg, 0.19 mmol) and chloromethyl pivalate (23 mg, 0.14 mmol) in DMF (1 mL) to afford 37 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 8.30 (s, 1H), 7.82-7.79 (m, 3H), 7.59-7.52 (m, 4H), 7.46 (d, 1H), 7.10 (s, 1H), 7.04-7.02 (d, = 7.8 Hz, 1H), 6.91-6.88 (d, = 7.2 Hz, 2H), 5.92 (s, 2H), 3.63 (s, 3H), 2.13 (s, 3H), 1.15 (s, 9H); MS (m/z): 587 (M+H)+.
Example 33
2-Ethoxy-2-oxoethyl 4-(4-carbamoyl-3-methoxyphenyl)-5-(2-methyl-4-(2-methyl-lH- imidazol-l-yl)phenyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate
Figure imgf000067_0001
The title compound was prepared following the procedure described in Example-31 using 4- (4-carbamoyl-3-methoxyphenyl)-5-(2-methyl-4-(2-methyl- lH-imidazol- l-yl)phenyl)-4H- thieno[3,2- ]pyrrole-2-carboxylic acid (Example-21, 68 mg, 0.13 mmol), ethyl -2- chloroacetate (26 mg, 0.20 mmol), Nal (52 mg, 0.34 mmol) and K2C03 (38 mg, 0.27 mmol) in DMF (0.5 mL) rt for 16 h to afford 25 mg of the title product. 1H NMR (300 MHz, DMSO- d6) δ 7.83-7.82 (m, 2H), 7.57 (m, 2H), 7.48-7.45 (d, = 7.8 Hz, 1H), 7.34-7.28 (m, 3H), 7.10- 7.08 (d, = 7.8 Hz, 1H), 6.90 (s, 2H), 6.82 (s, 1H), 4.87 (s, 2H), 4.19-4.12 (q, = 7.5 Hz, 2H), 3.60 (s, 3H), 2.27 (s, 3H), 2.10 (s, 3H), 1.22-1.17 (t, = 7.2 Hz, 3H); MS (m/z): 573 (M+H)+.
Example 34
5-(4-(lH-imidazol-l-yl)phenyl)-4-ethyl-4H-thieno[3,2-^]pyrrole-2-carboxylic acid
Figure imgf000067_0002
Method-C
Step- 1 : Preparation of ethyl 5-(4-(lH-imidazol-l-yl)phenyl)-4-ethyl-4H-thieno[3,2-^]pyrrole- 2-carboxylate
Figure imgf000067_0003
To a solution ethyl 5-(4-(lH-imidazol- l-yl)phenyl)-4H-thieno[3,2-^]pyrrole-2-carboxylate (Intermediate- 1, 35 mg, 0.1 mmol) in DMF (0.5 mL) was added NaH (8.3 mg, 0.21 mmol, 60% in mineral oil) at 0-5°C. The reaction mass was stirred at RT for 15-20 mins before it was treated with ethyl iodide (48 mg, 0.31 mmol). The reaction mass was stirred at RT for 2-3 h. Then the reaction mass was quenched with an aqueous solution of citric acid. The precipitated solid was filtered and purified by column chromatography to afford 30 mg of the title product. MS (m/z): 366 (M+H)+.
Step-2: Preparation of 5-(4-(lH-imidazol-l-yl)phenyl)-4-ethyl-4H-thieno[3,2-¾pyrrole-2- carboxylic acid The title compound was prepared following the procedure described in Method- A, Step-3, by using ethyl 5-(4-(lH-imidazol- l-yl)phenyl)-4-ethyl-4H-thieno[3,2-^]pyrrole-2-carboxylate (30 mg, 0.08 mmol), LiOH (14 mg, 0.33 mmol in 1.0 mL water) in THF (2.0 mL) to afford 10 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 12.86 (s, IH), 8.36 (s, IH), 7.92 (s, 1H),7.84-7.79 (m, 3H), 7.67-7.64 (d, = 8.4 Hz, 2H), 7.14 (s, IH), 6.62 (s, IH), 4.25-4.22 (q, / = 7.5 Hz, 2H), 1.26-1.21 (t, = 6.9 Hz, 3H); MS (m/z): 338 (M+H)+.
Table 4: Following Examples were synthesized by following the procedure described above
(Method C).
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Example Chemical Name Intermediate Analytical Data
No. and Structure
Example 51 Intermediate 3 1H NMR (300 MHz, DMSO d6)
and δ 12.83 (br s, IH), 8.35 (s, IH),
(2- 7.93 (s, 1H), 7.83 (s, IH), 7.73
(chloromethoxy)eth (s, IH), 7.59 (d, IH), 7.48-7.46 yl)trimethylsilane (d, = 8.1 Hz, IH), 7.14 (s,
5-(4-(lH-imidazol- l-yl)-2- IH), 6.58 (s, IH), 5.30 (s, 2H), methylphenyl)-4-((2- 3.33 (m, 2H), 2.27 (s, 3H), (trimethylsilyl)ethoxy)meth
0.72-0.66 (t, = 7.8 Hz, 2H), yl)-4H-thieno[3,2- 0.13 (s, 9H); MS (m/z): 454 ]pyrrole-2-carboxylic acid
(M+H)+.
Example 52 1H NMR (300 MHz, DMSO d6)
Intermediate 4 δ 8.40 (s, IH), 7.88 (s, IH), and 7.50 (s, IH), 7.39-7.34 (m, 3H),
4-iodo-2- 7.13 (s, IH), 6.28 (s, IH), 3.88 methylbutane (m, 5H), 1.44 (m, IH), 1.00-
5-(4-(lH-im Xidazol- l-yl)-2- 0.95 (t, = 7.2 Hz, 2H), 0.72- methoxyphenyl)-4- 0.70 (d, = 6.0 Hz, 6H); MS isopentyl-4H-thieno [3 ,2- (m/z): 410 (M+H)+. ]pyrrole-2-carboxylic acid
Example 53 Intermediate 3 1H NMR (300 MHz, DMSO d6)
\=/ N'J~^y t)H and δ 12.79 (s, IH), 8.35 (s, IH),
3-methoxy-3- 7.84 (s, 2H), 7.74 (s, IH), 7.60 methyl-1- (d, 1H), 7.48 (d, lH), 7.14 (s,
5-(4-(lH-im -iVdazol- l-yl)-2- iodobutane IH), 6.47 (s, IH), 3.94 (m, 2H), methylphenyl)-4-(3- 2.80 (s, 3H), 2.25 (s, 3H), 1.67 methoxy- 3 -methylbutyl) - (m, 2H), 0.97 (s, 6H); MS 4H-thieno[3,2-£]pyrrole-2- (m/z): 424 (M+H)+. carboxylic acid
Example 54 Intermediate 3 1H NMR (300 MHz, DMSO d6)
\=/ in and δ 13.00 (br s, IH), 8.35 (s, IH),
2-(3- 7.87 (s, IH), 7.83 (s, IH), 7.72 bromopropoxy)tetra (s, IH), 7.61-7.58 (d, = 7.8
5-(4-(lH-imidazol- l-yl)-2- hydro-2H-pyran Hz, IH), 7.46-7.43 (d, = 8.4 methylphenyl)-4-(3- Hz, 1H), 7.13 (s, IH), 6.45 (s, hydroxypropyl)-4H- IH), 4.46 (m, IH), 4.00 (t, 2H), thieno[3,2- ]pyrrole-2- 3.23 (m, 2H), 2.24 (s, 3H), 1.64 carboxylic acid (m, 2H); MS (m/z): 382
(M+H)+. Example Chemical Name Intermediate Analytical Data
No. and Structure
Example 55 Intermediate 3 1H NMR (300 MHz, DMSO d6) and δ 12.80 (br s, 1H), 8.35 (s, 1H),
2-(4- 7.90 (s, 1H), 7.84 (s, 1H), 7.73 bromobutoxy)tetrah (s, lH),7.62-7.60 (d, / = 7.5 ydro-2H-pyran Hz, 1H), 7.45-7.43 (d, = 8.1
5-(4-(lH-imidazol- l-yl)-2- Hz, 1H), 7.14 (s, 1H), 6.46 (s, methylphenyl)-4-(4- 1H), 4.34 (m, 1H), 3.97 (m, hydroxybutyl) -4H- 2H), 3.21 (m, 2H), 2.24 (s, 3H), thieno[3,2- ]pyrrole-2- 1.52 (m, 2H), 1.15 (m, 2H); MS carboxylic acid (m/z): 396 (M+H)+
Example 56 Intermediate 12 1H NMR (300 MHz, DMSO d6) and δ 7.89 (s, 1H), 7.49-7.35 (m,
4-iodo-2- 4H), 6.95 (s, 1H), 6.50 (s, 1H), methylbutane 3.98 (m, 2H), 2.33 (s, 3H), 2.25
4-Isopentyl X-5-(2-methyl-4- (s, 3H), 1.38 (m, 3H), 0.67-0.65 (2-methyl- lH-imidazol- 1 - (d, = 5.7 Hz, 6H); MS (m/z): yl)phenyl)-4H-thieno[3,2- 409 (M+H)+.
]pyrrole-2-carboxylic acid
Example 57 Intermediate 3 1H NMR (300 MHz, DMSO d6) and δ 8.35 (s, 1H), 7.83 (s, 2H), l-bromo-3- 7.72 (s, 1H), 7.59 (m, 1H), methoxyprop ane 7.46-7.43 (d, = 8.4 Hz, 1H),
7.13 (s, 1H), 6.45 (s, 1H), 4.00
5-(4-(lH ■-imidazol- l-yl)-2- (t, 2H), 3.09 (t, 2H), 3.04 (s, methylphenyl)-4-(3- 3H), 2.23 (s, 3H), 1.70 (t, 2H); methoxypropyl)-4H- MS (m/z): 394 (M-H)".
thieno[3,2- ]pyrrole-2- carboxylic acid
Example 58 1H NMR (300 MHz, DMSO d6)
Intermediate 3 δ 13.00 (br s, 1H), 8.47 (s, 1H), and 7.87 (s, 2H), 7.72 (s, 1H), 7.62-
2-((6- 7.59 (d, = 9.0 Hz, 1H), 7.48-
5-(4-(lH-im ϋidazol- l-yl)-2- bromoethyl)oxy)tet 7.45 (d, = 8.4 Hz, 1H), 7.20 methylphenyl)-4-(2- rahydro-2H-pyran (s, 1H), 6.44 (s, 1H), 4.90 (m, hydroxyethyl) -4H- 1H), 3.97 (m, 2H), 3.48 (m, thieno[3,2- ]pyrrole-2- 2H), 2.24 (s, 3H); MS (m/z): carboxylic acid
368 (M+H)+.
Figure imgf000074_0001
Figure imgf000075_0001
Example Chemical Name Intermediate Analytical Data
No. and Structure
Example 67 Intermediate 3 1H NMR (300 MHz, DMSO d6)
5 8.32 (s, IH), 7.81 (s, IH), 7.67 (s, IH), 7.55 (s, IH), 7.43- 7.40 (d, = 8.4 Hz, IH), 7.24
5-(4-(lH-imidazol- l-yl)-2- (s, 1H), 7.11 (s, IH), 6.22 (s, methylphenyl)-4-(2- IH), 3.76 (t, 2H), 2.83-2.81 (t, (azetidin- 1 -yl)ethyl)-4H- = 6.6 Hz, 2H), 2.67 (m, 2H), thieno[3,2- ]pyrrole-2- 2.26 (s, 3H), 1.79-1.76 (m, 2H), carboxylic acid 1.64 (m, 2H); MS (m/z): 405
(M-H)~.
Example 68 Intermediate 3 1H NMR (300 MHz, DMSO d6)
5 8.33 (s, IH), 7.82 (s, IH), 7.69 (s, IH), 7.78-7.56 (d, = 6.3 Hz, IH), 7.51 (s, IH), 7.43-
5-(4-(lH-imidazol- l-yl)-2- 7.41 (d, = 8.1 Ηζ,ΙΗ), 7.12 (s, methylphenyl)-4-(2- IH), 6.31 (s, IH), 3.96 (t, 2H), (dimethylamino)ethyl)-4H- 2.33-2.25 (t, = 6.9 Hz, 2H), thieno[3,2- ]pyrrole-2- 2.19 (s, 3H), 1.93 (s, 6H); MS carboxylic acid (m/z): 395 (M+H)+.
Example 69 Hi Intermediate 3 1H NMR (300 MHz, DMSO d6)
,^S /0H
5 8.33 (s, IH), 7.81 (s, IH), 7.67 (s, IH), 7.55 (d, IH), 7.45 (d, IH), 7.28 (s, IH), 7.21 (s, lH), 7.12 (s, IH), 6.78 (s, IH),
Figure imgf000076_0001
6.24 (s, IH), 3.79 (m, 2H), 3.50
5-(4-(lH-imidazol- l-yl)-2- (m, IH), 3.04 (m, 2H), 2.82 (m, methylphenyl)-4-(2-(3- 2H), 2.27 (s, 3H), 1.23 (s, 2H); carbamoylazetidin- 1 - MS (m/z): 450 (M+H)+.
yl)ethyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid
Example 70 Intermediate 3 1H NMR (300 MHz, DMSO and N-(4- d6) 5 8.33-8.25 (m, 2H), 7.81
(bromomethyl)benz (s, IH), 7.69 (s, 2H), 7.55 (d, yl)acetamide IH), 7.44-7.42 (d, = 8.1 Hz,
IH), 7.10-7.08 (d, = 8.4 Hz, 3H), 6.84-6.82 (d, = 7.8 Hz,
5-(4-(lH-imidazol- l-yl)-2- 2H), 6.55 (s, IH), 5.16 (s, 2H), methylphenyl)-4-(4- 4.14-4.12 (d, = 6.0 Hz, 2H), (acetamidomethyl)benzyl) - 2.19 (s, 3H), 1.80 (s, 3H); MS 4H-thieno[3,2-£]pyrrole-2- (m/z): 485 (M+H)+.
carboxylic acid
Figure imgf000077_0001
Example Chemical Name Intermediate Analytical Data
No. and Structure
carboxylic acid
Example 75 Intermediate 3 1H NMR (300 MHz, DMSO d6) and δ 12.80 (br s, IH), 8.53 (s, IH),
4-(3- 8.00-7.89 (m, 3H), 7.76 (s, IH), iodopropyl)thiazole 7.69 (s, 1H),7.52 (m, IH), 7.43-
5-(4-(lH-imidazol- l-yl)-2- -2-carboxamide 7.38 (m, 2H), 7.27 (br s, IH), methylphenyl)-4-(3-(2- 6.47 (s, IH), 4.05 (br s, 2H), carbamoylthiazol-4- 2.72 (s, IH), 2.20 (s, 3H), 1.94 yl)propyl)-4H-thieno[3,2- (m, 2H); MS (m z): 492 ]pyrrole-2-carboxylic acid (M+H)+.
Example 76 Intermediate 3 1H NMR (300 MHz, DMSO d6) and δ 8.42 (d, 2H), 8.32 (s, IH),
4- 7.80-7.78 (d, = 8.4 Hz, 2H),
(bromomethyl)pyri 7.68 (s, IH), 7.55-7.53 (d, =
5-(4-(lH-imidazol- l-yl)-2- dine hydrobromide 8.1 Hz, IH), 7.41-7.38 (d, J = methylphenyl)-4-(pyridin- 8.4 Hz, IH), 7.12 (s, IH), 6.82 4-ylmethyl)-4H-thieno[3,2- (d, 2H), 6.62 (s, IH), 5.28 (s, ]pyrrole-2-carboxylic acid 2H), 2.19 (s, 3H); MS (m/z):
415 (M+H)+.
Example 77 1H NMR (300 MHz, DMSO d6) δ 9.70 (s, IH), 8.30 (s, IH), 7.88-7.85 (m, 2H), 7.77 (s, IH),
Intermediate 3 7.72-7.70 (d, = 7.5 Hz, 3H), and 7.58 (d, IH), 7.46 (m, IH), 7.30
5-(4-(lH-imidazol- l-yl)-2- 4- (m, 1H), 7.13 (m, IH), 6.90- methylphenyl)-4-(4- (bromomethyl)benz 6.88 (d, = 7.8 Hz, 2H), 6.61 carbamoylbenzyl)-4H- amide (s, IH), 5.27 (s, 2H), 2.20 (s, thieno[3,2- ]pyrrole-2- 3H); MS (m/z): 457 (M+H)+. carboxylic acid
Example 78 Intermediate 3 1H NMR (300 MHz, DMSO d6) and δ 12.78 (br s, IH), 9.17 (s, IH),
4- 8.50 (s, 1H), 7.89 (s, 2H), 7.71
(cyclopentyloxy)ph (s, IH), 7.54 (d, IH), 7.23 (m, enethyl 2H), 6.63 (d, 2H), 6.55 (d, 2H),
Figure imgf000078_0001
methanesulfonate 6.42 (s, IH), 4.09 (m, 2H), 2.70
5-(4-(lH-imidazol- l-yl)-2- (m, 2H), 2.17 (s, 3H); MS methylphenyl)-4-(4- (m/z): 444 (M+H)+.
hydroxyphenethyl) -4H- thieno[3,2- ]pyrrole-2- carboxylic acid
Figure imgf000079_0001
Figure imgf000080_0001
&]pyrrole-2-carboxylic acid Example Chemical Name Intermediate Analytical Data
No. and Structure
Example 87 Intermediate 3 1H NMR (300 MHz, DMSO- and d6) δ 8.37 (s, IH), 7.99 (s, IH),
3- 7.81 (s, 1H), 7.66 (s, IH), 7.57-
(bromomethyl)imid 7.53 (m, 2H), 7.42-7.40 (d, =
5-(4-(lH-im 4idazol- l-yl)-2- azo [5 , 1 -b] thiazole 7.8 Hz, IH), 7.14 (s, IH), 6.98 methylphenyl)-4- (s, IH), 6.60 (s, 2H), 5.49 (s, (imidazo [5 , 1 -b] thiazol-3 - 2H), 2.09 (s, 3H); MS (m/z): ylmethyl)-4H-thieno[3,2- 457 (M-H)".
]pyrrole-2-carboxylic acid
Example 88 Intermediate 3 1H NMR (300 MHz, DMSO- and ά6) δ 12.91 (br s, IH), 8.53 (s,
5- IH), 8.10 (s, IH), 8.05 (s, IH),
(bromomethyl)picol 7.90 (m, 3H), 7.72 (s, IH), 7.59 inonitrile (m, 2H), 7.46-7.43 (d, = 8.4
5-(4-(lH-imidazol- l-yl)-2- Hz, IH), 7.38-7.36 (d, = 7.8 methylphenyl)-4-((6- Hz, IH), 7.24 (s, IH), 6.61 (s, carbamoylpyridin-3 - IH), 5.36 (s, 2H), 2.15 (s, 3H); yl)methyl)-4H-thieno[3,2- MS (m/z): 458 (M+H)+.
]pyrrole-2-carboxylic acid
Example 89 Intermediate 3 lU NMR (300 MHz, DMSO-i¾ δ and 8.31 (s, IH), 8.01-799 (d, =
4-(chloromethyl)-2- 4.8 Hz, IH), 7.80 (m, IH), 7.67 methoxypyridine (m, 2H), 7.60-7.54 (d, IH),
5-(4-(lH-imidazol-l-yl)-2- 7.39-7.37 (d, = 8.1Hz, IH), methylphenyl)-4-((2- 7.11 (s, IH), 6.58 (s, IH), 6.46- methoxypyridin-4-yl)methyl)- 6.44 (m, IH), 6.17 (s, IH), 5.20 4H-thieno[3,2- ?]pyrrole-2- (s, 2H), 3.75 (s, 3H), 2.24 (s, carboxylic acid
3H); MS (m/z): 445 (M+H)+.
Example 90 Intermediate 3 1H NMR (300 MHz, DMSO- d6) δ 8.35 (s, IH), 7.83 (s, 2H), 7.68 (s, IH), 7.54-7.51 (d, = 7.5 Hz, IH), 7.18 (s, IH), 7.14 (s, IH), 7.09-7.06 (d, = 8.1
5-(4-(lH-imidazol- l-yl)-2- Hz, IH), 6.80 (s, IH), 6.71 (s, methylphenyl)-4-(2-( 1H- IH), 6.44 (s, IH), 4.27 (m, 2H), imidazol- 1 -yl)ethyl)-4H- 4.17 (m, 2H), 2.14 (s, 3H); MS thieno[3,2- ]pyrrole-2- (m/z): 416 (M-H)".
carboxylic acid
Example 91 Intermediate 3 1H NMR (300 MHz, DMSO- and 6) δ 8.31 (m, IH), 7.80-7.67
4- (m, 5H), 7.53 (d, IH), 7.39 (d,
(bromomethyl)benz lH), 7.12 (m, IH), 6.98 (d,
Figure imgf000082_0001
Example 95
5-(4-(lH-imidazol-l-yl)phenyl)-6-butyl-4-methyl-4H-thieno[3,2-^]pyrrole-2-carboxylic acid
Figure imgf000082_0002
Figure imgf000083_0001
To a solution of methyl 5-(4-(lH-imidazol-l-yl)phenyl)-4H-thieno[3,2-^]pyrrole-2- carboxylate (Intermediate-2, 400 mg, 1.23 mmol) in acetic acid (0.6 mL) were added acetic anhydride (1.4 g, 12.3 mmol), butyraldehyde (890 mg, 12.3 mmol) and phosphoric acid (279 mg, 2.84 mmol). The reaction mixture was heated at 80°C for 3 h before it was quenched with a cold aqueous ΝΗ4ΟΗ solution and was extracted with EtOAc. The organic layer was washed with water, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 200 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 12.03 (s, 1H), 8.36 (s, 1H), 8.32 (s, 1H), 7.85-7.82 ( (d, = 7.8 Hz, 2H), 7.73-7.70 (d, = 9.0 Hz, 2H), 7.68 (s, 1H), 7.14 (s, 1H), 6.63-6.58 (d, = 15.9 Hz, 1H), 5.96-5.91 (m, 1H), 3.84 (s, 3H), 2.28-2.24 (m 2H), 1.14-1.07 (t, = 7.8Hz, 3H).
Step-2: Preparation of methyl 5-(4-(lH-imidazol-l-yl)phenyl)-6-butyl-4H-thieno[3,2- ]pyrrole-2-carboxylate
Figure imgf000083_0002
To a solution of (E)-methyl 5-(4-(lH-imidazol-l-yl)phenyl)-6-(but-l-en- l-yl)-4H-thieno[3,2- &]pyrrole-2-carboxylate (200 mg, 0.53 mmol) in MeOH (5.0 mL) was added Pd/C (20 mg) and the reaction mixture was stirred in Parr apparatus under hydrogen for 12 h. Then the reaction mass was filtered through a pad of Celite and filtrate was concentrated to afford 180 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 11.78 (s, 1H), 8.35 (s, 1H), 7.83- 7.81 (d, = 6.3 Hz, 2H), 7.78 (s, 1H), 7.68-7.67 (d, = 7.8 Hz, 3H), 7.14 (s, 1H), 3.81 (s, 3H), 2.76-2.73 (m, 2H), 1.69 (m, 2H), 1.36 (m, 2H), 0.92-0.87 (t, = 7.2 Hz, 3H).
Step-3: Preparation of 5-(4-(lH-imidazol-l-yl)phenyl)-6-butyl-4-methyl-4H-thieno[3,2- ]pyrrole-2-carboxylic acid
The title compound was prepared following the procedure described in Method-C, Step- 1, using methyl 5-(4-(lH-imidazol-l-yl)phenyl)-6-butyl-4H-thieno[3,2-^]pyrrole-2-carboxylate (180 mg, 0.47 mmol), NaH (37 mg, 0.94 mmol, 60% in mineral oil) and methyliodide (199 mg, 1.42 mmol) in DMF (5 mL) at 60°C for 30-40 mins to afford 20 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 8.36 (s, 1H), 7.84 (s, 1H), 7.80-7.78 (d, = 8.1 Hz, 2H), 7.55-7.52 (m, 3H), 7.14 (s, 1H), 3.60 (s, 3H), 2.50 (m, 2H), 1.59 (m, 2H), 1.27- 1.23 (m, 2H), 0.85-0.80 (t, / = 7.5 Hz, 3H); MS (m/z): 380(M+H)+.
Example 96
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-((6-cyanopyridin-3-yl)methyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid
Figure imgf000084_0001
To a solution of 5-(4-(lH-imidazol- l-yl)-2-methylphenyl)-4-((6-carbamoylpyridin-3- yl)methyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid (Example-88, 80 mg, 0.175 mmol) in CH2CI2 (4.0 mL) were added Et3N (70 mg, 0.70 mmol) and trifluoroacetic anhydride (110 mg, 0.525 mmol) at 0°C. The reaction mass was stirred at rt for 16 h before it was concentrated and the residue was diluted with water. The aqueous solution was acidified with citric acid and was extracted with 10 % MeOH in CH2CI2. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 15 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 8.30 (s, 1H), 8.22 (s, 1H), 7.92-7.89 (d, = 7.8 Hz, 1H), 7.81 (s, 1H), 7.73 (s, 1H), 7.69 (s, 1H), 7.57- 7.54 (d, = 9.3 Hz, 2H), 7.41 (d, 2H), 7.12 (s, 1H), 6.56 (s, 1H), 5.37 (s, 2H), 2.15 (s, 3H); MS (m/z): 440 (M+H)+.
Example 97
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-((2-cyanopyridin-4-yl)methyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid
Figure imgf000084_0002
The title compound was prepared following the procedure described in Example-96 using 5- (4-(lH-imidazol-l-yl)-2-methylphenyl)-4-((2-carbamoylpyridin-4-yl)methyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid (Example-92). 1H NMR (300 MHz, DMSO-i¾ δ 8.58 (s, l: 8.30 (s, 1H), 7.78 (s, 1H), 7.66-7.48 (m, 4H), 7.39 (d, 1H), 7.11 (s, 1H), 7.03 (s, 1H), 6.57 1H), 5.32 (m, 2H), 2.18 (s, 3H); MS (m/z): 440 (M+H)+.
Example 98 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(p
thieno[3,2- ]pyrrole
Figure imgf000085_0001
Step- 1 : Preparation of methyl 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(pyridin-4- ylmethyl)-4H-thieno[3,2- ]pyrrol -2-carboxylate
Figure imgf000085_0002
The title compound was prepared following the procedure described in Method-C, Step- 1 using methyl 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4H-thieno[3,2-^]pyrrole-2- carboxylate (Intermediate-3, 350 mg, 1.05 mmol), NaH (168 mg, 4.20 mmol, 60% in mineral oil), 4-(bromomethyl)pyridine hydrobromide (347 mg, 1.37 mmol) in DMF (4 mL) to afford 503 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 9.06 (s, 1H), 8.67-8.09 (m, 2H), 7.94-7.50 (m, 6H), 6.83 (br s, 2H), 6.68 (s, 1H),5.33 (s, 2H), 3.80 (s, 3H), 2.21 (s, 3H); MS (m/z): 429 (M+H)+.
Step-2: Preparation of (5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(pyridin-4-ylmethyl)-4H- thieno[3,2- ]pyrrol-2-yl)methano
Figure imgf000085_0003
The title compound was prepared following the procedure described in Example-26, Step-3, using methyl 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(pyridin-4-ylmethyl)-4H- thieno[3,2- ]pyrrole-2-carboxylate (50 mg, 1.18 mmol), LiAlH4 (90 mg, 2.36 mmol) in THF (4 mL) to afford of the 480 mg of title product. 1H NMR (300 MHz, DMSO-i¾) δ 8.41-8.40 (d, = 4.2 Hz, 2H), 8.32 (s, 1H), 7.78 (s, 1H), 7.65 (s, 1H), 7.52-7.49 (d, = 5.4 Hz, 1H), 7.10 (s, 1H), 6.94 (s, 1H), 6.80-6.79 (d, = 4.5 Hz, 2H), 6.70 (br s, 1H), 6.48 (s, 1H), 5.45 (m, 1H), 5.16 (s, 2H), 3.59 (t, 2H), 2.21 (s, 3H); MS (m/z): 401 (M+H)+.
Step-3: Preparation of 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(pyridin-4-ylmethyl)-4H- thieno[3,2- ]pyrrole-2-carbaldehyde
Figure imgf000086_0001
The title compound was prepared following the procedure described in Method-B, Step-1, using 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(pyridin-4-ylmethyl)-4H-thieno[3,2- ]pyrrol-2-yl)methanol (450 mg, 1.12 mmol) and Mn02 (1.0 g, 11.84 mmol) in THF (4 mL) to afford 180 mg of the title product. 1H NMR (300 MHz, DMSO-i¾ δ 9.80 (s, 1H), 8.42- 8.40 (m, 3H), 8.04 (s, 1H), 7.83 (s, 1H), 7.69 (s, 1H), 7.57-7.55 (d, J = 7.8 Hz, 1H), 7.42-7.40 (d, J = 8.4 Hz, 1H), 7.17 (s, 1H), 6.84-6.82 (d, J = 5.4 Hz, 2H), 6.69 (s, 1H), 5.29 (s, 2H), 2.18 (s, 3H); MS (m/z): 399 (M+H)+.
Step-4: Preparation of 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(pyridin-4-ylmethyl)-4H- thieno[3,2- ]pyrrole-2-carbonitril
Figure imgf000086_0002
The title compound was prepared following the procedure described in Method-B, Step-2, using 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(pyridin-4-ylmethyl)-4H-thieno[3,2- ]pyrrole-2-carbaldehyde (180 mg, 0.45 mmol), aq. ammonia (1.0 mL) and iodine (700 mg, 2.75 mmol) in THF (1.0 mL) to afford 130 mg of the title product. 1H NMR (300 MHz, DMSO-i¾ δ 8.42-8.38 (m, 3H), 8.07 (s, 1H), 7.82 (s, 1H), 7.69 (s, 1H), 7.59-7.55 (d, = 7.2 Hz, 1H), 7.40-7.38 (d, = 7.5 Hz, 1H), 7.15 (s, 1H), 6.81-6.79 (d, = 4.8 Hz, 2H), 6.69 (s, 1H), 5.27 (s, 2H), 2.16 (s, 3H); MS (m/z): 396 (M+H)+.
Step-5: Preparation of 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(pyridin-4-ylmethyl)-2- (lH-tetrazol-5-yl)-4H-thieno[3,2-£]pyrrole
The title compound was prepared following the procedure described in Method-B, Step-3, using 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(pyridin-4-ylmethyl)-4H-thieno[3,2- &]pyrrole-2-carbonitrile (130 mg, 0.3 mmol), NaN3 (260 mg, 4.01 mmol) and NH4C1 (214 mg, 4.01 mmol) in DMF (1.0 mL) to afford 35 mg of the title product. 1H NMR (300 MHz, DMSO-i¾ δ 8.42-8.41 (d, = 4.8 Hz, 2H), 8.30 (s, 1H), 7.79 (s, 1H), 7.65 (s, 1H), 7.53-7.51 (d, = 7.8 Hz, 1H), 7.40-7.37 (d, = 8.4 Hz, 1H), 7.33 (s, 1H), 7.11 (s, 1H), 6.86-6.84 (d, = 5.1 Hz, 2H), 6.51 (s, 1H), 5.23 (s, 2H), 2.25 (s, 3H). Table 5: Following Examples were synthesized by following the procedure described above.
Figure imgf000087_0001
Example Chemical Name Intermediate Analytical Data
No. and Structure
Example Intermediate- 3 1H NMR (300 MHz, DMSO- 103 d6) δ 8.82 (br s, 1H), 8.32 (s,
1H), 7.98 (s, 1H), 7.77 (m, 2H), 7.69 (m, 1H), 7.48-7.41 (m,
5-(4-( lH-im vidazol- 1 -yl)-2- 2H), 6.81 (s, 1H), 6.68 (br s, methylphenyl)-4-((2- 2H), 5.24 (s, 2H), 2.63 (s, 3H), methylpyridin-4- 2.23 (s, 3H); MS (m/z): 453 yl)methyl)-2-(lH-tetrazol- (M+H)+.
5-yl)-4H-thieno[3,2- b] pyrrole
Example 104
5-(5-(4-(lH-imidazol-l-yl)phenyl)-4-butyl-4H-thieno[3,2-^]pyrrol-2-yl)-l,3,4-oxadiazol- 2(3H)-one
Figure imgf000088_0001
Step 1 : Preparation of 5-(4-(lH-imidazol-l-yl)phenyl)-4-butyl-4H-thieno[3,2-^]pyrrole-2- carbohydrazide
Figure imgf000088_0002
To a solution of ethyl 5-(4-(lH-imidazol-l-yl)phenyl)-4-butyl-4H-thieno[3,2-^]pyrrole-2- carboxylate (Prepared from Intermedidate- 1 following the procedure described in Method-C, Step- 1, 50 mg, 0.13 mmol) in EtOH (2 mL) was added hydrazine hydrate (51 mg, 1.08 mmol) and the reaction mass was heated in a sealed tube at 90 °C for 16 h. Then the reaction mixture was concentrated and the residue was triturated with diethyl ether to afford 40 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 9.62 (s, 1H), 8.35 (s, 1H), 7.89-7.77 (m, 4H), 7.64- 7.61 (d, = 7.5 Hz, 2H), 7.14 (s, 1H), 6.57 (s, 1H), 4.44 (br s, 2H), 4.12 (m, 2H), 1.65 (m, 2H), 1.14- 1.12 (m, 2H), 0.80-0.76 (t, = 7.2 Hz,3H); MS (m/z): 380 (M+H)+.
Step 2: Preparation of 5-(5-(4-(lH-imidazol- l-yl)phenyl)-4-butyl-4H-thieno[3,2-^]pyrrol-2- yl)- 1 ,3 ,4-oxadiazol-2(3H)-one
To a solution of 5-(4-(lH-imidazol- l-yl)phenyl)-4-butyl-4H-thieno[3,2-^]pyrrole-2- carbohydrazide (40 mg, 0.11 mmol) in THF (1 mL) were added carbonyl diimidazole (20 mg, 0.13 mmol) and Et3N (15 μί, 0.21 mmol) and the reaction mass was stirred at 80°C for 6 h. Then the reaction mixture was concentrated and acidified with an aqueous solution of citric acid. The precipitated solid was filtered and dried to afford 8 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 12.47 (s, 1H), 8.36 (s, 1H), 7.86-7.78 (m, 4H), 7.67-7.64 (d, = 8.4 Hz, 2H), 7.14 (s, 1H), 6.64 (s, 1H), 4.24 (m, 2H), 1.56 (m, 2H), 1.10- 1.08 (m, 2H), 0.76-0.71 (t, = 7.5 Hz, 3H); MS (m/z): 406 (M+H)+.
Example 105
5-(4-(lH-imidazol- l-yl)-2-methylphenyl)-4-isopentyl-2-(4H- l,2,4-triazol-3-yl)-4H- thieno[3,2- ]pyrrole
Figure imgf000089_0001
Step- 1 : Preparation of 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-isopentyl-4H-thieno[3,2- ]pyrrole-2-carboxamide
Figure imgf000089_0002
To a solution of 5-(4-(lH-imidazol- l-yl)-2-methylphenyl)-4-isopentyl-4H-thieno[3,2- ]pyrrole-2-carboxylic acid (Example-46, 200 mg, 0.51 mmol) in DMSO (2.0 mL) were added DIPEA (197 mg, 1.5 mmol), BOP (338 g, 0.764 mmol) and NH4C1 (54 mg, 1.02 mmol). The reaction mass was stirred at rt for 16 h. Then the reaction mass was diluted with water and was extracted with EtOAc. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 205 mg of the title product.
Step-2: Preparation of 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-isopentyl-2-(4H- 1,2,4- triazol-3-yl)-4H-thieno[3,2- ]pyrrole
A solution of 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-isopentyl-4H-thieno[3,2-^]pyrrole- 2-carboxamide (200 mg, 0.508 mmol) in DMF-DMA (2.0 mL) was heated at 90°C for 20 mins. Then the solvent was removed under reduced pressure and the residue was treated with acetic acid (2.0 mL) and hydrazine hydrate (2.0 mL) and heating was continued at 80°C for 15 mins. Then water was added to the reaction mass and it was extracted with 10% MeOH in CH2CI2. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatoraphy to afford 29 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 1 1.72 (d, 1H), 9.22-9.19 (d, = 8.7 Hz, 1H), 8.67 (br s, 1H), 8.38 (s, 1H), 7.97 (br s, 1H), 7.78 (s, 1H), 7.64 (d, 1H), 7.49-7.47 (d, = 7.8 Hz, 1H), 7.31 (br s, 1H), 6.53 (s, 1H), 3.91 (m, 2H), 2.26 (s, 3H), 1.50 (m, 2H), 1.31 (m, 1H), 0.74-0.72 (d, J = 7.5 Hz, 6H).
Example 106
4-(4-Carbamoylphenyl)-5-(4-hydroxy-2-(trifluoromethyl)phenyl)-4H-thieno[3,2-^]pyrrole-2- carboxylic acid
Figure imgf000090_0001
Method-D
Step- 1 : Preparation of methyl 4-(4-cyanophenyl)-5-(4-(cyclopentyloxy)-2- (trifluoromethyl)phenyl)-4H-thien -^]pyrrole-2-carboxylate
Figure imgf000090_0002
The title compound was prepared following the procedure described in Method-A, Step-1, using methyl 5-(4-(cyclopentyloxy)-2-(trifluoromethyl)phenyl)-4H-thieno[3,2-^]pyrrole-2- carboxylate (Intermediate- 14, 800 mg, 1.95 mmol), 4-fluorobenzonitrile (710 mg, 5.86 mmol) and K2C03 (404 mg, 2.93 mmol) in DMF (4 mL) at 100°C for 16 h to afford 590 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 7.90-7.87 (d, = 8.1 Hz, 2H), 7.71 (s, 1H), 7.41-7.38 (d, = 8.1 Hz, 2H), 7.34-7.31 (d, = 8.7 Hz, 1H), 7.23 (s, 1H), 7.17-7.14 (d, = 8.7 Hz, 1H), 6.82 (s, 1H), 4.93 (m, 1H), 3.82 (s, 3H), 1.92 (m, 2H), 1.70- 1.58 (m, 6H); MS (m/z): 511 (M+H)+.
Step-2: Preparation of 4-(4-carbamoylphenyl)-5-(4-(cyclopentyloxy)-2-
(trifluoromethyl)phenyl)-4H-thien -^]pyrrole-2-carboxylic acid
Figure imgf000090_0003
The title compound was prepared following the procedure described in Method-A, Step-2, using methyl 4-(4-cyanophenyl)-5-(4-(cyclopentyloxy)-2-(trifluoromethyl)phenyl)-4H- thieno[3,2- ]pyrrole-2-carboxylate (584 mg, 1.14 mmol), Η2Ο2 (1 mL, 30% in water) and NaOH (229 mg, 5.72 mmol) in MeOH (5 mL) to afford 350 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 7.98 (s, 1H), 7.88-7.85 (d, 7 = 8.4 Hz, 2H), 7.55 (s, 1H), 7.43 (s, 1H), 7..32-7.22 (m, 4H), 7.15-7.12 (d, 7 = 8.7 Hz, 1H), 6.75 (s, 1H), 4.92 (m, 1H), 1.93 (m, 2H), 1.69.- 1.57 (m, 6H); MS (m z): 515 (M+H)+.
Step-3: Preparation of 4-(4-carbamoylphenyl)-5-(4-hydroxy-2-(trifluoromethyl)phenyl)-4H- thieno[3,2-^]pyrrole-2-carboxylic acid
To a solution of 4-(4-carbamoylphenyl)-5-(4-(cyclopentyloxy)-2-(trifluoromethyl)phenyl)- 4H-thieno[3,2- ]pyrrole-2-carboxylic acid (50 mg, 0.09 mmol) in CH2CI2 (0.5 mL) was added BBr3 (0.3 mL, 0.29 mmol, 1M solution in CH2CI2) at -78°C. The reaction mixture was stirred at -50°C over a period of 1 h. Then the reaction mass was concentrated and the residue was diluted with EtOAc and was washed with an aqueous solution of NaHC03, water and brine. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 8 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 10.41 (s, 1H), 7.98 (s, 1H), 7.87-7.84 (d, 7 = 8.4 Hz, 2H), 7.56 (s, 1H), 7.42 (s, 1H), 7.28-7.25 (d, 7 = 8.4 Hz, 2H), 7.22-7.19 (d, 7 = 8.7 Hz, 1H), 7.12 (s, 1H), 6.96-6.93 (d, 7 = 8.7 Hz, 1H), 6.72 (s, 1H); MS (m/z): 445 (M-H)~.
Table 6: Following Examples were synthesized by following the procedure described above (Method D).
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
carboxylic acid
Example 118
5-(2-Chloro-4-hydroxyphenyl)-4-(2,2-dimethyl-4-oxo-3,4-dihydro-2H-benzo[e][l,3]oxazin-7- yl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid
Figure imgf000094_0002
To a solution of 4-(4-carbamoyl-3-hydroxyphenyl)-5-(2-chloro-4-hydroxyphenyl)-4H- thieno[3,2- ]pyrrole-2-carboxylic acid (Example-110, 70 mg, 0.163 mmol) in C¾CN (1.0 mL) were added 2,2-dimethoxypropane (1.0 mL) and PTSA (22 mg, 0.11 mmol). The reaction mass was stirred at 60-70 °C for 1 h and then at rt for 16 h. Then the reaction mixture was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 17 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 10.22 (s, 1H), 8.72 (s, 1H), 7.77-7.74 (d, 7 = 9.0 Hz, 1H), 7.64 (s, 1H), 7.30-7.27 (d, 7 = 8.4 Hz, 1H), 6.98-6.96 (d, 7 = 7.2 Hz, 1H), 6.82-6.76 (m, 3H), 6.67 (s, 1H), 1.49 (s, 6H); MS (m/z): 469 (M+H)+.
Table 7: Following Examples were synthesized by following the procedure described above.
Figure imgf000095_0001
Example 121
5-(2-Chloro-4-hydroxyphenyl)-4-(2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)-4H- thieno[3,2-^]pyrrole-2-carboxylic acid
Figure imgf000096_0001
Step- 1 : Preparation of methyl 5-(2-chloro-4-(cyclopentyloxy)phenyl)-4-(4-cyano-3- nitrophenyl)-4H-thieno[3,2- ]p
Figure imgf000096_0002
The title compound was prepared following the procedure described in Method-A, Step-1, using methyl 5-(2-chloro-4-(cyclopentyloxy)phenyl)-4H-thieno[3,2-^]pyrrole-2-carboxylate (Intermediate- 16, 280 mg, 0.74 mmol), 4-fluoro-2-nitrobenzonitrile-(247 mg, 1.49 mmol) and K2C03 (123 mg, 0.89 mmol) in DMF (2.0 mL) at at 110°C for 5 h to afford 280 mg of the title product. 1H NMR (300 MHz, CDC13) δ 8.08 (s, 1H), 7.87-7.85 (d, = 8.4 Hz, 1H), 7.75 (s, 1H), 7.61-7.58 (d, 7 = 8.1 Hz, 1H), 7.34-7.3 l(d, J = 9.0 Hz, 1H), 6.87 (m, 2H), 6.70 (s, 1H), 4.76 (m, 1H), 3.92 (s, 3H), 1.86- 1.62 (m, 8H).
Step-2: Preparation of methyl 4-(4-carbamoyl-3-nitrophenyl)-5-(2-chloro-4- (cyclopentyloxy)phenyl)-4H-thien -^]pyrrole-2-carboxylate
Figure imgf000096_0003
The title compound was prepared following the procedure described in Method-A, Step-2, using methyl 5-(2-chloro-4-(cyclopentyloxy)phenyl)-4-(4-cyano-3-nitrophenyl)-4H- thieno[3,2- ]pyrrole-2-carboxylate (270 mg, 0.51 mmol), H202 (1.0 mL, 50% in water) and NaOH (62 mg, 1.15 mmol) in THF: MeOH (1 : 1, 4 mL) to afford 180 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 8.21 (s, 1H), 7.82 (s, 3H), 7.67-7.61 (m, 2H), 7.50-7.47 (d, J = 8.1 Hz, 1H), 7.02-6.97 (m, 2H), 6.87 (s, 1H), 4.90 (m, 1H), 3.84 (s, 3H), 1.99- 1.59 (m, 8H); MS (m z): 540 (M+H)+.
Step-3: Preparation of methyl 4-(3-amino-4-carbamoylphenyl)-5-(2-chloro-4- (cyclopentyloxy)phenyl)-4H-thieno[3,2-^]pyrrole-2-carboxylate
Figure imgf000097_0001
To a solution of methyl 4-(4-carbamoyl-3-nitrophenyl)-5-(2-chloro-4- (cyclopentyloxy)phenyl)-4H-thieno[3,2-^]pyrrole-2-carboxylate (186 mg, 3.33 mmol) in EtOH : H20 (1 : 1 ; 4 mL) were added NH4C1 (142 mg, 2.67 mmol) and iron powder (47 mg, 0.84 mmol). The reaction mass was heated at reflux for 16 h. The reaction mass was quenched with a saturated aqueous solution of NaHC03 at RT. The organic layer was separated, washed with water, brine, dried and concentrated. The residue was purified by column chromatography to afford 80 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 7.68 (s, 2H), 7.48-7.45 (d, = 8.7 Hz, 1H), 7.33-7.30 (d, = 8.7 Hz, 1H), 7.03 (m, 1H), 7.02 (s, 1H), 6.92-6.90 (d, = 8.4 Hz, 1H), 6.83 (s, 2H), 6.76 (s, 1H), 6.72 (s, 1H), 6.11 (d, 1H), 4.87 (m, 1H), 3.82 (s, 3H), 1.93- 1.57 (m, 8H); MS (m/z): 510 (M+H)+.
Step-4: Preparation of methyl 5-(2-chloro-4-(cyclopentyloxy)phenyl)-4-(2-methyl-4-oxo-3,4- dihydroquinazolin-7-yl)-4H-thieno[3,2-^]pyrrole-2-carboxylate
Figure imgf000097_0002
A solution of methyl 4-(3-amino-4-carbamoylphenyl)-5-(2-chloro-4-(cyclopentyloxy)phenyl)- 4H-thieno[3,2-£]pyrrole-2-carboxylate (80 mg) and PTSA (10 mg, 0.05 mmol) in triethylortho acetate (1.0 mL) was heated at 130°C for 24 h. Then the reaction mass was quenched with ice- water and was extracted with a 5% MeOH in CHC13. The organic layer was washed with an aqueous solution of NaHC03, water and brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 70 mg of the title product. MS (m/z): 534 (M+H)+.
Step-5: Preparation of methyl 5-(2-chloro-4-hydroxyphenyl)-4-(2-methyl-4-oxo-3,4- dihydroquinazolin-7-yl)-4H-thieno[3,2-^]pyrrole-2-carboxylate
Figure imgf000098_0001
The title compound was prepared following the procedure described in Method-D, Step-3, using methyl 5-(2-chloro-4-(cyclopentyloxy)phenyl)-4-(2-methyl-4-oxo-3,4- dihydroquinazolin-7-yl)-4H-thieno[3,2-^]pyrrole-2-carboxylate (70 mg, 0.13 mmol) and BBr3 (0.39 mL, 0.39 mmol, 1M solution in CH2C12) in CH2C12 (1.0 mL) to afford 50 mg of the title product.
Step-6: Preparation of 5-(2-chloro-4-hydroxyphenyl)-4-(2-methyl-4-oxo-3,4- dihydroquinazolin-7-yl)-4H-thieno[3,2-^]pyrrole-2-carboxylic acid
The title compound was prepared following the procedure described in Method-A, Step-3, using methyl 5-(2-chloro-4-hydroxyphenyl)-4-(2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)-
4H-thieno[3,2-&]pyrrole-2-carboxylate (20 mg, 0.04 mmol) and NaOH (8.5 mg, 0.21 mmol in
0.5 mL H20) in THF : MeOH (1 : 1, 1 mL) to afford 10 mg of the title product. 1H NMR (300
MHz, DMSO d6) δ 8.07-8.04 (d, = 8.4 Hz, 1H), 7.30-7.28 (m, 3H), 7.19 (s, 1H), 6.79-6.76
(m, 2H), 6.63 (s, 1H), 2.31 (s, 3H).
Example 122
4-(5-(2-chloro-4-hydroxyphenyl)-2-(lH-tetrazol-5-yl)-4H-thieno[3,2-^]pyrrol-4-yl)-2- methylbenzamide
Figure imgf000098_0002
Step- 1 : Preparation of methyl 5-(2-chloro-4-(cyclopentyloxy)phenyl)-4-(4-cyano-3- methylphenyl)-4H-thieno[3,2- ]p
Figure imgf000098_0003
The title compound was prepared following the procedure described in Method-A, Step- 1 using methyl 5-(2-chloro-4-(cyclopentyloxy)phenyl)-4H-thieno[3,2-^]pyrrole-2-carboxylate (Intermediate- 16, 300 mg, 0.79 mmol), K2C03 (165 mg, 1.2 mmol) and 4-fluoro-2- methylbenzonitrile (323 mg, 2.39 mmol) in DMF (2 mL) at 130°C for 4 h to afford 140 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 7.71 (s, IH), 7.54-7.52 (d, = 7.8 Hz, IH), 7.17 (m, 2H), 7.01-6.98 (d, = 9.3 Hz, IH), 6.87 (s, IH), 6.78-6.75 (d, = 8.4 Hz, IH), 6.64 (s, IH), 4.74 (m, IH), 3.90 (s, 3H), 2.51 (s, 3H), 1.85- 1.81 (m, 8H).
Step-2: Preparation of methyl 4-(4-carbamoyl-3-methylphenyl)-5-(2-chloro-4- (cyclopentyloxy)phenyl)-4H-thien -^]pyrrole-2-carboxylate
Figure imgf000099_0001
The title compound was prepared following the procedure described in Method-A, Step-2, using methyl 5-(2-chloro-4-(cyclopentyloxy)phenyl)-4-(4-cyano-3-methylphenyl)-4H- thieno[3,2- ]pyrrole-2-carboxylate (430 mg, 0.88 mmol), H202 (2.0mL, 30% in water) and NaOH (70.40 mg, 1.76 mmol) in MeOH (1 mL) to afford 350 mg of the title product.
Step-3: Preparation of 4-(5-(2-chloro-4-(cyclopentyloxy)phenyl)-2-(hydroxymethyl)-4H- thieno[3,2- ]pyrrol-4-yl)-2-methylbenzamide
Figure imgf000099_0002
The title compound was prepared following the procedure described in Example-26, Step-3, using methyl 4-(4-carbamoyl-3-methylphenyl)-5-(2-chloro-4-(cyclopentyloxy)phenyl)-4H- thieno[3,2-£]pyrrole-2-carboxylate (350 mg, 0.70 mmol), LiAlH4 (80 mg, 2.16 mmol) in THF (4 mL) to afford 210 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 7.76 (s, IH), 7.38-7.32 (m, 3H), 7.10 (br s, IH), 6.95-6.90 (m, 4H), 6.59 (s, IH), 4.86 (m, IH), 4.63 (s, IH), 4.10 (m, 2H), 2.31 (s, 3H), 1.91 (m, 2H), 1.68 (m, 6H); MS (m/z): 479 (M-H)~.
Step-4: Preparation of 4-(5-(2-chloro-4-(cyclopentyloxy)phenyl)-2-formyl-4H-thieno[3,2- ]pyrrol-4-yl)-2-methylbenzamide
Figure imgf000100_0001
The title compound was prepared following the procedure described in Method-B, Step-1, using 4-(5-(2-chloro-4-(cyclopentyloxy)phenyl)-2-(hydroxymethyl)-4H-thieno[3,2-^]pyrrol- 4-yl)-2-methylbenzamide (210 mg, 0.43 mmol), Mn02 (374 mg, 4.3 mmol) in CH2C12 (3 mL) to afford 120 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 9.85 (s, 1H), 8.30 (s, 1H), 7.96 (s, 1H), 7.78 (m, 1H), 7.40-7.35 (m, 2H), 7.23 (s, 1H), 7.00-6.90 (m, 3H), 6.81 (s, 1H), 4.86 (m, 1H), 2.33 (s, 3H), 1.89 (m, 2H), 1.68- 1.56 (m, 6H); MS (m/z): 479 (M+H)+. Step-5: Preparation of 4-(5-(2-chloro-4-(cyclopentyloxy)phenyl)-2-cyano-4H-thieno[3,2- ]pyrrol-4-yl)-2-methylbenzamide
Figure imgf000100_0002
The title compound was prepared following the procedure described in Method-B, Step-2, using 4-(5-(2-chloro-4-(cyclopentyloxy)phenyl)-2-formyl-4H-thieno[3,2-¾pyrrol-4-yl)-2- methylbenzamide (120 mg, 0.25 mmol), aq. ammonia (3.0 mL) and iodine (955 mg, 3.80 mmol) in THF (3.0 mL) to afford 110 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 7.94 (s, 1H), 7.79 (s, 1H), 7.39-7.32 (m, 3H), 7.22 (s, 1H), 7.00 (s, 1H), 6.94-6.91 (t, = 7.2 Hz, 2H), 6.81 (s, 1H), 4.87 (m, 1H), 2.34 (s, 3H), 1.90 (m, 2H), 1.70- 1.66 (m, 6H); MS (m/z): 463 (M+H)+.
Step-6: Preparation of 4-(5-(2-chloro-4-hydroxyphenyl)-2-cyano-4H-thieno[3,2-^]pyrrol-4- yl)-2-methylbenzamide
Figure imgf000100_0003
The title compound was prepared following the procedure described in Method-D, Step-3, using 4-(5-(2-chloro-4-(cyclopentyloxy)phenyl)-2-cyano-4H-thieno[3,2-¾pyrrol-4-yl)-2- methylbenzamide (110 mg, 0.23 mmol), BBr3 (1.4 mL, 1.43 mmol, 1M solution in CH2C12) in CH2C12 (2.0 mL) to afford 30 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 10.23 (s, 1H), 8.31 (s, 1H), 7.93 (s, 1H), 7.79 (s, 1H), 7.41-7.22 (m, 2H), 7.17 (s, 1H), 6.94-6.91 (d, J = 9.0 Hz, 1H), 6.81-6.74 (m, 3H), 2.34 (s, 3H).
Step-7: Preparation of 4-(5-(2-chloro-4-hydroxyphenyl)-2-(lH-tetrazol-5-yl)-4H-thieno[3,2- ]pyrrol-4-yl)-2-methylbenzamide
The title compound was prepared following the procedure described in Method-B, Step-3, using 4-(5-(2-chloro-4-hydroxyphenyl)-2-cyano-4H-thieno[3,2-¾pyrrol-4-yl)-2- methylbenzamide (40 mg, 0.10 mmol), NaN3 (97.5 mg, 1.50 mmol) and NH4C1 (80.0 mg, 1.50 mmol) in DMF (1.0 mL) to afford 10 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 10.19 (s, 1H), 7.80 (m, 1H), 7.71 (s, 1H), 7.37-7.23 (m, 4H), 7.01 (m, 1H), 6.82- 6.75 (m, 3H), 2.36 (s, 3H); MS (m/z): 451 (M+H)+.
Table 8: Following Examples were synthesized by following the procedure described above.
Figure imgf000101_0001
Example Chemical Name Intermediate Analytical Data No. and
Structure
4-hydroxyphenyl)-2-( 1H- 7.23-7.21 (d, 7 = 7.8 Hz, tetrazol-5-yl)-4H- 1H), 6.85-6.78 (m, 3H); MS thieno[3,2- ]pyrrol-4- (m/z): 473 (M+H)+.
yl)benzamide
Example 126
7-(5-(2-Chloro-4-hydroxyphenyl)-2-(lH-tetrazol-5-yl)-4H-thieno[3,2-^]pyrrol-4-yl)-2,2- dimethyl-2H-benzo [e] [ 1 ,3 ] oxazin-4 -one
Figure imgf000102_0001
The title compound was prepared following the procedure described in Example- 118 using 4- (5-(2-Chloro-4-hydroxyphenyl)-2-(lH-tetrazol-5-yl)-4H-thieno[3,2-^]pyrrol-4-yl)-2- hydroxybenzamide (Example- 124). 1H NMR (300 MHz, DMSO d6) δ 10.21 (s, 1H), 8.74 (s, 1H), 7.76 (s, 2H), 7.31-7.28 (d, = 7.8 Hz, 1H), 6.98-6.95 (d, = 8.1 Hz, 1H), 6.83-6.74 (m, 4H), 1.51 (s, 6H); MS (m/z): 491 (M-H)~.
Example 127
4-Butyl-5-(4-hydroxy-2-(trifluoromethyl)phenyl)-4H-thieno[3,2-^]pyrrole-2-carboxylic acid
Figure imgf000102_0002
Step- 1 : Preparation of methyl 4-butyl-5-(4-(cyclopentyloxy)-2-(trifluoromethyl)phi thieno[3,2- ]pyrrole-2-carboxylate
Figure imgf000102_0003
The title compound was prepared following the procedure described in Method-C, Step- 1, using methyl 5-(4-(cyclopentyloxy)-2-(trifluoromethyl)phenyl)-4H-thieno[3,2-^]pyrrole-2- carboxylate (Intermediate- 14, 100 mg, 0.13 mmol), NaH (19 mg, 0.48 mmol, 60 % in mineral oil) and 1-iodobutane (111 mg, 0.61 mmol) in DMF (3.0 mL) to afford 90 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 7.96 (s, IH), 7.50-7.47 (d, = 8.7 Hz, IH), 7.28 (m, 2H), 6.41 (s, IH), 4.99 (m, IH), 3.81 (s, 3H), 3.56 (s, 2H), 1.97- 1.60 (m, 8H), 1.45- 1.42 (m, 2H), 1.22-1.07 (m, 2H), 0.72-0.67 (t, = 7.5 Hz, 3H).
Step-2: Preparation of methyl 4-butyl-5-(4-hydroxy-2-(trifluoromethyl)phenyl)-4H- thieno[3,2- ]pyrrole-2-carboxylate
Figure imgf000103_0001
The title compound was prepared following the procedure described in Method-D, Step-3, using methyl 4-butyl-5-(4-(cyclopentyloxy)-2-(trifluoromethyl)phenyl)-4H-thieno[3,2- &]pyrrole-2-carboxylate (90 mg, 0.19 mmol) and BBr3 (0.25 mL, 1M solution in CH2CI2) in CH2CI2 (3 mL) to afford 70 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 10.48 (s, IH), 7.96 (s, IH), 7.41-7.38 (d, = 11.7 Hz, IH), 7.21 (s, IH), 7.14 (d, = 8.7 Hz, IH), 6.40 (s, IH), 3.82 (s, 3H), 3.58 (s, 2H), 1.46 (m, 2H), 1.23- 1.07 (m, 2H), 0.74-0.69 (t, = 7.5Hz, 3H).
Step-3: Preparation of 4-butyl-5-(4-hydroxy-2-(trifluoromethyl)phenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid
The title compound was prepared following the procedure described in Method-A, Step-3, using methyl 4-butyl-5-(4-hydroxy-2-(trifluoromethyl)phenyl)-4H-thieno[3,2-^]pyrrole-2- carboxylate (70 mg, 0.17 mmol) and LiOH (20 mg, 0.25 mmol in 0.5 mL water) in THF: MeOH (1 : 1, 1 mL) to afford 10 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 12.55 (br s, IH), 10.47 (s, IH), 7.86 (s, IH), 7.40-7.37 (d, = 8.1 Hz, IH), 7.20 (s, IH), 7.14- 7.11 (d, = 8.1 Hz, IH), 6.37 (s, IH), 3.85 (br s, 2H), 1.46- 1.44 (m, 2H), 1.11- 1.08 (m, 2H), 0.74-0.69 (t, = 7.5 Hz, 3H); MS (m/z): 384 (M+H)+.
Table 9: Following Examples were synthesized by following the procedure described above.
Figure imgf000103_0002
Example No. Chemical Name Intermediate Analytical Data and Structure
carboxylic acid 0.65 (t, J = 7.2 Hz, 3H); MS
(m z): 350 (M+H)+.
Example 129 ci-3 Intermediate 14 1H NMR (300 MHz, DMSO- and d6) δ 10.51 (br s, IH), 7.84 (s,
4-iodo-2- IH), 7.40-7.37 (d, = 8.4 Hz, methylbutane IH), 7.23 (s, IH), 7.15-7.12
(d, J = 8.4 Hz, IH), 6.38 (s,
5-(4-H "ydrox Xy-2- IH), 3.83 (m, 2H), 1.38 (m, (trifluoromethyl)phenyl)-4- 3H), 0.72-0.70 (d, J = 4.8 Hz, isopentyl-4H-thieno[3,2- 6H); MS (m/z): 396 (M-H)~. ]pyrrole-2-carboxylic acid
Example 130 Intermediate 14 1H NMR (300 MHz, DMSO and d6) δ 12.69 (m, IH), 10.46 (s, l-bromo-2- IH), 7.83 (s, IH), 7.42-7.40 ethoxyethane (d, J = 8.4 Hz, IH), 7.19 (s,
5-(4-Hydroxy-2- IH), 7.12-7.10 (d, J = 6.3 Hz, (trifluoromethyl)phenyl)-4- IH), 6.37 (s, IH), 4.84 (m, (2-hydroxyethyl)-4H- IH), 3.79 (m, 2H), 3.49 (m, thieno[3,2- ]pyrrole-2- 2H); MS (m/z): 371 (M+H)+. carboxylic acid
Example 131 CF3 Intermediate 14 1H NMR (300 MHz, DMSO-
ΗΟ— ~ _ jT and d6) δ 12.50 (br s, IH), 10.46
3- (s, IH), 8.08 (m, 2H), 7.87 (s, hydroxypyridine IH), 7.37-7.34 (d, J = 9.0 Hz,
IH), 7.25-7.17 (m, 3H), 7.04- 7.02 (d, J = 7.8 Hz, IH), 6.39
5-( ό4-Hydroxy-2- (s, IH), 4.07 (m, 2H), 3.88 (s, (trifluoromethyl)phenyl)-4- 2H), 1.97 (m, 2H).
(3-(pyridin-3-yloxy)propyl)- 4H-thieno[3,2-£]pyrrole-2- carboxylic acid
Example 132 CI Intermediate 16 1H NMR (300 MHz, DMSO-
HO-^— and d6) δ 12.8 (br s, IH), 10.25 (s, l-iodo-3-methyl IH), 7.85 (s, IH), 7.31-7.28 butane (d, J = 7.8 Hz, IH), 6.98 (s,
5-(2-Chloro-4- IH), 6.87 (d, IH), 6.39 (s, hydroxyphenyl)-4-isopentyl- IH), 3.95 (t, 2H), 1.37 (m, 4H-thieno[3,2-£]pyrrole-2- 3H), 0.68-0.66 (d, J = 6.3 Hz, carboxylic acid 6H); MS (m/z): 364 (M+H)+.
Figure imgf000105_0001
b]pyrrole-2-carboxylic acid
Figure imgf000106_0001
hydroxyazetidin- 1 -yl)butyl)- 2H); MS (m/z): 421 (M+H)+.
Figure imgf000107_0001
Example No. Chemical Name Intermediate Analytical Data and Structure
Example 145 CI Intermediate 16 1H NMR (300 MHz, DMSO- and 3- d6) δ 8.39 (br s, IH), 8.11 (br (Chloromethyl)p s, IH), 7.81 (s ,1H), 7.24 (br s, yridine 3H), 6.96 (s, IH), 6.82-6.79
(d, J = 8.4 Hz, IH), 6.50 (s,
5-(2-Chloro b-4- IH), 5.24 (s, 2H); MS (m/z): hydroxyphenyl)-4-(pyridin-3- 385 (M+H)+.
ylmethyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid
Example 146 CI Intermediate 16 1H NMR (300 MHz, DMSO-
HQ— — ^J^ ,—^ and 5- d6) δ 7.67 (s, IH), 7.54 (d,
(bromomethyl)- IH), 7.22 (d ,1H), 6.97 (s, 1- IH), 6.83 (d, IH), 6.51 (s, methylpyridin- IH), 5.72 (m, 2H), 5.01 (s,
5-(2-C ~hloro V-4- 2(lH)-one 2H), 3.30 (s, 3H); MS (m/z): hydroxyphenyl)-4-(( 1 - 415 (M+H)+. methyl-6-oxo- 1 ,6- dihydropyridin-3 -yl)methyl)- 4H-thieno[3,2-£]pyrrole-2- carboxylic acid
Example 147 CI Intermediate 16 1H NMR (300 MHz, DMSO- and d6) δ 8.26 (br s, IH), 8.17 (s,
6- IH), 7.89 (s ,1H), 7.82 (s,
(Bromomethyl)i IH), 7.54-7.43 (m, 2H), 7.32 midazo[l,2- (d, IH), 6.95 (s, IH), 6.75 (m,
5-(2-Chloro t-4- a]pyridine 2H),6.51 (s, IH), 5.19 (s, 2H); hydroxyphenyl)-4- MS (m/z): 422 (M-H)".
(imidazo[ 1 ,2-a]pyridin-6- ylmethyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid
Example 148 CI Intermediate 16 1H NMR (300 MHz, DMSO- and d6) δ 7.75 (s, IH), 7.64 (s,
5- IH), 7.28-7.25 (d, = 8.4 Hz,
(Chloromethyl)- IH), 7.21-7.19 (d, = 6.9 Hz,
/ 2- IH), 6.99 (s, IH), 6.85-6.82
5-(2-Chloro-4- methoxypyridin (d, = 10.2 Hz, IH), 6.69- hydroxyphenyl)-4-((6- e 6.66 (d, = 8.4 Hz, IH), 6.41 methoxypyridin- 3 - (s, IH), 5.09 (s, 2H), 3.76 (s, yl)methyl)-4H-thieno[3,2- 3H).
]pyrrole-2-carboxylic acid Example No. Chemical Name Intermediate Analytical Data and Structure
Example 149 Intermediate 16 lH NMR (300 MHz, DMSO- and 3- d6) δ 12.45 (br s, IH), 10.28 (Bromomethyl)i (s, IH), 7.91 (s, IH), 7.52 (s, midazo[5, l- lH),7.26-7.23 (d, = 7.8 Hz, b]thiazole IH), 6.99 (s, IH), 6.94 (s,
5-(2-chlor 4o-4- IH), 6.79 (d, IH), 6.68 (s, hydroxyphenyl)-4- IH), 6.55 (s, IH), 5.46 (s, (imidazo [5 , 1 -b] thiazol-3 - 2H).
ylmethyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid
Example 150 Intermediate 16 1H NMR (300 MHz, DMSO- d6) δ 8.30 (m, 2H), 7.82 (s, IH), 7.33-7.30 (d, J = 8.1 Hz, IH), 6.99 (s, IH), 6.87-6.84 (d, J = 8.4 Hz, IH), 6.75-6.73
5-(2-Chloro-4- (d, J = 5.4 Hz, 2H), 6.36 (s, hydroxyphenyl)-4-(2- IH), 4.31 (m, 2H), 4.16 (m, (pyridin-4-yloxy)ethyl)-4H- 2H); MS (m z): 415 (M+H)+. thieno[3,2- ]pyrrole-2- carboxylic acid
Example 151 ci Intermediate 16 1H NMR (300 MHz, DMSO- ^- ^ d6) δ 7.71 (s, IH), 7.30 (m,
2H), 7.08 (m, IH), 6.95 (m, IH), 6.74-6.68 (m, 3H), 6.38 (s, IH), 4.22 (m, 2H), 4.11 (m,
4-(2-(lH-imidazol- l- 2H); MS (m/z): 388 (M+H)+. yl)ethyl)-5-(2-chloro-4- hydroxyphenyl)-4H- thieno[3,2- ]pyrrole-2- carboxylic acid
Example 152 Intermediate 16 1H NMR (300 MHz, DMSO- and 4- d6) δ 12.79 (s, IH), 10.25 (s, (bromomethyl)b IH), 7.88 (s, IH), 7.72-7.68 enzamide (m, 3H), 7.32 (s, IH), 7.26- 7.24 (d, 7 = 8.4 Hz, IH), 6.96- 6.93 (m, 3H), 6.81-6.78 (d, 7
4-(4-carbamoylbenzyl)-5-(2- = 8.7 Hz, IH), 6.51 (s, IH), chloro-4-hydroxyphenyl)-4H- 5.23 (s, 2H).
thieno[3,2-^]pyrrole-2- carboxylic acid
Figure imgf000110_0001
Example 156
6-Cyclohexyl-5-(4-hydroxy-2-(trifluoromethyl)phenyl)-4-methyl-4H-thieno[3,2-^]pyrrole-2- carboxylic acid
Figure imgf000110_0002
Step- 1 : Preparation of methyl 6-(cyclohex- l-en- l-yl)-5-(4-(cyclopentyloxy)-2- (trifluoromethyl)phenyl)-4H-thieno[3,2-^]pyrrole-2-carboxylate
Figure imgf000111_0001
The title compound was prepared following the procedure described in Example-95, Step- 1, using methyl 5-(4-(cyclopentyloxy)-2-(trifluoromethyl)phenyl)-4H-thieno[3,2-^]pyrrole-2- carboxylate (Intermediate- 14, 250 mg, 0.61 mmol), Ac20 (1.4 g, 12.3 mmol), cyclohexanone (599 mg, 6.11 mmol) and phosphoric acid (137 mg, 1.40 mmol) in AcOH (0.6 mL) to afford 210 mg of the title product. 1H NMR (300 MHz, CDC13) δ 8.20 (s, 1H), 7.66 (s, 1H), 7.39- 7.36 (d, = 8.1 Hz, 1H), 7.04-7.01 (d, = 8.7 Hz, 1H), 5.38 (m, 1H), 8.48 (m, 1H), 3.89 (s, 3H), 3.67 (s, 1H), 2.11- 1.85 (m, 8H), 1.66 (m 8H).
Step-2: Preparation of methyl 6-cyclohexyl-5-(4-(cyclopentyloxy)-2- (trifluoromethyl)phenyl)-4H-thie -^]pyrrole-2-carboxylate
Figure imgf000111_0002
The title compound was prepared following the procedure described in Example-95, Step-2, using methyl 6-(cyclohex-l-en- l-yl)-5-(4-(cyclopentyloxy)-2-(trifluoromethyl)phenyl)-4H- thieno[3,2- ]pyrrole-2-carboxylate (210 mg) and Pd/C (100 mg) in MeOH (3.0 mL) to afford 200 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 11.24 (s, 1H), 7.60 (s, 1H), 7.42-7.29 (d, = 9.3 Hz, 1H), 7.27 (m, 1H), 4.98 (m, 1H), 4.10-4.08 (m, 1H), 3.79 (s, 3H), 1.95-1.60 (m, 15H), 1.14 (m, 4H).
Step-3: Preparation of methyl 6-cyclohexyl-5-(4-(cyclopentyloxy)-2- (trifluoromethyl)phenyl)-4-methyl-4H-thieno[3,2-^]pyrrole-2-carboxylate
Figure imgf000111_0003
The title compound was prepared following the procedure described in Method C, Step- 1, using methyl 6-cyclohexyl-5-(4-(cyclopentyloxy)-2-(trifluoromethyl)phenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylate (200 mg, 0.40 mmol), NaH (32 mg, 0.81 mmol, 60% in mineral oil) and Mel (57 mg, 0.40 mmol) in DMF (2.0 mL) to afford 180 mg of the title product. Step-4: Preparation of methyl 6-cyclohexyl-5-(4-hydroxy-2-(trifluoromethyl)ph< methyl-4H-thieno[3,2- ]pyrrole- -carboxylate
Figure imgf000112_0001
The title compound was prepared following the procedure described in Method-D, Step-3, using methyl 6-cyclohexyl-5-(4-(cyclopentyloxy)-2-(trifluoromethyl)phenyl)-4-methyl-4H- thieno[3,2-£]pyrrole-2-carboxylate (180 mg, 0.36 mmol) and BBr3 (0.50 mL, 0.50 mmol, 1M solution in CH2C12) in CH2C12 (3.0 mL) to afford 140 mg of the title product. 1H NMR (300 MHz, CDC13) δ 7.69 (s, IH), 7.30 (s, IH), 7.22-7.20 (d, J = 7.8 Hz, IH), 7.10-7.08 (d, J = 8.1 Hz, IH), 3.90 (s, 3H), 3.35 (s, 3H), 2.14 (m, IH), 1.77- 1.18 (m, 10H); MS (m/z): 438 (M+H)+. Step-5: Preparation of 6-cyclohexyl-5-(4-hydroxy-2-(trifluoromethyl)phenyl)-4-methyl-4H- thieno[3,2-^]pyrrole-2-carboxylic acid
The title compound was prepared following the procedure described in Method-A, Step-3, using methyl 6-cyclohexyl-5-(4-hydroxy-2-(trifluoromethyl)phenyl)-4-methyl-4H-thieno[3,2- ]pyrrole-2-carboxylate (50 mg, 0.114 mmol) and LiOH (24 mg, 0.57 mmol in 1.0 mL water) in THF:MeOH (3.0 mL : 2.0 mL) to afford 15 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 12.62 (br s, IH), 10.49 (s, IH), 7.82 (s, IH), 7.30-7.27 (d, = 7.8 Hz, IH), 7.22 (s, IH), 7.15-7.12 (d, = 8.7 Hz, IH), 3.33 (s, 3H), 2.08 (m, IH), 1.63- 1.08 (m, 10H); MS (m/z): 424 (M+H)+.
Example 157
4-Isopentyl-5-(4-methoxy-2-(trifluoromethyl)phenyl)-4H-thieno[3,2-&]pyrrole-2-carboxylic acid
Figure imgf000112_0002
Step-1 : Preparation of methyl 4-isopentyl-5-(4-methoxy-2-(trifluoromethyl)phi
thieno[3,2- ]pyrrole-2-carboxylate
Figure imgf000112_0003
The title compound was prepared following the procedure described in Method-C, Step- 1, using methyl 5-(4-hydroxy-2-(trifluoromethyl)phenyl)-4-isopentyl-4H-thieno[3,2-^]pyrrole- 2-carboxylate (Prepared from Intermedidate-14 following the procedure described in Method- B, Step- 1 and Method-C, Step-3; 100 mg, 0.27 mmol), NaH (33 mg, 0.81 mmol, 60% in mineral oil) and methyliodide (192 mg, 1.35 mmol) in DMF (1.0 mL) to afford 78 mg of the title product. 1H NMR (300 MHz, CDC13) δ 7.72 (s, 1H), 7.35-7.26 (m, 2H), 7.14-7.11 (d, = 8.4 Hz, 1H), 6.35 (s, 1H), 3.92-3.91 (m, 5H), 1.58- 1.42 (m, 6H), 0.88-0.78 (d, = 6.3 Hz, 6H); MS (m/z): 426 (M+H)+.
Step-2: Preparation of 4-isopentyl-5-(4-methoxy-2-(trifluoromethyl)phenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid
The title compound was prepared following the procedure described in Method-A, Step-3, using methyl 4-isopentyl-5-(4-methoxy-2-(trifluoromethyl)phenyl)-4H-thieno[3,2-^]pyrrole- 2-carboxylate (70 mg, 0.16 mmol) and NaOH (26 mg, 0.65 mmol in 0.5 mL water) in THF: MeOH (1 : 1, 1 mL) to afford 41 mg of the title product. 1H NMR (300 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.55-7.52 (d, = 8.4 Hz, 1H), 7.37-7.33 (m, 2H), 6.40 (s, 1H), 3.90 (s, 5H), 1.39-1.23 (m, 3H), 0.72-0.70 (d, = 5.1 Hz, 6H); MS (m/z): 412 (M+H)+.
Example 158
5-(2-Chloro-4-hydroxyphenyl)-4-(4-cyanobenzyl)-4H-thieno[3,2-^]pyrrole-2-carboxylic acid
Figure imgf000113_0001
The title compound was prepared following the procedure described in Example-96 using 5- (4-(lH-imidazol-l-yl)-2-methylphenyl)-4-((2-carbamoylpyridin-4-yl)methyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid (Example- 152). 1H NMR (300 MHz, DMSO-i¾ δ 7.46-7.40 (m, 3H), 7.02-6.89 (m, 4H), 6.67-6.61 (m, 1H), 6.38 (s, 1H), 5.09 (s, 2H).
Example 159
4-(4-Butyl-2-(lH-tetrazol-5-yl)-4H-thieno[3,2-b]pyrrol-5-yl)-3-chlorophenol
Figure imgf000113_0002
Figure imgf000114_0001
The title compound was prepared following the procedure described in Example-26, Step-3, using methyl 4-butyl-5-(2-chloro-4-(cyclopentyloxy)phenyl)-4H-thieno[3,2-^]pyrrole-2- carboxylate (Prepared following the procedure described in Method-B, Step- 1, using Intermediate- 16; 200 mg, 0.49 mmol) and LiAl¾ (75 mg, 1.98 mmol) in THF (20 mL) to afford 180 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 7.35-7.32 (d, = 8.7 Hz, 1H), 7.11 (s, 1H), 7.04 (s, 1H), 6.98-6.95 (d, = 7.8 Hz, 1H), 6.26 (s, 1H), 4.91 (m, 1H), 4.63- 4.61 (d, = 5.4 Hz, 2H), 4.39-4.35 (t, = 4.8 Hz, 1H), 3.84-3.81 (t, = 7.5 Hz, 2H), 1.98- 1.42 (m, 10H), 1.06-0.98 (m, 2H), 0.69-0.64 (t, = 7.5 Hz, 3H); MS (m/z): 404 (M+H)+.
Step-2: Preparation of 4-butyl-5-(2-chloro-4-(cyclopentyloxy)phenyl)-4H-thieno[3,2- ]pyrrole-2-carbaldehyde
Figure imgf000114_0002
The title compound was prepared following the procedure described in Method-B, Step-1, using (4-butyl-5-(2-chloro-4-(cyclopentyloxy)phenyl)-4H-thieno[3,2-^]pyrrol-2-yl)methanol (180 mg, 0.44 mmol) and Mn02 (388 mg, 4.46 mmol) in CH2C12 (2 mL) to afford 150 mg of the title product. 1H NMR (300 MHz, CDC13) δ 9.86 (s, 1H), 7.62 (s, 1H), 7.24 (s, 2H), 7.01 (s, 1H), 6.87-6.84 (dd, = 2.4, 8.4 Hz, 1H), 6.38 (s, 1H), 4.80 (m, 1H), 4.13-4.11 (q, = 7.5 Hz, 1H), 3.95-3.90 (t, = 7.2 Hz, 2H), 2.04- 1.62 (m, 8H), 1.18- 1.11 (m, 2H), 0.81-0.76 (t, = 7.5 Hz, 3H); MS (m/z): 402 (M+H)+.
Step-3: Preparation of 4-butyl-5-(2-chloro-4-(cyclopentyloxy)phenyl)-4H-thieno[3,2- ]pyrrole-2-carbonitrile
Figure imgf000114_0003
The title compound was prepared following the procedure described in Method-B, Step-2, using 4-butyl-5-(2-chloro-4-(cyclopentyloxy)phenyl)-4H-thieno[3,2-^]pyrrole-2-carbaldehyde (150 mg, 0.37 mmol), ammonia (1.0 mL) and iodine (948 mg, 3.73 mmol) in THF (1.0 mL) to afford 140 mg of the title product. 1H NMR (300 MHz, CDC13) δ 7.47 (s, 1H), 7.22-7.18 (m, 1H), 7.03-7.01 (m, 1H), 6.91-6.86 (m, 1H), 6.34 (s, 1H), 4.81(m, 1H), 3.96-3.89 (m, 2H), 2.04-1.63 (m, 10H), 1.16- 1.08 (m, 2H), 0.87-0.75 (m, 3H); MS (m/z): 399 (M+H)+.
Step-4: Preparation of 4-butyl-5-(2-chloro-4-hydroxyphenyl)-4H-thieno[3,2-^]pyrrole-2- carbonitrile
Figure imgf000115_0001
The title compound was prepared following the procedure described in Method-D, Step-3, using 4-butyl-5-(2-chloro-4-(cyclopentyloxy)phenyl)-4H-thieno[3,2-&]pyrrole-2-carbonitrile (140 mg, 0.35 mmol) and BBr3 (0.75 mL, 0.75 mmol, 1M solution in CH2C12) in CH2C12 (2.0 mL) to afford 90 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 10.29 (s, 1H), 8.15 (s, 1H), 7 '.32-7.29 (d, = 9.0 Hz, 1H), 6.98 (s, 1H), 6.88-6.84 (m, 1H), 6.47 (s, 1H), 3.93 (t, 2H), 1.47 (m, 2H), 1.03 (m, 2H), 0.70-0.65 (t, = 7.2 Hz, 3H); MS (m/z): 331 (M+H)+.
Step-5: Preparation of 4-(4-butyl-2-(lH-tetrazol-5-yl)-4H-thieno[3,2-^]pyrrol-5-yl)-3- (trifluoromethyl)phenol
The title compound was prepared following the procedure described in Method-B, Step-3, using 4-butyl-5-(2-chloro-4-hydroxyphenyl)-4H-thieno[3,2-^]pyrrole-2-carbonitrile (90 mg, 0.27 mmol), NaN3 (212 mg, 3.26 mmol) and NH4C1 (174 mg, 3.26 mmol) in DMF (1.0 mL) to afford 23 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 10.25 (s, 1H), 7.87 (s, 1H), 7.32-7.29 (d, = 8.4 Hz, 1H), 6.98 (s, 1H), 6.87-6.85 (d, = 8.4 Hz, 1H), 6.44 (s, 1H), 3.94 (m, 2H), 1.54 (m, 2H), 1.08-1.06 (m, 2H), 0.73-0.68 (t, = 6.9 Hz, 3H); MS (m/z): 374 (M+H)+.
Table 10: Following Examples were synthesized by following the procedure described above.
Figure imgf000115_0002
Figure imgf000116_0001
Figure imgf000117_0001
Example No. Chemical Name Intermediate Analytical Data
and Structure
Example 170 Intermediate 20 1H NMR (300 MHz, DMSO d6) δ
\=/ N^-^y N'N 9.60 (s, IH), 7.85 (s, IH), 7.08 (d,
IH), 6.70 (s, IH), 6.70 (d, IH), 6.37 (s, IH), 3.90 (t, 2H), 2.09 (s,
4-(4-Isope Xntyl-2-(2H- 3H), 1.43 (m, 3H), 0.72-0.69 (t, J tetrazol-5-yl)-4H- = 6.3 Hz, 6H); MS (m/z): 368 thieno[3,2- ]pyrrol-5- (M+H)+.
yl)-3-methylphenol
Example 171 Intermediate 16 1H NMR (300 MHz, DMSO d6) δ
10.22 (s, IH), 7.86 (s, IH), 7.33- 7.31 (d, J = 6.3 Hz, IH), 6.96 (s, IH), 6.85 (m, IH), 6.43 (s, IH),
3-Chloro-4-(4-(2- 4.89 (m, IH), 3.95 (m, 2H), 3.52 hydroxyethyl)-2-( 1H- (m, 2H); MS (m/z): 363 (M+H)+. tetrazol-5-yl)-4H- thieno[3,2- ]pyrrol-5- yl)phenol
Example 172 Intermediate 16 1H NMR (300 MHz, DMSO-i¾) δ
10.28 (br s, IH), 7.83 (s, IH), 7.31-7.29 (d, J = 8.7 Hz, IH), 6.99 (s, IH), 6.87-6.84 (d, = 8.1 Hz, IH), 6.41 (s, IH), 3.92 (t, 2H),
3-chloro-4-(4-(5- 3.27-3.25 (t, = 6.6 Hz, 2H), hydroxypentyl)-2-( 1H- 1.58-1.56 (m, 2H), 1.33-1.22 (m, tetrazol-5-yl)-4H- 2H), 1.08 (m, 2H); MS (m/z): 404 thieno[3,2- ]pyrrol-5- (M+H)+.
yl)phenol
Example 173 CI Intermediate 16 1H NMR (300 MHz, DMSO-i¾) δ
10.28 (s, IH), 7.86 (m, IH), 7.71 (s, IH), 7.47 (d, IH), 7.29-7.27 (m, 2H), 6.98 (s, IH), 6.86-6.79
NH2 (m, 2H), 6.48 (s, IH), 5.30 (s,
5-((5-(2-Chloro-4- 2H).
hydroxyphenyl)-2-(lH- tetrazol-5-yl)-4H- thieno[3,2-b]pyrrol-4- yl)methyl)thiophene-2- carboxamide Example 174
4-Butyl-5-(4-hydroxy-2-(trifluoromethyl)phenyl)-N-(methylsulfonyl)-4H-thieno[3,2- ]pyrrole-2-carboxamide
Figure imgf000119_0001
Step- 1 : Preparation of 4-butyl-5-(4-(cyclopentyloxy)-2-(trifluoromethyl)phi
thieno[3,2- ]pyrrole-2-carboxylic acid
Figure imgf000119_0002
The title compound was prepared following the procedure described in Method-C, Step- 1, using methyl 5-(4-(cyclopentyloxy)-2-(trifluoromethyl)phenyl)-4H-thieno[3,2-^]pyrrole-2- carboxylate (Intermediate- 14, 100 mg, 0.24 mmol), NaH (19 mg, 0.48 mmol, 60% in mineral oil), 1-iodobutane (111 mg, 0.61 mmol) in DMF (3.0 mL) to afford 90 mg of the title product.
1H NMR (300 MHz, DMSO-d6) δ 12.53 (br s, 1H), 7.87 (s, 1H), 7.51-7.48 (d, J = 9.3 Hz, 1H),
7.29 (s, 2H), 6.40 (s, 1H), 5.00 (m, 1H), 3.85 (m, 2H), 1.71-1.46 (m, 10H), 1.20- 1.10 (m, 2H),
0.74-0.69 (t, 7 = 7.5 Hz, 3H).
Step-2: Preparation of 4-nitrophenyl 4-butyl-5-(4-(cyclopentyloxy)-2-
(trifluoromethyl)phenyl)-4H-thieno[3,2-^]pyrrole-2-carboxylate
Figure imgf000119_0003
To a solution of 4-butyl-5-(4-(cyclopentyloxy)-2-(trifluoromethyl)phenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid (200 mg, 0.44 mmol) in THF (5.0 mL) were added /?-nitrophenol (73 mg, 0.53 mmol), EDCI (127 mg, 0.66 mmol) and DMAP (64 mg, 0.53 mmol). The reaction mass was stirred at rt for 5-7 h. The reaction mixture was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 180 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 8.37-8.34 (d, = 8.7 Hz, 2H), 8.29 (s, 1H), 8.63-8.60 (d, J = 9.0 Hz, 2H), 7.52 (d, 1H), 7.32 (s, 2H), 6.52 (s, 1H), 5.01 (m, 1H), 4.04 (m, 2H), 1.96- 1.49 (m, 6H), 1.23-1.14 (m, 6H), 0.74-0.69 (t, J = 6.9 Hz, 3H). Step-3: Preparation of 4-butyl-5-(4-(cyclopentyloxy)-2-(trifluoromethyl)phi
(methylsulfonyl)-4H-thieno[3,2-&]pyrrole-2-carboxamide
Figure imgf000120_0001
The title compound was prepared following the procedure described in Method-C, Step- 1, using 4-nitrophenyl 4-butyl-5-(4-(cyclopentyloxy)-2-(trifluoromethyl)phenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylate (50 mg, 0.08 mmol), NaH (9.0 mg, 0.21 mmol, 60% in mineral oil) and methanesulfonamide (21 mg, 0.21 mmol) in DMF (3.0 mL) to afford 50 mg of the title product. MS (m/z): 528 (M+H)+.
Step-4: Preparation of 4-butyl-5-(4-hydroxy-2-(trifluoromethyl)phenyl)-N-(methylsulfonyl)- 4H-thieno[3,2- ]pyrrole-2-carboxamide
The title compound was prepared following the procedure described in Method-D, Step-3, using 4-butyl-5-(4-(cyclopentyloxy)-2-(trifluoromethyl)phenyl)-N-(methylsulfonyl)-4H- thieno[3,2-£]pyrrole-2-carboxamide (50 mg, 0.09 mmol) and BBr3 (0.10 mmol, 0.10 mL, 1M solution in CH2C12) in CH2C12 (1.0 mL) to afford 20 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 12.39 (br s, 1H), 10.50 (s, 1H), 8.23 (s, 1H), 7.40-7.37 (d, / = 8.4 Hz, 1H), 7.21 (s, 1H), 7.15-7.12 (d, J = 8.4 Hz, 1H), 6.41 (s, 1H), 3.84 (m, 2H), 3.33 (s, 3H), 1.56 (m, 2H), 1.23- 1.12 (m, 2H), 0.78-0.73 (t, J = 6.9 Hz, 3H); MS (m/z): 460 (M+H)+.
Example 175
4-Butyl-5-(4-hydroxy-2-(trifluoromethyl)phenyl)-N-(phenylsulfonyl)-4H-thieno[3,2- ]pyrrole-2-carboxamide
Figure imgf000120_0002
Step- 1 : Preparation of 4-butyl-5-(4-(cyclopentyloxy)-2-(trifluoromethyl)phi
(phenylsulfonyl)-4H-thieno[3,2- ]pyrrole-2-carboxamide
Figure imgf000120_0003
The title compound was prepared following the procedure described in Method-C, Step- 1, using 4-nitrophenyl 4-butyl-5-(4-(cyclopentyloxy)-2-(trifluoromethyl)phenyl)-4H-thieno[3,2- &]pyrrole-2-carboxylate (Example-174, Step-2; 90 mg, 0.15 mmol), NaH (16.0 mg, 0.39 mmol, 60% in mineral oil) and benzenesulfonamide (61 mg, 0.39 mmol) in DMF (3.0 mL) to afford 40 mg of the title product. MS (m/z): 591 (M+H)+.
Step-2: Preparation of 4-butyl-5-(4-hydroxy-2-(trifluoromethyl)phenyl)-N-(phenylsulfonyl)- 4H-thieno[3,2- ]pyrrole-2-carboxamide
The title compound was prepared following the procedure described in Method-D, Step-3, using 4-butyl-5-(4-(cyclopentyloxy)-2-(trifluoromethyl)phenyl)-N-(phenylsulfonyl)-4H- thieno[3,2-£]pyrrole-2-carboxamide (40 mg, 0.07 mmol) and BBr3 (0.10 mL, 0.10 mmol, 1M solution in CH2C12) in CH2C12 (1.0 mL) to afford 20 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 10.51 (s, 1H), 8.19 (s, 1H), 8.00-7.98 (d, 7 = 7.2 Hz, 2H), 7.81-7.58 (m, 2H), 7.39-7.36 (m, 2H), 7.20 (s, 1H), 7.14-7.11 (d, 7 = 7.8 Hz, 1H), 6.37 (s, 1H), 3.50-3.43 (m, 2H), 1.58- 1.53 (m, 2H), 1.13- 1.08 (m, 2H), 0.78-0.73 (t, 7 = 7.5 Hz, 3H); MS (m/z): 521 (M- H)-.
Example 176
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-N-cyano-4-(4-hydroxybutyl)-4H-thieno[3,2- ]pyrrole-2-carboxamide
Figure imgf000121_0001
Step- 1 : Preparation of 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-N-cyano-4-(4- hydroxybutyl)-4H-thieno [3 ,2- ]pyrrole-2-carboxamide
The title compound was synthesized following the procedure described in Example- 174, Step- 2, using 5-(4-(lH-imidazol- l-yl)-2-methylphenyl)-4-(4-hydroxybutyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid (Example 55, 100 mg, 0.25 mmol) EDCI.HC1 (72.53mg, 0.37 mmol), /?-nitrophenol (52.7 mg, 0.37 mmol) and DIPEA (131 mg, 1.01 mmol) in DMF (1 mL) to afford 40 mg of 4-nitrophenyl 5-(4-(lH-imidazol- l-yl)-2-methylphenyl)-4-(4- hydroxybutyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate which was taken to the next step without further purification.
Step-2: Preparation of 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-N-cyano-4-(4- hydroxybutyl)-4H-thieno [3 ,2- ]pyrrole-2-carboxamide
To a solution of 54-nitrophenyl 5-(4-(lH-imidazol- l-yl)-2-methylphenyl)-4-(4- hydroxybutyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (40 mg) in DMF (2 mL) was added sodium hydrogencynamide (10 mg, 0.15 mmol). The reaction mass was stirred at rt for 16 h before it was quenched with an aqueous solution of citric acid and was extracted with 10 % MeOH in CH2CI2. The organic layer was washed with water and brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 12 mg of the title product. 1H NMR (300 MHz, DMSO-^) δ 8.69 (br s, IH), 7.96 (s, IH), 7.75- 7.61 (m, 3H), 7.45 (m, IH), 7.28 (m, IH), 7.11 (s, IH), 6.34 (s, IH), 5.44 (m, IH), 3.91 (t, 2H), 3.16 (m, 2H), 2.25 (s, 3H), 1.25 (m, 2H), 1.22- 1.15 (m, 2H); MS (m/z): 420 (M+H)+.
Table 11 : Following Examples were synthesized by following the procedure described above.
Figure imgf000122_0002
Example 179
4-(4-carbamoylphenyl)-5-(4-chloro-2-methoxyphenyl)-4H-thieno[3,2-&]pyrrole-2-carboxylic acid
Figure imgf000122_0001
Step- 1 : Preparation of ethyl 5-(4-chloro-2-methoxyphenyl)-4-(4-cyanophenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylate
Figure imgf000123_0001
The title compound was prepared following the procedure described in Method-A, Step-1, using ethyl 5-(4-chloro-2-methoxyphenyl)-4H-thieno[3,2-^]pyrrole-2-carboxylate
(Intermediate-21, 390 mg, 1.16 mmol), 4-fluorobenzonitrile (562 mg, 4.65 mmol) and K2CO3 (320 mg, 4.65 mmol) in DMF (4 mL) at 100°C for 16 h to afford 280 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 7.91-7.88 (d, 7 = 8.4 Hz, 2H), 7.68 (s, 1H), 7.45-7.39 (m, 3H), 7.13-7.10 (d, 7 = 8.1 Hz, 1H), 7.01 (s, 1H), 6.84 (s, 1H), 4.30-4.27 (q, 7 = 7.2 Hz, 2H), 3.29 (s, 3H), 1.11- 1.06 (t, 7 = 6.9 Hz, 3H); MS (m z): 437 (M+H)+.
Step-2: Preparation of 4-(4-carbamoylphenyl)-5-(4-chloro-2-methoxyphenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid
The title compound was prepared following the procedure described in Method-A, Step-2, using ethyl 5-(4-chloro-2-methoxyphenyl)-4-(4-cyanophenyl)-4H-thieno[3,2-^]pyrrole-2- carboxylate (80 mg, 0.183 mmol), H202 (1 mL, 30% in water) and NaOH (44 mg, 1.16 mmol) in MeOH (1 mL) to afford 40 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 12.93 (br s, 1H), 8.00 (s, 1H), 7.90-7.88 (d, 7 = 7.8 Hz, 2H), 7.58 (s, 1H), 7.41-7.38 (m, 2H), 7.28- 7.25 (d, 7 = 7.8 Hz, 2H), 7.10-7.09 (d, 7 = 7.2 Hz, 1H), 7.01 (s, 1H), 6.78 (s, 1H), 3.31 (s, 3H); MS (m/z): 427 (M+H)+.
Example 180
4-(4-(lH-tetrazol-5-yl)phenyl)-5-(4-chloro-2-methoxyphenyl)-4H-thieno[3,2-^]pyrrole-2- carboxylic acid
Figure imgf000123_0002
Step- 1 : Preparation of ethyl 4-(4-(lH-tetrazol-5-yl)phenyl)-5-(4-chloro-2-methoxyphenyl)- 4H-thieno[3,2- ]pyrrole-2-carboxylate
Figure imgf000124_0001
The title compound was prepared following the procedure described in Method-B, Step-3 using ethyl 5-(4-chloro-2-methoxyphenyl)-4-(4-cyanophenyl)-4H-thieno[3,2-^]pyrrole-2- carboxylate (Example- 179, Step- 1 ; 80 mg, 0.183 mmol), NaN3 (143 mg, 2.2 mmol) and NH4C1 (118 mg, 2.2mmol) in DMF (0.5 mL) to afford 60 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 8.08-8.05 (d, = 8.4 Hz, 2H), 7.69 (s, 1H), 7.45-7.43 (d, = 8.1 Hz, 3H), 7.12-7.09 (d, = 7.8 Hz, 2H), 7.01 (s, 1H), 6.82 (s, 1H), 4.30-4.27 (q, , = 6.9 Hz, 2H), 3.33 (s, 3H), 1.32- 1.27 (t, = 6.9 Hz, 3H); MS (m/z): 480 (M+H)+.
Step-2: Preparation of 4-(4-(lH-tetrazol-5-yl)phenyl)-5-(4-chloro-2-methoxyphenyl)-4H- thieno[3,2-^]pyrrole-2-carboxylic acid
The title compound was prepared following the procedure described in Method-A, Step-3, using ethyl 4-(4-(lH-tetrazol-5-yl)phenyl)-5-(4-chloro-2-methoxyphenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylate (55 mg, 0.12 mmol) and LiOH (29 mg, 0.68 mmol in 1.0 mL water) in THF (2 mL) to afford 35 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 12.95 (br s, 1H), 8.07-8.04 (d, = 7.8 Hz, 2H), 7.64 (s, 1H), 7.45-7.42 (d, = 7.8 Hz, 3H), 7.12-7.09 (d, = 8.7 Hz, 1H), 7.01 (s, 1H), 6.81 (s, 1H), 3.32 (s, 3H); MS (m/z): 451 (M+H)+.
Example 181
4-(4-Carbamoylphenyl)-5-(4-(methylthio)phenyl)-4H-thieno[3,2-&]pyrrole-2-carboxylic acid
Figure imgf000124_0002
Step- 1 : Preparation of ethyl 4-(4-cyanophenyl)-5-(4-(methylthio)phenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylate
Figure imgf000124_0003
The title compound was prepared following the procedure described in Method-A, Step-1, using of ethyl 5-(4-(methylthio)phenyl)-4H-thieno[3,2-^]pyrrole-2-carboxylate (Intermediate-22, 500 mg, 1.5 mmol), 4-fluorobenzonitrile (108 mg, 0.89 mmol) and K2CO3 (62 mg, 0.44 mmol) in DMF (2 mL) at 100°C for 16 h to afford 120 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 7.98-7.91 (m, 2H), 7.63 (s, 1H), 7.54-7.51 (d, = 8.1 Hz, 2H), 7.28-7.17 (m, 4H), 6.98 (s, 1H), 4.29-4.26 (q, J = 6.9 Hz, 2H), 2.46 (s, 3H), 1.31- 1.19 (t, 7 = 6.9 Hz, 3H).
Step-2: Preparation of ethyl 4-(4-carbamoylphenyl)-5-(4-(methylthio)phenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylate
Figure imgf000125_0001
The title compound was prepared following the procedure described in Method-A, Step-2, using ethyl 4-(4-cyanophenyl)-5-(4-(methylthio)phenyl)-4H-thieno[3,2-^]pyrrole-2- carboxylate (80 mg, 0.13 mmol), H202 (1 mL, 30% in water) and NaOH (30 mg, 0.384 mmol) in MeOH (1 mL) to afford 20 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 8.06 (s, 1H), 7.95-7.92 (d, J = 7.8 Hz, 2H), 7.54 (s, 1H), 7.48 (s, 1H), 7.39-7.37 (d, J = 7.8 Hz, 2H), 7.17-7.16 (m, 4H), 6.93 (s, 1H) 4.26-4.24 (q, = 7.2 Hz, 2H), 2.43 (s, 3H), 1.28-1.24 (t, = 6.9 Hz, 3H); MS (m z): 437 (M+H)+.
Step-3: Preparation of 4-(4-carbamoylphenyl)-5-(4-(methylthio)phenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid
The title compound was prepared following the procedure described in Method-A, Step-3, using ethyl 4-(4-carbamoylphenyl)-5-(4-(methylthio)phenyl)-4H-thieno[3,2-^]pyrrole-2- carboxylate (70 mg, 0.160 mmol) and LiOH (27 mg, 0.64 mmol in 1.0 mL water) in THF (2 mL) to afford 15 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 12.91 (s, 1H), 8.07 (s, 1H), 7.96-7.93 (d, J = 7.8 Hz, 2H), 7.52-7.49 (m, 2H), 7.40-7.37 (d, J = 7.8 Hz, 2H), 7.19- 7.17 (q, 4H), 6.93 (s, 1H), 2.45 (s, 3H); MS (m/z): 409 (M+H)+.
Example 182
4-(4-Carbamoylphenyl)-5-(4-(methylsulfonyl)phenyl)-4H-thieno[3,2-&]pyrrole-2-carboxylic acid
Figure imgf000125_0002
Step- 1 : Preparation of ethyl 4-(4-carbamoylphenyl)-5-(4-(methylsulfonyl)phi
thieno[3,2- ]pyrrole-2-carboxylate
Figure imgf000126_0001
The title compound was prepared following the procedure described in Method-A, Step-2, using ethyl 4-(4-cyanophenyl)-5-(4-(methylthio)phenyl)-4H-thieno[3,2-^]pyrrole-2- carboxylate (Example-181, Step-1 ; 80 mg, 0.13 mmol), Η202 (1 mL, 30% in water), NaOH (30 mg, 0.38 mmol) in MeOH (3 mL) to afford 15 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 8.09 (s, 1H), 7.98-7.96 (d, = 7.2 Hz, 2H), 7.88.7.85 (d, = 6.6 Hz, 2H), 7.60 (m, 1H), 7.50 (m, 5H), 7.16 (s, 1H), 4.29 (m, 2H), 3.23 (s, 3H), 1.29 (t, 3H).
Step-2: Preparation of 4-(4-carbamoylphenyl)-5-(4-(methylsulfonyl)phenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylic acid
The title compound was prepared following the procedure described in Method-A, Step-3, using ethyl 4-(4-carbamoylphenyl)-5-(4-(methylsulfonyl)phenyl)-4H-thieno[3,2-^]pyrrole-2- carboxylate (30 mg, 0.06 mmol) and LiOH (5 mg, 0.13 mmol in 0.5 mL water) in MeOH:THF (0.5 mL: l mL) to afford 12 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 8.08 (t, 1H), 7.97-7.95 (d, = 8.1 Hz, 2H), 7.85 (m, 1H), 7.83-7.81 (d, = 8.1 Hz, 2H), 7.44-7.36 (m, 4H), 7.19 (t, 1H), 7.02 (s, 1H), 3.21 (s, 3H); MS (m/z): 441 (M+H)+.
Example 183
4-(4-Carbamoylphenyl)-5-(4-(pyrimidin-5-yl)phenyl)-4H-thieno[3,2-b]pyrrole-2-carboxylic acid
Figure imgf000126_0002
Step- 1 : Preparation of methyl 4-(4-cyanophenyl)-5-(4-(pyrimidin-5-yl)phenyl)-4H-thieno[3,2- ]pyrrole-2-carboxylate
Figure imgf000126_0003
The title compound was prepared following the procedure described in Method-A, Step-1, using methyl 5-(4-(pyrimidin-5-yl)phenyl)-4H-thieno[3,2-^]pyrrole-2-carboxylate (Intermediate-23, 340 mg, 1.01 mmol), 4-fluorobenzonitrile (491 mg, 4.05 mmol) and K2CO3 (419 mg, 3.0 mmol) in DMF (3 mL) at 100°C for 16 h to afford 115 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 9.17 (s, 2H), 8.03-7.97 (m, 3H), 7.85-7.83 (d, = 8.4 Hz, 2H), 7.69 (s, 1H), 7.60-7.57 (d, = 8.1 Hz, 2H), 7.41-7.38 (d, = 8.4 Hz, 2H), 7.12 (s, 1H), 3.82 (s, 3H); MS (m z): 437 (M+H)+.
Step-2: Preparation of 4-(4-carbamoylphenyl)-5-(4-(pyrimidin-5-yl)phenyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid
The title compound was prepared following the procedure described in Method-A, Step-2, using methyl 4-(4-cyanophenyl)-5-(4-(pyrimidin-5-yl)phenyl)-4H-thieno[3,2-^]pyrrole-2- carboxylate (110 mg, 0.25 mmol), H202 (3.0 mL, 30% in water) and NaOH (150 mg, 3.75 mmol) in MeOH (3 mL) to afford 14 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 9.15 (s, 2H), 8.06 (s, 1H), 7.97-7.95 (d, J = 8.4 Hz, 2H), 7.81-7.78 (d, J = 8.4 Hz, 2H), 7.46 (s, 1H), 7.41-7.35 (m, 4H) 7.22 (s, 2H), 6.94 (s, 1H); MS (m/z): 441 (M+H)+.
Example 184
4-(4-Carbamoylphenyl)-5-(4-(imidazo[l,2-(3]pyridin-3-yl)phenyl)-4H-thieno[3,2-&]pyrrole-2- carboxylic acid
Figure imgf000127_0001
Step- 1 : Preparation of methyl 4-(4-cyanophenyl)-5-(4-(imidazo[l,2-a]pyridin-3-yl)phenyl)- 4H-thieno[3,2- ]pyrrole-2-carboxylate
Figure imgf000127_0002
The title compound was prepared following the procedure described in Method-A, Step-1, using methyl 5-(4-(imidazo[l,2-<3]pyridin-3-yl)phenyl)-4H-thieno[3,2-&]pyrrole-2- carboxylate (Intermediate-24, 225 mg, 0.60 mmol), 4-fluorobenzonitrile (87 g, 0.72 mmol) and K2C03 (166 mg, 1.20 mmol) in DMF (5.0 mL) at 100°C for 16 h to afford 60 mg of the title product. MS (m/z): 475 (M+H)+. Step-2: Preparation of 4-(4-carbamoylphenyl)-5-(4-(imidazo[l,2-(3]pyridin-3-yl)phenyl)-4H- thieno[3,2- ]pyrrole-2-carboxylic acid
The title compound was prepared following the procedure described in Method-A, Step-2, using methyl 4-(4-cyanophenyl)-5-(4-(imidazo[l,2-a]pyridin-3-yl)phenyl)-4H-thieno[3,2- &]pyrrole-2-carboxylate (157 mg, 0.075 mmol), H202 (0.13 mL, 30% in water) and NaOH (55 mg, 1.37 mmol) in MeOH (3 mL) to afford 22 mg of the title product. 1H NMR (300 MHz, DMSO d6) δ 13.12 (br s, 1H), 8.57 (s, 2H), 8.06 (br s, 1H), 7.98-7.95 (d, J = 7.8 Hz, 2H), 7.79 (br s, 1H), 7.66-7.63 (m, 3H), 7.52 (s, 1H), 7.47-7.44 (d, = 8.4 Hz, 2H), 7.40-7.37 (d, = 7.8 Hz, 2H), 7.29 (m, 1H), 7.03 (s, 1H), 6.95 (br s, 1H); MS (m/z): 479 (M+H)+.
Pharmacological Activity
In-vitro GSNOR inhibition assay of compounds of the invention: GSNOR activity for the reduction of GSNO (5-Nitrosoglutathione) was determined by measuring the NADH- and GSNO-dependent decrease in absorbance at 340 nm (A340) as previously described by Jansen et al. The assay utilized human recombinant GSNOR enzyme (His tagged) and was set up in 96 well UV (Ultra-violate) plate. The test compounds were dissolved in 100% DMSO to prepare 10 mM stock and then further diluted in DMSO to get the desired concentration (100 x). Final concentration of DMSO in the reaction was 1% (v/v). Stock concentrations of GSNO and NADH were freshly prepared in Na phosphate buffer, pH 7.4. 2.0 μΐ of test compounds (or controls at final 1% DMSO concentration) were added to each well containing 174 μΐ of Na phosphate buffer. This was followed by addition of 9.5 μΐ stock GSNO solution. The reaction was initiated by adding 14.5 μΐ of Enzyme/NADH mix. The final assay components contained 100 mM sodium phosphate buffer, pH 7.4, 0.240 mM GSNO, 0.3 mM NADH and 20 nM of GSNO reductase in 200 μΐ volume. The plate was read in FLUOstar plate reader and change in 340 nm absorbance/min at 25°C was recorded for 3 minutes. IC50 values were calculated from non-linear regression analysis of the initial rate data using the GraphpadPrism software.
The compounds prepared were tested using the above assay procedure and the results obtained are given in Table 12. The percentage inhibition of the compounds of the present invention at concentrations of 1.0 μΜ and 10.0 μΜ is provided below in Table 12.
The IC50 (nM) values of the compounds are set forth in Table 12 wherein "A" refers to an IC50 value of less than 50 nM, "B" refers to IC50 value in range of 50.01 to 100 nM, "C" refers to IC50 value in range of 100.01 to 500 nM and "D" refers to IC50 value greater than 500 nM. Table 12: In- vitro screening results of compounds of the present invention
Figure imgf000129_0001
Example No % Inhibition of GSNOR activity ICso
(nM) at l μΜ at 10 μΜ
42 89.22 93.28 B
43 76.39 88.91 C
44 78.8 94.22 C
45 83.11 91.62 C
46 92.57 93.11 A
47 89.1 94.68 B
48 93.18 96.61 A
49 85.43 88.69 B
50 91.37 84.54 A
51 82.3 86.49 C
52 85.3 91.41 B
53 86.54 93.5 B
54 89.63 91.92 A
55 90.58 92.19 A
56 85.46 89.63 B
57 86.05 92.72 C
58 79.6 91.13 C
59 88.07 91.96 A
60 91.01 94.29 A
61 81.44 90.41 C
62 79.92 95.17 C
63 75.05 92.9 C
64 81.63 90.87 C
65 46.87 83.43 -
66 83.77 87.45 B
67 30.89 64.74 -
68 48.75 81.43 -
69 72.43 91.22 -
70 87.33 92.15 B
71 77.34 89.31 C
72 86.29 90.8 A
73 79.42 87.41 C
74 82.89 91.92 B
75 79.07 90.4 C
76 91.54 93.09 A
77 89.34 93.03 A
78 87.65 91.11 A Example No % Inhibition of GSNOR activity ICso
(nM) at l μΜ at 10 μΜ
79 59.4 87.14 -
80 86.54 94.67 B
81 88.32 93.68 A
82 90.66 96.44 A
83 93.44 95.35 A
84 86.88 92.24 B
85 84.07 95.39 C
86 89.45 92.13 A
87 79.97 89.14 C
88 91.33 94.87 A
89 91.19 93.38 A
90 77.74 91.42 C
91 94.11 92.1 A
92 78.1 92.85 C
93 86.6 89.33 B
94 72.17 89.17 C
95 84.62 88.95 B
96 89.72 92.49 A
97 84.6 94.43 C
98 92.69 93.88 A
99 75.83 81.14 C
100 85.7 89.73 B
101 71.91 84.98 C
102 91.84 95 A
103 86.15 92.11 B
104 65.13 55.17 D
106 89.35 95.16 B
107 89.07 91.57 A
108 87.43 92.17 C
109 88.16 90.31 B
110 92.55 92.89 A
111 90.37 91.67 A
112 91.66 93.86 A
113 87.22 92.18 A
114 86.62 92.14 A
115 88.23 91.51 C
116 90.35 90.86 A
117 89.49 93.7 A Example No % Inhibition of GSNOR activity ICso
(nM) at l μΜ at 10 μΜ
118 93.27 94.78 A
119 93.19 93.76 A
120 88.96 90.79 A
121 90.57 94.47 B
122 92.12 92.59 A
123 85.72 90.91 B
124 94.88 95.6 A
125 90.76 94.36 A
126 91.34 94.48 A
127 88.71 94.09 B
128 88.01 92.02 A
129 91.11 92.8 A
130 83.1 92.09 B
131 88.45 90.34 C
132 93.02 95.05 A
133 88.75 90.7 A
134 89.57 92.51 B
135 82.33 91.22 C
136 86.14 93.15 C
137 84.92 93.31 B
138 89.33 91.32 A
139 64.22 88.3 -
140 56.62 87.81 -
141 63.71 84.93 -
142 72.38 91.03 -
143 76.17 - -
144 87.88 95.82 B
145 87.82 94.7 B
146 84.23 93.93 A
147 82.36 89.58 C
148 79.85 90.1 C
149 85.7 90.67 B
150 83.54 95.23 C
151 72.89 86.8 -
152 90.25 94.71 A
153 93.2 95.36 A
154 93.2 95.36 A Example No % Inhibition of GSNOR activity ICso
(nM) at l μΜ at 10 μΜ
155 91.16 93.8 A
156 82.08 87.18 C
158 85.31 93.3 C
159 90.93 95.23 A
160 85.13 94.85 C
161 89.82 90.98 A
162 88.22 93.65 B
163 87.56 93.73 A
164 88.44 93.41 A
165 84.3 89.5 B
166 87.65 91.01 A
167 88.64 93.07 B
168 84.34 92.7 B
169 71.97 84.04 C
170 82.91 91.42 C
171 83.22 92.81 C
172 93.31 94.2 A
173 92.58 93.13 A
174 75.73 83.56 C
175 77.27 91.2 C
176 84.26 93.17 C
177 89.86 92.19 A
178 49 82.07 -
(-): Not determined

Claims

WHAT IS CLAIMED IS:
1. A compound of formula (lb)
Figure imgf000134_0001
(lb)
or a pharmaceutically acceptable salt thereof,
wherein,
A is selected from
Figure imgf000134_0002
Q is selected from
(R2)„
N
OH and ;
Ra is selected from hydrogen, Ci_8alkyl, -(CRcRd)yOC(0)Rc and -(CH2)yC(0)ORc; at each occurrence, R1 is independently selected from halogen, hydroxyl, Ci_8alkyl, Ci_
8alkoxy and haloCi_8alkyl;
at each occurrence, R is Ci_8alkyl;
R is selected from Ci_8alkyl, Ci_8alkoxyCi_8alkyl, hydroxyCi_8alkyl, (CH2)yC(0)NRcRd, -(CH2)yNRcRd, -(CRcRd)yORc, -(CRcRd)yO(CRcRd)ySiRcRcRc, C3_ i2cycloalkylCi_8alkyl, C6-i4aryl, C6-i4arylCi_8alkyl, 3 to 15 membered heterocyclylCi_8alkyl, 5 to 15 membered heteroaryl and 5 to 15 membered heteroarylCi_8alkyl each of which being optionally substituted by one or more R6.
at each occurrence, R6 is independently selected from halogen, hydroxyl, cyano, carbamoyl, Ci_8alkyl, Ci_8alkoxy, hydroxyCi_8alkyl, haloCi_8alkyl, 5 to 15 membered heteroaryl, -(CH2)yC(0)NReRf, -(CH2)yNReC(0)Rf, -0(CReRf)yRe and -S(0)zRe; or two R6 together with the 'C atom to which they are attached, form a C3_i2cycloalkyl ring or a 3 to 15 membered heterocyclyl ring.
R5 is selected from hydrogen, Ci_8alkyl and C3_i2cycloalkyl; at each occurrence, Rc and Rd are independently selected from hydrogen, Ci-galkyl and 5 to 15 membered heteroaryl;
at each occurrence, Re and Rf are independently selected from hydrogen, hydroxyl, Ci_ galkyl and C6-14aryl; wherein C6 i4aryl is optionally substituted by hydroxyl;
m is selected from '0' to '4', both inclusive;
n is selected from '0' to '3', both inclusive;
y is selected from '0' to '6', both inclusive; and
z is selected from '0' to '2', both inclusive.
2. The com ound according to claim 1, wherein A is
Figure imgf000135_0001
3. The compound according to claim 1 or 2, wherein which Q is
Figure imgf000135_0002
4. The compound according to any one of claims 1 to 3, wherein R1 is independently selected from R1 is independently selected from hydroxyl, methyl, ethyl, methoxy, chloro, bromo, fluoro and trifluoromethyl.
5. The compound according to any one of claims 1 to 4, wherein R is selected from methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl, heptyl, methyoxyethyl, 3-methoxypropyl, 2-hydroxyethyl, 4-hydroxybutyl, 3-hydroxypropyl, 4- hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, 4-amino-4-oxobutyl, 2- (dimethylamino)ethyl, phenyl, cyclopropylmethyl, cyclohexylmethyl, benzyl, phenethyl, 4- morpholinobutyl, 4-(piperazin-l-yl)butyl, 4-(azetidin-l-yl)butyl, 3-(azetidin-l-yl)propyl, azetidin-l-ylethyl, 4-oxo-3,4-dihydro-2H-benzo[e][l,3]oxazin-7-yl, 4-oxo-3,4- dihydroquinazolin-7-yl, (thiazol-4-yl)methyl, (thiazol-4-yl)propyl, thiazol-4-ylethyl, pyridin- 3-ylmethyl, 3-(lH-pyrazol-4-yl)propyl, 6-oxo-l,6-dihydropyridin-3-ylmethyl, imidazo[l,2- a]pyridin-6-ylmethyl, imidazo[5,l-b]thiazol-3-ylmethyl, lH-imidazol-l-yl)ethyl, thiophen-2- yl, pyridin-4-ylmethyl, 2-ethoxyethyl, 3-methoxy-3-methylbutyl, 3-(pyridin-3-yloxy)propyl, 2-(pyridin-4-yloxy)ethyl, 4-(pyridin-3-yloxy)butyl and (2-(trimethylsilyl)ethoxy)methyl) each of which being optionally substituted by one or more R6.
6. The compound according to any one of claims 1 to 5, wherein R6 is selected from cyano, hydroxyl, carbamoyl, chloro, fluoro, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, 3- isobutoxy, 3-hydroxypropyl, tetrazolyl, 5-oxo-2,5-dihydro-l,2,4-oxadiazol-3-yl, 4- hydroxybenzamido, acetamidomethyl, acetamido, isobutyramidomethyl, 2-hydroxyethoxy, methylsulfonyl and cyclohexyl or two R6 together with the 'C atom to which they are attached, form cyclohexyl ring or a tetrahydropyran ring.
7. The compound according to any one of claims 1 to 6, wherein R5 is selected from hydrogen, butyl and cyclohexyl.
8. The compound according to claim 1, wherein
Figure imgf000136_0001
R is hydroxyl, methyl, ethyl, methoxy, chloro, bromo, fluoro or trifluoromethyl, R is methyl, ethyl, propyl, butyl, isobutyl, isopentyl, pentyl, 4-methylpentyl, hexyl, heptyl, methyoxyethyl, 3-methoxypropyl, 2-hydroxyethyl, 4-hydroxybutyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, 4-amino-4-oxobutyl, 2-
(dimethylamino)ethyl, phenyl, cyclopropylmethyl, cyclohexylmethyl, benzyl, phenethyl, 4- morpholinobutyl, 4-(piperazin-l-yl)butyl, 4-(azetidin-l-yl)butyl, 3-(azetidin-l-yl)propyl, azetidin-l-ylethyl, 4-oxo-3,4-dihydro-2H-benzo[e][l,3]oxazin-7-yl, 4-oxo-3,4- dihydroquinazolin-7-yl, (thiazol-4-yl)methyl, (thiazol-4-yl)propyl, thiazol-4-ylethyl, pyridin- 3-ylmethyl, 3-(lH-pyrazol-4-yl)propyl, 6-oxo-l,6-dihydropyridin-3-ylmethyl, imidazo[l,2- a]pyridin-6-ylmethyl, imidazo[5,l-b]thiazol-3-ylmethyl, lH-imidazol-l-yl)ethyl, thiophen-2- yl, pyridin-4-ylmethyl, 2-ethoxyethyl, 3-methoxy-3-methylbutyl, 3-(pyridin-3-yloxy)propyl, 2-(pyridin-4-yloxy)ethyl, 4-(pyridin-3-yloxy)butyl or (2-(trimethylsilyl)ethoxy)methyl) each of which being optionally substituted by one or more R6,
R6 is cyano, hydroxyl, carbamoyl, chloro, fluoro, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, 3-isobutoxy, 3-hydroxypropyl, tetrazolyl, 5-oxo-2,5-dihydro- 1,2,4- oxadiazol-3-yl, 4-hydroxybenzamido, acetamidomethyl, acetamido, isobutyramidomethyl, 2- hydroxyethoxy, methylsulfonyl, cyclohexyl or two R together with the 'C atom to which they are attached, form cyclohexyl ring or a tetrahydropyran ring,
R5 is hydrogen, butyl or cyclohexyl,
m is 0 or 1 and n is 0 or 1.
9. A compound of formula (Ic)
Figure imgf000137_0001
(Ic)
or a pharmaceutically acceptable salt thereof,
wherein,
is selected from
Figure imgf000137_0002
selected from
„
Figure imgf000137_0003
Ra is selected from hydrogen, Ci_8alkyl, -(CRcRd)yOC(0)Rc and -(CH2)yC(0)ORc; at each occurrence, R1 is independently selected from halogen, hydroxyl, Ci_8alkyl, Ci_ 8alkoxy and haloCi_8alkyl;
at each occurrence, R is Ci_8alkyl;
U is Ci-8alkyl;
V is -CR6, -CH or N;
at each occurrence, R6 is independently selected from halogen, hydroxyl, cyano, carbamoyl, Ci_8alkyl, Ci_8alkoxy, hydroxyCi_8alkyl, haloCi_8alkyl, 5 to 15 membered heteroaryl, -(CH2)yC(0)NReRf, -(CH2)yNReC(0)Rf, -0(CReRf)yRe and -S(0)zRe; or two R6 together with the 'C atom to which they are attached, form a C3_i2cycloalkyl ring or a 3 to 15 membered heterocyclyl ring; at each occurrence, Rc and Rd are independently selected from hydrogen, Ci-galkyl and 5 to 15 membered heteroaryl;
at each occurrence, Re and Rf are independently selected from hydrogen, hydroxyl, Ci_ galkyl and C6-14aryl; wherein C6 i4aryl is optionally substituted by hydroxyl;
m is selected from '0' to '4', both inclusive;
n is selected from '0' to '3', both inclusive;
y is selected from '0' to '6', both inclusive;
z is selected from '0' to '2', both inclusive; and
p is selected from '0' to '5', both inclusive.
10. The compound according to claim 9, wherein A is
Figure imgf000138_0001
11. The compound according to claim 9 or 10, wherein Q is
Figure imgf000138_0002
12. The compound according to any one of claims 9 to 11, wherein R1 is independently selected from hydroxyl, methyl, ethyl, methoxy, chloro, bromo, fluoro and trifluoromethyl.
13. The compound according to any one of claims 9 to 12, wherein R6 is selected from cyano, hydroxyl, carbamoyl, chloro, fluoro, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, 3-isobutoxy, 3-hydroxypropyl, tetrazolyl, 5-oxo-2,5-dihydro-l,2,4-oxadiazol-3-yl, 4- hydroxybenzamido, acetamidomethyl, isobutyramidomethyl, acetamido, 2-hydroxyethoxy and methylsulfonyl.
14. The compound according to claim 9 to 13, wherein U is methyl, ethyl, propyl or butyl.
15. The compound according to claim 9 to 14, -C(cyano), -C(hydroxyl), -C(carbamoyl), - C(C1), -C(F)), -C(CF3)), -C(CH3), -C(C2H5), -C(methoxy), -C(ethoxy) or -C(3-isobutoxy)), - C(3-hydroxypropyl)), -C(tetrazolyl), -C(5-oxo-2,5-dihydro-l,2,4-oxadiazol-3-yl), -C(4- hydroxybenzamido), -C(acetamidomethyl), -C(isobutyramidomethyl) or -C(acetamido)), - C(2-hydroxyethoxy), -C(methylsulfonyl)), CH or N.
16. The compound according to claim 9, wherein
Q is
Figure imgf000139_0001
R is hydroxyl, methyl, ethyl, methoxy, chloro, bromo, fluoro or trifluoromethyl,
R6 is cyano, hydroxyl, carbamoyl, chloro, fluoro, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, 3-isobutoxy, 3-hydroxypropyl, tetrazolyl, 5-oxo-2,5-dihydro- 1,2,4- oxadiazol-3-yl, 4-hydroxybenzamido, acetamidomethyl, isobutyramidomethyl, acetamido, 2- hydroxyethoxy or methylsulfonyl,
R5 is hydrogen, butyl or cyclohexyl,
U is methyl, ethyl, propyl or butyl,
V is -C(cyano), -C(hydroxyl), -C(carbamoyl), -C(C1), -C(F)), -C(CF3)), -C(CH3), - C(C2H5), -C(methoxy), -C(ethoxy) or -C(3-isobutoxy)), -C (3-hydroxypropyl)), -C (tetrazolyl), -C(5-oxo-2,5-dihydro-l,2,4-oxadiazol-3-yl), -C(4-hydroxybenzamido), -C (acetamidomethyl), -C(isobutyramidomethyl) or -C(acetamido)), -C(2-hydroxyethoxy), -C(methylsulfonyl)), CH or N,
P is 0, 1 or 2, m is 0 or 1 and n is 0 or 1.
17. A compound selected from
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-carbamoyl-3-isobutoxyphenyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)phenyl)-4-(4-cyanophenyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
5-(4-(lH-imidazol-l-yl)phenyl)-4-(4-carbamoylphenyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
5-(4-(lH-imidazol-l-yl)phenyl)-4-(4-(5H-tetrazol-5-yl)phenyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)phenyl)-4-(4-carbamoyl-3-chlorophenyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid; 5-(4-(lH midazol-l-yl)phenyl)-4-(4-acetamido-2-methylphenyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)phenyl)-4-(4-carbamoyl-2-methylphenyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)phenyl)-4-(4-carbamoyl-3-methylphenyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methoxyphenyl)-4-(4-carbamoylphenyl)-4H-thieno[3,2- b]pyrroe-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)phenyl)-4-(4-(5-oxo-2,5-dihydro-l,2,4-oxadiazol-3- yl)phenyl)-4H-thieno[3,2-b]pyrrole-2-carboxylic acid;
4- (4-carbamoylphenyl)-5-(2-chloro-4-(lH-imidazol-l-yl)phenyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5- (4-(lH-imidazol-l-yl)phenyl)-4-(4-(4-hydroxybenzamido)phenyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
4- (4-carbamoylphenyl)-5-(2-fluoro-4-(lH-imidazol-l-yl)phenyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5- (4-(lH-imidazol-l-yl)phenyl)-4-(4-carbamoyl-2-fluorophenyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-carbamoylphenyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)phenyl)-4-(4-carbamoyl-3-(trifluoromethyl)phenyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-(trifluoromethyl)phenyl)-4-(4-carbamoylphenyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-Imidazol-l-yl)phenyl)-4-(4-carbamoyl-3-methoxyphenyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-carbamoyl-3-methoxyphenyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-carbamoyl-3-hydroxyphenyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
4-(4-Carbamoyl-3-methoxyphenyl)-5-(2-methyl-4-(2-methyl-lH-imidazol-l- yl)phenyl)-4H-thieno[3,2-b]pyrrole-2-carboxylic acid;
4-(4-Carbamoyl-3-hydroxyphenyl)-5-(2-methyl-4-(2-methyl-lH-imidazol-l- yl)phenyl)-4H-thieno[3,2-b]pyrrole-2-carboxylic acid, 4-(4-Carbamoyl-3-ethoxyphenyl)-5-(2-methyl-4-(2-methyl-lH-imidazol-l-yl)phenyl)- 4H-thieno[3,2-b]pyrrole-2-carboxylic acid;
4- (4-Carbamoyl-3-(2-hydroxyethoxy)phenyl)-5-(2-methyl-4-(2-methyl-lH-imidazol- l-yl)phenyl)-4H-thieno[3,2-b]pyrrole-2-carboxylic acid;
5- (4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(2,2-dimethyl-4-oxo-3,4-dihydro-2H- benzo[e][l,3]oxazin-7-yl)-4H-thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-carbamoyl-3-methoxyphenyl)-4H- thieno[3,2-b]pyrrole-2-carboxamide;
Methyl 5-(4-(lH-imidazol-l-yl)phenyl)-4-(4-carbamoylphenyl)-4H-thieno[3,2- b]pyrrole-2-carboxylate;
(Pivaloyloxy)methyl 5-(4-(lH-imidazol-l-yl)phenyl)-4-(4-carbamoylphenyl)-4H- thieno[3,2-b]pyrrole-2-carboxylate;
(Pivaloyloxy)methyl 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-carbamoyl-3- methoxyphenyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate;
2-Ethoxy-2-oxoethyl 4-(4-carbamoyl-3-methoxyphenyl)-5-(2-methyl-4-(2-methyl-lH- imidazol-l-yl)phenyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate;
5-(4-(lH-imidazol-l-yl)phenyl)-4-ethyl-4H-thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)phenyl)-4-butyl-4H-thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)phenyl)-4-(2-methoxyethyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
5-(4-(lH-imidazol-l-yl)phenyl)-4-isopentyl-4H-thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)phenyl)-4-pentyl-4H-thieno[3,2-b]pyrrole-2-carboxylic acid; 5-(4-(lH-imidazol-l-yl)phenyl)-4-isobutyl-4H-thieno[3,2-b]pyrrole-2-carboxylic acid; 5-(4-(lH-imidazol-l-yl)phenyl)-4-heptyl-4H-thieno[3,2-b]pyrrole-2-carboxylic acid; 5-(4-(lH-imidazol-l-yl)phenyl)-4-(4-amino-4-oxobutyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
5-(4-(lH-imidazol -l-yl)phenyl)-4-(4-carbamoylbenzyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
5-(5-(lH-imidazol-l-yl)pyridin-2-yl)-4-butyl-4H-thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)phenyl)-4-(3-carbamoylbenzyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid; 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(2-ethoxyethyl)-4H-thieno[3,2-b]pyrrole- 2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-isopentyl-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
5-(2-Hydroxy-4-(lH-imidazol-l-yl)phenyl)-4-isopentyl-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(3-(pyridin-3-yloxy)propyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(2-Bromo-4-(lH-imidazol-l-yl)phenyl)-4-isopentyl-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-methylpentyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5-(4-(lH-iinidazol-l-yl)-2-methylphenyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methoxyphenyl)-4-isopentyl-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(3-methoxy-3-methylbutyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(3-hydroxypropyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-hydroxybutyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
4- Isopentyl-5-(2-methyl-4-(2-methyl-lH-imidazol-l-yl)phenyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5- (4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(3-methoxypropyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(2-hydroxyethyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(6-hydroxyhexyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5-(2-Ethyl-4-(lH-imidazol-l-yl)phenyl)-4-isopentyl-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(5-hydroxypentyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid; 5-(4-(lH-iinidazol-l-yl)-2-methylphenyl)-4-(4-morpholinobutyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5-(4-(lH-iinidazol-l-yl)-2-methylphenyl)-4-(4-(4-methylpiperazin-l-yl)butyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-((2-carbamoyl-5-methylthiazol-4- yl)methyl)-4H-thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(3-(3-hydroxyazetidin-l-yl)propyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(2-chloro-5- (isobutyramidomethyl)benzyl)-4H-thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH midazol-l-yl)-2-methylphenyl)-4-(2-(azetidin-l-yl)ethyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5-(4-(lH midazol -yl)-2-methylphenyl)-4-(2-(dimethylamino)ethyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(2-(3-carbamoylazetidin-l-yl)ethyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-(acetamidomethyl)benzyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(3-(acetamidomethyl)benzyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-iinidazol-l-yl)-2-methylphenyl)-4-((2-carbamoylthiazol-4-yl)methyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-(methylsulfonyl)phenethyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-acetamidophenethyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(3-(2-carbamoylthiazol-4-yl)propyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-iinidazol-l-yl)-2-methylphenyl)-4-(pyridin-4-ylmethyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-carbamoylbenzyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5-(4-(lH midazol-l-yl)-2-methylphenyl)-4-(4-hydroxyphenethyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid; 5-(4-(lH midazol-l-yl)-2-methylphenyl)-4-(2-(2-acetamidothiazol-4-yl)ethyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-iinidazol-l-yl)-2-methylphenyl)-4-(pyridin-3-ylmethyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(3-(lH-pyrazol-4-yl)propyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(2-methyl-4-(2-methyl-lH-iinidazol-l-yl)phenyl)-4-(pyridin-4-ylmethyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-carbamoyl-3-methoxybenzyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-((l-methyl-6-oxo-l,6-dihydropyridin-3- yl)methyl)-4H-thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(imidazo[l,2-a]pyridin-6-ylmethyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-((6-methoxypyridin-3-yl)methyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH midazol -yl)-2-methylphenyl)-4-(imidazo[5,l-b]thiazol-3-ylmethyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-((6-carbamoylpyridin-3-yl)methyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-iinidazol-l-yl)-2-methylphenyl)-4-((2-methoxypyridin-4-yl)methyl)-4H- thieno[3,2-b] pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(2-(lH-imidazol-l-yl)ethyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-cyanobenzyl)-4H-thieno[3,2-b]pyrrole- 2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-((2-carbamoylpyridin-4-yl)methyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-benzyl-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
5-(5-(lH-imidazol-l-yl)thiophen-2-yl)-4-ethyl-4H-thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)phenyl)-6-butyl-4-methyl-4H-thieno[3,2-b]pyrrole-2- carboxylic acid; 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-((6-cyanopyridin-3-yl)methyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-((2-cyanopyridin-4-yl)methyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
4-(4-Carbamoylphenyl)-5-(4-hydroxy-2-(trifluoromethyl)phenyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
4-(4-Carbamoylphenyl)-5-(2-fluoro-4-hydroxyphenyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
4-(4-Carbamoyl-3-methoxyphenyl)-5-(4-hydroxy-2-(trifluoromethyl)phenyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
4-(4-Carbamoyl-3-hydroxyphenyl)-5-(4-hydroxy-2-(trifluoromethyl)phenyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
4-(4-Carbamoyl-3-hydroxyphenyl)-5-(2-chloro-4-hydroxyphenyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
4-(4-Carbamoylphenyl)-5-(2-chloro-4-hydroxyphenyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
4-(4-Carbamoyl-3-methylphenyl)-5-(2-chloro-4-hydroxyphenyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
4-(4-Carbamoyl-3-(trifluoromethyl)phenyl)-5-(2-chloro-4-hydroxyphenyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
4-(4-Carbamoyl-2-methylphenyl)-5-(2-chloro-4-hydroxyphenyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
4-(4-Carbamoyl-3-methoxyphenyl)-5-(2-chloro-4-hydroxyphenyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
4-(4-carbamoyl-3-(3-hydroxypropyl)phenyl)-5-(2-chloro-4-hydroxyphenyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
4- (4-Carbamoyl-3-ethylphenyl)-5-(2-chloro-4-hydroxyphenyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5- (2-Chloro-4-hydroxyphenyl)-4-(2,2-dimethyl-4-oxo-3,4-dihydro-2H- benzo[e][l,3]oxazin-7-yl)-4H-thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(2-Chloro-4-hydroxyphenyl)-4-(4-oxo-3,4-dihydrospiro[benzo[e][l,3]oxazine-2, - cyclohexan]-7-yl)-4H-thieno[3,2-b]pyrrole-2-carboxylic acid; 5-(2-chloro-4-hydroxyphenyl)-4-(4-oxo-2',3,3',4,5',6'- hexa ydrospiro[benzo[e][l,3]oxazine-2,4'-pyran]-7-yl)-4H-thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(2-Chloro-4-hydroxyphenyl)-4-(2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid ;
4-Butyl-5-(4-hydroxy-2-(trifluoromethyl)phenyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
4- Butyl-5-(2-chloro-4-hydroxyphenyl)-4H-thieno[3,2-b]pyrrole-2-carboxylic acid;
5- (4-Hydroxy-2-(trifluoromethyl)phenyl)-4-isopentyl-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
5-(4-Hydroxy-2-(trifluoromethyl)phenyl)-4-(2-hydroxyethyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5-(4-Hydroxy-2-(trifluoromethyl)phenyl)-4-(3-(pyridin-3-yloxy)propyl)-4H- thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(2-Chloro-4-hydroxyphenyl)-4-isopentyl-4H-thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(2-Chloro-4-hydroxyphenyl)-4-(4-methylpentyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
5-(2-Chloro-4-hydroxyphenyl)-4-(4-(pyridin-3-yloxy)butyl)-4H-thieno[3,2-b]pyrrole- 2-carboxylic acid;
5-(2-Chloro-4-hydroxyphenyl)-4-(3-hydroxypropyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
5-(2-Chloro-4-hydroxyphenyl)-4-(4-hydroxybutyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
5-(2-Chloro-4-hydroxyphenyl)-4-(6-hydroxyhexyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
5-(2-Chloro-4-hydroxyphenyl)-4-(5-hydroxypentyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
5-(2-Chloro-4-hydroxyphenyl)-4-(4-morpholinobutyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
5-(2-Chloro-4-hydroxyphenyl)-4-(4-(3-hydroxyazetidin-l-yl)butyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5-(2-chloro-4-hydroxyphenyl)-4-(3-(3-hydroxyazetidin-l-yl)propyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid; 5-(2-chloro-4-hydroxyphenyl)-4-(2-(3-hydroxyazetidin-l-yl)ethyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5-(2-chloro-4-hydroxyphenyl)-4-(2-(dimethylamino)ethyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
5-(2-Chloro-4-hydroxyphenyl)-4-(pyridin-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
5-(2-Chloro-4-hydroxyphenyl)-4-(pyridin-3-ylmethyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
5-(2-Chloro-4-hydroxyphenyl)-4-((l-methyl-6-oxo-l,6-dihydropyridin-3-yl)methyl)- 4H-thieno[3,2-b]pyrrole-2-carboxylic acid;
5-(2-Chloro-4-hydroxyphenyl)-4-(imidazo[l,2-a]pyridin-6-ylmethyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5-(2-Chloro-4-hydroxyphenyl)-4-((6-methoxypyridin-3-yl)methyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5-(2-chloro-4-hydroxyphenyl)-4-(imidazo[5,l-b]thiazol-3-ylmethyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
5-(2-Chloro-4-hydroxyphenyl)-4-(2-(pyridin-4-yloxy)ethyl)-4H-thieno[3,2-b]pyrrole- 2-carboxylic acid;
4-(2-(lH-imidazol-l-yl)ethyl)-5-(2-chloro-4-hydroxyphenyl)-4H-thieno[3,2-b]pyrrole- 2-carboxylic acid;
4- (4-carbamoylbenzyl)-5-(2-chloro-4-hydroxyphenyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
5- (2-Chloro-4-hydroxyphenyl)-4-(3-cyanobenzyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
4-(3-carbamoylbenzyl)-5-(2-chloro-4-hydroxyphenyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
4-((5-carbamoylthiophen-2-yl)methyl)-5-(2-chloro-4-hydroxyphenyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
6- Cyclohexyl-5-(4-hydroxy-2-(trifluoromethyl)phenyl)-4-methyl-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
4- Isopentyl-5-(4-methoxy-2-(trifluoromethyl)phenyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
5- (2-Chloro-4-hydroxyphenyl)-4-(4-cyanobenzyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid; 4-Butyl-5-(4-hydroxy-2-(trifluoromethyl)phenyl)-N-(methylsulfonyl)-4H-thieno[3,2- b]pyrrole-2-carboxamide;
4- Butyl-5-(4-hydroxy-2-(trifluoromethyl)phenyl)-N-(phenylsulfonyl)-4H-thieno[3,2- b]pyrrole-2-carboxamide;
5- (4-(lH-imidazol-l-yl)-2-methylphenyl)-N-cyano-4-(4-hydroxybutyl)-4H-thieno[3,2- b]pyrrole-2-carboxamide;
5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-carbamoyl-3-methoxyphenyl)-N- cyano-4H-thieno[3,2-b]pyrrole-2-carboxamide;
4-(4-carbamoyl-3-methylphenyl)-5-(2-chloro-4-hydroxyphenyl)-N-cyano-4H- thieno[3,2-b]pyrrole-2-carboxamide;
4-(4-carbamoylphenyl)-5-(4-chloro-2-methoxyphenyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
4-(4-(lH-tetrazol-5-yl)phenyl)-5-(4-chloro-2-methoxyphenyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
4-(4-Carbamoylphenyl)-5-(4-(methylthio)phenyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
4-(4-Carbamoylphenyl)-5-(4-(methylsulfonyl)phenyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
4-(4-Carbamoylphenyl)-5-(4-(pyrimidin-5-yl)phenyl)-4H-thieno[3,2-b]pyrrole-2- carboxylic acid;
4-(4-Carbamoylphenyl)-5-(4-(imidazo[l,2-a]pyridin-3-yl)phenyl)-4H-thieno[3,2- b]pyrrole-2-carboxylic acid;
and pharmaceutically acceptable salt thereof.
18. A compound selected from
2-Methoxy-4-(5-(2-methyl-4-(2-methyl-lH-imidazol-l-yl)phenyl)-2-(lH-tetrazol-5- yl)-4H-thieno[3,2-b]pyrrol-4-yl)benzamide;
4- (5-(4-(lH-imidazol-l-yl)phenyl)-2-(lH-tetrazol-5-yl)-4H-thieno[3,2-b]pyrrol-4- yl)benzamide;
5- (4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(pyridin-4-ylmethyl)-2-(lH-tetrazol-5-yl)- 4H-thieno[3,2-b]pyrrole;
5-(4-(lH-imidazol-l-yl)phenyl)-4-butyl-2-(2H-tetrazol-5-yl)-4H-thieno[3,2-b]pyrrole; 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-butyl-2-(2H-tetrazol-5-yl)-4H-thieno[3,2- b]pyrrole; 5-(4-(lH-imidazol-l-yl)phenyl)-4-(cyclohexylmethyl)-2-(lH-tetrazol-5-yl)-4H- thieno[3,2-b]pyrrole;
4- ((5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-2-(lH-tetrazol-5-yl)-4H-thieno[3,2- b]pyrrol-4-yl)methyl)benzamide;
5- (4-(lH midazol -yl)-2-methylphenyl)-4-((2-methylpyridin-4-yl)methyl)-2-(lH- tetrazol-5-yl)-4H-thieno[3,2-b]pyrrole;
5-(5-(4-(lH-imidazol-l-yl)phenyl)-4-butyl-4H-thieno[3,2-b]pyrrol-2-yl)-l,3,4- oxadiazol-2(3H)-one;
4-(5-(2-chloro-4-hydroxyphenyl)-2-(lH-tetrazol-5-yl)-4H-thieno[3,2-b]pyrrol-4-yl)-2- methylbenzamide ;
4-(5-(4-Hydroxy-2-(trifluoromethyl)phenyl)-2-(lH-tetrazol-5-yl)-4H-thieno[3,2- b]pyrrol-4-yl)benzamide;
4-(5-(2-Chloro-4-hydroxyphenyl)-2-(lH-tetrazol-5-yl)-4H-thieno[3,2-b]pyrrol-4-yl)- 2-hydroxybenzamide;
2-Chloro-4-(5-(2-chloro-4-hydroxyphenyl)-2-(lH-tetrazol-5-yl)-4H-thieno[3,2- b]pyrrol-4-yl)benzamide;
7-(5-(2-Chloro-4-hydroxyphenyl)-2-(lH-tetrazol-5-yl)-4H-thieno[3,2-b]pyrrol-4-yl)- 2,2-dimethyl-2H-benzo[e][l,3]oxazin-4(3H)-one;
4-(4-Butyl-2-(lH-tetrazol-5-yl)-4H-thieno[3,2-b]pyrrol-5-yl)-3-chlorophenol;
4-(4-Butyl-2-(lH-tetrazol-5-yl)-4H-thieno[3,2-b]pyrrol-5-yl)phenol;
4-(4-Butyl-2-(2H-tetrazol-5-yl)-4H-thieno[3,2-b]pyrrol-5-yl)-3- (trifluoromethyl)phenol;
4-(4-Heptyl-2-(2H-tetrazol-5-yl)-4H-thieno[3,2-b]pyrrol-5-yl)-3- (trifluoromethyl)phenol;
4-(4-Hexyl-2-(2H-tetrazol-5-yl)-4H-thieno[3,2-b]pyrrol-5-yl)-3- (trifluoromethyl)phenol;
4-(4-Pentyl-2-(2H-tetrazol-5-yl)-4H-thieno[3,2-b]pyrrol-5-yl)-3- (trifluoromethyl)phenol;
4-(4-Propyl-2-(2H-tetrazol-5-yl)-4H-thieno[3,2-b]pyrrol-5-yl)-3- (trifluoromethyl)phenol;
4-(4-Butyl-2-(2H-tetrazol-5-yl)-4H-thieno[3,2-b]pyrrol-5-yl)-3-fluorophenol;
4-(4-(Cyclopropylmethyl)-2-(2H-tetrazol-5-yl)-4H-thieno[3,2-b]pyrrol-5-yl)-3- (trifluoromethyl)phenol;
4-(4-Benzyl-2-(2H-tetrazol-5-yl)-4H-thieno[3,2-b]pyrrol-5-yl)-3-fluorophenol; 4-(4-Butyl-2-(2H-tetrazol-5-yl)-4H-thieno[3,2-b]pyrrol-5-yl)-3-methylphenol;
4- (4-Isopentyl-2-(2H-tetrazol-5-yl)-4H-thieno[3,2-b]pyrrol-5-yl)-3-methylphenol; 3-Chloro-4-(4-(2-hydroxyethyl)-2-(lH-tetrazol-5-yl)-4H-thieno[3,2-b]pyrrol-5- yl)phenol;
3-chloro-4-(4-(5-hydroxypentyl)-2-(lH-tetrazol-5-yl)-4H-thieno[3,2-b]pyrrol-5- yl)phenol;
5- ((5-(2-Chloro-4-hydroxyphenyl)-2-(lH-tetrazol-5-yl)-4H-thieno[3,2-b]pyrrol-4- yl)methyl)thiophene-2-carboxamide;
and pharmaceutically acceptable salt thereof.
19. A compound of formula
Figure imgf000150_0001
or a pharmaceutically acceptable salt thereof.
20 A compound of formula
Figure imgf000150_0002
or a pharmaceutically acceptable salt thereof.
21 A compound of formula
Figure imgf000150_0003
or a pharmaceutically acceptable salt thereof.
22, A compound of formula
Figure imgf000150_0004
or a pharmaceutically acceptable salt thereof.
A compound of formula
Figure imgf000151_0001
or a pharmaceutically acceptable salt thereof.
A compound of formula
Figure imgf000151_0002
or a pharmaceutically acceptable salt thereof.
A compound of formula
Figure imgf000151_0003
or a pharmaceutically acceptable salt thereof.
26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 and a pharmaceutically acceptable excipient.
27. The pharmaceutical composition according to claim 26, wherein the pharmaceutically acceptable excipient is a carrier or diluent.
28. A method of treating a GSNOR mediated disease, disorder or syndrome in a subject comprising administering an effective amount of a compound according to any one of claims 1 to 25.
29. The method according to claim 28, wherein the disease is a respiratory disease.
30. The method according to claim 29, wherein the respiratory disease is selected from the group consisting of pulmonary hypertension, Acute respiratory distress syndrome (ARDS), asthma, bronchospasm, cough, pneumonia, pulmonary fibrosis/interstitial lung diseases, cystic fibrosis and chronic obstructive pulmonary disease (COPD).
31. The method according to claim 29, wherein the respiratory disease is asthma, cystic fibrosis or chronic obstructive pulmonary disease (COPD).
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