WO2016055947A1 - Alkyne compounds as s-nitrosoglutathione reductase inhibitors - Google Patents

Alkyne compounds as s-nitrosoglutathione reductase inhibitors Download PDF

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WO2016055947A1
WO2016055947A1 PCT/IB2015/057661 IB2015057661W WO2016055947A1 WO 2016055947 A1 WO2016055947 A1 WO 2016055947A1 IB 2015057661 W IB2015057661 W IB 2015057661W WO 2016055947 A1 WO2016055947 A1 WO 2016055947A1
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Prior art keywords
propyl
ethynyl
phenyl
trifluoromethyl
hydroxy
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PCT/IB2015/057661
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French (fr)
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Laxmikant Atmaram Gharat
Nagarajan Muthukaman
Dnyandeo PISAL
Neelima Khairatkar-Joshi
Daisy Manish Shah
Sheetal R KADAM
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Glenmark Pharmaceuticals S.A.
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Publication of WO2016055947A1 publication Critical patent/WO2016055947A1/en

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    • C07C65/28—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups having unsaturation outside the aromatic rings
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Definitions

  • the present patent application is directed to alkyne 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).
  • the present invention relates to compound of formula (I)
  • P is selected from C 3 _i 2 cycloalkyl, C 6-14 aryl, 3 to 15 membered heterocyclyl and 5 to 14 membered heteroaryl;
  • Q is selected from C 3 _i 2 cycloalkyl, C 6 -i 4 aryl, 3 to 15 membered heterocyclyl and 5 to 14 membered heteroaryl;
  • A is selected from
  • Ci_ 8 alkyl is selected from hydrogen, Ci_ 8 alkyl, Ci_ 8 alkoxyCi_ 8 alkyl, -(CH 2 ) x C(0)NR b R c
  • R d is selected from hydrogen and Ci_ 8 alkyl
  • R 1 is independently selected from halogen, nitro, amino, cyano, Ci_ 8 alkoxy, Ci_ 8 alkoxyCi_ 8 alkyl, hydroxyCi_ 8 alkyl, haloCi_ 8 alkyl, haloCi_ 8 alkoxy, -(CH 2 ) x NR b R c , -(CR b R c ) x OR b , -0(CR b R c ) x R b , -(CH 2 ) X CN, -(CH 2 ) x C(0)NR b R c , -(CH 2 ) x NHC(0)R b , - (CH 2 ) x N(R b )S0 2 R c , C 6 -i 4 aryl, C 6 -i 4 arylalkyl, C 3 -i 2 cycloalkyl, C 3 _i 2 cycloalkylCi_
  • R is independently selected from halogen, nitro, amino, cyano, Ci_ galkoxy, Ci- 8 alkoxyCi_ 8 alkyl, hydroxyCi_ 8 alkyl, haloCi_ 8 alkyl, haloCi_ 8 alkoxy, 3 to 15 membered heterocyclylCi_ 8 alkyl, -(CH 2 ) x NR b R c , -(CR b R c ) x OR b , -0(CR b R c ) x R b , -(CH 2 ) X CN and -(CH 2 ) x C(0)NR b R c ;
  • R is selected from hydrogen and Ci_ 8 alkyl
  • R 4 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 _ 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 14 membered heteroaryl, 5
  • R b and R c which may be same or different, are independently selected from hydrogen, halogen, hydroxyl, nitro, amino, cyano, Ci_ 8 alkyl, C 2 _ioalkenyl, C 2 _ l oalkynyl, 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, C 6- i 4 aryl optionally substituted with halogen or Ci_ 8 alkoxy, C 6 -i 4 aryloxy, C 6 -i 4 arylCi_ 8 alkyl, 3 to 15 membered heterocyclyl
  • n is selected from '0' to '4', both inclusive;
  • n is selected from '0' to '4', both inclusive;
  • x is selected from '0' to '4', both inclusive;
  • y is selected from '0' to '4', both inclusive.
  • the compounds of formula (I) may involve one or more embodiments.
  • Embodiments of formula (I) include compounds of formula (la) and (lb) as described hereinafter. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments.
  • the invention provides compounds of formula (I) as defined above wherein P is C 6 i 4 aryl (e.g. phenyl) or 5 to 14 membered heteroaryl (e.g. thiophene) (according to one embodiment defined below), Q is (e.g. phenyl) (according to
  • B is OH or (according to yet another embodiment defined below), m is 0, 1 or 2 (according to yet another embodiment defined below), n is 0, 1 or 2 (according to yet another embodiment defined below).
  • P is C 6 i 4 aryl (e.g. phenyl) or 5 to 14 membered heteroaryl (e.g. thiophene).
  • A is ethyl or hexyl
  • -( CH 2)x NRbRCRC e .g. N,N,N-trimethylethanaminium
  • -(CH 2 ) x C(0)NR b R c e.g. (diethylamino)-2-oxoethyl or (dimethylamino)-2-oxoethyl
  • R a is hydrogen, methyl, ethyl, hexyl
  • R 3 is hydrogen
  • R 1 is independently selected from halogen (e.g. CI or F), haloCi-galkyl (e.g. trifluoromethyl or 3-fluoropropyl), Ci-galkoxy (e.g. methoxy), Ci_ galkoxyCi-galkyl (e.g. 3-ethoxypropyl, 3-methoxypropyl, 3-propoxypropyl or 4-ethoxybutyl), hydroxyCi-galkyl (e.g. 3-hydroxypropyl, 4-hydroxybutyl or 3-hydroxy-3-methylbutyl), - (CH 2 ) x CN (e.g.
  • cyanomethyl, cyanoethyl or 3-Cyanopropyl -0(CR b R c ) x R b (e.g. pyridin-3- ylmethoxy), -(CH 2 ) x C(0)NR b R c (e.g. 4-(N-ethylamino-4-oxo)butyl, 3-amino-3-oxopropyl, 3- (N-ethyl-3-oxo)propyl or 3-amino-3-oxopropyl), -(CR b R c ) x OR b (e.g.
  • 3-morpholinopropyl 4-carbamoylpiperidin-l-ylpropyl or 4- ethoxypiperidin-l-ylpropyl), 3 to 15 membered heterocyclyl optionally substituted with one or more R 4 (e.g. 1-acetyl piperidin-4-yl), C6-i 4 aryl optionally substituted with one or more R 4 (e.g.
  • R 1 is independently selected from halogen (e.g. CI or F), haloCi-galkyl (e.g. trifluoromethyl or 3-fluoropropyl), Ci-galkoxy (e.g. methoxy), Ci_ salkoxyCi-galkyl (e.g. 3-ethoxypropyl, 3-methoxypropyl, 3-propoxypropyl or 4-ethoxybutyl), hydroxyCi-galkyl (e.g. 3-hydroxypropyl, 4-hydroxybutyl or 3-hydroxy-3-methylbutyl), - (CH 2 ) x CN (e.g.
  • cyanomethyl, cyanoethyl or 3-Cyanopropyl -0(CR b R c ) x R b (e.g. pyridin-3- ylmethoxy), -(CH 2 ) x C(0)NR b R c (e.g. 4-(N-ethylamino-4-oxo)butyl, 3-amino-3-oxopropyl, 3- (N-ethyl-3-oxo)propyl or 3-amino-3-oxopropyl), -(CR b R c ) x OR b (e.g.
  • 3-morpholinopropyl 4-carbamoylpiperidin-l-ylpropyl or 4- ethoxypiperidin-l-ylpropyl), 3 to 15 membered heterocyclyl optionally substituted with one or more R 4 (e.g. 1-acetyl piperidin-4-yl), C 6 -i 4 aryl optionally substituted with one or more R 4 (e.g.
  • R b and R c are independently selected from hydrogen, Ci_ 8 alkyl (e.g. methyl, ethyl or isopropyl), Ci_ 8 alkoxyCi_ 8 alkyl (e.g.
  • C3_i 2 cycloalkylCi_ 8 alkyl e.g. cyclopropylmethyl
  • C 6 i 4 arylalkyl e.g. benzyl
  • C 6 i 4 aryl optionally substituted with halogen or Ci- 8 alkoxy e.g. 2,6-Dichlorophenyl, 2-Chlorophenyl, 3-methoxyphenyl or 2,6- Difluorophenyl
  • Ci- 8 alkoxy e.g. 2,6-Dichlorophenyl, 2-Chlorophenyl, 3-methoxyphenyl or 2,6- Difluorophenyl
  • 5 to 14 membered heteroaryl optionally substituted with halogen
  • CN or Ci_ galkyl e.g.
  • pyridine 6-chloropyridin-3-yl, 6-methylpyridin-3-yl, 2-methylpyridin-3-yl, 5- Fluoropyridin-3-yl, 5-Cyanopyridin-3-yl or pyrazine) and 5 to 14 membered heteroarylCi- galkyl optionally substituted with Ci-galkyl (e.g. 4-methylthiazol-2-yl)methyl) and x is 1, 2, 3 or 4.
  • Ci-galkyl e.g. 4-methylthiazol-2-yl
  • R 1 is independently selected from CI, F, trifluoromethyl, 3-fluoropropyl, methoxy, 3-ethoxypropyl, 3-methoxypropyl, 3- propoxypropyl, 4-ethoxybutyl, 3-hydroxypropyl, 4-hydroxybutyl, 3-hydroxy-3-methylbutyl, cyanomethyl, cyanoethyl, 3-Cyanopropyl, pyridin-3-ylmethoxy, 4-(N-ethylamino-4-oxo)butyl, 3-amino-3-oxopropyl, 3-(V-ethyl-3-oxo)propyl, 3-amino-3-oxopropyl, 3-(2- methoxyethoxy)propyl, 3-(2-ethoxyethoxy)propyl, 3-(cyclopropylmethoxy)propyl, 3- (benzyloxy)propyl,
  • R 4 is independently selected from is cyano, halogen (e.g. CI or F), Ci-galkyl (e.g. methyl or ethyl), hydroxyl, Ci-galkoxy (e.g. methoxy, ethoxy or propoxy), -(CH 2 ) x C(0)NR b R c (e.g. -CONH 2 ) and -(CH 2 ) x C(0)R b (e.g. acetyl).
  • R 4 is independently selected from is cyano, halogen (e.g.
  • Ci_ 8 alkyl e.g. methyl or ethyl
  • hydroxyl Ci_ 8 alkoxy (e.g. methoxy, ethoxy or propoxy)
  • -(CH 2 ) x C(0)NR b R c e.g. -CONH 2
  • -(CH 2 ) x C(0)R b e.g. acetyl
  • R b and R c are independently selected from hydrogen
  • Ci_ 8 alkyl e.g. methyl or ethyl
  • x is 0.
  • R 4 is independently selected from cyano, CI, F, methyl, ethyl, hydroxyl, methoxy, ethoxy, propoxy, -CONH 2 and acetyl.
  • R is independently selected from halogen (e.g. CI or F), Ci- 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. ethoxymethyl or propoxymethyl), haloCi_ 8 alkyl (e.g. CF 3 , fluoromethyl or difluoromethyl), 3 to 15 membered heterocyclylCi- 8 alkyl (e.g. pyrrolidin-l-ylmethyl) and -(CR b R c ) x OR b (e.g. 2-(methoxyethoxy)methyl).
  • halogen e.g. CI or F
  • Ci- 8 alkoxy e.g. methoxy
  • Ci_ 8 alkoxyCi_ 8 alkyl e.g. ethoxymethyl or propoxymethyl
  • haloCi_ 8 alkyl e.g. CF 3 , fluoromethyl or difluoromethyl
  • R is independently selected from halogen (e.g. CI or F), Ci- 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. ethoxymethyl or propoxymethyl), haloCi_ 8 alkyl (e.g. CF 3 , fluoromethyl or difluoromethyl), 3 to 15 membered heterocyclylCi- 8 alkyl (e.g. pyrrolidin-l-ylmethyl) and -(CR b R c ) x OR b (e.g. 2-(methoxyethoxy)methyl).
  • halogen e.g. CI or F
  • Ci- 8 alkoxy e.g. methoxy
  • Ci_ 8 alkoxyCi_ 8 alkyl e.g. ethoxymethyl or propoxymethyl
  • haloCi_ 8 alkyl e.g. CF 3 , fluoromethyl or difluoromethyl
  • R b and R c are independently selected from hydrogen, Ci_ 8 alkyl (e.g. methyl or ethyl) and Ci_ 8 alkoxyCi_ 8 alkyl (e.g. methoxyethyl) and 'x' is 1 or 2.
  • R is independently selected from CI, F, methoxy, ethoxymethyl, propoxymethyl, CF 3 , fluoromethyl, difluoromethyl, pyrrolidin-l-ylmethyl, pyrrolidin-l-ylmethyl and 2-(methoxyethoxy)methyl.
  • R is independently selected from CI, F and CF 3 .
  • n 0, 1 or 2.
  • P is C6-i 4 aryl (e.g. phenyl) or 5 to 14 membered heteroaryl (e.g. thiophene), Q is C 6 -i 4 aryl (e.g. phenyl),
  • R a is hydrogen, Ci_ 8 alkyl (e.g. methyl, ethyl or hexyl), (e.g. ⁇ , ⁇ , ⁇ -
  • R 1 is halogen (e.g. CI or F), haloCi_ 8 alkyl (e.g. trifluoromethyl or 3-fluoropropyl), Ci_ 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. 3-ethoxypropyl, 3-methoxypropyl, 3- propoxypropyl or 4-ethoxybutyl), hydroxyCi_ 8 alkyl (e.g. 3-hydroxypropyl, 4-hydroxybutyl or 3-hydroxy-3-methylbutyl), -(CH 2 ) X CN (e.g.
  • halogen e.g. CI or F
  • haloCi_ 8 alkyl e.g. trifluoromethyl or 3-fluoropropyl
  • Ci_ 8 alkoxy e.g. methoxy
  • Ci_ 8 alkoxyCi_ 8 alkyl e.g. 3-ethoxypropyl, 3-methoxypropy
  • 3-morpholinopropyl 4- carbamoylpiperidin-l-ylpropyl or 4-ethoxypiperidin- l-ylpropyl), 3 to 15 membered heterocyclyl optionally substituted with one or more R 4 (e.g. 1-acetyl piperidin-4-yl), C 6 i 4 aryl optionally substituted with one or more R 4 (e.g.
  • R is halogen (e.g. CI or F), Ci_ 8 alkoxy (e.g. methoxy), Ci- 8 alkoxyCi_ 8 alkyl (e.g. ethoxymethyl or propoxymethyl), haloCi_ 8 alkyl (e.g. CF 3 , lluoromethyl or dilluoromethyl), 3 to 15 membered heterocyclylCi_ 8 alkyl (e.g. pyrrolidin-l-ylmethyl) or -(CR b R c ) x OR b (e.g. 2- (methoxyethoxy )methyl) ,
  • R is hydrogen or Ci_ 8 alkyl (e.g. methyl),
  • R 4 is cyano, halogen (e.g. CI or F), Ci_ 8 alkyl (e.g. methyl or ethyl), hydroxyl, Ci_ salkoxy (e.g. methoxy, ethoxy or propoxy), -(CH 2 ) x C(0)NR b R c (e.g. -CONH 2 ) or - (CH 2 ) x C(0)R b (e.g. acetyl),
  • halogen e.g. CI or F
  • Ci_ 8 alkyl e.g. methyl or ethyl
  • Ci_ salkoxy e.g. methoxy, ethoxy or propoxy
  • -(CH 2 ) x C(0)NR b R c e.g. -CONH 2
  • - (CH 2 ) x C(0)R b e.g. acetyl
  • R b and R c are hydrogen, Ci_ 8 alkyl (e.g. methyl, ethyl or isopropyl), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. methoxyethyl or ethoxyethyl), C 3 _i 2 cycloalkylCi_ 8 alkyl (e.g. cyclopropylmethyl), C 6- i 4 arylalkyl (e.g. benzyl), C 6 -i 4 aryl optionally substituted with halogen or Ci_ 8 alkoxy (e.g.
  • Ci_ 8 alkyl e.g. pyridine, 6- chloropyridin-3-yl, 6-methylpyridin-3-yl, 2-methylpyridin-3-yl, 5-Fluoropyridin-3-yl, 5- Cyanopyridin-3-yl or pyrazine
  • Ci_ 8 alkyl e.g. 4-methylthiazol-2-yl
  • x 0, 1, 2 or 3
  • n 0, 1 or 2
  • n 0, 1 or 2.
  • P is phenyl or thiophene
  • R 1 is CI, F, trifluoromethyl, 3-fluoropropyl, methoxy, 3-ethoxypropyl, 3- methoxypropyl, 3-propoxypropyl, 4-ethoxybutyl, 3-hydroxypropyl, 4-hydroxybutyl, 3- hydroxy-3-methylbutyl, cyanomethyl, cyanoethyl, 3-Cyanopropyl, pyridin-3-ylmethoxy, 4- (N-ethylamino-4-oxo)butyl, 3-amino-3-oxopropyl, 3-(7V-ethyl-3-oxo)propyl, 3-amino-3- oxopropyl, 3-(2-methoxyethoxy)propyl, 3-(2-ethoxyethoxy)propyl, 3-(2-ethoxyethoxy)propyl, 3-
  • R is CI, F, methoxy, ethoxymethyl, propoxymethyl, CF 3 , fluoromethyl, difluoromethyl, pyrrolidin- l-ylmethyl or 2-(methoxyethoxy)methyl, m is 0, 1 or 2, and
  • n 0, 1 or 2.
  • the invention also provides a compound of formula (la), which is an embodiment of a compound of formula (I).
  • the invention provides a compound of formula (la) or a pharmaceutically acceptable salt thereof,
  • A is selected from
  • R a is selected from hydrogen, Ci_ 8 alkyl, -(CH 2 ) x C(0)NR b R c and -( CH 2) X NR R R .
  • R 1 is independently selected from halogen, Ci_ 8 alkoxy, C 8 alkoxyCi_ 8 alkyl, hydroxyCi_ 8 alkyl, haloCi_ 8 alkyl, -(CH 2 ) x NR b R c , -(CR b R c ) x OR b , 0(CR b R c ) x R b , -(CH 2 ) X CN, -(CH 2 ) x C(0)NR b R c , -(CH 2 ) x NHC(0)R b , -(CH 2 ) x N(R b )S0 2 R c , C i 4 aryl, 3 to 15 membered heterocyclyl, 3 to 15 membered heterocyclyl
  • R is independently selected from halogen, Ci_ 8 alkoxy, Ci_ 8 alkoxyCi_ 8 alkyl, haloCi_ 8 alkyl, 3 to 15 membered heterocyclylCi_ 8 alkyl and -(CR b R c ) x OR b ;
  • R is selected from hydrogen and Ci_ 8 alkyl
  • R 4 is independently selected from halogen, hydroxyl, cyano, Ci_ 8 alkyl, Ci_ 8 alkoxy, 5 to 14 membered heteroaryl, -(CH 2 ) x C(0)R b and -(CH 2 ) x C(0)NR b R c ; at each occurrence, R b and R c which may be same or different, are independently selected from hydrogen, Ci_ 8 alkyl, Ci_ 8 alkoxyCi_ 8 alkyl, C3_i 2 cycloalkylCi_ 8 alkyl, C 6 -i 4 aryl optionally substituted with halogen or Ci_ 8 alkoxy, C 6 -i 4 arylCi_ 8 alkyl, 5 to 14 membered heteroaryl optionally substituted with halogen, CN or Ci_ 8 alkyl and 5 to 14 membered heteroarylCi_ 8 alkyl optionally substituted with Ci_ 8 alkyl;
  • n is selected from '0' to '4', both inclusive;
  • n is selected from '0' to '4', both inclusive;
  • x is selected from '0' to '4', both inclusive;
  • the compounds of formula (la) may involve one or more embodiments.
  • Embodiments of formula (la) include compounds of formula (lb) as described hereinafter. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (la) as defined above wherein A is
  • B is OH or (according to another embodiment defined below), m is 0, 1 or 2 (according to yet another embodiment defined below), n is 0, 1 or 2 (according to yet another embodiment defined below).
  • R a is hydrogen, methyl, ethyl, hexyl,
  • R 1 is independently selected from halogen (e.g. CI or F), haloCi_ 8 alkyl (e.g. trifluoromethyl or 3-fluoropropyl), Ci_ 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. 3-ethoxypropyl, 3-methoxypropyl, 3-propoxypropyl or 4-ethoxybutyl), hydroxyCi_ 8 alkyl (e.g. 3-hydroxypropyl, 4-hydroxybutyl or 3-hydroxy-3-methylbutyl), - (CH 2 ) x CN (e.g.
  • cyanomethyl, cyanoethyl or 3-Cyanopropyl -0(CR b R c ) x R b (e.g. pyridin-3- ylmethoxy), -(CH 2 ) x C(0)NR b R c (e.g. 4-(N-ethylamino-4-oxo)butyl, 3-amino-3-oxopropyl, 3- (N-ethyl-3-oxo)propyl or 3-amino-3-oxopropyl), -(CR b R c ) x OR b (e.g.
  • 3-morpholinopropyl 4-carbamoylpiperidin- l-ylpropyl, 4- ethoxypiperidin-l-ylpropyl), 3 to 15 membered heterocyclyl optionally substituted with one or more R 4 (e.g. 1-acetyl piperidin-4-yl), C6-i 4 aryl optionally substituted with one or more R 4 (e.g.
  • R 1 is independently selected from halogen (e.g. CI or F), haloCi_ 8 alkyl (e.g. trifluoromethyl or 3-fluoropropyl), Ci_ 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. 3-ethoxypropyl, 3-methoxypropyl, 3-propoxypropyl or 4-ethoxybutyl), hydroxyCi_ 8 alkyl (e.g. 3-hydroxypropyl, 4-hydroxybutyl or 3-hydroxy-3-methylbutyl), - (CH 2 ) x CN (e.g.
  • cyanomethyl, cyanoethyl or 3-Cyanopropyl -0(CR b R c ) x R b (e.g. pyridin-3- ylmethoxy), -(CH 2 ) x C(0)NR b R c (e.g. 4-(N-ethylamino-4-oxo)butyl, 3-amino-3-oxopropyl, 3- (N-ethyl-3-oxo)propyl or 3-amino-3-oxopropyl), -(CR b R c ) x OR b (e.g.
  • 1-acetyl piperidin-4-yl C 6 i 4 aryl optionally substituted with one or more R 4 (e.g. 4-cyanophenyl, 4-Carbamoylphenyl, 3-Carbamoylphenyl, 4-Carbamoyl-3 -fluorophenyl, 4-Carbamoyl-3,5-difluorophenyl, 4-Carbamoyl-3-chlorophenyl or 4-Carbamoyl-3- methylphenyl), 5 to 14 membered heteroaryl optionally substituted with one or more R 4 (e.g.
  • R b and R c are independently selected from hydrogen, Ci_ 8 alkyl (e.g. methyl, ethyl or isopropyl), Ci_ 8 alkoxyCi_ 8 alkyl (e.g.
  • C3_i 2 cycloalkylCi_ 8 alkyl e.g. cyclopropylmethyl
  • C 6 i 4 arylalkyl e.g. benzyl
  • C 6 i 4 aryl optionally substituted with halogen or Ci- 8 alkoxy e.g. 2,6-Dichlorophenyl, 2-Chlorophenyl, 3-methoxyphenyl or 2,6- Difluorophenyl
  • Ci- 8 alkoxy e.g. 2,6-Dichlorophenyl, 2-Chlorophenyl, 3-methoxyphenyl or 2,6- Difluorophenyl
  • 5 to 14 membered heteroaryl optionally substituted with halogen
  • CN or Ci_ 8 alkyl e.g.
  • pyridine 6-chloropyridin-3-yl, 6-methylpyridin-3-yl, 2-methylpyridin-3-yl, 5- Fluoropyridin-3-yl, 5-Cyanopyridin-3-yl or pyrazine) and 5 to 14 membered heteroarylCi- 8 alkyl optionally substituted with Ci_ 8 alkyl (e.g. 4-methylthiazol-2-yl)methyl) and x is 1, 2, 3 or 4.
  • Ci_ 8 alkyl e.g. 4-methylthiazol-2-yl
  • R 1 is independently selected from CI, F, trifluoromethyl, 3-fluoropropyl, methoxy, 3-ethoxypropyl, 3-methoxypropyl, 3- propoxypropyl, 4-ethoxybutyl, 3-hydroxypropyl, 4-hydroxybutyl, 3-hydroxy-3-methylbutyl, cyanomethyl, cyanoethyl, 3-Cyanopropyl, pyridin-3-ylmethoxy, 4-(N-ethylamino-4-oxo)butyl,
  • R 4 is independently selected from is cyano, halogen (e.g. CI or F), Ci_ 8 alkyl (e.g. methyl or ethyl), hydroxyl, Ci_ 8 alkoxy (e.g. methoxy, ethoxy or propoxy), -(CH 2 ) x C(0)NR b R c (e.g. -CONH 2 ) and -(CH 2 ) x C(0)R b (e.g. acetyl).
  • halogen e.g. CI or F
  • Ci_ 8 alkyl e.g. methyl or ethyl
  • Ci_ 8 alkoxy e.g. methoxy, ethoxy or propoxy
  • -(CH 2 ) x C(0)NR b R c e.g. -CONH 2
  • -(CH 2 ) x C(0)R b e.g. acetyl
  • R 4 is independently selected from is cyano, halogen (e.g. CI or F), Ci_ 8 alkyl (e.g. methyl or ethyl), hydroxyl, Ci_ 8 alkoxy (e.g. methoxy, ethoxy or propoxy), -(CH 2 ) x C(0)NR b R c (e.g. -CONH 2 ) and -(CH 2 ) x C(0)R b (e.g. acetyl).
  • R b and R c are independently selected from hydrogen
  • Ci_ 8 alkyl (e.g. methyl or ethyl) and x is 0.
  • R 4 is independently selected from cyano, CI, F, methyl, ethyl, hydroxyl, methoxy, ethoxy, propoxy, -CONH 2 and acetyl.
  • R is independently selected from halogen (e.g. CI or F), Ci_ 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. ethoxymethyl or propoxymethyl), haloCi_ 8 alkyl (e.g. CF 3 , fluoromethyl or difluoromethyl), 3 to 15 membered heterocyclylCi- 8 alkyl (e.g. pyrrolidin-l-ylmethyl) and -(CR b R c ) x OR b (e.g. 2-(methoxyethoxy)methyl).
  • halogen e.g. CI or F
  • Ci_ 8 alkoxy e.g. methoxy
  • Ci_ 8 alkoxyCi_ 8 alkyl e.g. ethoxymethyl or propoxymethyl
  • haloCi_ 8 alkyl e.g. CF 3 , fluoromethyl or difluoromethyl
  • R is independently selected from halogen (e.g. CI or F), Ci-galkoxy (e.g. methoxy), Ci- 8 alkoxyCi_ 8 alkyl (e.g. ethoxymethyl or propoxymethyl), haloCi-galkyl (e.g. CF 3 , fluoromethyl or difluoromethyl), 3 to 15 membered heterocyclylCi- 8 alkyl (e.g. pyrrolidin-l-ylmethyl) and -(CR b R c ) x OR b (e.g. 2-(methoxyethoxy)methyl).
  • halogen e.g. CI or F
  • Ci-galkoxy e.g. methoxy
  • Ci- 8 alkoxyCi_ 8 alkyl e.g. ethoxymethyl or propoxymethyl
  • haloCi-galkyl e.g. CF 3 , fluoromethyl or difluoromethyl
  • R b and R c are independently selected from hydrogen, Ci_ 8 alkyl (e.g. methyl or ethyl) and Ci_ 8 alkoxyCi_ 8 alkyl (e.g. methoxyethyl) and 'x' is 1 or 2.
  • R is independently selected from CI, F, methoxy, ethoxymethyl, propoxymethyl, CF 3 , fluoromethyl, difluoromethyl, pyrrolidin-l-ylmethyl, pyrrolidin-l-ylmethyl and 2-(methoxyethoxy)methyl.
  • R is independently selected from CI, F and CF 3 .
  • n 0, 1 or 2.
  • R a is hydrogen, Ci_ 8 alkyl (e.g. methyl, ethyl or hexyl), -( CH 2)x NR R R ( e .g. NJfJf- trimethylethanaminium) or -(CH 2 ) x C(0)NR b R c (e.g. (diethylamino)-2-oxoethyl or (dimethylamino)-2-oxoethyl),
  • R 1 is halogen (e.g. CI or F), haloCi_ 8 alkyl (e.g. trifluoromethyl or 3-fluoropropyl), Ci_ 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. 3-ethoxypropyl, 3-methoxypropyl, 3- propoxypropyl or 4-ethoxybutyl), hydroxyCi_ 8 alkyl (e.g. 3-hydroxypropyl, 4-hydroxybutyl or 3-hydroxy-3-methylbutyl), -(CH 2 ) X CN (e.g.
  • halogen e.g. CI or F
  • haloCi_ 8 alkyl e.g. trifluoromethyl or 3-fluoropropyl
  • Ci_ 8 alkoxy e.g. methoxy
  • Ci_ 8 alkoxyCi_ 8 alkyl e.g. 3-ethoxypropyl, 3-methoxypropy
  • 3-morpholinopropyl 4- carbamoylpiperidin-l-ylpropyl or 4-ethoxypiperidin- l-ylpropyl), 3 to 15 membered heterocyclyl optionally substituted with one or more R 4 (e.g. 1-acetyl piperidin-4-yl), C6 i 4 aryl optionally substituted with one or more R 4 (e.g.
  • R is halogen (e.g. CI or F), Ci_ 8 alkoxy (e.g. methoxy), Ci- 8 alkoxyCi_ 8 alkyl (e.g. ethoxymethyl or propoxymethyl), haloCi_ 8 alkyl (e.g. CF 3 , iluoromethyl or difluoromethyl), 3 to 15 membered heterocyclylCi_ 8 alkyl (e.g. pyrrolidin-l-ylmethyl) or -(CR b R c ) x OR b (e.g. 2- (methoxyethoxy )methyl) ,
  • R is hydrogen or Ci_ 8 alkyl (e.g. methyl), R 4 is cyano, halogen (e.g. CI or F), Ci_ 8 alkyl (e.g. methyl or ethyl), hydroxyl, Ci_ salkoxy (e.g. methoxy, ethoxy or propoxy), -(CH 2 ) x C(0)NR b R c (e.g. -CONH 2 ) or - (CH 2 ) x C(0)R b (e.g. acetyl),
  • R b and R c are hydrogen, Ci_ 8 alkyl (e.g. methyl, ethyl or isopropyl), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. methoxyethyl or ethoxyethyl), C3_i 2 cycloalkylCi_ 8 alkyl (e.g. cyclopropylmethyl), C 6- i 4 arylalkyl (e.g. benzyl), C6-i 4 aryl optionally substituted with halogen or Ci_ 8 alkoxy (e.g.
  • Ci_ 8 alkyl e.g. pyridine, 6- chloropyridin-3-yl, 6-methylpyridin-3-yl, 2-methylpyridin-3-yl, 5-Fluoropyridin-3-yl, 5- Cyanopyridin-3-yl or pyrazine
  • Ci_ 8 alkyl e.g. 4-methylthiazol-2-yl
  • x 0, 1, 2 or 3
  • n 0, 1 or 2
  • n 0, 1 or 2.
  • R 1 is CI, F, trifluoromethyl, 3-fluoropropyl, methoxy, 3-ethoxypropyl, 3- methoxypropyl, 3-propoxypropyl, 4-ethoxybutyl, 3-hydroxypropyl, 4-hydroxybutyl, 3- hydroxy-3-methylbutyl, cyanomethyl, cyanoethyl, 3-Cyanopropyl, pyridin-3-ylmethoxy, 4- (N-ethylamino-4-oxo)butyl, 3-amino-3-oxopropyl, 3-(V-ethyl-3-oxo)propyl, 3-amino-3- oxopropyl, 3-(2-methoxyethoxy)propyl, 3-(2-ethoxyethoxy)propyl, 3-(2-ethoxyethoxy)propyl, 3-
  • R is CI, F, methoxy, ethoxymethyl, propoxymethyl, CF 3 , fluoromethyl, difluoromethyl, pyrrolidin- l-ylmethyl or 2-(methoxyethoxy)methyl,
  • n 0, 1 or 2
  • n 0, 1 or 2.
  • the invention also provides a compound of formula (lb), which is an embodiment of a compound of formula (I).
  • A is selected from
  • R a is selected from hydrogen, Ci_ 8 alkyl, -(CH 2 ) x C(0)NR b R c and
  • R is independently selected from halogen, Ci_ 8 alkoxy, Ci
  • R is independently selected from halogen, Ci_ 8 alkoxy, ( 8 alkoxyCi_ 8 alkyl, haloCi_ 8 alkyl, 3 to 15 membered heterocyclylCi_ 8 alkyl and -(CR b R c ) x OR b ; at each occurrence, R 4 is independently selected from halogen, hydroxyl, cyano, Ci_ salkyl, Ci_ 8 alkoxy, 5 to 14 membered heteroaryl, -(CH 2 ) x C(0)R b and -(CH 2 ) x C(0)NR b R c ; at each occurrence, R b and R c which may be same or different, are independently selected from hydrogen, Ci_ 8 alkyl, Ci_ 8 alkoxyCi_ 8 alkyl, C3_i 2 cycloalkylCi_ 8 alkyl, C6-i 4 aryl optionally substituted with halogen or Ci_ 8 alkoxy, C6-i 4
  • n is selected from '0' to '4', both inclusive;
  • n is selected from '0' to '4', both inclusive;
  • x is selected from '0' to '4', 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 wherein m is 0, 1 or 2 (according to one embodiment defined below), n is 0, 1 or 2 (according to another embodiment defined below).
  • R is hydrogen, Ci_ 8 alkyl (e.g. methyl, ethyl or hexyl), -( CH 2)x NRbRCRC ( e .g. N,N,N-trimethylethanaminium) or -(CH 2 ) x C(0)NR b R c (e.g. (diethylamino)-2-oxoethyl or (dimethylamino)-2-oxoethyl).
  • R is hydrogen, methyl, ethyl, hexyl, N,N,N-trimethylethanaminium, 2-(diethylamino)-2-oxoethyl or (dimethylamino)-2-oxoethyl).
  • R 1 is independently selected from halogen (e.g. CI or F), haloCi-galkyl (e.g. trifluoromethyl or 3-fluoropropyl), Ci-galkoxy (e.g. methoxy), Ci_ salkoxyCi-galkyl (e.g. 3-ethoxypropyl, 3-methoxypropyl, 3-propoxypropyl or 4-ethoxybutyl), hydroxyCi_ 8 alkyl (e.g. 3-hydroxypropyl, 4-hydroxybutyl or 3-hydroxy-3-methylbutyl), - (CH 2 ) x CN (e.g.
  • cyanomethyl, cyanoethyl or 3-Cyanopropyl -0(CR b R c ) x R b (e.g. pyridin-3- ylmethoxy), -(CH 2 ) x C(0)NR b R c (e.g. 4-(N-ethylamino-4-oxo)butyl, 3-amino-3-oxopropyl, 3- (N-ethyl-3-oxo)propyl or 3-amino-3-oxopropyl), -(CR b R c ) x OR b (e.g.
  • 3-morpholinopropyl 4-carbamoylpiperidin-l-ylpropyl or 4- ethoxypiperidin-l-ylpropyl), 3 to 15 membered heterocyclyl optionally substituted with one or more R 4 (e.g. 1-acetyl piperidin-4-yl), C6 i 4 aryl optionally substituted with one or more R 4 (e.g.
  • R 1 is independently selected from halogen (e.g. CI or F), haloCi-galkyl (e.g. trifluoromethyl or 3-fluoropropyl), Ci-galkoxy (e.g. methoxy), Ci_ galkoxyCi-galkyl (e.g. 3-ethoxypropyl, 3-methoxypropyl, 3-propoxypropyl or 4-ethoxybutyl), hydroxyCi_ 8 alkyl (e.g. 3-hydroxypropyl, 4-hydroxybutyl or 3-hydroxy-3-methylbutyl), - (CH 2 ) X CN (e.g.
  • cyanomethyl, cyanoethyl or 3-Cyanopropyl -0(CR b R c ) x R b (e.g. pyridin-3- ylmethoxy), -(CH 2 ) x C(0)NR b R c (e.g. 4-(N-ethylamino-4-oxo)butyl, 3-amino-3-oxopropyl, 3- (N-ethyl-3-oxo)propyl or 3-amino-3-oxopropyl), -(CR b R c ) x OR b (e.g.
  • 3-morpholinopropyl 4-carbamoylpiperidin-l-ylpropyl or 4- ethoxypiperidin-l-ylpropyl), 3 to 15 membered heterocyclyl optionally substituted with one or more R 4 (e.g. 1-acetyl piperidin-4-yl), C6-i 4 aryl optionally substituted with one or more R 4 (e.g.
  • R b and R c are independently selected from hydrogen, Ci_ 8 alkyl (e.g. methyl, ethyl or isopropyl), Ci_ 8 alkoxyCi_ 8 alkyl (e.g.
  • C3_i 2 cycloalkylCi_ 8 alkyl e.g. cyclopropylmethyl
  • C 6 -i 4 arylalkyl e.g. benzyl
  • C 6 -i 4 aryl optionally substituted with halogen or Ci-galkoxy e.g. 2,6-Dichlorophenyl, 2-Chlorophenyl, 3-methoxyphenyl or 2,6- Difluorophenyl
  • Ci-galkoxy e.g. 2,6-Dichlorophenyl, 2-Chlorophenyl, 3-methoxyphenyl or 2,6- Difluorophenyl
  • 5 to 14 membered heteroaryl optionally substituted with halogen
  • CN or Ci_ 8 alkyl e.g.
  • pyridine 6-chloropyridin-3-yl, 6-methylpyridin-3-yl, 2-methylpyridin-3-yl, 5- Fluoropyridin-3-yl, 5-Cyanopyridin-3-yl or pyrazine) and 5 to 14 membered heteroarylCi- 8 alkyl optionally substituted with Ci_ 8 alkyl (e.g. 4-methylthiazol-2-yl)methyl) and x is 1, 2, 3 or 4.
  • Ci_ 8 alkyl e.g. 4-methylthiazol-2-yl
  • R 1 is independently selected from CI, F, trifluoromethyl, 3-fluoropropyl, methoxy, 3-ethoxypropyl, 3-methoxypropyl, 3- propoxypropyl, 4-ethoxybutyl, 3-hydroxypropyl, 4-hydroxybutyl, 3-hydroxy-3-methylbutyl, cyanomethyl, cyanoethyl, 3-Cyanopropyl, pyridin-3-ylmethoxy, 4-(N-ethylamino-4-oxo)butyl, 3-amino-3-oxopropyl, 3-(V-ethyl-3-oxo)propyl, 3-amino-3-oxopropyl, 3-(2- methoxyethoxy)propyl, 3-(2-ethoxyethoxy)propyl, 3-(cyclopropylmethoxy)propyl, 3- (benzyloxy)propyl
  • R 4 is independently selected from is cyano, halogen (e.g. CI or F), Ci_ 8 alkyl (e.g. methyl or ethyl), hydroxyl, Ci_ 8 alkoxy (e.g. methoxy, ethoxy or propoxy), -(CH 2 ) x C(0)NR b R c (e.g. -CONH 2 ) and -(CH 2 ) x C(0)R b (e.g. acetyl).
  • halogen e.g. CI or F
  • Ci_ 8 alkyl e.g. methyl or ethyl
  • Ci_ 8 alkoxy e.g. methoxy, ethoxy or propoxy
  • -(CH 2 ) x C(0)NR b R c e.g. -CONH 2
  • -(CH 2 ) x C(0)R b e.g. acetyl
  • R 4 is independently selected from is cyano, halogen (e.g. CI or F), Ci_ 8 alkyl (e.g. methyl or ethyl), hydroxyl, Ci_ 8 alkoxy (e.g. methoxy, ethoxy or propoxy), -(CH 2 ) x C(0)NR b R c (e.g. -CONH 2 ) and -(CH 2 ) x C(0)R b (e.g. acetyl).
  • R b and R c are independently selected from hydrogen
  • Ci_ 8 alkyl (e.g. methyl or ethyl) and x is 0.
  • R 4 is independently selected from cyano, CI, F, methyl, ethyl, hydroxyl, methoxy, ethoxy, propoxy, -CONH 2 and acetyl.
  • R is independently selected from halogen (e.g. CI or F), Ci_ 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. ethoxymethyl or propoxymethyl), haloCi_ 8 alkyl (e.g. CF 3 , fluoromethyl or difluoromethyl), 3 to 15 membered heterocyclylCi- 8 alkyl (e.g. pyrrolidin-l-ylmethyl) and -(CR b R c ) x OR b (e.g. 2-(methoxyethoxy)methyl).
  • halogen e.g. CI or F
  • Ci_ 8 alkoxy e.g. methoxy
  • Ci_ 8 alkoxyCi_ 8 alkyl e.g. ethoxymethyl or propoxymethyl
  • haloCi_ 8 alkyl e.g. CF 3 , fluoromethyl or difluoromethyl
  • R is independently selected from halogen (e.g. CI or F), Ci- 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. ethoxymethyl or propoxymethyl), haloCi_ 8 alkyl (e.g. CF 3 , fluoromethyl or difluoromethyl), 3 to 15 membered heterocyclylCi- 8 alkyl (e.g. pyrrolidin- l-ylmethyl) and -(CR b R c ) x OR b (e.g. 2-(methoxyethoxy)methyl).
  • halogen e.g. CI or F
  • Ci- 8 alkoxy e.g. methoxy
  • Ci_ 8 alkoxyCi_ 8 alkyl e.g. ethoxymethyl or propoxymethyl
  • haloCi_ 8 alkyl e.g. CF 3 , fluoromethyl or difluoromethyl
  • R b and R c are independently selected from hydrogen, Ci_ 8 alkyl (e.g. methyl or ethyl) and Ci_ 8 alkoxyCi_ 8 alkyl (e.g. methoxyethyl) and 'x' is 1 or 2.
  • R is independently selected from CI, F, methoxy, ethoxymethyl, propoxymethyl, CF 3 , fluoromethyl, difluoromethyl, pyrrolidin- l-ylmethyl, pyrrolidin- l-ylmethyl and 2-(methoxyethoxy)methyl.
  • R is independently selected from CI, F and CF 3 .
  • n 0, 1 or 2.
  • R a is hydrogen, Ci_ 8 alkyl (e.g. methyl, ethyl or hexyl), (e.g. ⁇ , ⁇ , ⁇ - trimethylethanaminium) or -(CH 2 ) x C(0)NR b R c (e.g. (diethylamino)-2-oxoethyl or (dimethylamino)-2-oxoethyl),
  • Ci_ 8 alkyl e.g. methyl, ethyl or hexyl
  • R c e.g. (diethylamino)-2-oxoethyl or (dimethylamino)-2-oxoethyl
  • R 1 is halogen (e.g. CI or F), haloCi_ 8 alkyl (e.g. trifluoromethyl or 3-fluoropropyl), Ci_ 8 alkoxy (e.g. methoxy), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. 3-ethoxypropyl, 3-methoxypropyl, 3- propoxypropyl or 4-ethoxybutyl), hydroxyCi_ 8 alkyl (e.g. 3-hydroxypropyl, 4-hydroxybutyl or 3-hydroxy-3-methylbutyl), -(CH 2 ) X CN (e.g.
  • halogen e.g. CI or F
  • haloCi_ 8 alkyl e.g. trifluoromethyl or 3-fluoropropyl
  • Ci_ 8 alkoxy e.g. methoxy
  • Ci_ 8 alkoxyCi_ 8 alkyl e.g. 3-ethoxypropyl, 3-methoxypropy
  • 3-morpholinopropyl 4- carbamoylpiperidin-l-ylpropyl or 4-ethoxypiperidin- l-ylpropyl), 3 to 15 membered heterocyclyl optionally substituted with one or more R 4 (e.g. 1-acetyl piperidin-4-yl), C 6 -i 4 aryl optionally substituted with one or more R 4 (e.g.
  • R is halogen (e.g. CI or F), Ci_ 8 alkoxy (e.g. methoxy), Ci- 8 alkoxyCi_ 8 alkyl (e.g. ethoxymethyl or propoxymethyl), haloCi_ 8 alkyl (e.g. CF 3 , iluoromethyl or diiluoromethyl), 3 to 15 membered heterocyclylCi_ 8 alkyl (e.g. pyrrolidin-l-ylmethyl) or -(CR b R c ) x OR b (e.g. 2- (methoxyethoxy )methyl) ,
  • R 4 is cyano, halogen (e.g. CI or F), Ci_ 8 alkyl (e.g. methyl or ethyl), hydroxyl, Ci_ 8 alkoxy (e.g. methoxy, ethoxy or propoxy), -(CH 2 ) x C(0)NR b R c (e.g. -CONH 2 ) or - (CH 2 ) x C(0)R b (e.g. acetyl),
  • halogen e.g. CI or F
  • Ci_ 8 alkyl e.g. methyl or ethyl
  • Ci_ 8 alkoxy e.g. methoxy, ethoxy or propoxy
  • -(CH 2 ) x C(0)NR b R c e.g. -CONH 2
  • - (CH 2 ) x C(0)R b e.g. acetyl
  • R b and R c are hydrogen, Ci_ 8 alkyl (e.g. methyl, ethyl or isopropyl), Ci_ 8 alkoxyCi_ 8 alkyl (e.g. methoxyethyl or ethoxyethyl), C 3 _i 2 cycloalkylCi_ 8 alkyl (e.g. cyclopropylmethyl), C 6 - i 4 arylalkyl (e.g. benzyl), C 6 -i 4 aryl optionally substituted with halogen or Ci_ 8 alkoxy (e.g.
  • Ci_ 8 alkyl e.g. pyridine, 6- chloropyridin-3-yl, 6-methylpyridin-3-yl, 2-methylpyridin-3-yl, 5-Fluoropyridin-3-yl, 5- Cyanopyridin-3-yl or pyrazine
  • Ci_ 8 alkyl e.g. 4-methylthiazol-2-yl
  • x 0, 1, 2 or 3
  • n 0, 1 or 2
  • n 0, 1 or 2.
  • R 1 is CI, F, trifluoromethyl, 3-f uoropropyl, methoxy, 3-ethoxypropyl, 3- methoxypropyl, 3-propoxypropyl, 4-ethoxybutyl, 3-hydroxypropyl, 4-hydroxybutyl, 3- hydroxy-3-methylbutyl, cyanomethyl, cyanoethyl, 3-Cyanopropyl, pyridin-3-ylmethoxy, 4- (N-ethylamino-4-oxo)butyl, 3-amino-3-oxopropyl, 3-(7V-ethyl-3-oxo)propyl, 3-amino-3- oxopropyl, 3-(2-methoxyethoxy)propyl, 3-(2-ethoxyethoxy)propyl, 3-(2-ethoxyethoxy)propyl, 3-
  • R is CI, F, methoxy, ethoxymethyl, propoxymethyl, CF 3 , fluoromethyl, difluoromethyl, pyrrolidin- l-ylmethyl or 2-(methoxyethoxy)methyl,
  • n 0, 1 or 2
  • n 0, 1 or 2.
  • Compounds of the present invention include the compounds in Examples 1-159.
  • 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).
  • one or more diseases, conditions and/or disorders selected from pulmonary hypertension, ARDS, asthma, bronchospasm, cough, pneumonia, pulmonary fibrosis/interstitial lung diseases, cystic fibrosis and Chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the present patent application provides a method for treating, controlling, delaying or preventing in a mammalian patient in need of treatment of one or more diseases, conditions and/or disorders selected from asthma, cystic fibrosis and Chronic obstructive pulmonary disease (COPD).
  • one or more diseases, conditions and/or disorders selected from asthma, cystic fibrosis and Chronic obstructive pulmonary disease (COPD).
  • COPD Chronic obstructive pulmonary disease
  • the present patent application provides a method for treating, controlling, delaying or preventing in a mammalian patient in need of treatment of asthma.
  • the present patent application provides a method for treating, controlling, delaying or preventing in a mammalian patient in need of treatment of cystic fibrosis.
  • the present patent application provides a method for treating, controlling, delaying or preventing in a mammalian patient in need of treatment of Chronic obstructive pulmonary disease (COPD).
  • COPD Chronic obstructive pulmonary disease
  • the present patent application provides use of a compound of the present invention for treating, controlling, delaying or preventing in a mammalian patient in need of treatment of one or more diseases, conditions and/or disorders selected from pulmonary hypertension, ARDS, asthma, bronchospasm, cough, pneumonia, pulmonary fibrosis/interstitial lung diseases, cystic fibrosis, Chronic obstructive pulmonary disease (COPD), hypertension, ischemic coronary syndromes, atherosclerosis, heart disease, glaucoma, coronary artery disease, AIDS related dementia, inflammatory bowel disease (IBD), Crohn's disease, colitis, psoriasis, heart failure, atherosclerosis, degenerative neurologic disorders, arthritis, drug induced liver injury, ischemic liver injury, 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 COPD.
  • diseases, conditions and/or disorders selected from pulmonary hypertension, ARDS, asthma, bronchospasm, cough, pneumonia, pulmonary fibrosis/interstitial lung diseases, cystic fibrosis and COPD.
  • halogen or halo means fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo).
  • alkyl refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e. Ci_ 8 alkyl), and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t- butyl).
  • C 1-6 alkyl refers to an alkyl chain having 1 to 6 carbon atoms.
  • the term “Ci_ 4 alkyl” refers to an alkyl chain having 1 to 4 carbon atoms. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched.
  • 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 _io alkynyl).
  • alkynyl groups include ethynyl, propynyl, and butynyl.
  • 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 H5. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched.
  • alkoxyalkyl or alky loxy alky 1 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-galkyloxyCi-galkyl).
  • alkoxyalkyl moiety includes, but are not limited to, - CH 2 OCH 3 and -CH 2 OC 2 H 5 . Unless set forth or recited to the contrary, all alkoxyalkyl groups described herein may be straight chain or branched.
  • haloalkyl refers to at least one halo group (selected from F, CI, Br or I), linked to an alkyl group as defined above (i.e. haloCi_ 8 alkyl).
  • haloalkyl moiety include, but are not limited to, trifluoromethyl, difluoromethyl and fluoromethyl groups. Unless set forth or recited to the contrary, all haloalkyl groups described herein may be straight chain or branched.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms (i.e. haloCi_ 8 alkoxy).
  • haloalkoxy include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1-bromoethoxy.
  • all haloalkoxy groups described herein may be straight chain or branched.
  • 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 C3_ 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 Cs-gcycloalkenylCi-galkyl.
  • 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 substituted or unsubstituted non-aromatic 3 to 15 membered ring radical (i.e. 3 to 15 membered heterocyclyl) which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s).
  • heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2- oxoazepinyl, octahydroin
  • 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.
  • heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group (i.e. 3 to 15 membered heterocyclylCi-galkyl).
  • the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • heteroaryl refers to substituted or unsubstituted
  • heteroaryl may be a mono-, bi- or tricyclic ring system.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, iso
  • heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group (i.e. 5 to 14 membered heterarylCi-galkyl).
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulf
  • 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.
  • 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.
  • 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.
  • 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, Formula II or Formula III, 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 compounds of general formula (la') and (lb') can be prepared as described in scheme 1.
  • the compound of general formula (1) undergoes reduction in presence of suitable reagent to give compound of formula (2).
  • the reaction may be carried out in presence of iron and cone. HC1 or Pd/C.
  • the solvent may be an alcohol.
  • the alcoholic solvent may be methanol.
  • the Compound of formula (2) is converted to the compound of formula (3).
  • the reaction is carried out by using potassium iodide in presence of an acid and a suitable oxidizing agent.
  • the acid may be /?-toluenesulfonic acid.
  • the oxidizing agent may be NaN0 2 .
  • the reaction may be carried out in a suitable solvent.
  • the suitable solvent may be acetonitrile.
  • the compound of formula (3) is reacted with a suitable alkynylating agent to give compound of formula (4).
  • the alkynylating agent may be trimethylsilyl acetylene.
  • the reaction may be carried out in presence of a suitable palladium catalyst.
  • the palladium catalyst may be bis(triphenylphosphine)palladium(II) dichloride.
  • the reaction may be carried out in presence of a suitable coupling agent.
  • the coupling agent may be Cul.
  • the reaction may be carried out in presence of a suitable base.
  • the base may be triethylamine, di-isopropyl ethylamine or combination thereof.
  • the reaction may be carried out in a suitable solvent.
  • the suitable solvent may be DMSO.
  • the ocmpound of formula (4) is then reacted with a suitable phenol derivative of formula (5) (wherein X is a halogen) to form compound of formula (6).
  • the reaction may be carried out in presence of a base.
  • the base may be aq. ammonia.
  • the reaction may be carried out in presence of a suitable palladium catalyst.
  • the palladium catalyst may be bis(triphenylphosphine)palladium(II) dichloride.
  • the reaction may also involve a suitable coupling agent.
  • the coupling reagent may be Cul.
  • the reaction may be carried out in a suitable solvent.
  • the suitable solvent may be THF.
  • the compound of formula (6) on alkaline hydrolysis gives the compound of formula (7).
  • the reaction may be carried out in presence of a suitable base.
  • the base may be aq. NaOH.
  • the reaction may be carried out in a suiatble solvent.
  • the suitable solvent may be analcohol.
  • the alcoholic solvent used for the reaction may be ethanol.
  • the compound of formula (7) on esterification gives the compound of formula (la').
  • the esterification may be carried out in presence of an acid.
  • the acid may be selected from hydrochloric acid and sulphuric acid.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be selected from ethanol or methanol.
  • Alkyne nitrile compound of formula (4) is reacted with the compound of formula (8) (wherein X is a halogen) to give the compound of formula (9).
  • the reaction may be carried out in presence of a base.
  • the base may be aq. ammonia.
  • the reaction may be carried out in presence of a suitable palladium catalyst.
  • the palladium catalyst may be bis(triphenylphosphine)palladium(II) dichloride.
  • the reaction may be carried out in presence of a coupling agent.
  • the coupling agent may be Cul.
  • the reaction may be carried out in a suitable solvent.
  • the solvent used for the reation may be THF.
  • the compound of formula (9) on alkaline hydrolysis yields the compound of formula (10).
  • the reaction may be carried out by using a suitable base.
  • the base may be aq. NaOH.
  • the reaction may be carried out in a suitable solvent.
  • the suitable solvent may be ethanol.
  • the compound of formula (10) further undergoes esterification to give the compound of formula (lb').
  • the esterification reaction may be carried out in the presence of an acid.
  • the acid may be selected from hydrochloric acid and sulphuric acid.
  • the reaction may be carried out in a suitable solvent.
  • the suitable solvent may be selected from ethanol and methanol.
  • Alkyne compounds of the general formula (la') can also be prepared by using a general approach as depicted in scheme 2 and scheme 3 wherein R 1 , R 2 , R a , m and n are as defined in formula (I).
  • cheme 2
  • the compound of formula (la') is also prepared from 4-amino benzoate derivative of formula (11) (wherein R a is hydrogen, Ci_ 8 alkyl, -(CH 2 ) x C(0)NR b R c or -(CH 2 ) x NR b R c R c ⁇ in a same manner as depicted in scheme 1.
  • R a is hydrogen, Ci_ 8 alkyl, -(CH 2 ) x C(0)NR b R c or -(CH 2 ) x NR b R c R c ⁇ in a same manner as depicted in scheme 1.
  • the compound of formula (13) is reacted with the compound of formula (5) to give the compound of formula (la').
  • the reaction may be carried out in presence of a base.
  • the base may be aq. ammonia.
  • the reaction may be carried out in presence of a suitable palladium catalyst.
  • the palladium catalyst may be bis(triphenylphosphine)
  • the reaction may also involve a suitable coupling agent.
  • the coupling reagent may be Cul.
  • the reaction may be carried out in the presence of suitable solvent.
  • the suitable solvent may be THF.
  • the compound of formula (la') on alkaline hydrolysis gives the compound of formula (7).
  • the reaction may be carried out using a suitable base.
  • the base may be aq. NaOH.
  • the reaction may be carried out in a suitable alcoholic solvent.
  • the solvent may be ethanol.
  • (la') 4- nitrophenol compound of formula (14) is reacted with methanesulfonyl chloride to give the compound of formula (15).
  • the reaction may be carried out in the presence of a base.
  • the base may be triethylamine.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be dichloromethane.
  • the compound of formula (15) is hydrogenated to give the compound of formula (16).
  • the reaction may be carried out in presence of a suitable palladium catalyst.
  • the palladium catalyst may be Pd/C.
  • the reaction may be carried out in a suitable alcoholic solvent.
  • the solvent may be ethanol.
  • the compound of formula (16) is further reacted with a suitable reagent to give compound of formula (17).
  • the reaction may be carried out using potassium iodide.
  • the reaction may be carried out in presence of an acid.
  • the acid may be H 2 S0 4 .
  • the reaction may be carried out by using an oxidizing agent.
  • the oxidizing agent may be NaN0 2 .
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be acetonitrile.
  • the compound of formula (17) is reacted with an alkyne compound of formula (4) to give the compound of formula (6).
  • the reaction may be carried out in presence of a base.
  • the base may be TBAF.
  • the reaction may be carried out in a suitable palladium catalyst.
  • the palladium catalyst may be bis(triphenylphosphine)palladium(II) dichloride.
  • the compound of formula (6) on alkaline hydrolysis yields the compound of formula (7).
  • the reaction may be carried out using a suitable base.
  • the base may be aq. NaOH.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be ethanol.
  • the compound of formula (7) further undergoes esterification to give compound of formula (la').
  • the reaction is carried out in presence of an acid.
  • the acid may be such as hydrochloric acid or sulphuric acid.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be ethanol or methanol.
  • Alkyne compounds of the general formula (Ic') and (Ic") can be prepared by using a general approach as depicted in scheme 4A and scheme 4B wherein R 1 , R 2 , R 4 , R a , r, m and n are as defined in formula (I).
  • 4-amino benzoate derivative of formula (11) is halogenated to give the compound of formula (18).
  • the reaction may be carried out using a suitable halogenating agent.
  • the halogenating agent may be N-bromosuccinamide.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be carbon tetrachloride, acetonitrile or mixture thereof.
  • the compound of formula (18) is further reacted with suitable boronic acids of formula (19) (wherein W is CH, N or CR 4 and r is 0 to 4) to give the compound of formula (20).
  • the reaction may be carried out in presence of suitable palladium catalyst.
  • the palladium catalyst may be Fd(dppf)C .
  • the reaction may be carried out in a suitable base.
  • the base may be potassium carbonate.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be diglyme.
  • the compound of formula (20) is further reacted with suitable reagents to give the compound of formula (21).
  • the reaction may be carried out using potassium iodide.
  • the reaction may be carried out in presence of an acid.
  • the acid may be H 2 S0 4 .
  • the reaction may be carried out in presence of an oxidizing agent.
  • the oxidizing agent may be NaN0 2 .
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be acetonitrile.
  • the compound of formula (21) on alkynylation gives the compound of formula (22).
  • the reaction may be carried out using a suitable alkynylating agent.
  • the alkynylating agent may be trimethylsilyl acetylene.
  • the reaction may be carried out in presence of a suitable palladium catalyst.
  • the palladium catalyst may be Bis(triphenylphosphine)palladium(II) dichloride.
  • the reaction may be carried out in presence of a coupling agent.
  • the coupling agent may be Cul.
  • the reaction may be carried out in presence of a base.
  • the base may be triethylamine.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be DMSO.
  • the compound of formula (17) is further converted to the compound of formula (23) by reacting it with an ester derivative of formula (22) (wherein W is CH, N or CR 4 and r is 0 to 4).
  • the reaction may be carried out in presence of a base.
  • the base may be TBAF.
  • the reaction may be carried out using a suitable palladium catalyst.
  • the palladium catalyst may be bis(triphenylphosphine)palladium(II) dichloride.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be DMSO.
  • the compound of formula (23) is converted to the compound of formula (Ic') by using a suitable hydrolysing agent.
  • the hydrolyzing agent may be hydrogen peroxide.
  • the reaction may be carried out in presence of a base.
  • the base may be potassium carbonate.
  • the reaction is carried out in a suitable solvent.
  • the solvent may be DMSO.
  • the compound of formula (Ic') on reaction with lithium hydroxide in a suitable solvent gives the compound of formula (Ic").
  • the reaction may be carried out in a suitable solvent.
  • the suitable solvent may be tetrahydrofuran and water.
  • Alkyne compounds of the general formula (Ic') and (Ic") can also be prepared by using a general approach as depicted in scheme 5A and scheme 5B wherein R 1 , R2 , R 4 , r, m and n are as defined in formula (I).
  • Scheme 5A Compound of formula (24) can be prepared from compound of formula (17) as per the process described for the preparation of compound formula (4)from compound formula (3) described in scheme- 1.
  • the compound of formula (18) is reacted with corresponding boronic acids of formula (25) (wherein W is CH, N or CR 4 and r is 0 to 4) to give the compound of formula (26).
  • the reaction is carried out in presence of suitable palladium catalyst.
  • the palladium catalyst may be ⁇ ' ⁇ !ppj) ⁇
  • the reaction is carried out in presence of a base.
  • the base may be potassium carbonate.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be diglyme.
  • the compound of formula (26) is reacted with suitable reagents to give the compound of formula (27).
  • the reaction may be carried out by using potassium iodide.
  • the reaction may be carried out in presence of an acid.
  • the acid may be H 2 S0 4 .
  • the reaction may be carried out using an oxidizing agent.
  • the oxidizing agnet may be NaN0 2 .
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be acetonitrile.
  • the compound of formula (27) is further treated with hydroxyl amine hydrochloride to give the compound of formula (21).
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be DMSO.
  • the compound of formula (21) is reacted with a compound of formula (24) to give compound of formula (23).
  • the reaction may be carried out in presence of a base.
  • the base may be TBAF.
  • the reaction may be carried out in presence of a suitable palladium catalyst.
  • the palladium catalyst may be bis(triphenylphosphine)palladium(II) dichloride.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be DMSO.
  • Compound of formula (23) is further converted to compound of formula (Ic') by using a hydrolysing agent.
  • the hydrolyzing agent may be hydrogen peroxide.
  • the reaction may be carried out in presence of a base.
  • the base may be potassium carbonate.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be DMSO.
  • Compound of formula (Ic') on reaction with lithium hydroxide in a suitable solvent system yields compound of formula (Ic").
  • the solvent may be tetrahydrofuran and water.
  • the compound of formula (3) is reacted with an acetylene derivative of formula (24) to form the compound of formula (6).
  • the reaction may be carried out in presence of a base.
  • the base may be TBAF.
  • the reaction may be carried out using a suitable palladium catalyst.
  • the palladium catalyst may be bis(triphenylphosphine)palladium(II) dichloride.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be DMSO.
  • Compound of formula (6) is converted to compound of formula (7) by using a suitable hydrolysing agent.
  • the suitable hydrolyzing agent may be a base.
  • the base may be NaOH.
  • Compound of formula (7) is converted to compound of formula (la') by reacting it with a suitable alcohol.
  • the reaction may be carried out in presence of an acid.
  • the acid may be such as hydrochloric acid or sulphuric acid.
  • the compound of formula (3) is reacted with an acetylene derivative of formula (24) to obtain compound of formula (6).
  • the reaction may be carried out in presence of a base.
  • the base may be TBAF.
  • the reaction may be carried out using a suitable palladium catalyst.
  • the palladium catalyst may be bis(triphenylphosphine)palladium(II) dichloride.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be DMSO.
  • the compound of formula (6) is further reacted with an azide to obtain the compound of formula (la").
  • the azide may be sodium azide.
  • the reaction may be carried out in presence of a base.
  • the base may be ammonium chloride or triethyl ammonium chloride.
  • the reaction may be carried out in a suitable solvent.
  • the solvent may be DMF.
  • the reaction may be carried out at a suitable temperature.
  • the suitable temperature may range from 0 to 150°C.
  • work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over anhydrous sodium sulfate, filtration and evaporation of the solvent.
  • Purification includes purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase. Use of a different eluent system is indicated within parentheses.
  • Step- 1 -Preparation of 4-amino- -fluorobenzonitrile
  • step-3 of Intermediate- 1 The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-fluorobenzonitrile (step-3 of Intermediate- 1, 100 mg, 0.689 mmol), 1- (4-iodophenyl)-lH-imidazole (186 mg, 0.689 mmol), THF (5.0 mL), aq.NH 3 (2.0 ml), PdCl 2 (PPh 3 ) 2 (25 mg, 0.03 mmol), Cul (10 mg, 0.052 mmol) to afford 50 mg of the title product.
  • 1H NMR 300 MHz, DMSO-i3 ⁇ 4: ⁇ 8.41 (m, 1H), 8.06 (m, 1H), 7.77 (m, 3H), 7.47- 7.15 (m, 5H)
  • Step- 1 -Preparation of 3-chloro- -iodobenzonitrile
  • Step- 1 -Preparation of methyl 4-iodo-3-methoxybenzoate
  • Step- 1 -Preparation of 3-fluoro-4-nitrophenyl methanesulfonate
  • Step- 1 -Preparation of 4-nitro-3-(trifluoromethyl)phenyl methanesulfonate
  • step-3 The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-iodo-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-9, 0.252 g, 0.68 mmol), 4-ethynyl-3-fluorobenzonitrile (step-3, Intermediate- 1, 0.100 g, 0.68 mmol), TBAF (0.216 g, 0.82 mmol), PdCl 2 (PPh 3 ) 2 (0.009 g, 0.01 mmol) in DMSO to afford 0.075 g of the title product.
  • 4-iodo-3-(trifluoromethyl)phenyl methanesulfonate Intermediate-9, 0.252 g, 0.68 mmol
  • 4-ethynyl-3-fluorobenzonitrile step-3, Intermediate- 1, 0.100 g, 0.68 mmol
  • TBAF 0.216 g, 0.82 mmol
  • Step- 1 -Preparation of 4-nitrophenyl methanesulfonate
  • step-3 The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 3-chloro-4-iodophenyl methanesulfonate (Intermediate- 12, 0.228 g, 0.68 mmol), 4- ethynyl-3-fluorobenzonitrile (step-3, Intermediate- 1, 0.100 g, 0.68 mmol), TBAF (0.216 g, 0.82 mmol), PdCl 2 (PPh 3 ) 2 (0.009 g, 0.01 mmol) in DMSO to afford 0.065 g of the title product.
  • 3-chloro-4-iodophenyl methanesulfonate Intermediate- 12, 0.228 g, 0.68 mmol
  • 4- ethynyl-3-fluorobenzonitrile step-3, Intermediate- 1, 0.100 g, 0.68 mmol
  • TBAF 0.216 g, 0.82 mmol
  • PdCl 2 (PPh 3 ) 2 0.009
  • step-2 Intermediate-3, 0.100 g, 0.62 mmol
  • 4- iodo-3-(trifluoromethyl)phenyl methanesulfonate Intermediate-9, 0.227 g, 0.62 mmol
  • TBAF 0.194 g, 7.4 mmol
  • PdCl 2 (PPh 3 ) 2 0.009 g, 0.01 mmol
  • step-2 Intermediate-3, 0.100 g, 0.62 mmol
  • 3- fluoro-4-iodophenyl methanesulfonate Intermediate-6, 0.195 g, 0.62 mmol
  • TBAF 0.194 g, 7.4 mmol
  • PdCl 2 (PPh 3 ) 2 0.009 g, 0.01 mmol
  • Step-2 Preparation 3-methoxy-4-nitrophenyl methanesulfonate The title compound was prepared following the procedure described in step-1 of Intermediate-
  • step-3 Intermediate- 1, 0.150 g, 1.03 mmol
  • step-3 Intermediate- 1, 0.150 g, 1.03 mmol
  • 4- iodo-3-methoxyphenyl methanesulfonate Intermediate- 16, 0.339 g, 1.03 mmol
  • TBAF 0.323 g, 1.24 mmol
  • PdCl 2 (PPh 3 ) 2 0.014 g, 0.02 mmol
  • DMSO 2.0 mL
  • step-2 Intermediate-3, 0.100 g, 0.61 mmol
  • 3- chloro-4-iodophenyl methanesulfonate Intermediate- 12, 0.205 g, 0.61 mmol
  • TBAF 0.177 g, 7.4 mmol
  • PdCl 2 (PPh 3 ) 2 0.009 g, 0.01 mmol
  • Step-1 Preparation of methyl -nitro-3-(trifluoromethyl)benzoate
  • Step-2 Preparation of methyl -amino-3-(trifluoromethyl)benzoate
  • Step-3 Preparation of methyl 4-iodo-3-(trifluoromethyl)benzoate
  • Step-4 Preparation of methyl 4-ethynyl-3-(trifluoromethyl)benzoate
  • Step-1 - Preparation of 5-((ieri-butyldimethylsilyl)oxy)-2-iodobenzaldehyde
  • Step-2 - Preparation of (5-((ieri-butyldimethylsilyl)oxy)-2-iodophenyl)methanol
  • Step-3 Preparation of ieri-butyl(3-(ethoxymethyl)-4-iodophenoxy)dimethylsilane
  • Step-2 Preparation of methyl 3-fluoro-4-iodobenzoate
  • Step-3 Preparation of methyl 4-ethynyl-3-fluorobenzoate
  • step-2 Intermediate-24, 0.500 g, 1.52 mmol
  • DCM dry DCM
  • DAST 0.90 g, 3.04 mmol
  • the reaction mixture was stirred at rt for 3-4 h.
  • the reaction mixture was quenched with water, basified with aq. NaHC0 3 solution and extracted with DCM.
  • the organic layers were dried over Na 2 S0 4 and concentrated to afford 350 mg of title compound.
  • Step-2 Preparation of ethyl 4-amino-3-bromobenzoate
  • Step-3 - Preparation of ethyl 6-amino-4'-cyano-[l, -biphenyl]-3-carboxylate
  • Step-4 - Preparation of ethyl 4'-cyano-6-iodo-[l,l'-biphenyl]-3-carboxylate
  • Step-5 Preparation of ethyl 4'-cyano-6-ethynyl-[l,l'-biphenyl]-3-carboxylate
  • Step- 1 - Preparation of ethyl 6-amino-3'-fluoro-4'-formyl-[l,r-biphenyl]-3-carboxylate
  • Step-2 - Preparation of ethyl 3'- iphenyl]-3-carboxylate
  • Step-3 - Preparation of ethyl 4'-cyano-3'-fluoro-6-iodo-[l, -biphenyl]-3-carboxylate
  • Step-2 - Preparation of ethyl 3',5 l, -biphenyl]-3-carboxylate
  • Step-3 Preparation of ethyl 4'-cyano-3',5'-difluoro-6-iodo-[l, -biphenyl]-3-carboxylate
  • the title compound was prepared following the procedure described in step-3 of Intermediate- 34 by using ethyl 3',5'-difluoro-4'-formyl-6-iodo-[l, -biphenyl]-3-carboxylate (180 mg, 0.430 mmol), DMSO (2.0 mL), NH 2 OH.HCl (38.7 mg, 0.56 mmol) to afford 130 mg of title product.
  • Step-3 - Preparation of 2,5-difluoro-4-((4-hydroxy-2-(trifluoromethyl)phenyl) ethynyl) benzonitrile
  • Step-4 - Preparation of 2,5-difluoro-4-iodophenyl methanesulfonate
  • Step 1 - Preparation of (E)-methyl 3-(2-amino-5-cyanophenyl)acrylate
  • reaction mixture was heated to reflux for 48 h.
  • reaction mass was filtered through celite and washed the bed with ethyl acetate. The filtrate was concentrated to afford
  • Step 2 Preparation of methyl 3-(2-amino-5-cyanophenyl)propanoate
  • Step 3 Preparation of methyl 3-(5-cyano-2-iodophenyl)propanoate
  • Step 6 - Preparation of 3-(3-ethoxypropyl)-4-((4-hydroxy-2-(trifluoromethyl) phenyl)ethynyl)benzonitrile
  • Step 2 - Preparation of 3-(2-fluoropropyl)-4-((4-hydroxy-2-(trifluoromethyl) phenyl)ethynyl)benzonitrile
  • Step 2 Preparation of 3-fluoro-4-((4-(methoxycarbonyl)phenyl)ethynyl)pyridine 1-oxide
  • m-CPBA 156.2 mg, 0.862 mmol
  • the reaction mixture was stirred at rt for 16 h.
  • the reaction mixture was quenched with water, basified with aq. K 2 C0 3 and extracted with DCM.
  • the organic layers were dried over Na 2 S0 4 and concentrated to afford 160 mg of title compound.
  • Step 3 Preparation of methyl 5-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl) thiophene-2- carboxylate
  • Step-2 - Preparation of ethyl 6-amin -3'-chloro-4'-cyano-[l, -biphenyl]-3-carboxylate
  • Step-3 - Preparation of ethyl 3'-chlo -4'-cyano-6-iodo-[l, -biphenyl]-3-carboxylate
  • Step-4 - Preparation of ethyl 3'-chloro-4'-cyano-6-((4-hydroxy-2-(trifluoromethyl)phenyl) ethynyl)-[l,l'-biphenyl]-3-carboxylate
  • step-4 Intermediate-38
  • NaH 125 mg, 3.13 mmol, 60% in mineral oil
  • methyl iodide 1.0 g, 4.18 mmol
  • DMF 5.0 mL
  • Step 2 - Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3- methoxypropyl)benzonitrile
  • Step- 1 - Preparation of (E)-et ate
  • Step-2 Preparation of ethyl 4-amino-3-(2-cyanoethyl)benzoate
  • Step-3 Preparation of ethyl 3-(2-cyanoethyl)-4-iodobenzoate
  • Step-4 - Preparation of ethyl 3-(2-cyanoethyl)-4-((4-hydroxy-2-(trifluoromethyl) phenyl)ethynyl)benzoate
  • Step-2 Preparation of ethyl 6-amin -4'-cyano-3'-methyl-[l, -biphenyl]-3-carboxylate
  • Step-3 Preparation of ethyl 4'-cyano-6-iodo-3'-methyl-[l,r-biphenyl]-3-carboxylate
  • Step-4 - Preparation of ethyl 4'-cyano-6-((4-hydroxy-2-(trifluoromethyl)phenyl) ethynyl)-3'- methyl-[l,l'-biphenyl]-3-carboxylate
  • Step-5 - Preparation of ethyl 4'-carbamoyl-6-((4-hydroxy-2-(trifluoromethyl) phenyl)ethynyl)-3'-methyl-[l,l'-biphenyl]-3-carboxylate
  • Step-1 - Preparation of 4-iodo-3-(3-(2-methoxyethoxy)propyl)benzonitrile
  • step-4 Intermediate-38, 300 mg, 1.04 mmol
  • l-bromo-2-methoxyethane 217 mg, 1.56 mmol
  • NaH 63 mg, 1.56 mmol, 60% in mineral oil
  • DMF 3 mL
  • step-4 Intermediate-38, 1.2 g, 4.18 mmol
  • Et 3 N 0.63 mL, 4.39 mmol
  • mesyl chloride 0.35 mL, 4.39 mmol
  • Step 1 - Preparation of ethyl 4-ami -3-(6-methoxypyridin-3-yl)benzoate
  • Step 2 Preparation of ethyl 4-iodo- -(6-methoxypyridin-3-yl)benzoate
  • Step 3 Preparation of ethyl 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(6- methoxypyridin-3-yl)benzoate
  • step- 1 To a solution of 3-(5-cyano-2-iodophenyl)propyl methanesulfonate (step- 1, Intermediate-48, 400 mg, 1.09 mmol) in DMF (10 mL) was added K 2 C0 3 (302 mg. 2.19 mmol), imidazole (150 mg, 2.19 mmol). The reaction mixture was heated at 120°C for 24 h. The reaction mass was quenched with water, extracted with DCM. The organic layers were dried over Na 2 S0 4 and concentrated to afford 180 mg of title compound.
  • step- 1 of Intermediate-48 400 mg, 1.05 mmol was added morpholine (10.0 mL). The reaction mixture was heated at reflux for 24 h. The excess of morpholine was removed under vacuum and the reaction mass was diluted with water, extracted with DCM. The organic layers were dried over Na 2 S0 4 and concentrated to afford 210 mg of title compound.
  • Step 2 - Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3- morpholinopropyl) benzonitrile
  • Step 2 Preparation of ethyl 4-amin -3-(6-cyanopyridin-3-yl)benzoate
  • Step 3 Preparation of ethyl 3-(6-cyanopyridin-3-yl)-4-iodobenzoate
  • Step 4 Preparation of ethyl 3-(6-cyanopyridin-3-yl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl) benzoate
  • Step-2 - Preparation of 3-(3-(cyclopropylmethoxy)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl) ethynyl)benzonitrile
  • Step-2 Preparation of ethyl 4-amino-3-(4-hydroxybut-l-yn-l-yl)benzoate
  • Step-4 - Preparation of ethyl 3-( -hydroxybutyl)-4-iodobenzoate
  • Step-5 Preparation of ethyl 3-(4-ethoxybutyl)-4-iodobenzoate
  • Step-6 Preparation of ethyl 3-(4-ethoxybutyl)-4-((4-hydroxy-2-
  • Step- 1 Preparation of ethyl 4-amino-3-ethynylbenzoate
  • step- 1 of Intemediate-66, 3.0 g, 10.34 mmol trimethyl sillyl acetylene (1.52 g, 15.5 mmol)
  • PdCl 2 (PPh 3 ) 2 (0.144 g, 0.200 mmol)
  • Cul 0.039 g, 0.200 mmol
  • Et 3 N (1.56 g, 15.50 mmol)
  • 1.0 M TBAF 17.17 mL in THF, 15.49 mmol
  • Step-2 Preparation of ethyl 4-amino-3-((6-propoxypyridin-3-yl)ethynyl)benzoate
  • Step- 1 -Preparation of 3-(3-(lH-l,2,3-triazol-l-yl)propyl)-4-iodobenzonitrile
  • step-1 Intermediate-48, 400 mg, 1.09 mmol
  • lH- l,2,3-triazole 0.113 g, 1.64 mmol
  • NaH 0.066 g, 1.64 mmol, 60% in mineral oil
  • DMF 50 mL
  • Step-2 - Preparation of 3-(3-(lH- l,2,3-triazol- l-yl)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzonitrile
  • Step-1 - Preparation of 4-iodo-3-(3-(pyridin-3-yloxy)propyl)benzonitrile
  • step-1 Intermediate-48, 300 mg, 0.82 mmol
  • pyridin-3-ol 154 mg, 1.64 mmol
  • NaH 65 mg, 1.64 mmol, 60% in mineral oil
  • DMF 10 mL
  • Step-2 - Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(pyridin-3- yloxy)propyl)benzonitrile
  • Step-1 - Preparation of 3-(3-(2-ethoxyethoxy)propyl)-4-iodobenzonitrile
  • step-4 Intermediate-38, 300 mg, 1.04 mmol
  • l-bromo-2-ethoxyethane 318 mg, 2.08 mmol
  • NaH 62 mg, 1.55 mmol, 60% in mineral oil
  • DMF 10 mL
  • Step-2 - Preparation of 3-(3-(2-ethoxyethoxy)propyl)-4-((4-hydroxy-2-
  • Step-1 - Preparation of 4-(3-(cyclopropylmethoxy)propyl)-2-iodobenzoic acid
  • Step-2 - Preparation of ethyl 4- -(cyclopropylmethoxy)propyl)-2-iodobenzoate
  • Step 2 - Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(2-methyl-lH- imidazol- 1 -yl)propyl)benzonitrile
  • step-4 Intermediate-38, 300 mg, 1.04 mmol
  • l-bromo-2-methoxyethane 256 mg, 1.56 mmol
  • NaH 63 mg, 1.56 mmol, 60% in mineral oil
  • DMF 3 mL
  • Step-2 - Preparation of 3-(3-(benzyloxy)propyl)-4-((4-hydroxy-2-
  • Step-2 Preparation of 2-propoxy- -(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine
  • Step-3 Preparation of ethyl 4-amino-3-(6-propoxypyridin-3-yl)benzoate
  • Step-4 - Preparation of ethyl 4-iodo- -(6-propoxypyridin-3-yl)benzoate
  • Step-5 Preparation of ethyl 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(6- propoxypyridin-3-yl)benzoate
  • Step- 1 - Preparation of ethyl 4-amin -3-(6-chloropyridin-3-yl)benzoate
  • Step-3 Preparation of ethyl 3-(6-chloropyridin-3-yl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl) benzoate

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Abstract

Provided are compounds of formula (Ia) and pharmaceutically acceptable salts thereof, wherein A, B, R 1, R 2, m and n 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

ALKYNE COMPOUNDS AS
S-NITROSOGLUTATHIONE REDUCTASE INHIBITORS
RELATED APPLICATIONS
This application claims the benefit of Indian Provisional Application Nos.
3181/MUM/2014 filed on October 07, 2014, which is hereby incorporated by reference in its entirety.
TECHNICAL FIELD
The present patent application is directed to alkyne 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
In one aspect, the present invention relates to compound of formula (I)
Figure imgf000005_0001
(I)
or a pharmaceutically acceptable salt thereof,
wherein,
P is selected from C3_i2cycloalkyl, C6-14aryl, 3 to 15 membered heterocyclyl and 5 to 14 membered heteroaryl;
Q is selected from C3_i2cycloalkyl, C6-i4aryl, 3 to 15 membered heterocyclyl and 5 to 14 membered heteroaryl;
A is selected from
Figure imgf000005_0002
B is selected from
Figure imgf000005_0003
is selected from hydrogen, Ci_8alkyl, Ci_8alkoxyCi_8alkyl, -(CH2)xC(0)NRbRc
-(CH2)XNR R R _(CH2)xNRbRcRc, -(CH2)xC(0)Rb and -(CRbRc)xOC(0)Rb;
Rd is selected from hydrogen and Ci_8alkyl;
at each occurrence, R1 is independently selected from halogen, nitro, amino, cyano, Ci_ 8alkoxy, Ci_8alkoxyCi_8alkyl, hydroxyCi_8alkyl, haloCi_8alkyl, haloCi_8alkoxy, -(CH2)xNRbRc, -(CRbRc)xORb, -0(CRbRc)xRb, -(CH2)XCN, -(CH2)xC(0)NRbRc, -(CH2)xNHC(0)Rb, - (CH2)xN(Rb)S02Rc, C6-i4aryl, C6-i4arylalkyl, C3-i2cycloalkyl, C3_i2cycloalkylCi_8alkyl, 3 to 15 membered heterocyclyl, 3 to 15 membered heterocyclylCi_8alkyl, 5 to 14 membered heteroaryl and 5 to 14 membered heteroarylCi_8alkyl, wherein C6-i4aryl, C6-i4arylalkyl, C3_ i2cycloalkyl, C3_i2cycloalkylCi_8alkyl, 3 to 15 membered heterocyclyl, 3 to 15 membered heterocyclylCi_8alkyl, 5 to 14 membered heteroaryl and 5 to 14 membered heteroarylCi- 8alkyl optionally substituted with one or more R4; 2
at each occurrence, R is independently selected from halogen, nitro, amino, cyano, Ci_ galkoxy, Ci-8alkoxyCi_8alkyl, hydroxyCi_8alkyl, haloCi_8alkyl, haloCi_8alkoxy, 3 to 15 membered heterocyclylCi_8alkyl, -(CH2)xNRbRc, -(CRbRc)xORb, -0(CRbRc)xRb, -(CH2)XCN and -(CH2)xC(0)NRbRc;
R is selected from hydrogen and Ci_8alkyl;
at each occurrence, R4 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 14 membered heteroaryl, 5 to 14 membered heteroarylCi_8alkyl, -(CH2)xC(0)Rb, -C(0)(CH2)xRb, -(CH2)xC(0)NRbRc, - (CH2)xC(0)ORb, -(CH2)xCHRbRc, -(CH2)xNRbRc, -(CH2)xNRbC(0)Rc, -NRb(CRbRc)xORb, - NRb(CRbRc)xCN, -NRb(CRbRc)xCONRbRc, -(CRbRc)xORb, -0(CRbRc)xRb, -OC(0)Rb, - N(Rb)S02Rc, -OC(0)NRbRc, S02NRbRc, -(CH2)xS(0)yRb and -S(0)yRb;
at each occurrence, Rb and Rc which may be same or different, are independently selected from hydrogen, halogen, hydroxyl, nitro, amino, cyano, Ci_8alkyl, C2_ioalkenyl, C2_ loalkynyl, Ci_8alkoxy, Ci_8alkoxyCi_8alkyl, hydroxyCi_8alkyl, haloCi_8alkyl, haloCi_8alkoxy, C3_i2cycloalkyl, C3_i2cycloalkylCi_8alkyl, C3_8cycloalkenyl, C3_8cycloalkenylCi_8alkyl, C6- i4aryl optionally substituted with halogen or Ci_8alkoxy, C6-i4aryloxy, C6-i4arylCi_8alkyl, 3 to 15 membered heterocyclyl, 3 to 15 membered heterocyclylCi_8alkyl, 5 to 14 membered heteroaryl optionally substituted with halogen, CN or Ci_8alkyl and 5 to 14 membered heteroarylCi-8alkyl optionally substituted with Ci_8alkyl; -(CH2)xNRbRc or Rb and Rc together with the atom to which they are attached form a carbocyclic or heterocyclic ring which is substituted or unsubstituted;
m is selected from '0' to '4', both inclusive;
n is selected from '0' to '4', both inclusive;
x is selected from '0' to '4', both inclusive; and
y is selected from '0' to '4', both inclusive.
The compounds of formula (I) may involve one or more embodiments. Embodiments of formula (I) include compounds of formula (la) and (lb) as described hereinafter. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (I) as defined above wherein P is C6 i4aryl (e.g. phenyl) or 5 to 14 membered heteroaryl (e.g. thiophene) (according to one embodiment defined below), Q is (e.g. phenyl) (according to
another embodiment defined below), B is OH or
Figure imgf000007_0001
(according to yet another embodiment defined below), m is 0, 1 or 2 (according to yet another embodiment defined below), n is 0, 1 or 2 (according to yet another embodiment defined below).
According to one embodiment, specifically provided are compounds of formula (I), in which P is C6 i4aryl (e.g. phenyl) or 5 to 14 membered heteroaryl (e.g. thiophene).
According to another embodiment, specifically provided are compounds of formula (I), in which P is phenyl or thiophene.
According to yet another embodiment, specifically provided are compounds of formula (I), in which Q is C6-i4aryl (e.g. phenyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which Q is phenyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which A is
Figure imgf000007_0002
According to yet another embodiment, specifically provided are compounds of formula (I), in which A is
Figure imgf000007_0003
ethyl or hexyl), -(CH2)xNRbRCRC (e.g. N,N,N-trimethylethanaminium) or -(CH2)xC(0)NRbRc (e.g. (diethylamino)-2-oxoethyl or (dimethylamino)-2-oxoethyl).
According to yet another embodiment, specifically provided are compounds of formul ich A is
Figure imgf000007_0004
In this embodiment Ra is hydrogen, methyl, ethyl, hexyl,
N,N,N-trimethylethanaminium, 2-(diethylamino)-2-oxoethyl or (dimethylamino)-2-oxoethyl). According to yet another embodiment, specifically provided are compounds formula (I), in which A is
Figure imgf000008_0001
According to yet another embodiment, specifically provided are compounds (I), in which A is
Figure imgf000008_0002
According to yet another embodiment, specifically provided are compounds of formula (I), in which A is
Figure imgf000008_0003
According to yet another embodiment, specifically provided are compounds of formula (I), in which B is
Figure imgf000008_0004
According to yet another embodiment, specifically provided are compounds of formula (I), in which B is
N
OH or L / . In this embodiment R 3 is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (I), in which B is
OH or "^** .
According to yet another embodiment, specifically provided are compounds of formula (I), in which B is OH.
According to yet another embodiment, specifically provided are compounds of formula (I), in which at each occurrence, R1 is independently selected from halogen (e.g. CI or F), haloCi-galkyl (e.g. trifluoromethyl or 3-fluoropropyl), Ci-galkoxy (e.g. methoxy), Ci_ galkoxyCi-galkyl (e.g. 3-ethoxypropyl, 3-methoxypropyl, 3-propoxypropyl or 4-ethoxybutyl), hydroxyCi-galkyl (e.g. 3-hydroxypropyl, 4-hydroxybutyl or 3-hydroxy-3-methylbutyl), - (CH2)xCN (e.g. cyanomethyl, cyanoethyl or 3-Cyanopropyl), -0(CRbRc)xRb (e.g. pyridin-3- ylmethoxy), -(CH2)xC(0)NRbRc (e.g. 4-(N-ethylamino-4-oxo)butyl, 3-amino-3-oxopropyl, 3- (N-ethyl-3-oxo)propyl or 3-amino-3-oxopropyl), -(CRbRc)xORb (e.g. 3-(2- methoxyethoxy)propyl, 3-(2-ethoxyethoxy)propyl, 3-(cyclopropylmethoxy)propyl, 3- (benzyloxy)propyl, 4-(pyrazin-2-yloxy)butyl, 3-((6-chloropyridin-3-yl)oxy)propyl, 3-((6- methylpyridin-3-yl)oxy)propyl, 3-((2-methylpyridin-3-yl)oxy)propyl, 3-((4-methylthiazol-2- yl)methoxy)propyl, 3-(2,6-Dichlorophenoxy)propyl, 3-((2-methylpyridin-3-yl)oxy)propyl, 3- (pyridin-4-yloxy)propyl, 3-(2-Chlorophenoxy)propyl, 3-(3-methoxyphenoxy)propyl, 3-(2,6- Difluorophenoxy)propyl, 3-((5-Fluoropyridin-3-yl)oxy)propyl, 3-((5-Cyanopyridin-3- yl)oxy)propyl, (pyridin-3-yloxy)methyl, 3-(pyridin-3-yloxy)propyl or 3-(pyrazin-2- yloxy)propyl), -(CH2)xNRbRc (e.g. 3-(diethylamino)propyl or 3-Aminopropyl), (CH2)xNHC(0)Rb (e.g. 3-isobutyramidopropyl or 2-isobutyramidoethyl), -(CH2)xN(Rb)S02Rc (e.g. 3-(l-methylethylsulfonamido)propyl), 5 to 14 membered heteroarylCi-galkyl optionally substituted with one or more R4 (e.g. 3-(l-H-imidazol- l-yl)propyl, 6-(propoxypyridin-3- yl)ethyl, 3-(lH-l,2,3-triazol- l-yl)propyl, 3-(2-methyl- lH-imidazol-l-yl)propyl, 4-(2-methyl- lH-imidazol- l-yl)butyl, 3-(3-methyl- lH-pyrazol- l-yl)propyl, 3-(4-methyl- lH-pyrazol-1- yl)propyl, 3-(lH-pyrazol- l-yl)propyl, 3-(lH-l,2,4-triazol- l-yl)propyl, 2-(pyridin-3-yl)ethyl, 2-(pyridin-4-yl)ethyl, 2-(pyridin-2-yl)ethyl, 3-(2H-tetrazol-2-yl)propyl, 2-(thiazol-2-yl)ethyl or 3-(lH-tetrazol-l-yl)propyl), 3 to 15 membered heterocyclylCi-galkyl optionally substituted with one or more R4 (e.g. 3-morpholinopropyl, 4-carbamoylpiperidin-l-ylpropyl or 4- ethoxypiperidin-l-ylpropyl), 3 to 15 membered heterocyclyl optionally substituted with one or more R4 (e.g. 1-acetyl piperidin-4-yl), C6-i4aryl optionally substituted with one or more R4 (e.g. 4-cyanophenyl, 4-Carbamoylphenyl, 3-Carbamoylphenyl, 4-Carbamoyl-3 -fluorophenyl, 4-Carbamoyl-3,5-difluorophenyl, 4-Carbamoyl-3-chlorophenyl or 4-Carbamoyl-3- methylphenyl), 5 to 14 membered heteroaryl optionally substituted with one or more R4 (e.g. 6-methoxypyridin-3-yl, 6-carbamoylpyridin-3-yl, 6-propoxypyridin-3-yl, 6-chloropyridin-3-yl, 6-hydroxypyridin-3-yl, 2-carbamoylpyrimidin-5-yl, 6-cyanopyridin-3-yl, pyridin-4-yl, pyridin-3-yl, pyrimidin-5-yl or l-methyl-lH-pyrazol-4-yl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which at each occurrence, R1 is independently selected from halogen (e.g. CI or F), haloCi-galkyl (e.g. trifluoromethyl or 3-fluoropropyl), Ci-galkoxy (e.g. methoxy), Ci_ salkoxyCi-galkyl (e.g. 3-ethoxypropyl, 3-methoxypropyl, 3-propoxypropyl or 4-ethoxybutyl), hydroxyCi-galkyl (e.g. 3-hydroxypropyl, 4-hydroxybutyl or 3-hydroxy-3-methylbutyl), - (CH2)xCN (e.g. cyanomethyl, cyanoethyl or 3-Cyanopropyl), -0(CRbRc)xRb (e.g. pyridin-3- ylmethoxy), -(CH2)xC(0)NRbRc (e.g. 4-(N-ethylamino-4-oxo)butyl, 3-amino-3-oxopropyl, 3- (N-ethyl-3-oxo)propyl or 3-amino-3-oxopropyl), -(CRbRc)xORb (e.g. 3-(2- methoxyethoxy)propyl, 3-(2-ethoxyethoxy)propyl, 3-(cyclopropylmethoxy)propyl, 3- (benzyloxy)propyl, 4-(pyrazin-2-yloxy)butyl, 3-((6-chloropyridin-3-yl)oxy)propyl, 3-((6- methylpyridin-3-yl)oxy)propyl, 3-((2-methylpyridin-3-yl)oxy)propyl, 3-((4-methylthiazol-2- yl)methoxy)propyl, 3-(2,6-Dichlorophenoxy)propyl, 3-((2-methylpyridin-3-yl)oxy)propyl, 3- (pyridin-4-yloxy)propyl, 3-(2-Chlorophenoxy)propyl, 3-(3-methoxyphenoxy)propyl, 3-(2,6- Difluorophenoxy)propyl, 3-((5-Fluoropyridin-3-yl)oxy)propyl, 3-((5-Cyanopyridin-3- yl)oxy)propyl, (pyridin-3-yloxy)methyl, 3-(pyridin-3-yloxy)propyl or 3-(pyrazin-2- yloxy)propyl), -(CH2)xNRbRc (e.g. 3-(diethylamino)propyl or 3-Aminopropyl), (CH2)xNHC(0)Rb (e.g. 3-isobutyramidopropyl or 2-isobutyramidoethyl), -(CH2)xN(Rb)S02Rc (e.g. 3-(l-methylethylsulfonamido)propyl), 5 to 14 membered heteroarylCi_8alkyl optionally substituted with one or more R4 (e.g. 3-(l-H-imidazol- l-yl)propyl, 6-(propoxypyridin-3- yl)ethyl, 3-(lH-l,2,3-triazol- l-yl)propyl, 3-(2-methyl- lH-imidazol-l-yl)propyl, 4-(2-methyl- lH-imidazol- l-yl)butyl, 3-(3-methyl- lH-pyrazol- l-yl)propyl, 3-(4-methyl- lH-pyrazol-1- yl)propyl, 3-(lH-pyrazol- l-yl)propyl, 3-(lH-l,2,4-triazol- l-yl)propyl, 2-(pyridin-3-yl)ethyl, 2-(pyridin-4-yl)ethyl, 2-(pyridin-2-yl)ethyl, 3-(2H-tetrazol-2-yl)propyl, 2-(thiazol-2-yl)ethyl or 3-(lH-tetrazol-l-yl)propyl), 3 to 15 membered heterocyclylCi_8alkyl optionally substituted with one or more R4 (e.g. 3-morpholinopropyl, 4-carbamoylpiperidin-l-ylpropyl or 4- ethoxypiperidin-l-ylpropyl), 3 to 15 membered heterocyclyl optionally substituted with one or more R4 (e.g. 1-acetyl piperidin-4-yl), C6-i4aryl optionally substituted with one or more R4 (e.g. 4-cyanophenyl, 4-Carbamoylphenyl, 3-Carbamoylphenyl, 4-Carbamoyl-3 -fluorophenyl, 4-Carbamoyl-3,5-difluorophenyl, 4-Carbamoyl-3-chlorophenyl or 4-Carbamoyl-3- methylphenyl), 5 to 14 membered heteroaryl optionally substituted with one or more R4 (e.g. 6-methoxypyridin-3-yl, 6-carbamoylpyridin-3-yl, 6-propoxypyridin-3-yl, 6-chloropyridin-3-yl, 6-hydroxypyridin-3-yl, 2-carbamoylpyrimidin-5-yl, 6-cyanopyridin-3-yl, pyridin-4-yl, pyridin-3-yl, pyrimidin-5-yl or l-methyl- lH-pyrazol-4-yl). In this embodiment Rb and Rc are independently selected from hydrogen, Ci_8alkyl (e.g. methyl, ethyl or isopropyl), Ci_ 8alkoxyCi_8alkyl (e.g. methoxyethyl or ethoxyethyl), C3_i2cycloalkylCi_8alkyl (e.g. cyclopropylmethyl), C6 i4arylalkyl (e.g. benzyl), C6 i4aryl optionally substituted with halogen or Ci-8alkoxy (e.g. 2,6-Dichlorophenyl, 2-Chlorophenyl, 3-methoxyphenyl or 2,6- Difluorophenyl), 5 to 14 membered heteroaryl optionally substituted with halogen, CN or Ci_ galkyl (e.g. pyridine, 6-chloropyridin-3-yl, 6-methylpyridin-3-yl, 2-methylpyridin-3-yl, 5- Fluoropyridin-3-yl, 5-Cyanopyridin-3-yl or pyrazine) and 5 to 14 membered heteroarylCi- galkyl optionally substituted with Ci-galkyl (e.g. 4-methylthiazol-2-yl)methyl) and x is 1, 2, 3 or 4.
According to yet another embodiment, specifically provided are compounds of formula (I), in which at each occurrence, R1 is independently selected from CI, F, trifluoromethyl, 3-fluoropropyl, methoxy, 3-ethoxypropyl, 3-methoxypropyl, 3- propoxypropyl, 4-ethoxybutyl, 3-hydroxypropyl, 4-hydroxybutyl, 3-hydroxy-3-methylbutyl, cyanomethyl, cyanoethyl, 3-Cyanopropyl, pyridin-3-ylmethoxy, 4-(N-ethylamino-4-oxo)butyl, 3-amino-3-oxopropyl, 3-(V-ethyl-3-oxo)propyl, 3-amino-3-oxopropyl, 3-(2- methoxyethoxy)propyl, 3-(2-ethoxyethoxy)propyl, 3-(cyclopropylmethoxy)propyl, 3- (benzyloxy)propyl, 4-(pyrazin-2-yloxy)butyl, 3-((6-chloropyridin-3-yl)oxy)propyl, 3-((6- methylpyridin-3-yl)oxy)propyl, 3-((2-methylpyridin-3-yl)oxy)propyl, 3-((4-methylthiazol-2- yl)methoxy)propyl, 3-(2,6-Dichlorophenoxy)propyl, 3-((2-methylpyridin-3-yl)oxy)propyl, 3- (pyridin-4-yloxy)propyl, 3-(2-Chlorophenoxy)propyl, 3-(3-methoxyphenoxy)propyl, 3-(2,6- Difluorophenoxy)propyl, 3-((5-Fluoropyridin-3-yl)oxy)propyl, 3-((5-Cyanopyridin-3- yl)oxy)propyl, (pyridin-3-yloxy)methyl, 3-(pyridin-3-yloxy)propyl, 3-(pyrazin-2- yloxy)propyl), 3-(diethylamino)propyl, 3-Aminopropyl, 3-isobutyramidopropyl, 2- isobutyramidoethyl, 3-(l-methylethylsulfonamido)propyl, 3-(l-H-imidazol-l-yl)propyl, 6- (propoxypyridin-3-yl)ethyl, 3-(lH-l,2,3-triazol- l-yl)propyl, 3-(2-methyl-lH-imidazol- l- yl)propyl, 4-(2-methyl- lH-imidazol-l-yl)butyl, 3-(3-methyl- lH-pyrazol- l-yl)propyl, 3-(4- methyl-lH-pyrazol- l-yl)propyl, 3-(lH-pyrazol- l-yl)propyl, 3-(lH- l,2,4-triazol- l-yl)propyl, 2-(pyridin-3-yl)ethyl, 2-(pyridin-4-yl)ethyl, 2-(pyridin-2-yl)ethyl, 3-(2H-tetrazol-2-yl)propyl, 2-(thiazol-2-yl)ethyl, 3-(lH-tetrazol-l-yl)propyl, 3-morpholinopropyl, 4-carbamoylpiperidin- 1-ylpropyl, 4-ethoxypiperidin-l-ylpropyl, 1 -acetyl piperidin-4-yl, 4-cyanophenyl, 4- Carbamoylphenyl, 3-Carbamoylphenyl, 4-Carbamoyl-3 -fluorophenyl, 4-Carbamoyl-3,5- difluorophenyl, 4-Carbamoyl-3-chlorophenyl, 4-Carbamoyl-3-methylphenyl, 6- methoxypyridin-3-yl, 6-carbamoylpyridin-3-yl, 6-propoxypyridin-3-yl, 6-chloropyridin-3-yl, 6-hydroxypyridin-3-yl, 2-carbamoylpyrimidin-5-yl, 6-cyanopyridin-3-yl, pyridin-4-yl, pyridin-3-yl, pyrimidin-5-yl and 1 -methyl- lH-pyrazol-4-yl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which at each occurance, R4 is independently selected from is cyano, halogen (e.g. CI or F), Ci-galkyl (e.g. methyl or ethyl), hydroxyl, Ci-galkoxy (e.g. methoxy, ethoxy or propoxy), -(CH2)xC(0)NRbRc (e.g. -CONH2) and -(CH2)xC(0)Rb (e.g. acetyl). According to yet another embodiment, specifically provided are compounds of formula (I), in which at each occurance, R4 is independently selected from is cyano, halogen (e.g. CI or F), Ci_8alkyl (e.g. methyl or ethyl), hydroxyl, Ci_8alkoxy (e.g. methoxy, ethoxy or propoxy), -(CH2)xC(0)NRbRc (e.g. -CONH2) and -(CH2)xC(0)Rb (e.g. acetyl). In this embodiment Rb and Rc are independently selected from hydrogen, and Ci_8alkyl (e.g. methyl or ethyl) and x is 0.
According to yet another embodiment, specifically provided are compounds of formula (I), in which at each occurance, R4 is independently selected from cyano, CI, F, methyl, ethyl, hydroxyl, methoxy, ethoxy, propoxy, -CONH2 and acetyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which at each occurrence, R is independently selected from halogen (e.g. CI or F), Ci-8alkoxy (e.g. methoxy), Ci_8alkoxyCi_8alkyl (e.g. ethoxymethyl or propoxymethyl), haloCi_8alkyl (e.g. CF3, fluoromethyl or difluoromethyl), 3 to 15 membered heterocyclylCi- 8alkyl (e.g. pyrrolidin-l-ylmethyl) and -(CRbRc)xORb (e.g. 2-(methoxyethoxy)methyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which at each occurrence, R is independently selected from halogen (e.g. CI or F), Ci-8alkoxy (e.g. methoxy), Ci_8alkoxyCi_8alkyl (e.g. ethoxymethyl or propoxymethyl), haloCi_8alkyl (e.g. CF3, fluoromethyl or difluoromethyl), 3 to 15 membered heterocyclylCi- 8alkyl (e.g. pyrrolidin-l-ylmethyl) and -(CRbRc)xORb (e.g. 2-(methoxyethoxy)methyl). In this embodiment Rb and Rc are independently selected from hydrogen, Ci_8alkyl (e.g. methyl or ethyl) and Ci_8alkoxyCi_8alkyl (e.g. methoxyethyl) and 'x' is 1 or 2.
According to yet another embodiment, specifically provided are compounds of formula (I), in which at each occurrence, R is independently selected from CI, F, methoxy, ethoxymethyl, propoxymethyl, CF3, fluoromethyl, difluoromethyl, pyrrolidin-l-ylmethyl, pyrrolidin-l-ylmethyl and 2-(methoxyethoxy)methyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which at each occurrence, R is independently selected from CI, F and CF3.
According to yet another embodiment, specifically provided are compounds of formula (I), in which m is 0, 1 or 2.
According to yet another embodiment, specifically provided are compounds of formula (I), in which n is 0, 1 or 2.
According to yet another embodiment, specifically provided are compounds of formula (I), in which
P is C6-i4aryl (e.g. phenyl) or 5 to 14 membered heteroaryl (e.g. thiophene), Q is C6-i4aryl (e.g. phenyl),
R
Figure imgf000013_0001
a is hydrogen, Ci_8alkyl (e.g. methyl, ethyl or hexyl), (e.g. Ν,Ν,Ν-
-(CH2)xC(0)NRbRc (e.g. (diethylamino)-2-oxoethyl
Figure imgf000013_0002
R1 is halogen (e.g. CI or F), haloCi_8alkyl (e.g. trifluoromethyl or 3-fluoropropyl), Ci_ 8alkoxy (e.g. methoxy), Ci_8alkoxyCi_8alkyl (e.g. 3-ethoxypropyl, 3-methoxypropyl, 3- propoxypropyl or 4-ethoxybutyl), hydroxyCi_8alkyl (e.g. 3-hydroxypropyl, 4-hydroxybutyl or 3-hydroxy-3-methylbutyl), -(CH2)XCN (e.g. cyanomethyl, cyanoethyl or 3-Cyanopropyl), - 0(CRbRc)xRb (e.g. pyridin-3-ylmethoxy), -(CH2)xC(0)NRbRc (e.g. 4-(N-ethylamino-4- oxo)butyl, 3-amino-3-oxopropyl, 3-(V-ethyl-3-oxo)propyl or 3-amino-3-oxopropyl), - (CRbRc)xORb (e.g. 3-(2-methoxyethoxy)propyl, 3-(2-ethoxyethoxy)propyl, 3- (cyclopropylmethoxy)propyl, 3-(benzyloxy)propyl, 4-(pyrazin-2-yloxy)butyl, 3-((6- chloropyridin-3-yl)oxy)propyl, 3-((6-methylpyridin-3-yl)oxy)propyl, 3-((2-methylpyridin-3- yl)oxy)propyl, 3-((4-methylthiazol-2-yl)methoxy)propyl, 3-(2,6-Dichlorophenoxy)propyl, 3- ((2-methylpyridin-3-yl)oxy)propyl, 3-(pyridin-4-yloxy)propyl, 3-(2-Chlorophenoxy)propyl, 3-(3-methoxyphenoxy)propyl, 3-(2,6-Difluorophenoxy)propyl, 3-((5-Fluoropyridin-3- yl)oxy)propyl, 3-((5-Cyanopyridin-3-yl)oxy)propyl, (pyridin-3-yloxy)methyl, 3-(pyridin-3- yloxy)propyl or 3-(pyrazin-2-yloxy)propyl), -(CH2)xNRbRc (e.g. 3-(diethylamino)propyl or 3- Aminopropyl), -(CH2)xNHC(0)Rb (e.g. 3-isobutyramidopropyl or 2-isobutyramidoethyl), - (CH2)xN(Rb)S02Rc (e.g. 3-(l-methylethylsulfonamido)propyl), 5 to 14 membered heteroarylCi_8alkyl optionally substituted with one or more R4 (e.g. 3-(l-H-imidazol-l- yl)propyl, 6-(propoxypyridin-3-yl)ethyl, 3-(lH-l,2,3-triazol-l-yl)propyl, 3-(2-methyl- lH- imidazol-l-yl)propyl, 4-(2-methyl-lH-imidazol-l-yl)butyl, 3-(3-methyl- lH-pyrazol- l- yl)propyl, 3-(4-methyl- lH-pyrazol- l-yl)propyl, 3-(lH-pyrazol- l-yl)propyl, 3-(lH-l,2,4- triazol- l-yl)propyl, 2-(pyridin-3-yl)ethyl, 2-(pyridin-4-yl)ethyl, 2-(pyridin-2-yl)ethyl, 3-(2H- tetrazol-2-yl)propyl, 2-(thiazol-2-yl)ethyl or 3-(lH-tetrazol- l-yl)propyl), 3 to 15 membered heterocyclylCi-galkyl optionally substituted with one or more R4 (e.g. 3-morpholinopropyl, 4- carbamoylpiperidin-l-ylpropyl or 4-ethoxypiperidin- l-ylpropyl), 3 to 15 membered heterocyclyl optionally substituted with one or more R4 (e.g. 1-acetyl piperidin-4-yl), C6 i4aryl optionally substituted with one or more R4 (e.g. 4-cyanophenyl, 4-Carbamoylphenyl, 3- Carbamoylphenyl, 4-Carbamoyl-3-fluorophenyl, 4-Carbamoyl-3,5-difluorophenyl, 4- Carbamoyl-3-chlorophenyl or 4-Carbamoyl-3-methylphenyl) or 5 to 14 membered heteroaryl optionally substituted with one or more R4 (e.g. 6-methoxypyridin-3-yl, 6-carbamoylpyridin- 3-yl, 6-propoxypyridin-3-yl, 6-chloropyridin-3-yl, 6-hydroxypyridin-3-yl, 2- carbamoylpyrimidin-5-yl, 6-cyanopyridin-3-yl, pyridin-4-yl, pyridin-3-yl, pyrimidin-5-yl or 1-methyl- lH-pyrazol-4-yl),
R is halogen (e.g. CI or F), Ci_8alkoxy (e.g. methoxy), Ci-8alkoxyCi_8alkyl (e.g. ethoxymethyl or propoxymethyl), haloCi_8alkyl (e.g. CF3, lluoromethyl or dilluoromethyl), 3 to 15 membered heterocyclylCi_8alkyl (e.g. pyrrolidin-l-ylmethyl) or -(CRbRc)xORb (e.g. 2- (methoxyethoxy )methyl) ,
R is hydrogen or Ci_8alkyl (e.g. methyl),
R4 is cyano, halogen (e.g. CI or F), Ci_8alkyl (e.g. methyl or ethyl), hydroxyl, Ci_ salkoxy (e.g. methoxy, ethoxy or propoxy), -(CH2)xC(0)NRbRc (e.g. -CONH2) or - (CH2)xC(0)Rb (e.g. acetyl),
Rb and Rc are hydrogen, Ci_8alkyl (e.g. methyl, ethyl or isopropyl), Ci_8alkoxyCi_8alkyl (e.g. methoxyethyl or ethoxyethyl), C3_i2cycloalkylCi_8alkyl (e.g. cyclopropylmethyl), C6- i4arylalkyl (e.g. benzyl), C6-i4aryl optionally substituted with halogen or Ci_8alkoxy (e.g. 2,6- Dichlorophenyl, 2-Chlorophenyl, 3-methoxyphenyl or 2,6-Difluorophenyl), 5 to 14 membered heteroaryl optionally substituted with halogen, CN or Ci_8alkyl (e.g. pyridine, 6- chloropyridin-3-yl, 6-methylpyridin-3-yl, 2-methylpyridin-3-yl, 5-Fluoropyridin-3-yl, 5- Cyanopyridin-3-yl or pyrazine) or 5 to 14 membered heteroarylCi_8alkyl optionally substituted with Ci_8alkyl (e.g. 4-methylthiazol-2-yl)methyl),
x is 0, 1, 2 or 3,
m is 0, 1 or 2,
n is 0, 1 or 2.
According to yet another embodiment, specifically provided are compounds of formula (I), in which
P is phenyl or thiophene,
Q is phenyl,
A is
Figure imgf000015_0001
R1 is CI, F, trifluoromethyl, 3-fluoropropyl, methoxy, 3-ethoxypropyl, 3- methoxypropyl, 3-propoxypropyl, 4-ethoxybutyl, 3-hydroxypropyl, 4-hydroxybutyl, 3- hydroxy-3-methylbutyl, cyanomethyl, cyanoethyl, 3-Cyanopropyl, pyridin-3-ylmethoxy, 4- (N-ethylamino-4-oxo)butyl, 3-amino-3-oxopropyl, 3-(7V-ethyl-3-oxo)propyl, 3-amino-3- oxopropyl, 3-(2-methoxyethoxy)propyl, 3-(2-ethoxyethoxy)propyl, 3-
(cyclopropylmethoxy)propyl, 3-(benzyloxy)propyl, 4-(pyrazin-2-yloxy)butyl, 3-((6- chloropyridin-3-yl)oxy)propyl, 3-((6-methylpyridin-3-yl)oxy)propyl, 3-((2-methylpyridin-3- yl)oxy)propyl, 3-((4-methylthiazol-2-yl)methoxy)propyl, 3-(2,6-Dichlorophenoxy)propyl, 3- ((2-methylpyridin-3-yl)oxy)propyl, 3-(pyridin-4-yloxy)propyl, 3-(2-Chlorophenoxy)propyl, 3-(3-methoxyphenoxy)propyl, 3-(2,6-Difluorophenoxy)propyl, 3-((5-Fluoropyridin-3- yl)oxy)propyl, 3-((5-Cyanopyridin-3-yl)oxy)propyl, (pyridin-3-yloxy)methyl, 3-(pyridin-3- yloxy)propyl, 3-(pyrazin-2-yloxy)propyl), 3-(diethylamino)propyl, 3-Aminopropyl, 3- isobutyramidopropyl, 2-isobutyramidoethyl, 3-(l-methylethylsulfonamido)propyl, 3-(l-H- imidazol-l-yl)propyl, 6-(propoxypyridin-3-yl)ethyl, 3-(lH-l,2,3-triazol- l-yl)propyl, 3-(2- methyl- lH-imidazol- 1 -yl)propyl, 4-(2-methyl- lH-imidazol- 1 -yl)butyl, 3-(3-methyl- 1H- pyrazol- l-yl)propyl, 3-(4-methyl- lH-pyrazol- l-yl)propyl, 3-(lH-pyrazol- l-yl)propyl, 3-(lH- l,2,4-triazol-l-yl)propyl, 2-(pyridin-3-yl)ethyl, 2-(pyridin-4-yl)ethyl, 2-(pyridin-2-yl)ethyl, 3- (2H-tetrazol-2-yl)propyl, 2-(thiazol-2-yl)ethyl, 3-(lH-tetrazol-l-yl)propyl, 3- morpholinopropyl, 4-carbamoylpiperidin-l-ylpropyl, 4-ethoxypiperidin- l-ylpropyl, 1 -acetyl piperidin-4-yl, 4-cyanophenyl, 4-Carbamoylphenyl, 3-Carbamoylphenyl, 4-Carbamoyl-3- fluorophenyl, 4-Carbamoyl-3,5-difluorophenyl, 4-Carbamoyl-3-chlorophenyl, 4-Carbamoyl- 3-methylphenyl, 6-methoxypyridin-3-yl, 6-carbamoylpyridin-3-yl, 6-propoxypyridin-3-yl, 6- chloropyridin-3-yl, 6-hydroxypyridin-3-yl, 2-carbamoylpyrimidin-5-yl, 6-cyanopyridin-3-yl, pyridin-4-yl, pyridin-3-yl, pyrimidin-5-yl or 1 -methyl- lH-pyrazol-4-yl,
R is CI, F, methoxy, ethoxymethyl, propoxymethyl, CF3, fluoromethyl, difluoromethyl, pyrrolidin- l-ylmethyl or 2-(methoxyethoxy)methyl, m is 0, 1 or 2, and
n is 0, 1 or 2.
According to one embodiment, specifically provided are compounds of formula (I) 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.
Further embodiments relating to groups A, 1 2
B, R , R , m and n (and groups defined therein) are described hereinafter in relation to the compounds of formula (la) and formula (lb). It is to be understood that these embodiments are not limited to use in conjunction with formula (la) and formula (lb), but apply independently and individually to the compounds of formula (I). For example, in an embodiment described hereinafter, the invention specifically provides compounds of formula (la), in which 'm' is 0, 1 or 2 and consequently, there is also provided a compound of formula (I) in which 'm' is 0, 1 or 2.
The invention also provides a compound of formula (la), which is an embodiment of a compound of formula (I).
Accordingly the invention provides a compound of formula (la)
Figure imgf000016_0001
or a pharmaceutically acceptable salt thereof,
wherein,
A is selected from
B is sele
OH and
Figure imgf000016_0002
Ra is selected from hydrogen, Ci_8alkyl, -(CH2)xC(0)NRbRc and -(CH2)XNR R R . at each occurrence, R1 is independently selected from halogen, Ci_8alkoxy, C 8alkoxyCi_8alkyl, hydroxyCi_8alkyl, haloCi_8alkyl, -(CH2)xNRbRc, -(CRbRc)xORb, 0(CRbRc)xRb, -(CH2)XCN, -(CH2)xC(0)NRbRc, -(CH2)xNHC(0)Rb, -(CH2)xN(Rb)S02Rc, C i4aryl, 3 to 15 membered heterocyclyl, 3 to 15 membered heterocyclylCi_8alkyl, 5 to 14 membered heteroaryl and 5 to 14 membered heteroarylCi-8alkyl, wherein C6-14aryl, 3 to 15 membered heterocyclyl, 3 to 15 membered heterocyclylCi_8alkyl, 5 to 14 membered heteroaryl and 5 to 14 membered heteroarylCi-8alkyl optionally substituted with one or more R4;
at each occurrence, R is independently selected from halogen, Ci_8alkoxy, Ci_ 8alkoxyCi_8alkyl, haloCi_8alkyl, 3 to 15 membered heterocyclylCi_8alkyl and -(CRbRc)xORb;
R is selected from hydrogen and Ci_8alkyl;
at each occurrence, R4 is independently selected from halogen, hydroxyl, cyano, Ci_ 8alkyl, Ci_8alkoxy, 5 to 14 membered heteroaryl, -(CH2)xC(0)Rb and -(CH2)xC(0)NRbRc; at each occurrence, Rb and Rc which may be same or different, are independently selected from hydrogen, Ci_8alkyl, Ci_8alkoxyCi_8alkyl, C3_i2cycloalkylCi_8alkyl, C6-i4aryl optionally substituted with halogen or Ci_8alkoxy, C6-i4arylCi_8alkyl, 5 to 14 membered heteroaryl optionally substituted with halogen, CN or Ci_8alkyl and 5 to 14 membered heteroarylCi_8alkyl optionally substituted with Ci_8alkyl;
m is selected from '0' to '4', both inclusive;
n is selected from '0' to '4', both inclusive; and
x is selected from '0' to '4', both inclusive;
The compounds of formula (la) may involve one or more embodiments. Embodiments of formula (la) include compounds of formula (lb) as described hereinafter. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (la) as defined above wherein A is
(according to one embodiment defined below), B is OH or
Figure imgf000017_0001
(according to another embodiment defined below), m is 0, 1 or 2 (according to yet another embodiment defined below), n is 0, 1 or 2 (according to yet another embodiment defined below).
According to yet another embodiment, specifically provided are compounds of formula (la), in which A is
Figure imgf000018_0001
According to yet another embodiment, specifically provided are compounds of formula (la), in which A is
Figure imgf000018_0002
ethyl or hexyl), -(CH2)xNRbRcRc ^e g y,N,N-trimethylethanaminium) or -(CH2)xC(0)NRbRc (e.g. (diethylamino)-2-oxoethyl or (dimethylamino)-2-oxoethyl).
According to yet another embodiment, specifically provided are compounds of formula (la), in which A is
■x 0R or
Figure imgf000018_0003
In this embodiment Ra is hydrogen, methyl, ethyl, hexyl,
N,N,N-trimethylethanaminium, 2-(diethylamino)-2-oxoethyl or (dimethylamino)-2-oxoethyl).
According to yet another embodiment, specifically provided are compounds of formula (la), in which A is
Figure imgf000018_0004
According to yet another embodiment, specifically provided are compounds of formula (la), in which A is
Figure imgf000018_0005
According to yet another embodiment, specifically provided are compounds of formula (la), in which A is According to yet another embodiment, specifically provided are compounds of formula (la), in which B is
Figure imgf000019_0001
According to yet another embodiment, specifically provided are compounds of formula (la), in which B is
Figure imgf000019_0002
OH or is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (la), in which B is
Figure imgf000019_0003
According to yet another embodiment, specifically provided are compounds of formula (la), in which B is OH.
According to yet another embodiment, specifically provided are compounds of formula (la), in which at each occurrence, R1 is independently selected from halogen (e.g. CI or F), haloCi_8alkyl (e.g. trifluoromethyl or 3-fluoropropyl), Ci_8alkoxy (e.g. methoxy), Ci_ 8alkoxyCi_8alkyl (e.g. 3-ethoxypropyl, 3-methoxypropyl, 3-propoxypropyl or 4-ethoxybutyl), hydroxyCi_8alkyl (e.g. 3-hydroxypropyl, 4-hydroxybutyl or 3-hydroxy-3-methylbutyl), - (CH2)xCN (e.g. cyanomethyl, cyanoethyl or 3-Cyanopropyl), -0(CRbRc)xRb (e.g. pyridin-3- ylmethoxy), -(CH2)xC(0)NRbRc (e.g. 4-(N-ethylamino-4-oxo)butyl, 3-amino-3-oxopropyl, 3- (N-ethyl-3-oxo)propyl or 3-amino-3-oxopropyl), -(CRbRc)xORb (e.g. 3-(2- methoxyethoxy)propyl, 3-(2-ethoxyethoxy)propyl, 3-(cyclopropylmethoxy)propyl, 3- (benzyloxy)propyl, 4-(pyrazin-2-yloxy)butyl, 3-((6-chloropyridin-3-yl)oxy)propyl, 3-((6- methylpyridin-3-yl)oxy)propyl, 3-((2-methylpyridin-3-yl)oxy)propyl, 3-((4-methylthiazol-2- yl)methoxy)propyl, 3-(2,6-Dichlorophenoxy)propyl, 3-((2-methylpyridin-3-yl)oxy)propyl, 3- (pyridin-4-yloxy)propyl, 3-(2-Chlorophenoxy)propyl, 3-(3-methoxyphenoxy)propyl, 3-(2,6- Difluorophenoxy)propyl, 3-((5-Fluoropyridin-3-yl)oxy)propyl, 3-((5-Cyanopyridin-3- yl)oxy)propyl, (pyridin-3-yloxy)methyl, 3-(pyridin-3-yloxy)propyl or 3-(pyrazin-2- yloxy)propyl), -(CH2)xNRbRc (e.g. 3-(diethylamino)propyl or 3-Aminopropyl), (CH2)xNHC(0)Rb (e.g. 3-isobutyramidopropyl or 2-isobutyramidoethyl), -(CH2)xN(Rb)S02Rc (e.g. 3-(l-methylethylsulfonamido)propyl), 5 to 14 membered heteroarylCi_8alkyl optionally substituted with one or more R4 (e.g. 3-(l-H-imidazol- l-yl)propyl, 6-(propoxypyridin-3- yl)ethyl, 3-(lH-l,2,3-triazol- l-yl)propyl, 3-(2-methyl- lH-imidazol-l-yl)propyl, 4-(2-methyl- lH-imidazol- l-yl)butyl, 3-(3-methyl- lH-pyrazol- l-yl)propyl, 3-(4-methyl- lH-pyrazol-1- yl)propyl, 3-(lH-pyrazol- l-yl)propyl, 3-(lH-l,2,4-triazol- l-yl)propyl, 2-(pyridin-3-yl)ethyl, 2-(pyridin-4-yl)ethyl, 2-(pyridin-2-yl)ethyl, 3-(2H-tetrazol-2-yl)propyl, 2-(thiazol-2-yl)ethyl or 3-(lH-tetrazol-l-yl)propyl), 3 to 15 membered heterocyclylCi_8alkyl optionally substituted with one or more R4 (e.g. 3-morpholinopropyl, 4-carbamoylpiperidin- l-ylpropyl, 4- ethoxypiperidin-l-ylpropyl), 3 to 15 membered heterocyclyl optionally substituted with one or more R4 (e.g. 1-acetyl piperidin-4-yl), C6-i4aryl optionally substituted with one or more R4 (e.g. 4-cyanophenyl, 4-Carbamoylphenyl, 3-Carbamoylphenyl, 4-Carbamoyl-3 -fluorophenyl, 4-Carbamoyl-3,5-difluorophenyl, 4-Carbamoyl-3-chlorophenyl or 4-Carbamoyl-3- methylphenyl), 5 to 14 membered heteroaryl optionally substituted with one or more R4 (e.g. 6-methoxypyridin-3-yl, 6-carbamoylpyridin-3-yl, 6-propoxypyridin-3-yl, 6-chloropyridin-3-yl, 6-hydroxypyridin-3-yl, 2-carbamoylpyrimidin-5-yl, 6-cyanopyridin-3-yl, pyridin-4-yl, pyridin-3-yl, pyrimidin-5-yl or l-methyl-lH-pyrazol-4-yl).
According to yet another embodiment, specifically provided are compounds of formula (la), in which at each occurrence, R1 is independently selected from halogen (e.g. CI or F), haloCi_8alkyl (e.g. trifluoromethyl or 3-fluoropropyl), Ci_8alkoxy (e.g. methoxy), Ci_ 8alkoxyCi_8alkyl (e.g. 3-ethoxypropyl, 3-methoxypropyl, 3-propoxypropyl or 4-ethoxybutyl), hydroxyCi_8alkyl (e.g. 3-hydroxypropyl, 4-hydroxybutyl or 3-hydroxy-3-methylbutyl), - (CH2)xCN (e.g. cyanomethyl, cyanoethyl or 3-Cyanopropyl), -0(CRbRc)xRb (e.g. pyridin-3- ylmethoxy), -(CH2)xC(0)NRbRc (e.g. 4-(N-ethylamino-4-oxo)butyl, 3-amino-3-oxopropyl, 3- (N-ethyl-3-oxo)propyl or 3-amino-3-oxopropyl), -(CRbRc)xORb (e.g. 3-(2- methoxyethoxy)propyl, 3-(2-ethoxyethoxy)propyl, 3-(cyclopropylmethoxy)propyl, 3- (benzyloxy)propyl, 4-(pyrazin-2-yloxy)butyl, 3-((6-chloropyridin-3-yl)oxy)propyl, 3-((6- methylpyridin-3-yl)oxy)propyl, 3-((2-methylpyridin-3-yl)oxy)propyl, 3-((4-methylthiazol-2- yl)methoxy)propyl, 3-(2,6-Dichlorophenoxy)propyl, 3-((2-methylpyridin-3-yl)oxy)propyl, 3- (pyridin-4-yloxy)propyl, 3-(2-Chlorophenoxy)propyl, 3-(3-methoxyphenoxy)propyl, 3-(2,6- Difluorophenoxy)propyl, 3-((5-Fluoropyridin-3-yl)oxy)propyl, 3-((5-Cyanopyridin-3- yl)oxy)propyl, (pyridin-3-yloxy)methyl, 3-(pyridin-3-yloxy)propyl or 3-(pyrazin-2- yloxy)propyl), -(CH2)xNRbRc (e.g. 3-(diethylamino)propyl or 3-Aminopropyl), (CH2)xNHC(0)Rb (e.g. 3-isobutyramidopropyl or 2-isobutyramidoethyl), -(CH2)xN(Rb)S02Rc (e.g. 3-(l-methylethylsulfonamido)propyl), 5 to 14 membered heteroarylCi_8alkyl optionally substituted with one or more R4 (e.g. 3-(l-H-imidazol- l-yl)propyl, 6-(propoxypyridin-3- yl)ethyl, 3-(lH-l,2,3-triazol- l-yl)propyl, 3-(2-methyl- lH-imidazol-l-yl)propyl, 4-(2-methyl- lH-imidazol- l-yl)butyl, 3-(3-methyl- lH-pyrazol- l-yl)propyl, 3-(4-methyl- lH-pyrazol-1- yl)propyl, 3-(lH-pyrazol- l-yl)propyl, 3-(lH-l,2,4-triazol- l-yl)propyl, 2-(pyridin-3-yl)ethyl,
2- (pyridin-4-yl)ethyl, 2-(pyridin-2-yl)ethyl, 3-(2H-tetrazol-2-yl)propyl, 2-(thiazol-2-yl)ethyl or 3-(lH-tetrazol-l-yl)propyl), 3 to 15 membered heterocyclylCi_8alkyl optionally substituted with one or more R4 (e.g. 3-morpholinopropyl, 4-carbamoylpiperidin-l-ylpropyl or 4- ethoxypiperidin-l-ylpropyl), 3 to 15 membered heterocyclyl optionally substituted with one or more R4 (e.g. 1-acetyl piperidin-4-yl), C6 i4aryl optionally substituted with one or more R4 (e.g. 4-cyanophenyl, 4-Carbamoylphenyl, 3-Carbamoylphenyl, 4-Carbamoyl-3 -fluorophenyl, 4-Carbamoyl-3,5-difluorophenyl, 4-Carbamoyl-3-chlorophenyl or 4-Carbamoyl-3- methylphenyl), 5 to 14 membered heteroaryl optionally substituted with one or more R4 (e.g. 6-methoxypyridin-3-yl, 6-carbamoylpyridin-3-yl, 6-propoxypyridin-3-yl, 6-chloropyridin-3-yl, 6-hydroxypyridin-3-yl, 2-carbamoylpyrimidin-5-yl, 6-cyanopyridin-3-yl, pyridin-4-yl, pyridin-3-yl, pyrimidin-5-yl or l-methyl- lH-pyrazol-4-yl). In this embodiment Rb and Rc are independently selected from hydrogen, Ci_8alkyl (e.g. methyl, ethyl or isopropyl), Ci_ 8alkoxyCi_8alkyl (e.g. methoxyethyl or ethoxyethyl), C3_i2cycloalkylCi_8alkyl (e.g. cyclopropylmethyl), C6 i4arylalkyl (e.g. benzyl), C6 i4aryl optionally substituted with halogen or Ci-8alkoxy (e.g. 2,6-Dichlorophenyl, 2-Chlorophenyl, 3-methoxyphenyl or 2,6- Difluorophenyl), 5 to 14 membered heteroaryl optionally substituted with halogen, CN or Ci_ 8alkyl (e.g. pyridine, 6-chloropyridin-3-yl, 6-methylpyridin-3-yl, 2-methylpyridin-3-yl, 5- Fluoropyridin-3-yl, 5-Cyanopyridin-3-yl or pyrazine) and 5 to 14 membered heteroarylCi- 8alkyl optionally substituted with Ci_8alkyl (e.g. 4-methylthiazol-2-yl)methyl) and x is 1, 2, 3 or 4.
According to yet another embodiment, specifically provided are compounds of formula (la), in which at each occurrence, R1 is independently selected from CI, F, trifluoromethyl, 3-fluoropropyl, methoxy, 3-ethoxypropyl, 3-methoxypropyl, 3- propoxypropyl, 4-ethoxybutyl, 3-hydroxypropyl, 4-hydroxybutyl, 3-hydroxy-3-methylbutyl, cyanomethyl, cyanoethyl, 3-Cyanopropyl, pyridin-3-ylmethoxy, 4-(N-ethylamino-4-oxo)butyl,
3- amino-3-oxopropyl, 3-(V-ethyl-3-oxo)propyl, 3-amino-3-oxopropyl, 3-(2- methoxyethoxy)propyl, 3-(2-ethoxyethoxy)propyl, 3-(cyclopropylmethoxy)propyl, 3- (benzyloxy)propyl, 4-(pyrazin-2-yloxy)butyl, 3-((6-chloropyridin-3-yl)oxy)propyl, 3-((6- methylpyridin-3-yl)oxy)propyl, 3-((2-methylpyridin-3-yl)oxy)propyl, 3-((4-methylthiazol-2- yl)methoxy)propyl, 3-(2,6-Dichlorophenoxy)propyl, 3-((2-methylpyridin-3-yl)oxy)propyl, 3- (pyridin-4-yloxy)propyl, 3-(2-Chlorophenoxy)propyl, 3-(3-methoxyphenoxy)propyl, 3-(2,6- Difluorophenoxy)propyl, 3-((5-Fluoropyridin-3-yl)oxy)propyl, 3-((5-Cyanopyridin-3- yl)oxy)propyl, (pyridin-3-yloxy)methyl, 3-(pyridin-3-yloxy)propyl, 3-(pyrazin-2- yloxy)propyl), 3-(diethylamino)propyl, 3-Aminopropyl, 3-isobutyramidopropyl, 2- isobutyramidoethyl, 3-(l-methylethylsulfonamido)propyl, 3-(l-H-imidazol-l-yl)propyl, 6- (propoxypyridin-3-yl)ethyl, 3-(lH-l,2,3-triazol- l-yl)propyl, 3-(2-methyl-lH-imidazol- l- yl)propyl, 4-(2-methyl- lH-imidazol-l-yl)butyl, 3-(3-methyl- lH-pyrazol- l-yl)propyl, 3-(4- methyl-lH-pyrazol- l-yl)propyl, 3-(lH-pyrazol- l-yl)propyl, 3-(lH- l,2,4-triazol- l-yl)propyl, 2-(pyridin-3-yl)ethyl, 2-(pyridin-4-yl)ethyl, 2-(pyridin-2-yl)ethyl, 3-(2H-tetrazol-2-yl)propyl, 2-(thiazol-2-yl)ethyl, 3-(lH-tetrazol-l-yl)propyl, 3-morpholinopropyl, 4-carbamoylpiperidin- 1-ylpropyl, 4-ethoxypiperidin-l-ylpropyl, 1 -acetyl piperidin-4-yl, 4-cyanophenyl, 4- Carbamoylphenyl, 3-Carbamoylphenyl, 4-Carbamoyl-3 -fluorophenyl, 4-Carbamoyl-3,5- difluorophenyl, 4-Carbamoyl-3-chlorophenyl, 4-Carbamoyl-3-methylphenyl, 6- methoxypyridin-3-yl, 6-carbamoylpyridin-3-yl, 6-propoxypyridin-3-yl, 6-chloropyridin-3-yl, 6-hydroxypyridin-3-yl, 2-carbamoylpyrimidin-5-yl, 6-cyanopyridin-3-yl, pyridin-4-yl, pyridin-3-yl, pyrimidin-5-yl and 1 -methyl- lH-pyrazol-4-yl.
According to yet another embodiment, specifically provided are compounds of formula (la), in which at each occurance, R4 is independently selected from is cyano, halogen (e.g. CI or F), Ci_8alkyl (e.g. methyl or ethyl), hydroxyl, Ci_8alkoxy (e.g. methoxy, ethoxy or propoxy), -(CH2)xC(0)NRbRc (e.g. -CONH2) and -(CH2)xC(0)Rb (e.g. acetyl).
According to yet another embodiment, specifically provided are compounds of formula (la), in which at each occurance, R4 is independently selected from is cyano, halogen (e.g. CI or F), Ci_8alkyl (e.g. methyl or ethyl), hydroxyl, Ci_8alkoxy (e.g. methoxy, ethoxy or propoxy), -(CH2)xC(0)NRbRc (e.g. -CONH2) and -(CH2)xC(0)Rb (e.g. acetyl). In this embodiment Rb and Rc are independently selected from hydrogen, and Ci_8alkyl (e.g. methyl or ethyl) and x is 0.
According to yet another embodiment, specifically provided are compounds of formula (la), in which at each occurance, R4 is independently selected from cyano, CI, F, methyl, ethyl, hydroxyl, methoxy, ethoxy, propoxy, -CONH2 and acetyl.
According to yet another embodiment, specifically provided are compounds of formula (la), in which at each occurrence, R is independently selected from halogen (e.g. CI or F), Ci_8alkoxy (e.g. methoxy), Ci_8alkoxyCi_8alkyl (e.g. ethoxymethyl or propoxymethyl), haloCi_8alkyl (e.g. CF3, fluoromethyl or difluoromethyl), 3 to 15 membered heterocyclylCi- 8alkyl (e.g. pyrrolidin-l-ylmethyl) and -(CRbRc)xORb (e.g. 2-(methoxyethoxy)methyl). According to yet another embodiment, specifically provided are compounds of formula (la), in which at each occurrence, R is independently selected from halogen (e.g. CI or F), Ci-galkoxy (e.g. methoxy), Ci-8alkoxyCi_8alkyl (e.g. ethoxymethyl or propoxymethyl), haloCi-galkyl (e.g. CF3, fluoromethyl or difluoromethyl), 3 to 15 membered heterocyclylCi- 8alkyl (e.g. pyrrolidin-l-ylmethyl) and -(CRbRc)xORb (e.g. 2-(methoxyethoxy)methyl). In this embodiment Rb and Rc are independently selected from hydrogen, Ci_8alkyl (e.g. methyl or ethyl) and Ci_8alkoxyCi_8alkyl (e.g. methoxyethyl) and 'x' is 1 or 2.
According to yet another embodiment, specifically provided are compounds of formula (la), in which at each occurrence, R is independently selected from CI, F, methoxy, ethoxymethyl, propoxymethyl, CF3, fluoromethyl, difluoromethyl, pyrrolidin-l-ylmethyl, pyrrolidin-l-ylmethyl and 2-(methoxyethoxy)methyl.
According to yet another embodiment, specifically provided are compounds of formula (la), in which at each occurrence, R is independently selected from CI, F and CF3.
According to yet another embodiment, specifically provided are compounds of formula (la), in which m is 0, 1 or 2.
According to yet another embodiment, specifically provided are compounds of formula (la), in which n is 0, 1 or 2.
According to yet another embodiment, specifically provided are compounds of formula (la), in which
A is
Figure imgf000023_0001
+ V>c c
Ra is hydrogen, Ci_8alkyl (e.g. methyl, ethyl or hexyl), -(CH2)xNR R R (e.g. NJfJf- trimethylethanaminium) or -(CH2)xC(0)NRbRc (e.g. (diethylamino)-2-oxoethyl or (dimethylamino)-2-oxoethyl),
B is
Figure imgf000023_0002
R1 is halogen (e.g. CI or F), haloCi_8alkyl (e.g. trifluoromethyl or 3-fluoropropyl), Ci_ 8alkoxy (e.g. methoxy), Ci_8alkoxyCi_8alkyl (e.g. 3-ethoxypropyl, 3-methoxypropyl, 3- propoxypropyl or 4-ethoxybutyl), hydroxyCi_8alkyl (e.g. 3-hydroxypropyl, 4-hydroxybutyl or 3-hydroxy-3-methylbutyl), -(CH2)XCN (e.g. cyanomethyl, cyanoethyl or 3-Cyanopropyl), - 0(CRbRc)xRb (e.g. pyridin-3-ylmethoxy), -(CH2)xC(0)NRbRc (e.g. 4-(N-ethylamino-4- oxo)butyl, 3-amino-3-oxopropyl, 3-(V-ethyl-3-oxo)propyl or 3-amino-3-oxopropyl), - (CRbRc)xORb (e.g. 3-(2-methoxyethoxy)propyl, 3-(2-ethoxyethoxy)propyl, 3- (cyclopropylmethoxy)propyl, 3-(benzyloxy)propyl, 4-(pyrazin-2-yloxy)butyl, 3-((6- chloropyridin-3-yl)oxy)propyl, 3-((6-methylpyridin-3-yl)oxy)propyl, 3-((2-methylpyridin-3- yl)oxy)propyl, 3-((4-methylthiazol-2-yl)methoxy)propyl, 3-(2,6-Dichlorophenoxy)propyl, 3- ((2-methylpyridin-3-yl)oxy)propyl, 3-(pyridin-4-yloxy)propyl, 3-(2-Chlorophenoxy)propyl, 3-(3-methoxyphenoxy)propyl, 3-(2,6-Difluorophenoxy)propyl, 3-((5-Fluoropyridin-3- yl)oxy)propyl, 3-((5-Cyanopyridin-3-yl)oxy)propyl, (pyridin-3-yloxy)methyl, 3-(pyridin-3- yloxy)propyl or 3-(pyrazin-2-yloxy)propyl), -(CH2)xNRbRc (e.g. 3-(diethylamino)propyl or 3- Aminopropyl), -(CH2)xNHC(0)Rb (e.g. 3-isobutyramidopropyl or 2-isobutyramidoethyl), - (CH2)xN(Rb)S02Rc (e.g. 3-(l-methylethylsulfonamido)propyl), 5 to 14 membered heteroarylCi-galkyl optionally substituted with one or more R4 (e.g. 3-(l-H-imidazol-l- yl)propyl, 6-(propoxypyridin-3-yl)ethyl, 3-(lH-l,2,3-triazol-l-yl)propyl, 3-(2-methyl- lH- imidazol-l-yl)propyl, 4-(2-methyl-lH-imidazol-l-yl)butyl, 3-(3-methyl- lH-pyrazol- l- yl)propyl, 3-(4-methyl- lH-pyrazol- l-yl)propyl, 3-(lH-pyrazol- l-yl)propyl, 3-(lH-l,2,4- triazol- l-yl)propyl, 2-(pyridin-3-yl)ethyl, 2-(pyridin-4-yl)ethyl, 2-(pyridin-2-yl)ethyl, 3-(2H- tetrazol-2-yl)propyl, 2-(thiazol-2-yl)ethyl or 3-(lH-tetrazol- l-yl)propyl), 3 to 15 membered heterocyclylCi_8alkyl optionally substituted with one or more R4 (e.g. 3-morpholinopropyl, 4- carbamoylpiperidin-l-ylpropyl or 4-ethoxypiperidin- l-ylpropyl), 3 to 15 membered heterocyclyl optionally substituted with one or more R4 (e.g. 1-acetyl piperidin-4-yl), C6 i4aryl optionally substituted with one or more R4 (e.g. 4-cyanophenyl, 4-Carbamoylphenyl, 3- Carbamoylphenyl, 4-Carbamoyl-3-fluorophenyl, 4-Carbamoyl-3,5-difluorophenyl, 4- Carbamoyl-3-chlorophenyl or 4-Carbamoyl-3-methylphenyl) or 5 to 14 membered heteroaryl optionally substituted with one or more R4 (e.g. 6-methoxypyridin-3-yl, 6-carbamoylpyridin- 3-yl, 6-propoxypyridin-3-yl, 6-chloropyridin-3-yl, 6-hydroxypyridin-3-yl, 2- carbamoylpyrimidin-5-yl, 6-cyanopyridin-3-yl, pyridin-4-yl, pyridin-3-yl, pyrimidin-5-yl or 1-methyl- lH-pyrazol-4-yl),
R is halogen (e.g. CI or F), Ci_8alkoxy (e.g. methoxy), Ci-8alkoxyCi_8alkyl (e.g. ethoxymethyl or propoxymethyl), haloCi_8alkyl (e.g. CF3, iluoromethyl or difluoromethyl), 3 to 15 membered heterocyclylCi_8alkyl (e.g. pyrrolidin-l-ylmethyl) or -(CRbRc)xORb (e.g. 2- (methoxyethoxy )methyl) ,
R is hydrogen or Ci_8alkyl (e.g. methyl), R4 is cyano, halogen (e.g. CI or F), Ci_8alkyl (e.g. methyl or ethyl), hydroxyl, Ci_ salkoxy (e.g. methoxy, ethoxy or propoxy), -(CH2)xC(0)NRbRc (e.g. -CONH2) or - (CH2)xC(0)Rb (e.g. acetyl),
Rb and Rc are hydrogen, Ci_8alkyl (e.g. methyl, ethyl or isopropyl), Ci_8alkoxyCi_8alkyl (e.g. methoxyethyl or ethoxyethyl), C3_i2cycloalkylCi_8alkyl (e.g. cyclopropylmethyl), C6- i4arylalkyl (e.g. benzyl), C6-i4aryl optionally substituted with halogen or Ci_8alkoxy (e.g. 2,6- Dichlorophenyl, 2-Chlorophenyl, 3-methoxyphenyl or 2,6-Difluorophenyl), 5 to 14 membered heteroaryl optionally substituted with halogen, CN or Ci_8alkyl (e.g. pyridine, 6- chloropyridin-3-yl, 6-methylpyridin-3-yl, 2-methylpyridin-3-yl, 5-Fluoropyridin-3-yl, 5- Cyanopyridin-3-yl or pyrazine) or 5 to 14 membered heteroarylCi_8alkyl optionally substituted with Ci_8alkyl (e.g. 4-methylthiazol-2-yl)methyl),
x is 0, 1, 2 or 3,
m is 0, 1 or 2,
n is 0, 1 or 2.
According to yet another embodiment, specifically provided are compounds formula (la), in which
Figure imgf000025_0001
R1 is CI, F, trifluoromethyl, 3-fluoropropyl, methoxy, 3-ethoxypropyl, 3- methoxypropyl, 3-propoxypropyl, 4-ethoxybutyl, 3-hydroxypropyl, 4-hydroxybutyl, 3- hydroxy-3-methylbutyl, cyanomethyl, cyanoethyl, 3-Cyanopropyl, pyridin-3-ylmethoxy, 4- (N-ethylamino-4-oxo)butyl, 3-amino-3-oxopropyl, 3-(V-ethyl-3-oxo)propyl, 3-amino-3- oxopropyl, 3-(2-methoxyethoxy)propyl, 3-(2-ethoxyethoxy)propyl, 3-
(cyclopropylmethoxy)propyl, 3-(benzyloxy)propyl, 4-(pyrazin-2-yloxy)butyl, 3-((6- chloropyridin-3-yl)oxy)propyl, 3-((6-methylpyridin-3-yl)oxy)propyl, 3-((2-methylpyridin-3- yl)oxy)propyl, 3-((4-methylthiazol-2-yl)methoxy)propyl, 3-(2,6-Dichlorophenoxy)propyl, 3- ((2-methylpyridin-3-yl)oxy)propyl, 3-(pyridin-4-yloxy)propyl, 3-(2-Chlorophenoxy)propyl, 3-(3-methoxyphenoxy)propyl, 3-(2,6-Difluorophenoxy)propyl, 3-((5-Fluoropyridin-3- yl)oxy)propyl, 3-((5-Cyanopyridin-3-yl)oxy)propyl, (pyridin-3-yloxy)methyl, 3-(pyridin-3- yloxy)propyl, 3-(pyrazin-2-yloxy)propyl), 3-(diethylamino)propyl, 3-Aminopropyl, 3- isobutyramidopropyl, 2-isobutyramidoethyl, 3-(l-methylethylsulfonamido)propyl, 3-(l-H- imidazol-l-yl)propyl, 6-(propoxypyridin-3-yl)ethyl, 3-(lH-l,2,3-triazol- l-yl)propyl, 3-(2- methyl- lH-imidazol- 1 -yl)propyl, 4-(2-methyl- lH-imidazol- 1 -yl)butyl, 3-(3-methyl- 1H- pyrazol- l-yl)propyl, 3-(4-methyl- lH-pyrazol- l-yl)propyl, 3-(lH-pyrazol- l-yl)propyl, 3-(lH- l,2,4-triazol-l-yl)propyl, 2-(pyridin-3-yl)ethyl, 2-(pyridin-4-yl)ethyl, 2-(pyridin-2-yl)ethyl, 3- (2H-tetrazol-2-yl)propyl, 2-(thiazol-2-yl)ethyl, 3-(lH-tetrazol-l-yl)propyl, 3- morpholinopropyl, 4-carbamoylpiperidin-l-ylpropyl, 4-ethoxypiperidin- l-ylpropyl, 1 -acetyl piperidin-4-yl, 4-cyanophenyl, 4-Carbamoylphenyl, 3-Carbamoylphenyl, 4-Carbamoyl-3- fluorophenyl, 4-Carbamoyl-3,5-difluorophenyl, 4-Carbamoyl-3-chlorophenyl, 4-Carbamoyl- 3-methylphenyl, 6-methoxypyridin-3-yl, 6-carbamoylpyridin-3-yl, 6-propoxypyridin-3-yl, 6- chloropyridin-3-yl, 6-hydroxypyridin-3-yl, 2-carbamoylpyrimidin-5-yl, 6-cyanopyridin-3-yl, pyridin-4-yl, pyridin-3-yl, pyrimidin-5-yl or 1 -methyl- lH-pyrazol-4-yl,
R is CI, F, methoxy, ethoxymethyl, propoxymethyl, CF3, fluoromethyl, difluoromethyl, pyrrolidin- l-ylmethyl or 2-(methoxyethoxy)methyl,
m is 0, 1 or 2, and
n is 0, 1 or 2.
According to one embodiment, specifically provided are compounds of formula (la) 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.
1 2
Further embodiments relating to groups A, R , R , m and n (and groups defined therein) are described hereinafter in relation to the compounds of formula (lb). It is to be understood that these embodiments are not limited to use in conjunction with formula (lb), but apply independently and individually to the compounds of formula (I). For example, in an embodiment described hereinafter, the invention specifically provides compounds of formula (lb), in which 'm' is 0, 1 or 2 and consequently, there is also provided a compound of formula (I) in which 'm' is 0, 1 or 2.
The invention also provides a compound of formula (lb), which is an embodiment of a compound of formula (I).
Accordingly the invention provides a compound of formula (lb)
Figure imgf000027_0001
(lb)
or a pharmaceutically acceptable salt thereof,
wherein,
A is selected from
Figure imgf000027_0002
Ra is selected from hydrogen, Ci_8alkyl, -(CH2)xC(0)NRbRc and
Figure imgf000027_0003
at each occurrence, R is independently selected from halogen, Ci_8alkoxy, Ci
8alkoxyCi_8alkyl, hydroxyCi_8alkyl, haloCi_8alkyl, -(CH2)xNRbRc, -(CRbRc)xORb, - 0(CRbRc)xRb, -(CH2)XCN, -(CH2)xC(0)NRbRc, -(CH2)xNHC(0)Rb, -(CH2)xN(Rb)S02Rc, C6_ i4aryl, 3 to 15 membered heterocyclyl, 3 to 15 membered heterocyclylCi_8alkyl, 5 to 14 membered heteroaryl and 5 to 14 membered heteroarylCi_8alkyl, wherein C6-i4aryl, 3 to 15 membered heterocyclyl, 3 to 15 membered heterocyclylCi_8alkyl, 5 to 14 membered heteroaryl and 5 to 14 membered heteroarylCi_8alkyl optionally substituted with one or more R4;
2
at each occurrence, R is independently selected from halogen, Ci_8alkoxy, ( 8alkoxyCi_8alkyl, haloCi_8alkyl, 3 to 15 membered heterocyclylCi_8alkyl and -(CRbRc)xORb; at each occurrence, R4 is independently selected from halogen, hydroxyl, cyano, Ci_ salkyl, Ci_8alkoxy, 5 to 14 membered heteroaryl, -(CH2)xC(0)Rb and -(CH2)xC(0)NRbRc; at each occurrence, Rb and Rc which may be same or different, are independently selected from hydrogen, Ci_8alkyl, Ci_8alkoxyCi_8alkyl, C3_i2cycloalkylCi_8alkyl, C6-i4aryl optionally substituted with halogen or Ci_8alkoxy, C6-i4arylCi_8alkyl, 5 to 14 membered heteroaryl optionally substituted with halogen, CN or Ci_8alkyl and 5 to 14 membered heteroarylCi_8alkyl optionally substituted with Ci_8alkyl;
m is selected from '0' to '4', both inclusive;
n is selected from '0' to '4', both inclusive; and
x is selected from '0' to '4', 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 wherein m is 0, 1 or 2 (according to one embodiment defined below), n is 0, 1 or 2 (according to another embodiment defined below).
According to yet another embodiment, specifically provided are compounds of formula (lb), in which A is
Figure imgf000028_0001
According to yet another embodiment, specifically provided are compounds formula (lb), in which A is
Figure imgf000028_0002
. In this embodiment R is hydrogen, Ci_8alkyl (e.g. methyl, ethyl or hexyl), -(CH2)xNRbRCRC (e.g. N,N,N-trimethylethanaminium) or -(CH2)xC(0)NRbRc (e.g. (diethylamino)-2-oxoethyl or (dimethylamino)-2-oxoethyl).
According to yet another embodiment, specifically provided are compounds of formula (lb), in which A is
Figure imgf000028_0003
. In this embodiment R is hydrogen, methyl, ethyl, hexyl, N,N,N-trimethylethanaminium, 2-(diethylamino)-2-oxoethyl or (dimethylamino)-2-oxoethyl).
According to yet another embodiment, specifically provided are compounds of formula (lb), in which A is
Figure imgf000028_0004
According to yet another embodiment, specifically provided are compounds of formula (lb), in which A is
Figure imgf000028_0005
According to yet another embodiment, specifically provided are compounds formul hich A is
Figure imgf000029_0001
According to yet another embodiment, specifically provided are compounds of formula (lb), in which at each occurrence, R1 is independently selected from halogen (e.g. CI or F), haloCi-galkyl (e.g. trifluoromethyl or 3-fluoropropyl), Ci-galkoxy (e.g. methoxy), Ci_ salkoxyCi-galkyl (e.g. 3-ethoxypropyl, 3-methoxypropyl, 3-propoxypropyl or 4-ethoxybutyl), hydroxyCi_8alkyl (e.g. 3-hydroxypropyl, 4-hydroxybutyl or 3-hydroxy-3-methylbutyl), - (CH2)xCN (e.g. cyanomethyl, cyanoethyl or 3-Cyanopropyl), -0(CRbRc)xRb (e.g. pyridin-3- ylmethoxy), -(CH2)xC(0)NRbRc (e.g. 4-(N-ethylamino-4-oxo)butyl, 3-amino-3-oxopropyl, 3- (N-ethyl-3-oxo)propyl or 3-amino-3-oxopropyl), -(CRbRc)xORb (e.g. 3-(2- methoxyethoxy)propyl, 3-(2-ethoxyethoxy)propyl, 3-(cyclopropylmethoxy)propyl, 3- (benzyloxy)propyl, 4-(pyrazin-2-yloxy)butyl, 3-((6-chloropyridin-3-yl)oxy)propyl, 3-((6- methylpyridin-3-yl)oxy)propyl, 3-((2-methylpyridin-3-yl)oxy)propyl, 3-((4-methylthiazol-2- yl)methoxy)propyl, 3-(2,6-Dichlorophenoxy)propyl, 3-((2-methylpyridin-3-yl)oxy)propyl, 3- (pyridin-4-yloxy)propyl, 3-(2-Chlorophenoxy)propyl, 3-(3-methoxyphenoxy)propyl, 3-(2,6- Difluorophenoxy)propyl, 3-((5-Fluoropyridin-3-yl)oxy)propyl, 3-((5-Cyanopyridin-3- yl)oxy)propyl, (pyridin-3-yloxy)methyl, 3-(pyridin-3-yloxy)propyl or 3-(pyrazin-2- yloxy)propyl), -(CH2)xNRbRc (e.g. 3-(diethylamino)propyl or 3-Aminopropyl), (CH2)xNHC(0)Rb (e.g. 3-isobutyramidopropyl or 2-isobutyramidoethyl), -(CH2)xN(Rb)S02Rc (e.g. 3-(l-methylethylsulfonamido)propyl), 5 to 14 membered heteroarylCi-galkyl optionally substituted with one or more R4 (e.g. 3-(l-H-imidazol- l-yl)propyl, 6-(propoxypyridin-3- yl)ethyl, 3-(lH-l,2,3-triazol- l-yl)propyl, 3-(2-methyl- lH-imidazol-l-yl)propyl, 4-(2-methyl- lH-imidazol- l-yl)butyl, 3-(3-methyl- lH-pyrazol- l-yl)propyl, 3-(4-methyl- lH-pyrazol-1- yl)propyl, 3-(lH-pyrazol- l-yl)propyl, 3-(lH-l,2,4-triazol- l-yl)propyl, 2-(pyridin-3-yl)ethyl, 2-(pyridin-4-yl)ethyl, 2-(pyridin-2-yl)ethyl, 3-(2H-tetrazol-2-yl)propyl, 2-(thiazol-2-yl)ethyl or 3-(lH-tetrazol-l-yl)propyl), 3 to 15 membered heterocyclylCi-galkyl optionally substituted with one or more R4 (e.g. 3-morpholinopropyl, 4-carbamoylpiperidin-l-ylpropyl or 4- ethoxypiperidin-l-ylpropyl), 3 to 15 membered heterocyclyl optionally substituted with one or more R4 (e.g. 1-acetyl piperidin-4-yl), C6 i4aryl optionally substituted with one or more R4 (e.g. 4-cyanophenyl, 4-Carbamoylphenyl, 3-Carbamoylphenyl, 4-Carbamoyl-3 -fluorophenyl, 4-Carbamoyl-3,5-difluorophenyl, 4-Carbamoyl-3-chlorophenyl or 4-Carbamoyl-3- methylphenyl), 5 to 14 membered heteroaryl optionally substituted with one or more R4 (e.g. 6-methoxypyridin-3-yl, 6-carbamoylpyridin-3-yl, 6-propoxypyridin-3-yl, 6-chloropyridin-3-yl, 6-hydroxypyridin-3-yl, 2-carbamoylpyrimidin-5-yl, 6-cyanopyridin-3-yl, pyridin-4-yl, pyridin-3-yl, pyrimidin-5-yl or l-methyl-lH-pyrazol-4-yl).
According to yet another embodiment, specifically provided are compounds of formula (lb), in which at each occurrence, R1 is independently selected from halogen (e.g. CI or F), haloCi-galkyl (e.g. trifluoromethyl or 3-fluoropropyl), Ci-galkoxy (e.g. methoxy), Ci_ galkoxyCi-galkyl (e.g. 3-ethoxypropyl, 3-methoxypropyl, 3-propoxypropyl or 4-ethoxybutyl), hydroxyCi_8alkyl (e.g. 3-hydroxypropyl, 4-hydroxybutyl or 3-hydroxy-3-methylbutyl), - (CH2)XCN (e.g. cyanomethyl, cyanoethyl or 3-Cyanopropyl), -0(CRbRc)xRb (e.g. pyridin-3- ylmethoxy), -(CH2)xC(0)NRbRc (e.g. 4-(N-ethylamino-4-oxo)butyl, 3-amino-3-oxopropyl, 3- (N-ethyl-3-oxo)propyl or 3-amino-3-oxopropyl), -(CRbRc)xORb (e.g. 3-(2- methoxyethoxy)propyl, 3-(2-ethoxyethoxy)propyl, 3-(cyclopropylmethoxy)propyl, 3- (benzyloxy)propyl, 4-(pyrazin-2-yloxy)butyl, 3-((6-chloropyridin-3-yl)oxy)propyl, 3-((6- methylpyridin-3-yl)oxy)propyl, 3-((2-methylpyridin-3-yl)oxy)propyl, 3-((4-methylthiazol-2- yl)methoxy)propyl, 3-(2,6-Dichlorophenoxy)propyl, 3-((2-methylpyridin-3-yl)oxy)propyl, 3- (pyridin-4-yloxy)propyl, 3-(2-Chlorophenoxy)propyl, 3-(3-methoxyphenoxy)propyl, 3-(2,6- Difluorophenoxy)propyl, 3-((5-Fluoropyridin-3-yl)oxy)propyl, 3-((5-Cyanopyridin-3- yl)oxy)propyl, (pyridin-3-yloxy)methyl, 3-(pyridin-3-yloxy)propyl or 3-(pyrazin-2- yloxy)propyl), -(CH2)xNRbRc (e.g. 3-(diethylamino)propyl or 3-Aminopropyl), (CH2)xNHC(0)Rb (e.g. 3-isobutyramidopropyl or 2-isobutyramidoethyl), -(CH2)xN(Rb)S02Rc (e.g. 3-(l-methylethylsulfonamido)propyl), 5 to 14 membered heteroarylCi-galkyl optionally substituted with one or more R4 (e.g. 3-(l-H-imidazol- l-yl)propyl, 6-(propoxypyridin-3- yl)ethyl, 3-(lH-l,2,3-triazol- l-yl)propyl, 3-(2-methyl- lH-imidazol-l-yl)propyl, 4-(2-methyl- lH-imidazol- l-yl)butyl, 3-(3-methyl- lH-pyrazol- l-yl)propyl, 3-(4-methyl- lH-pyrazol-1- yl)propyl, 3-(lH-pyrazol- l-yl)propyl, 3-(lH-l,2,4-triazol- l-yl)propyl, 2-(pyridin-3-yl)ethyl, 2-(pyridin-4-yl)ethyl, 2-(pyridin-2-yl)ethyl, 3-(2H-tetrazol-2-yl)propyl, 2-(thiazol-2-yl)ethyl or 3-(lH-tetrazol-l-yl)propyl), 3 to 15 membered heterocyclylCi-galkyl optionally substituted with one or more R4 (e.g. 3-morpholinopropyl, 4-carbamoylpiperidin-l-ylpropyl or 4- ethoxypiperidin-l-ylpropyl), 3 to 15 membered heterocyclyl optionally substituted with one or more R4 (e.g. 1-acetyl piperidin-4-yl), C6-i4aryl optionally substituted with one or more R4 (e.g. 4-cyanophenyl, 4-Carbamoylphenyl, 3-Carbamoylphenyl, 4-Carbamoyl-3 -fluorophenyl, 4-Carbamoyl-3,5-difluorophenyl, 4-Carbamoyl-3-chlorophenyl or 4-Carbamoyl-3- methylphenyl), 5 to 14 membered heteroaryl optionally substituted with one or more R4 (e.g. 6-methoxypyridin-3-yl, 6-carbamoylpyridin-3-yl, 6-propoxypyridin-3-yl, 6-chloropyridin-3-yl, 6-hydroxypyridin-3-yl, 2-carbamoylpyrimidin-5-yl, 6-cyanopyridin-3-yl, pyridin-4-yl, pyridin-3-yl, pyrimidin-5-yl or l-methyl- lH-pyrazol-4-yl). In this embodiment Rb and Rc are independently selected from hydrogen, Ci_8alkyl (e.g. methyl, ethyl or isopropyl), Ci_ 8alkoxyCi_8alkyl (e.g. methoxyethyl or ethoxyethyl), C3_i2cycloalkylCi_8alkyl (e.g. cyclopropylmethyl), C6-i4arylalkyl (e.g. benzyl), C6-i4aryl optionally substituted with halogen or Ci-galkoxy (e.g. 2,6-Dichlorophenyl, 2-Chlorophenyl, 3-methoxyphenyl or 2,6- Difluorophenyl), 5 to 14 membered heteroaryl optionally substituted with halogen, CN or Ci_ 8alkyl (e.g. pyridine, 6-chloropyridin-3-yl, 6-methylpyridin-3-yl, 2-methylpyridin-3-yl, 5- Fluoropyridin-3-yl, 5-Cyanopyridin-3-yl or pyrazine) and 5 to 14 membered heteroarylCi- 8alkyl optionally substituted with Ci_8alkyl (e.g. 4-methylthiazol-2-yl)methyl) and x is 1, 2, 3 or 4.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which at each occurrence, R1 is independently selected from CI, F, trifluoromethyl, 3-fluoropropyl, methoxy, 3-ethoxypropyl, 3-methoxypropyl, 3- propoxypropyl, 4-ethoxybutyl, 3-hydroxypropyl, 4-hydroxybutyl, 3-hydroxy-3-methylbutyl, cyanomethyl, cyanoethyl, 3-Cyanopropyl, pyridin-3-ylmethoxy, 4-(N-ethylamino-4-oxo)butyl, 3-amino-3-oxopropyl, 3-(V-ethyl-3-oxo)propyl, 3-amino-3-oxopropyl, 3-(2- methoxyethoxy)propyl, 3-(2-ethoxyethoxy)propyl, 3-(cyclopropylmethoxy)propyl, 3- (benzyloxy)propyl, 4-(pyrazin-2-yloxy)butyl, 3-((6-chloropyridin-3-yl)oxy)propyl, 3-((6- methylpyridin-3-yl)oxy)propyl, 3-((2-methylpyridin-3-yl)oxy)propyl, 3-((4-methylthiazol-2- yl)methoxy)propyl, 3-(2,6-Dichlorophenoxy)propyl, 3-((2-methylpyridin-3-yl)oxy)propyl, 3- (pyridin-4-yloxy)propyl, 3-(2-Chlorophenoxy)propyl, 3-(3-methoxyphenoxy)propyl, 3-(2,6- Difluorophenoxy)propyl, 3-((5-Fluoropyridin-3-yl)oxy)propyl, 3-((5-Cyanopyridin-3- yl)oxy)propyl, (pyridin-3-yloxy)methyl, 3-(pyridin-3-yloxy)propyl, 3-(pyrazin-2- yloxy)propyl), 3-(diethylamino)propyl, 3-Aminopropyl, 3-isobutyramidopropyl, 2- isobutyramidoethyl, 3-(l-methylethylsulfonamido)propyl, 3-(l-H-imidazol-l-yl)propyl, 6- (propoxypyridin-3-yl)ethyl, 3-(lH-l,2,3-triazol- l-yl)propyl, 3-(2-methyl-lH-imidazol- l- yl)propyl, 4-(2-methyl- lH-imidazol-l-yl)butyl, 3-(3-methyl- lH-pyrazol- l-yl)propyl, 3-(4- methyl-lH-pyrazol- l-yl)propyl, 3-(lH-pyrazol- l-yl)propyl, 3-(lH- l,2,4-triazol- l-yl)propyl, 2-(pyridin-3-yl)ethyl, 2-(pyridin-4-yl)ethyl, 2-(pyridin-2-yl)ethyl, 3-(2H-tetrazol-2-yl)propyl, 2-(thiazol-2-yl)ethyl, 3-(lH-tetrazol-l-yl)propyl, 3-morpholinopropyl, 4-carbamoylpiperidin- 1-ylpropyl, 4-ethoxypiperidin-l-ylpropyl, 1 -acetyl piperidin-4-yl, 4-cyanophenyl, 4- Carbamoylphenyl, 3-Carbamoylphenyl, 4-Carbamoyl-3 -fluorophenyl, 4-Carbamoyl-3,5- difluorophenyl, 4-Carbamoyl-3-chlorophenyl, 4-Carbamoyl-3-methylphenyl, 6- methoxypyridin-3-yl, 6-carbamoylpyridin-3-yl, 6-propoxypyridin-3-yl, 6-chloropyridin-3-yl, 6-hydroxypyridin-3-yl, 2-carbamoylpyrimidin-5-yl, 6-cyanopyridin-3-yl, pyridin-4-yl, pyridin-3-yl, pyrimidin-5-yl and 1 -methyl- lH-pyrazol-4-yl.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which at each occurance, R4 is independently selected from is cyano, halogen (e.g. CI or F), Ci_8alkyl (e.g. methyl or ethyl), hydroxyl, Ci_8alkoxy (e.g. methoxy, ethoxy or propoxy), -(CH2)xC(0)NRbRc (e.g. -CONH2) and -(CH2)xC(0)Rb (e.g. acetyl).
According to yet another embodiment, specifically provided are compounds of formula (lb), in which at each occurance, R4 is independently selected from is cyano, halogen (e.g. CI or F), Ci_8alkyl (e.g. methyl or ethyl), hydroxyl, Ci_8alkoxy (e.g. methoxy, ethoxy or propoxy), -(CH2)xC(0)NRbRc (e.g. -CONH2) and -(CH2)xC(0)Rb (e.g. acetyl). In this embodiment Rb and Rc are independently selected from hydrogen, and Ci_8alkyl (e.g. methyl or ethyl) and x is 0.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which at each occurance, R4 is independently selected from cyano, CI, F, methyl, ethyl, hydroxyl, methoxy, ethoxy, propoxy, -CONH2 and acetyl.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which at each occurrence, R is independently selected from halogen (e.g. CI or F), Ci_8alkoxy (e.g. methoxy), Ci_8alkoxyCi_8alkyl (e.g. ethoxymethyl or propoxymethyl), haloCi_8alkyl (e.g. CF3, fluoromethyl or difluoromethyl), 3 to 15 membered heterocyclylCi- 8alkyl (e.g. pyrrolidin-l-ylmethyl) and -(CRbRc)xORb (e.g. 2-(methoxyethoxy)methyl).
According to yet another embodiment, specifically provided are compounds of formula (lb), in which at each occurrence, R is independently selected from halogen (e.g. CI or F), Ci-8alkoxy (e.g. methoxy), Ci_8alkoxyCi_8alkyl (e.g. ethoxymethyl or propoxymethyl), haloCi_8alkyl (e.g. CF3, fluoromethyl or difluoromethyl), 3 to 15 membered heterocyclylCi- 8alkyl (e.g. pyrrolidin- l-ylmethyl) and -(CRbRc)xORb (e.g. 2-(methoxyethoxy)methyl). In this embodiment Rb and Rc are independently selected from hydrogen, Ci_8alkyl (e.g. methyl or ethyl) and Ci_8alkoxyCi_8alkyl (e.g. methoxyethyl) and 'x' is 1 or 2.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which at each occurrence, R is independently selected from CI, F, methoxy, ethoxymethyl, propoxymethyl, CF3, fluoromethyl, difluoromethyl, pyrrolidin- l-ylmethyl, pyrrolidin- l-ylmethyl and 2-(methoxyethoxy)methyl. According to yet another embodiment, specifically provided are compounds of formula (lb), in which at each occurrence, R is independently selected from CI, F and CF3.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which m is 0, 1 or 2.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which n is 0, 1 or 2.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which
A is
R
Figure imgf000033_0001
a is hydrogen, Ci_8alkyl (e.g. methyl, ethyl or hexyl), (e.g. Ν,Ν,Ν- trimethylethanaminium) or -(CH2)xC(0)NRbRc (e.g. (diethylamino)-2-oxoethyl or (dimethylamino)-2-oxoethyl),
R1 is halogen (e.g. CI or F), haloCi_8alkyl (e.g. trifluoromethyl or 3-fluoropropyl), Ci_ 8alkoxy (e.g. methoxy), Ci_8alkoxyCi_8alkyl (e.g. 3-ethoxypropyl, 3-methoxypropyl, 3- propoxypropyl or 4-ethoxybutyl), hydroxyCi_8alkyl (e.g. 3-hydroxypropyl, 4-hydroxybutyl or 3-hydroxy-3-methylbutyl), -(CH2)XCN (e.g. cyanomethyl, cyanoethyl or 3-Cyanopropyl), - 0(CRbRc)xRb (e.g. pyridin-3-ylmethoxy), -(CH2)xC(0)NRbRc (e.g. 4-(N-ethylamino-4- oxo)butyl, 3-amino-3-oxopropyl, 3-(V-ethyl-3-oxo)propyl or 3-amino-3-oxopropyl), - (CRbRc)xORb (e.g. 3-(2-methoxyethoxy)propyl, 3-(2-ethoxyethoxy)propyl, 3- (cyclopropylmethoxy)propyl, 3-(benzyloxy)propyl, 4-(pyrazin-2-yloxy)butyl, 3-((6- chloropyridin-3-yl)oxy)propyl, 3-((6-methylpyridin-3-yl)oxy)propyl, 3-((2-methylpyridin-3- yl)oxy)propyl, 3-((4-methylthiazol-2-yl)methoxy)propyl, 3-(2,6-Dichlorophenoxy)propyl, 3- ((2-methylpyridin-3-yl)oxy)propyl, 3-(pyridin-4-yloxy)propyl, 3-(2-Chlorophenoxy)propyl, 3-(3-methoxyphenoxy)propyl, 3-(2,6-Difluorophenoxy)propyl, 3-((5-Fluoropyridin-3- yl)oxy)propyl, 3-((5-Cyanopyridin-3-yl)oxy)propyl, (pyridin-3-yloxy)methyl, 3-(pyridin-3- yloxy)propyl or 3-(pyrazin-2-yloxy)propyl), -(CH2)xNRbRc (e.g. 3-(diethylamino)propyl or 3- Aminopropyl), -(CH2)xNHC(0)Rb (e.g. 3-isobutyramidopropyl or 2-isobutyramidoethyl), - (CH2)xN(Rb)S02Rc (e.g. 3-(l-methylethylsulfonamido)propyl), 5 to 14 membered heteroarylCi-8alkyl optionally substituted with one or more R4 (e.g. 3-(l-H-imidazol-l- yl)propyl, 6-(propoxypyridin-3-yl)ethyl, 3-(lH-l,2,3-triazol-l-yl)propyl, 3-(2-methyl- lH- imidazol-l-yl)propyl, 4-(2-methyl-lH-imidazol-l-yl)butyl, 3-(3-methyl- lH-pyrazol- l- yl)propyl, 3-(4-methyl- lH-pyrazol- l-yl)propyl, 3-(lH-pyrazol- l-yl)propyl, 3-(lH-l,2,4- triazol- l-yl)propyl, 2-(pyridin-3-yl)ethyl, 2-(pyridin-4-yl)ethyl, 2-(pyridin-2-yl)ethyl, 3-(2H- tetrazol-2-yl)propyl, 2-(thiazol-2-yl)ethyl or 3-(lH-tetrazol- l-yl)propyl), 3 to 15 membered heterocyclylCi-galkyl optionally substituted with one or more R4 (e.g. 3-morpholinopropyl, 4- carbamoylpiperidin-l-ylpropyl or 4-ethoxypiperidin- l-ylpropyl), 3 to 15 membered heterocyclyl optionally substituted with one or more R4 (e.g. 1-acetyl piperidin-4-yl), C6-i4aryl optionally substituted with one or more R4 (e.g. 4-cyanophenyl, 4-Carbamoylphenyl, 3- Carbamoylphenyl, 4-Carbamoyl-3-fluorophenyl, 4-Carbamoyl-3,5-difluorophenyl, 4- Carbamoyl-3-chlorophenyl or 4-Carbamoyl-3-methylphenyl) or 5 to 14 membered heteroaryl optionally substituted with one or more R4 (e.g. 6-methoxypyridin-3-yl, 6-carbamoylpyridin- 3-yl, 6-propoxypyridin-3-yl, 6-chloropyridin-3-yl, 6-hydroxypyridin-3-yl, 2- carbamoylpyrimidin-5-yl, 6-cyanopyridin-3-yl, pyridin-4-yl, pyridin-3-yl, pyrimidin-5-yl or 1-methyl- lH-pyrazol-4-yl),
R is halogen (e.g. CI or F), Ci_8alkoxy (e.g. methoxy), Ci-8alkoxyCi_8alkyl (e.g. ethoxymethyl or propoxymethyl), haloCi_8alkyl (e.g. CF3, iluoromethyl or diiluoromethyl), 3 to 15 membered heterocyclylCi_8alkyl (e.g. pyrrolidin-l-ylmethyl) or -(CRbRc)xORb (e.g. 2- (methoxyethoxy )methyl) ,
R4 is cyano, halogen (e.g. CI or F), Ci_8alkyl (e.g. methyl or ethyl), hydroxyl, Ci_ 8alkoxy (e.g. methoxy, ethoxy or propoxy), -(CH2)xC(0)NRbRc (e.g. -CONH2) or - (CH2)xC(0)Rb (e.g. acetyl),
Rb and Rc are hydrogen, Ci_8alkyl (e.g. methyl, ethyl or isopropyl), Ci_8alkoxyCi_8alkyl (e.g. methoxyethyl or ethoxyethyl), C3_i2cycloalkylCi_8alkyl (e.g. cyclopropylmethyl), C6- i4arylalkyl (e.g. benzyl), C6-i4aryl optionally substituted with halogen or Ci_8alkoxy (e.g. 2,6- Dichlorophenyl, 2-Chlorophenyl, 3-methoxyphenyl or 2,6-Difluorophenyl), 5 to 14 membered heteroaryl optionally substituted with halogen, CN or Ci_8alkyl (e.g. pyridine, 6- chloropyridin-3-yl, 6-methylpyridin-3-yl, 2-methylpyridin-3-yl, 5-Fluoropyridin-3-yl, 5- Cyanopyridin-3-yl or pyrazine) or 5 to 14 membered heteroarylCi_8alkyl optionally substituted with Ci_8alkyl (e.g. 4-methylthiazol-2-yl)methyl),
x is 0, 1, 2 or 3,
m is 0, 1 or 2,
n is 0, 1 or 2.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which
A is
Figure imgf000035_0001
R1 is CI, F, trifluoromethyl, 3-f uoropropyl, methoxy, 3-ethoxypropyl, 3- methoxypropyl, 3-propoxypropyl, 4-ethoxybutyl, 3-hydroxypropyl, 4-hydroxybutyl, 3- hydroxy-3-methylbutyl, cyanomethyl, cyanoethyl, 3-Cyanopropyl, pyridin-3-ylmethoxy, 4- (N-ethylamino-4-oxo)butyl, 3-amino-3-oxopropyl, 3-(7V-ethyl-3-oxo)propyl, 3-amino-3- oxopropyl, 3-(2-methoxyethoxy)propyl, 3-(2-ethoxyethoxy)propyl, 3-
(cyclopropylmethoxy)propyl, 3-(benzyloxy)propyl, 4-(pyrazin-2-yloxy)butyl, 3-((6- chloropyridin-3-yl)oxy)propyl, 3-((6-methylpyridin-3-yl)oxy)propyl, 3-((2-methylpyridin-3- yl)oxy)propyl, 3-((4-methylthiazol-2-yl)methoxy)propyl, 3-(2,6-Dichlorophenoxy)propyl, 3- ((2-methylpyridin-3-yl)oxy)propyl, 3-(pyridin-4-yloxy)propyl, 3-(2-Chlorophenoxy)propyl, 3-(3-methoxyphenoxy)propyl, 3-(2,6-Difluorophenoxy)propyl, 3-((5-Fluoropyridin-3- yl)oxy)propyl, 3-((5-Cyanopyridin-3-yl)oxy)propyl, (pyridin-3-yloxy)methyl, 3-(pyridin-3- yloxy)propyl, 3-(pyrazin-2-yloxy)propyl), 3-(diethylamino)propyl, 3-Aminopropyl, 3- isobutyramidopropyl, 2-isobutyramidoethyl, 3-(l-methylethylsulfonamido)propyl, 3-(l-H- imidazol-l-yl)propyl, 6-(propoxypyridin-3-yl)ethyl, 3-(lH-l,2,3-triazol- l-yl)propyl, 3-(2- methyl- lH-imidazol- 1 -yl)propyl, 4-(2-methyl- lH-imidazol- 1 -yl)butyl, 3-(3-methyl- 1H- pyrazol- l-yl)propyl, 3-(4-methyl- lH-pyrazol- l-yl)propyl, 3-(lH-pyrazol- l-yl)propyl, 3-(lH- l,2,4-triazol-l-yl)propyl, 2-(pyridin-3-yl)ethyl, 2-(pyridin-4-yl)ethyl, 2-(pyridin-2-yl)ethyl, 3- (2H-tetrazol-2-yl)propyl, 2-(thiazol-2-yl)ethyl, 3-(lH-tetrazol-l-yl)propyl, 3- morpholinopropyl, 4-carbamoylpiperidin-l-ylpropyl, 4-ethoxypiperidin- l-ylpropyl, 1 -acetyl piperidin-4-yl, 4-cyanophenyl, 4-Carbamoylphenyl, 3-Carbamoylphenyl, 4-Carbamoyl-3- fluorophenyl, 4-Carbamoyl-3,5-difluorophenyl, 4-Carbamoyl-3-chlorophenyl, 4-Carbamoyl- 3-methylphenyl, 6-methoxypyridin-3-yl, 6-carbamoylpyridin-3-yl, 6-propoxypyridin-3-yl, 6- chloropyridin-3-yl, 6-hydroxypyridin-3-yl, 2-carbamoylpyrimidin-5-yl, 6-cyanopyridin-3-yl, pyridin-4-yl, pyridin-3-yl, pyrimidin-5-yl or 1 -methyl- lH-pyrazol-4-yl,
R is CI, F, methoxy, ethoxymethyl, propoxymethyl, CF3, fluoromethyl, difluoromethyl, pyrrolidin- l-ylmethyl or 2-(methoxyethoxy)methyl,
m is 0, 1 or 2, and
n is 0, 1 or 2. 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, preferably, less than 100 nM, more preferably, less than 50 nM with respect to GSNOR inhibitory activity.
Compounds of the present invention include the compounds in Examples 1-159.
It should be understood that the formulas (I), (la) and (lb) 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 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 "C1-6 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 "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_io alkynyl). Non-limiting examples of alkynyl groups include ethynyl, propynyl, and butynyl.
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 "alkoxyalkyl" or "alky loxy alky 1" 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-galkyloxyCi-galkyl). 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 "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 Cs-gcycloalkenylCi-galkyl. 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 substituted or unsubstituted non-aromatic 3 to 15 membered ring radical (i.e. 3 to 15 membered heterocyclyl) which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur. The heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. 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-galkyl). 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 substituted or unsubstituted
5 to 14 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S (i.e. 5 to 14 membered heteroaryl). The heteroaryl may be a mono-, bi- or tricyclic ring system. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. 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 "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, Formula II or Formula III, 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) and formula (lb) and specific examples can be prepared using techniques known to one skilled in the art through the reaction sequences depicted in schemes 1-7, 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 alkyne compounds of the general formula (la') and (lb') is depicted in scheme 1, wherein R1, R2, Ra, m and n are as defined in formula (I). Schem
Figure imgf000048_0001
Figure imgf000048_0002
7)
Figure imgf000048_0003
(la) (lb')
The compounds of general formula (la') and (lb') can be prepared as described in scheme 1. Thus, the compound of general formula (1) undergoes reduction in presence of suitable reagent to give compound of formula (2). The reaction may be carried out in presence of iron and cone. HC1 or Pd/C. The solvent may be an alcohol. The alcoholic solvent may be methanol. The Compound of formula (2) is converted to the compound of formula (3). The reaction is carried out by using potassium iodide in presence of an acid and a suitable oxidizing agent. The acid may be /?-toluenesulfonic acid. The oxidizing agent may be NaN02. The reaction may be carried out in a suitable solvent. The suitable solvent may be acetonitrile. The compound of formula (3) is reacted with a suitable alkynylating agent to give compound of formula (4). The alkynylating agent may be trimethylsilyl acetylene. The reaction may be carried out in presence of a suitable palladium catalyst. The palladium catalyst may be bis(triphenylphosphine)palladium(II) dichloride. The reaction may be carried out in presence of a suitable coupling agent. The coupling agent may be Cul. The reaction may be carried out in presence of a suitable base. The base may be triethylamine, di-isopropyl ethylamine or combination thereof. The reaction may be carried out in a suitable solvent. The suitable solvent may be DMSO. The ocmpound of formula (4) is then reacted with a suitable phenol derivative of formula (5) (wherein X is a halogen) to form compound of formula (6). The reaction may be carried out in presence of a base. The base may be aq. ammonia. The reaction may be carried out in presence of a suitable palladium catalyst. The palladium catalyst may be bis(triphenylphosphine)palladium(II) dichloride. The reaction may also involve a suitable coupling agent. The coupling reagent may be Cul. The reaction may be carried out in a suitable solvent. The suitable solvent may be THF. The compound of formula (6) on alkaline hydrolysis gives the compound of formula (7). The reaction may be carried out in presence of a suitable base. The base may be aq. NaOH. The reaction may be carried out in a suiatble solvent. The suitable solvent may be analcohol. The alcoholic solvent used for the reaction may be ethanol. The compound of formula (7) on esterification gives the compound of formula (la'). The esterification may be carried out in presence of an acid. The acid may be selected from hydrochloric acid and sulphuric acid. The reaction may be carried out in a suitable solvent. The solvent may be selected from ethanol or methanol.
Similarly, Alkyne nitrile compound of formula (4) is reacted with the compound of formula (8) (wherein X is a halogen) to give the compound of formula (9). The reaction may be carried out in presence of a base. The base may be aq. ammonia. The reaction may be carried out in presence of a suitable palladium catalyst. The palladium catalyst may be bis(triphenylphosphine)palladium(II) dichloride. The reaction may be carried out in presence of a coupling agent. The coupling agent may be Cul. The reaction may be carried out in a suitable solvent. The solvent used for the reation may be THF. The compound of formula (9) on alkaline hydrolysis yields the compound of formula (10). The reaction may be carried out by using a suitable base. The base may be aq. NaOH. The reaction may be carried out in a suitable solvent. The suitable solvent may be ethanol. The compound of formula (10) further undergoes esterification to give the compound of formula (lb'). The esterification reaction may be carried out in the presence of an acid. The acid may be selected from hydrochloric acid and sulphuric acid. The reaction may be carried out in a suitable solvent. The suitable solvent may be selected from ethanol and methanol.
Alkyne compounds of the general formula (la') can also be prepared by using a general approach as depicted in scheme 2 and scheme 3 wherein R1, R2, Ra, m and n are as defined in formula (I). cheme 2:
Figure imgf000050_0001
The compound of formula (la') is also prepared from 4-amino benzoate derivative of formula (11) (wherein Ra is hydrogen, Ci_8alkyl, -(CH2)xC(0)NRbRc or -(CH2)xNRbRcRc ^ in a same manner as depicted in scheme 1. Thus, the compound of formula (13) is reacted with the compound of formula (5) to give the compound of formula (la'). The reaction may be carried out in presence of a base. The base may be aq. ammonia. The reaction may be carried out in presence of a suitable palladium catalyst. The palladium catalyst may be bis(triphenylphosphine)palladium(II) dichloride. The reaction may also involve a suitable coupling agent. The coupling reagent may be Cul. The reaction may be carried out in the presence of suitable solvent. The suitable solvent may be THF. The compound of formula (la') on alkaline hydrolysis gives the compound of formula (7). The reaction may be carried out using a suitable base. The base may be aq. NaOH. The reaction may be carried out in a suitable alcoholic solvent. The solvent may be ethanol.
A general approach for the preparation of alkyne compounds of the general formula (la') is depicted in scheme 3, wherein R1, R2, Ra m and n are as defined in formula (I).
Scheme 3:
Figure imgf000051_0001
(la') 4- nitrophenol compound of formula (14) is reacted with methanesulfonyl chloride to give the compound of formula (15). The reaction may be carried out in the presence of a base. The base may be triethylamine. The reaction may be carried out in a suitable solvent. The solvent may be dichloromethane. The compound of formula (15) is hydrogenated to give the compound of formula (16). The reaction may be carried out in presence of a suitable palladium catalyst. The palladium catalyst may be Pd/C. The reaction may be carried out in a suitable alcoholic solvent. The solvent may be ethanol. The compound of formula (16) is further reacted with a suitable reagent to give compound of formula (17). The reaction may be carried out using potassium iodide. The reaction may be carried out in presence of an acid. The acid may be H2S04. The reaction may be carried out by using an oxidizing agent. The oxidizing agent may be NaN02. The reaction may be carried out in a suitable solvent. The solvent may be acetonitrile. The compound of formula (17) is reacted with an alkyne compound of formula (4) to give the compound of formula (6). The reaction may be carried out in presence of a base. The base may be TBAF. The reaction may be carried out in a suitable palladium catalyst. The palladium catalyst may be bis(triphenylphosphine)palladium(II) dichloride. The compound of formula (6) on alkaline hydrolysis yields the compound of formula (7). The reaction may be carried out using a suitable base. The base may be aq. NaOH. The reaction may be carried out in a suitable solvent. The solvent may be ethanol. The compound of formula (7) further undergoes esterification to give compound of formula (la'). The reaction is carried out in presence of an acid. The acid may be such as hydrochloric acid or sulphuric acid. The reaction may be carried out in a suitable solvent. The solvent may be ethanol or methanol. Alkyne compounds of the general formula (Ic') and (Ic") can be prepared by using a general approach as depicted in scheme 4A and scheme 4B wherein R1, R2, R4, Ra, r, m and n are as defined in formula (I).
Scheme 4 A:
Figure imgf000052_0001
<22> (21 )
4-amino benzoate derivative of formula (11) is halogenated to give the compound of formula (18). The reaction may be carried out using a suitable halogenating agent. The halogenating agent may be N-bromosuccinamide. The reaction may be carried out in a suitable solvent. The solvent may be carbon tetrachloride, acetonitrile or mixture thereof. The compound of formula (18) is further reacted with suitable boronic acids of formula (19) (wherein W is CH, N or CR4 and r is 0 to 4) to give the compound of formula (20). The reaction may be carried out in presence of suitable palladium catalyst. The palladium catalyst may be Fd(dppf)C . The reaction may be carried out in a suitable base. The base may be potassium carbonate. The reaction may be carried out in a suitable solvent. The solvent may be diglyme. The compound of formula (20) is further reacted with suitable reagents to give the compound of formula (21). The reaction may be carried out using potassium iodide. The reaction may be carried out in presence of an acid. The acid may be H2S04. The reaction may be carried out in presence of an oxidizing agent. The oxidizing agent may be NaN02. The reaction may be carried out in a suitable solvent. The solvent may be acetonitrile. The compound of formula (21) on alkynylation gives the compound of formula (22). The reaction may be carried out using a suitable alkynylating agent. The alkynylating agent may be trimethylsilyl acetylene. The reaction may be carried out in presence of a suitable palladium catalyst. The palladium catalyst may be Bis(triphenylphosphine)palladium(II) dichloride. The reaction may be carried out in presence of a coupling agent. The coupling agent may be Cul. The reaction may be carried out in presence of a base. The base may be triethylamine. The reaction may be carried out in a suitable solvent. The solvent may be DMSO.
Scheme
Figure imgf000053_0001
ec") ec')
The compound of formula (17) is further converted to the compound of formula (23) by reacting it with an ester derivative of formula (22) (wherein W is CH, N or CR4 and r is 0 to 4). The reaction may be carried out in presence of a base. The base may be TBAF. The reaction may be carried out using a suitable palladium catalyst. The palladium catalyst may be bis(triphenylphosphine)palladium(II) dichloride. The reaction may be carried out in a suitable solvent. The solvent may be DMSO. The compound of formula (23) is converted to the compound of formula (Ic') by using a suitable hydrolysing agent. The hydrolyzing agent may be hydrogen peroxide. The reaction may be carried out in presence of a base. The base may be potassium carbonate. The reaction is carried out in a suitable solvent. The solvent may be DMSO. The compound of formula (Ic') on reaction with lithium hydroxide in a suitable solvent gives the compound of formula (Ic"). The reaction may be carried out in a suitable solvent. The suitable solvent may be tetrahydrofuran and water.
Alkyne compounds of the general formula (Ic') and (Ic") can also be prepared by using a general approach as depicted in scheme 5A and scheme 5B wherein R 1 , R2 , R 4 , r, m and n are as defined in formula (I).
Scheme 5A:
Figure imgf000053_0002
Compound of formula (24) can be prepared from compound of formula (17) as per the process described for the preparation of compound formula (4)from compound formula (3) described in scheme- 1.
Scheme 5B:
Figure imgf000054_0001
The compound of formula (18) is reacted with corresponding boronic acids of formula (25) (wherein W is CH, N or CR4 and r is 0 to 4) to give the compound of formula (26). The reaction is carried out in presence of suitable palladium catalyst. The palladium catalyst may be \' \ !ppj) \ The reaction is carried out in presence of a base. The base may be potassium carbonate. The reaction may be carried out in a suitable solvent. The solvent may be diglyme. The compound of formula (26) is reacted with suitable reagents to give the compound of formula (27). The reaction may be carried out by using potassium iodide. The reaction may be carried out in presence of an acid. The acid may be H2S04. The reaction may be carried out using an oxidizing agent. The oxidizing agnet may be NaN02. The reaction may be carried out in a suitable solvent. The solvent may be acetonitrile. The compound of formula (27) is further treated with hydroxyl amine hydrochloride to give the compound of formula (21). The reaction may be carried out in a suitable solvent. The solvent may be DMSO. The compound of formula (21) is reacted with a compound of formula (24) to give compound of formula (23). The reaction may be carried out in presence of a base. The base may be TBAF. The reaction may be carried out in presence of a suitable palladium catalyst. The palladium catalyst may be bis(triphenylphosphine)palladium(II) dichloride. The reaction may be carried out in a suitable solvent. The solvent may be DMSO. Compound of formula (23) is further converted to compound of formula (Ic') by using a hydrolysing agent. The hydrolyzing agent may be hydrogen peroxide. The reaction may be carried out in presence of a base. The base may be potassium carbonate. The reaction may be carried out in a suitable solvent. The solvent may be DMSO. Compound of formula (Ic') on reaction with lithium hydroxide in a suitable solvent system yields compound of formula (Ic"). The solvent may be tetrahydrofuran and water.
A general approach for the preparation of alkyne compounds of the general formula (la') is depicted in scheme 6, wherein R1, R2, Ra, m and n are as defined in formula (I).
Scheme 6:
Figure imgf000055_0001
(F?i )m R,)n
OH The compound of formula (3) is reacted with an acetylene derivative of formula (24) to form the compound of formula (6). The reaction may be carried out in presence of a base. The base may be TBAF. The reaction may be carried out using a suitable palladium catalyst. The palladium catalyst may be bis(triphenylphosphine)palladium(II) dichloride. The reaction may be carried out in a suitable solvent. The solvent may be DMSO. Compound of formula (6) is converted to compound of formula (7) by using a suitable hydrolysing agent. The suitable hydrolyzing agent may be a base. The base may be NaOH. Compound of formula (7) is converted to compound of formula (la') by reacting it with a suitable alcohol. The reaction may be carried out in presence of an acid. The acid may be such as hydrochloric acid or sulphuric acid.
A general approach for the preparation of alkyne compounds of the general formula
(la') is depicted in scheme 7, wherein R 1 , R 2 , m and n are as defined in formula (I). Scheme 7:
Figure imgf000056_0001
The compound of formula (3) is reacted with an acetylene derivative of formula (24) to obtain compound of formula (6). The reaction may be carried out in presence of a base. The base may be TBAF. The reaction may be carried out using a suitable palladium catalyst. The palladium catalyst may be bis(triphenylphosphine)palladium(II) dichloride. The reaction may be carried out in a suitable solvent. The solvent may be DMSO. The compound of formula (6) is further reacted with an azide to obtain the compound of formula (la"). The azide may be sodium azide. The reaction may be carried out in presence of a base. The base may be ammonium chloride or triethyl ammonium chloride. The reaction may be carried out in a suitable solvent. The solvent may be DMF. The reaction may be carried out at a suitable temperature. The suitable temperature may range from 0 to 150°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: AIBN Azobisisobutyronitrile; BOC: N-tert-butoxycarbonyl; CDC13: Deuterated chloroform; CH3I: Methyl iodide; m-CPBA: meta-Chloroperoxybenzoic acid; CuCN: Copper(I) cyanide; Cul: Copper(I) iodide; DAST: Diethylamino sulfur trifluoride; DCM: Dichloromethane; DIPEA: Ν,Ν-Diisopropylethylamine; DMF: Dimethylformamide; DMSO: Dimethyl sulfoxide; DMSO-i : Hexadeuterodimethyl sulfoxide; EDTA: Ethylenediaminetetraacetic acid; Et3N: Triethylamine; EtOAc: Ethyl acetate; EtOH: Ethanol; HC1: Hydrochloric acid; HN03: Nitric acid; K2C03: Potassium carbonate; KI: Potassium iodide; H20: Water; H202: Hydrogen peroxide; H2S04: Sulfuric acid; LiOH: Lithium hydroxide; LiOH.H20: Lithium hydroxide monohydrate; MeOH: Methanol; NaBH4: Sodium borohydride; NaBr Sodium bromide; NaHC03: Sodium bicarbonate; NaN02: Sodium nitrite; NaOH: Sodium hydroxide; NaOMe: Sodium methoxide; Na2S04: Sodium sulfate; NaH: Sodium hydride; NH2OH.HCl: Hydroxylamine hydrochloride; NH3: Ammonia; NH4OH: Ammonium hydroxide; NaHS03: Sodium bisulfite; Pd: Palladium; Pd/C: Palladium on carbon; Pd/CaC03: palladium deposited on calcium carbonate; PdCl2(PPh3)2: Bis(triphenylphosphine)palladium(II) dichloride; Pd(dppfiC : [1, 1 '-
Bis(diphenylphosphino)ferrocene]dichloropalladium(II); PCC: Pyridinium chlorochromate; psi: pound-force per square inch; TEA: Triethylamine; TBAF: Tetra-n-butylammonium fluoride; TBAI Tetrabutylammonium iodide; THF: Tetrahydrofuran; THF:MeOH: Tetrahydrofuran: Methanol; dil.: Dilute; aq.: Aqueous; cone: Concentrated; g: Gram; mg: Milligrams; mL: Milliliter; mmol: Millimoles; mol: mole; mins: Minutes; °C: Degree Celsius; h: Hours; M: Molar; N: Normal; 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.
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
3-Fluoro-4-((4-hydroxyphenyl)ethynyl)benzonitrile
Figure imgf000057_0001
Step- 1 : -Preparation of 4-amino- -fluorobenzonitrile
Figure imgf000057_0002
To a solution of 3-fluoro-4-nitrobenzonitrile (5.0 g, 0.030 mmol) in MeOH (50 mL) were added iron powder (5 g) and conc.HCl (20 mL). The reaction mass was stirred at RT for 2 h. The reaction mass was filtered. The filtrate was concentrated and then diluted with water, extracted with EtOAc and basified with 10% NaHC03 solution. The organic portion was dried over Na2S04 and concentrated to afford 4.5 g of the title product.1H NMR (300 MHz, DMSO-d6): δ 7.52-7.48 (d, J = 11.7 Hz, 1H), 7.31-7.29 (d, = 8.1 Hz, 1H), 6.82.-6.76 (d, = 8.7 Hz, 1H), 6.24 (s, 2H).
Stej 2: -Preparation of 3-fluoro- -iodobenzonitrile
Figure imgf000058_0001
A mixture of 4-amino-3-fluorobenzonitrile (5.0 g, 36.76 mmol) and /?-toluenesulfonic acid (20.0 g, 105.2 mmol) in acetonitrile (50 mL) was stirred at RT for 4 h. Then aq. solution of NaN02 (3.8 g, 55.07 mmol) and KI (9.15 g, 55.07 mmol) were added at 0°C and stirred further for lh. After the reaction completion, the reaction mixture was quenched with water, washed with an aqueous solution of NaHS03 and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2S04 and concentrated to afford 4.0 g of the title product. 1H NMR (300 MHz, CDClj): δ 7.94-7.89 (t,
1H), 7.21-7.19 (d, = 8.1 Hz, 1H).
Stej 3: -Preparation of 4-ethyny -3-fluorobenzonitrile
Figure imgf000058_0002
A mixture of 3-fluoro-4-iodobenzonitrile (1.0 g, 4.06 mmol), trimethylsilyl acetylene (0.595 g, 6.07 mmol), Cul (50 mg, 0.26 mmol), PdCl2(PPh3)2 (50 mg, 0.071 mmol) and TEA (3 mL) in DMSO (7 mL) was stirred at RT for 16 h. After the reaction, the reaction mixture was quenched with water, extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2S04 and concentrated to afford 750 mg of crude 2-chloro-5-((trimethylsilyl)- ethynyl) benzoate. To this crude solution of 2-chloro-5-((trimethylsilyl)ethynyl)benzoate (500 mg, 1.87 mmol) in DCM (10 mL) was added TBAF (1.0 g, 3.83 mmol) and stirred further at RT for ½ h. Then the reaction mixture was quenched with water, extracted with DCM, washed with water, brine, dried over Na2S04 and concentrated to afford 450 mg of the title product. 1H NMR (300 MHz, CDC13): δ 7.61-7.56 (t, = 7.2 Hz, 1H), 7.44-7.38 (d, = 8.1 Hz, 2H), 3.52(s, 1H).
S tep-4 : -Preparation of 3-fluoro-4-((4-hydroxyphenyl)ethynyl)benzonitrile
To a mixture of 4-ethynyl-3-fluorobenzonitrile (100 mg, 0.689 mmol) and 4-iodophenol (151 mg, 0.689 mmol) in THF (5.0 mL) were added aq. NH3 (2.0 ml), PdCl2(PPh3)2 (25 mg, 0.03 mmol), Cul (10 mg, 0.052 mmol). The reaction mass was stirred at RT for 2h. The reaction mixture was quenched with water, extracted with EtOAc, washed with water, brine, dried over Na2S04 and concentrated to afford 60 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 10.1 1 (s, 1H), 7.72 (m, 2H), 7.42-7.40 (d, = 8.4 Hz, 2H), 6.82-6.80 (d, = 7.8 Hz, 2H).
Intermediate-2
4-((4-(lH-imidazol- l-yl)phenyl)ethynyl)-3-fluorobenzonitrile
Figure imgf000059_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-fluorobenzonitrile (step-3 of Intermediate- 1, 100 mg, 0.689 mmol), 1- (4-iodophenyl)-lH-imidazole (186 mg, 0.689 mmol), THF (5.0 mL), aq.NH3 (2.0 ml), PdCl2(PPh3)2 (25 mg, 0.03 mmol), Cul (10 mg, 0.052 mmol) to afford 50 mg of the title product. 1H NMR (300 MHz, DMSO-i¾: δ 8.41 (m, 1H), 8.06 (m, 1H), 7.77 (m, 3H), 7.47- 7.15 (m, 5H)
Intermediate-3
3-Chloro-4-((4-hydroxyphenyl)ethynyl)benzonitrile
Figure imgf000059_0002
Step- 1 : -Preparation of 3-chloro- -iodobenzonitrile
Figure imgf000059_0003
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using 4-amino-3-chlorobenzonitrile (3.0 g, 19.66 mmol), /?-toluenesulfonic acid (11.20 g, 55.98 mmol), acetonitrile (30 mL), aq.NaN02 (2.03 g, 29.49 mmol in 7 mL water) and KI (4.89 g, 29.49 mmol) to afford 4.0 g of the title product. 1H NMR (300 MHz, CDClj): δ 8.02- 7.99 (d, 7 = 8.4 Hz, 1H), 7.71 (s, 1H), 7.23-7.21 (d, J = 8.1 Hz, 1H).
S_tej 2: -Preparation of 4-ethyny -3-chlorobenzonitrile
Figure imgf000059_0004
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 3-chloro-4-iodobenzonitrile (4.0 g, 23.12mmol), trimethylsilyl acetylene (3.39g, 34.68mmol ), Cul (87.8 mg, 0.46 mmol), PdCl2(PPh3)2 (324.1 mg, 0.46 mmol), DIPEA (5 mL), TBAF (10.92g, 34.68 mmol) in DMSO (15.0 mL) to afford 1.6 g of title product. 1H NMR (300 MHz, CDC13): δ 7.71 (s, 1H), 7.64-7.61 (d, = 8.4 Hz, 1H), 7.53-7.50 (d, = 8.1Hz, 1H), 3.67(s, 1H).
Stej 3: -Preparation of 3-Chloro-4-((4-hydroxyphenyl)ethynyl)benzonitrile
Figure imgf000060_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-chlorobenzonitrile (100 mg, 0.621 mmol) and 4-iodophenol (136 mg, 0.621 mmol), PdCl2(PPh3)2 (8.7 mg, 0.01 mmol), TBAF (586 mg, 1.86 mmol) in DMSO (2.0 mL) at 100 °C for 1 h to afford 70 mg of the title crude product, which was carried forward to the next step without any purification.
Intermediate-4
Methyl 4-((4-hydroxyphenyl)ethynyl)-3-methoxybenzoate
Figure imgf000060_0002
Step- 1 : -Preparation of methyl 4-iodo-3-methoxybenzoate
Figure imgf000060_0003
To an aqueous solution of methyl 4-amino-3-methoxybenzoate (10 g, 50 mmol) maintained in an ice-bath was added 20% sulphuric acid (30 ml). The reaction mass was stirred for 10 mins. Then aq. NaN02 (4.19 g, 60 mmol) was added drop wise to the reaction mixture and stirred at 0°C for 1 h. Urea (0.99 g, 16 mmol) was then added lot wise to the reaction mixture and stirred at 0°C for 15 mins. Then aq. KI (9.6 g, 58 mmol) was added drop wise to the reaction mixture and stirred at 0 °C for 1 h. The reaction mixture was further heated to 55 °C for 2 h. The reaction mass was quenched with water, extracted with EtOAc and the organic layer was separated, washed with water, sodium thiosulphate, dried over Na2S04 and concentrated to afford 10 g of the title product which was carried forward to the next step. 1H NMR (300 MHz, CDClj): δ 7.84 (d, = 7.8 Hz, 1H), 7.44 (s, 1H), 7.35 (d, = 7.8 Hz, 1H), 3.93 (s, 3H), 3.91 (s, 3H).
S_tej 2: -Preparation of methyl 4-ethynyl-3-methoxybenzoate
Figure imgf000060_0004
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using methyl 4-iodo-3-methoxybenzoate (4.0 g, 13 mmol), trimethylsilyl acetylene (2.7 g, 27 mmol), Cul (52 mg, 0.20 mmol), PdCl2(PPh3)2 (192 mg, 0.2 mmol), TEA (5-10mL) in DMSO (25 mL) to afford crude silyl compound. K2C03 (2.3 g, 19 mmol) was added to this crude compound in THF/MeOH (1: 1 ratio, 20 + 20 mL) and stirred further at RT for 1-2 h. Then the reaction mixture was quenched with water, extracted with DCM, washed with water, brine, dried over Na2S04 and concentrated to afford 2.0 g of the title product. 1H NMR (300 MHz, CDClj): δ 7.49-7.61 (m, 3H), 3.95 (s, 3H), 3.92 (s, 3H), 3.45 (s, 1H).
Stej 3: -Preparation of methyl 4-((4-hydroxyphenyl)ethynyl)-3-methoxybenzoate
Figure imgf000061_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using methyl 4-ethynyl-3-methoxybenzoate (200 mg, 1.05 mmol), 4-iodophenol (231 mg, 1.05 mmol), PdCl2(PPh3)2 (7.3 mg, 0.01 mmol), TBAF (663 mg, 2.10 mmol) in DMSO (2.0 mL) to afford 70 mg of the title product after column chromatography. 1H NMR (300 MHz, CDClj): δ 7.61 (d, = 7.8 Hz, 1H), 7.44- 7.55 (m, 4H), 6.81 (d, = 8.4 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H). MS [M+H]+: 283.32
Intermediate-5
-ethynylbenzonitrile
Figure imgf000061_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-iodobenzonitrile (6.0 g, 26 mmol), trimethylsilyl acetylene (5.13 g, 52 mmol), Cul (lOmg, 0.0005 mmol), PdCl2(PPh3)2 (367 mg, 0.0005 mmol), TEA (5-10mL) in DMSO (25 mL) at RT for 16 h to afford crude silyl compound. K2C03 (5.43 g, 39 mmol) was added to the crude compound in THF/MeOH (1: 1 ratio, 20+20 mL) and stirred further at RT for 1-2 h. Then the reaction mixture was quenched with water, extracted with DCM, washed with water, brine, dried over Na2S04 and concentrated to afford 1.80 g of title product. 1H NMR
(300 MHz, CDClj ): δ 7.56-7.63 (m, 4H), 3.30 (s, 1H).
Intermediate-6
3 -fluoro-4-iodophenyl methanesulfonate
Figure imgf000062_0001
Step- 1 : -Preparation of 3-fluoro-4-nitrophenyl methanesulfonate
Figure imgf000062_0002
To a mixture of 3-fluoro-4-nitrophenol (3.0 g, 19 mmol) and TEA (2.9 ml, 20 mmol) in DCM (50 mL) was added methanesulfonyl chloride (1.56 ml, 20 mmol) under nitrogen atmosphere at 0 °C. The reaction mass was allowed to come at RT and stirred further for 1 h. The reaction mixture was quenched with water, extracted with EtOAc and the organic layer was separated, washed with water, dilute HCl, dried over Na2S04 and concentrated to afford 4.0 g of the title product. 1H NMR (300 MHz, CDClj): δ 8.18 (t, J = 8.7 Hz, 1H), 7.24- 7.31 (m, 2H), 3.20 (s, 3H).
S_tej 2: -Preparation of 4-amino-3-fluorophenyl methanesulfonate
Figure imgf000062_0003
To a solution of 3-fluoro-4-nitrophenyl methanesulfonate (4.0 g, 17 mmol) in ethyl acetate and EtOH (1: 1 ratio, 100+100 ml) was added 10% Pd/C (400 mg) and the reaction mass was hydrogenated at 70 psi for 2-3 h. The reaction mixture was then filtered through celite pad, quenched with water, extracted with EtOAc and the organic layer was separated, dried over Na2S04 and concentrated to afford 3.2 g of the title product. 1H NMR (300 MHz, DMSO-d6): 5 7.11 (d, = 9.6 Hz, 1H), 6.91(d, = 8.7 Hz, 1H), 6.81(t, = 9.3 Hz, 1H), 4.71 (bs, 2H), 3.29 (s, 3H).
S_tej 3: -Preparation of 3-fluoro-4-iodophenyl methanesulfonate
Figure imgf000062_0004
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using 3-fluoro-4-aminophenyl methanesulfonate (2.0 g, 9.75 mmol), ice (5.7 g), aq. NaN02 (1.21 g, 17.56 mmol), Aq. KI (5.66 g, 34.14 mmol) and sulphuric acid (5.7 ml) in acetonitrile (5.7 ml) to afford 1.6 g of the title product. 1H NMR (300 MHz, CDClj): δ 7.80 (t, = 7.2 Hz, 1H), 7.06 (d, 7 = 8.1 Hz, 1H), 6.91 (d, = 9 Hz, 1H), 3.18 (s, 3H).
Intermediate-7
4-((2-fluoro-4-hydroxyphenyl)ethynyl)benzonitrile
Figure imgf000063_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 3-fluoro-4-iodophenyl methanesulfonate (Intermediate- 6, 367 mg, 1.17 mmol), 4- ethynylbenzonitrile (Intermediate-5, 150 mg, 1.17 mmol), TBAF (367 mg, 1.4 mmol), PdCl2(PPh3)2 (16.4 mg, 0.023 mmol) in DMSO to afford 100 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.58 (s, 1H), 7.87 (d, = 7.8 Hz, 2H), 7.68 (d, = 8.4 Hz, 2H), 7.47 (t, = 8.4 Hz, 1H), 6.68 (m, 2H).
Intermediate- 8
3-fluoro-4-((2-fluoro-4-hydroxyphenyl)ethynyl)benzonitrile
Figure imgf000063_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-fluorobenzonitrile (step-3, Intermediate- 1, 150 mg, 1.03 mmol), 3- fluoro-4-iodophenyl methanesulfonate (Intermediate- 6, 324 mg, 1.03 mmol), TBAF (323 mg, 1.24 mmol), PdCl2(PPh3)2 (14.5 mg, 0.02 mmol) in DMSO to afford 100 mg of the title product H NMR (300 MHz, DMSO- 6): δ 10.65 (br, 1H), 7.98 (d, = 9.9 Hz, 1H), 7.75-7.78 (m, 2H), 7.47 (t, = 8.1 Hz, 1H), 6.70 (m, 2H); MS [M-H]~: 254.31.
Intermediate-9
4-iodo-3-(trifluoromethyl)phenyl methanesulfonate
Figure imgf000063_0003
Step- 1 : -Preparation of 4-nitro-3-(trifluoromethyl)phenyl methanesulfonate
Figure imgf000063_0004
The title compound was prepared following the procedure described in step-1 of Intermediate- 6 by using 4-nitro-3-(trifluoromethyl)phenol (4.0 g, 19 mmol), methansulfonyl chloride (1.58 ml, 20 mmol), TEA (2.9 ml, 20 mmol) and DCM (50.0 mL) to afford 4.0 g of the title product. 1H NMR (300 MHz, CDClj): δ 8.01 (d, = 9.6 Hz, 1H), 7.66-7.72 (m, 2H), 3.31 (s, 3H).
Stej 2: -Preparation of 4-amino-3-(trifluoromethyl)phenyl methanesulfonate
Figure imgf000064_0001
The title compound was prepared following the procedure described in step-2 of Intermediate- 6 by using 4-nitro-3-(trifluoromethyl)phenyl methanesulfonate (4.0 g, 18.0 mmol), ethyl acetate and EtOH (1: 1 ratio, 100+100 ml), 10% Pd/C (500 mg) to afford 4.0 g of the crude title product which was used in the next step without any purification.
Stej 3: -Preparation of 4-iodo-3-(trifluoromethyl)phenyl methanesulfonate
Figure imgf000064_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-amino-3-(trifluoromethyl)phenyl methanesulfonate (4.0 g, 15.6 mmol), ice (12 g) and sulphuric acid (12 ml), aq. NaN02 (1.94 g, 28.23 mmol), aq. KI (9.11 g, 54.90 mmol) to afford 1.8 g of the title product. 1H NMR (300 MHz, CDClj): δ 8.06 (d, = 8.7 Hz, 1H), 7.55 (s, 1H), 7.18 (m, 1H), 3.21 (s, 3H).
Intermediate- 10
4-((4-hydroxy- -(trifluoromethyl)phenyl)ethynyl)benzonitrile
Figure imgf000064_0003
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-iodo-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-9, 428 mg, 1.17 mmol), 4-ethynylbenzonitrile (Intermediate- 5, 150 mg, 1.17 mmol), TBAF (367 mg, 1.4 mmol), PdCl2(PPh3)2 (10 mg, 0.023 mmol) in DMSO to afford 120 mg of the title product. 1H
NMR (300 MHz, DMSO- 6): δ 10.77 (br, 1H), 7.89 (d,
7.17 (s, 1H), 7.08 (d, = 8.4 Hz, 1H); MS [M-H]~: 286.38. Intermediate- 11
3-fluoro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzonitrile
Figure imgf000065_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-iodo-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-9, 0.252 g, 0.68 mmol), 4-ethynyl-3-fluorobenzonitrile (step-3, Intermediate- 1, 0.100 g, 0.68 mmol), TBAF (0.216 g, 0.82 mmol), PdCl2(PPh3)2 (0.009 g, 0.01 mmol) in DMSO to afford 0.075 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.84 (s, 1H), 7.99 (d, = 9.9 Hz, 1H), 7.75 (s, 2H), 7.67 (d, J = 8.7 Hz, 1H), 7.17 (s, 1H), 7.09 (d, J = 9 Hz, 1H); MS [M-H]~: 304.49.
Intermediate- 12
3 -chloro-4-iodophenyl methanesulfonate
Figure imgf000065_0002
Step- 1 : -Preparation of 4-nitrophenyl methanesulfonate
Figure imgf000065_0003
The title compound was prepared following the procedure described in step-1 of Intermediate- 6 by using 4-nitro phenol (4.0 g, 28 mmol), methansulfonyl chloride (2.35 ml, 30 mmol), TEA (4.35 ml, 30 mmol) and DCM (50.0 mL) to afford 4.2 g of the title product. 1H NMR (300 MHz, CDClj): δ 8.31 (d, J = 8.7 Hz, 2H), 7.46 (d, / = 8.7 Hz, 2H), 3.26 (s, 3H).
S_tej 2: -Preparation of 4-aminophenyl methanesulfonate
Figure imgf000065_0004
The title compound was prepared following the procedure described in step-2 of Intermediate- 6 by using 4-nitrophenyl methanesulfonate(5.0 g, 23 mmol), ethyl acetate and EtOH (100+100 ml 10% Pd/C (1.0 g) to afford 4.5 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 6.97-7.07 (m, 2H), 6.57-6.67 (m, 2H), 5.41 (bs, 2H), 3.23 (s, 3H).
S_tej 3: -Preparation of 4-amino-3-chlorophenyl methanesulfonate
Figure imgf000066_0001
To a solution of 4-aminophenyl methanesulfonate (1.0 g, 5.34 mmol) in dry DMF (10 ml) was added soln. of N-chlorosuccinamide in DMF (0.713 g, 5.34 mmol) at 0° C under inert atmosphere and reaction mass was stirred at RT for 16 h. The reaction mixture was quenched with water, extracted with EtOAc and organic layer was separated, dried over Na2S04 and concentrated to afford 0.500 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 7.24 (s, 1H), 7.03(d, J = 8.7 Hz, 1H),6.80 (d, J = 8.7 Hz, 1H), 5.55 (bs, 2H), 3.29 (s, 3H).
S tep-4 : -Preparation of 3-chloro-4-iodophenyl methanesulfonate
The title compound was prepared following the procedure described in step-2 of Intermediate- 6 by using 4-amino-3-chlorophenyl methanesulfonate (0.500 g, 2.26 mmol), ice (3 g), cone, sulphuric acid (3 ml), aq. NaN02 (0.280 g, 4.07 mmol), aq. KI (0.751 g, 4.52 mmol) to afford 0.300 g of the title product. 1H NMR (300 MHz, CDClj): δ 7.89 (d, = 8.7 Hz, 1H), 7.41 (s, 1H), 6.94 (d, = 8.1 Hz, lH), 3.18 (s, 3H).
Intermediate- 13
4-((2-chloro-4-hydroxyphenyl)ethynyl)-3-fluorobenzonitrile
Figure imgf000066_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 3-chloro-4-iodophenyl methanesulfonate (Intermediate- 12, 0.228 g, 0.68 mmol), 4- ethynyl-3-fluorobenzonitrile (step-3, Intermediate- 1, 0.100 g, 0.68 mmol), TBAF (0.216 g, 0.82 mmol), PdCl2(PPh3)2 (0.009 g, 0.01 mmol) in DMSO to afford 0.065 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.64 (s, 1H), 7.99 (d, = 9.3 Hz, 1H), 7.76-7.78 (m, 2H), 7.53 (d, = 8.1 Hz, 1H), 6.97 (s, 1H), 6.82 (d, = 8.4 Hz, 1H); MS [M-H]~: 270.61.
Intermediate- 14
3-Chloro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzonitrile
CF3 CI
H0 H^r CN
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-chlorobenzonitrile (step-2, Intermediate-3, 0.100 g, 0.62 mmol), 4- iodo-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-9, 0.227 g, 0.62 mmol), TBAF (0.194 g, 7.4 mmol), PdCl2(PPh3)2 (0.009 g, 0.01 mmol) in DMSO to afford 0.100 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.87 (bs, 1H), 8.21 (s, 1H), 7.87 (d, = 8.1 Hz, 1H), 7.77 (d, / = 8.1 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.19 (s, 1H), 7.1 l(d, J = 8.4 Hz, 1H); MS [M-H]": 320.35.
Intermediate- 15
3-Chloro-4-((2-fluoro-4-hydroxyphenyl)ethynyl)benzonitrile
Figure imgf000067_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-chlorobenzonitrile (step-2, Intermediate-3, 0.100 g, 0.62 mmol), 3- fluoro-4-iodophenyl methanesulfonate (Intermediate-6, 0.195 g, 0.62 mmol), TBAF (0.194 g, 7.4 mmol), PdCl2(PPh3)2 (0.009 g, 0.01 mmol) in DMSO to afford 0.085 g of the title product. 1H NMR (300 MHz, DMSO- 6): δ 10.67 (bs, 1H), 8.22 (s, 1H), 7.78-7.97 (m, 2H), 7.48 (t, J = 9.3 Hz, 1H), 6.70 (d, J = 9.6 Hz, 2H); MS [M-H]": 270.31.
Intermediate- 16
4-Iodo-3-methoxyphenyl methanesulfonate
Figure imgf000067_0002
Preparation 3 -methoxy-4-nitrophenol
Figure imgf000067_0003
To a solution of 3-fluoro-4-nitrophenol (3.0 g, 19.0 mmol) in methanol (50 mL) was added NaOMe (3.09 g, 57.32 mmol). The reaction mass was heated at reflux for 60 h. After the reaction completion, the reaction mass was concentrated, diluted with water, acidified with dil. HC1 and extracted with DCM. The organic portion was dried over Na2S04 and concentrated to afford 2.7 g of the title product.1H NMR (300 MHz, DMSO- 6): δ 10.90 (s, 1H), 7.89-7.86 (d, J = 9.3 Hz, 1H), 6.59 (s, 1H), 6.48-6.45 (d, J = 9.3 Hz, 1H), 3.86 (s, 3H); MS [M-H]": 168.07
Step-2:- Preparation 3-methoxy-4-nitrophenyl methanesulfonate
Figure imgf000067_0004
The title compound was prepared following the procedure described in step-1 of Intermediate-
6 by using 3-methoxy-4-nitrophenol (2.79 g, 15.97 mmol), dry DCM (30.0 mL), TEA (1.69 g,
16.7 mmol) and methanesulfonyl chloride (1.91 g, 16.77 mmol) to afford 2.5 g of the title product.1!! NMR (300 MHz, CDClj): δ 7.95-7.93 (d, J = 8.7 Hz, 1H), 7.04 (s, 1H), 6.97-6.94
(d, J = 9.0 Hz, 1H), 3.98 (s, 3H), 3.24 (s, 3H).
Step-3:- Preparation of 4-amino-3-methoxyphenyl methanesulfonate
Figure imgf000068_0001
The title compound was prepared following the procedure described in step-2 of Intermediate- 6 by using 3-methoxy-4-nitrophenyl methanesulfonate (2.5 g, 10.10 mmol), ethyl acetate and EtOH (1: 1 ratio, 50+50 ml), 10% Pd/C (300 mg) to afford 2.0 g of the of the title product. 1H NMR (300 MHz, DMSO-d6): δ 6.85 (s, 1H), 6.73 (brs, 2H), 3.80 (s, 3H), 3.29 (s, 3H), 3.18 (s, 2H); MS [M-H]": 168.07
Step-4:- Preparation of 4-iodo-3-methoxyphenyl methanesulfonate
The title compound was prepared following the procedure described in step-3 of Intermediate- 6 by using 4-amino-3-methoxyphenyl methanesulfonate (2.5 g, 11.51 mmol), ice (6.0 g), cone. sulphuric acid (6.0 ml), aq. NaN02 (1.43 g, 20.23 mmol), aq. KI (6.7 g, 40.10 mmol) to afford 1.8 g of the title product.1!! NMR (300 MHz, CDClj): δ 7.80-7.77 (d, = 8.4 Hz, 1H), 6.77 (s, 1H), 6.70-6.67 (d, J = 8.1 Hz, 1H), 3.82 (s, 3H), 3.14 (s, 3H).
Intermediate- 17
3-Fluoro-4-((4-hydroxy-2-methoxyphenyl)ethynyl)benzonitrile
Figure imgf000068_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-fluorobenzonitrile (step-3, Intermediate- 1, 0.150 g, 1.03 mmol), 4- iodo-3-methoxyphenyl methanesulfonate (Intermediate- 16, 0.339 g, 1.03 mmol), TBAF (0.323 g, 1.24 mmol), PdCl2(PPh3)2 (0.014 g, 0.02 mmol) in DMSO (2.0 mL) to afford 0.080 g of the title product. 1H NMR (300 MHz, DMSO- 6): δ 10.20 (s, 1H), 7.97-7.94 (d, = 8.7 Hz, 1H), 7.71 (s, 2H), 7.33-7.30 (d, = 7.8 Hz, 1H), 7.33-7.30 (d, = 7.8 Hz, 1H), 6.47 (s, 1H), 6.43-6.40 (d, J = 7.8 Hz, 1H), 3.79 (s, 3H); MS [M-H]": 168.07
Intermediate- 18
3-chloro-4-((2-chloro-4-hydroxyphenyl)ethynyl)benzonitrile
Figure imgf000069_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-chlorobenzonitrile (step-2, Intermediate-3, 0.100 g, 0.61 mmol), 3- chloro-4-iodophenyl methanesulfonate (Intermediate- 12, 0.205 g, 0.61 mmol), TBAF (0.177 g, 7.4 mmol), PdCl2(PPh3)2 (0.009 g, 0.01 mmol) in DMSO to afford 0.100 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.63 (s, 1H), 8.20 (s, 1H), 7.85-7.81 (m, 2H), 7.56-7.53 (d, / = 8.4 Hz, 1H), 6.97 (s, 1H), 6.84-6.81 (d, / = 8.7 Hz, 1H); MS [M+H]+: 288.31
Intermediate- 19
Methyl -ethynyl-3 -(trifluoromethyl)benzoate
Figure imgf000069_0002
Step-1:- Preparation of methyl -nitro-3-(trifluoromethyl)benzoate
Figure imgf000069_0003
To a solution of 4-nitro-3-(trifluoromethyl)benzoic acid (5.0 g, 0.02 mmol) in MeOH (100 mL) was added 1.25 M HC1 (10 mL). The reaction mixture was heated to reflux for 20 h. The reaction mass was concentrated under vaccum diluted with water, basified with NaHC03 solution and extracted with DCM. The organic layers were dried over Na2S04 and concentrated to afford 4.0 g of the title product. 1H NMR (300 MHz, CDC13): δ 8.49 (s, 1H), 8.40-8.37 (d, J = 8.4Hz, 1H), 7.94-7.91 (d, J = 8.4 Hz, 1H), 4.01 (s, 3H).
Step-2:- Preparation of methyl -amino-3-(trifluoromethyl)benzoate
Figure imgf000069_0004
The title compound was prepared following the procedure described in step-2 of Intermediate- 6 by using methyl 4-nitro-3-(trifluoromethyl)benzoate (4.0 g, 0.016 mmol) 10% Pd/C in MeOH (50 mL) to afford 3.5 g of title product. 1H NMR (300 MHz, DMSO- 6): δ 7.89 (s, 1H), 7.82-7.79 (d, J = 8.7 Hz, 1H), 6.87-6.84 (d, J = 8.7 Hz, 1H), 6.49 (s, 2H); MS [M+H]+: 220.
Step-3:- Preparation of methyl 4-iodo-3-(trifluoromethyl)benzoate
Figure imgf000070_0001
Sodium nitrite (1.21 g, 0.017 mmol) was added to tetrafluoro boric acid (20 mL) in lot wise manner at -10°C. The solution was stirred for 1 h at same tempreture then added methyl 4- amino-3-(trifluoromethyl)benzoate (3.5 g, 0.015 mmol) and continued stirring for ½ h at same tempreture followed by addition of solution of KI (3.18 g, 0.019 mmol) in acetone : water (40 mL:60 mL).The reaction mass was stirred at rt for 1 h. The reaction mass was diluted with water and filtered to afford 4.8 g of title compound. 1H NMR (300 MHz, CDC13): δ 8.28 (s, 1H), 8.15-8.12 (d, / = 8.1Hz, 1H), 7.84-7.81 (d, 7 = 8.1Hz, 1H), 3.95(s, 3H).
Step-4:- Preparation of methyl 4-ethynyl-3-(trifluoromethyl)benzoate
Part A:-Sillvlation
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using methyl 4-iodo-3-(trifluoromethyl)benzoate (4.8 g,14.54 mmol), trimethyl sillyl acetylene (4 mL, 29.03 mmol), PdCl2 (PPh3)2 (203 mg, 0.289 mmol), Cul (55 mg, 0.28 mmol), Et3N (4.2 mL, 29.26 mmol) and DMSO (10 mL) to afford 4.0 g of methyl 3- (trifluoromethyl)-4-((trimethylsilyl)ethynyl)benzoate.
Part B:- Desillylation
To the crude solution of methyl 3-(trifluoromethyl)-4-((trimethylsilyl)ethynyl)benzoate (4.0 g) in THF was added 1M TBAF solution in THF (18 mL, 15.90 mmol) at -20°C.The reaction mixture was stirred at same tempreture for 1 h. The reaction mixture was quenched with water acidified with dil. HC1 and extracted with DCM. The organic layers were dried over Na2S04 and concentrated to afford 2.0 g of title compound. 1H NMR (300 MHz, DMSO- 6): δ 8.18 (s, 2H), 7.91-7.88 (d, J = 7.8 Hz, 1H), 4.94 (s, 1H), 3.89 (s, 3H).
Intermediate-20
Methyl 4-((2-fluoro-4-hydroxyphenyl)ethynyl)-3-(trifluoromethyl)benzoate
Figure imgf000070_0002
The title compound was prepared following the procedure described in step-3, Intermediate- 1 by using 3-fluoro-4-iodophenyl methanesulfonate (Intermediate- 6, 0.150 g, 0.65 mmol), methyl 4-ethynyl-3-(trifluoromethyl)benzoate (Intermediate- 19, 0.207 g, 0.65 mmol), TBAF (0.206 g, 0.78 mmol), PdCl2(PPh3)2 (0.010 g, 0.013 mmol), DMSO (2.0 mL) to afford 0.110 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.21 (br s, 2H), 7.91-7.88 (d, = 8.4 Hz, 1H), 7.44 (s, 1H), 6.72-6.69 (d, J = 9.6 Hz, 2H), 3.90 (s, 3H); MS [M+H]+: 220. Intermediate-21
5-Hydroxy-2-iodobenzaldehyde
Figure imgf000071_0001
To a solution of 3-hydroxybenzaldehyde (16.0 g, 0.13 mmol) in aq. NH4OH (150 mL) was slowly added a solution of I2 (37.2 g, 0.14 mmol) and 28% Aq.KI (250 mL). The reaction mixture was stirred at rt for 3-4 h. The reaction mass was acidified with dil.HCl. The precipitated solid was filtered and dissolved in diethyl ether again filtered off insoluble part and concentrated the organic layer to afford 15.0 g of title product. 1H NMR (300 MHz, DIVISOR): δ 10.60 (br br s, 1H), 9.87 (s, 1H), 7.94-7.92 (d, J = 7.2 Hz, 1H), 7.30 (s, 1H), 7.12-7.10 (d, = 7.5 Hz, 1H); MS [M+H]+: 247.
Intermediate-22
Methyl 4-ethynylbenzoate
MeOQC— ^ ^— =— H
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using methyl-4-iodo benzoate (20 g, 0.076 mmol), trimethyl sillyl acetylene (16.03g, 0.114 mmol), PdCl2 (PPh3)2 (1.06 g, 0.001 mmol), Cul (288 mg, 1.51 mmol) and Et3N (21.93 g, 0.151 mmol), 1M TBAF solution in THF (24.28 g, 0.08 mmol) to afford 10 g of title product. 1H NMR (300 MHz, CDC13): δ 8.01-7.98 (d, = 7.8Hz, 2H), 7.56-7.54 (d, = 7.8Hz, 2H), 3.92 (s, 3H), 3.23 (s, 1H).
Intermediate-23
Methyl 4-((2-formyl-4-hydroxyphenyl)ethynyl)benzoate
Figure imgf000071_0002
The title compound was prepared following the procedure described in step-3, Intermediate- 1 by using methyl 4-ethynylbenzoate (Intermediate-22, 0.500 g, 3.12 mmol), 5-hydroxy-2- iodobenzaldehyde (Intermediate-21, 0.768 g, 3.12 mmol), TBAF (0.978 g, 3.75 mmol), PdCl2(PPh3)2 (0.044 g, 0.062 mmol), DMSO (3.0 mL) to afford 0.300 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.82 (s, 1H), 8.19 (s, 1H), 8.12 (m, 4H), 7.91-7.83 (m, 2H), 7.78 (s, 1H), 3.89 (s, 3H); MS [M+H]+: 281.
Intermediate-24
ieri-Butyl(3-(ethoxymethyl)-4-iodophenoxy)dimethylsilane
Figure imgf000072_0001
Step-1:- Preparation of 5-((ieri-butyldimethylsilyl)oxy)-2-iodobenzaldehyde
Figure imgf000072_0002
The title compound was prepared following the procedure described in step-1 of Intermediate-
6 by using 5-hydroxy-2-iodobenzaldehyde (Intermediate-21, 7.0 g, 28.45 mmol), tert- butyldimethylsilyl chloride (4.69 g, 31.26 mmol), Et3N (3.16 g, 31.28 mmol) in DCM (100 mL) to afford 6.5 g of title compound. 1H NMR (300 MHz, CDC13): δ 9.90 (s, 1H), 7.98-7.96 (d, = 7.8Hz, 1H), 7.25 (s, 1H), 7.18-7.15 (d, = 7.8Hz, 1H), 1.07 (s, 9H), 0.32 (s, 6H); MS [M+H]+: 363.
Step-2:- Preparation of (5-((ieri-butyldimethylsilyl)oxy)-2-iodophenyl)methanol
Figure imgf000072_0003
To a cold solution of 5-((ieri-butyldimethylsilyl)oxy)-2-iodobenzaldehyde (5.0 g, 0.013 mol) in MeOH (50 mL) was added solution of NaBH4 (1.53 g, 0.014 mol in 5 mL water) at 0°C. The reaction mixture was stirred at rt for 4-5h.The reaction mixture was quenched with dil.HCl and extracted with DCM. The organic layers were dried over Na2S04 and concentrated to afford 4.2 g of title compound. 1H NMR (300 MHz, DMSO- 6): δ 10.22 (s, 1H), 7.57-7.54 (d, = 7.8Hz, 1H), 6.88 (s, 1H), 6.53-6.51 (d, = 7.2 Hz, 1H), 4.41-4.37 (m, 2H), 1.02 (s, 9H), 0.25 (s, 6H); MS [M+H]+: 364.
Step-3:- Preparation of ieri-butyl(3-(ethoxymethyl)-4-iodophenoxy)dimethylsilane
To a solution of (5-((ieri-butyldimethylsilyl)oxy)-2-iodophenyl)methanol (1.0 g, 2.71 mmol) in dry DMF (10 mL) was added NaH (0.164 g, 4.12 mmol, 60% in mineral oil). The reaction mass was stirred for 30 mins at 0°C followed by addition of ethyl bromide (0.449 g, 4.12 mmol). The reaction mixture was stirred at rt for 4-5 h.The reaction mixture was quenched with water and extracted with DCM. The organic layers were dried over Na2S04 and concentrated to afford 0.500 g of title compound. 1H NMR (300 MHz, CDC13): δ 7.69-7.66 (d, = 7.8Hz, 1H), 6.83 (s, 1H), 6.64-6.61 (d, = 7.8Hz, 1H), 4.68 (s, 2H), 4.12-4.05 (q, = 6.9Hz, 2H), 1.49-1.45 (t, = 6.9Hz, 3H), 1.14 (s, 9H), 0.13 (s, 6H); MS [M+H]+: 363. Intermediate-25
ieri-Butyl(4-iodo-3-((2-methoxyethoxy)methyl)phenoxy)dimethylsilane
Figure imgf000073_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 24 by using (5-((ieri-butyldimethylsilyl)oxy)-2-iodophenyl)methanol (Step-2, Intermediate-24, 1.0 g, 2.74 mmol), l-bromo-2-methoxyethane (0.572 g, 4.12 mmol), NaH (0.164 g, 4.12 mmol, 60% in mineral oil), DMF (10 mL) to afford 0.520 g title compound. 1H NMR (300 MHz, CDCI3): δ 7.69-7.67 (d, = 7.8Hz, 1H), 6.85 (s, 1H), 6.66-6.64 (d, = 7.5Hz, 1H), 4.68-4.66(d, = 6.3Hz, 2H), 4.16-4.14 (t, = 5.1Hz, 2H), 3.84-3.82 (t, = 4.8Hz, 2H), 3.50 (s, 3H), 0.93 (s, 9H), 0.90 (s, 6H).
Intermediate-26
ieri-Butyl(4-io -3-(propoxymethyl)phenoxy)dimethylsilane
Figure imgf000073_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 24 by using (5-((ieri-butyldimethylsilyl)oxy)-2-iodophenyl)methanol (Step-2, Intermediate-24, 2.0 g, 5.49 mmol), 1-bromopropane (1.01 g, 8.24 mmol), NaH (0.329 g, 8.24 mmol, 60% in mineral oil), DMF (10 mL) to afford 1.10 g title compound. 1H NMR (300 MHz, CDCI3): δ 7.68-7.66 (d, J = 7.8Hz, 1H), 6.82 (s, 1H), 6.64-6.61 (d, J = 7.2Hz, 1H), 4.68 (s, 2H), 3.97- 3.95 (d, J = 6.6Hz, 2H), 1.86-1.84 (q, J = 6.3Hz, 2H), 1.10-1.06 (t, J = 7.2Hz, 3H), 0.93 (s, 9H), 0.08 (s, 6H).
Intermediate-27
Methyl 4-ethynyl-3-fluorobenzoate
Figure imgf000073_0003
Step-1:- Preparation of 3-fluoro-4-iodobenzoic acid
Figure imgf000074_0001
The title compound was prepared following the procedure described in step-1 of Intermediate- 4 by using 4-amino-3-fluorobenzoic acid (25.0 g, 0.16 mol), crushed ice (45 g), aq. NaN02 (13.5 g, 0.20 mol) and water (100 mL), KI (45.0 g, 0.27 mol) in 6 N H2S04 (150 mL) to afford 30.0 g of title compound. 1H NMR (300 MHz, DMSO-d6): δ 8.02-7.97 (t, = 7.2Hz, 1H), 7.66-7.63(d, = 8.4Hz, 1H), 7.54-7.51(d, = 7.8 Hz, 1H).
Step-2:- Preparation of methyl 3-fluoro-4-iodobenzoate
Figure imgf000074_0002
To a solution of 3-fluoro-4-iodobenzoic acid (30 g, 0.11 mol) in DMF (100 mL) was added K2CO3 (23.34g, 0.16 mol) and the reaction mass was stirred at rt for 1 h. Then added CH3I (24.0 g, 0.16 mol) and continued stirring at rt for 4-5 h. The reaction mixture was quenched with water and filtered off precipitate to afford 25.0 g of title compound. lH NMR (300 MHz, DMSO-d6): δ 8.03-7.99 (t, = 7.8Hz, 1H), 7.67-7.64(d, = 8.7Hz, 1H), 7.54-7.51(d, = 8.1 Hz, 1H),3.05 (s, 3H).
Step-3:- Preparation of methyl 4-ethynyl-3-fluorobenzoate
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using methyl 3-fluoro-4-iodobenzoate (20 g, 0.071 mol), trimethyl sillyl acetylene (14.0 g, 0.14 mol), PdCl2 (PPh3)2 (1.0 g, 0.001 mol), Cul (0.271 g, 0.001 mol), Et3N (17.7 g, 0.14 mol) and 1.0 M TBAF (86 mL in THF, 0.08 mol) to afford 4.0 g of title compound. 1H NMR (300 MHz, CDCI3): δ 7.80-7.72 (m, 2H), 7.57-7.52 (t, = 7.2Hz, 1H), 3.93 (s, 3H), 3.45 (s, 1H).
Intermediate-28
ieri-Butyl(3-(fluoromethyl)-4-iodophenoxy)dimethylsilane
Figure imgf000074_0003
To a solution of (5-((ieri-butyldimethylsilyl)oxy)-2-iodophenyl)methanol (step-2, Intermediate-24, 0.500 g, 1.52 mmol) in dry DCM (10 mL) was added DAST (0.490 g, 3.04 mmol) at 0°C.The reaction mixture was stirred at rt for 3-4 h. The reaction mixture was quenched with water, basified with aq. NaHC03 solution and extracted with DCM. The organic layers were dried over Na2S04 and concentrated to afford 350 mg of title compound. 1H NMR (300 MHz, CDC13): δ 7.77-7.75 (d, = 7.8Hz, 1H),6.82 (s, 1H), 6.70-6.67 (d, = 7.8Hz, 1H), 5.37 (s, 1H), 5.21(s, 1H), 1.01(s, 9H), 0.29 (s, 6H).
Intermediate-29
ieri-Butyl(3-(difluoromethyl)-4-iodophenoxy)dimethylsilane
Figure imgf000075_0001
The title compound was prepared following the procedure described in Intermediate-28 by using 5-((ieri-butyldimethylsilyl)oxy)-2-iodobenzaldehyde (Step- 1, Intermediate-24, 1.0 g, 2.76 mmol), DAST (1.11 g, 6.90 mmol), dry DCM (20 mL) to afford 530 mg of title compound. 1H NMR (300 MHz, CDC13): δ 7.85-7.82 (d, = 8.4Hz, 1H),6.92 (s, 1H), 6.82- 6.79 (d, = 7.8Hz, 1H), 6.74-6.36 (t, = 56.7Hz, 1H),1.06 (s, 9H), 0.29(s, 6H).
Intermediate- 30
4-Ethynyl-3-(trifluoromethyl)phenyl methanesulfonate
Figure imgf000075_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-iodo-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-9, 2.0 g, 5.46 mol), trimethyl sillyl acetylene (0.800 g, 8.19 mol), PdCl2 (PPh3)2 (0.128 g, 0.49 mol), Cul (20 mg,0.105 mmol), TBAF (2.2 mL in 1.0 M THF, 6.01 mol) to afford 800 mg of title compound. 1H NMR (300 MHz, DMSOd-63): δ 10.57 (s, 1H), 7.87-7.85 (d, = 8.4Hz, 1H), 7.76 (s, 1H), 7.69-7.66 (d, J = 8.1Hz, 1H), 3.47 (s, 3H).
Intermediate- 31
3,5-Difluoro-4-iodobenzonitrile
Figure imgf000075_0003
To a solution of 5-bromo- l,3-difluoro-2-iodobenzene (10.0 g, 0.048 mol) in N-methyl pyrrolidone (50 mL) was added CuCN (5.2 g, 0.057 mol). The reaction mixture was heated to reflux for 1.5 h. The reaction mixture was added EDTA, water and extracted with EtOAc. The organic layers were dried over Na2S04 and concentrated to afford 1.6 g of title compound.
Intermediate-32
3,5-Difluoro-4-iodophenyl methanesulfonate
Figure imgf000076_0001
Preparation of 3,5-difluoro-4-nitrophenol
Figure imgf000076_0002
To a solution of 3,5-difluorophenol (3.5 g, 0.026 mol) in DCM (100 mL) was added 70% HN03 (1.7 g, 0.026 mol) at 0°C.The reaction mixture was stirred at 30-40 mins. The reaction mixture was quenched with water and extracted with DCM. The organic layers were dried over Na2S04 and concentrated to afford 2.0 g of title compound. 1H NMR (300 MHz, DMSO- d6): δ 11.81 (br s, 1H), 6.76 (s, 1H), 6.71 (s, 1H).
Stej 2: -Preparation of 3,5-difluoro-4-nitrophenyl methanesulfonate
Figure imgf000076_0003
The title compound was prepared following the procedure described in step-1 of Intermediate- 6 by using 3,5-difluoro-4-nitrophenol (2.0 g, 0.011 mmol), methansulfonyl chloride (1.02 ml, 0.012 mmol), Et3N (1.81 ml, 0.012 mmol) and DCM (50.0 mL) to afford 2.0 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 7.71 (s, 1H), 7.68 (s, 1H), 3.57 (s, 3H).
Stej 3: -Preparation of 4-amino-3,5-difluorophenyl methanesulfonate
Figure imgf000076_0004
The title compound was prepared following the procedure described in step-2 of Intermediate- 6 by using 3,5-difluoro-4-nitrophenyl methanesulfonate (2.00 g, 0.007 mmol), ethyl acetate and EtOH (1: 1 ratio, 100 ml), 10% Pd/C (0.500 g) to afford 2.0 g of the crude title product which was used in the next step without any purification. 1H NMR (300 MHz, DMSO- ): δ 7.06 (s, 1H), 7.04 (s, 1H), 5.36 (br s, 2H),3.33 (s, 3H); MS [M+H]+:224.
S tep-4 : -Preparation of 3,5-difluoro-4-iodophenyl methanesulfonate
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using 4-amino-3,5-difluorophenyl methanesulfonate (2.0 g, 8.9 mmol), ice (12 g) and conc.H2S04 (6.0 ml), aq. NaN02 (1.11 g, 16.14 mmol), aq. KI (2.97 g, 17.9 mmol), acetonitrile (8.0 mL), water (8.0 mL) to afford 1.8 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 7.34 (s, 1H), 7.31 (s, 1H), 3.47 (s, 3H).
Intermediate-33
Ethyl 4'-cyan -6-ethynyl-[l, l'-biphenyl]-3-carboxylate
Figure imgf000077_0001
Preparation of ethyl 4-aminobenzoate
Figure imgf000077_0002
To a solution of 4-aminobenzoic acid (1.0 g, 7.29 mmol) in EtOH (50 mL) was added cone. H2S04 (5.0 mL) The reaction mass was heated at reflux for 16 h. The reaction mixture was diluted with EtOAc. The organic layer was washed with water and brine, dried and concentrated to afford 0.700 g of title product.
Step-2:- Preparation of ethyl 4-amino-3-bromobenzoate
Figure imgf000077_0003
To a solution of ethyl 4-aminobenzoate (8.0 g, 0.048 mol) in chloroform (100 ml) was added N-bromosuccinamide (8.62 g, 0.048 mol) at 0°C under inert atmosphere and reaction mass was stirred for 3 h at 0°C. Then the reaction mixture was diluted with EtOAc. The reaction mixture was quenched with water, extracted with EtOAc and organic layer was separated, dried over Na2S04 and concentrated to afford 4.0 g of title product. 1H NMR (300 MHz, DMSO-i¾): δ 7.87 (s, 1H), 7.65-7.62 (d, J = 9.0 Hz, 1H), 6.80-6.78 (d, J = 8.7 Hz, 1H), 6.18 (s, 2H), 4.28-4.18 (d, J = 6.9Hz, 2H), 1.29-1.24 (t, J = 6.9Hz, 3H); MS [M+H]+: 244.
Step-3:- Preparation of ethyl 6-amino-4'-cyano-[l, -biphenyl]-3-carboxylate
Figure imgf000077_0004
To a solution of ethyl 4-amino-3-bromobenzoate (5.0 g, 20.66 mmol), (4- cyanophenyl)boronic acid (3.33 g, 22.72 mmol) and ~Pd(dppf)Ch (0.843 g, 1.03 mmol) in diglyme (10 mL) was added K2C03 (4.27 g, 30.99 mmol). The reaction mixture was heated at 80°C for 4 h. The reaction mass was quenched with water and extracted with EtOAc. The organic layer was washed with water and brine. The organic layer was separated, dried, filtered and concentrated to afford 2.7 g of title product. 1H NMR (300 MHz, DMSO-i¾): δ 7.92-7.89 (d, = 7.8 Hz, 2H), 7.69-7.67 (d, = 8.7 Hz, 1H), 7.63-7.60 (d, = 7.8 Hz, 2H), 7.56 (s, 1H), 6.81-6.78 (d, = 8.4Hz, 1H), 5.83 (br s, 2H), 4.22-4.20 (q, = 6.9 Hz, 2H),1.28- 1.23 (t, 7 = 7.5 Hz, 3H).
Step-4:- Preparation of ethyl 4'-cyano-6-iodo-[l,l'-biphenyl]-3-carboxylate
Figure imgf000078_0001
The title compound was prepared following the procedure described in step-1 of Intermediate- 4 by using ethyl 6-amino-4'-cyano-[l, l'-biphenyl]-3-carboxylate (5.2 g, 19.54 mmol), ice (10 g), cone. H2S04 (10 ml), aq.NaN02 (2.42 g, 35.17 mmol), aq. KI (6.49 g, 39.09 mmol) to afford 3.0 g of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 8.20-8.17 (d, = 8.4 Hz, 1H), 7.97-7.95 (d, J = 7.8 Hz, 2H), 6.78 (s, 1H), 7.70-7.68 (d, J = 7.2 Hz, 1H), 7.59-7.56 (d, J = 8.4Hz, 2H), 4.32-4.30 (q, J = 7.8Hz, 2H), 1.32- 1.28 (t, J = 7.5 Hz, 3H).
Step-5:- Preparation of ethyl 4'-cyano-6-ethynyl-[l,l'-biphenyl]-3-carboxylate
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using ethyl 4'-cyano-6-iodo-[l, l'-biphenyl]-3-carboxylate (3.0 g, 7.95 mmol), trimethylsilyl acetylene (1.56 g, 15.91 mmol), Cul (30 mg, 0.157 mmol), PdCl2(PPh3)2 (111 mg, 0.158 mmol) and Et3N (1.6 g, 15.84 mmol), 1M TBAF in THF (9.2 ml, 8.33 mmol), DMSO (20 mL), THF (10 mL) to afford 1.5 g of the title product. 1H NMR (300 MHz, OMSO-d6): δ 8.01-7.95 (m, 4H), 7.79-7.77 (m, 3H), 4.49 (s, 1H), 4.37-4.30 (q, J = 6.9 Hz, 2H), 1.34-1.30 (t, 7 = 6.9 Hz, 3H).
Intermediate- 34
Ethyl 4'-cyano-3 '-fluoro-6-iodo- [1,1 '-biphenyl] -3 -carboxylate
Figure imgf000078_0002
Step- 1 :- Preparation of ethyl 6-amino-3'-fluoro-4'-formyl-[l,r-biphenyl]-3-carboxylate
Figure imgf000079_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 33 by using (3-fluoro-4-formylphenyl)boronic acid (1.66 g, 9.91 mmol), ethyl 4-amino-3- bromobenzoate (step-2 of Intermediate-33, 2.0 g, 8.26 mmol), Pd(dppj)Ch (0.337 g, 0.413 mmol), diglyme (10 mL), K2C03 (1.70 g, 12.39 mmol) to afford 1.5 g of title product. 1H NMR (300 MHz, DMSO-i¾: δ 10.26 (s, 1H), 7.94-7.89(t, = 7.8Hz, 1H), 7.70-7.67 (d, = 8.7Hz, 1H), 7.60 (s, 1H), 7.48-7.42(m, 2H), 6.81-6.78 (d, = 8.7Hz, 1H), 5.97 (br s, 2H), 4.23-4.20 (q, = 7.2Hz, 2H), 1.33-1.28 (t, 3H).
Step-2:- Preparation of ethyl 3'- iphenyl]-3-carboxylate
Figure imgf000079_0002
The title compound was prepared following the procedure described in step- 1 of Intermediate-4 by using ethyl 6-amino-3'-fluoro-4'-formyl-[l, -biphenyl]-3-carboxylate (700 mg, 2.43 mmol), ice (10 g), cone. (6 ml), aq. NaNO2 (302 mg, 4.37 mmol), aq. KI (810 mg, 4.37 mmol) to afford 120 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 10.27 (s, 1H), 8.21-8.18 (d, = 7.8Hz, 1H), 7.94-7.92 (t, = 7.2 Hz, 1H), 7.82 (s, 1H), 7.72-7.69 (d, = 8.4Hz, 1H), 7.51-7.48 (s, 1H), 7.41-7.38 (d, = 7.8 Hz, 1H), 4.35-4.28 (q, = 6.9 Hz, 2H), 1.33-1.28 (t, = 7.2Hz, 3H).
Step-3:- Preparation of ethyl 4'-cyano-3'-fluoro-6-iodo-[l, -biphenyl]-3-carboxylate
To a solution of ethyl 3'-fluoro-4'-formyl-6-iodo-[l, -biphenyl]-3-carboxylate (120 mg, 0.300 mmol) in DMSO (2.0 mL) was added NH2OH.HCl (28 mg, 0.40 mmol). The reaction mixture was heated at 90°C for 5-6 h. The reaction mixture was quenched in water, extracted with DCM. The organic layer was washed with water, brine, dried over Na2S04 and concentrated to afford 72 mg of title product. 1H NMR (300 MHz, DMSO-i¾): δ 8.21-8.18 (d, = 8.4 Hz, 1H), 8.09-8.04 (t, = 7.2 Hz, 1H), 7.81 (s, 1H), 7.72-7.64 (m, 2H), 7.45-7.42 (d, = 7.8Hz, 1H), 4.35-4.28 (q, = 7.5 Hz, 2H), 1.33- 1.28 (t, = 7.2Hz, 3H).
Intermediate-35
Ethyl 4'-cyano-3 ',5 '-difluoro-6-iodo- [1,1 '-biphenyl] -3 -carboxylate Step- 1 :- Preparation of ethyl 6- -[l, -biphenyl]-3-carboxylate
Figure imgf000080_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 33 by using (3,5-difluoro-4-formylphenyl)boronic acid (1.03 g, 5.45 mmol), ethyl 4-amino-3- bromobenzoate (step-2, Intermediate-33, 1.2 g, 4.95 mmol), Pd(dppf)C (0.202 g, 0.24 mmol), diglyme (10 mL), K2C03 (1.02 g, 7.42 mmol) to afford 0.850 g of title product. 1H NMR (300 MHz, DMSO-i¾): δ 10.25 (s, 1H), 7.71-7.68 (d, = 9.9 Hz, 1H), 7.61 (s, 1H), 7.33-7.30 (d, = 9.6Hz, 2H), 6.80-6.78 (d, = 8.4 Hz, 1H), 6.05 (s, 2H), 4.23-4.21(q, = 6.9Hz, 2H), 1.33- 1.26 (t, 3H).
Step-2:- Preparation of ethyl 3',5 l, -biphenyl]-3-carboxylate
Figure imgf000080_0002
The title compound was prepared following the procedure described in step-1 of Intermediate- 4 by using ethyl 6-amino-3',5'-difluoro-4'-formyl-[l, -biphenyl]-3-carboxylate (500 mg, 1.6 mmol), ice (10 g), conc.H2S04 acid (5 ml), aq. NaNO2 (205 mg, 2.97 mmol), aq. KI (550 mg, 3.33 mmol) to afford 180 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 10.26 (s, 1H), 8.21-8.18 (d, = 8.1Hz, 1H), 7.82 (s, 1H), 7.73-7.70 (d, = 7.8Hz, 1H), 7.38 (s, 1H), 7.35 (s, 1H), 4.33-4.28 (q, = 7.2 Hz, 2H), 1.33-1.28 (t, = 6.9Hz, 3H).
Step-3:- Preparation of ethyl 4'-cyano-3',5'-difluoro-6-iodo-[l, -biphenyl]-3-carboxylate The title compound was prepared following the procedure described in step-3 of Intermediate- 34 by using ethyl 3',5'-difluoro-4'-formyl-6-iodo-[l, -biphenyl]-3-carboxylate (180 mg, 0.430 mmol), DMSO (2.0 mL), NH2OH.HCl (38.7 mg, 0.56 mmol) to afford 130 mg of title product. 1H NMR (300 MHz, DMSO-i¾): 8.22-8.19 (d, = 8.1Hz, 1H), 7.83 (s, 1H), 7.74- 7.71 (d, = 7.8Hz, 1H), 7.59-7.56 (d, = 9.3Hz, 2H), 4.36-4.29 (q, = 7.5 Hz, 2H), 1.33-1.28 (t, = 6.9Hz, 3H). Intermediate-36
2,5-Difluoro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzonitrile
Figure imgf000081_0001
Step-1:- Preparation of 4-amino-2,5-difluorobenzonitrile
Figure imgf000081_0002
The title compound was prepared following the procedure described in Intermediate-31 by using 4-bromo-2,5-difluoroaniline (10.0 g, 48.07 mmol), N-methyl pyrrolidone (50 mL), CuCN (5.2 g, 0.057 mol) to afford 5.0 g of title compound.
Step-2:- Preparation of 2,5-difluoro-4-iodobenzonitrile
Figure imgf000081_0003
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using 4-amino-2,5-difluorobenzonitrile (4.0 g, 25.97 mmol), ice (12 mL), cone. H2S04 (12.0 mL), NaN02 (3.22 g, 46.66 mmol), KI (8.62 g, 51.45 mmol), acetonitrile (16.0 mL), water (8.0 mL) to afford 3.0 g of the title product. 1H NMR (300 MHz, DMSO-i¾): 8.19-8.15 (m, 1H), 8.01-7.97 (m, 1H),
Step-3:- Preparation of 2,5-difluoro-4-((4-hydroxy-2-(trifluoromethyl)phenyl) ethynyl) benzonitrile
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 2,5-difluoro-4-iodobenzonitrile (0.108 g, 0.40 mmol), 4-ethynyl-3- (trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 0.100 g, 0.40 mmol), TBAF (0.128 g, 0.49 mmol), PdCl2(PPh3)2 (0.006 g, 0.008 mmol), DMSO (2.0 mL) to afford 0.080 g of the title product. MS [M-H]": 322.
Intermediate-37
Methyl 4-((2,5-difluoro-4-hydroxyphenyl)ethynyl)-3-(trifluoromethyl)benzoate
Figure imgf000082_0001
Preparation of 2,5-difluoro-4-nitrophenol
Figure imgf000082_0002
The title compound was prepared following the procedure described in step-1 of Intermediate- 32 by using 2,5-difluorophenol (3.5 g, 0.026 mol), 70% HN03(1.7 g, 0.026 mol), DCM (100 mL) to afford 2.0 g of title compound.
Stej 2: -Preparation of 2,5-difluoro-4-nitrophenyl methanesulfonate
Figure imgf000082_0003
The title compound was prepared following the procedure described in step-1 of Intermediate- 6 by using 2,5-difluoro-4-nitrophenol (2.0 g, 0.011 mmol), methansulfonyl chloride (1.02 ml, 0.012 mmol), Et3N (1.81 ml, 0.012 mmol) and DCM (50.0 mL) to afford 2.0 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.49-8.46 (m, 1H), 8.06-8.00 (m, 1H), 3.64 (s, 3H).
Stej 3: -Preparation of 4-amino-2,5-difluorophenyl methanesulfonate
Figure imgf000082_0004
The title compound was prepared following the procedure described in step-2 of Intermediate- 6 by using 2,5-difluoro-4-nitrophenyl methanesulfonate (2.00 g, 0.007 mmol), ethyl acetate and EtOH (1: 1 ratio, 50+50 ml), 10% Pd/C (0.500 g) to afford 2.0 g of the crude title product which was used in the next step without any purification.
Step-4:- Preparation of 2,5-difluoro-4-iodophenyl methanesulfonate
Figure imgf000082_0005
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using 4-amino-2,5-difluorophenyl methanesulfonate (2.0 g, 8.9 mmol), ice (12 g) and conc.H2S04 (6.0 ml), aq. NaN02 (1.11 g, 16.14 mmol), aq. KI (2.97 g, 17.9 mmol), acetonitrile (8.0 mL), water (8.0 mL) to afford 1.8 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.10-8.05 (m, 1H), 7.65-7.60 (t, J = 6.3 Hz, 1H), 3.53 (s, 3H). MS [M+H]:334 Step-5:- Preparation of methyl 4-((2,5-difluoro-4-hydroxyphenyl)ethynyl)-3- (trifluoromethyl)benzoate
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using methyl 4-ethynyl-3-(trifluoromethyl)benzoate (Intermediate- 19, 150 mg, 0.65 mmol), 2,5-difluoro-4-iodophenyl methanesulfonate (219 mg, 0.65 mmol), TBAF (206 mg, 0.78 mmol), PdCl2(PPh3)2 (10 mg, 0.013 mmol), DMSO (2.0 mL) to afford 0.110 g of the title product. 1H NMR (300 MHz, DMSO-i¾): 11.22 (s, 1H), 8.22 (s, 2H), 7.93-7.90 (d, J = 7.8Hz, 1H), 7.50-7.44 (m, 1H), 6.93-6.87 (m, 1H), 3.90 (s, 3H).
Intermediate-38
3-(3-Ethoxypropyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzonitrile
Figure imgf000083_0001
Step 1 :- Preparation of (E)-methyl 3-(2-amino-5-cyanophenyl)acrylate
Figure imgf000083_0002
To a mixture of 4-amino-3-bromobenzonitrile (10.0 g, 0.050 mmol) and methyl acrylate (9.19 mL, 0.101 mmol) in acetonitrile (200 mL) was added palladium acetate (0.568 g, 0.0025 mmol) and tri-o-tolyl phosphine (1.54 g, 0.005 mmol) and Et3N (14.64 mL, 0.105 mmol).
The reaction mixture was heated to reflux for 48 h. The reaction mass was filtered through celite and washed the bed with ethyl acetate. The filtrate was concentrated to afford
6.0 g of title product. 1H NMR (300 MHz, DMSO-i¾): δ 7.92 (s, 1H), 7.82-7.77 (d, J = 15.6 Hz, 1H), 7.41-7.38 (d, J = 8.7 Hz, 1H), 6.77-6.74(d, J = 8.7 Hz, 1H), 6.64 (s, 2H), 6.56-6.51 (d, J = 15.6 Hz, 1H), 3.70 (s, 3H).
Step 2:- Preparation of methyl 3-(2-amino-5-cyanophenyl)propanoate
Figure imgf000083_0003
To a solution of (E)-methyl 3-(2-amino-5-cyanophenyl)acrylate (5.0 g, 0.024 mmol) in EtOH (100 mL) was added Pd/CaC03 (1.5 g).The reaction mixture was hydrogenated in Parr apparatus under 45-50 psi for 20 h. The reaction mass was filtered through celite and washed the bed with ethanol. The filtrate was concentrated to afford 5.0 g of title product. 1H NMR (300 MHz, DMSO-i¾: δ 7.29 (s, 2H), 6.67-6.64 (d, = 8.4 Hz, 1H), 6.02 (s, 2H), 3.58 (s, 3H), 2.71-2.66 (m, 2H), 2.57-2.50 (m, 2H).
Step 3:- Preparation of methyl 3-(5-cyano-2-iodophenyl)propanoate
Figure imgf000084_0001
The title compound was prepared following the procedure described in step-1 of Intermediate- 4 by using methyl 3-(2-amino-5-cyanophenyl)propanoate (5.0 g, 24.50 mmol), conc.H2S04 (15.0 ml), aq.NaNO2 (3.04 g, 44.11 mmol), KI (8.13 g, 49.01 mmol), acetonitrile (20.0 mL), water (30.0 mL) to afford 3.0 g of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 8.07- 8.04 (d, = 8.4 Hz, 1H), 7.76 (s, 1H), 7.42-7.39 (dd, = 1.8 Hz, 1H), 3.61 (s, 3H), 2.99-2.94 (m, 2H), 2.67-2.62 (m, 2H).
Step 4:- Preparation of 3-(3-hydroxypropyl)-4-iodobenzonitrile
Figure imgf000084_0002
The title compound was prepared following the procedure described in step-2 of Intermediate- 24 by using methyl 3-(5-cyano-2-iodophenyl)propanoate (3.0 g, 9.5 mmol), NaBH4, MeOH (10 mL) in THF (50.0 mL) to afford 2.0 g of title product. 1H NMR (300 MHz, DMSO-i¾: δ 8.05-8.03 (d, = 7.8 Hz, 1H), 7.72 (s, 1H), 7.39-7.37 (d, = 8.1 Hz, 1H), 4.61-4.57 (t, = 5.4 Hz, lH),3.59-3.42 (q, = 9.6 Hz, 2H), 2.76-2.71 (m, 2H), 1.75-1.63 (m, 2H).
Step 5:- Preparation of 3-(3-ethoxypropyl)-4-iodobenzonitrile
Figure imgf000084_0003
The title compound was prepared following the procedure described in step-3 of Intermediate- 24 by using 3-(3-hydroxypropyl)-4-iodobenzonitrile (900 mg, 3.13 mmol), NaH (188 mg, 4.70 mmol, 60% in mineral oil), ethyl bromide (68 mg, 6.27 mmol), DMF (5.0 mL) to afford 400 mg title compound. 1H NMR (300 MHz, DMSO-i¾) : δ 7.95-7.2 (d, = 7.8 Hz, 1H), 7.48 (s, 1H), 7.16-7.13 (d, = 8.1 Hz, 1H), 3.53-3.42 (m, 4H), 2.86-2.74 (m, 2H), 1.90- 1.85 (m, 2H), 1.25- 1.20 (t, 7 = 7.5 Hz, 3H).
Step 6:- Preparation of 3-(3-ethoxypropyl)-4-((4-hydroxy-2-(trifluoromethyl) phenyl)ethynyl)benzonitrile
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 100 mg, 0.40 mmol), 3-(3-ethoxypropyl)-4-iodobenzonitrile (129 mg, 0.40 mmol), TBAF (129 mg, 0.49 mmol), PdCl2(PPh3)2 (6 mg, 0.008 mmol), DMSO (2.0 mL) to afford 80 mg of the title product.1!! NMR (300 MHz, DMSO-i¾ : δ 10.75 (s, 1Η),7.83-7.80 (d, = 9.0 Hz, 1H), 7.72- 7.61 (m, 2H), 7.72-7.61 (m, 2H), 7.51-7.44 (m, 1H),7.17-7.09 (m, 2H), 3.39-3.17 (m, 2H), 2.87 (m, 2H), 1.83-1.81 (m, 2H), 1.23-1.08 (t, = 8.40 Hz, 3H); MS [M-H]": 372.
Intermediate-39
3-(2-Fluoropropyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzonitrile
Figure imgf000085_0001
Preparation of 3-(3-fluoropropyl)-4-iodobenzonitrile
Figure imgf000085_0002
The title compound was prepared following the procedure described Intermediate-28 by using 3-(3-hydroxypropyl)-4-iodobenzonitrile (step-4, Intermediate-38, 1.2 g, 4.18 mmol), DAST (1.12 mL, 8.36 mmol), dry DCM (20 mL) to afford 500 mg of title compound. 1H NMR (300 MHz, DMSO-i¾): δ 7.97-7.95 (d, J = 1.2 Hz, 1H), 7.48 (s, 1H), 7.18-7.16 (d, J = 8.4 Hz, 1H), 4.60-4.56 (t, = 5.4 Hz, 1H), 4.44-4.41 (t, = 5.4 Hz, 1H), 2.93-2.88 (m, 2H), 2.07-2.02 (m, 1H), 2.00- 1.95 (m, 1H).
Step 2:- Preparation of 3-(2-fluoropropyl)-4-((4-hydroxy-2-(trifluoromethyl) phenyl)ethynyl)benzonitrile
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 100 mg, 0.40 mmol), 3-(3-fluoropropyl)-4-iodobenzonitrile (119 mg, 0.40 mmol), TBAF (129 mg, 0.49 mmol), PdCl2(PPh3)2 (6 mg, 0.008 mmol), DMSO (2.0 mL) to afford 95 mg of the title product.1!! NMR (300 MHz, DMSO-i¾): δ 10.76 (s, 1H),7.84 (s, 1H), 7.75-7.63 (m, 3H), 7.17 (s, 1H), 7.12-7.09 (d, = 8.4 Hz, 1H), 4.58-4.54 (t, = 5.7 Hz, 1H), 4.42-4.38 (t, = 5.7 Hz, 1H), 2.95-2.90 (m, 2H), 2.05 (m, 1H),1.95 (m, 1H).
Intermediate-40
3-Fluoro-4-((4-(methoxycarbonyl)phenyl)ethynyl)pyridine 1 -oxide
Figure imgf000086_0001
Preparation of methyl 4- -fluoropyridin-4-yl)ethynyl)benzoate
Figure imgf000086_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using methyl 4-ethynylbenzoate (Intermediate-22, 350 mg, 2.18 mmol), 4-iodo-3-fluoro pyridine (487 mg, 2.18 mmol), TBAF (685 mg, 2.62 mmol), PdCl2(PPh3)2 (31.0 mg, 0.043 mmol), DMSO (2.0 mL) to afford 320 mg of the title product. 1H NMR (300 MHz, DMSO- d6): δ 8.75 (s, 1H), 8.53-8.51 (d, = 4.8 Hz, 1H), 8.04-8.02 (d, = 7.8 Hz, 2H), 7.79-7.77 (d, = 7.8 Hz, 2H), 7.40-7.72 (m, 1H), 3.88 (s, 3H);MS [M+H]+: 256.
Step 2:- Preparation of 3-fluoro-4-((4-(methoxycarbonyl)phenyl)ethynyl)pyridine 1-oxide To a solution of methyl 4-((3-fluoropyridin-4-yl)ethynyl)benzoate (200 mg, 0.784 mmol) in DCM (5.0 mL) was added m-CPBA (156.2 mg, 0.862 mmol) at 0°C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with water, basified with aq. K2C03 and extracted with DCM. The organic layers were dried over Na2S04 and concentrated to afford 160 mg of title compound. 1H NMR (300 MHz, DMSO-i¾): δ 8.70 (s, 1H), 8.20-8.18 (d, J = 5.7Hz, 1H), 8.03-8.00 (d, = 8.1 Hz, 2H), 7.75-7.72 (m, 3H), 3.87 (s, 3H); MS [M+H]+: 272.
Intermediate-41
Methyl 5-((4-hydroxy- -(trifluoromethyl)phenyl)ethynyl)thiophene-2-carboxylate
Figure imgf000086_0003
Preparation of methyl 5-bromothiophene-2-carboxylate Br
COOMe
The title compound was prepared following the procedure described in step-1 of Intermediate- 33 by using 5-bromothiophene-2-carboxylic acid (2.0 g), MeOH (20.0 mL), cone. H2S04 (5.0 mL) to afford 1.15 g of title compound.
Step 2:- Preparation of methyl 5- ylate
Figure imgf000087_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using methyl 5-bromothiophene-2-carboxylate (500 mg, 2.27 mmol), trimethylsilyl acetylene (0.5 mL), Cul (7.0 mg, 0.045 mmol), PdCl2(PPh3)2 (24 mg, 0.045 mmol) and DIPEA (0.7 mL, 4.54 mmol), 1M TBAF in THF (2.7 ml, 2.49 mmol), DMSO (2.0 mL), THF (10 mL) to afford 300 mg of title compound. 1H NMR (300 MHz, DMSO-i¾): δ 7.65 (s, 1H), 7.38 (s, 1H), 3.81(s, 4H).
Step 3:- Preparation of methyl 5-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl) thiophene-2- carboxylate
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-iodo-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-9, 160 mg, 0.96 mmol), methyl 5-ethynylthiophene-2-carboxylate (351 mg , 0.96 mmol), TBAF (300 mg, 1.15 mmol), PdCl2(PPh3)2 (13.0 mg, 0.01 mmol), DMSO (2.0 mL) to afford 120 mg of the title product. 1H NMR (300 MHz, OMSO-d6): δ 10.81 (s, 1H), 7.78 (s, 1H), 7.67-7.64 (d, = 7.8Hz, 1H), 7.42 (s, 1H), 7.17 (s, 1H), 7.09-7.07 (d, = 6.6 Hz, 1H), 3.83 (s, 3H); MS [M+H]+: 327.
Intermediate-42
Ethyl 3'-chloro-4'-cyano-6-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-[l, -biphenyl]-3- carboxylate
Figure imgf000087_0002
Preparation of 2-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile
Figure imgf000088_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 33 by using 4-bromo-2-chlorobenzonitrile (1.0 g, 4.61 mmo), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (1.29 g, 4.33 mmol), potassium acetate (0.9063 g, 9.23 mmol), Pd(dppf)C12 (0.190 g, 0.23 mmol) in 1,4-dioxane to afford 0.850 g of title compound. 1H NMR (300 MHz, DMSO-i¾): δ 7.99-7.91 (d, = 7.8Hz, 1H), 7.82 (s, 1H), 7.75-7.73 (d, = 7.2 Hz, 1H), 1.31 (s, 12H).
Step-2:- Preparation of ethyl 6-amin -3'-chloro-4'-cyano-[l, -biphenyl]-3-carboxylate
Figure imgf000088_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 33 by using 2-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile (0.950 g, 3.58mmol), ethyl 4-amino-3-bromobenzoate (step-2 of Intermediate-33, 0.850 g, 3.51 mmol), PdidppfiC (0.145 g, 0.177 mmol), diglyme (10 mL), K2C03 (0.728 g, 5.27 mmol) to afford 0.720 g of title product. 1H NMR (300 MHz, DMSO-i¾: δ 8.04-8.01(d, = 8.4Hz, 1H), 7.76 (m, 2H), 7.57 (m, 2H), 6.80 (d, 1H), 5.96 (s, 2H), 4.22-4.20 (q, J = 6.9Hz, 2H), 1.28-1.23 (t, J = 6.9Hz, 3H).
Step-3:- Preparation of ethyl 3'-chlo -4'-cyano-6-iodo-[l, -biphenyl]-3-carboxylate
Figure imgf000088_0003
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using ethyl 6-amino-3'-chloro-4'-cyano-[l, -biphenyl]-3-carboxylate (0.720 g, 2.41mmol), ice (5 g) and conc.H2S04 (5.0 ml), aq. NaN02 (0.300 g, 4.34 mmol), aq.KI (0.805 g, 4.84 mmol), acetonitrile (5.0 mL), water (3.0 mL) to afford 0.610 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.20-8.18 (d, = 7.2Hz, 1H), 8.11-8.09 (d, = 7.8Hz, 1H), 7.82 (s, 2H),7.72 (d, 1H), 7.57-7.55 (d, = 6.6Hz, 1H), 4.33-4.30 (q, = 6.6Hz, 2H), 1.32- 1.22 (t, / = 6.9Hz, 3H).
Step-4:- Preparation of ethyl 3'-chloro-4'-cyano-6-((4-hydroxy-2-(trifluoromethyl)phenyl) ethynyl)-[l,l'-biphenyl]-3-carboxylate
The title compound was prepared following the procedure described in ste-3 of Intermediate- 1 by using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 148 mg, 0.608 mmol), ethyl 3'-chloro-4'-cyano-6-iodo-[l, -biphenyl]-3-carboxylate (250 mg, 0.608 mmol), TBAF (190 mg, 0.729 mmol), PdCl2(PPh3)2 (9 mg, 0.012 mmol), DMSO (3.0 mL) to afford 0.150 g of the title product. 1H NMR (300 MHz, DMSO- 6): δ 10.75 (s, 1H), 8.12-8.09 (m, 4H), 7.80-7.77 (d, = 8.4Hz, 2H), 7.48-7.45 (d, = 8.4Hz, 1H), 7.11 (s, 1Η),7.08-7.04 (d, = 8.7Hz, 1H), 4.39-4.31 (d, = 7.2Hz, 2H), 1.35-1.31 (t, = 7.2Hz, 3H); MS [M-H]~: 468.11.
Intermediate-43
4-Ethyny -3-(trifluoromethyl)phenol
Figure imgf000089_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-iodo-3-(trifluoromethyl)phenol (4.0 g, 0.010 mol), trimethylsilyl acetylene (2.3 mL, 0.016 mol), Cul (0.041 g, 0.0002 mol), PdCl2(PPh3)2 (0.153 g, 0.0002 mol) and Et3N (3.2 mL, 0.02 mol), 1M TBAF in THF (13.2 ml, 0.013 mol), DMSO (2.0 mL), THF (50 mL) to afford 1.0 g of title compound.
Intermediate-44
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-methoxypropyl)benzonitrile
Figure imgf000089_0002
Preparation of 4-iodo-3-(3-methoxypropyl)benzonitrile
Figure imgf000089_0003
The title compound was prepared following the procedure described in step-3 of Intermediate- 24 by using 3-(3-hydroxypropyl)-4-iodobenzonitrile (step-4, Intermediate-38, 600 mg, 2.09 mmol), NaH (125 mg, 3.13 mmol, 60% in mineral oil), methyl iodide (1.0 g, 4.18 mmol), DMF (5.0 mL) to afford 250 mg title compound. 1H NMR (300 MHz, DMSO-i¾): δ 7.95-7.92 (d, 7 = 8.4 Hz, 1H), 7.47 (s, 1H), 7.16-7.14 (d, J = 7.8 Hz, 1H), 3.43-3.36 (m, 5H).
Step 2:- Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3- methoxypropyl)benzonitrile
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-(trifluoromethyl)phenol (Intermediate-43, 100 mg, 0.53 mmol), 4- iodo-3-(3-methoxypropyl)benzonitrile (154 mg, 0.53 mmol), TBAF (168 mg, 0.64 mmol), PdCl2(PPh3)2 (8 mg, 0.010 mmol), DMSO (2.0 mL) to afford 90 mg of the title product.1H NMR (300 MHz, DMSO-i¾): δ 10.76 (s, 1H),7.80 (s, 1H), 7.73-7.64 (m, 3H), 7.17 (s, 1H), 7.12-7.09 (d, J = 8.4 Hz, 1H), 3.61 (s, 2H), 3.33 (s, 3H), 2.88-2.83 (t, J = 7.8 Hz, 2H), 1.86- 1.81(m, 2H).
Intermediate-45
Ethyl 3-(2-cyanoethyl)- -((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoate
Step- 1 :- Preparation of (E)-et ate
Figure imgf000090_0001
The title compound was prepared following the procedure described in step-1 of Intermediate- 38 by using ethyl 4-amino-3-bromobenzoate (3.0 g, 0.012 mmol), acrylonitrile (1.30 g, 0.024 mmol), palladium acetate (0.137 g, 0.0006 mmol), tri-o-tolyl phosphine (0.373 g, 0.0012 mmol), Et3N (3.54 mL, 0.024 mmol) in acetonitrile (30 mL) to afford 1.0 g of tilte product. 1H NMR (300 MHz, DMSO-i¾: δ 7.97 (s, 1Η),7.82-7.77 (d, = 16.5 Hz, 1Η),7.67-7.64 (d, = 8.7 Hz, 1H), 6.71-6.68 (d, = 9.0 Hz, 1H),6.54 (s, 2H), 6.29-6.23 (d, = 16.5 Hz, 1H), 4.25- 4.18 (q, J = 9.9 Hz, 2H), 1.33- 1.23(t, 3H); MS [M+H]+: 217
Step-2:- Preparation of ethyl 4-amino-3-(2-cyanoethyl)benzoate
Figure imgf000091_0001
The title compound was prepared following the procedure described in step-2 of Intermediate- 38 by using (E)-ethyl 4-amino-3-(2-cyanovinyl)benzoate (1.0 g, 0.004 mmol), Pd/CaC03 (0.300 g) in EtOH (30 mL) to afford 1.0 g of title product. 1H NMR (300 MHz, OMSO-d6): δ 7.68 (s, lH),7.00-6.97 (d, = 7.8 Hz, 1H), 6.64-6.61 (d, = 8.7 Hz, 1H), 5.94 (br s, 2H), 4.26- 4.16 (q, = 6.9 Hz, 2H), 2.82-2.78 (t, = 6.9 Hz, 2H), 2.70-2.65 (t, = 6.9 Hz, 2H), 1.36- 1.17 (m, 3H).
Step-3:- Preparation of ethyl 3-(2-cyanoethyl)-4-iodobenzoate
Figure imgf000091_0002
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using ethyl 4-amino-3-(2-cyanoethyl)benzoate (1.0 g, 4.62 mmol), conc.H2S04 (3.0 ml), aq.NaN02 (0.574 g, 8.33 mmol), KI (1.53 g, 9.23 mmol), acetonitrile (4.0 mL), water (6.0 mL) to afford 0.420 g of the title product. 1H NMR (300 MHz, DMSO-i¾: δ 7.95-7.92 (d, = 8.1 Hz, 2H), 7.63-7.62 (d, = 1.8 Hz, 1H), 4.44-4.34 (q, = 6.9Hz, 2H), 3.17-3.12 (t, = 7.8 Hz, 2H), 2.71-2.66 (t, = 7.8 Hz, 2H), 1.42- 1.37 (t, = 7.2 Hz, 3H).
Step-4:- Preparation of ethyl 3-(2-cyanoethyl)-4-((4-hydroxy-2-(trifluoromethyl) phenyl)ethynyl)benzoate
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-(trifluoromethyl)phenol (Intermediate-43, 150 mg, 0.80 mmol), ethyl 3-(2-cyanoethyl)-4-iodobenzoate (265 mg, 0.80 mmol), TBAF (252 mg, 0.96 mmol), PdCl2(PPh3)2 (12 mg, 0.0016 mmol) in DMSO (2.0 mL) to afford 120 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 10.75 (br s, 1H), 7.98 (s, 1H), 7.89-7.86 (d, = 7.8 Hz, 1H), 7.60-7.62 (m, 2H), 7.16 (s, 1H), 7.10-7.07 (d, = 9.0 Hz, 1H), 4.32-4.30 (q, = 7.5 Hz, 2H), 3.14 (t, 2H), 2.86 (t, 2H), 1.33- 1.28 (t, = 6.9 Hz, 3H).
Intermediate-46
Ethyl 4'-carbamoyl-6-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3 '-methyl- [ 1,1'- biphenyl]-3-carboxylate
Figure imgf000092_0001
Preparation of 2-methyl-4-(4,4 -tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile
Figure imgf000092_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 33 by using 4-bromo-2-methylbenzonitrile (1.5 g, 7.65 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (2.13 g, 8.38 mmol), potassium acetate (1.5 g, 15.28 mmol), Pd(dppf)C12 (0.313 g, 0.383 mmol) in 1,4-dioxane to affrd 1.30 g of title compound. 1H NMR (300 MHz, CDC13): δ 7.73 (s, 1H), 7.68-7.65 (d, = 7.2Hz, 1H), 7.59-7.56 (d, = 7.8 Hz, 1H), 2.54 (s, 3H), 1.34 (s, 12H).
Step-2:- Preparation of ethyl 6-amin -4'-cyano-3'-methyl-[l, -biphenyl]-3-carboxylate
Figure imgf000092_0003
The title compound was prepared following the procedure described in step-3 of Intermediate- 33 by using 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile (1.00 g, 4.09 mmol), ethyl 4-amino-3-bromobenzoate (step-2 of Intermediate-33, 0.900 g, 3.71 mmol), PdidppfiC (0.152 g, 0.185 mmol), diglyme (10 mL), K2C03 (0.770 g, 5.57 mmol) to afford 0.700 g of title product. 1H NMR (300 MHz, OMSO-d6): δ 7.84-7.81(d, = 8.4Hz, 1H), 7.69- 7.66 (d, = 8.1 Hz, 1H), 7.56 (s, 1H), 7.50 (s, 1H), 7.41-7.38 (d, = 7.8 Hz, 1H), 6.79-6.77 (d, = 8.1 Hz, 1H),5.84 (s, 2H), 4.24-4.17 (q, = 7.2Hz, 2H), 2.52 (s, 3H), 1.28-1.23 (t, = 6.9Hz, 3H); MS [M+H]+: 281
Step-3:- Preparation of ethyl 4'-cyano-6-iodo-3'-methyl-[l,r-biphenyl]-3-carboxylate
Figure imgf000093_0001
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using ethyl 6-amino-4'-cyano-3'-methyl-[l, -biphenyl]-3-carboxylate (0.680 g, 2.40mmol), ice (5 g) and cone. H2S04 (5.0 ml), aq. NaN02 (0.300 g, 4.34 mmol), aq. KI (0.798 g, 4.80 mmol), acetonitrile (5.0 mL), water (3.0 mL) to afford 0.900 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.19-8.16 (d, = 8.1Hz, 1H), 7.89-7.87 (d, = 7.8Hz, 1H), 7.77 (s, 1Η),7.69-7.67 (d, J = 8.1 Hz, 1H), 7.48 (s, 1H), 7.39-7.36 (d, J = 7.8 Hz, 1H), 4.36-4.27 (q, J = 6.6Hz, 2H), 2.54 (s, 3H), 1.32-1.27 (t, J = 6.9Hz, 3H).
Step-4:- Preparation of ethyl 4'-cyano-6-((4-hydroxy-2-(trifluoromethyl)phenyl) ethynyl)-3'- methyl-[l,l'-biphenyl]-3-carboxylate
Figure imgf000093_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate- 30, 142 mg, 0.761 mmol), ethyl 4'-cyano-6-iodo-3'-methyl-[l,r-biphenyl]-3-carboxylate (300 mg, 0.761 mmol), TBAF (238 mg, 0.916 mmol), PdCl2(PPh3)2 (10.6 mg, 0.0152 mmol), DMSO (3.0 mL) to afford 0.100 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.72 (s, 1H), 8.04-8.01 (d, = 7.8 Hz, 1H), 7.97 (s, 1H), 7.91-7.88 (d, = 7.8 Hz, 1H), 7.78- 7.75 (d, = 8.4 Hz, 1H), 7.70 (s, 1H), 7.64-7.62 (d, = 7.8 Hz, 1H), 7.43-7.40 (d, = 8.1 Hz, 1H), 7.10 (s, 1H), 7.07-7.05 (d, J = 8.4 Hz, 1H), 4.36-4.30 (q, J = 6.9 Hz, 1H),2.55 (s, 3H), 1.35-1.31(t, = 7.2 Hz, 3H).
Step-5:- Preparation of ethyl 4'-carbamoyl-6-((4-hydroxy-2-(trifluoromethyl) phenyl)ethynyl)-3'-methyl-[l,l'-biphenyl]-3-carboxylate
To a solution of ethyl 4'-cyano-6-((4-hydroxy-2-(trifluoromethyl)phenyl) ethynyl)-3'-methyl- [l,r-biphenyl]-3-carboxylate (70 mg, 0.155 mmol) in DMSO (5 mL) was added 50% H202 (2.5 mL), K2C03 (15 mg, 0.108 mmol). The reaction mass was stirred at rt for 3 h. The reaction mixture was quenched in water, acidified with dil HCl and extracted with DCM. The organic layers were dried over Na2S04 and concentrated to afford 50 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.72 (s, 1H), 7.96 (s, 2H), 7.80 (br s, 1H), 7.74-7.71(d, J = 7.8Hz, 1H), 7.50-7.43 (m, 2H), 7.40-7.37 (d, = 8.1 Hz, 3H), 7.12 (s, 1H), 7.07-7.04 (d, = 8.7 Hz, 1H), 4.36-4.33 (q, J = 7.5 Hz, 2H), 2.44 (s, 3H), 1.35-1.31 (t, J = 8.7 Hz, 3H).
Intermediate-47
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(2-methoxyethoxy)propyl)
benzonitrile
Figure imgf000094_0001
Step-1:- Preparation of 4-iodo-3-(3-(2-methoxyethoxy)propyl)benzonitrile
—
Figure imgf000094_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 24 by using 3-(3-hydroxypropyl)-4-iodobenzonitrile (step-4, Intermediate-38, 300 mg, 1.04 mmol), l-bromo-2-methoxyethane (217 mg, 1.56 mmol), NaH (63 mg, 1.56 mmol, 60% in mineral oil), DMF (3 mL) to afford 160 g title compound. 1H NMR (300 MHz, CDC13): δ 7.95-7.92 (d, J = 8.4Hz, 1H), 7.49 (s, 1H), 7.15-7.13 (d, 7 = 8.1Hz, 1H), 3.59-3.58 (br s, 4H), 3.52-3.48 (t, J = 6.3Hz, 2H), 3.41 (s, 3H), 2.87-2.82 (t, J = 7.8Hz, 2H), 1.94-1.87 (m, 2H). Step-2:- Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(2- methoxyethoxy)propyl)benzonitrile
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-(trifluoromethyl)phenol (Intermediate-43, 100 mg, 0.53 mmol), 4- iodo-3-(3-(2-methoxyethoxy)propyl)benzonitrile (185 mg, 0.538 mmol), TBAF (168 mg, 0.64 mmol), PdCl2(PPh3)2 (8 mg, 0.010 mmol), DMSO (2.0 mL) to afford 70 mg of the title product.1!! NMR (300 MHz, DMSO-i¾: δ 10.76 (s, 1H),7.80 (s, 1H), 7.72-7.67 (t, = 6.9Hz, 2H), 7.63-7.61 (d, = 7.8Hz, 1H),7.17 (s, 1H), 7.11-7.09 (d, = 8.7Hz, 1H), 3.45-3.40 (m, 6H), 3.22 (s, 3H), 2.86 (m, 2H), 1.84 (m, 2H). Intermediate-48
3-(3-(diethylamino)propyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl) benzonitrile
Figure imgf000095_0001
Preparation of 3-(5-cyano-2-iodophenyl)propyl methanesulfonate
Figure imgf000095_0002
The title compound was prepared following the procedure described in step-1 of Intermediate- 6 by using 3-(3-hydroxypropyl)-4-iodobenzonitrile (step-4, Intermediate-38, 1.2 g, 4.18 mmol), Et3N (0.63 mL, 4.39 mmol), mesyl chloride (0.35 mL, 4.39 mmol) in DCM (30 mL) to afford 1.0 g of title compound. 1H NMR (300 MHz, CDC13): δ 7.98-7.95 (d, = 7.8 Hz, 1H), 7.49 (s, 1H), 7.20-7.18 (m, 1H), 4.32-4.24 (t, = 5.7Hz, 1H), 3.05-3.02 (m, 3H), 2.87- 2.80 (m, 2H), 2.11-2.02 (m, 2H).
Step 2:- Preparation of 3-(3-(diethylamino)propyl)-4-iodobenzonitrile
Figure imgf000095_0003
To 3-(5-cyano-2-iodophenyl)propyl methanesulfonate (0.200 g, 0.54 mmol) was added diethyl amine (5.0 mL). The reaction mixture was heated at reflux for 15 h. The excess of diethyl amine was removed under vacuum and the reaction mass was diluted with water, extracted with DCM. The organic layers were dried over Na2S04 and concentrated to afford 180 mg of title compound. 1H NMR (300 MHz, CDC13): δ 7.95-7.93 (d, = 8.1 Hz, 1H), 7.49 (s, 1H), 7.17-7.14 (d, = 7.8 Hz, 1H), 2.83-2.72 (m, 8H), 2.02 (m, 2H), 1.24-1.15 (t, = 6.9Hz, 6H).
Step 3:- Preparation of 3-(3-(diethylamino)propyl)-4-((4-hydroxy-2-
(trifluoromethyl)phenyl)ethynyl) benzonitrile The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 3-(3-(diethylamino)propyl)-4-iodobenzonitrile (0.151 g, 0.48 mmol), 4-ethynyl-3- (trifluoromethyl)phenol (Intermediate-43, 0.090 g, 0.48 mmol), TBAF (0.151 g, 0.58 mmol), PdCl2(PPh3)2 (0.007 g, 0.009 mmol), DMSO (2.0 mL) to afford 0.050 g of the title product. 1H NMR (300 MHz, OMSO-d6): δ 7.89 (s, 1H), 7.73-7.64 (m, 3H), 7.20 (s, 1H), 7.13-7.10 (d, 7 = 8.7 Hz, 1H), 3.15 (m, 6H), 2.87 (m, 2H), 1.90 (s, 2H), 1.31-1.23 (m, 6H).
Intermediate-49
ethyl 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(6-methoxypyridin-3-yl)benzoate
Figure imgf000096_0001
Step 1 :- Preparation of ethyl 4-ami -3-(6-methoxypyridin-3-yl)benzoate
Figure imgf000096_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 33 by using (6-methoxypyridin-3-yl)boronic acid (0.695 g, 4.54 mmol), ethyl 4-amino-3- bromobenzoate (step-2 of Intermediate-33, 1.0 g, 4.13 mmol), Pdidppf )C (0.168 g, 0.205 mmol), diglyme (10 mL), K2C03 (0.854 g, 6.18 mmol) to afford 0.910 g of title product. 1H NMR (300 MHz, DMSO-i¾: δ 8.15 (s, 1H), 7.72-7.64 (m, 2H), 7.51 (s, 1H), 6.91-6.88 (d, / = 8.1 Hz, 1H), 6.77-6.74 (d, = 8.4 Hz, 1H), 5.73 (s, 21H), 4.24-4.17 (q, = 6.6 Hz, 2H), 3.89 (s, 3H), 1.28- 1.23 (t, J = 6.9 Hz, 3H).
Step 2:- Preparation of ethyl 4-iodo- -(6-methoxypyridin-3-yl)benzoate
Figure imgf000096_0003
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using ethyl 4-amino-3-(6-methoxypyridin-3-yl)benzoate (0.910 g, 3.33 mmol), ice (5.0 g), cone. H2S04 (5.0 mL), NaN02 (0.414 g, 6.0 mmol), KI (1.10 g, 6.66 mmol), acetonitrile (5.0 mL), water (3.0 mL) to afford 1.03 g of the title product. 1H NMR (300 MHz, DMSO-<fc): δ 8.18-8.15 (dd, J = 3.3 Hz & 2.4Hz, 2H), 7.81 (s, 1H), 7.75-7.72 (dd, J = 2.4 Hz, 1H), 7.67- 7.64 (d, = 2.1 Hz & 1.8 Hz, 1H), 6.94-6.91 (d, = 8.1 Hz, 1H), 4.35-4.28 (q, = 6.9 Hz, 2H), 3.91 (s, 3H), 1.33- 1.28 (t, J = 6.6 Hz, 3H).
Step 3:- Preparation of ethyl 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(6- methoxypyridin-3-yl)benzoate
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using ethyl 4-iodo-3-(6-methoxypyridin-3-yl)benzoate (0.315 g, 0.820 mmol), 4-thynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 0.200 g, 0.819 mmol), TBAF (0.256 g, 0.98 mmol), PdCl2(PPh3)2 (0.012 g, 0.016 mmol), DMSO (2.0 mL) to afford 0.100 g of the title product.
Intermediate-50
3-(3-(lH-imidazol-l-yl)propyl)-4-((4-hydroxy-2-(trifluoromethyl)ph(
ethynyl)benzonitrile
Figure imgf000097_0001
Preparation of 3-(3-(lH-imidazol- l-yl)propyl)-4-iodobenzonitrile
Figure imgf000097_0002
To a solution of 3-(5-cyano-2-iodophenyl)propyl methanesulfonate (step- 1, Intermediate-48, 400 mg, 1.09 mmol) in DMF (10 mL) was added K2C03 (302 mg. 2.19 mmol), imidazole (150 mg, 2.19 mmol). The reaction mixture was heated at 120°C for 24 h. The reaction mass was quenched with water, extracted with DCM. The organic layers were dried over Na2S04 and concentrated to afford 180 mg of title compound. 1H NMR (300 MHz, DMSO-i¾): δ 8.05- 8.03 (d, J = 8.4 Hz, 1H), 7.73 (s, 1H), 7.66-7 '.63 (d, J = 8.7 Hz, 1H), 7.41-7.38 (t, J = 7.8 Hz, 1H), 7.21 (s, 1H), 6.89 (s, 1H), 4.06-4.01 (t, J = 7.2Hz, 2H), 2.68-2.63 (m, 2H), 2.05- 1.97 (m, 2H); MS [M+H]+: 338. Step 2:- Preparation of 3-(3-(lH-imidazol- l-yl)propyl)-4-((4-hydroxy-2-
(trifluoromethyl)phenyl)ethynyl)benzonitrile
The title compound was prepared following the procedure described in ste-3 of Intermediate- 1 by using 3-(3-(lH-imidazol- l-yl)propyl)-4-iodobenzonitrile (181 mg, 0.53 mmol), 4-ethynyl- 3-(trifluoromethyl)phenol (Intermediate-43, 100 mg, 0.53 mmol),TBAF (168 mg, 0.64 mmol), PdCl2(PPh3)2 (8.0 mg, 0.010 mmol), DMSO (2.0 mL) to afford 90 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 10.78 (s, 1H), 7.81 (s, 1H), 7.74-7.71 (d, = 7.8 Hz, 1H), 7.63-7.60 (m, 3H), 7.17 (s, 2H), 7.12-7.09 (d, = 8.4 Hz, 1H), 6.87 (s, 1H), 4.04- 3.99 (t, J = 6.9 Hz, 2H), 2.80-2.77 (t, J = 8.4 Hz, 2H), 2.08 (t, 2H); MS [M-H]~: 394.
Intermediate-51
4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-morpholinopropyl) benzonitrile
Figure imgf000098_0001
Preparation of 4-iodo-3-(3-morpholinopropyl)benzonitrile
Figure imgf000098_0002
To 3-(5-cyano-2-iodophenyl)propyl methanesulfonate (step- 1 of Intermediate-48, 400 mg, 1.05 mmol) was added morpholine (10.0 mL). The reaction mixture was heated at reflux for 24 h. The excess of morpholine was removed under vacuum and the reaction mass was diluted with water, extracted with DCM. The organic layers were dried over Na2S04 and concentrated to afford 210 mg of title compound. 1H NMR (300 MHz, CDC13): δ 7.96-7.93 (d, = 8.4 Hz, 1H), 7.48 (s, 1H), 7.17-7.14 (d, = 8.1 Hz, 1H), 3.83 (m, 4H), 3.72-3.67 (m, 2H), 2.84-2.78 (m, 2H), 2.61 (m, 4H), 1.67 (m, 2H).
Step 2:- Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3- morpholinopropyl) benzonitrile
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-iodo-3-(3-morpholinopropyl)benzonitrile (191 mg, 0.53 mmol), 4-ethynyl-3- (trifluoromethyl)phenol (Intermediate-43, 100 mg, 0.53 mmol), TBAF (168 mg, 0.64 mmol), PdCl2(PPh3)2 (8.0 mg, 0.010 mmol), DMSO (2.0 mL) to afford 85 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 10.76 (s, 1H), 7.84 (s, lH), 7.69-7.61 (m, 3H), 7.17 (s, 1H), 7.12-7.09 (d, = 7.2 Hz, 1H), 3.49 (m, 4H), 3.15-3.13 (m, 2H), 2.84 (t, 2H), 2.29 (m, 4H), 1.76 (m, 2H); MS [M+H]+: 415.
Intermediate-52
4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-hydroxypropyl)benzonitrile
Figure imgf000099_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-(trifluoromethyl)phenol (Intermediate-43, 100 mg, 0.53 mmol), 3-(3- hydroxypropyl)-4-iodobenzonitrile (step-4, Intermediate-38, 208 mg, 0.53 mmol), TBAF (168 mg, 0.64 mmol), PdCl2(PPh3)2 (8.0 mg, 0.010 mmol), DMSO (2.0 mL) to afford 70 mg of the title product. 1H NMR (300 MHz, DMSO-i¾: δ 10.75 (s, 1H), 7.79 (s, 1H), 7.71-7.60 (m, 3H), 7.17 (s. 1H), 7.11-7.09 (d, = 8.7Hz, 1H), 4.55 (br s, 1H), 3.44-3.40 (d, J = 6.3Hz, 2H), 2.87- 2.82 (t, J = 7.5 Hz, 2H), 1.78-1.73 (m, 2H); MS [M+H]+: 346.
Intermediate-53
Ethyl 3-(6-cyanopyridin-3- -4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl) benzoate
Figure imgf000099_0002
Preparation of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)picolinonitrile
Figure imgf000099_0003
The title compound was prepared following the procedure described in step-3 of Intermediate- 33 by using 5-bromopicolinonitrile (1.1 g, 6.04 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(l,3,2-dioxaborolane) (1.68 g, 6.66 mmol), potassium acetate (1.18 g, 12.04 mmol), Pd(dppf)C12 (0.246 g, 0.303 mmol) in 1,4-dioxane (50 mL) to afford 0.615 mg of title compound. 1H NMR (300 MHz, DMSO-i¾) : δ 8.87 (s, 1H), 8.22-8.20 (d, 7 = 7.5 Hz, 1H), 8.04-8.01 (d, 7 = 7.5 Hz, 1H), 1.32 (s, 12H).
Step 2:- Preparation of ethyl 4-amin -3-(6-cyanopyridin-3-yl)benzoate
Figure imgf000100_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 33 by using 5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)picolinonitrile (0.870 g, 3.59 mmol), ethyl 4-amino-3-bromobenzoate (step-2 of Intermediate-33, 0.870 g, 3.59 mmol), PdidppfiC (0.146 g, 0.179 mmol), diglyme (10 mL), K2C03 (0.744 g, 5.39 mmol) to afford 0.220 g of title product. 1H NMR (300 MHz, OMSO-d6): δ 8.78 (s, 1H), 8.10 (s, 2H), 7.73- 7.70 (m, 1H), 7.59 (s, 1H), 6.81-6.78 (d, 7 = 8.7 Hz, 1H), 6.01 (s, 2H), 4.25-4.18 (q, 7 = 6.9 Hz, 2H), 1.28-1.24 (t, 7 = 6.9 Hz, 3H); MS [M+H]+: 268.
Step 3:- Preparation of ethyl 3-(6-cyanopyridin-3-yl)-4-iodobenzoate
Figure imgf000100_0002
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using ethyl 4-amino-3-(6-cyanopyridin-3-yl)benzoate (400 mg, 1.49 mmol), ice (3.0 g), conc.H2S04 (3 ml), aq. NaN02 (186 mg, 2.69 mmol), aq. KI (497 mg, 2.99 mmol) to afford 3.03 mg of the title product. 1H NMR (300 MHz, DMSO-i¾) : δ 8.80 (s, 1H), 8.23- 8.14 (m, 3H), 7.88 (s, 1H), 7.75-7.72 (d, 7 = 7.2 Hz, 1H), 4.33-4.31 (q, 7 = 6.9 Hz, 2H), 1.33- 1.28 (t, 7 = 7.2 Hz, 3H); MS [M+H]+: 379.
Step 4:- Preparation of ethyl 3-(6-cyanopyridin-3-yl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl) benzoate
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 200 mg, 0.81 mmol), ethyl 3-(6-cyanopyridin-3-yl)-4-iodobenzoate (309 mg, 0.81 mmol), TBAF (256 mg, 0.98 mmol), PdCl2(PPh3)2 (11.4 mg, 0.016 mmol), DMSO (2.0 mL) to afford 250 mg of the title product.1!! NMR (300 MHz, DMSO-i¾) : δ 10.75 (s, 1H), 8.82-8.83 (d, 7 = 6.0 Hz, 1H), 8.33-8.31 (d, J = 6.0 Hz, 1H), 8.10-8.06 (m, 2H), 7.88-7.81 (m, 2H), 7.48-7.45 (d, J = 8.4 Hz, 1H), 7.10 (s, 1Η),7.08-7.05 (d, J = 7.8 Hz, 1H), 4.36-4.34 (q, = 6.9 Hz, 2H), 1.36- 1.31 (t, J = 7.5 Hz, 3H); MS [M+H]+: 437.
Intermediate-54
3-(3-(cyclopropylmethoxy)propyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)
ethynyl)benzonitrile
Figure imgf000101_0001
Preparation of 3-(3-(cyclopropylmethoxy)propyl)-4-iodobenzonitrile
Figure imgf000101_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 24 by using 3-(3-hydroxypropyl)-4-iodobenzonitrile (Step-4, Intermediate-38, 200 mg, 0.69 mmol), (bromomethyl)cyclopropane (141 mg, 1.04 mmol), NaH (42 mg, 1.04 mmol, 60% in mineral oil), DMF (15 mL) to afford 200 mg title compound. 1H NMR (300 MHz, CDC13): δ 7.94-7.92 (d, = 8.4Hz, 1H), 7.48 (s, 1H), 7.15-7.13 (d, = 6.3Hz, 1H), 3.48-3.44 (t, = 6.0 Hz, 2H), 3.29-3.26 (d, = 6.9Hz, 2H), 2.87-2.82 (t, = 7.2Hz, 2H), 1.91-1.86 (m, 2H), 1.07 (m, 1H), 0.56-0.54 (m, 2H), 0.22-0.21 (m, 2H); MS [M+H]+: 341.
Step-2:- Preparation of 3-(3-(cyclopropylmethoxy)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl) ethynyl)benzonitrile
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-(trifluoromethyl)phenol (Intermediate-43, 100 mg, 0.53 mmol), 3-(3-(cyclopropylmethoxy)propyl)-4-iodobenzonitrile (183 mg, 0.53 mmol), TBAF (169 mg, 0.64 mmol), PdCl2(PPh3)2 (8 mg, 0.010 mmol), DMSO (2.0 mL) to afford 75 mg of the title product.1!! NMR (300 MHz, DMSO-i¾): δ 10.75 (s, 1H),7.80 (s, 1H), 7.70-7.68 (t, = 7.2 Hz, 2H), 7.63-7.61 (d, J = 7.8 Hz, 1H), 7.17 (s, 1H), 7.11 (d, 1H), 3.19-3.17(d, = 7.8 Hz, 2H), 2.89-2.87 (t, = 6.9 Hz, 2H), 1.86-1.84 (m, 2H),1.23 (m, 1H), 0.86-0.81 (m, 2H), 0.43-0.41 (d, J = 7.8 Hz, 2H), 0.13-0.11 (m, 2H); MS [M+H]+: 400.
Intermediate- 55
Ethyl 3-(4-ethoxybutyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoate
Figure imgf000102_0001
Preparation of ethyl 4-amino-3-iodobenzoate
Figure imgf000102_0002
To a solution of iodine (3.01 g, 11.8 mmol) in EtOH (50 mL) was added silver sulphate (3.75 g, 11.8 mmol) and ethyl 4-aminobenzoate (step-1, Intermediate-33, 1.0 g).The reaction mixture was stirred at RT for 1 h. The reaction mass was filtered and excess of EtOH was removed under vacuum. The reaction mass was diluted with DCM and washed with aq. sodium thiosulphate and again concentrated to afford 1.5 g of title compound. 1H NMR (300 MHz, DMSO-i¾): δ 8.10 (s, 1Η),7.66-7.63 (d, = 8.4 Hz, 1H), 6.75-6.72 (d, = 8.7 Hz, 1H), 6.05 (s, 2H), 4.23-4.16 (q, = 7.2Hz, 2H), 1.28-1.24 (t, = 7.Hz, 2H).
Step-2:- Preparation of ethyl 4-amino-3-(4-hydroxybut-l-yn-l-yl)benzoate
Figure imgf000102_0003
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using ethyl 4-amino-3-iodobenzoate (3.0 g, 10.30 mmol), but-3-yn-l-ol (1.08 g, 15.46 mmol), PdCl2 (PPh3)2 (0.144 g, 0.200 mmol), Cul (0.040g, 0.20 mmol), Et3N (2.97 mL, 20.6 mmol), in DMSO (10.0 mL) to afford 1.90 g of title compound. 1H NMR (300 MHz, DMSO-i¾: δ 7.67 (s, 1Η),7.61-6.58 (d, = 8.4Hz, 1H), 6.71-6.88 (t, = 6.0 Hz, 1H),6.12 (s, 2H), 4.95-4.92 (t, = 5.4 Hz, 1H), 4.23-4.16 (q, = 6.9 Hz, 2H), 3.63-3.57 (q, = 6.0 Hz, 2H), 2.61-2.57 (t, = 6.9 Hz, 2H), 1.28-1.24 (t, = 6.9 Hz, 3H); MS [M+H]+: 234. Step-3:- Preparation of ethyl 4-amino-3-(4-hydroxybutyl)benzoate
Figure imgf000103_0001
The title compound was prepared following the procedure described in step-2 of Intermediate- 38 by using ethyl 4-amino-3-(4-hydroxybut-l-yn-l-yl)benzoate (1.9 g, 8.15 mmol), Pd/CaC03 (0.700 g) in EtOH (50 mL) to afford 1.7 g of title product. 1H NMR (300 MHz, DMSO-i¾): δ 7.52 (s, 2H),6.61-6.58 (d, = 8.7 Hz, 1H), 5.71 (s, 2H), 4.39 (t, 1H), 4.22-4.15 (q, = 6.9 Hz, 2H), 3.43-3.41(m, 2H), 2.45-2.41 (t, = 6.9 Hz, 2H), 1.49 (m, 4H), 1.28-1.23 (t, 7 = 6.9 Hz, 3H).
Step-4:- Preparation of ethyl 3-( -hydroxybutyl)-4-iodobenzoate
Figure imgf000103_0002
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using ethyl 4-amino-3-(4-hydroxybutyl)benzoate (1.70 g, 7.17 mmol), ice-water (10.2 mL), conc.H2S04 (5.2 ml), aq. NaNO2 (8.90 g, 12.9 mmol), aq. KI (2.38 g, 14.34 mmol) to afford 0.600 g of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 7.99-7.97 (d, = 8.4 Hz, 1H), 7.81 (s, 1H), 7.49-7.45 (d, = 7.8 Hz, 1H), 4.42 (t, 1H), 4.33-4.26 (q, = 6.9 Hz, 2H), 3.43-3.41 (m, 2H), 2.76-2.741 (t, = 7.5 Hz, 2H), 1.54-1.48 (m, 4H),1.33-1.28 (t, = 6.9 Hz, 3H); MS [M+H]+: 349.
Step-5:- Preparation of ethyl 3-(4-ethoxybutyl)-4-iodobenzoate
Figure imgf000103_0003
The title compound was prepared following the procedure described in step-2 of Intermediate- 27 by using ethyl 3-(4-hydroxybutyl)-4-iodobenzoate (300 mg, 0.86 mmol), K2C03 (178 mg, 1.29 mmol), bromoethane (141 mg, 1.29 mmol) in DMF (10 mL) to afford 230 mg of title product. 1H NMR (300 MHz, DMSO-i¾: δ 7.89 (s, 1Η),7.86-7.83 (d, = 8.4 Hz, 1H), 7.51- 7.49 (d, = 6.3 Hz, 1H), 4.39-4.32 (d, = 7.2 Hz, 2H), 3.51-3.44 (m, 4H), 2.78 (m, 2H), 1.68 (m, 4H), 1.41-1.36 (d, = 6.9 Hz, 3H), 1.25-1.18 (m, 3H); MS [M+H]+: 377.
Step-6:- Preparation of ethyl 3-(4-ethoxybutyl)-4-((4-hydroxy-2-
(trifluoromethyl)phenyl)ethynyl) benzoate
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-(trifluoromethyl)phenol (Intermediate-43, 100 mg, 0.53 mmol), ethyl 3-(4-ethoxybutyl)-4-iodobenzoate (202 mg, 0.53 mmol), TBAF (169 mg, 0.64 mmol), PdCl2(PPh3)2 (10 mg, 0.010 mmol), DMSO (2.0 mL) to afford 50 mg of the title product H NMR (300 MHz, DMSO-i¾): δ 10.71 (s, 1H), 7.86 (s, 1H), 7.82-7.80 (d, = 7.5 Hz, 1H), 7.68-7.65 (d, = 8.7 Hz, 1H), 7.61-7.58 (d, = 7.8 Hz, 1H), 7.16 (s, 1H), 7.11-7.08 (d, = 7.8 Hz, 1H), 4.33-4.31 (q, = 7.2 Hz, 2H), 3.34 (m, 2H), 2.85 (m, 2H), 2.17-2.05 (m, 2H), 1.64- 1.53 (m, 4H), 1.34-1.30 (t, J = 6.6 Hz, 3H), 1.07- 1.02 (t, J = 7.2 Hz, 3H); MS [M-H]": 433.
Intermediate-56
5- e
Figure imgf000104_0001
Preparation of 5-nitro-2-propoxypyridine
Figure imgf000104_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 24 by using 2-chloro-5-nitropyridine (1.0 g, 6.32 mmol), propan- l-ol (0.760 g, 12.36 mmol), NaH (0.503 g, 12.57 mmol, 60% in mineral oil), DMF (5.0 mL) to afford 0.480 g title compound. 1H NMR (300 MHz, OMSO-d6): δ 9.08 (s, 1H), 8.48-8.44 (dd, = 7.2 Hz, 1H), 7.04-7.01 (d, = 9.3 Hz, 1H), 4.37-4.33 (t, = 6.9 Hz, 2H), 1.79-1.72 (q, = 6.9 Hz, 2H), 0.99-0.94 (t, = 7.8 Hz, 3H); MS [M+H]+: 182.
Step-2:- Preparation of 6-propoxypyridin-3-amine
Figure imgf000104_0003
The title compound was prepared following the procedure described in step-1 of Intermediate- 1 by using 5-nitro-2-propoxypyridine (2.13 g, 11.67 mmol), iron powder (3.90 g, 69.6 mmol), cone. HC1 (5 mL) in methanol (15 mL) to afford 1.5 g of title product. 1H NMR (300 MHz, DMSO-i¾: δ 7.47 (s, 1H), 6.99-6.91 (m, 1H), 6.52-6.49 (d, J = 9.0 Hz, 1H), 4.70 (s, 2H), 4.04-4.0 (t, J = 6.3 Hz, 2H), 1.73- 1.61 (m, 2H), 0.94-0.89 (t, J = 7.5 Hz, 3H).
Step-3:- Preparation of 5-iodo-2-propoxypyridine
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using 6-propoxypyridin-3 -amine (1.65 g, 10.8 mmol), ice-water (10.2 mL), conc.H2S04 (6.0 ml), aq. NaN02 (1.34 g, 19.4 mmol), aq. KI (3.58 g, 21.6 mmol) in acetonitrile (5.0 mL) to afford 1.45 g of the title product. 1H NMR (300 MHz DMSO-i¾): δ 8.35 (s, 1H), 7.97-7.94 (dd, J = 2.4 Hz, 1H), 6.72-6.69 (d, 8.7 Hz, 1H), 4.17-4.13 (t, = 6.3 Hz, 2H), 1.73- 1.66 (q, = 6.9 Hz, 2H), 0.96-0.91 (t, J = 7.5 Hz, 3H); [M+H]+: 264. Intermediate-57
ethyl 4- l)benzoate
Figure imgf000105_0001
Step- 1 :- Preparation of ethyl 4-amino-3-ethynylbenzoate
Figure imgf000105_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using ethyl 4-amino-3-iodobenzoate (step- 1 of Intemediate-66, 3.0 g, 10.34 mmol), trimethyl sillyl acetylene (1.52 g, 15.5 mmol), PdCl2 (PPh3)2 (0.144 g, 0.200 mmol), Cul (0.039 g, 0.200 mmol), Et3N (1.56 g, 15.50 mmol) and 1.0 M TBAF (17 mL in THF, 15.49 mmol) to afford 1.6 g of title compound. 1H NMR (300 MHz, DMSO-i¾): δ 7.74 (s, 1H), 7.65-7.63 (d, = 8.4 Hz, 1H),6.73-6.71 (d, = 8.14 Hz, 1H), 6.21 (br s, 2H), 4.40 (s, 1H), 4.23-4.16 (q, = 6.9Hz, 2H), 1.29-1.24 (d, = 8.4 Hz, 3H),.
Step-2:- Preparation of ethyl 4-amino-3-((6-propoxypyridin-3-yl)ethynyl)benzoate
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using ethyl 4-amino-3-ethynylbenzoate (1.0 g, 5.29 mmol), 5-iodo-2-propoxypyridine (Intermediate-56, 1.39 g, 5.28 mmol), TBAF (1.65 g, 6.30 mmol), PdCl2(PPh3)2 (0.074 g, 0.105 mmol), DMSO (3.0 mL) to afford 0.900 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.45 (s, 1H), 7.97-7.94 (d, = 9.0 Hz, 1H), 7.81 (s, 1H), 7.67-7.64 (d, = 8.7 Hz, 1H), 6.87-6.84 (d, = 8.4 Hz, 1H), 6.77-6.74 (d, = 8.7 Hz, 1H), 6.37 (br s, 2H), 4.26- 4.21 (q, = 6.9 Hz, 4H), 1.76- 1.69 (q, = 7.5 Hz, 2H), 1.30- 1.26 (t, = 7.2 Hz, 3H), 0.99- 0.94 (t, = 7.2 Hz, 3H).
Intermediate- 58
3-(3-(lH-l,2,3-triazol- l-yl)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzonitrile
Figure imgf000106_0001
Step- 1 : -Preparation of 3-(3-(lH-l,2,3-triazol-l-yl)propyl)-4-iodobenzonitrile
The title compound was prepared following the procedure described in step-3 of Intermediate- 24 by using 3-(5-cyano-2-iodophenyl)propyl methanesulfonate (step-1, Intermediate-48, 400 mg, 1.09 mmol), lH- l,2,3-triazole (0.113 g, 1.64 mmol), NaH (0.066 g, 1.64 mmol, 60% in mineral oil), DMF (50 mL) to afford 0.100 g title compound. 1H NMR (300 MHz, CDC13): δ 7.96-7.94 (d, = 8.4 Hz, 1H), 7.78 (brs, 1H), 7.63 (br s, 1H), 7.47-7.43 (m, 1H), 7.20-7.16 (d, 1H), 4.53-4.48 (t, = 8.4Hz, 2H), 2.80-2.77 (m, 2H), 2.26 (m, 2H).
Step-2:- Preparation of 3-(3-(lH- l,2,3-triazol- l-yl)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzonitrile
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 3-(3-(lH- l,2,3-triazol- l-yl)propyl)-4-iodobenzonitrile (0.100 g, 0.53 mmol), 4- ethynyl-3-(trifluoromethyl)phenol (Intermediate-43, 0.181 g, 0.53 mmol), TBAF (0.169 g, 0.64 mmol), PdCl2(PPh3)2 (0.008 g, 0.010 mmol), DMSO (2.0 mL) to afford 0.060 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.76 (s, 1H), 8.14 (s, 1H), 7.82 (s, 1H), 7.75-7.70 (m, 1H), 7.64-7.56 (m, 3H), 7.17 (s, 1H), 7.12-7.10 (d, = 8.1 Hz, 1H), 4.45-4.40 (t, = 6.9 Hz, 2H), 2.83 (m, 2H), 2.19 (m, 2H); MS [M+H]+: 395.
Intermediate- 59
4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(pyridin-3-yloxy)propyl)benzonitrile
Figure imgf000107_0001
Step-1:- Preparation of 4-iodo-3-(3-(pyridin-3-yloxy)propyl)benzonitrile
Figure imgf000107_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 24 by using 3-(5-cyano-2-iodophenyl)propyl methanesulfonate (step-1, Intermediate-48, 300 mg, 0.82 mmol), pyridin-3-ol (154 mg, 1.64 mmol), NaH (65 mg, 1.64 mmol, 60% in mineral oil), DMF (10 mL) to afford 150 mg title compound.
Step-2:- Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(pyridin-3- yloxy)propyl)benzonitrile
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-iodo-3-(3-(pyridin-3-yloxy)propyl)benzonitrile (195 mg, 0.53 mmol), 4-ethynyl- 3-(trifluoromethyl)phenol (Intermediate-43, 100 mg, 0.53 mmol), TBAF (169 mg, 0.64 mmol), PdCl2(PPh3)2 (8.0 mg, 0.010 mmol), DMSO (2.0 mL) to afford 60 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.75 (s, 1H), 8.21 (s, 1H), 8.19 (s, 1H), 7.85 (s, 1H), 7.75-7.72 (d, = 8.4 Hz, 1H), 7.65 (m, 2H), 7.30 (m, 2H), 7.16 (s, 1H), 7.09-7.06 (d, = 7.8 Hz, 1H), 4.07 (t, 2H), 3.00 (m, 2H), 2.09 (m, 2H).
Intermediate- 60
3-(3-(2-ethoxyethoxy)propyl)- -((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzonitrile
Figure imgf000107_0003
Step-1:- Preparation of 3-(3-(2-ethoxyethoxy)propyl)-4-iodobenzonitrile
Figure imgf000108_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 24 by using 3-(3-hydroxypropyl)-4-iodobenzonitrile (step-4, Intermediate-38, 300 mg, 1.04 mmol), l-bromo-2-ethoxyethane (318 mg, 2.08 mmol), NaH (62 mg, 1.55 mmol, 60% in mineral oil), DMF (10 mL) to afford 150 mg title compound. 1H NMR (300 MHz, CDC13): δ 7.95-7.92 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.15-7.12 (d, J = 8.4 Hz, 1H), 3.70-3.48 (m, 7H), 2.87-2.82 (m, 2H), 2.04-1.08 (m„ 2H), 2.04-2.08 (m, s, 3H), 1.25-1.21 (m, 2H).
Step-2:- Preparation of 3-(3-(2-ethoxyethoxy)propyl)-4-((4-hydroxy-2-
(trifluoromethyl)phenyl)ethynyl)benzonitrile
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 3-(3-(2-ethoxyethoxy)propyl)-4-iodobenzonitrile (192 mg, 0.53 mmol), 4-ethynyl-3-(trifluoromethyl)phenol (Intermediate-43, 100 mg, 0.53 mmol), TBAF (168 mg, 0.64 mmol), PdCl2(PPh3)2 (8.0 mg, 0.010 mmol), DMSO (2.0 mL) to afford 50 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.78 (brs, 1H), 7.81 (s, 1H), 7.71- 7.61 (m, 3H), 7.17 (m, 1H), 7.11-7.09 (d, = 8.7 Hz, 1H), 3.45-3.38 (m, 8H), 2.87 (m, 2H), 1.90-1.84 (m, 2H), 1.09-1.04 (d, / = 8.4 Hz, 3H).
Intermediate-61
Ethyl 4-(3-(cyclopropylmethoxy)propyl)-2-iodobenzoate
Figure imgf000108_0002
Step-1:- Preparation of 4-(3-(cyclopropylmethoxy)propyl)-2-iodobenzoic acid
Figure imgf000108_0003
To a solution of 4-(3-(cyclopropylmethoxy)propyl)-2-iodobenzonitrile (300 mg, 0.87 mmol) in EtOH (10.0 mL) was added 2N NaOH (10.0 mL). The reaction mass was heated to reflux for 12 h. The reaction mass was concentrated under vaccum and diluted with water and aqueous layer was acidified with dil HCl and filtered off the precipitate to afford 250 mg of title product.1!! NMR (300 MHz, DMSO- 6): δ 7.96-7.94 (d, = 7.8 Hz, 1H),7.79 (s, 1H), 3.38 (t, 2H), 3.21-3.19 (d, J = 6.6 Hz, 2H), 2.77 (t, 2H), 1.76 (m, 2H), 0.99 (m, 1H), 0.43 (m, 2H), 0.16 (m, 2H)
Step-2:- Preparation of ethyl 4- -(cyclopropylmethoxy)propyl)-2-iodobenzoate
Figure imgf000109_0001
The title compound was prepared following the procedure described in step-2 of Intermediate- 27 by using 4-(3-(cyclopropylmethoxy)propyl)-2-iodobenzoic acid (250 mg, 0.69 mmol), K2C03 (143 mg, 1.04 mmol), bromoethane (113 mg, 1.04 mmol) in DMF (10 mL) to afford 165 mg of title product. 1H NMR (300 MHz, CDCI3): δ 7.90-7.87 (m, 2H), 7.53-7.50 (d, = 8.1 Hz, 1H), 4.39-4.32 (q, = 7.2 Hz, 2H), 3.49-3.45 (t, = 6.6 Hz, 2H),3.29-3.27 (d, = 6.9 Hz, 2H), 2.88-2.83 (t, = 7.2 Hz, 2H), 1.93-1.88 (m, 2H), 1.41-1.36 (t, = 6.9 Hz, 3H), 1.09 (br s, 1H), 0.56-0.53 (q, / = 8.4 Hz, 2H),0.23-0.22 (m, 2H); MS [M+H]+: 388.
Intermediate- 62
4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(2-methyl- lH-imidazol-l- yl)propyl)benzonitrile
Figure imgf000109_0002
Preparation of 4-iodo-3-(3- -methyl-lH-imidazol-l-yl)propyl) benzonitrile
Figure imgf000109_0003
The title compound was prepared following the procedure described in step-1 of Intermediate- 50 by using 3-(5-cyano-2-iodophenyl)propyl methanesulfonate (Step- 1, Intermediate-48, 200 mg, 0.547 mmol), DMF (10 mL) was added K2C03 (113 mg, 0.82 mmol), 2-methyl imidazole (89 mg, 1.09 mmol) to afford 150 mg of title compound.
Step 2:- Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(2-methyl-lH- imidazol- 1 -yl)propyl)benzonitrile
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-iodo-3-(3-(2-methyl- lH-imidazol- l-yl)propyl)benzonitrile (80 mg, 0.217 mmol), 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 53 mg, 0.21 mmol), TBAF (68 mg, 0.26 mmol), PdCl2(PPh3)2 (3.0 mg, 0.004 mmol), DMSO (2.0 mL) to afford 45 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 7.89-7.84 (m, 1H), 7.72 (m, 2H), 7.63 (d, 1H), 7.17 (s, 1H), 7.05 (s, 2H), 6.72 (s, 1H), 3.92 (m, 2H), 2.82 (d, 2H), 2.22 (s, 3H), 2.01 (m, 2H).
Intermediate-63
3-(3-(benzyloxy)propyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl) benzonitrile
Figure imgf000110_0001
Step 1:- Preparation of 3-(3-(benzyloxy)propyl)-4-iodobenzonitrile
Figure imgf000110_0002
The title compound was prepared follow the procedure described in step-3 of Intermediate- 24 by using 3-(3-hydroxypropyl)-4-iodobenzonitrile (step-4, Intermediate-38, 300 mg, 1.04 mmol), l-bromo-2-methoxyethane (256 mg, 1.56 mmol), NaH (63 mg, 1.56 mmol, 60% in mineral oil), DMF (3 mL) to afford 120 g title compound. 1H NMR (300 MHz, DMSO-D6): δ 8.05-8.02 (d, J = 7.8 Hz, 1H), 7.71 (s, 1H), 7.36-7.33 (m, 6H), 4.52 (s, 2H), 3.48-3.46 (t, J = 6.6 Hz, 2H), 2.78-2.75 (t, J = 8.7 Hz, 2H), 1.82 (m, 2H).
Step-2:- Preparation of 3-(3-(benzyloxy)propyl)-4-((4-hydroxy-2-
(trifluoromethyl)phenyl)ethynyl)benzonitrile
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 3-(3-(benzyloxy)propyl)-4-iodobenzonitrile (108 mg, 0.287 mmol), 4-ethynyl-3- (trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 70 mg, 0.28 mmol), TBAF (89 mg, 0.34 mmol), PdCl2(PPh3)2 (4.0 mg, 0.005 mmol), DMSO (2.0 mL) to afford 40 mg of the title product. 1H NMR (300 MHz, CdCl3): δ 7.55-7.48 (m, 4H), 7.33 (s, 4H), 7.16 (s, 2H), 6.94 (m, 1H), 4.51 (s, 2H), 3.51-3.49 (t, J = 6.3 Hz, 2H), 2.97 (m, 2H), 1.99 (m, 2H).
Intermediate- 64
Ethyl 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(6-propoxypyridin-3-yl)benzoate
Figure imgf000111_0001
Preparation of 5-bromo-2-propoxypyridine
Figure imgf000111_0002
To a solution of 5-bromo-2-chloropyridine (3.0 g, 15.59 mmol) in THF (10 mL) was added N- propyl alcohol (1.2 mL, 16.0 mmol), potassium ie/t-butoxide (1.90 g, 16.96 mmol). The reaction mixture was heated at 120°C for 5-6 h. The reaction mixture was quenched in water, extracted with ethyl acetate. The organic layers were dried over Na2S04 and concentrated to afford 1.5 g of title compound. 1H NMR (300 MHz, DMSO-d6): δ 8.26 (s, 1H), 7.89-7.85 (dd, = 3.0 Hz, 1H), 6.82-6.79 (d, = 8.7 Hz, 1H), 4.19-4.14 (t, = 6.6 Hz, 2H), 1.73-1.66 (dq = 7.2 Hz, 2H), 0.94-0.91 (t, = 7.2 Hz, 3H); MS [M+H]+: 216.
Step-2:- Preparation of 2-propoxy- -(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine
Figure imgf000111_0003
The title compound was prepared following the procedure described in step-3 of Intermediate- 33 by using 5-bromo-2-propoxypyridine (3.0 g, 13.95 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (3.54 g, 13.95 mmol), potassium acetate (2.87 g, 29.25 mmol), Pd(dppf)C12 (0.569 g, 0.697 mmol) in 1,4-dioxane (50 mL) to afford 1.5 g of title compound. 1H NMR (300 MHz, DMSO-i¾: δ 8.36 (s, 1H), 7.85-7.83 (d, = 8.4 Hz, 1H), 6.78-6.75 (d, = 8.1 Hz, 1H), 4.23-4.18 (t, = 6.6 Hz, 2H), 1.73-1.66 (q, = 7.2 Hz, 2H), 1.14 (s, 6H), 1.05 (s, 6H), 0.95-0.90 (t, = 7.2 Hz, 3H).
Step-3:- Preparation of ethyl 4-amino-3-(6-propoxypyridin-3-yl)benzoate
Figure imgf000112_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 33 by using 2-propoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1.5 g, 6.1 mmol), ethyl 4-amino-3-bromobenzoate (step-2 of Intermediate-33, 1.34 g, 5.08 mmol), Pd(dppf)Cl2 (0.207 g, 0.25 mmol), diglyme (50 mL), K2C03 (1.05 g, 7.62 mmol) to afford 0.500 g of title product. 1H NMR (300 MHz, OMSO-d6): δ 8.13 (s, 1H), 7.68-7.63 (m, 2H), 7.51 (s, 1H), 6.88-6.85 (d, J = 8.4 Hz, 1H), 6.76-6.73 (d, J = 8.7 Hz, 1H), 5.75-5.72 (br s, 2H), 4.26-4.19 (q, J = 6.9 Hz, 4H), 1.75- 1.73 (m, 2H), 1.27- 1.23 (t, J = 6.6Hz, 3H), 1.0-0.95 (t, J = 7.2 Hz, 3H).
Step-4:- Preparation of ethyl 4-iodo- -(6-propoxypyridin-3-yl)benzoate
Figure imgf000112_0002
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using ethyl 4-amino-3-(6-propoxypyridin-3-yl)benzoate (0.500 g, 1.6 mmol), ice (10 g), conc.H2S04 (3 ml), aq. NaN02 (0.207 g, 2.9 mmol), aq. KI (0.531 g, 3.2 mmol) to afford 0.440 g of the title product. 1H NMR (300 MHz, DMS0i¾: δ 8.18 (s, 1H), 8.15-8.14 (br s, 1H), 7.78 (s, 1H), 7.74-7.71 (d, = 6.3 Hz, 1H), 7.67-7.64 (d, = 8.1 Hz, 1H), 6.91-6.88 (d, = 9.0 Hz, 1H), 4.35-4.30 (q, J = 7.5 Hz, 2H),4.28-4.24(t, J = 6.9 Hz, 2H), 1.79-1.72 (q, J = 6.9 Hz, 2H), 1.33-1.28 (t, = 7.2 Hz, 3H), 1.01-0.96 (t, = 7.8 Hz, 3H).
Step-5:- Preparation of ethyl 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(6- propoxypyridin-3-yl)benzoate
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using ethyl 4-iodo-3-(6-propoxypyridin-3-yl)benzoate (0.442 g, 1.07 mmol), 4-ethynyl- 3-(trifluoromethyl)phenol (Intermediate-43, 0.200 g, 1.07 mmol), TBAF (0.338 g, 1.2 mmol), PdCl2(PPh3)2 (0.015 g, 0.02 mmol), DMSO (2.0 mL) to afford 0.200 g of the title product. 1H NMR (300 MHz, DMSCfcfc): δ 10.70 (s, 1H), 8.35 (s, 1H), 7.98-7.95 (m, 3H), 7.74-7.71 (d, = 8.4 Hz, 1H), 7.44-7.41 (d, J = 9.0 Hz, 1H), 7.10 (s, 1H), 7.05-7.02 (d, J = 8.4 Hz, 1H),6.92- 6.89 (d, = 8.4 Hz, 1H), 4.36-4.32 (q, = 7.2 Hz, 2H), 4.27-4.23 (t, = 6.3 Hz, 2H), 1.77- 1.70 (q, J = 6.9 Hz, 2H), 1.34-1.29 (t, J = 7.2 Hz, 3H),0.99-0.94 (t, J = 7.5 Hz, 3H); MS [M+H]+: 470.
Intermediate-65
Ethyl 3-(6-chloropyridin-3- -4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl) benzoate
Figure imgf000113_0001
Step- 1 :- Preparation of ethyl 4-amin -3-(6-chloropyridin-3-yl)benzoate
Figure imgf000113_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 33 by using (6-chloropyridin-3-yl)boronic acid (1.43 g, 9.1 mmol), ethyl 4-amino-3- bromobenzoate (step-2 of Intermediate-33, 2.0 g, 8.2 mmol), Fd(dppfiC (0.337 g, 0.41 mmol), diglyme (5.0 mL), K2C03 (1.71 g, 0.012 mmol) to afford 1.02 g of title product. 1H NMR (300 MHz, OMSO-d6): δ 8.41 (s, 1H), 7.88-7.86 (d, = 8.4 Hz, 1H), Ί .10-1.61 (d, = 8.1 Hz, 1H), 7.58-7.54 (m, 2H), 6.79-6.76 (d, J = 9.0 Hz, 2H), 1.28- 1.24 (t, J = 6.9 Hz, 3H). Step-2:- Preparation of ethyl 3-(6-chloropyridin-3-yl)-4-iodobenzoate
Figure imgf000113_0003
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using ethyl 4-amino-3-(6-chloropyridin-3-yl)benzoate (0.200 g, 0.51 mmol), ice (10 g), conc.H2S04 (3 ml), aq. NaN02 (0.090 g, 1.29 mmol), aq. KI (0.240 g, 1.44 mmol) to afford 0.280 g of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.44 (s, 1H), 8.21-8.18 (d, = 8.4 Hz, 1H), 7.93-7.90 (d, J = 7.8 Hz, 1H), 7.85 (m, 1H), 7.71-7.64 (m, 2H), 4.33-4.30 (q, J = 6.9 Hz, 2H), 1.33-1.28 (t, J = 6.6 Hz, 3H); MS [M+H]+: 388.
Step-3:- Preparation of ethyl 3-(6-chloropyridin-3-yl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl) benzoate
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using ethyl 3-(6-chloropyridin-3-yl)-4-iodobenzoate (0.144 g, 0.77 mmol), 4-ethynyl-3- (trifluoromethyl)phenol (Intermediate-43, 0.144 g, 0.51 mmol), PdCl2 (PPh3)2 (0.144 g, 0.200 mmol), Cul (0.002 g, 0.010 mmol), Et3N (51 mg, 0.51 mmol) in DMSO (10 mL) to afford 0.150 g of title compound. 1H NMR (300 MHz, OMSO-d6): δ 10.74 (s, 1H), 8.65 (s, 1H), 8.13-8.11 (d, J = 8.1 Hz, 1H), 8.06-8.01 (m, 1H), 7.81-7.78 (d, J = 8.4 Hz, 1H), 7.67-7.64 (d, = 8.4 Hz, 1H), 7.48-7.45 (d, = 9.0 Hz, 1H), 7.10 (s, 1H), 7.08-7.05 (d, = 9.0 Hz, 1H), 4.36-4.34 (q, J = 7.2 Hz, 2H), 1.35-1.31 (t, J = 6.9 Hz, 3H).
Intermediate-66
Ethyl 3-(6-hydroxypyridin-3-yl)-4-((4-((methylsulfonyl)oxy)-2-(trifluoromethyl)
phenyl)ethynyl)benzoate
Figure imgf000114_0001
Preparation of ethyl 3-(6-hydroxypyridin-3-yl)-4-iodobenzoate
Figure imgf000114_0002
To a solution of ethyl 4-iodo-3-(6-methoxypyridin-3-yl)benzoate (100 mg, 0.26 mmol) in acetonitrile (5.0 mL) was added trimethylsillyl iodide (261 mg, 1.30 mmol). The reaction mass was heated at 80°C for 16 h. The reaction mixture was quenched in water, extracted with ethyl acetate. The organic layers were dried over Na2S04 and concentrated to afford 60 mg of title compound. 1H NMR (300 MHz, DMSO-d6): δ 11.84 (s, 1H), 8.14-8.11 (d, J = 8.1 Hz, 1H), 7.79 (s, 1H), 7.63-7.60 (d, J = 8.4 Hz, 1H), 7.48-7.45 (s, 2H), 6.41-6.38 (d, J = 6.9 Hz, 1H), 4.34-4.27 (q, = 7.2 Hz, 2H), 1.33-1.28 (d, 7 = 7.2 Hz, 3H); MS [M+H]+: 370. Step-2:- Preparation of ethyl 3-(6-hydroxypyridin-3-yl)-4-((4-((methylsulfonyl)oxy)-2- (trifluoromethyl) phenyl)ethynyl)benzoate
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using ethyl 3-(6-hydroxypyridin-3-yl)-4-iodobenzoate (70 mg, 0.19 mmol), 4-ethynyl-3- (trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 75 mg, 0.28 mmol), PdCl2 (PPh3)2 (68 mg, 0.003 mmol), Cul (2 mg, 0.003 mmol), Et3N (19 mg, 0.19 mmol) in DMSO (10 mL) to afford 60 mg of title compound. 1H NMR (300 MHz, DMSO-i¾): δ 11.89 (br s, IH), 7.95 (m, 2H), 7.78 (m, 5H), 7.45 (m, IH), 6.46 (m, IH), 4.36 (m, 2H), 3.50 (s, 3H), 1.33 (t, 3H).
Intermediate- 67
4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(pyrazin-2-yloxy)propyl)benzonitrile
Preparation of 4-iodo- nzonitrile
Figure imgf000115_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 24 by using 3-(3-hydroxypropyl)-4-iodobenzonitrile (Step-4, Intermediate-38, 0.300 g, 1.04 mmol), 2-iodopyrazine (0.321 g, 1.56 mmol), NaH (0.062 g, 1.56 mmol, 60% in mineral oil), DMF (10 mL) to afford 0.150 g title compound. 1H NMR (300 MHz, DMSO d6): δ 8.27 (br s, IH), 8.19 (s, 2H), 8.06-8.03 (d, J = 7.8 Hz, IH), 7.79 (s, IH), 7.40-7.38 (d, J = 8.4 Hz, IH), 4.34 (t, 2H), 2.87 (t, 2H), 2.04 (m, 2H); MS [M+H]+: 365.
Step-2:- Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(pyrazin-2- yloxy)propyl)benzonitrile
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate- 30, 100 mg, 0.40 mmol), 4-iodo-3-(3-(pyrazin-2-yloxy)propyl)benzonitrile (146 mg, 0.40 mmol), TBAF (128 mg, 0.49 mmol), PdCl2(PPh3)2 (6 mg, 0.008 mmol), DMSO (2.0 mL) to afford 80 mg of the title product.1H NMR (300 MHz, DMSO-i¾): δ 10.75 (s, 1H), 8.15 (s, 2H), 7.86 (s, 1H), 7.74-7.71 (d, J = 8.4 Hz, 1H), 7.64-7.62 (m, 3H), 7.15 (s, 1H), 7.09-7.06 (d, 7 = 8.1 Hz, 1H), 4.34-4.30 (t, J = 6.3 Hz, 2H), 3.02-2.97 (t, J = 6.9 Hz, 2H), 2.11(m, 2H); MS [M+H]+: 424.
Intermediate- 68
4-((2-(3-(4-carbamoylpiperidin-l-yl)propyl)-4-cyanophenyl)ethynyl)-3- (trifluoromethyl)phenyl methanesulfonate
Figure imgf000116_0001
Step-1:- Preparation of l-(3-( -cyano-2-iodophenyl)propyl)piperidine-4-carboxamide
Figure imgf000116_0002
The title compound was prepared following the procedure described in step-1 of Intermediate- 50 by using 3-(5-cyano-2-iodophenyl)propyl methanesulfonate (step-1, Intermediate-48, 400 mg, 1.09 mmol), DMF (35 mL), K2C03 (302 mg, 2.19 mmol), piperidine-4-carboxamide (210 mg, 1.63 mmol) to afford 135 mg of title compound. 1H NMR (300 MHz, CDClj): δ 7.96- 7.94 (d, = 7.8 Hz, 1H), 7.47 (s, 1H), 7.17-7.15 (d, = 6.6 Hz, 1H), 5.50 (br s, 2H), 4.18-4.13 (m, 4H), 2.89-2.81 (m, 4H), 2.35 (m, 1H), 1.98-1.86 (m, 4H), 1.65 (m, 2H).
Step-2:- Preparation of 4-((2-(3-(4-carbamoylpiperidin-l-yl)propyl)-4-cyanophenyl)ethynyl)-
3- (trifluoromethyl)phenyl methanesulfonate
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using l-(3-(5-cyano-2-iodophenyl)propyl)piperidine-4-carboxamide (135 mg, 0.34 mmol),
4- ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 83 mg, 0.31 mmol), PdCl2 (PPh3)2 (4 mg, 0.006 mmol), Cul (1 mg, 0.006 mmol), Et3N (0.2mL) in DMSO (2 mL) to afford 70 mg of title compound. 1H NMR (300 MHz, CDClj): δ 7.79-7.74 (d, = 9.0 Hz, 1H), 7.61-7.48 (m, 5H), 5.91-5.74 (m, 2H), 3.26 (s, 3H), 3.08 (m, 2H), 2.90 (m, 2H), 2.77 (m, 1H), 2.62-2.54 (m, 4H), 2.22 (m, 2H), 1.93-1.82 (m, 4H). Intermediate-69
4-((4-cyano-2-(3-(4-ethoxypiperidin-l-yl)propyl)phenyl)ethynyl)-3-(trifluoromethyl)phenyl methanesulfonate
Step-1:- Preparation of tert-but ylate
Figure imgf000117_0001
To a solution of piperidinol (3.0 g, 0.029 mmol) in DCM (50 mL) was added Et3N (5 mL) and BOC anhydride (6.47 g, 0.029 mmol) at 0°C. The reaction mass was stirred at rt for 16 h. The reaction mixture was quenched in water, extracted with DCM. The organic layers were dried over Na2S04 and concentrated to afford 4.0 g of title compound. 1H NMR (300 MHz, CDC13): δ 3.87-3.82 (m, 3H), 3.06-2.98 (m, 2H), 2.83-2.81 (q, J = 6.9 Hz, 1H), 1.88-1.83 (m, 2H), 1.50 (m, 11H).
Step-2:- Preparation of ieri-butyl 4-ethoxypiperidine-l-carboxylate
Figure imgf000117_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 24 by using ie/ -butyl 4-hydroxypiperidine-l-carboxylate (2.0 g, 9.95 mmol), 1-bromoethane (1.6 g, 14.8 mmol), NaH (0.477 g, 11.9 mmol, 60% in mineral oil), DMF (10 mL) to afford 1.00 g title compound. 1H NMR (300 MHz, CDC13): δ 3.82-3.55 (m, 2H), 3.52-3.44 (m, 2H), 3.43-3.40 (m, 1H), 3.07-2.98(m, 2H), 1.85-1.82 (m, 2H), 1.65-1.53 (m, 11H), 1.22-1.18 (t, J = 6.9 Hz, 3H).
Step-3:- Preparation of 4-ethoxypiperidine
Figure imgf000117_0003
To a solution of ieri-butyl 4-ethoxypiperidine- 1-carboxylate (1.0 g, 4.36 mmol) in DCM (5.0 mL) was added trifluoro acetic acid (5.0 mL) at 0-5°C. The reaction mass was stirred at rt for 2-3 h.The excess of solvent was removed under vacume, the reaction mass was basified with aq.NaHC03 solution and extracted with DCM. The organic layers were dried over Na2S04 and concentrated to afford 0.500 g of title compound. 1H NMR (300 MHz, CDC13): δ 3.51- 3.48 (m, 3H), 3.18 (m, 1H), 2.84 (m, 2H), 2.69 (m, 2H), 1.98 (m, 2H), 1.66 (m, 2H), 1.22- 1.18 (t, 7 = 6.6 Hz, 3H).
Step-4:- Preparation of 3-(3-(4-ethoxypiperidin-l-yl)propyl)-4-iodobenzonitrile
Figure imgf000118_0001
The title compound was prepared following the procedure described in step-1 of Intermediate- 50 by using 3-(5-cyano-2-iodophenyl)propyl methanesulfonate (step-1, Intermediate-48, 0.300 g, 0.821 mmol), DMF (35 mL), K2C03 (0.136 g, 0.986 mmol), 4-ethoxypiperidine (0.127 g, 0.986 mmol) to afford 0.150 g of title compound. MS [M+H]+: 399.
Step-5:- Preparation of 4-((4-cyano-2-(3-(4-ethoxypiperidin-l-yl)propyl)phenyl) ethynyl)-3- (trifluoromethyl)phenyl methanesulfonate
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using 3-(3-(4-ethoxypiperidin-l-yl)propyl)-4-iodobenzonitrile (138 mg, 0.34 mmol), 4- ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 85 mg, 0.34 mmol), PdCl2 (PPh3)2 (5 mg, 0.006 mmol), Cul (1 mg, 0.006 mmol), Et3N (0.2mL) in DMSO (2 mL) to afford 80 mg of title compound. 1H NMR (300 MHz, DMSO-i¾: δ 7.76 (s, 1H),7.61-7.51 (m, 5H), 3.47 (m, 4H), 3.25 (s, 3H), 2.90 (m, 4H), 2.60 (m, 3H), 2.01 (m, 4H), 1.72 (m, 2H), 1.24-1.18 (m, 3H).
Intermediate-70
3-(3-((6-chloropyridin-3-yl)oxy)propyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)
ethynyl)benzonitrile
Figure imgf000118_0002
Preparation of 3-(3-((6-chloropyridin-3-yl)oxy)propyl)-4-iodobenzonitrile
Figure imgf000119_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 24 by using 3-(5-cyano-2-iodophenyl)propyl methanesulfonate (step-1, Intermediate-48, 0.300 g, 0.82 mmol), 6-chloropyridin-3-ol (0.160 g, 1.23 mmol), NaH (0.050 g, 1.23 mmol, 60% in mineral oil), DMF (10 mL) to afford 0.100 g title compound. 1H NMR (300 MHz, DMSO d6): δ 8.10 (s, 1H), 8.06-8.04 (d, = 8.1Hz, 1H), 7.78 (s, 1H), 7.51-7.40 (m, 3H), 4.11-4.07 (t, = 5.7 Hz, 2H), 2.90-2.084 (t, = 6.9 Hz, 2H), 2.04-2.01 (m, 2H); MS [M+H]+: 399.
Step-2:- Preparation of 3-(3-((6-chloropyridin-3-yl)oxy)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl) ethynyl)benzonitrile
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 0.100 g, 0.40 mmol), 3-(3-((6-chloropyridin-3-yl)oxy)propyl)-4-iodobenzonitrile (0.163 g, 0.40 mmol), TBAF (128 mg, 0.49 mmol), PdCl2(PPh3)2 (6 mg, 0.008 mmol), DMSO (2.0 mL) to afford 70 mg of the title product H NMR (300 MHz, DMSO-i¾): δ 10.76 (s, 1H), 8.25 (s, 1H), 8.02 (s, 1H), 7.85 (m, 1H), 7.74-7.71 (d, = 8.7 Hz, 1H), 7.65-7.62 (d, = 7.8 Hz, 2H), 7.38 (m, 1H), 7.15 (s, 1H), 7.06 (d, 1H), 4.07 (t, 2H), 2.99 (t, 2H), 2.09 (m, 2H), MS [M-H]~: 456.
Intermediate-71
Hexyl 3-fluoro-4-iodobenzoate
Figure imgf000119_0002
The title compound was prepared following the procedure described in step-2 of Intermediate- 27 by using 3-fluoro-4-iodobenzoic acid (step-lof Intermediate-34, 1.0 g, 3.75 mmol), K2C03 (0.778 g, 5.63 mmol), 1-bromohexane (0.930 g, 5.63 mmol) in DMF (10 mL) to afford 500 mg of title product. 1H NMR (300 MHz, DMSO-i¾): δ 8.05-8.00 (t, = 6.6 Hz, 1H), 7.67-7.65 (d, = 6.9 Hz, 1H), 7.55-7.52 (d, = 8.4 Hz, 1H), 4.28-4.23 (t, = 6.6 Hz, 2H), 1.71-1.66 (m, 2H), 1.37-1.28 (m, 6H), 088-0.86 (t, 3H). Intermediate-72
2-(diethylamino)-2-oxoethyl 3-fluoro-4-iodobenzoate
Figure imgf000120_0001
Preparation of 2-bromo-N,N-diethylacetamide
Figure imgf000120_0002
To a solution of diethyl amine (2.0 g, 27.39 mmol) and N,N-di-isopropyl ethyl amine (3.53 g, 27.24 mmol) in DCM (100 mL) was added bromoacetyl bromide (5.51 g, 201.84 mmol) at 0°C. The reaction mass was stirred for 1 h at 0°C. The reaction mixture was quenched with water, extracted with DCM. The organic layers were dried over Na2S04 and concentrated to afford 4.0 g of title compound. 1H NMR (300 MHz, CDClj): δ 3.82 (s, 2H), 3.40-3.33 (q, 7 = 7.5 Hz, 4H), 1.26-1.21 (t, 7 = 7.2 Hz, 3H), 1.14-1.06 (t, 7 = 7.2 Hz, 3H); MS [M+H]+: 194 Step-2:- Preparation of 2-(diethylamino)-2-oxoethyl 3-fluoro-4-iodobenzoate
To a solution of 3-fluoro-4-iodobenzoic acid (step-lof Intermediate-27, 1.0 g, 3.75 mmol) in DMF (10 mL) was added K2C03 (1.07 g, 7.51 mmol), 2-bromo-N,N-diethylacetamide (1.09 g, 5.63 mmol).The reaction mass was stirred at 80-90°C for 16 h. The reaction mixture was quenched with water, extracted with DCM. The organic layers were dried over Na2S04 and concentrated to afford 0.500 g of title compound. 1H NMR (300 MHz, DMSO-i¾): δ 8.09- 8.04 (t, 7 = 6.6 Hz, 1H), 7.73-7.70 (t, 7 = 8.1 Hz, 1H), 7.60-7.57 (t, 7 = 7.8 Hz, 1H), 5.03 (s, 2H), 3.30-3.19 (q, 7 = 7.5 Hz, 4H), 1.17-1.13 (t, 7 = 7.5 Hz, 3H), 1.04-0.99 (t, 7 = 7.2 Hz, 3H); MS [M+H]+: 380.
Intermediate-73
Ethyl 3-(2-carbamoylpyrimidin-5-yl)-4-((4-hydroxy-2-(trifluoromethyl)phi
ethynyl)benzoate
Figure imgf000120_0003
Step-1:- Preparation of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine-2- carbonitrile
Figure imgf000121_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 33 by using 5-bromopyrimidine-2-carbonitrile (0.500 g, 2.71 mmol), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (0.758 g, 2.98 mmol), potassium acetate (0.533 g, 5.43 mmol), Pd(dppf)C12 (0.110 g, 0.135 mmol) in 1,4-dioxane (10 mL) to affrd 1.40 g of title compound. 1H NMR (300 MHz, DMSO-i¾): δ 9.06 (s, 2H), 1.32 (s, 12H),
Step-2:- Preparation of ethyl 4-amin -3-(2-cyanopyrimidin-5-yl)benzoate
Figure imgf000121_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 33 by using 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine-2-carbonitrile (0.780 g, 3.37 mmol), ethyl 4-amino-3-iodobenzoate (step- 1 of Intermediate-66, 1.17 g, 4.05 mmol), ?d{dppf)C\2 (0.137 g, 0.168 mmol), diglyme (10 mL), K2C03 (0.931 g, 6.74 mmol) to afford 0.500 g of title product. 1H NMR (300 MHz, DMSO-i¾: δ 8.09-8.04 (t, = 6.6 Hz, 1H), 7.73- 7.70 (t, = 8.1 Hz, 1H), 7.60-7.57 (t, = 7.8 Hz, 1H), 5.03 (s, 2H), 3.30-3.19 (q, = 7.5 Hz, 4H), 1.17- 1.13 (t, J = 7.5 Hz, 3H), 1.04-0.99 (t, = 7.2 Hz, 3H); MS [M+H]+: 380.
Step-3:- Preparation of ethyl 3-(2-cyanopyrimidin-5-yl)-4-iodobenzoate
Figure imgf000121_0003
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using ethyl 4-amino-3-(2-cyanopyrimidin-5-yl)benzoate (0.430 g, 1.60 mmol), ice (5.0 g), conc.H2S04 (3 ml), aq. NaN02 (0.199 g, 2.88 mmol), aq. KI (0.532 g, 3.20 mmol) to afford 0.190 g of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 9.16 (s, 2H), 8.26-8.23 (d, = 8.4 Hz, 1H), 8.01 (s, 1H), 7.78-7.76 (d, = 6.3 Hz, 1H), 4.36-4.29 (q, = 7.2 Hz, 2H), 1.33-1.29 (t, = 7.2 Hz, 3H). Step-4:- Preparation of ethyl 3-(2-cyanopyrimidin-5-yl)-4-((4-((methylsulfonyl)oxy)-2- (trifluoromethyl)phenyl)ethynyl)benzoate
Figure imgf000122_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using ethyl 3-(2-cyanopyrimidin-5-yl)-4-iodobenzoate (190 mg, 0.50 mmol), 4-ethynyl- 3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 122 g, 0.50 mmol), PdCl2 (PPh3)2 (7 mg, 0.01 mmol), Cul (2 mg, 0.02 mmol), Et3N (O. lmL) in DMSO (2.0 mL) to afford 150 mg of title compound.1H NMR (300 MHz, DMSO-i¾): δ 9.32 (s, 2H), 8.20-8.10 (m, 2H), 7.96-7.94 (d, J = 7.8 Hz, 1H), 7.83-7.79 (m, 3H), 4.39-4.36 (q, J = 6.6 Hz, 2H), 3.50 (s, 3H), 1.37-1.32 (t, J = 6.9 Hz, 3H).
Step-5:- Preparation of ethyl 3-(2-cyanopyrimidin-5-yl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoate
Figure imgf000122_0002
To a solution of ethyl 3-(2-cyanopyrimidin-5-yl)-4-((4-((methylsulfonyl)oxy)-2- (trifluoromethyl)phenyl)ethynyl)benzoate (150 mg, 0.291 mmol) in TBAF (1.0 mL; 1M in THF ) was added at rt. The reaction mass was stirred at rt for 1 h. The reaction mixture was quenched in water, extracted with DCM. The organic layers were dried over Na2S04 and concentrated to afford 100 mg of title compound.1H NMR (300 MHz, DMSO-i¾): δ 11.0 (br s, 1H), 9.30 (s, 2H), 8.16-8.12 (m, 2H), 7.87-7.85 (d, J = 8.1 Hz, 1H), 7.53-7.50 (t, J = 9.0 Hz, 1H), 7.14-7.06 (m, 2H), 4.40-4.35 (q, J = 7.2 Hz, 2H), 1.36-1.31 (t, J = 6.9 Hz, 3H).
Step-6:- Preparation of ethyl 3-(2-carbamoylpyrimidin-5-yl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl) ethynyl)benzoate
The title compound was prepared following the procedure described in step-5 of Intermediate- 46 using ethyl 3-(2-cyanopyrimidin-5-yl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoate (90 mg, 0.20 mmol), DMSO (5 mL), 50% H202 (2.5 mL), K2C03 (71.0 mg, 0.51 mmol) to afford 50 mg of the title product.1!! NMR (300 MHz, DMSO-i¾): δ 10.77 (br s, 1H), 9.19 (s, 2H), 8.31 (s, 1H), 8.1 1-8.07 (m, 2H), 7.87-7.80 (m, 2H), 7.47-7.44 (d, J = 7.8 Hz, 1H), 7.10 (m, 2H), 4.35 (q, 2H), 1.22 (t, 3H).
Intermediate-74
-Iodo-3-(4-(2-methyl- lH-imidazol- l-yl)butyl)benzonitrile
Figure imgf000123_0001
To a solution of 4-aminobenzonitrile (10 g) in DMA (50 mL) was added N-iodosuccinamide (19.80 g).The reaction mixture was stirred at 45-50°C for 72 h. The reaction mass was quenched in water and obtained solid was filtered to afford 10 g of title product.
Step 2: Preparation of 4-amino-3-(4-hydroxybut- l-yn-l-yl)benzonitrile
Figure imgf000123_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-amino-3-iodobenzonitrile (10.0 g, 41 mmol), but-3-yn-l-ol (2.8 g, 41 mmol), Cul (0.155 g, 0.81 mmol), PdCl2(PPh3)2 (0.574 g, 0.81 mmol), Et3N (3.5 mL) in DMSO (15 mL) to afford 5.0 g of title compound. 1H NMR (300 MHz, DMSO-d6): δ 10.20 (s, 1H), 7.97- 7.94 (d, = 8.7 Hz, 1H), 7.71 (s, 2H), 7.33-7.30 (d, = 7.8 Hz, 1H), 7.33-7.30 (d, = 7.8 Hz, 1H), 6.47 (s, 1H), 6.43-6.40 (d, J = 7.8 Hz, 1H), 3.79 (s, 3H); MS [M-H]~: 168.07
Step 3: Preparation of 4-amino-3-(4-hydroxybutyl)benzonitrile
Figure imgf000123_0003
To a solution of 4-amino-3-(4-hydroxybut-l-yn- l-yl)benzonitrile (2.5 g, 10.10 mmol) in EtOH (100 ml) was added 10% Pd/C (500 mg) and the reaction mass was hydrogenated in Parr apparatus at 40 psi for 72 h. The reaction mixture was filtered through celite pad, quenched with water, extracted with EtOAc and the organic layers were separated, dried over Na2S04 and concentrated to afford 2.0 g of the of the title product.
Step 4: Preparation of 3-(4-hydroxybutyl)-4-iodobenzonitrile
Figure imgf000124_0001
The title compound was prepared following the procedure described in step-2, Intermediate- 1 using 4-amino-3-(4-hydroxybutyl)benzonitrile (5.0 g, 25.90 mmol), ice (20.0 g), cone. H2S04 (20.0 ml) , aq. NaN02 (2.7 g, 39.13 mmol), Aq. KI (8.5 g, 51.20 mmol) in acetonitrile (15 mL) to afford 2.8 g of the title product.
Step 5: Preparation of 4-iodo-3-(4-( -methyl-lH-imidazol-l-yl)butyl)benzonitrile
Figure imgf000124_0002
To a solution of 2-methyl- lH- imidazole (179 mg, 2.19 mmol) and triphenyl phosphine (626 mg, 2.39 mmol) in THF (20 mL) was added 3-(4-hydroxybutyl)-4-iodobenzonitrile (600 mg, 1.99 mmol) and di-tert butyl azodicarboxylate (573 mg, 2.49 mmol) and the reaction mass was stirred at rt for 16 h. The reaction mass was concentrated and purified by column chromatography to afford 150 mg of title product.1H NMR (300 MHz, DMSO- 6): δ 8.05- 8.02 (d, J = 7.8 Hz, 1H), 7.75 (s, 2H), 7.40-7.37 (d, / = 8.4 Hz, 1H), 7.04 (s, 1H), 6.71 (s, 1H), 3.91-3.86 (t, J = 6.9 Hz, 2H), 2.75-2.70 (t, J = 7.2 Hz, 2H), 2.25 (s, 3H), 1.70 (m, 2H), 1.52 (m, 2H); MS [M+H]+: 366.
Intermediate-75
4-Iodo-3-(4-(pyrazin-2-yloxy)butyl)benzonitrile
I
Figure imgf000124_0003
The title compound was prepared following the procedure described in step-3 of Intermediate- 24 by using 3-(4-hydroxybutyl)-4-iodobenzonitrile (step-4, Intermediate-74, 300 mg, 0.99 mmol), NaH (77 mg, 1.99 mmol, 60% in mineral oil), 2-iodopyrazine (410 mg, 1.99 mmol) in dry DMF (10 mL) to afford 200 mg of title compound. 1H NMR (300 MHz, DMSO-d6): δ 8.28 (s, 1H), 8.18 (s, 2H), 8.05-8.03 (d, J = 8.4 Hz, 1H), 7.78 (s, 1H), 7.39-7.37(d, J = 6.3 Hz, 1H), 4.35-4.31 (t, = 6.0 Hz, 2H), 2.80-2.75 (t, = 7.2 Hz, 2H), 1.80-1.78 (m, 2H), 1.70 (m, 2H); MS [M+H]+: 380.
Intermediate-76
-(Dimethylamino)ethyl 3-fluoro-4-iodobenzoate
Figure imgf000125_0001
To a solution of 3-fluoro-4-iodobenzoic acid (step-lof Intermediate-27, 1.0 g, 3.75 mmol) in DCM (20.0 mL) was added oxalyl chloride (947 mg, 7.57 mmol) and stirred at rt for 3-4 h. Meanwhile, to a solution of 2-(dimethylamino)ethanol (501 mg, 5.63 mmol) in THF (20.0 mL) was added Et3N (759 mg, 7.51 mmol) and stirred for 5-10 mins followed by addition of above prepared acid chloride solution. The reaction mass was stirred at rt for 16 h before it was quenched with water and extracted with DCM. The organic layer was concentrated to afford 400 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.54 (br s, 1H), 8.08-8.03 (t, = 7.8 Hz, 1H), 7.95-7.91 (d, J = 9.3 Hz, 1H), 7.68-7.66 (m, 1H), 4.59 (t, 2H), 3.50 (br s, 2H), 2.84 (s, 6H); MS [M+H]+: 338.
Intermediate-77
4-Iodo-3-(3-((6-methylpyridin-3-yl)oxy)propyl)benzonitrile
Figure imgf000125_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 24 using 3-(5-cyano-2-iodophenyl)propyl methanesulfonate (step-1, Intermediate-48, 300 mg, 0.82 mmol), NaH (66 mg, 1.64 mmol, 60% in mineral oil), 6-methylpyridin-3-ol (133 mg, 1.23 mmol), DMF (10.0 mL) to afford 200 mg of title product.1!! NMR (300 MHz, DMSO- d6): δ 8.14-8.07 (m, 2H), 7.78 (br s, 1H), 7.41 (m, 1H), 7.27 (d, 1H), 7.18 (d, 1H), 4.05 (m, 2H), 2.88 (br s, 2H), 2.39 (s, 3H), 2.01 (br s, 2H); MS [M+H]+: 379.
Intermediate-78
4-Iodo-3-(3-((2-methylpyridin-3-yl)oxy)propyl)benzonitrile
Figure imgf000126_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 24 using3-(5-cyano-2-iodophenyl)propyl methanesulfonate (step-1, Intermediate-48, 300 mg, 0.82 mmol), NaH (66 mg, 1.64 mmol, 60% in mineral oil), 2-methylpyridin-3-ol (133 mg, 1.23 mmol), DMF (10.0 mL) to afford 200 mg of title product.1!! NMR (300 MHz, DMSO- d6): δ 8.07-8.05 (t, J = 7.8 Hz, 1H), 8.0-7.98 (d, J = 7.8 Hz, 1H), 7.80 (s, 1H), 7.41-7.39 (d, = 8.1 Hz, 1H), 7.32-7.30 (d, = 7.8 Hz, 1H), 7.19-7.15 (m, 1H), 4.07-4.05 (t, = 6.0 Hz, 2H), 2.94-2.89 (t, = 7.8 Hz, 2H), 2.36 (s, 3H), 2.04 (m, 2H).
Intermediate-79
l-Ethynyl- -(trifluoromethyl)benzene
Figure imgf000126_0002
The title compound was prepared following the procedure described in step-3, Intermediate- 1 using l-iodo-2-(trifluoromethyl)benzene (5.0 g, 0.018 mol), trimethylsilyl acetylene (2.70 g, 0.027 mol), Cul (0.070 g, 0.0003 mmol), PdCl2(PPh3)2 (0.257 g, 0.0003 mmol), Et3N (2.8 g, 0.027 mol) in DMSO (20 mL) to afford crude 3.0 g of trimethyl((2- (trifluoromethyl)phenyl)ethynyl)silane. 1H NMR (300 MHz, DMSO-d6): δ 7.79-7.76 (d, = 7.2 Hz, 1H), 7.68-7.57 (m, 3H), 0.17 (s, 91H).
The crude trimethyl((2-(trifluoromethyl)phenyl)ethynyl)silane (3.0 g) was desyllated by THF (5.0 mL), 1M TBAF solution in THF (7.2 mL, 0.027 mol) to afford 1.5 g of title compound. 1H NMR (300 MHz, DMSO-d6): δ 7.80-7.59 (m, 4H), 4.62 (s, 1H).
Intermediate- 80
Ethyl 4-iodo-3-( -(pyridin-3-yloxy)propyl)benzoate
Figure imgf000126_0003
Step 1: Preparation of 4-iodo-3-(3-(pyridin-3-yloxy)propyl)benzonitrile
Figure imgf000127_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 24 using 3-(5-cyano-2-iodophenyl)propyl methanesulfonate (step-1, Intermediate-48, 300 mg, 0.82 mmol), NaH (66 mg, 1.64 mmol, 60% in mineral oil), pyridin-3-ol (77 mg, 1.23 mmol), DMF (10.0 mL) to afford 200 mg of title product.
Step 2: Preparation of 4-iodo-3-(3-(p yl)benzoic acid
Figure imgf000127_0002
The title compound was prepared following the procedure described in step-1 of Intermediate- 61 using 4-iodo-3-(3-(pyridin-3-yloxy)propyl)benzonitrile (700 mg), 2N NaOH (10.0 mL) ) in EtOH (10.0 mL to afford 500 mg of title product.
Step 3: Preparation of ethyl 4-iodo-3-(3-(pyridin-3-yloxy)propyl)benzoate
To a solution of 4-iodo-3-(3-(pyridin-3-yloxy)propyl)benzoic acid (500 mg, 1.30 mmol) in DMF (10.0 mL) was added K2CO3 (270 mg, 1.95 mmol) and the reaction mass was stirred at 60°C for 1 h. Then added ethyl bromide (213 mg, 1.95 mmol) and continued stirring at rt for 4-5 h. The reaction mixture was quenched with water and filtered off precipitate to afford 500 mg of title compound.
Intermediate- 81
Butyl 4-iodo-3- -((4-methylthiazol-2-yl)methoxy)propyl)benzoate
Figure imgf000127_0003
Step 1: Preparation of (4-methylthiazol-2-yl)methanol
Figure imgf000127_0004
The title compound was prepared following the procedure described in step-2 of Intermediate- 24 by using 4-methylthiazole-2-carbaldehyde (1.0 g, 7.87mmol), NaBH4 (1.19 g, 36.3 mmol) in MeOH (15.0 mL) to afford 500 mg of title product.
Step 2: Preparation of 4-iodo-3- -((4-methylthiazol-2-yl)methoxy)propyl)benzonitrile
Figure imgf000128_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 24 using 3-(5-cyano-2-iodophenyl)propyl methanesulfonate (step-1, Intermediate-48, 310 mg, 0.84 mmol), NaH (41 mg, 1.01 mmol, 60% in mineral oil), (4-methylthiazol-2-yl)methanol (131 mg, 1.01 mmol), DMF (2.0 mL) to afford 150 mg of title product.
Step 3: Preparation of 4-iodo- -(3-((4-methylthiazol-2-yl)methoxy)propyl)benzoic acid
Figure imgf000128_0002
The title compound was prepared following the procedure described in step-1, Intermediate - 61 by using 4-iodo-3-(3-((4-methylthiazol-2-yl)methoxy)propyl)benzonitrile (200 mg), EtOH (15.0 mL) was added 2N NaOH (15.0 mL) to afford 150 mg of title product.
Step 4: Preparation of butyl 4-iodo-3-(3-((4-methylthiazol-2-yl)methoxy)propyl)benzoate The title compound was prepared following the procedure described in step-3, Intermediate - 80 using 4-iodo-3-(3-((4-methylthiazol-2-yl)methoxy)propyl)benzoic acid (180 mg. 0.43 mmol), K2C03 (89 mg, 0.64 mmol), n-butyl iodide (158 mg, 0.86 mmol) to afford 100 mg of title product.
Intermediate- 82
Hexyl 3-(4-ethoxybutyl)-4-iodobenzoate
Figure imgf000128_0003
Step 1: Preparation of 3-(4-ethoxybutyl)-4-iodobenzonitrile
Figure imgf000129_0001
The title compound was prepared following the procedure described in step-3 of Intermediate-24 using 3-(4-hydroxybutyl)-4-iodobenzonitrile (step-4, Intermediate-74, 600 mg, 1.99 mmol), NaH (119 mg, 2.97 mmol, 60% in mineral oil), ethyl bromide (322 mg, 2.99 mmol), DMF (5.0 mL) to afford 400 mg of title product
Step 2: Preparation of 3-(4-ethoxybutyl)-4-iodobenzoic acid
Figure imgf000129_0002
The title compound was prepared following the procedure described in step-1, Intermediate - 61 using 3-(4-ethoxybutyl)-4-iodobenzonitrile (400 mg), EtOH (15.0 mL), 2N NaOH (15.0 mL) to afford 250 mg of title product.
Step 3: Preparation of hexyl 3-(4-ethoxybutyl)-4-iodobenzoate
The title compound was prepared following the procedure described in step-3, Intermediate - 80 using 3-(4-ethoxybutyl)-4-iodobenzoic acid (200 mg. 0.57 mmol), K2C03 (118 mg, 0.86 mmol), n-hexyl iodide (181 mg, 0.85 mmol) in DMF (5.0 mL) to afford 100 mg of title product.
Intermediate- 83
2-(Dimethylamino)-2-oxoethyl 3-(6-carbamoylpyridin-3-yl)-4-iodobenzoate
Figure imgf000129_0003
Step 1: Preparation of 3-(6-carbamoylpyridin-3-yl)-4-iodobenzoic acid
Figure imgf000130_0001
To a solution of ethyl 3-(6-cyanopyridin-3-yl)-4-iodobenzoate (step-3, Intermediate-53, 600 mg, 1.58 mmol) in THF+H20 (10.0+10.0 ml) was added LiOH.H20 (166 mg, 3.96 mmol) at RT. The reaction mass was stirred at rt for 16 h. The reaction mass was diluted with water and aqueous layer was washed with diethyl ether and acidified with dil.HCl and the precipitate obtained was collected by filtration and dried to afford 580 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.20-8.12 (m, 2H), 8.02-7.99 (d, = 7.8 Hz, 1H), 7.85 (s, 1H), 7.71- 7.69 (d, J = 7.8 Hz, 2H); MS [M+H]+: 369.
Step 2: Preparation of 2-(dimethylamino)-2-oxoethyl 3-(6-carbamoylpyridin-3-yl)-4- iodobenzoate
To a solution of 3-(6-carbamoylpyridin-3-yl)-4-iodobenzoic acid (580 mg, 1.57 mmol) in DMF (5.0 mL) was added K2C03 (326 mg, 2.36 mmol) at 65°C.The reaction mixture was stirred for 30 mins followed by addition of 2-bromo-N,N-dimethylacetamide (258 mg, 1.57 mmol),TBAI (116 mg, 0.315 mmol) and continued stirring at 70°C for 16 h. The reaction mixture was quenched with water and extracted with water acidified and extracted with EtOAc. The organic layer were concentrated to afford 450 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 8.65 (s, 1H), 8.23 (m, 2H), 8.12 (d, 2H), 8.03 (m, 1H), 7.74 (m, 2H), 5.04 (s, 2H), 2.96 (s, 3H), 2.83 (s, 3H); MS [M+H]+: 453.
Intermediate- 84
Hexyl 3-(3-ethoxypropyl)-4-iodobenzoate
Figure imgf000130_0002
Step 1 : Preparation of 3-(3-ethoxypropyl)-4-iodobenzoic acid
Figure imgf000130_0003
The title compound was prepared following the procedure described in step- 1, Intermediate - 61 using 3-(3-ethoxypropyl)-4-iodobenzonitrile (step-5, Intermediate-38, 300 mg), EtOH (10.0 mL), 2N NaOH (10.0 mL) to afford 200 mg of title product.
Step 2: Preparation of hexyl 3-(3-ethoxypropyl)-4-iodobenzoate
The title compound was prepared following the procedure described in step-3, Intermediate - 80 using 3-(3-ethoxypropyl)-4-iodobenzoic acid (300 mg. 0.67 mmol), K2CO3 (139 mg, 1.0 mmol), n-hexyl iodide (284 mg, 1.34 mmol) in DMF (5.0 mL) to afford 150 mg of title product.
Intermediate- 85
4-Iodo-3-(3-(3-methyl-lH-pyrazol- l-yl)propyl)benzonitrile
Figure imgf000131_0001
The title compound was prepared following the procedure described in step-3, Intermediate - 80 using 3-(5-cyano-2-iodophenyl)propyl methanesulfonate (step-1, Intermediate-48, 300 mg, 0.82 mmol), K2C03 (136 mg, 0.98 mmol), 3-methyl- lH-pyrazole (74 mg, 0.90 mmol) at 100°C for 16 h to afford 100 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 7.92-7.90 (d, = 7.8 Hz, 1H), 7.39 (m, 1H), 7.28-7.26 (d, = 6.9 Hz, 1H), 7.14-7.1 l(d, = 8.4 Hz, 1H), 6.02 (s, 1H), 4.15-4.10 (t, = 6.6 Hz, 2H), 2.74-2.69 (m, 2H), 2.28 (s, 3H), 2.15-2.10 (m, 2H).
Intermediate- 86
4-Iodo-3-(3-(4-methyl-lH-pyrazol- l-yl)propyl)benzonitrile
Figure imgf000131_0002
The title compound was prepared following the procedure described in step-3, Intermediate - 80 using 3-(5-cyano-2-iodophenyl)propyl methanesulfonate (step-1, Intermediate-48, 300 mg, 0.82 mmol), K2C03 (136 mg, 0.98 mmol), 4-methyl-lH-pyrazole (74 mg, 0.90 mmol) at 70°C for 16 h to afford 120 mg of title product H NMR (300 MHz, DMSO-d6): δ 7.96-7.90 (t, = 8.7 Hz, 1H), 7.42-7.35 (m, 1H), 7.28-7.26 (d, = 6.9 Hz, 1H), 7.20-7.13(m, 3H), 4.20-4.18 (m, 2H), 2.76-2.71 (m, 2H), 2.14 (m, 2H), 2.08 (m, 3H).
Intermediate- 87
3 - (3 - ( 1 H-pyrazol- 1 - yl)propyl) -4 -iodobenzonitrile
Figure imgf000132_0001
The title compound was prepared following the procedure described in step-3, Intermediate - 80 using 3-(5-cyano-2-iodophenyl)propyl methanesulfonate (step-1, Intermediate-48, 300 mg, 0.82 mmol), K2C03 (136 mg, 0.98 mmol), IH-pyrazole (65 mg, 0.98 mmol) at 70°C for 16 h to afford 120 mg of title product.1H NMR (300 MHz, DMSO-d6): δ 7.94-7.91 (t, = 8.4 Hz, 1H), 7.55 (s, 1H), 7.42 (s, 2H), 7.16-7.13 (d, J = 8.4 Hz, 1H), 6.29-6.28 (s, 1H), 4.25-4.21 (t, = 6.6 Hz, 2H), 2.76-2.70 (t, J = 7.8 Hz, 2H), 2.21-2.17 (m, 2H).
Intermediate- 88
3-(3-(2,6-Dichlorophenoxy)propyl)-4-iodobenzonitrile
Figure imgf000132_0002
The title compound was prepared following the procedure described in step-3, Intermediate - 80 using 3-(5-cyano-2-iodophenyl)propyl methanesulfonate (step-1, Intermediate-48, 250 mg, 0.68 mmol), K2C03 (35 mg, 0.89 mmol), 2,6-dichlorophenol (145 mg, 0.89 mmol) at 70°C for 16 h to afford 140 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 7.98-7.95 (t, = 8.1 Hz, 1H), 7.60 (s, 1H), 7.32-7.24 (m, 3H), 7.19-7.16 (d, J = 8.4 Hz, 1H), 4.11-4.07 (t, J = 8.7 Hz, 2H), 3.10-3.05 (t, J = 7.8 Hz, 2H), 2.17-2.14 (m, 2H).
Intermediate-89
3-Chloro-4-ethynylphenyl methanesulfonate
Figure imgf000132_0003
The title compound was prepared following the procedure described in step-3, Intermediate- 1 by using 3-chloro-4-iodophenyl methanesulfonate (Intermediate- 12, 2.0 g, 6.02 mmol), trimethylsilyl acetylene (0.880 g, 9.03 mmol), Cul (0.022 g, 0.12 mmol), PdCl2(PPh3)2 (0.084 g, 0.12 mmol), Et3N (0.912 g, 9.03 mmol) to afford 1.0 g of 3-chloro-4- ((trimethylsilyl)ethynyl)phenyl methanesulfonate. 1H NMR (300 MHz, DMSO- 6): δ 7.70- 7.67 (d, = 8.7 Hz, 1H), 7.62 (s, 1H), 7.36-7.33 (dd, = 1.8 Hz, 1H), 3.44 (s, 3H), 0.24 (s, 9H).
The crude 3-chloro-4-((trimethylsilyl)ethynyl)phenyl methanesulfonate (1.0 g) desyllalted by 1M TBAF solution in THF (2.36 g, 9.03 mol) in DMSO (20 mL), THF (20 mL) to afford 0.700 g of title product. 1H NMR (300 MHz, DMSO-d6): δ 7.74-7.71 (d, = 8.4 Hz, 1H), 7.64 (s, 1H), 7.38-7.36 (d, = 6.3 Hz, 1H), 4.68 (s, 1H), 3.45 (s, 3H).
Intermediate- 90
3-(3-(lH-l,2,4 dobenzonitrile
Figure imgf000133_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 24 by using 3-(5-cyano-2-iodophenyl)propyl methanesulfonate (step-1, Intermediate-48, 200 mg, 0.54 mmol), sodium l,2,4-triazol-4-ide (75 mg, 0.82 mmol), DMF 10.0 mL) to afford 170 mg of title product H NMR (300 MHz, DMSO-d6): δ 8.56 (s, 1H), 8.05-8.03 (d, = 8.4 Hz, 1H), 7.97 (s, 1H), 7.76 (s, 1H), 7.41-7.38 (d, = 8.1 Hz, 1H), 4.27-4.22 (t, = 3.9 Hz, 2H),2.72-2.67 (m, 2H), 2.06 (m, 2H); MS [M+H]+: 339.
Intermediate- 91
4-Iodo-3-(3-(pyridin-4-yloxy)propyl)benzonitrile
Figure imgf000133_0002
The title compound was prepared following the procedure described in step-3, Intermediate - 80 using 3-(5-cyano-2-iodophenyl)propyl methanesulfonate (step-1, Intermediate-48, 300 mg, 0.82 mmol), K2C03 (136 mg, 1.23 mmol), pyridin-4-ol (91 mg, 1.23 mmol) at 70°C for 16 h to afford 180 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 7.97-7.94 (d, = 8.4 Hz, 1H), 7.47 (m, 3H), 7.21-7.18 (d, = 8.4 Hz, 1H), 6.51-6.49 (d, = 6.3 Hz, 2H), 3.96 (t, 2H), 2.82-2.77 (t, = 7.5 Hz, 2H), 2.09 (m, 2H).
Intermediate- 92
3-(3-(2-Chlorophenoxy)propyl)-4-iodobenzonitrile
Figure imgf000134_0001
The title compound was prepared following the procedure described in step-3, Intermediate - 80 using 3-(5-cyano-2-iodophenyl)propyl methanesulfonate (step-1, Intermediate-48, 300 mg, 0.82 mmol), K2C03 (136 mg, 1.23 mmol), 2-chlorophenol (126 mg, 0.98 mmol) at 70°C for 16 h to afford 190 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 8.07-8.04 (d, = 7.8 Hz, 1H), 7.76 (br s, 1H), 7.40-7.38 (m, 2H), 7.29 (m, 1H), 7.15-7.12 (d, J = 8.4 Hz, 1H), 6.97- 6.95 (m, 1H), 4.10 (m, 2H), 2.92 (t, 2H), 2.05 (m, 2H).
Intermediate-93
4-Iodo-3-(2-(pyridin-3-yl)ethyl)benzonitrile
Step 1: Preparation of 4-amino-3-(p zonitrile
Figure imgf000134_0002
The title compound was prepared following the procedure described in step-3, Intermediate- 1 using 3-ethynylpyridine (371 mg, 3.61 mmol), 4-amino-3-iodobenzonitrile (step-1, Intermediate-74, 800 mg, 3.27 mmol), Et3N (0.5 mL), PdCl2(PPh3)2 (46 mg, 0.06 mmol), Cul (12.0 mg, 0.01 mmol) in DMSO (2.0 mL) to afford 580 mg of the title product.1!! NMR (300 MHz, DMSO-d6): δ 8.90 (br s, 2H), 8.07-8.05 (d, J = 7.2 Hz, 1H), 7.69 (s, 1H), 7.62-7.44 (m, 2H), 6.81-6.78 (d, J = 9.0 Hz, 1H), 6.63 (br s, 2H); MS [M+H]+: 220.
Step 2: Preparation of 4-amino-3-(2-(pyridin-3-yl)ethyl)benzonitrile
Figure imgf000135_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 74 by using 4-amino-3-(pyridin-3-ylethynyl)benzonitrile (500 mg), EtOH (25 mL), 10% Pd/C (150 mg) to afford 300 mg of the title product. 1H NMR (300 MHz, DMSO- 6): δ 8.48 (br s, 2H), 7.66 (m, 1H), 7.54-7.51 (d, = 7.8 Hz, 2H), 7.34-7.23 (m, 3H), 6.68-6.65 (d, = 8.4 Hz, 1H), 2.98-2.93 (t, J = 6.9 Hz, 2H), 2.90-2.75 (t, J = 8.4 Hz, 2H).
Step 3: Preparation of 4-iodo-3-(2-(pyridin-3-yl)ethyl)benzonitrile
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using 4-amino-3 -(2-(pyridin-3-yl)ethyl)benzonitrile (400 mg, 1.79 mmol), p- toluenesulphonic acid (923 mg, 5.3 mmol), NaN02 (185 mg, 2.69 mmol) and KI (923 mg, 5.7 mmol) in acetonitrile (20.0 mL) to afford 250 mg of title product.1H NMR (300 MHz, DMSO-d6): δ 8.48 (br s, 2H), 8.08-8.05 (d, = 7.8 Hz, 1H), 7.77 (s, 1H), 7.63 (d, 1H), 7.42- 7.39 (d, J = 8.1 Hz, 1H), 7.33 (br s, 1H), 3.02-32.99 (m, 2H), 2.89-2.87 (m, 2H) ; MS [M+H]+: 335.
Intermediate- 94
4-Iodo-3-(3-( -methoxyphenoxy)propyl)benzonitrile
Figure imgf000135_0002
The title compound was prepared following the procedure described in step-3, Intermediate - 80 using 3-(5-cyano-2-iodophenyl)propyl methanesulfonate (step-1, Intermediate-48, 300 mg,
0.82 mmol), K2C03 (136 mg, 1.23 mmol), 3-methoxyphenol (121 mg, 0.98 mmol) at 70°C for 16 h to afford 170 mg of title product.1H NMR (300 MHz, DMSO-d6): δ 7.96-7.94 (d, J = 8.1 Hz, 1H), 7.49 (s, 1H), 7.22-7.14 (m, 2H), 6.89-6.84 (m, 1H), 6.53-6.47 (m, 2H), 4.02-3.98 (t, J = 6.0 Hz, 2H), 3.82-3.78 (s, 3H), 2.98-2.93 (t, J = 6.9 Hz, 2H), 2.11-2.05 (m, 2H).
Intermediate-95
3-(3-(2,6-Difluorophenoxy)propyl)-4-iodobenzonitrile
Figure imgf000136_0001
The title compound was prepared following the procedure described in step-3, Intermediate - 80 using 3-(5-cyano-2-iodophenyl)propyl methanesulfonate (step-1, Intermediate-48, 300 mg, 0.82 mmol), K2C03 (136 mg, 1.23 mmol), 2,6-difluorophenol (128 mg, 0.98 mmol) at 70°C for 16 h to afford 190 mg of title product.1H NMR (300 MHz, DMSO-d6): δ 7.97-7.94 (d, = 8.4 Hz, 1H), 7.54 (s, 1H), 7.18-7.15 (d, = 7.8 Hz, 1H), 6.95-6.91 (m, 3H), 4.19-4.15 (t, = 6.0 Hz, 2H), 3.04-2.98 (t, = 7.8 Hz, 2H), 2.08-2.06 (m, 2H).
Intermediate-96
3-(3-((5-Fluoropyridin-3-yl)oxy)propyl)-4-iodobenzonitrile
Figure imgf000136_0002
The title compound was prepared following the procedure described in step-3, Intermediate - 80 using 3-(5-cyano-2-iodophenyl)propyl methanesulfonate (step-1, Intermediate-48, 200 mg, 0.45 mmol), K2C03 (93 mg, 0.67 mmol), 5-fluoropyridin-3-ol (51 mg, 0.45 mmol) at 70°C for 16 h to afford 150 mg of title product.1!! NMR (300 MHz, DMSO-d6): δ 8.16 (s, 2H), 7.06-7.03 (d, J = 8.1 Hz, 1H), 7.78 (s, 1H), 7.44-7.38 (m, 2H), 4.11 (t, 2H), 2.87-2.84 (t, J = 8.4 Hz, 2H), 2.02 (t, 2H).
Intermediate- 97
Ethyl 4-io -3-(3-isobutyramidopropyl)benzoate
Figure imgf000136_0003
Step 1: Preparation of ethyl 4-amino-3-(3-((ieri-butoxycarbonyl)amino)prop
yl)benzoate
Figure imgf000137_0001
The title compound was prepared following the procedure described in step-3, Intermediate- 1 using ethyl 4-amino-3-iodobenzoate (2.0 g, 8.19 mmol), ieri-butyl prop-2-yn-l-ylcarbamate (1.52 g, 9.8 mmol), Et3N (0.5 mL), PdCl2(PPh3)2 (0.114 g, 0.163 mmol), Cul (0.030 g, 0.16 mmol) in DMSO (15.0 mL) to afford 1.5 g of the title product.
Step 2: Preparation of ethyl 4- yl)amino)propyl)benzoate
Figure imgf000137_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 74 by using ethyl 4-amino-3-(3-((ieri-butoxycarbonyl)amino)prop-l-yn-l-yl)benzoate (1.0 g), EtOH (30 mL), 10% Pd/C (350 mg) to afford 600 mg of the title product. 1H NMR (300 MHz, DMSO-d6): 57.52-7.49 (m, 2H), 6.85 (br s, 1H), 6.60-6.57 (d, / = 8.7 Hz, 1H), 5.74 (br s, 2H), 4.19-4.17 (q, J = 6.6 Hz, 2H), 3.45-3.41 (m, 2H), 2.97 (m, 2H), 1.59 (m, 2H), 1.37 (s, 9H), 1.28-1.23 (t, 7 = 7.2 Hz, 3H).
Step 3: Preparation of ethyl 3-(3-((ieri-butoxycarbonyl)amino)propyl)-4-iodobenzoate
Figure imgf000137_0003
To a solution of ethyl 4-amino-3-(3-((ieri-butoxycarbonyl)amino)propyl)benzoate (100 mg, 0.31 mmol) in chloroform (2 mL) was added isopentyl nitrite (62.0 mg, 0.46 mmol). The reaction mass was stirred at rt for 30 mins followed by addition of iodine (157.0 mg, 0.62 mmol). The reaction mass was heated to reflux for 2 h. The reaction mass was cooled at rt and quenched with water and extracted with EtOAc. The organic layers were concentrated to afford 80 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 7.90-7.87 (d, 1H), 7.84 (s, 1H), 7.53-7.51(d, J = 8.1 Hz, 1H), 4.05-4.33 (q, J = 6.9 Hz, 2H), 3.21 (m, 2H), 2.82-2.77 (t, J = 7.5 Hz, 2H),1.82-7.78 (m, 2H), 1.45 (s, 9H), 1.42-1.37 (t, J = 7.2 Hz, 3H). Step 4: Preparation of ethyl 3-(3-aminopropyl)-4-iodobenzoate hydrochloride
Figure imgf000138_0001
To a solution of ethyl 3-(3-((ieri-butoxycarbonyl)amino)propyl)-4-iodobenzoate (300 mg) in EtOAc (1.0 mL) was added HCI saturated in EtOAc (3.0 mL). The reaction mass was stirred at rt for 4-5 h. The excess of solvent was removed under vacuum to afford 250 mg of the title product.
Step 5: Preparation of ethyl 4-iodo-3-(3-isobutyramidopropyl)benzoate
To a solution of ethyl 3-(3-aminopropyl)-4-iodobenzoate hydrochloride (200 mg), in THF (10 mL) was added Et3N (3.0 mL), isobutyryl chloride (0.3 mL).The reaction mass was stirred at rt for 16 h. The reaction mass was quenched in water and extracted with EtOAc.The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 120 mg of the title product.1!! NMR (300 MHz, DMSO-d6): δ 7.95-7.92 (d, = 7.8 Hz, 1H), 7.89 (s, 1H), 7.59-7.56 (d, = 7.8 Hz, 1H), 4.42-4.37 (q, = 6.9 Hz, 2H), 3.78-3.75 (m, 2H), 3.19- 3.14 (m, 2H), 2.82-2.80 (m, 2H), 2.72-2.67 (m, 1H), 1.46-1.41 (t, = 6.9 Hz, 3H), 1.26 (m, 6H).
Intermediate- 98
Ethyl 3-(3-cyanopropyl)-4-iodobenzoate
Figure imgf000138_0002
Step 1: Preparation of ethyl 4-iodo-3-( -oxobutyl)benzoate
Figure imgf000138_0003
To a solution of ethyl 3-(4-hydroxybutyl)-4-iodobenzoate (2.0 g, 5.7 mmol) in DCM (10 mL) was added PCC (2.4 g, 11.4 mmol).The reaction mass was stirred at rt for 2-3 h. The reaction mass was quenched with water and extracted with EtOAc. The organic layers were concentrated to afford 1.0 g of the title product.
Step 2: Preparation of (E)-ethyl 3-(4-(hydroxyimino)butyl)-4-iodobenzoate
Figure imgf000139_0001
To a solution of ethyl 4-iodo-3-(4-oxobutyl)benzoate (200 mg, 0.57 mmol) in EtOH (15 mL) was added pyridine (0.3 mL) and hydroxylamine hydrochloride (48 mg, 0.68 mmol). The reaction mass was heated at 90°C for 16 h. The excess of solvent was removed under vacuum and diluted with water. The aqueous layer was acidified and obtained solid was filtered to afford 150 mg the title product.
Step 3: Preparation of ethyl 3-(3-cyanopropyl)-4-iodobenzoate
To a cool solution of DMAP (67.2 mg, 0.55 mmol) in DCM (10 mL) was added thionyl chloride (129 mg, 1.1 mmol) at 0-5 °C. The reaction mass was stirred for 30 mins. Then the solution of (E)-ethyl 3-(4-(hydroxyimino)butyl)-4-iodobenzoate (200 mg, 0.55 mmol) in DCM (5 mL) was added followed by again addition of DMAP (100.8 mg, 0.82 mmol). The reaction mass was stirred at rt for 16 h. The reaction mass was quenched with water and extracted with DCM. The organic layers were concentrated to afford 108 mg of title product.
Intermediate-99
Ethyl 3-(3-(lH- )-4-iodobenzoate
Figure imgf000139_0002
To a solution of ethyl 3-(3-aminopropyl)-4-iodobenzoate hydrochloride (step-4, Intermediate- 97, 250 mg, 0.67 mmol) in acetic acid (10 mL) was added ethyl chloroformate (5 mL) and sodium azide (250 mg, 3.8 mmol).The reaction mixture was heated at 100°C for 3 h. The excess of solvent was removed under vacuum, diluted with water and extracted with DCM. The organic layers were concentrated to afford 150 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 8.66 (s, 1H), 7.92-7.89(d, = 8.1Hz, 1H), 7.82 (s, 1H), 7.58-7.55 (d, = 7.8 Hz, 1H), 4.54-4.49 (t, = 6.9 Hz, 2H), 4.41-4.33 (q, = 7.5 Hz, 2H), 2.87-2.82 (m, 2H), 2.32-2.27 (m, 2H), 1.41-1.37 (t, J = 7.2 Hz, 3H); MS [M+H]+: 373.
Intermediate- 100
Ethyl 3-(3-((5-cyanopyridin-3-yl)oxy)propyl)-4-iodobenzoate
Step-l:-Preparation of ethyl 4- yl)benzoate
Figure imgf000140_0001
The title compound was prepared following the procedure described in step-3, Intermediate- 1 using ethyl 4-amino-3-iodobenzoate (7.0 g, 24.05 mmol), prop-2-yn-l-ol (2.69 g, 48.10 mmol), PdCl2 (PPh3)2 (0.337 g, 0.48 mmol), Cul (0.091g, 0.48 mmol), Et3N (7.0 mL, 0.048 mmol) in DMSO (10.0 mL) to afford 3.6 g of title compound.
Step-2:- Preparation of ethyl 4- nzoate
Figure imgf000140_0002
The title compound was prepared following the procedure described in step-2 of Intermediate- 38 by using ethyl 4-amino-3-(3-hydroxyprop-l-yn-l-yl)benzoate (3.6 g, 16.43 mmol), EtOH (10 ml), Pd/CaC03(1.5 g) to afford 3.0 g of the title product.
Step-3:- Preparation of ethyl 3-(3-hydroxypropyl)-4-iodobenzoate
Figure imgf000140_0003
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using ethyl 4-amino-3-(3-hydroxypropyl)benzoate (3.0 g, 13.45 mmol), ice (3 g), conc.H2S04 (9 ml), aq. NaN02 (1.67 g, 24.21 mmol), aq. KI (4.46 g, 26.90 mmol) to afford 1.5 g of the title product.
Step-4:- Preparation of ethyl 4-io -3-(3-((methylsulfonyl)oxy)propyl)benzoate
Figure imgf000140_0004
The title compound was prepared following the procedure described in step-1 of Intermediate- 6 by using ethyl 3-(3-hydroxypropyl)-4-iodobenzoate (1.0 g, 2.99 mmol), mesyl chloride (0.377 g, 3.29 mmol), Et3N (0.332 g, 3.29 mmol), DCM (20.0 mL) to afford 1.0 g of title product. 1H NMR (300 MHz, DMSO-d6): δ 7.92-7.90 (d, = 8.1Hz, 1H), 7.86 (s, 1H), 7.57- 7.54 (d, = 8.4 Hz, 1H), 4.41-4.33 (q, = 7.5 Hz, 2H), 4.31-4.27 (t, = 6.3 Hz, 2H), 3.05 (s, 3H), 2.94-2.89 (m, 2H), 2.13-2.06 (m, 2H), 1.42-1.37 (t, J = 7.2 Hz, 3H).
Step-5:- Preparation of ethyl 3-(3-((5-cyanopyridin-3-yl)oxy)propyl)-4-iodobenzoate
The title compound was prepared following the procedure described in step-3, Intermediate - 80 using ethyl 4-iodo-3-(3-((methylsulfonyl)oxy)propyl) benzoate (200 mg, 0.45 mmol), K2C03 (93 mg, 0.67 mmol), 5-hydroxynicotinonitrile (54 mg, 0.45 mmol) at 70°C for 16 h to afford 100 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 8.49 (br s, 2H), 7.93-7.90 (d, J = 7.8 Hz, 1H), 7.86 (s, 1H), 7.57-7.54 (d, J = 8.4 Hz, 1H), 7.57 (s, 1H), 4.39-4.32 (q, J = 6.9 Hz, 2H), 4.11-4.07 (t, J = 6.3 Hz, 2H), 3.02-2.97 (t, J = 7.2 Hz, 2H), 2.19-2.15 (m, 2H), 1.39- 1.35 (t, 7 = 6.6 Hz, 3H).
Intermediate- 101
Ethyl 4-iodo-3-(3-(l-methylethylsulfonamido)propyl)benzoate
Figure imgf000141_0001
The title compound was prepared following the procedure described in step-5 of Intermediate- 97 by using ethyl 3-(3-aminopropyl)-4-iodobenzoate hydrochloride (step-4, Intermediate- 97,
100 mg, 0.27 mmol), propane-2-sulfonyl chloride (42 mg, 0.29 mmol), Et3N (68 mg, 0.67 mmol), THF (2.0 mL) to afford 80 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 8.00-7.98 (d, J = 7.8 Hz, 1H), 7.85 (s, 1H), 7.50 (m, 1H), 7.11 (m, 1H), 4.31-4.29 (q, J = 6.9 Hz, 2H), 3.16-2.72 (m, 5H), 1.71 (m, 2H), 1.46-1.43 (m, 9H).
Intermediate- 102
3-(3-Hydroxy-3-methylbutyl)-4-iodobenzonitrile
Figure imgf000141_0002
Preparation of 4-amino-3-(3-hydroxy-3-methylbut-l-yn-l-yl)benzonitrile
Figure imgf000142_0001
The title compound was prepared following the procedure described in step-3, Intermediate- 1 using 4-amino-3-iodobenzonitrile (step-1, Intermediate-74, 500 mg, 2.0 mmol), 2-methylbut- 3-yn-2-ol (225 mg, 2.5 mmol), PdCl2 (PPh3)2 (30.0 g, 0.040 mmol), Cul (10 mg, 0.040 mmol), Et3N (01.0 mL) in DMSO (10.0 mL) to afford 450 mg of title compound. 1H NMR (300 MHz, DMSO-d6): δ 7.45 (s, 1H), 7.40-7.37 (d, J = 8.7 Hz, 1H), 6.75-6.72 (q, J = 8.1 Hz, 1H), 6.28 (s, 2H), 1.45 (s, 6H).
Step-2:- Preparation of 4-amino-3-(3-hydroxy-3-methylbutyl)benzonitrile
Figure imgf000142_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 74 by using 4-amino-3-(3-hydroxy-3-methylbut-l-yn-l-yl)benzonitrile (400 mg), EtOH (30 mL), 10% Pd/C (250 mg) to afford 400 mg of the title product.
Step-3:- Preparation of 3-(3-hydroxy-3-methylbutyl)-4-iodobenzonitrile
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using 4-amino-3-(3-hydroxy-3-methylbutyl)benzonitrile (500 mg, 2.4 mmol), p- toluenesulphonic acid (1.23 g, 7.2 mmol), aq.NaN02 (248 mg, 3.6 mmol), aq. KI (598 mg, 3.6 mmol) in acetonitrile (25 mL) to afford 300 mg of the title product.
Intermediate- 103
3-Chloro-4-ethynylphenol
Figure imgf000142_0003
The title compound was prepared following the procedure described in step-3, Intermediate- 1 by using 3-chloro-4-iodophenyl methanesulfonate (Intermediate- 12, 2.0 g, 6.02 mmol), trimethylsilyl acetylene (0.880 g, 9.03 mmol), Cul (0.022 g, 0.12 mmol), PdCl2(PPh3)2 (0.084 g, 0.12 mmol), Et3N (0.912 g, 9.03 mmol), 1M TBAF solution in THF (2.36 g, 9.03 mol) in DMSO (20 mL), THF (20 mL) to afford 0.700 g of title product.
Intermediate- 104 4-Iodo-3-(pyridin-4-yl)benzonitrile
Step- 1 : Preparation of 4-amino-3-(p
Figure imgf000143_0001
The title compound was prepared following the procedure described in step-3, Intermediate - 33 by using 4-amino-3-iodobenzonitrile (step- 1, Intermediate-74, 1.0 g, 4.09 mmol), pyridin- 4-ylboronic acid (3.33 g, 22.72 mmol), K2C03 (0.848 g, 0.06 mmol) and Pd(dppf)Ci2 (0.094 g, 0.08 mmol) in DMSO (10 mL) to afford 0.700 g of title product.
Step-2:- Preparation of 4-iodo-3-(pyridin-4-yl)benzonitrile
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using 4-amino-3-(pyridin-4-yl)benzonitrile (600 mg, 1.96 mmol), /?-toluenesulphonic acid (1.11 g, 5.88 mmol), aq. NaNO2 (202 mg, 2.94 mmol), aq. KI (488 mg, 2.94 mmol) in acetonitrile (30 mL) to afford 400 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.70 (s, 2H), 8.25-8.23 (d, J = 8.4 Hz, 1H), 7.85 (s, 1H), 7.64-7.61 (d, J = 8.4 Hz, 1H), 7.42 (s, 2H); MS [M+H]+: 30
Intermediate- 105
2-B ole
Figure imgf000143_0002
To a cool solution of thiazol-2-amine (5.0 g, 50 mmol) in 85% H3P04 was added cone, nitric acid and stirred the reaction mixture for 10 mins followed by addition of aq.NaN02 (4.14 g, 60 mmol), continued stirring for 1 h at 0°C.Then added aq.CuS04 (6.36 g, 40 mmol) & NaBr (14.49 g,145 mmol). The reaction mass was further stirred at 0°C for 6 h then at rt for 16 h. The reaction mass was basified with KOH & Na2C03 up to pH-9 and extracted with DCM. The organic layers were separated and concentrated to afford 2.5 g of title compound . 1H
NMR (300 MHz, DMSO-d6): δ 7.62-7.61 (d, 7 = 3.0 Hz, 1H), 7.31-7.30 (d,
Intermediate- 106
4-Iodo-3-(2-(thiazol-2-yl)ethyl)benzonitrile
Figure imgf000144_0001
Step 1: Preparation of 4-amino-3-ethynylbenzonitrile
Figure imgf000144_0002
The title compound was prepared following the procedure described in step-3, Intermediate- 1 using 4-amino-3-iodobenzonitrile (step-1, Intermediate-74, 4.5 g, 0.018 mol), trimethylsilyl acetylene (2.70 g, 0.027 mol), Cul (0.070 g, 0.0003 mmol), PdCl2(PPh3)2 (0.257 g, 0.0003 mmol), Et3N (2.8 g, 0.027 mol) in DMSO (20 mL) to afford crude 2.5 g of trimethyl((2- (trifluoromethyl)phenyl)ethynyl)silane compound.
The crude trimethyl((2-(trifluoromethyl)phenyl)ethynyl)silane (3.0 g) desyllalated by THF (5.0 mL), 1M TBAF solution in THF (7.2 mL, 0.027 mol) to afford 1.0 g of title compound, Step 2: Preparation of 4-amino-3-( onitrile
Figure imgf000144_0003
The title compound was prepared following the procedure described in step-3, Intermediate- 1 using 4-amino-3-ethynylbenzonitrile (300 mg, 2.11 mmol), 2-bromothiazole (Intermediate- 105, 381 mg, 2.32 mmol),diethyl amine (10 mL), PdCl2(PPh3)2 (30 mg, 0.040 mmol), Cul (8.0 mg, 0.02 mmol) in DCM (10.0 mL) at 40-50°C for 16 h to afford 300 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 7.71 (s, 1H), 7.62-7.58 (m, 2H), 7.48-7.45 (d, = 6.9 Hz, 1H), 6.80-6.77 (d, = 8.7 Hz, 1H), 6.69 (s, 2H); MS [M+H]+: 307.
Step 3: Preparation of 4-amino-3-(2-( benzonitrile
Figure imgf000144_0004
The title compound was prepared following the procedure described in step-3 of Intermediate- 74 by using 4-amino-3-(thiazol-2-ylethynyl)benzonitrile (300 mg), EtOH (20 mL), 10% Pd/C (100 mg) to afford 300 mg of the title product. Step 4: Preparation of 4-iodo-3-(2-(thiazol-2-yl)ethyl)benzonitrile
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using 4-amino-3-(2-(thiazol-2-yl)ethyl)benzonitrile (300 mg, 1.3 mmol), p- toluenesulphonic acid (746 mg, 3.9 mmol), aq. NaN02 (135 mg, 1.9 mmol), aq. KI (326 mg, 1.9 mmol) in acetonitrile (30 mL) to afford 200 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.08-8.06 (d, J = 8.4 Hz, 1H), 7.80 (s, 1H), 7.72-7.71 (d, J = 3.0 Hz, 1H), 7.61- 7.60 (d, = 3.0 Hz, 1H), 7.43-7.40 (d, = 7.8Hz, 1H), 3.29-3.26 (d, = 7.8 Hz, 2H), 3.19- 3.17 (d, J = 7.2 Hz, 2H); MS [M+H]+: 341.
Intermediate- 107
N-(3-(5-cyan -2-iodophenyl)propyl)isobutyramide
Figure imgf000145_0001
Step 1: Preparation of tert-butyl (3- 2-amino-5-cyanophenyl)prop-2-yn-l-yl)carbamate
Figure imgf000145_0002
The title compound was prepared following the procedure described in step-3, Intermediate- 1 using 4-amino-3-iodobenzonitrile (step-1, Intermediate-74, 2.0 g, 8.19 mmol), tert-butyl prop- 2-yn-l-ylcarbamate (1.52 g, 9.8 mmol), Et3N (0.5 mL), PdCl2(PPh3)2 (0.114 g, 0.163 mmol), Cul (0.030 g, 0.16 mmol) in DMSO (15.0 mL) to afford 1.8 g of the title product.
Step 2: Preparation of tert-butyl (3- -amino-5-cyanophenyl)propyl)carbamate
Figure imgf000145_0003
The title compound was prepared following the procedure described in step-3 of Intermediate- 74 by using tert-butyl (3-(2-amino-5-cyanophenyl)prop-2-yn-l-yl)carbamate (1.0 g), EtOH (30 mL), 10% Pd/C (350 mg) to afford 800 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 7.25 (m, 2H), 6.85 (s, 1H), 6.64-6.61 (d, J = 9.0 Hz, 1H), 5.93 (s, 2H), 2.94 (m, 2H), 2.40 (t, 2H), 1.58 (m, 2H), 1.22 (s, 9H).
Step 3: Preparation of ie/ -butyl (3- -cyano-2-iodophenyl)propyl)carbamate
Figure imgf000146_0001
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using ie/ -butyl (3-(2-amino-5-cyanophenyl)propyl)carbamate (100 mg, 0.36 mmol), p- toluenesulphonic acid (187 mg, 1.09 mmol), aq. NaN02 (37 mg, 0.57 mmol), aq. KI (90 mg, 0.54 mmol) in acetonitrile (10 mL) to afford 100 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.05-8.02 (d, = 8.4 Hz, 1H), 7.76 (s, 1H), 7.397.37 (d, = 7.8 Hz, 1H), 6.82 (m, 1H), 2.94 (m, 2H), 2.69 (t, 2H), 1.64 (m, 2H), 1.31 (s, 9H).
Step 4: Preparation of 3-(3-aminopropyl)-4-iodobenzonitrile
Figure imgf000146_0002
HCl
To a solution of ie/ -butyl (3-(5-cyano-2-iodophenyl)propyl)carbamate (300 mg) in EtOAc (1.0 mL) was added HCl saturated in EtOAc (3.0 mL). The reaction mass was stirred at rt for 4-5 h. The excess of solvent was removed under vacuum to afford 250 mg of the title product. Step 5: Preparation of ethyl N-(3-(5-cyano-2-iodophenyl)propyl)isobutyramide
The title compound was prepared following the procedure described in step-5 of Intermediate- 97 using ie/ -butyl (3-(5-cyano-2-iodophenyl)propyl)carbamate (200 mg), Et3N (3.0 mL), isobutyryl chloride (0.3 mL) in THF (10 mL) to afford 120 mg of the title product.
Intermediate- 108
4-iodo-3-(2-(pyridin-4-yl)ethyl)benzonitrile
Figure imgf000146_0003
Step 1 : Preparation of 4-amino-3-(pyridin-4-ylethynyl)benzonitrile
Figure imgf000147_0001
The title compound was prepared following the procedure described in step-3, Intermediate- 1 using 3-ethynylpyridine (371 mg, 3.61 mmol), 4-amino-3-iodobenzonitrile (step-1, Intermediate-74, 800 mg, 3.27 mmol), Et3N (0.5 mL), PdCl2(PPh3)2 (46 mg, 0.06 mmol), Cul (12.0 mg, 0.01 mmol) in DMSO (2.0 mL) to afford 460 mg of the title product.1!! NMR (300 MHz, DMSO-d6): δ 7.72 (br s, 2H), 7.49-7.46 (d, = 6.9 Hz, 2H), 6.82-6.79 (d, = 8.7 Hz, 2H), 6.68 (s, 2H).
Step 2: Preparation of 4-amino-3-(2-(pyridin-4-yl)ethyl)benzonitrile
Figure imgf000147_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 74 by using 4-amino-3-(pyridin-4-ylethynyl)benzonitrile (500 mg), EtOH (25 mL), 10% Pd/C (150 mg) to afford 280 mg of the title product. 1H NMR (300 MHz, DMSO- 6): δ 8.47 (br s, 2H), 7.62-7.58 (m, 2H), 7.32 (br s, 2H), 6.68-6.65 (d, = 8.4 Hz, 1H), 6.06 (br s, 2H), 2.81 (br s, 2H), 2.76 (br s, 2H).
Step 3: Preparation of 4-iodo-3-(2-(pyridin-4-yl)ethyl)benzonitrile
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using 4-amino-3-(2-(pyridin-4-yl)ethyl)benzonitrile (400 mg, 1.79 mmol), p- toluenesulphonic acid (923 mg, 5.3 mmol), NaN02 (185 mg, 2.69 mmol) and KI (923 mg, 5.7 mmol) in acetonitrile (20.0 mL) to afford 230 mg of title product.1H NMR (300 MHz, DMSO-d6): δ 8.08-8.05 (d, = 8.4 Hz, 1H), 7.78 (s, 1H), 7.62-7.58 (m, 3H), 7.42-7.39 (d, = 7.8 Hz, 2H), 3.03-3.0 (m, 2H), 2.88 (m, 2H).
Intermediate- 109
3-(6-chloropyridin-3-yl)-4-iodobenzonitrile
Figure imgf000148_0001
Ste l : Preparation of 4-amino-3-(6-chloropyridin-3-yl)benzonitrile
Figure imgf000148_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 33 by using 4-amino-3-iodobenzonitrile (step- 1, Intermediate-74, 250 mg, 1.02 mmol), (6- chloropyridin-3-yl)boronic acid (161 mg, 1.02 mmol), Pd(dppf)C (166 mg, 0.20 mmol), K2C03 (426 mg, 3.09 mmol) in dioxane (15 mL) and water (2.0 mL) to afford 0.220 g of title product.
Step 2: Preparation of 3-(6-chloropyridin-3-yl)-4-iodobenzonitrile
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using 4-amino-3-(6-chloropyridin-3-yl)benzonitrile (200 mg, 0.87 mmol), p- toluenesulphonic acid (450 mg, 2.62 mmol), NaN02 (90 mg, 1.3 mmol) and KI (216 mg, 1.3 mmol) in acetonitrile (20.0 mL) and water (2 mL) to afford 180 mg of title product.
Intermediate- 110
4-bromo-3-((p yl)benzonitrile
Figure imgf000148_0003
Step 1: Preparation of 4-bromo-3-(bromomethyl)benzonitrile
Figure imgf000148_0004
To a solution of 4-bromo-3-methylbenzonitrile (2.0 g, 10.20 mmol) in carbon tetrachloride (50 ml) was added N-bromosuccinamide (2.72 g, 15.30 mmol), AIBN (0.836 g, 6.1 mmol) under inert atmosphere and reaction mass was stirred for 90-100°C for 16 h. Then the reaction mixture was diluted with EtOAc. The reaction mixture was quenched with water, extracted with DCM and organic layer was separated, dried over Na2S04 and concentrated to afford 1.0 g of title product. 1H NMR (300 MHz, DMSO-d6): δ 8.02-7.99 (d, = 9.0 Hz, 1H), 7.62-7.59 (d, J = 8.4 Hz, 1H), 7.52 (s, 1H), 3.99 (s, 2H).
Step 2: Preparation of 4-bromo-3-((pyridin-3-yloxy)methyl)benzonitrile
The title compound was prepared following the procedure described in step-3, Intermediate - 80 using 4-bromo-3-(bromomethyl)benzonitrile (1.0 g, 3.63 mmol), K2C03 (1.0 g, 7.24 mmol), pyridin-3-ol (0.345 g, 3.63 mmol) in DMF (10 mL) to afford 700 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 8.42 (br s, 1H), 8.22 (br s, 1H), 8.10 (s, 1H), 7.96-7.93 (d, = 8.1 Hz, 1H), 7.82-7.80 (d, = 8.4 Hz, 1H), 7.54-7.52 (m, 1H), 7.40-7.38 (m, 1H), 5.23 (s, 2H).
Intermediate-I l l
4-iodo-3-(6-methoxypyridin-3-yl)benzonitrile
Figure imgf000149_0001
Step 1 : Preparation of 4-amino-3-(6-methoxypyridin-3-yl)benzonitrile
Figure imgf000149_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 33 by using 4-amino-3-iodobenzonitrile (step- 1, Intermediate-74, 700 mg, 2.86 mmol), (6- methoxypyridin-3-yl)boronic acid (526 mg, 3.44 mmol), Pd(dppf)C ( 117 mg, 0.14 mmol ), K2C03 (593 mg, 4.30 mmol) in dioxane (50 mL) and water (5.0 mL) to afford 0.400 g of title product. 1H NMR (300 MHz, DMSO-d6): δ 8.16 (s, 1H), 7.74-7.70 (d d, = 1.8 Hz, 1H), 7.44-7.41 (d, = 8.4 Hz, 1H), 7.34 (s, 1H), 6.91-6.88 (d, = 8.4 Hz, 1H), 6.80-6.78 (d, = 8.7 Hz, 1H), 5.90 (s, 2H), 3.89 (s, 3H); MS [M+H]+: 226.
Step 2: Preparation of 4-iodo-3-(6-methoxypyridin-3-yl)benzonitrile
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using 4-amino-3-(6-methoxypyridin-3-yl)benzonitrile (400 mg, 1.77 mmol), ice (500 mg), conc.H2S04 (2 ml), aq. NaN02 (220 mg, 3.19 mmol), aq. KI (590 mg, 3.55 mmol), acetonitrile (2.0 mL), water (2.0 mL) to afford 250 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.23 (d, 7 = 8.4 Hz, 1H), 8.17 (s, 1H), 7.84 (s, 1H), 7.76-7.73 (d, 7 = 10.5 Hz, 1H), 7.58-7.55 (d, 7 = 8.4 Hz, 1H), 6.94-6.91 (d, 7 = 8.4 Hz, 1H), 3.91 (s, 3H).
Intermediate- 112
5'-cyano-2'-i carboxamide
Figure imgf000150_0001
Step 1: Preparation of 2'-amino-5'-cyano-[l, -biphenyl]-4-carboxamide
Figure imgf000150_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 33 by using 4-amino-3-iodobenzonitrile (step-1, Intermediate-74, 500 mg, 2.04 mmol), (4- carbamoylphenyl)boronic acid (252 mg, 2.04 mmol), Pd(dppf)Ch 034 mg, 0.4 mmol), K2CO3 (844 mg, 6.12 mmol) in dioxane (15 mL) and water (1.0 mL) to afford 0.480 g of title product. 1H NMR (300 MHz, DMSO-d6): δ 7.98-7.95 (d, 7 = 8.4 Hz, 3H), 7.50-7.37 (m, 5H), 6.83- 6.80 (d, 7 = 8.7 Hz, 1H), 5.91 (s, 2H).
Step 2: Preparation of 5'-cyano-2'-iodo-[l, -biphenyl]-4-carboxamide
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using 2'-amino-5'-cyano-[l, -biphenyl]-4-carboxamide (400 mg, 1.68 mmol), p- toluenesulphonic acid (870 mg, 5.06 mmol), NaN02 (174 mg, 2.52 mmol) and KI (418 mg, 2.52 mmol) in acetonitrile (20.0 mL) and water (2 mL) to afford 310 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 8.24-8.21 (d, 7 = 7.8 Hz, 1H), 8.09 (s, 1H), 7.97-7.95 (d, 7 = 7.8 Hz, 2H), 7.81 (s, 1H), 7.59-7.56 (d, 7 = 7.8 Hz, 1H), 7.45-7.43 (d, 7 = 7.8 Hz, 3H).
Intermediate- 113
4-iodo-3-(pyridin-3-yl)benzonitrile
Figure imgf000150_0003
Step 1 : Preparation of 4-amino-3-(p le
Figure imgf000151_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 33 by using 4-amino-3-iodobenzonitrile (step-1, Intermediate-74, 700 mg, 2.86 mmol), pyridin-3-ylboronic acid (423 mg, 3.44 mmol), Pd(dppf)Cl2 (117 mg, 0.14 mmol), K2CO3 (593 mg, 4.30 mmol) in dioxane (50 mL) and water (5.0 mL) to afford 400 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 8.59 (s, 2H), 7.84-7.81 (d, = 7.8 Hz, 1H), 7.49-7.45 (m, 2H), 7.39 (s, 1H), 6.84-6.81 (d, = 8.1 Hz, 1H), 5.98 (s, 2H); MS [M+H]+: 196.
Step 2: Preparation of 4-iodo-3-(pyridin-3-yl)benzonitrile
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using 4-amino-3-(pyridin-3-yl)benzonitrile (400 mg, 2.05 mmol), ice (400 mg), conc.H2S04 (2 ml), aq. NaN02 (254 mg, 3.69 mmol), aq. KI (681 g, 4.10 mmol), acetonitrile (4.0 mL), water (2.0 mL) to afford 200 mg of the title product. 1H NMR (300 MHz, DMSO- d6): δ 8.65-8.64 (d, = 3.3 Hz, 1H), 8.58 (s, 1H), 8.26-8.23 (d, = 8.1 Hz, 1H), 7.88 (s, 1H), 7.84-7.81 (d, = 8.1 Hz, 1H), 7.62-7.60 7.84-7.81 (d, = 7.8 Hz, 1H), 7.54-7.50 (m, 1H); MS [M+H]+: 307.
Intermediate- 114
4-iodo-3 enzonitrile
Step 1 : Preparation of 4-nitro-3-(p zonitrile
Figure imgf000151_0002
The title compound was prepared following the procedure described in step-3, Intermediate- 80 by using 3-fluoro-4-nitrobenzonitrile (5 g, 30.1 mmol), pyridin-3-ylmethanol (5.0 g, 45.1 mmol), K2CO3 (6.3 g, 45.1 mmol) in DMF (30.0 mL) to afford 4.5 g of title compound. Step 2: Preparation of 4-amino-3-(p enzonitrile
Figure imgf000152_0001
The title compound was prepared following the procedure described in step-1, Intermediate- 1 by using4-nitro-3-(pyridin-3-ylmethoxy)benzonitrile (3.0 g) in methanol (100 mL) was added cone. HC1 (10.0 mL) and Fe powder (1.00 g) and stirred for 2 h. The reaction mixture was quenched with water, neutralized with sat.NaHC03 solution and extracted with EtOAc. The organic layer was concentrated to afford 2.3 g of title product.
Step 3: Preparation of 4-iodo-3-(pyridin-3-ylmethoxy)benzonitrile
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using 4-amino-3-(pyridin-3-ylmethoxy)benzonitrile (1.0 g, 4.44 mmol), p- toluenesulfonic acid (2.54 g, 13.30 mmol), aq. NaN02 (0.455 g, 6.5 mmol in 20 mL water) and KI (1.1 g, 6.5 mmol) in acetonitrile (40 mL) to afford 0.900 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.77 (br s, 1H), 8.64 (br s, 1H), 8.04-8 (d, = 7.8 Hz, 2H), 7.62-5.62 (m, 2H), 7.25-7.22 (d, / = 8.4 Hz, 1H), 5.34 (s, 2H); MS (m z): 337 (M+H)+.
Intermediate- 115
4-iodo-3-(2-(pyridin-2-yl)ethyl)benzonitrile
Step 1: Preparation of 4-amino-3-(p zonitrile
Figure imgf000152_0002
The title compound was prepared following the procedure described in step-3, Intermediate- 1 using 2-ethynylpyridine (371 mg, 3.61 mmol), 4-amino-3-iodobenzonitrile (step-1, Intermediate-74, 800 mg, 3.27 mmol), Et3N (0.5 mL), PdCl2(PPh3)2 (46 mg, 0.06 mmol), Cul (12.0 mg, 0.01 mmol) in DMSO (2.0 mL) to afford 460 mg of the title product.
Step 2: Preparation of 4-amino-3-(2-(pyridin-2-yl)ethyl)benzonitrile
Figure imgf000153_0001
The title compound was prepared following the procedure described in step-2 of Intermediate- 93 by using 4-amino-3-(pyridin-2-ylethynyl)benzonitrile (500 mg), EtOH (25 mL), 10% Pd/C (150 mg) to afford 280 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.76 (m, 1H), 8.67 (m, 1H), 8.36 (t, 1H), 7.86-7.77 (m, 3H), 7.30-7.28 (m, 2H), 6.68-6.65 (d, 7 = 9.0 Hz, 1H), 3.0-2.97 (m, 2H), 2.92-2.89 (m, 2H).
Step 3: Preparation of 4-iodo-3-(2-(pyridin-2-yl)ethyl)benzonitrile
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using 4-amino-3-(2-(pyridin-2-yl)ethyl)benzonitrile (400 mg, 1.79 mmol), p- toluenesulphonic acid (923 mg, 5.3 mmol), NaN02 (185 mg, 2.69 mmol) and KI (923 mg, 5.7 mmol) in acetonitrile (20.0 mL) to afford 230 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 8.51 (br s, 1H), 8.06-8.04 (d, 7 = 7.8 Hz, 1H), 7.71 (s, 2H), 7.39-7.37 (d, 7 = 7.8 Hz, 1H), 7.28-7.24 (m, 2H), 3.11-3.09 (m, 2H), 3.03-3.00 (m, 2H); MS (m z): 335 (M+H)+.
Intermediate- 116
4-iodo-3-(pyrimidin-5-yl)benzonitrile
Step 1 : Preparation of 4-amino-3-(py nitrile
Figure imgf000153_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 33 by using 4-amino-3-iodobenzonitrile (step-1, Intermediate-74, 500 mg, 2.04 mmol), pyrimidin-5-ylboronic acid (266 mg, 2.15 mmol), PdidppfiC (84 mg, 0.10 mmol), K2C03 (424 mg, 3.07 mmol) in dioxane (20 mL) and water (5.0 mL) to afford 400 mg of title product. 1H NMR (300 MHz, DMSO d6): δ 9.19 (s, 1H), 8.82 (s, 2H), 7.50-7.48 (s, 2H), 6.83-6.80 (d, 7 = 8.1 Hz, 1H), 6.16 (s, 2H); MS [M+H]+: 195.
Step 2: Preparation of 4-iodo-3-(pyrimidin-5-yl)benzonitrile The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using 4-amino-3-(pyrimidin-5-yl)benzonitrile (300 mg, 1.5 mmol), ice (300 mg), conc.H2S04 (2 ml), aq. NaNO2 (190 mg, 2.75 mmol), aq. KI (508 g, 3.06 mmol), acetonitrile (3.0 mL), water (2.0 mL) to afford 150 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 9.28 (s, 1H), 8.90 (s, 2H), 8.29-8.26 (d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.68-7.65 (d, = 8.1 Hz, 1H).
Intermediate- 117
5'-cyano-2'-iod - [ 1 , 1 '-biphenyl] -3 -carboxamide
Figure imgf000154_0001
Step 1 : Preparation of 2'-amino-5'-cya -[l, -biphenyl]-3-carboxylic acid
Figure imgf000154_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 33 by using 4-amino-3-iodobenzonitrile (step-1, Intermediate-74, 250 mg, 1.02 mmol), 3- boronobenzoic acid (168 mg, 1.02 mmol), Pd(dppf)C (166 mg, 0.20 mmol), K2C03 (422 mg, 3.06 mmol) in dioxane (20 mL) and water (2.0 mL) to afford 200 mg of title product. 1H NMR (300 MHz, DMSO d6): δ 13.04 (br s, 1H), 7.94 (s, 2H), 7.63-7.43 (m, 3H), 7.37 (s, 1H), 6.84-6.81 (d, = 8.1 Hz, 1H), 5.93 (s, 2H).
Step 2: Preparation of 5'-cyano-2'-iodo- -biphenyl]-3-carboxylic acid
Figure imgf000154_0003
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using 2'-amino-5'-cyano-[l, -biphenyl]-3-carboxylic acid (300 mg, 1.26 mmol), p- toluenesulphonic acid (650 mg, 3.78 mmol), NaN02 (130 mg, 1.89 mmol) and KI (313 mg, 1.89 mmol) in acetonitrile (20.0 mL) and water (2.0 mL) to afford 200 mg of title product. 1H NMR (300 MHz, DMSO d6): δ 8.24-8.21 (d, = 8.1 Hz, 1H), 8.01 (s, 1H), 7.89 (s, 1H), 7.84 (s, 1H), 7.62-7.56 (m, 3H).
Step 3: Preparation of 5'-cyano-2'-iodo-[l,r-biphenyl]-3-carboxamide
To a solution of 5'-cyano-2'-iodo-[l,r-biphenyl]-3-carboxylic acid (200 mg, 0.57 mmol) in THF (10 mL) was added oxalyl chloride (87 mg, 0.68 mmol). The reaction mass was stirred at rt for 3-4 h. Excess of solvent was then removed under vacuum. The concentrated reaction mass was dissolved in THF and ammonia gas was purged at 5- 10°C for lh.The reaction mass was quenched with water and extracted with ethyl acetate. The organic layer was concentrated to afford 400 mg of title product.
Intermediate-118
3-(5-cyano-2-iodophenyl)- V-ethylpropan amide
Figure imgf000155_0001
Step 1 : Preparation of 3-(5-cyano-2-iodophenyl)propanoic acid
Figure imgf000155_0002
To a solution of 3-(3-hydroxypropyl)-4-iodobenzonitrile (step-4, Intermediate-38, 800 mg, 2.76 mmol) in acetone (10 mL) was added Jone' s reagent (10 mL) {Na2Cr207(2 g)+ water (1 mL)+ conc.H2S04 (2.0 mL) } .The reaction mass was stirred at rt for 2 h. The reaction mass was filtered through celite and filtrated was basified with sodium bicarbonate and again acidified with citric acid. Then extracted with mixture of DCM : MeOH. The organic layer was washed with water, brine, dried over Na2S04 and concentrated. The crude product was purified by column chromatography to afford 400 mg of title compound. 1H NMR (300 MHz, DMSO-d6): δ 12.28 (br s, 1H), 8.07-8.04 (d, = 7.8 Hz, 1H), 7.74 (s, 1H), 7.41-7.38 (d, = 7.2 Hz, 1H), 2.95-2.90 (t, = 7.8 Hz, 2H), 2.57-2.50 (t, = 8.1Hz, 2H).
Step 2: Preparation of 3-(5-cyano-2-iodophenyl)-N-ethylpropanamide
The title compound was prepared following the procedure described in step-3 of Intermediate- 117 by using 3-(5-cyano-2-iodophenyl)propanoic acid (200 mg, 0.66 mmol), oxalyl chloride (101 mg, 0.79 mmol), ethyl amine (35 mg, 0.79 mmol) in DCM (10 mL) to afford 150 mg of title product.
Intermediate- 119
3 - (3 - ( 1 H-tetrazol- - yl)propyl) -4 -iodobenzonitrile
Figure imgf000156_0001
The title compound was prepared following the procedure described in Intermediate-99 using 3-(3-aminopropyl)-4-iodobenzonitrile (step-4, Intermediate- 107, 220 mg, 0.67 mmol) in acetic acid (10 mL) was added ethyl chloroformate (5 mL) and sodium azide (250 mg, 3.8 mmol) to afford 150 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 9.43 (s, 1H), 8.04-8.01 (d, = 8.1 Hz, 1H), 7.77 (s, 1H), 7.39-7.37 (d, = 7.8 Hz, 1H), 4.54-4.49 (t, = 6.9 Hz, 2H), 2.73-2.68 (t, J = 6.9 Hz, 2H), 2.14-2.09 (m, 2H).
Intermediate- 120
3-(5-cyano- -iodophenyl)propanamide
Figure imgf000156_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 117 by using 3-(5-cyano-2-iodophenyl)propanoic acid (step-1, Intermedaite- 118, 200 mg, 0.66 mmol), oxalyl chloride (101 mg, 0.79 mmol), ammonia gas in DCM (10 mL) to afford 100 mg of title product. 1H NMR (300 MHz, DMSO-d6): 57.96-7.93 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 7.19-7.16 (d, / = 8.4 Hz, 1H), 5.42 (m, 2H), 3.14-3.09 (t, J = 7.2 Hz, 2H), 2.56-2.51 (t, 7 = 7.8 Hz, 2H).
Intermediate- 121
N-(5-cyano-2-iodophenethyl)isobutyramide
Figure imgf000157_0001
Step- 1 : Preparation of 3-(2-aminoethyl)- -iodobenzonitrile
Figure imgf000157_0002
To a solution of 3-(5-cyano-2-iodophenyl)propanamide (250 mg, 0.83 mmol) in DMF:H20 (3mL: lmL) was added pyridine (0.5mL) and [bis(trifluoroacetoxy)iodo]benzene (428 mg, 0.99 mmol). The reaction mass was stirred at rt for 1 h. The reaction mass was quenched with water and extracted with ethyl acetate. The organic portion was separated, washed with water, brine, dried over Na2S04 and concentrated to afford to afford 180 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.0-7.91 (m, IH), 7.50 (m, IH), 7.15 (m, IH), 3.07-3.04 (m, 2H), 2.66-2.64 (m, 2H).
Step-2: Preparation of N-(5-cyano-2-iodophenethyl)isobutyramide
The title compound was prepared following the procedure described in step-5, Intermediate - 97 using 3-(2-aminoethyl)-4-iodobenzonitrile (250 mg), Et3N (1.0 mL), isopropyl chloride (0.5 mL) in THF (5 mL) to afford 100 mg of the title product. 1H NMR (300 MHz, OMSO-ek): δ 10.02 (br s, IH), 8.06-8.03 (d, = 8.4 Hz, IH), 7.80 (t, IH), 7.61 (s, IH), 7.41-7.39 (d, = 6.3 Hz, IH), 3.31-3.27 (m, 2H), 2.88-2.84 (m, 2H), 2.28-2.26 (m, IH), 0.95-0.96 (t, J = 6.9 Hz, 6H).
Intermediate- 122
4-iodo-3-(l-methyl-lH-pyrazol-4-yl)benzonitrile
Figure imgf000157_0003
Step- 1 : Preparation of 4-amino-3-(l-methyl- lH-pyrazol-4-yl)benzonitrile
Figure imgf000158_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 33 by using 4-amino-3-iodobenzonitrile (step- 1, Intermediate-74, 1.0 g, 4.09 mmol), 1- methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole (895 mg, 4.30 mmol), Pd(4¾¾ Cl2 (167 mg, 0.24 mmol), K2C03 (848 mg, 6.14 mmol) in dioxane (20 mL) and water (5.0 mL) to afford 600 mg of title product.
Step-2: Preparation of 4-iodo-3-(l-methyl- lH-pyrazol-4-yl)benzonitrile
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using 4-amino-3-(l-methyl- lH-pyrazol-4-yl)benzonitrile (600 mg, 3.03 mmol), ice (300 mg), conc.H2S04 (3 ml), aq. NaN02 (376 mg, 5.45 mmol), aq. KI (1.08 g, 6.06 mmol), acetonitrile (3.0 mL), water (3.0 mL) to afford 250 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.16-8.13 (d, = 8.1 Hz, 1H), 8.11 (s, 1H), 7.87-7.76 (d, = 6.3 Hz, 2H), 7.42-7.39 (d, = 7.8 Hz, 1H), 3.88 (s, 3H).
Intermediate- 123
3-(l-acetylpiperidin-4-yl)-4-iodobenzonitrile
Figure imgf000158_0002
Step 1 : Preparation of tert-butyl 4-(2-amino-5-cyanophenyl)-5,6-dihydropyridine- l(2H)- carboxylate
Figure imgf000158_0003
The title compound was prepared according to the procedure described in step-3, Intermediate- 1 using 4-amino-3-iodobenzonitrile (step- 1, Intermediate-74, 1.0 g, 4.09 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine- l(2H)- carboxylate (1.26 g, 4.09 mmol), Pd(dppf)Cl2 (0.067 g, 0.08 mmol) and aq. K2C03 (1.69 g, 12.27 mmol), dioxane (15 mL), water (2 mL) to afford 500 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 7.32-7.30 (d, = 7.8 Hz, 1H), 7.23 (s, 1H), 6.71-6.68 (d, = 7.8 Hz, 1H), 5.75 (s, 2H), 5.70 (s, 1H), 3.93 (s, 2H), 2.34 (s, 2H), 1.42 (br s, 9H), 1.19 (m, 2H).
Step 2: Preparation of ie/ -butyl 4-( -amino-5-cyanophenyl)piperidine-l-carboxylate
Figure imgf000159_0001
The title compound was prepared following the procedure described in step-2 of Intermediate- 6 by using ie/ -butyl 4-(2-amino-5-cyanophenyl)-5,6-dihydropyridine-l(2H)-carboxylate (500 mg), EtOH (20 mL), 10% Pd/C (150 mg) to afford 380 mg of the title product.
Step 3: Preparation of ie/ -butyl 4-( -cyano-2-iodophenyl)piperidine-l-carboxylate
Figure imgf000159_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 97 by using ieri-butyl 4-(2-amino-5-cyanophenyl)piperidine-l-carboxylate (500 mg, 1.74 mmol), isopentyl nitrite (305 mg, 2.61 mmol), iodine (880 mg, 3.48 mmol) in chloroform (15 mL) in chloroform (15 mL) to afford to afford 400 mg of the title product. 1H NMR (300 MHz, CDC13): δ 7.98-7.95 (d, = 7.8 Hz, 1H), 7.39 (s, 1H), 7.18-7.15 (d, = 7.8 Hz, 1H), 4.26 (m, 1H), 2.96-2.75 (m, 4H), 1.87-1.83 (m, 2H), 1.60 (s, 2H), 1.48 (s, 9H).
Step 4: Preparation of 4-iodo-3-(piperid -4-yl)benzonitrile hydrochloride
Figure imgf000159_0003
To tert-butyl 4-(5-cyano-2-iodophenyl)piperidine-l-carboxylate (400 mg) was added HChEtOAc. The solution was stirred at rt for 2 h. The reaction mass was concentrated under vacuum and crude used for next reaction. Step 5: Preparation of 3-(l-acetylpiperidin-4-yl)-4-iodobenzonitrile
The title compound was prepared following the procedure described in step-5, Intermediate - 97 using 4-iodo-3-(piperidin-4-yl)benzonitrile hydrochloride (350 mg, ), acetyl chloride (0.5 mL) in THF (15 mL) to afford 200 mg of the title product. 1H NMR (300 MHz, CDC13): δ 7.99-7.97 (d, J = 7.8 Hz, 1H), 7.38 (s, 1H), 7.20-7.17 (d, J = 6.6 Hz, 1H), 4.83 (m, 1H), 3.07 (m, 2H), 2.22 (s, 2H), 2.09 (s, 3H), 1.91 (m, 2H), 1.54- 1.43 (m, 2H).
Intermediate- 124
4-(5-cyano-2-iodophenyl)-N-ethylbutanamide
Figure imgf000160_0001
Step- 1 :- Preparation of 4-(5-cyano-2-iodophenyl)butanoic acid
Figure imgf000160_0002
To a solution of ethyl 4-iodo-3-(4-oxobutyl)benzoate (300 mg, 1.0 mmol) in acetone was added sulphamic acid (126 mg, 1.30 mmol) and aq. sodium chlorite (117 mg, 1.3 mmol).The reaction mass was stirred at rt for 16 h.The reaction mass was concentrated and quenched in water and extracted with ethyl acetate. The organic layers were concentrated to afford 100 mg of the title product.
Step-2:- Preparation of 4-(5-cyano-2-iodophenyl)-N-ethylbutanamide
The title compound was prepared following the procedure described in Intermediate-76 using 4-(5-cyano-2-iodophenyl)butanoic acid (200 mg),oxalyl chloride (0.5 mL), ethyl amine (0.5 mL), DCM (5 mL), THF (5 mL) to afford (150 mg) of title compound.
Examples
Example- 1
3-Fluoro-4-((4-hydroxyphenyl)ethynyl)benzoic acid
Figure imgf000161_0001
To a solution of 3-fluoro-4-((4-hydroxyphenyl)ethynyl)benzonitrile (Intermediate- 1, 50 mg, 0.210 mmol) in EtOH (7.0 ml) was added aq.NaOH (7.0 mL). The reaction mass was heated at reflux for 4-6 h. After the reaction completion, the reaction mass was concentrated, diluted with water, acidified with dil. HC1 and the precipitate obtained was collected by filtration and dried to afford 10 mg of the title product. 1H NMR (300 MHz, DMSO- 6): δ 13.37 (br, 1H), 10.08 (s, 1H), 7.79-7.69 (m, 3H), 7.43-7.41 (d, = 8.4 Hz, 2H), 6.83-6.81 (d, = 7.2 Hz, 2H); MS [M+H]+: 257.23.
Example-2
4-((4-(lH-imidazol-l-yl)phenyl)ethynyl)-3-fluorobenzoic acid
Figure imgf000161_0002
The title compound was prepared following the procedure described in Example- 1 by using 4- ((4-(lH-imidazol-l-yl)phenyl)ethynyl)-3-fluorobenzonitrile (Intermediate-2, 50 mg, 0.174 mmol), EtOH (7.0 ml), aq.NaOH (7.0 mL) to afford 10 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 9.66 (s, 1H), 8.32 (s, 1H), 7.92-7.82 (m, 8H); MS [M+H]+: 307.45
Example-3
3-Chloro-4-((4-hydroxyphenyl)ethynyl)benzoic acid
Figure imgf000161_0003
The title compound was prepared following the procedure described in Example- 1 by using 3- chloro-4-((4-hydroxyphenyl)ethynyl)benzonitrile (Intermediate-3, 50 mg, 0.197 mmol), EtOH (7.0 ml), aq.NaOH (7.0 mL) to afford 10 mg of the title product. 1H NMR (300 MHz, DMSO- d6): δ 13.60 (br, 1H), 10.1 1 (s, 1H), 7.99 (s, 1H), 7.89-7.86 (d, J = 7.8 Hz, 1H), 7.74-7.72 (d, = 7.8 Hz, 1H), 7.45-7.42 (d, = 8.1 Hz, 2H), 6.84-6.82 (d, = 8.1Hz, 2H); MS [M+H]+: 273.5.
Example-4
4-((4-Hydroxyphenyl)ethynyl)-3-methoxybenzoic acid
Figure imgf000161_0004
The title compound was prepared following the procedure described in Example- 1 by using methyl 4-((4-hydroxyphenyl)ethynyl)-3-methoxybenzoate (Intermediate-4, 60 mg, 0.22 mmol), THF+H20 (5.0+5.0 ml), LiOH (21 mg,0.49 mmol) at RT to afford 40 mg of the title product. 1H NMR (300 MHz, CDCI3): δ 7.56 (d, 1H), 7.53 (s, 1H), 7.51 (s, 1H), 7.44 (d, = 8.1Hz, 2H), 6.81 (d, J = 7.8 Hz, 2H), 3.96 (s, 3H); MS [M-H]": 267.07.
Example-5
4-((2-Fluoro-4-hydroxyphenyl)ethynyl)benzoic acid
Figure imgf000162_0001
The title compound was prepared following the procedure described in Example- 1 by using 4- (2-fluoro-4-hydroxyphenyl)ethynyl)benzonitrile(Intermediate-7, 70 mg,0.29 mmol), EtOH (7.0 ml), aq.NaOH (7.0 mL) to afford 60 mg of the title product. 1H NMR (300 MHz, DMSO- d6): δ 13.14 (br, 1H), 10.53 (s, 1H), 7.95 (d, = 7.8 Hz, 2H), 7.61 (d, = 7.2 Hz, 2H), 7.45 (t, = 7.8 Hz, 1H), 6.68 (m, 2H); MS [M-H]": 255.54.
Example-6
3-Fluoro-4-((2-fluoro-4-hydroxyphenyl)ethynyl)benzoic acid
Figure imgf000162_0002
The title compound was prepared following the procedure described in Example- 1 by using 3- fluoro-4-((2-fluoro-4-hydroxyphenyl)ethynyl)benzonitrile (Intermediate- 8, 100 mg, 0.39 mmol), EtOH (7.0 ml), aq.NaOH (7.0 mL) to afford 65 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.63 (bs, 1H), 7.70-7.80 (m, 3H), 7.46 (t, = 8.4 Hz, 1H), 6.68-6.72 (m, 2H); MS [M-H]": 273.30.
Example-7
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
Figure imgf000162_0003
The title compound was prepared following the procedure described in Example- 1 by using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzonitrile (Intermediate- 10, 120 mg, 0.41 mmol), EtOH (7.0 ml), aq.NaOH (7.0 mL) to afford 80 mg of the title product. 1H NMR (300 MHz, DMSO- 6): δ 13.23 (br, 1H), 10.74 (s, 1H), 7.97 (d, = 7.8 Hz, 2H), 7.57-7.67 (m, 3H), 7.17 (s, 1H), 7.08 (d, = 8.4 Hz, 1H); MS [M-H]": 305.54. Example-8
3-Fluoro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
Figure imgf000163_0001
The title compound was prepared following the procedure described in Example- 1 by using 3- fluoro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzonitrile (Intermediate- 11, 70 mg, 0.22 mmol), EtOH (7.0 ml), aq.NaOH (7.0 mL) to afford 45 mg of the title product. 1H NMR (300 MHz, DMSO- 6): δ 10.80 (s, 1H), 7.77-7.82 (m, 2H), 7.65-7.74 (m, 2H), 7.17 (s, 1H), 7.09 (d, / = 8.4 Hz, 1H); MS [M-H]": 323.28.
Example-9
4-((2-Chloro-4-hydroxyphenyl)ethynyl)-3-fluorobenzoic acid
Figure imgf000163_0002
The title compound was prepared following the procedure described in Example- 1 by using 4- ((2-chloro-4-hydroxyphenyl)ethynyl)-3-fluorobenzonitrile (Intermediate- 13, 60 mg, 0.22 mmol), EtOH (7.0 ml), aq.NaOH (7.0 mL) to afford 40 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.64 (s, 1H), 7.70-7.81 (m, 3H), 7.52 (d, = 7.2 Hz, 1H), 6.97 (s, 1H), 6.81 (d, / = 8.1 Hz, 1H); MS [M-H]": 289.57.
Example- 10
3-Chloro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
Figure imgf000163_0003
The title compound was prepared following the procedure described in Example- 1 by using 3-chloro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzonitrile (Intermediate- 14, 100 mg, 0.31 mmol), EtOH (7.0 ml), aq.NaOH (7.0 mL) to afford 60 mg of the title product. 1H NMR (300 MHz, DMSO- 6): δ 13.48 (bs, 1H), 10.80 (s, 1H), 8.00 (s, 1H), 7.90 (d, J= 8.4 Hz, 1H), 7.70 (t, J = 9.3 Hz, 2H), 7.18 (s, 1H), 7.10 (d, J = 7.8 Hz, 1H); MS [M-H]": 339.29.
Example- 11
3-Chloro-4-((2-fluoro-4-hydroxyphenyl)ethynyl)benzoic acid
Figure imgf000163_0004
The title compound was prepared following the procedure described in Example- 1 by using 3- chloro-4-((2-fluoro-4-hydroxyphenyl)ethynyl)benzonitrile (Intermediate- 15, 80 mg, 0.29 mmol), EtOH (7.0 ml), aq.NaOH (7.0 mL) to afford 50 mg of the title product. 1H NMR (300 MHz, DMSO- 6): δ 13.40 (bs, 1H), 10.63 (s, 1H), 8.00 (s, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.74 (d, / = 8.1 Hz, 1H), 7.47 (t, 1H), 6.69-6.72 (m, 2H); MS [M-H]": 289.28.
Example- 12
3-Fluoro-4-((4-hydroxy-2-methoxyphenyl)ethynyl)benzoic acid
Figure imgf000164_0001
The title compound was prepared following the procedure described in Example- 1 by using 3- fluoro-4-((4-hydroxy-2-methoxyphenyl)ethynyl)benzonitrile (Intermediate- 17, 0.080 g, 0.29 mmol), EtOH (5.0 ml), aq.NaOH (5.0 mL) to afford 40 mg of the title product. 1H NMR (300 MHz, DMSO- 6): δ 10.19 (br s, 1H), 7.82-7.63 (m, 3H), 7.32-7.29 (d, J = 8.7 Hz, 1H), 6.47- 6.39 (m, 2H), 3.79 (s, 3H); MS [M-H]": 285.50.
Example- 13
3-Chloro-4-((2-chloro-4-hydroxyphenyl)ethynyl)benzoic acid
Figure imgf000164_0002
The title compound was prepared following the procedure described in Example- 1 by using 3- chloro-4-((2-chloro-4-hydroxyphenyl)ethynyl)benzonitrile (Intermediate- 18, 0.100 mg, 0.34 mmol), EtOH (5.0 ml), aq.NaOH (5.0 mL) to afford 55 mg of the title product. 1H NMR (300 MHz, DMSO- 6): δ 10.19 (br s, 1H), 7.82-7.63 (m, 3H), 7.32-7.29 (d, J = 8.7 Hz, 1H), 6.47- 6.39 (m, 2H), 3.79 (s, 3H); MS [M-H]": 285.50
Example- 14
4-((2-fluoro-4-hydroxyphenyl)ethynyl)-3-(trifluoromethyl)benzoic acid
Figure imgf000164_0003
To a solution of methyl 4-((2-fluoro-4-hydroxyphenyl)ethynyl)-3-(trifluoromethyl)benzoate (Intermediate-20, 100 mg, 0.29 mmol) in THF+H20 (10.0+2.0 ml) was added LiOH.H20 (50 mg, 1.189 mmol) at RT. The reaction mass was stirred at rt for 16 h. The reaction mass was diluted with water and aqueous layer was washed with diethyl ether and acidified with dil. HC1 and the precipitate obtained was collected by filtration and dried to afford 55 mg of the title product. 1H NMR (300 MHz, OMSO-ek): δ 13.63 (br s, 1H), 10.70 (br s, 1H), 8.21 (s, 2H), 7.89-7.86 (d, 7 = 7.8 Hz, 1H), 7.47-7.41 (t, 7 = 8.4 Hz, 1H), 6.73-6.70 (d, 7 = 9.6Hz, 2H); MS [M+H]+: 220.
Example- 15
4-((4-Hydroxy-2-(pyrrolidin-l-ylmethyl)phenyl)ethynyl)benzoic acid
Figure imgf000165_0001
Step 1 :- Preparation of methyl 4-((4-hydroxy-2-(pyrrolidin-l- ylmethyl)phenyl)ethynyl)benzoate
Figure imgf000165_0002
To a solution of methyl 4-((2-formyl-4-hydroxyphenyl)ethynyl)benzoate (Intermediate-23, 150 mg, 0.537 mmol) in DCM (10 mL) were added pyrollidine (76 mg, 1.07 mmol), Et3N (162 mg, 1.60 mmol) and sodium triacetoxy borohydride (340 mg, 1.60 mmol). The reaction mixture was stirred at rt for 24 h. The reaction mixture was quenched in water, extracted with DCM. The organic layers were dried over Na2S04 and concentrated to afford 120 mg of title compound. 1H NMR (300 MHz, DMSO-d6): δ 8.05 (s, 4H), 7.63-7.56 (m, 2H), 7.26-7.23 (d, 7 = 7.8 Hz, 1H), 3.88 (s, 3H), 3.69 (s, 2H), 2.50-2.45 (m, 4H), 1.76-1.70 (m, 4H); MS [M+H]+: 336.
Step 2:- Preparation of 4-((4-hydroxy-2-(pyrrolidin- l-ylmethyl)phenyl)ethynyl) benzoic acid The title compound was prepared following the procedure described in Example- 14 by using methyl 4-((4-hydroxy-2-(pyrrolidin- l-ylmethyl)phenyl)ethynyl)benzoate (100 mg, 0.29 mmol), LiOH.H20 (50 mg, 1.19 mmol), THF (10 mL), water (2 mL) to afford 50 mg of title compound. 1H NMR (300 MHz, DMSO-d6): δ 13.10 (br s, 1H), 10.91 (br s, 1H), 8.06 (s, 3H), 7.96 (s, 1H), 7.78-7.75 (d, 7 = 7.8 Hz, 1H), 7.67 (s, 1H), 7.51-7.49 (d, 7 = 8.1 Hz, 1H), 4.46 (s, 2H), 3.33 (br br s, 4H), 1.94 (br br s, 4H); MS [M+H]+: 322.
Example- 16
4-((2-(Ethoxymethyl)-4-hydroxyphenyl)ethynyl)benzoic acid
Figure imgf000166_0001
Preparation of meth -((2-(ethoxymethyl)-4-hydroxyphenyl)ethynyl)benzoate
Figure imgf000166_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using methyl 4-ethynylbenzoate (Intermediate-22, 0.150 g, 0.930 mmol), ie/t-butyl(3- (ethoxymethyl)-4-iodophenoxy)dimethylsilane (Intermediate-24, 0.500 g, 3.12 mmol), TBAF (0.293 g, 1.12 mmol), PdCl2(PPh3)2 (0.014 g, 0.018 mmol), DMSO (2.0 mL) to afford 0.130 g of the title product. 1H NMR (300 MHz, CDC13): δ 8.02-7.99 (d, = 8.4 Hz, 2H), 7.60-7.57 (d, 7 = 7.8 Hz, 2H), 7.48-7.46 (d, J = 7.8 Hz, 1H), 6.95-6.90 (m, 2H), 4.71 (s, 2H), 4.19-4.12 (q, J = 6.9Hz, 2H), 3.92 (s, 3H), 1.53-1.48 (t, J = 7.2Hz, 3H).
Step-2:- Preparation of 4-((2-(ethoxymethyl)-4-hydroxyphenyl)ethynyl)benzoic acid
The title compound was prepared following the procedure described in Example- 14 by using methyl 4-((2-(ethoxymethyl)-4-hydroxyphenyl)ethynyl)benzoate (0.120 g, 0.38 mmol), THF+H20 (10.0+2.0 ml), LiOH.H20 (0.065g, 1.54 mmol) at RT to afford 70 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 13.13 (s, 1H), 7.97-7.94 (d, = 7.8Hz, 2H),7.61- 7.58 (d, = 7.8Hz, 2H), 7.46-7.43(d, = 7.5Hz, 1H), 7.04 (s, 1H), 6.93-6.91 (d, = 7.8 Hz, 1H), 5.32 (s, 1H), 4.52 (s, 2H), 4.13-4.11 (q, = 6.9Hz, 2H), 1.41-1.37 (t, = 6.9Hz, 3H); MS [M-H]": 295.
Example- 17
4-((4-Hydroxy-2-(( -methoxyethoxy)methyl)phenyl)ethynyl)benzoic acid
Figure imgf000166_0003
Step 1:- Preparation of methyl 4-((4-hydroxy-2-((2- methoxyethoxy)methyl)phenyl)ethynyl)benzoate MeOOC OH
Figure imgf000167_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using methyl 4-ethynylbenzoate (Intermediate-22, 0.150 g, 0.937 mmol), ie/t-butyl(4- iodo-3-((2-methoxyethoxy)methyl)phenoxy)dimethylsilane (Intermediate-25, 0.395 g, 0.936 mmol), TBAF (0.293 g, 1.12 mmol), PdCl2(PPh3)2 (0.013 g, 0.018 mmol), DMSO (2.0 mL) to afford 0.130 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.00-7.97 (d, = 8.1Hz, 2H),7.63-7.60 (d, = 8.1Hz, 2H), 7.47-7.41(d, = 7.5Hz, 1H), 7.06 (s, 1H), 6.96-6.93 (d, = 7.8 Hz, 1H), 5.33 (s, 1H), 4.52 (s, 2H), 4.19 (s, 2H), 3.87 (s, 3H), 3.74 (s, 2H), 3.38 (s, 3H). Step-2:- Preparation of 4-((4-hydroxy-2-((2-methoxyethoxy)methyl)phenyl)ethynyl)benzoic acid
The title compound was prepared following the procedure described in Example- 14 by using methyl 4-((4-hydroxy-2-((2-methoxyethoxy)methyl)phenyl)ethynyl)benzoate (0.150 g, 0.44 mmol), THF+H20 (10.0+2.0 ml), LiOH.H20 (0.074 g, 1.76 mmol) to afford 80 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 13.10 (br s, 1H), 7.97-7.94 (d, = 7.5Hz, 2H),7.60-7.57 (d, = 7.8. lHz, 2H), 7.46-7.44 (d, = 7.5Hz, 1H), 7.05 (s, 1H), 6.96-6.93 (d, = 7.2 Hz, 1H), 5.32 (s, 1H), 4.52 (s, 2H), 4.19 (s, 2H), 3.87 (s, 3H), 3.74 (s, 2H), 3.38 (s, 3H).
Example- 18
4-((4-Hydrox -2-(propoxymethyl)phenyl)ethynyl)benzoic
Figure imgf000167_0002
Step 1:- Preparation of methyl 4-((4-hydroxy-2-(propoxymethyl)phenyl)ethynyl)benzoate
Figure imgf000167_0003
The title compound was prepared following the procedure described in step-3 of Intermediate- lby using methyl 4-ethynylbenzoate (Intermediate-22, 0.150 g, 0.937 mmol), ie/ -butyl(4- iodo-3-(propoxymethyl)phenoxy)dimethylsilane (Intermediate-26, 0.380 g, 0.936 mmol), TBAF (0.293 g, 1.12 mmol), PdCl2(PPh3)2 (0.013 g, 0.018 mmol), DMSO (2.0 mL) to afford 0.120 g of the title compound. 1H NMR (300 MHz, DMSO- 6): δ 7.99-7.97 (d, = 7.5Hz, 2H),7.62-7.59 (d, J = 7.8Hz, 2H), 7.45-7.43 (d, J = 7.8Hz, 1H), 7.04 (s, 1H), 6.93-6.91 (d, J = 7.8 Hz, 1H), 5.32 (br s, 1H), 4.51 (s, 2H), 4.02 (t, 2H), 3.86 (s, 3H), 1.80- 1.78 (q, J = 7.8 Hz, 2H), 1.06- 1.01 (t, 7 = 6.6 Hz, 3H).
Step-2:- Preparation of 4-((4-hydroxy-2-(propoxymethyl)phenyl)ethynyl)benzoic acid
The title compound was prepared following the procedure described in Example- 14 by using methyl 4-((4-hydroxy-2-(propoxymethyl)phenyl)ethynyl)benzoate (0.130 g, 0.40 mmol), THF+H20 (10.0+2.0 ml), LiOH.H20 (0.068 g, 1.60 mmol) to afford 60 mg of the title compound. 1H NMR (300 MHz, DMSO- 6): δ 13.08 (br s, 1H), 7.95-7.93 (d, = 7.8Hz, 2H),7.57-7.55 (d, = 7.8Hz, 2H), 7.43-7.41 (d, = 7.8Hz, 1H), 7.02 (s, 1H), 6.91-6.89 (d, = 7.2 Hz, 1H), 5.31 (br s, 1H), 4.50 (s, 2H), 4.02-3.98 (t, = 6.3Hz, 2H), 1.80-1.74 (q, = 6.6 Hz, 2H), 1.05-1.08 (t, J = 6.6 Hz, 3H); MS [M-H]~: 295.
Example- 19
3-Fluoro-4-((4-hydroxy-2-(propoxymethyl)phenyl)ethynyl)benzoic acid
Figure imgf000168_0001
Step 1 :- Preparation of 3-fluoro- -((4-hydroxy-2-(propoxymethyl)phenyl)ethynyl)benzonitrile
Figure imgf000168_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-fluorobenzonitrile (step-3, Intermediate- 1, 0.150 g, 0.937 mmol), tert- butyl(4-iodo-3-(propoxymethyl)phenoxy)dimethylsilane (Intermediate-26, 0.378 g, 0.936 mmol), TBAF (0.293 g, 1.12 mmol), PdCl2(PPh3)2 (0.013 g, 0.018 mmol), DMSO (2.0 mL) to afford 0.120 g of the title compound. 1H NMR (300 MHz, DMSO- 6): δ 8.01-7.98 (d, = 9.6Hz, 1H),7.74 (s, 2H), 7.47-7.45 (d, = 7.8Hz, 1H), 7.06 (s, 1H), 6.95-6.93 (d, = 7.8 Hz, 1H), 5.35 (m, 1H), 4.53-4.52 (d, = 4.8Hz, 2H), 4.05-4.00(m, 2H), 1.81- 1.74 (q, = 6.9 Hz, 2H), 1.05- 1.01(t, / = 7.2Hz, 3H).
Step 2:- Preparation of 3-fluoro-4-((4-hydroxy-2-(propoxymethyl)phenyl)ethynyl)benzoic acid
The title compound was prepared following the procedure described in Example- 1 by using 3- fluoro-4-((4-hydroxy-2-(propoxymethyl)phenyl)ethynyl)benzonitrile (0.110 g, 0.35 mmol), EtOH (5.0 ml), aq.NaOH (5.0 mL) to afford 65 mg of the title compound. 1H NMR (300 MHz, DMSO-d6): δ 13.40 ( br s, 1H), 7.81 -7.64 (m, 3H),7.47-7.44 (d, = 8.1Hz, 1H),7.05 (s, 1H), 6.95-6.92 (d, = 7.8Hz, 1H), 5.33 (s, 1H), 4. 52 (s, 2H), 4.04-4.02 (t, = 6.3 Hz, 2H), 1.79- 1.75 (m, 2H), 1.06-1.01 (t, = 7.2 Hz, 3H); MS [M+H]+: 327.
Example-20
3-Fluoro-4-((2-(fluoromethyl)-4-hydroxyphenyl)ethynyl)benzoic acid
Figure imgf000169_0001
Step 1 :- Preparation of methyl 3-fluoro-4-((2-(fluoromethyl)-4- hydroxyphenyl)ethynyl)benzoate
Figure imgf000169_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using methyl 4-ethynyl-3-fluorobenzoate (Intermediate-27, 0.150 g, 0.84 mmol), tert- butyl(3-(fluoromethyl)-4-iodophenoxy)dimethylsilane (Intermediate-28, 0.308 g, 0.84 mmol), TBAF (0.263 g, 1.01 mmol), PdCl2(PPh3)2 (0.012 g, 0.016 mmol), DMSO (2.0 mL) to afford 0.110 g of the title compound. 1H NMR (300 MHz, DMSO- 6): δ 8.17-8.12 (t, = 7.8 Hz, 1H),7.96-7.81 (m, 4H), 7.54 (s, 1H), 7.40-7.37 (d, = 7.8Hz, 1H), 5.62 (s, 1H), 5.46 (s, 1H), 3.89(s, 3H).
Step 2:- Preparation of 3-fluoro-4-((2-(fluoromethyl)-4-hydroxyphenyl)ethynyl)benzoic acid The title compound was prepared following the procedure described in Example- 14 by using methyl 3-fluoro-4-((2-(fluoromethyl)-4-hydroxyphenyl)ethynyl)benzoate (0.110 g, 0.36 mmol), THF+H20 (10.0+2.0 ml), LiOH.H20 (0.062 g, 1.45 mmol) to afford 60 mg of the title compound. 1H NMR (300 MHz, DMSO- 6): δ 13.38 ( br s, 1H), 8.13-8.10 (t, = 7.8Hz, 1Η),7.94-7.92 (d, = 8.4 Hz, 1H), 7.86-7.77 (m, 3H), 7.52 (s, 1H), 7.40-7.37 (d, = 7.5 Hz, 1H), 5.63 (s, 1H), 5.47 (s, 1H); MS [M-H]~: 287.
Example-21
4-((2-(Difluoromethyl)-4-hydroxyphenyl)ethynyl)-3-fluorobenzoic acid
Figure imgf000170_0001
Step 1:- Preparation of methyl 4-((2-(difluoromethyl)-4-hydroxyphenyl)ethynyl)-3- fluorobenzoate
Figure imgf000170_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using methyl 4-ethynyl-3-fluorobenzoate (Intermediate-27, 0.150 g, 0.84 mmol), tert- butyl(3-(difluoromethyl)-4-iodophenoxy)dimethylsilane (Intermediate-29, 0.323 g, 0.84 mmol), TBAF (0.263 g, 1.01 mmol), PdCl2(PPh3)2 (0.012 g, 0.016 mmol), DMSO (2.0 mL) to afford 0.120 g of the title compound. 1H NMR (300 MHz, DMSO-d6): δ 8.19-8.14 (t, = 8.4 Hz, lH),7.97-7.88 (m, 4H), 7.59 (s, 1H), 7.54-7.51 (d, = 7.8Hz, 1H), 7.35-76.98 (t, = 56.1Hz, 1H), 3.89 (s, 3H).
Step 2:- Preparation of 4-((2-(difluoromethyl)-4-hydroxyphenyl)ethynyl)-3-fluorobenzoic acid
The title compound was prepared following the procedure described in Example- 14 by using methyl 4-((2-(difluoromethyl)-4-hydroxyphenyl)ethynyl)-3-fluorobenzoate (0.110 g, 0.34 mmol), THF+H20 (10.0+2.0 ml), LiOH.H20 (0.057 g, 1.37 mmol) to afford 80 mg of the title compound H NMR (300 MHz, DMSO-d6): δ 8.16-8.11 (t, = 7.8Hz, 1Η),7.95-7.82 (m, 4H), 7.57-7.51 (m, 2H), 7.35-6.98 (t, = 56.7 Hz, 1H); MS [M-H]~: 305.
Example-22
2-Fluoro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
Figure imgf000170_0003
Preparation of 4-ethynyl-2-fluorobenzonitrile
Figure imgf000170_0004
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-bromo-2-fluorobenzonitrile (3.0 g, 0.015 mol), trimethyl sillyl acetylene (3.15 mL, 0.022 mol), PdCl2 (PPh3)2 (0.210 g, 0.003 mol), Cul (0.057 g, 0.0003 mol) and Et3N (4.33 mL, 0.03 mol), 1M TBAF solution in THF (25.7 mL, 0.018 mol) to afford 1.5 g of title product
Step 2:- Preparation of 2-fluoro- -((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzonitrile
Figure imgf000171_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-2-fluorobenzonitrile (0.150 g, 1.03 mmol), 4-iodo-3- (trifluoromethyl)phenyl methanesulfonate (Intermediate- 9, 0.378 g, 0.936 mmol), TBAF (0.323 g, 1.24 mmol), PdCl2(PPh3)2 (0.015 g, 0.020 mmol), DMSO (2.0 mL) to afford 0.140 g of the title compound. 1H NMR (300 MHz, DMSO-d6): δ 10.82 (s, 1H), 7.98 (t, 1Η),7.69-7.63 (m, 2H), 7.50-7.47 (d, J = 8.4 Hz, 1H), 7.18 (s, 1H), 7.12 (d, 1H); MS [M-H]": 304.
Step 3:- Preparation of 2-fluoro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
The title compound was prepared following the procedure described in Example- 1 by using 2- fluoro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzonitrile (0.140 g, 0.459 mmol), EtOH (5.0 ml), aq.NaOH (5.0 mL) to afford 70 mg of the title compound.1H NMR (300 MHz, DMSO-d6): δ 14-13 (br s, 1H),10.78 (br s, 1H), 7.93-7.87(t, = 8.4 Hz, 1Η),7.67-7.65 (d, J = 8.1 Hz, lH),7.43-7.37 (m, 2H), 7.17 (s, 1H), 7.10 (d, / = 8.1 Hz, 1H); MS [M+H]+: 323.
Example-23
3,5-Difluoro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
Figure imgf000171_0002
Step 1:- Preparation of 3 ,5-difluoro-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzonitrile
Figure imgf000171_0003
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 3,5-difluoro-4-iodobenzonitrile (Intermediate-31, 0.108 g, 0.40 mmol), 4-ethynyl- 3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 0.100 g, 0.400 mmol), TBAF (0.128 g, 0.49 mmol), PdCl2(PPh3)2 (0.006 g, 0.008 mmol), DMSO (2.0 mL) to afford 0.050 g of the title compound. 1H NMR (300 MHz, DMSO-d6): δ 10.91 (s, 1H), 7.96-7.94 (d, = 6.9 Hz, 2H),7.70-7.67 (d, J = 8.7 Hz, 1H),7.19 (s, 1H), 7.12-7.09 (d, 7 = 9.0Hz, 1H); MS [M+H]+: 323.
Step 2:- Preparation of 3,5-difluoro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
The title compound was prepared following the procedure described in Example- 1 by using 3,5-difluoro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl) benzonitrile (0.050 g, 0.154 mmol), EtOH (5.0 ml), aq.NaOH (5.0 mL) to afford 15 mg of the title compound. 1H NMR (300 MHz, DMSO-d6): δ 13.82 (br s, 1H), 10.87 (s, 1H), 7.68-7.66 (s, 3H),7.18 (s, 1H),7.11- 7.09 (d, = 8.7 Hz, 1H); [M-H]~: 340.
Example-24
4-((2,6-Difluoro-4-hydroxyphenyl)ethynyl)benzoic acid
Figure imgf000172_0001
Step 1:- Preparation of methyl 4-((2,6-difluoro-4-hydroxyphenyl)ethynyl)benzoate
Figure imgf000172_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using methyl 4-ethynylbenzoate (Intermediate-22 , 0.150 g, 0.93 mmol), 3,5-difluoro-4- iodophenyl methanesulfonate (Intermediate-32, 0.313 g, 0.93 mmol), TBAF (0.293 g, 1.12 mmol), PdCl2(PPh3)2 (0.013 g, 0.018 mmol), DMSO (2.0 mL) to afford 0.095 g of the title compound. 1H NMR (300 MHz, DMSO- ): δ 11.07 (s, 1Η),8.02-7.97 (d, = 8.4 Hz, 2H),7.67-7.64 (d, = 8.1 Hz, 2H),6.63 (s, 1H), 6.60 (s, 1H), 3.86 (s, 3H); MS [M-H]": 287. Step- 2:- Preparation of 4-((2,6-difluoro-4-hydroxyphenyl)ethynyl)benzoic acid
The title compound was prepared following the procedure described in Example- 14 by using methyl 4-((2,6-difluoro-4-hydroxyphenyl)ethynyl)benzoate (0.090 g, 0.31 mmol), THF+H20 (5.0 mL+ 5.0 mL), LiOH.H20 (0.052 g, 1.25 mmol) to afford 45 mg of the title compound. 1H NMR (300 MHz, DMSO-d6): δ 1 1.16 (br s, 1H), 1 1.09 (br s, 1H), 7.98-7.95 (d, J
2H),7.64-7.62 (d, J = 8.1 Hz, 2H),6.64 (s, 1H), 6.60 (s, 1H); MS [M-H]": 273.
Example-25
4-((2,6-Difluoro-4-hydroxyphenyl)ethynyl)-3-fluorobenzoic acid
Figure imgf000173_0001
Stop 1 :- Preparation of methyl 4-((2,6-difluoro-4-hydroxyphenyl)ethynyl)-3-fluorobenzoate
Figure imgf000173_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using methyl 4-ethynyl-3-fluorobenzoate (Intermediate-27, 0.150 g, 0.84 mmol), 3,5- difluoro-4-iodophenyl methanesulfonate (Intermediate-32, 0.281 g, 0.84 mmol), TBAF (0.263 g, 1.01 mmol), PdCl2(PPh3)2 (0.012 g, 0.016 mmol), DMSO (2.0 mL) to afford 0.085 g of the title compound. 1H NMR (300 MHz, DMSO-d6): δ 1 1.15 (s, 1H), 7.81-7.74 (m, 3H), 6.64 (s, 1H), 6.61 (s, 1H), 3.88 (s, 3H); MS [M-H]": 305.
Step- 2:- Preparation of 4-((2,6-difluoro-4-hydroxyphenyl)ethynyl)-3-fluorobenzoic acid The title compound was prepared following the procedure described in Example- 14 by using methyl 4-((2,6-difluoro-4-hydroxyphenyl)ethynyl)-3-fluorobenzoate (0.080 g, 0.26 mmol), THF+H20 (5.0 mL+ 5.0 mL), LiOH.H20 (0.044 g, 1.04 mmol) to afford 60 mg of the title compound. 1H NMR (300 MHz, DMSO-d6): δ 7.81-7.68 (m, 3H), 6.66 (s, 1H), 6.63 (s, 1H); MS [M-H]": 291.
Example-26
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(trifluoromethyl)benzoic acid
Figure imgf000173_0003
Step 1 :- Preparation of methyl 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3 (trifluoromethyl)benzoate
Figure imgf000173_0004
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using methyl 4-ethynyl-3-(trifluoromethyl)benzoate (Intermediate- 19, 0.150 g, 0.65 mmol), 4-iodo-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-9, 0.240 g, 0.65 mmol), TBAF (0.206 g, 0.78 mmol), PdCl2(PPh3)2 (0.010 g, 0.013 mmol), DMSO (2.0 mL) to afford 0.110 g of the title compound. 1H NMR (300 MHz, DMSO-d6): δ 10.86 (s, 1H),8.26- 8.23 (m, 2H), 7.92-7.89 (d, = 8.1 Hz, 1Η),7.69-7.66 (d, = 8.7 Hz, 1H),7.18 (s, 1H), 7.13- 7.10 (d, = 8.7 Hz, 1H), 3.90 (s, 3H); MS [M-H]~: 387.
Step 2:- Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3- (trifluoromethyl)benzoic acid
The title compound was prepared following the procedure described in Example- 14 by using methyl 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(trifluoromethyl)benzoate (0.110 g, 0.28 mmol), THF+H20 (5.0 mL+ 5.0 mL), LiOH.H20 (0.048 g, 1.13 mmol) to afford 60 mg of the title compound. 1H NMR (300 MHz, DMSO-d6): δ 8.22 (s, 2H),7.89-7.86 (d, = 8.7 Hz, lH),7.68-7.66 (d, = 8.4 Hz, 1H),7.18 (s, 1H), 7.14-7.11 (d, = 8.1 Hz, 1H); MS [M- H]~: 373.
Example-27
4'-Cyano-6-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-[l, -biphenyl]-3-carboxylic acid
Figure imgf000174_0001
Step-1:- Preparation of ethyl 4'-cyano-6-((4-hydroxy-2-(trifluoromethyl)phenyl) ethynyl)- [l,l'-biphenyl]-3-carboxylate
Figure imgf000174_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using ethyl 4'-cyano-6-ethynyl-[l,l'-biphenyl]-3-carboxylate (Intermediate-33, 200 mg, 0.727 mmol), 4-iodo-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-9, 266 mg, 0.726 mmol), PdCl2(PPh3)2 (11 mg, 0.015 mmol) and TBAF (228 mg, 0.873 mmol), DMSO (5 mL) to afford 80 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.73 (s, 1H), 7.99-7.96 (m, 4H), 7.84-7.79 (m, 3H), 7.45-7.42 (d, = 8.4 Hz, 1H), 7.10-7.06 (m, 2H), 4.35- 4.33 (q, J = 6.3 Hz, 2H), 1.33 (t, 3H); MS [M-H]~: 434
Step 2:- Preparation of 4'-cyano-6-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-[l, - biphenyl]-3-carboxylic acid
The title compound was prepared following the procedure described in Example- 14 by using ethyl 4'-cyano-6-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-[l, -biphenyl]-3- carboxylate (80 mg, 0.18 mmol), LiOH.H20 (19.3 mg, 0.45 mmol in 1.0 mL water), THF : water (5 mL:3mL) to afford 10 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 13.35 (br s, 1H), 10.74 (br s, 1H), 8.03-7.96 (m, 4H), 7.85-7.82 (d, = 7.8 Hz, 2H), 7.77-7.74 (d, = 7.8 Hz, 1H), 7.45-7.42 (t, = 9.0Hz, 1H), 7.11-7.04 (m, 2H); MS [M-H]~: 406
Example-28
4'-Carbamoyl-6-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-[l, -biphenyl]-3-carboxylic acid
Figure imgf000175_0001
The title compound was prepared following the procedure described in Example- 14 by using ethyl 4'-carbamoyl-6-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-[l, -biphenyl]-3- carboxylate (Example-41, 40 mg, 0.08 mmol), LiOH.H20 (6.8 mg, 0.20 mmol in 1.0 mL water), THF:water (3 mL: 1 mL) to afford 10 mg of title product. 1H NMR (300 MHz, DMSO-i¾: δ 13.30 (br s, 1H), 10.69 (s, 1H), 8.06 (s, 1H), 7.96 (m, 4H), 7.72-7-7.70 (d, = 6.9 Hz, 3H), 7.43 (s, 1H), 7.39-7.37 (d, = 8.7Hz, 1H), 7.09 (s,lH),7.04-7.01 (d, = 9.0 Hz, 1H); MS [M+H]+: 426
Example-29
4'-Carbamoyl-6-((2-chloro-4-hydroxyphenyl)ethynyl)-[l,l'-biphenyl]-3-carboxylic acid
Figure imgf000176_0001
Step 1:- Preparation of ethyl 6-((2-chloro-4-hydroxyphenyl)ethynyl)-4'-cyano-[l,l'-biphenyl]- 3-carboxylate
Figure imgf000176_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using ethyl 4'-cyano-6-ethynyl-[l,l'-biphenyl]-3-carboxylate (Intermediate-33, 150 mg, 0.545 mmol), DMSO (5 mL), 3-chloro-4-iodophenyl methanesulfonate (Intermediate- 12, 182 mg, 0.548 mmol), PdCl2(PPh3)2 (10 mg, 0.014 mmol) and TBAF (171 mg, 0.655 mmol) to afford 75 mg of title product. 1H NMR (300 MHz, DMSO-i¾: δ 10.53 (s, 1H), 8.03-7.96 (m, 4H), 7.87-7.80 (m, 3H), 7.34-7.32 (d, = 6.9 Hz, 1H), 6.89 (s, 1H), 6.78-6.757 (d, = 8.7Hz, 1H), 4.36-4.33 (q, / = 7.2 Hz, 2H), 1.35-1.31 (t, = 6.3Hz, 3H); MS [M+H]+: 402.
Step 2:- Preparation of ethyl 4'-carbamoyl-6-((2-chloro-4-hydroxyphenyl)ethynyl)-[l, - biphenyl]-3-carboxylate
Figure imgf000176_0003
The title compound was prepared following the procedure described in step-5 of Intermediate- 46 using ethyl 6-((2-chloro-4-hydroxyphenyl)ethynyl)-4'-cyano-[l,l'-biphenyl]-3-carboxylate (80 mg, 0.199 mmol), K2C03 (54.9 mg, 0.398 mmol), 50% H202 (2.5 mL) in DMSO (5 mL) to afford 50 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 10.55 (br s, 1H), 8.08 (s, 1H), 8.00-7.98 (m, 4H), 7.81-7.78 (d, = 8.1Hz, 1H), 7.75-7.72 (d, = 8.4Hz, 2H), 7.45 (br s, 1H), 7 '.32-7.29 (d, 7 = 8.4 HZ, 2H), 6.90 (s, 1H), 6.78-6.75(d, 7 = 8.1Hz, 1H), 4.38-4.12 (q, 7 = 6.9Hz, 2H), 1.33-1.22 (t, 7 = 6.9Hz, 3H); MS [M+H]+: 420.
Step 3:- Preparation of 4'-carbamoyl-6-((2-chloro-4-hydroxyphenyl)ethynyl)-[l, -biphenyl]- 3-carboxylic acid
The title compound was prepared following the procedure described in Example- 14 using ethyl 4'-carbamoyl-6-((2-chloro-4-hydroxyphenyl)ethynyl)-[l, -biphenyl]-3-carboxylate (30 mg, 0.07 mmol), LiOH.H20 (7.5 mg, 0.17 mmol in 1.0 mL water), THF : water (3 mL: 1 mL) to afford 15 mg of title product. 1H NMR (300 MHz, DMSO-i¾): δ 14-13 (br s, 1H), 11-10 (br s, 1H), 8.06-7.96 (m, 5H), 7.74 (m, 3H), 7.43 (br s, 1H), 7.30-7.27 (d, 7 = 8.4Hz, 1H), 6387 (s, 1H), 6.75 (d, 1H); MS [M+H]+: 392.
Example- 30
4'-Carbamoyl-3'-fluoro-6-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-[l, -biphenyl]-3- carboxylic acid
Figure imgf000177_0001
Step 1:- Preparation of ethyl 4'-cyano-3'-fluoro-6-((4-hydroxy-2-(trifluoromethyl)phenyl)- ethynyl)-[l,l'-biphenyl]-3-carboxylate
Figure imgf000177_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using ethyl 4'-cyano-3'-fluoro-6-iodo-[l, -biphenyl]-3-carboxylate (Intermediate-34, 72 mg, 0.182 mmol), DMSO (5 mL), 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 45 mg, 0.184 mmol), PdCl2(PPh3)2 (5 mg, 0.02 mmol) and TBAF (57 mg, 0.218 mmol) to afford 40 mg of title product. 1H NMR (300 MHz, DMSO-i¾: δ 10.76 (s, 1H), 8.09-8.04 (m, 2H), 8.00 (s, 1H), 7.84-7.80 (m, 2H), 7.67-7.65 (d, 7 = 7.8 Hz, 1H), 7.50-7.47 (d, 7 = 8.1 Hz, 1H), 7.11-7.05 (m, 2H), 4.39-4.31 (q, 7 = 6.6 Hz, 2H), 1.33-1.28 (t, 7 = 6.9Hz, 3H). Step 2:- Preparation of ethyl 4'-carbamoyl-3'-fluoro-6-((4-hydroxy-2-(trifluoromethyl) phenyl)-ethynyl)-[l,l'-biphenyl]-3-carboxylate
Figure imgf000178_0001
The title compound was prepared following the procedure described in step-5 of Intermediate- 46 using ethyl 4'-cyano-3'-fluoro-6-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-[l, - biphenyl]-3-carboxylate (70 mg, 0.15 mmol), DMSO (5 mL), 50% H202 (2.5 mL), K2C03 (42.64 mg, 0.30 mmol) to afford 35 mg of the title product. 1H NMR (300 MHz, DMSO-i¾: δ 10.74 (s, 1H), 8.04-7.99 (m, 2H), 7.79-7.73 (m, 4H), 7.60-7.52 (m, 2H), 7.46-7.43 (d, = 8.1 Hz, 1H), 7.12 (s, 1H), 7.07-7.04 (d, = 9.0 Hz, 1H), 4.36-4.34 (q, J = 7.2 Hz, 2H), 1.36-1.31 (t, = 6.9Hz, 3H).
Step 3:- Preparation of 4'-carbamoyl-3'-fluoro-6-((4-hydroxy-2-(trifluoromethyl) phenyl)- ethynyl) -[1,1 '-biphenyl] - 3 -carboxylic acid
The title compound was prepared following the procedure described in Example- 14 using ethyl 4'-carbamoyl-3'-fluoro-6-((4-hydroxy-2-(trifluoromethyl)phenyl) ethynyl)-[l,l'- biphenyl] -3 -carboxylate (30 mg, 0.07 mmol), LiOH.H20 (7.5 mg, 0.17 mmol in 1.0 mL water), THF : water (3 mL: 1 mL) to afford 15 mg of title product. 1H NMR (300 MHz, DMSO-i¾: δ 13.34 (br s, 1H), 10.74 (s, 1H), 8.02-7.99 (m, 2H), 7.81-7.76 (m, 4H), 7.73-7.53 (m, 2H), 7.45-7.43 (d, = 8.7 Hz, 1H), 7.12 (s, 1H), 7.08-7.05 (d, = 8.1 Hz, 1H); MS [M+H]+: 442.
Example- 31
4'-Carbamoyl-3',5'-difluoro-6-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-[l, - biphenyl] -3 -carboxylic acid
Figure imgf000178_0002
Step 1:- Preparation of ethyl 4'-cyano-3',5'-difluoro-6-((4-hydroxy-2-(trifluoromethyl)- phenyl)ethynyl)- [1,1 '-biphen -3 -carboxylate
Figure imgf000179_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using ethyl 4'-cyano-3',5'-difluoro-6-iodo-[l,r-biphenyl]-3-carboxylate (Intermediate-35, 110 mg, 0.266 mmol), DMSO (5 mL), 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 65 mg, 0.266 mmol), PdCl2(PPh3)2 (5 mg, 0.07 mmol) and TBAF (85 mg, 0.325 mmol) to afford 20 mg of title product. 1H NMR (300 MHz, DMSO-i¾): δ 10.80 (br s, 1H), 8.10-8.07 (d, = 9.3 Hz, 1H), 8.02 (s, 1H), 7.84-7.82 (m, 1H), 7.76-7.72 (m, 2H), 7.55- 7.52 (d, = 9.0 Hz, 1H), 7.11 (m, 2H), 4.37-4.34 (q, = 6.9 Hz, 2H), 1.36-1.31 (t, = 7.2 Hz, 3H).
Step 2:- Preparation of ethyl 4'-carbamoyl-3',5'-difluoro-6-((4-hydroxy-2-(trifluoromethyl)- phenyl)ethynyl)- [1,1 '-biphen -3 -carboxylate
Figure imgf000179_0002
The title compound was prepared following the procedure described in step-5 of Intermediate- 46 using ethyl 4'-cyano-3',5'-difluoro-6-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-[l, - biphenyl] -3 -carboxylate (35 mg, 0.07 mmol), DMSO (5 mL), 50% H202 (2.5 mL), K2C03 (20.5 mg, 0.14 mmol) to afford 20 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 10.75 (s, 1H), 8.20 (s, 1H), 7.98-7.92 (m, 3H), 7.77 (m, 2H), 7.47-7.44 (m, 2H), 7.13-7.09 (m, 2H), 4.36 (q, 2H), 1.34 (t, 3H).
Step 3:- Preparation of 4'-carbamoyl-3',5'-difluoro-6-((4-hydroxy-2-
(trifluoromethyl)phenyl)ethynyl) -[1,1 '-biphenyl] -3 -carboxylic acid
The title compound was prepared following the procedure described in Example- 14 using ethyl 4'-carbamoyl-3',5'-difluoro-6-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-[l, - biphenyl] -3 -carboxylate (30 mg, 0.06 mmol), LiOH.H20 (6.3 mg, 0.15 mmol in 1.0 mL water), THF : water (3 mL: 1 mL) to afford 11 mg of title product. 1H NMR (300 MHz, DMSO-i¾): δ 13.36 (br s, 1H), 10.77(br s, 1H), 8.20 (s, 1H), 8.03-7.92 (m, 3H), 7.77-7.74 (d, 7 = 7.8 Hz, 1H), 7.47-7.45 (d, 7 = 7.8 Hz, 3H), 7.14 (s, 1H), 7.09-7.06 (d, 7 = 7.8 Hz, 1H); MS [M+H]+: 462.
Example- 32
2,5-Difluoro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
Figure imgf000180_0001
The title compound was prepared following the procedure described in Example- 1 using 2,5- difluoro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzonitrile (Intermediate-36, 0.050 g, 0.154 mmol), 2N aq.NaOH (5.0 mL) in EtOH (5.0 ml to afford 15 mg of the title compound. 1H NMR (300 MHz, DMSO-i¾): δ 13.69 (br s, 1H), 10.85 (s, 1H), 7.75-7.66 (m, 2H), 7.56-7.55 (m, 1H), 7.18 (s, 1H), 7.11-7.09 (d, 7 = 6.9 Hz, 1H); MS [M-H]": 341.
Example- 33
4-((2,5-Difluoro-4-hydroxyphenyl)ethynyl)-3-(trifluoromethyl)benzoic acid
Figure imgf000180_0002
The title compound was prepared following the procedure described in Example- 14 using methyl 4-((2,5-difluoro-4-hydroxyphenyl)ethynyl)-3-(trifluoromethyl)benzoate (Intermediate- 37, 100 mg, 0.28 mmol), LiOH.H20 (47 mg, 1.12 mmol in 5.0 mL water), THF : water (5 mL: 5 mL) to afford 70 mg of title product. 1H NMR (300 MHz, DMSO-i¾): δ 13.66 (br s, 1H), 11.21 (s, 1H), 8.22 (s, 2H), 7.91-7.88 (d, 7 = 7.8 Hz, 1H), 7.50-7.44 (m, 1H), 6.93-6.87 (m, 1H); MS [M-H]": 341.
Example- 34
3-(3-Ethoxypropyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
Figure imgf000180_0003
The title compound was prepared following the procedure described in Example- 1 by using 3- (3-ethoxypropyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzonitrile
(Intermediate-38, 70.0 mg, 0.018 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) afford 40 mg of title product.1H NMR (300 MHz, DMSO-i¾): δ 13.06 (br s, 1H), 10.70 (s, 1H), 7.85 (s, 1H), 7.81-7.78 (s, 1H), 7.69-7.66 (m, 1H), 7.58-7.55 (d, J = 8.1 Hz, 1H), 7.16 (s, 1H), 7.10-7.08 (d, = 7.8 Hz, 1H), 3.42-3.35 (m, 4H), 2.91-2.86 (m, 2H), 1.83-1.80 (m, 2H), 1.23-1.08 (t, = 8.40 Hz, 3H); MS [M-H]~: 391.
Example- 35
3-(3-Fluoropropyl)-4-(( -hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
Figure imgf000181_0001
The title compound was prepared following the procedure described in Example- 1 by using 3-(2-fluoropropyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzonitrile
(Intermediate-39, 85.0 mg, 0.23 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) afford 65 mg of title product.1H NMR (300 MHz, DMSO-i¾): δ 13.13 (br s, 1H), 10.71 (s, 1H), 7.88 (s, 1H), 7.83-7.80 (d, J = 8.7 Hz, 1H), 7.98-7.65 (d, J = 8.4 Hz, 1H), Ί .60-1.51 (d, J = 8.1 Hz, 1H), 7.16 (s, 1H), 7.11-7.08 (d, J = 8.4 Hz, 1H), 4.56 (t, 1H), 4.40 (t, 1H), 2.95-2.91 (m, 2H), 2.03 (m, 1H), 1.95 (m, 1H).
Example- 36
4-((2-Fluoro-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-(trifluoromethyl)phenol
Figure imgf000181_0002
To a solution of 3-fluoro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzonitrile (Intermediate- 11, 90 mg, 0.295 mmol) in DMF (2.0 mL) was added sodium azide (21.09 mg, 0.324 mmol) and ammonium chloride (17.3 mg, 0.323 mmol). The reaction mixture was heated at 90- 100°C for 12 h. The reaction mass was quenched with water and extracted with ethyl actate. The organic layers were separated, washed with brine concentrated to afford 15 mg of title product. 1H NMR (300 MHz, OMSO-d6): δ 10.77 (s, 1H), 7.95-7.92 (d, J = 9.3 Hz, 2H), 7.77 (t, 1H), 7.69-7.66 (d, 7 = 8.4 Hz, 1H), 7.18 (s, 1H), 7.11 (s, 1H); MS [M-H]": 346. Example-37
Ethyl 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoate
Figure imgf000182_0001
To a solution of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid (Example-7, 170 mg, 0.55 mmol) in EtOH (10.0 mL) was added cone. H2S04 (0.5mL). The reaction mixture was heated at reflux for 4-5 h. The reaction mixture was quenched with water, basified with aq.NaHC03 solution and extracted with DCM. The organic layers were dried over Na2S04 and concentrated to afford 70 mg of title compound. 1H NMR (300 MHz, DMSO-d6): δ 10.70 (s, 1H), 7.98-7.96 (d, J = 7.8 Hz, 2H),7.66-7.58 (m, 3H), 7.15 (s, 1H), 7.08-7.05 (d, / = 8.1 Hz, 1H), 4.32-4.29 (q, J = 7.5Hz, 2H), 1.33- 1.28 (t, J = 6.9 Hz, 3H).
Example- 38
4-((3-Fluoropyridin-4-yl-N-oxide)ethynyl)benzoic acid
Figure imgf000182_0002
The title compound was prepared following the procedure described in Example- 14 using 3- fluoro-4-((4-(methoxycarbonyl)phenyl)ethynyl)pyridine 1 -oxide (Intermediate-40, 150 mg,
0.55 mmol), LiOH.H20 (58 mg, 1.38 mmol in 5.0 mL water), THF : water (5 mL: 5 mL) to afford 60 mg of title product. 1H NMR (300 MHz, OMSO-d6): δ 13.27 (s, 1H), 8.71 (s, 1H), 8.20-8.18 (d, = 5.4Hz, 1H), 8.01-7.98 (d, = 7.2 Hz, 2H), 7.72-7.70 (m, 3H);MS [M+H]+: 258.
Example- 39
Ethyl 3-fluoro-4-( -hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoate
Figure imgf000182_0003
The title compound was prepared following the procedure described in Example-37 by using 3-fluoro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoicacid (Example-8, 0.250 g, 0.77 mmol), H2S04 (0.5mL) in EtOH (10.0 mL) to afford 110 mg of title compound. 1H NMR (300 MHz, DMSO-d6): δ 10.79 (s, 1H), 7.84-7.77 (t, = 8.7 Hz, 2H),7.73-7.66 (m, 2H), 7.18 (s, 1H), 7.11-7.08 (d, J = 8.1 Hz, 1H), 4.35-4.32 (q, J = 7.2Hz, 2H), 1.35- 1.30 (t, J = 7.5 Hz, 3H); MS [M+H]+: 351. Example-40
5-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)thiophene-2-carboxylic acid
Figure imgf000183_0001
The title compound was prepared following the procedure described in Example methyl 5-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)thiophene-2-carboxylate
(Intermediate-41, 100 mg, 0.30 mmol), LiOH.H20 (32 mg, 0.76 mmol in 5.0 mL water), THF : water (5 mL: 5 mL) to afford 60 mg of title product. 1H NMR (300 MHz, DMSO-i¾): δ 10.79 (s, 1H), 7.67-7.64 (m, 2H),7.38 (s, 1H), 7.16 (s, 1H), 7.09-7.06 (d, J = 8.4Hz, 1H); MS [M-H]~: 311
Example-41
Ethyl 4'-carbamoyl-6-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-[l, -biphenyl]-3- carboxylate
Figure imgf000183_0002
The title compound was prepared following the procedure described in step-5 of Intermediate- 46 by using ethyl 4'-cyano-6-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-[l, -biphenyl]- 3-carboxylate (Step-1, Example-27, 80 mg, 0.18 mmol), DMSO (5 mL), 50% H202 (2.5 mL), K2C03 (60 mg, 0.434 mmol) to afford 40 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 10.76 (s, 1H), 7.99 (m, 5H), 7.73 (m, 3H), 7.38 (m, 2H), 7.11 (m, 2H), 4.33 (q 2H), 1.34 (t, 3H); MS [M+H]+: 454
Example-42
4'-Carbamoyl-3'-chloro-6-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-[l, -biphenyl]-3- carboxylic acid
Figure imgf000184_0001
Step 1:- Preparation of ethyl 4'-carbamoyl-3'-chloro-6-((4-hydroxy-2- (trifluoromethyl)phenyl)ethyny -[1,1 '-biphenyl] - 3 -carboxylate
Figure imgf000184_0002
The title compound was prepared following the procedure described in step-5 of Intermediate- 46 by using ethyl 3'-chloro-4'-cyano-6-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-[l, - biphenyl] -3 -carboxylate (Intermediate-42, 140 nmg, 0.29 mmol), DMSO (5 mL), 50% H202 (2.5 mL), K2C03 (94.7 mg, 0.68 mmol) to afford 110 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.73 (s, 1H), 7.98 (s, 3H), 7.79-7.56 (m, 5H), 7.45-7.42(d, = 8.1Hz, 1H), 7.13 (s, 1H), 7.07-7.05 (d, = 8.4Hz, 1H), 4.36-4.34 (q, = 7.5Hz, 2H), 1.36-1.31 (t, = 7.2Hz, 3H); MS [M+H]+: 487.
Step 2:- Preparation of 4'-carbamoyl-3'-chloro-6-((4-hydroxy-2-
(trifluoromethyl)phenyl)ethynyl) -[1,1 '-biphenyl] - 3 -carboxylic acid
The title compound was prepared following the procedure described in Example- 14 using ethyl 4'-carbamoyl-3'-chloro-6-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-[l, - biphenyl] -3 -carboxylate (100 mg, 0.205 mmol), LiOH.H20 (22 mg, 0.52 mmol in 3.0 mL water), THF : water (3 mL: 1 mL) to afford 60 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 13.31 (br s, 1H), 10.72 (s, 1H), 7.96 (s, 3H), 7.77 (s, 1H), 7.72-7.62 (m, 2H), 7.56-7.54(d, = 7.8Hz, 2H), 7.43-7.40 (d, = 8.4Hz, 1H), 7.11 (s, 1H), 7.06-7.02 (d, = 9.3 Hz, 1H); MS [M+H]+: 459.
Example-43
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-methoxypropyl)benzoic acid
Figure imgf000185_0001
The title compound was prepared following the procedure described in Example- 1 by using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-methoxypropyl)benzonitrile
(Intermediate-44, 90.0 mg, 0.43 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) afford 40 mg of title product.1H NMR (300 MHz, DMSO-i¾: δ 13.00 (br s, 1H), 10.71 (s, 1H), 7.84 (s, 1H), 7.81-7.78 (d, = 8.1 Hz, 1H), 7.68-7.65 (d, = 8.7 Hz, 1H), 7.58-7.55 (d, = 7.8 Hz, 1H), 7.16 (s, 1H), 7.11-7.09 (d, = 8.4 Hz, 1H), 3.22 (s, 5H), 2.90-2.84(d, = 7.5 Hz, 2H), 1.86- 1.80 (m, 2H); MS [M+H]+: 379.
Example-44
3-(2-Cyanoethyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
Figure imgf000185_0002
The title compound was prepared following the procedure described in Example- 14 using ethyl 3-(2-cyanoethyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoate (Intermediate-45, 40 mg, 0.12 mmol), LiOH.H20 (20 mg, 0.48 mmol in 3.0 mL water), THF : water (3 mL: 1 mL) to afford 20 mg of title product. 1H NMR (300 MHz, DMSO- 6): δ 13.22 (br s, 1H), 10.77 (s, 1H), 7.98 (s, 1H), 7.89-7.86 (d, J = 8.1 Hz, 1H), 7.71-7.69 (d, J = 8.4 Hz, 1H), 7.64-7.62 (d, J = 7.8 Hz, 1H), 7.17 (s, 1H), 7.12-7.09 (d, J = 8.4 Hz, 1H), 3.18-3.13 (t, = 7.2 Hz, 1H), 2.88-2.83 (t, J = 6.9 Hz, 2H).
Example-45
3-(3-Amino-3-oxopropyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl) benzoic acid
Figure imgf000185_0003
Step-1:- Preparation of ethyl 3-(3-amino-3-oxopropyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoate
Figure imgf000186_0001
The title compound was prepared following the procedure described in step-5 of Intermediate- 46 using ethyl 3-(2-cyanoethyl)-4-((4-hydroxy-2(trifluoromethyl) phenyl)ethynyl)benzoate (Intermediate-45, 80 mg, 0.24 mmol), DMSO (2 mL), 50% H202 (2.0 mL), K2C03 (50 mg, 0.36 mmol) to afford 40 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 10.72 (br s, 1H), 7.89 (s, 1H), 7.83-7.80 (d, 7 = 8.1 Hz, 1H), 7.71-7.68 (d, = 8.1 Hz, 1H), 7.59-7.56 (d, J = 8.1 Hz, 1H), 7.30 (s, 1H), 7.16 (s, 1H), 7.11-7.08 (d, = 8.4 Hz, 1H), 6.79 (br s, 1H), 4.35- 4.28 (q, = 6.9 Hz, 2H), 3.08-3.03 (t, = 7.2Hz, 2H), 2.42-2.30 (m, 2H), 1.34-1.30 (t, = 7.2 Hz, 3H).
Step-2:- Preparation of 3-(3-amino-3-oxopropyl)-4-((4-hydroxy-2-
(trifluoromethyl)phenyl)ethynyl) benzoic acid
The title compound was prepared following the procedure described in Example- 14 using ethyl 3-(3-amino-3-oxopropyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoate (40 mg, 0.11 mmol), LiOH.H20 (20 mg, 0.48 mmol in 3.0 mL water), THF : water (3 mL: 1 mL) to afford 15 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 13.09 (br s, 1H), 10.71 (s, 1H), 7.87 (s, 1H), 7.81-7.78 (d, = 7.8 Hz, 1H), 7.70-7.67 (d, = 8.1 Hz, 1H), 7.56- 7.54 (d, 7 = 8.1Hz, 1H), 7.30 (s, 1H), 7.17 (s, 1H), 7.11-7.08 (d, J = 8.7 Hz, 1H), 6.79 (s, 1H), 3.05 (t, 2H), 2.44-2.39 (t, = 7.2 Hz, 2H).
Example-46
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-propoxypropyl)
benzoic acid
Figure imgf000186_0002
Step- 1 :- Preparation of 4-iodo-3-(3-propoxypropyl)benzonitrile
Figure imgf000187_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 24 by using 3-(3-hydroxypropyl)-4-iodobenzonitrile (step-4, Intermediate-38, 0.400 g, 1.39 mmol), 1-bromopropane (0.257 g, 2.09 mmol), NaH (0.083 g, 2.09 mmol, 60% in mineral oil), DMF (10 mL) to afford 0.150 g title compound. 1H NMR (300 MHz, CDC13): δ 7.95-7.92 (d, = 8.4 Hz, 1H), 7.48 (s, 1H), 7.15-7.13 (d, = 6.0 Hz, 1H), 3.46-3.42 (t, = 6.3Hz, 2H), 3.41-3.36 (t, = 6.9Hz, 2H), 2.87-2.81 (t, = 7.8 Hz, 2H), 1.92- 1.82 (m, 2H), 1.65-1.59 (m, 2H), 0.97-0.95 (t, J = 7.5 Hz, 3H).
Step-2:- Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3- propoxypropyl)benzonitrile
Figure imgf000187_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-(trifluoromethyl)phenol (Intermediate-43, 90 mg, 0.48 mmol), 4-iodo- 3-(3-propoxypropyl)benzonitrile (159 mg, 0.48 mmol), TBAF (151 mg, 0.58 mmol), PdCl2(PPh3)2 (7 mg, 0.009 mmol), DMSO (2.0 mL) to afford 80 mg of the title product.1H NMR (300 MHz, DMSO-i¾): δ 10.75 (s, 1H),7.79 (s, 1H), 7.72-7.61 (m, 3H), 7.16 (s, 1H), 7.11-7.08 (d, 7 = 8.1Hz, 1H), 3.39-3.26 (m, 4H), 2.89-2.84 (t, J = 6.9 Hz, 2H), 1.86- 1.81 (t, J = 7.20 Hz, 2H), 1.50- 1.43 (q, J = 6.9 Hz, 2H), 0.89-0.79(t, J = 7.50 Hz, 3H).
Step-3:- Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3- propoxypropyl)benzoic acid
The title compound was prepared following the procedure described in Example- 1 by using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-propoxypropyl)benzonitrile (70.0 mg, 0.21 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) afford 40 mg of title product.1!! NMR (300 MHz, DMSO-i¾): δ 13.09 (br s, 1H), 10.71 (s, 1H), 7.85 (s, 1H), 7.81-7.78 (d, = 8.1 Hz, 1H), 7.68-7.65 (d, = 8.4 Hz, 1H), 7.58-7.55 (d, = 7.8 Hz, 1H), 7.17 (s, 1H), 7.10-7.09 (d, = 8.1 Hz, 1H), 3.34-3.01 (m, 4H), 2.91-2.86 (t, = 7.5 Hz, 2H), 1.86-1.81 (m, 2H), 1.51-1.44 (m, 2H), 0.85-0.8 l(t, J = 7.2 Hz, 3H).
Example-47
4'-Carbamoyl-6-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3'-methyl-[l, -biphenyl]-3- carboxylic acid
Figure imgf000188_0001
The title compound was prepared following the procedure described in Example- 14 using ethyl 4'-carbamoyl-6-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3'-methyl-[l, - biphenyl]-3-carboxylate (Intermediate-46, 50 mg, 0.107 mmol), LiOH.H20 (13 mg, 0.30 mmol in 3.0 mL water), THF : water (3 mL: 1 mL) to afford 12 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 13.30 (br s, 1H), 10.70 (s, 1H), 7.96 (s, 2H), 7.80 (s, 1H), 7.72-7.69 (d, = 8.1 Hz, 1H), 7.52-7.50 (br s, 3H), 7.43-7.40 (d, = 7.8 Hz, 1H), 7.37 (s, 1H), 7.12 (s, 1H), 7.07-7.04 (d, / = 8.7 Hz, 1H), 2.45 (s, 3H).
Example-48
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(2-methoxyethoxy)propyl) benzoic acid
Figure imgf000188_0002
The title compound was prepared following the procedure described in Example- 1 by using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(2-methoxyethoxy)propyl)benzonitrile (Intermediate-47, 70.0 mg, 0.20 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) afford 25 mg of title product.1!! NMR (300 MHz, OMSO-d6): δ 13.0 (br s, 1H), 1 1.0 (br s, 1H), 7.85 (s, 1H), 7.81-7.78 (d, = 7.8Hz, 1H), 7.68-7.65 (d, = 8.7 Hz, 1H), 7.57-7.52 (d, = 8.1Hz, 1H), 7.16 (s, 1H), 7.11-7.08 (d, J = 8.4Hz, 1H), 3.46-3.41 (m, 6H), 3.22 (s, 3H), 2.90-2.85 (t, J = 6.9Hz, 2H), 1.86- 1.81 (t, J = 7.5Hz, 2H);MS [M+H]+: 422. Example-49
3-(3-(diethylamino)propyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl) benzoic acid
Figure imgf000189_0001
The title compound was prepared following the procedure described in Example- 1 by using 3- (3-(diethylamino)propyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl) benzonitrile (Intermediate-48, 50.0 mg, 0.12 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) afford 15 mg of title product. 1H NMR (300 MHz, DMSO-^): δ 7.83 (s, 1H), 7.75-7.73 (d, = 6.3 Hz, 1H), 7.64-7.62 (d, J = 6.9 Hz, 1H), 7.49-7.46 (d, J = 7.8 Hz, 1H), 7.18 (s, 1H), 7.10-7.07 (d, / = 8.7 Hz, 1H),3.50 (m, 6H), 2.81 (m, 2H), 1.74 (m, 2H), 0.95-0.91 (t, J = 6.9Hz, 6H); MS [M+H]+: 420.
Example-50
4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(6-methoxypyridin-3-yl)benzoic acid
Figure imgf000189_0002
The title compound was prepared following the procedure described in Example- 14 by using ethyl 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(6-methoxypyridin-3-yl)benzoate (Intermediate-49, 45 mg, 0.10 mmol), THF+H20 (2.0+3.0 ml), LiOH.H20 (10 mg, 0.25 mmol) at RT to afford 28 mg of the title product. 1H NMR (300 MHz, DMSO- 6): δ 13.27 (s, 1H), 10.70 (s, 1H), 8.40 (s, 1H), 8.02-7.98 (m, 3H), 7.74-7.71 (d, J = 8.4 Hz, 1H), 7.45-7.43 (d, J = 8.1 Hz, 1H), 7.11 (s, 1H), 7.07-7.04 (d, J = 8.4 Hz, 1H), 6.96-6.93 (t, = 8.7 Hz, 1H), 3.91 (s, 3H); MS [M+H]+: 414.
Example- 51
3-(3-(lH-imidazol-l-yl)propyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
Figure imgf000190_0001
The title compound was prepared following the procedure described in Example- 1 by using 3- (3-(lH-imidazol-l-yl)propyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzonitrile (Intermediate-50, 80 mg, 0.20 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) afford 40 mg of title product. 1H NMR (300 MHz, DMSO- 6): δ 10.89 (s, 1H), 9.12 (s, 1H), 7.89 (s, 1H), 7.84-7.81 (m, 2H), 7.63-7.57 (m, 3H), 7.22 (s, 1H), 7.16-7.13 (d, = 8.7Hz, 1Η),4.28-4.23 (t, = 6.9Hz, 2H), 2.89-2.84 (m, 2H), 2.20 (m, 2H); MS [M+H]+: 415.
Example-52
4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-morpholinopropyl)benzoic acid
Figure imgf000190_0002
The title compound was prepared following the procedure described in Example- 1 by using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-morpholinopropyl) benzonitrile (Intermediate-51, 80 mg, 0.19 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) afford 65 mg of title product H NMR (300 MHz, DMSO- 6): δ 13.14 (s, 1H), 10.82 (s, 1H), 7.93 (s, 1H), 7.85-7.82 (d, = 8.7 Hz, 1Η),7.73-7.70 (d, = 8.7Hz, 1H), 7.61-7.58 (d, = 8.4 Hz, 1H), 7.20 (s, 1H), 7.13-7.10 (d, = 8.4 Hz, 1H), 3.89 (m, 2H), 3.71 (m, 2H), 3.34 (m, 2H), 3.10 (m, 4H), 2.90-2.88(t, = 7.8Hz, 2H), 2.06 (m, 2H); MS [M-H]~: 432.
Example- 53
4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-hydroxypropyl)benzoic acid
Figure imgf000191_0001
The title compound was prepared following the procedure described in Example- 1 by using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-hydroxypropyl)benzonitrile
(Intermediate-52, 70 mg, 0.20 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) afford 45 mg of title product. 1H NMR (300 MHz, DMSO- 6): δ 13.10 (s, 1H), 10.70 (s, 1H), 7.85 (s, 1H), 7.80-7.78 (d, = 8.1Hz, 1Η),7.69-7.66 (d, = 9.0Hz, 1H), 7.57-7.54 (d, = 8.4Hz, 1H), 7.16 (s, 1H), 7.11-7.08 (d, = 8.4 Hz, 1H),4.53-4.51 (d, = 4.8 Hz, 1H), 3.44-3.42 (q, = 5.4 Hz, 2H), 2.89-2.84 (t, = 7.2 Hz, 2H), 1.77-1.73 (m, 2H); MS [M+H]+: 365.
Example-54
Ethyl 3-(6-carbamoylpyridin- -yl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoate
Figure imgf000191_0002
The title compound was prepared following the procedure described in step-5 of Intermediate-
46 by using ethyl 3-(6-carbamoylpyridin-3-yl)-4-((4-hydroxy-2-
(trifluoromethyl)phenyl)ethynyl)benzoate (Intermediate-53, 200 mg, 0.458 mmol), DMSO (5 mL), 50% H202 (5.0 mL), K2C03 (158 mg, 1.14 mmol) to afford 201 mg of the title product. 1H NMR (300 MHz, DMSO- 6): δ 10.72 (s, 1H), 8.82 (s, 1H), 8.21 (m, 2H), 8.14-8.11(d, = 7.8Hz, 1H), 8.06-8.02 (m, 2H), 7.80-7.78 (d, = 7.2 Hz, 1H), 7.70 (br s, 1H), 7.42-7.40 (d, = 8.4 Hz, 1H), 7.08 (s, 1H), 7.04-7.02 (d, = 8.1 Hz, 1H), 4.35-4.32 (q, = 7.5 Hz, 2H), 1.34- 1.29 (q, = 7.5 Hz, 3H); MS [M+H]+: 455.
Example- 55
3-(6-carbamoylpyridin-3-yl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl) ethynyl)benzoic acid
Figure imgf000192_0001
The title compound was prepared following the procedure described in Example- 14 by using ethyl 3-(6-carbamoylpyridin-3-yl)-4-((4-hydroxy-2-(trifluoromethyl) phenyl)ethynyl)benzoate (Example-54, 70 mg, 0.15 mmol), THF+H20 (2.0+3.0 ml), LiOH.H20 (16 mg, 0.37 mmol) at
RT to afford 48 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 13.38 (s, 10.74 (s, 1H), 8.84 (s, 1H),8.22 (br s, 2H), 8.15 (d, 1H), 8.03 (s, 2H), 7.80-7.77 (d, J = 8.1 1H), 7.71 (s, 1H), 7.44 (d, / = 8.4 Hz, 1H), 7.10 (s, 1H), 7.06 (d, 1H); MS [M+H]+: 427.
Example- 56
3-(3-(cyclopropylmethoxy)propyl)-4-((4-hydroxy-2-(trifluoromethyl) phenyl)ethynyl)benzoic acid
Figure imgf000192_0002
The title compound was prepared following the procedure described in Example- 1 by using 3- (3-(cyclopropylmethoxy)propyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)
ethynyl)benzonitrile (Intermediate-54, 70 mg, 0.17 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) afford 25 mg of title product.1H NMR (300 MHz, DMSO- 6): δ 13.09 (br s, 1H), 10.70 (s, 1H), 7.85 (s, 1H), 7.81-7.78 (d, J = 7.8Hz, 1Η),7.69-7.66 (d, J = 8.7 Hz, 1H), 7.58-7.55 (d, 7 = 8.1 Hz, 1H), 7.16 (s, 1H), 7.10-7.08 (d, J = 8.7 Hz, 1H), 3.40-3.33 (m, 2H), 3.19-3.17 (d, = 6.6Hz, 2H), 2.91-2.86 (t, J = 7.2Hz, 2H), 1.86-1.81 (m, 2H),0.96 (m, 1H), 0.43-0.40 (d, J = 7.2Hz, 2H),0.13-0.11 (m, 2H); MS [M-H]":417.
Example-57
3-(4-ethoxybutyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
Figure imgf000193_0001
The title compound was prepared following the procedure described in Example- 14 by using ethyl 3-(4-ethoxybutyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoate (Intermediate-55, 60 mg, 0.13 mmol), THF+H20 (5.0+5.0 ml), LiOH.H20 (23 mg, 0.55 mmol) to afford 48 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 13.03 (s, 1H), 10.80 (brs, 1H), 7.83 (s, 1H), 7.77-7.76 (d, J = 6.6 Hz, 1Η),7.66-7.63 (d, J = 9.0 Hz, 1H), 7.56-7.53 (d, = 7.8 Hz, 1H), 7.14 (s, 1H), 7.09-7.06 (d, = 8.7 Hz, 1H), 3.54-3.31 (m, 4H), 2.83 (t, 2H), 1.63-1.51 (m, 4H), 1.05-1.00 (t, J = 7.2 Hz, 3H); MS [M-H]": 405.
Example- 58
Ethyl 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(2-(6-propoxypyridin-3- yl)ethyl)benzoate
Figure imgf000193_0002
The title compound was prepared following the procedure described in step-2 of Intermediate- 38 by using ethyl 4-amino-3-((6-propoxypyridin-3-yl)ethynyl)benzoate (Intermediate-57, 0.900 g, 8.14 mmol), Pd/CaC03 (0.300 g) in EtOH (10 mL) to afford 0.400 g of title product. 1H NMR (300 MHz, DMSO-i¾): δ 8.0 (s, 1Η),7.65-7.62 (d, = 9.0 Hz, 1H),7.50 (s, 2H), 6.72-6.69 (d, = 8.1 Hz, 1H), 6.64-6.61 (d, = 8.4 Hz, 1H), 5.82 (br s, 2H), 4.21-4.12 (m, 4H), 2.71 (br s, 4H), 1.73-1.66 (q, J = 6.9 Hz, 2H), 1.27-1.22 (t, J = 7.2 Hz, 3H), 0.96-0.91 (t, = 7.2 Hz, 3H); MS [M+H]+: 329.
Step-2:- Preparation of ethyl 4-iodo-3-(2-(6-propoxypyridin-3-yl)ethyl)benzoate
Figure imgf000194_0001
The title compound was prepared following the procedure described in step-2 of Intermediate- 1 by using ethyl 4-amino-3-(2-(6-propoxypyridin-3-yl)ethyl)benzoate (300 mg, 0.91 mmol), ice-water (3.0 mL), conc.H2S04 (3.0 ml), aq. NaN02 (113 mg, 1.63 mmol), aq. KI (302 mg, 1.81 mmol) in acetonitrile (5.0 mL) to afford 300 mg of the title product. 1H NMR (300 MHz, DMSO-i¾): δ 8.02-7.99 (d, = 7.8 Hz, 1H),7.96 (s, 1H), 7.79 (s, 1H), 7.60-7.58 (d, = 7.8 Hz, 1H), 7.50-7.48 (d, = 7.8 Hz, 1H), 7.75-7.72 (d, = 9.0 Hz, 1H), 4.30-4.25 (q, = 6.9 Hz, 2H), 4.17-4.13 (t, = 6.3 Hz, 2H), 2.99 (m, 2H), 2.76 (m, 2H), 1.70-1.66 (m, 2H), 1.32-1.27 (t, = 7.5 Hz, 3H), 0.96-0.91 (t, = 7.2 Hz, 3H); MS [M+H]+: 440.
Step-3:- Preparation of ethyl 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(2-(6- propoxypyridin-3-yl)ethyl)benzoate
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 168 mg, 0.68 mmol), ethyl 4-iodo-3-(2-(6-propoxypyridin-3-yl)ethyl)benzoat (300 mg, 0.68 mmol), TBAF (215 mg, 0.81 mmol), PdCl2(PPh3)2 (10 mg, 0.013 mmol), DMSO (2.0 mL) to afford 160 mg of the title product.1H NMR (300 MHz, DMSO-i¾): δ 10.71 (s, 1H),7.87 (s, 1H), 7.81 (s, 2H), 7.66-7.58 (m, 2H), 7.50 (m, 1H), 7.16 (d, 1H), 7.11 (s, 1H), 6.69-6.66 (d, J = 8.7 Hz, 1H), 4.32-4.29 (q, = 7.2 Hz, 2H), 4.13-4.11 (t, = 6.3 Hz, 2H), 3.12 (m, 2H), 2.85 (m, 2H),1.68-1.66 (m, 2H), 1.34-1.29 (t, J = 6.9 Hz, 3H),0.95-0.90 (t, J = 7.5 Hz, 3H); ); MS [M+H]+: 498.
Example- 59
4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(2-(6-propoxypyridin-3-yl)ethyl)benzoic acid
Figure imgf000195_0001
The title compound was prepared following the procedure described in Example- 14 by using ethyl 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(2-(6-propoxypyridin-3- yl)ethyl)benzoate (Example-58, 60 mg, 0.12 mmol), THF+H20 (5.0+5.0 ml), LiOH.H20 (12 mg, 0.30 mmol) to afford 30 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 13.09 (br s, 1H), 10.70 (s, 1H), 7.89 (s, 1H), 7.84-7.79 (m, 2H), 7.66-7.63 (d, J = 9.0 Hz, 1H),7.58- 7.56 (d, = 7.8 Hz, 1H), 7.48 (d, 1H), 7.16 (s, 1H), 7.11-7.08 (br d, 1H), 6.68-6.66 (d, = 8.1 Hz, 1H), 4.13-4.11 (t, 2H), 3.11 (m, 2H), 2.85 (m, 2H), 1.68- 1.66 (q, = 6.9 Hz, 2H),0.95- 0.90 (t, = 7.2 Hz, 3H); MS [M+H]+: 470.
Example- 60
3-(3-(lH-l,2,3-triazol-l-yl)propyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
Figure imgf000195_0002
The title compound was prepared following the procedure described in Example- 1 by using 3- (3-(lH-l,2,3-triazol- l-yl)propyl)-4-((4-hydroxy-2-
(trifluoromethyl)phenyl)ethynyl)benzonitrile (Intermediate-58, 60 mg, 0.15 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) afford 22 mg of title product H NMR (300 MHz, DMSO-d6): δ 13.13 (br s, 1H), 10.73 (br s, 1H), 8.15 (s, 1H), 7.88 (s, 1H), 7.83-7.81(d, = 7.2 Hz, 1H),7.70 (s, 1H), 7.63-7.56 (t, = 8.7 Hz, 2H), 7.17 (s, 1H), 7.11-7.09 (d, = 6.9 Hz, 1H), 4.43 (t, 2H), 2.84 (s, 2H), 2.18 (s, 2H); MS [M-H]~: 414.
Example- 61
4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(pyridin-3-yloxy)propyl)benzoic acid
Figure imgf000196_0001
The title compound was prepared following the procedure described in Example- 1 by using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(pyridin-3-yloxy)propyl)benzonitrile (Intermediate-59, 60 mg, 0.14 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) afford 18 mg of title product.1!! NMR (300 MHz, DMSO- 6): δ 13.09 (s, 1H), 10.71 (s, 1H), 8.25 (s, 1H), 8.14 (d, 1H), 7.90 (s, 1H), 7.83-7.80 (d, J = 8.4 Hz, 1Η),7.65-7.57 (m, 2H), 7.35-7.3 l(m, 2H), 7.16 (s, 1H), 7.09-7.06 (d, J = 9.0 Hz, 1H), 4.09 (t, 2H), 3.03 (t, 2H), 2.09 (m, 2H); MS [M+H]+: 442.
Example- 62
3-(3-(2-ethoxyethoxy)propyl -4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
Figure imgf000196_0002
The title compound was prepared following the procedure described in Example- 1 by using 3- (3-(2-ethoxyethoxy)propyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzonitrile
(Intermediate-60, 70 mg, 0.16 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) afford 15 mg of title product.1H NMR (300 MHz, DMSO- 6): δ 10.71 (br s, 1H), 7.85 (s, 1H), 7.81-7.78 (d, = 7.8 Hz, lH),7.68-7.65 (d, J = 8.4 Hz, 1H), 7.57-7.55 (d, J = 8.1 Hz, 1H), 7.17 (s, 1H), 7.11- 7.08 (d, J = 8.7 Hz, 1H), 3.45-3.83 (m, 8H), 2.88 (m, 2H), 1.84 (m, 2H), 1.08-1.03 (t, J = 6.9 Hz, 3H); MS [M-H]": 435.
Example-63
Ethyl 3-(3-(cyclopropylmethoxy)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoate
Figure imgf000197_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 0.100 g, 0.40 mmol), ethyl 4-(3-(cyclopropylmethoxy)propyl)-2-iodobenzoate (Intermediate-61, 159 mg, 0.40 mmol), TBAF (128 mg, 0.49 mmol), PdCl2(PPh3)2 (6 mg, 0.008 mmol), DMSO (2.0 mL) to afford 35 mg of the title product.1!! NMR (300 MHz, DMSO-i¾): δ 10.71 (s, 1H),7.86 (s, 1H), 7.83-7.80 (d, = 7.8 Hz, 1H), 7.69-7.66 (d, = 8.4 Hz, 1Η),7.60-7.57 (d, = 8.4 Hz, 1H), 7.16 (s, 1H), 7.10-7.07 (d, J = 8.7 Hz, 1H), 4.35-4.28 (q, J = 6.9 Hz, 2H), 3.39-3.37 (t, J = 6.0 Hz, 2H), 3.19-3.17 (d, J = 6.9Hz, 2H), 2.89-2.87 (d, J = 7.5Hz, 2H), 1.83 (m, 2H), 1.34- 1.29 (t, = 7.2 Hz, 3H), 0.96 (brs, 1H), 0.43-0.41 (m, 2H), 0.13-0.12 (m, 2H); MS [M-H]": 445.
Example- 64
4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(2-methyl-lH-imidazol-l- yl)propyl)benzoic acid
Figure imgf000197_0002
The title compound was prepared following the procedure described in Example- 1 by using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(2-methyl-lH-imidazol-l- yl)propyl)benzonitrile (Intermediate-62, 50 mg, 0.16 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) afford 15 mg of title product.1!! NMR (300 MHz, DMSO- 6): δ 13.0 (br s, 1H), 10.84 (s, 1H), 7.90 (s, 1H), 7.84-7.81 (d, J = 8.4 Hz, 2H),7.65-7.52 (m, 4H), 7.20 (s, 1H), 7.15 (d, 1H), 4.15 (m, 2H), 2.89 (m, 2H), 2.53 (s, 3H), 2.13 (m, 2H).
Example-65
3-(3-(benzyloxy)propyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
Figure imgf000198_0001
The title compound was prepared following the procedure described in Example- 1 by
(3-(benzyloxy)propyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzonitrile
(Intermediate-63, 40 mg, 0.091 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) afford 15 mg of title product.1H NMR (300 MHz, DMSO- 6): δ 13.11 (s, 1H), 10.70 (s, 1H),7.87 (s, 1H), 7.81-7.79 (d, = 7.8 Hz, 1H), 7.63-7.55 (m, 2H), 7.30 (m, 5H), 7.16 (s, 1H), 7.04 (d, 1H), 4.45 (s, 2H), 3.47 (t, 2H), 2.92 (m, 2H), 1.90 (m, 2H); MS [M+H]+: 453.
Example-66
4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(6-propoxypyridin-3-yl)benzoic acid
Figure imgf000198_0002
The title compound was prepared following the procedure described in Example- 14 by using ethyl 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(6-propoxypyridin-3-yl)benzoate (Intermediate-64, 100 mg, 0.12 mmol), THF+H20 (5.0+5.0 ml), LiOH.H20 (22 mg, 0.530 mmol) to afford 70 mg of the title product. 1H NMR (300 MHz, DMSO- 6): δ 14.0-13.0 (br s, 1H), 11.0-10.0 (br s, 1H), 8.37 (s, 1H), 7.95 (br s, 3H), 7.73-7.70 (d, = 8.4 Hz, 1H),7.45- 7.40 (d, = 8.1 Hz, 1H), 7.11 (s, 1H), 7.07-7.04 (d, = 8.1 Hz, 1H), 6.93-6.90 (d, = 9.0 Hz, 1H), 4.29-4.24 (t, J = 6.9 Hz, 2H), 1.79- 1.72 (q, J = 7.5 Hz, 2H), 1.00-0.95 (t, J = 7.2 Hz, 3H); MS [M+H]+: 442.
Example- 67
3-(6-chloropyridin-3-yl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl) benzoic acid
Figure imgf000199_0001
The title compound was prepared following the procedure described in Example- 14 by using ethyl 3-(6-chloropyridin-3-yl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl) benzoate (Intermediate-65, 100 mg, 0.23 mmol), THF+H20 (5.0+5.0 ml), LiOH.H20 (25 mg, 0.58 mmol) to afford 60 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.64 (s, 1H), 8.14-8.12 (d, = 7.2 Hz, 1H), 8.04-8.0 (m, 2H), 7.78-7.75 (d, = 8.4 Hz, 1H), 7.66-7.63 (d, = 9.0 Hz, 1H), 7.47-7.44 (d, = 8.4 Hz, 1H), 7.11 (s, 1H), 7.08-7.05 (d, = 8.4 Hz, 1H); MS [M+H]+: 417.
Example- 68
4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(6-hydroxypyridin-3-yl)benzoic acid
Figure imgf000199_0002
The title compound was prepared following the procedure described in Example- 14 by using ethyl 3-(6-hydroxypyridin-3-yl)-4-((4-((methylsulfonyl)oxy)-2-(trifluoromethyl) phenyl)ethynyl)benzoate (Intermediate-66, 60 mg, 0.11 mmol), THF+H20 (5.0+5.0 ml), LiOH.H20 (13 mg, 0.35 mmol) to afford 30 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 13.13 (s, 1H), 11.95 (s, 1H), 10.73 (s, 1H), 7.91-7.89 (m, 2H), 7.78-7.60 (m, 2H), 7.54-7.51 (d, = 8.7 Hz, 2H), 7.13 (s, 1H), 7.10-7.07 (d, = 8.4 Hz, 1H), 6.45-6.42 (d, = 9.3 Hz, 1H); MS [M+H]+: 400.
Example-69
4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(pyrazin-2-yloxy)propyl)benzoic acid
Figure imgf000199_0003
The title compound was prepared following the procedure described in Example- 1 by using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(pyrazin-2-yloxy)propyl)benzonitrile (Intermediate-67, 80 mg, 0.18 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) afford 20 mg of title product.1!! NMR (300 MHz, DMSO- 6): δ 10.07 (br s, IH), 10.70 (s, IH), 8.18-8.15 (m, 3H), 7.89 (s, IH), 7.82-7.79 (d, J = 8.1 Hz, IH), 7.64-7.56 (m, 2H), 7.14 (s, IH), 7.09-7.06 (d, 7 = 8.1 Ηζ,ΙΗ), 4.35-4.31 (t, J = 8.7 Hz, 2H), 3.04-2.99 (t, J = 6.6 Hz, 2H), 2.11 (m, 2H); MS [M+H]+: 443.
Example-70
3-(3-(4-carbamoylpiperidin-l-yl)propyl)-4-((4-hydroxy-2-(trifluoromethyl)
phenyl)ethynyl)benzoic acid
Figure imgf000200_0001
The title compound was prepared following the procedure described in Example- 1 by using 4- ((2-(3-(4-carbamoylpiperidin-l-yl)propyl)-4-cyanophenyl)ethynyl)-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-68, 70 mg, 0.133 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) afford 18 mg of title product.1H NMR (300 MHz, DMSO- 6): δ 7.88 (s, IH), 7.78 (d, 1H),7.63 (d, IH), 7.57 (d, IH), 7.17 (s, IH), 7.11 (d, IH), 6.54 (s, IH), 6.02 (s, IH), 3.39 (m, 2H), 2.85 (m, 4H), 2.19 (m, 2H), 1.83 (m, 3H), 1.61 (m, 2H), 1.22 (m, 2H); MS [M+H]+: 476.
Example-71
3-(3-(4-ethoxypiperidin-l-yl)propyl)-4-((4-hydroxy-2-(trifluoromethyl)
phenyl)ethynyl)benzoic acid
Figure imgf000200_0002
The title compound was prepared following the procedure described in Example- 1 by using 4- ((4-cyano-2-(3-(4-ethoxypiperidin-l-yl)propyl)phenyl)ethynyl)-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-69, 70 mg, 0.130 mmol), EtOH (7.0 mL), 2N NaOH (7.0 mL) afford 12 mg of title product.1H NMR (300 MHz, DMSO- 6): δ 11 (br s, IH), 7.90 (s, lH),7.82-7.80 (d, = 7.8 Hz, IH), 7.70-7.67 (d, = 8.4 Hz, IH), 7.59-7.56 (d, = 7.8 Hz, IH), 7.18 (s, IH), 7.09 (d, IH), 3.42-3.34 (m, 4H), 2.96 (m, 2H), 2.86 (m, 2H), 2.73 (m, 2H), 2.50 (m, 2H), 1.90 (m, 3H), 1.56 (m, 2H), 1.10-1.06 (t, J = 6.9 Hz, 3H); MS [M+H]+: 476.
Example-72
3- 3-((6-chloropyridin-3-yl)oxy)propyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)
Figure imgf000201_0001
The title compound was prepared following the procedure described in Example- 1 by using 3- (3-((6-chloropyridin-3-yl)oxy)propyl)-4-((4-hydroxy-2-
(trifluoromethyl)phenyl)ethynyl)benzonitrile (Intermediate-70, 70 mg, 0.153 mmol), EtOH (7.0 mL), 2N NaOH (7.0 mL) afford 15 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 13.09 (br s, IH), 10.70 (s, IH), 8.04 (s, IH), 7.89 (s, IH), 7.82-7.80 (d, = 7.8 Hz, IH), 7.63-7.56 (m, 2H), 7.41-7.370 (m, 2H), 7.15 (s, IH), 7.09-7.06 (d, = 8.4 Hz, IH), 4.08 (t, 2H), 3.01 (t, 2H), 2.08 (m, 2H); MS [M+H]+: 476.
Example-73
Hexyl 3-fluoro- -((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoate
Figure imgf000201_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 100 mg, 0.40 mmol), hexyl 3-fluoro-4-iodobenzoate (Intermediate-71, 143 mg, 0.40 mmol), TBAF (128 mg, 0.48 mmol), PdCl2(PPh3)2 (6 mg, 0.008 mmol), DMSO (2.0 mL) to afford 60 mg of the title product H NMR (300 MHz, DMSO-i¾): δ 10.79 (s, 1Η),7.84-7.66 (m, 4H), 7.17 (s, IH), 7.11-7.08 (d, = 8.4 Hz, IH), 4.30-4.26 (t, = 6.3 Hz, 2H), 1.71-1.68 (m, 2H), 1.30 (m, 6H), 0.87 (s, 3H). Example-74
2-(diethylamino)-2-oxoethyl 3-fluoro-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoate
Figure imgf000202_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 100 mg, 0.40 mmol), 2-(diethylamino)-2-oxoethyl 3-fluoro-4-iodobenzoate (Intermediate-72, 155 mg, 0.40 mmol), TBAF (128 mg, 0.48 mmol), PdCl2(PPh3)2 (6 mg, 0.008 mmol), DMSO (2.0 mL) to afford 60 mg of the title product.1!! NMR (300 MHz, DMSO-i¾: δ 10.80 (s, 1Η),7.88-7.67 (m, 4H), 7.18 (s, 1H), 7.12-7.09 (d, J = 8.7 Hz, 1H), 5.05 (s, 2H), 3.33-3.26 (s, 4H),1.18-1.14 (t, J = 6.9 Hz, 3H), 1.05- 1.0 (t, J = 6.9 Hz, 3H).
Example-75
3-(2-carbamoylpyrimidin-5-yl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl) benzoic acid
Figure imgf000202_0002
The title compound was prepared following the procedure described in Example- 14 by using ethyl 3-(2-carbamoylpyrimidin-5-yl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoate (Intermediate-73, 50 mg, 0.10 mmol), THF+H20 (5.0+5.0 ml), LiOH.H20 (11 mg, 0.27 mmol) to afford 30 mg of the title product. 1H NMR (300 MHz, DMSO-i¾) : δ 14.0- 13.0 (br s, 1H), 10.78 (br s, 1H), 9.20 (s, 2H), 8.11-8.08 (m, 3H), 7.83-7.81 (d, = 8.1 Hz, 2H), 7.48 (d, = 8.4 Hz, 1H), 7.10 (s, 1H), 7.07-7.04 (d, = 9.0 Hz, 1H); MS [M+H]+: 429.
Example-76
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(4-(2-methyl-lH-imidazol- l- yl)butyl)benzoic acid
Figure imgf000203_0001
Step-1: Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(4-(2-methyl-lH- imidazol- 1 -yl)butyl)benzonitril
Figure imgf000203_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 by using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 67 mg, 0.27 mmol), 4-iodo-3-(4-(2-methyl-lH-imidazol-l-yl)butyl)benzonitrile (Intermediate-74, 100 mg, 0.27 mmol), PdCl2(PPh3)2 (3.8 mg, 0.005 mmol), TBAF (71.0 mg, 0.32 mmol) in DMSO (2.0 mL) to afford to afford 0.080 g of the title product.1H NMR (300 MHz, DMSO- d6): δ 7.81 (s, IH), Ί .13-1.10 (m, IH), 7.66-7.64 (m, 3H), 7.17 (s, IH), 7.11-7.09 (d, = 7.8 Hz, IH), 6.99 (s, IH), 6.69 (s, IH), 3.86 (t, 2H), 3.15 (m, 2H), 2.84(t, 2H), 2.22 (s. 3H), 1.60 (m, 2H); MS [M+H]+: 424.
Step-2: Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(4-(2-methyl-lH- imidazol-l-yl)butyl)benzoic acid
The title compound was prepared following the procedure described in Example- 1 by using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(4-(2-methyl-lH-imidazol-l- yl)butyl)benzonitrile (50 mg, 0.11 mmol), 2N NaOH (5.0 mL) in EtOH (5.0 mL) to afford 30 mg of title product H NMR (300 MHz, DMSO- 6): δ 14-13 (br s, IH), 10.81 (s, IH), 7.87 (s, IH), 7.82-7.79 (d, = 7.5 Hz, IH), 7.66-7.63 (d, = 9.3 Hz, IH), 7.59-7.56 (m, 2H), 7.45 (s, IH), 7.19 (s, IH), 7.13(d, IH), 4.09 (t, 2H), 2.88 (t, 2H), 2.52 (s, 3H), 1.76 (m, 2H), 1.63 (m, 2H); MS [M+H]+: 443.
Example-77
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(4-(pyrazin-2-yloxy)butyl)benzoic acid
Figure imgf000204_0001
Step 1 : Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(4-(pyrazin-2- yloxy)butyl)benzonitrile
Figure imgf000204_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 100 mg, 0.37 mmol), 4-iodo-3-(4-(pyrazin-2-yloxy)butyl)benzonitrile (Intermediate-75, 143 mg, 0.37 mmol), TBAF (119 mg, 0.45 mmol), PdCl2(PPh3)2 (5.3 mg, 0.007 mmol) in DMSO (2.0 mL) to afford 60 mg of the title product.1H NMR (300 MHz, DMSO-d6): δ 10.75 (s, 1H), 8.21 (s, 1H), 8.15 (s, 2H), 7.85 (s, 1H), 7.70 (d, 1H), 7.64 (t, 2H), 7.15 (s, 1H), 7.09-7.05 (d, J = 9.3 Hz, 1H), 4.30 (m, 2H), 2.88 (m, 2H), 1.77 (m, 4H); MS [M+H]+: 438.
Step 2: Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(4-(pyrazin-2- yloxy)butyl)benzoic acid
The title compound was prepared following the procedure described in Example- 1 using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(4-(pyrazin-2-yloxy)butyl)benzonitrile (70 mg, 0.16 mmol), EtOH (5.0 mL) and 2N NaOH (5.0 mL) to afford 30 mg of title product.1H NMR (300 MHz, DMSO- 6): δ 13.09 (br s, 1H), 10.71 (br s, 1H), 8.22 (s, 1H), 8.17 (s, 2H), 7.89 (s, 1H), 7.78 (d, 1H), 7.64-7.62 (d, J = 8.4 Hz, 1H), 7.58 (d, 1H), 7.14 (s, 1H), 7.08-7.05 (d, J = 7.8 Hz, 1H), 4.31 (br s, 2H),2.91 (m, 2H), 1.78 (br s, 4H); MS [M+H]+: 457.
Example-78
2-((3-Fluoro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoyl)oxy)-N,N,N- trimethylethanaminium iodide
Figure imgf000204_0003
\ Step 1 : Preparation of 2-(dimethylamino)ethyl 3-fluoro-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethyn
Figure imgf000205_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 100 mg, 0.37 mmol), 2-(dimethylamino)ethyl 3-fluoro-4-iodobenzoate (Intermediate-76, 127 mg, 0.37 mmol), TBAF (119 mg, 0.45 mmol), PdCl2(PPh3)2 (5.3 mg, 0.007 mmol) in DMSO (2.0 mL) to afford 80 mg of the title product.1H NMR (300 MHz, DMSO-d6): δ 1 1-10 (br s, 1H), 7.84 (m, 2H), 7.50 (br s, 2H), 7.18 (s, 1H), 7.11-7.08 (d, J = 8.1 Hz, 1H), 4.38 (t, 2H), 2.67 (t, 2H), 2.24 (s, 6H); MS [M+H]+: 396.
Step 2: Preparation of 2-((3-fluoro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl) benzoyl)oxy)-N,N,N-trimethylethanaminium iodide
In sealed tube to a solution of 2-(dimethylamino)ethyl 3-fluoro-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoate (50 mg, 0.12 mmol) in mixture of acetonitrile : toluene (5 mL: 2 mL) was added CH3I (56 mg, 0.37 mmol).The reaction mass was stirred at rt for 72 h. The excess of solvent was removed and remained solid was washed with mixture of
DEE : MeOH, filtered and suck dried to afford 20 mg of title product.1H NMR (300 MHz, DMSO-d6): δ 10.82 (br s, 1H), 7.89-7.86 (d, J = 7.8 Hz, 2H), 7.74-7.66 (m, 2H), 7.18 (s, 1H), 7.12-7.09 (d, J = 8.7 Hz, 1H), 4.73 (s, 2H), 3.83 (s, 2H), 3.19 (s, 9H); MS [M+H]+: 410.
Example-79
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-((6-methylpyridin-3- yl)oxy)propyl)benzoic acid
Figure imgf000205_0002
Step 1 : Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-((6- methylpyridin-3-yl)oxy)propyl)benzonitrile
Figure imgf000206_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 100 mg, 0.37 mmol), 4-iodo-3-(3-((6-methylpyridin-3-yl)oxy)propyl)benzonitrile (Intermediate-77, 143 mg, 0.37 mmol),TBAF (119 mg, 0.45 mmol), PdCl2(PPh3)2 (5.3 mg, 0.007 mmol) in DMSO (2.0 mL) to afford 80 mg of the title product.1!! NMR (300 MHz, DMSO-d6): δ 10.72 (s, 1H), 8.07-8.06 (d, J = 2.4 Hz, 1H), 7.83 (s, 1H), Ί .13-1.10 (d, J = 7.8 Hz, 1H), 7.64-7.56 (m, 3H), 7.22-7.05 (m, 3H), 4.06-4.00 (t, J = 6.3 Hz, 2H), 3.01-2.96 (d, J = 7.5 Hz, 2H), 2.36 (s, 3H), 2.07 (m, 2H); MS [M+H]+: 437.
Step 2: Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-((6- methylpyridin-3-yl)oxy)propyl)benzoic acid
The title compound was prepared following the procedure described in Example- 1 using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-((6-methylpyridin-3- yl)oxy)propyl)benzonitrile (70 mg, 0.15 mmol), EtOH (5.0 mL) and 2N NaOH (5.0 mL) to afford 60 mg of title product.1H NMR (300 MHz, DMSO- 6): δ 13.10 (br s, 1H), 10.71 (s, 1H), 8.12 (s, 1H), 7.89 (s, 1H), 7.82-7.80 (d, J = 7.2Hz, 1H), 7.64-7.57 (m, 2H), 7.27 (d, 1H), 7.16 (s, 2H), 7.09-7.06 (d, J = 8.4 Hz, 1H), 4.04 (t, 2H), 3.01 (t, 2H), 2.38 (s, 3H), 2.07 (m, 2H); MS [M+H]+: 456.
Example- 80
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-((2-methylpyridin-3- yl)oxy)propyl)benzoic acid
Figure imgf000206_0002
Step 1: Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-((2- methylpyridin-3-yl)oxy)propyl)benzonitrile
Figure imgf000207_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 100 mg, 0.37 mmol), 4-iodo-3-(3-((2-methylpyridin-3-yl)oxy)propyl)benzonitrile (Intermediate-78, 143 mg, 0.37 mmol),TBAF (119 mg, 0.45 mmol), PdCl2(PPh3)2 (5.3 mg, 0.007 mmol) in DMSO (2.0 mL) to afford 70 mg of the title product.1!! NMR (300 MHz, DMSO-d6): δ 10.74 (s, 1H), 7.96-7.94 (d, = 4.5 Hz, 1H), 7.84 (s, 1H), 7.73-7.68 (t, = 7.8 Hz, 1H), 7.64-7.60 (m, 3H), 7.28-7.25 (d, J = 8.1 Hz, 1H), 7.14 (s, 1H), 7.06-7.04 (d, J = 8.4 Hz, 1H), 4.04-4.02 (t, J = 5.7 Hz, 2H), 3.03-2.98 (t, J = 7.5 Hz, 2H), 2.29 (s, 3H), 2.11 (t, 2H); MS [M+H]+: 437.
Step 2: Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-((2- methylpyridin-3-yl)oxy)propyl)benzoic acid
The title compound was prepared following the procedure described in Example- 1 using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-((2-methylpyridin-3- yl)oxy)propyl)benzonitrile (70 mg, 0.15 mmol), EtOH (5.0 mL) and 2N NaOH (5.0 mL) to afford 30 mg of title product. 1H NMR (300 MHz, DMSO- 6): δ 10.79 (s, 1H), 8.27-8.25 (d, = 8.4 Hz, 1H), 7.98 (t, 1H), 7.90 (s, 1H), 7.83-7.80 (d, J = 8.4 Hz, 1H), 7.71 (br s, 1H), 7.63- 7.58 (t, J = 9.3 Hz, 2H), 7.18 (s, 1H), 7.10-7.08 (d, J = 8.7 Hz, 1H), 4.22 (t, 2H), 3.05 (t, 2H), 2.45 (s, 3H), 2.16 (t, 2H); MS [M+H]+: 456.
Example- 81
3-(3-(Pyridin-3-yloxy)prop -4-((2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
Figure imgf000207_0002
Step 1: Preparation of ethyl 3-(3-(pyridin-3-yloxy)propyl)-4-((2- (trifluoromethyl)phenyl)ethynyl)benzoate
Figure imgf000208_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using ethyl 4-iodo-3-(3-(pyridin-3-yloxy)propyl)benzoate (Intermediate- 80, 100 mg, 0.24 mmol),l-ethynyl-2-(trifluoromethyl)benzene (Intermediate-79, 62 mg, 0.36 mmol), TBAF (76 mg, 0.29 mmol), PdCl2(PPh3)2 (4.0 mg, 0.004 mmol) in DMSO (2.0 mL) to afford 70 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.20 (s, 1H), 8.12 (s, 1H), 7.91-7.83 (m, 4H), 7.75-7.65 (m, 3H), 7.29-7.26 (m, 2H), 4.33-4.28(q, J = 7.5 Hz, 2H), 4.06-4.00 (t, J = 6.0 Hz, 2H), 3.05-3.03 (t, J = 7.5 Hz, 2H), 2.09 (t, 2H), 1.31-1.26 (t, J = 6.9 Hz, 3H).
Step 2: Preparation of 3-(3-(pyridin-3-yloxy)propyl)-4-((2-
(trifluoromethyl)phenyl)ethynyl)benzoic acid
The title compound was prepared following the procedure described in Example- 14 using ethyl 3-(3-(pyridin-3-yloxy)propyl)-4-((2-(trifluoromethyl)phenyl)ethynyl)benzoate (70 mg, 0.15 mmol) in THF+H20 (5.0+5.0 ml) and LiOH.H20 (26 mg, 0.61 mmol) to afford 55 mg of the title product.1!! NMR (300 MHz, DMSO-d6): δ 13.20 (br s, 1H), 8.22 (s, 1H), 8.12 (s, 1H), 7.93 (s, 1H), 7.86-7.83 (m, 3H), 7.76-7.74 (t, = 7.2 Hz, 1H), 7.66-7.64 (d, = 6.6 Hz, 2H), 7.31-7.29 (m, 2H), 4.09 (t, 2H), 3.06 (t, 2H), 2.10 (m, 2H); MS [M+H]+: 426.
Example- 82
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-((4-methylthiazol-2- yl)methoxy)propyl)benzoic
Figure imgf000208_0002
Step 1: Preparation of butyl 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-((4- methylthiazol-2-yl)methoxy)propyl)benzoate
Figure imgf000209_0001
The title compound was prepared following the procedure described in step-3, Intermediate- 1 using butyl 4-iodo-3-(3-((4-methylthiazol-2-yl)methoxy)propyl)benzoate (Intermediate-81, 250 mg, 0.52 mmol), 4-ethynyl-3-(trifluoromethyl)phenol (Intermediate-43, 98 mg, 0.52 mmol), Et3N (0.5 mL), PdCl2(PPh3)2 (4.0 mg, 0.004 mmol), Cul (2.0 mg, 0.01 mmol) in DMSO (2.0 mL) to afford 80 mg of the title product.1H NMR (300 MHz, DMSO-d6): δ 7.91 (s, 1H), 7.85-7.83 (d, J = 7.8 Hz, 1H), 7.55-7.48 (m, 2H), 7.18 (s, 1H), 7.00-6.98 (d, J = 7.2 Hz, 1H), 6.90 (s, 1H), 4.80 (s, 2H), 4.34-4.30 (t, J = 6.3 Hz, 2H), 3.67-3.62 (t, J = 5.7 Hz, 2H), 3.02-2.97 (t, J = 6.9 Hz, 2H), 2.45 (s, 3H), 2.03 (t, 2H, 1.77-1.72 (m, 2H), 1.51-1.43 (m, 2H), 1.0-0.95 (t, J = 7.2 Hz, 3H); MS [M+H]+: 532.
Step 2: Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-((4- methylthiazol-2-yl)methoxy)propyl)benzoic acid
The title compound was prepared following the procedure described in Example- 14 using butyl 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-((4-methylthiazol-2- yl)methoxy)propyl)benzoate (75 mg, 0.12 mmol), LiOH.H20 (25 mg, 0.59 mmol) ) in THF+H20 (5.0+5.0 ml) to afford 55 mg of the title product.1!! NMR (300 MHz, DMSO-d6): δ 7.88 (s, 1H), 7.86-7.83 (d, J = 9.6 Hz, 1H), 7.54-7.51 (d, J = 7.8 Hz, 1H), 7.47 (d, 1H), 7.06 (s, 2H), 6.80 (d, 1H), 4.99 (s, 2H), 3.68 (t, 2H), 2.98 (t, 2H), 2.55 (s, 3H), 2.02 (m, 2H); MS [M+H]+: 476.
Example- 83
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(4-hydroxybutyl)benzoic acid
Figure imgf000209_0002
Step 1: Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(4- hydroxybutyl)benzonitrile
Figure imgf000210_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 70 mg, 0.37 mmol), 3-(4-hydroxybutyl)-4-iodobenzonitrile (step-4, Intermediate-74, 113 mg, 0.37 mmol), TBAF (130 mg, 0.49 mmol), PdCl2(PPh3)2 (5.0 mg, 0.007 mmol) in DMSO (2.0 mL) to afford 50 mg of the title product.
Step 2: Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(4- hydroxybutyl)benzoic acid
The title compound was prepared following the procedure described in Example- 1 using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(4-hydroxybutyl)benzonitrile (70 mg), EtOH (5.0 mL) and 2N NaOH (5.0 mL) to afford 20 mg of title product.1H NMR (300 MHz, DMSO- 6): δ 13.10 (s, 1H), 10.68 (s, 1H), 7.85 (s, 1H), 7.80-7.78 (d, = 8.4 Hz, 1H), 7.68- 7.65 (d, = 8.4 Hz, 1H), 7.58-7.55 (d, = 7.2 Hz, 1H), 7.17 (s, 1H), 7.11-7.08 (d, = 7.8 Hz, 1H), 4.38 (t, 1H), 3.41-3.39 (m, 2H), 2.84 (t, 2H), 1.63 (m, 2H), 1.49-1.47 (m, 2H); MS [M+H]+: 379.
Example- 84
Hexyl 3-(4-ethoxybutyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoate
Figure imgf000210_0002
The title compound was prepared following the procedure described in step-3, Intermediate- 1 using hexyl 3-(4-ethoxybutyl)-4-iodobenzoate (Intermediate- 82, 100 mg, 0.53 mmol), 4- ethynyl-3-(trifluoromethyl)phenol (Intermediate-43, 100 mg, 0.53 mmol), Et3N (0.5 mL), PdCl2(PPh3)2 (7.40 mg, 0.010 mmol), Cul (2.0 mg, 0.01 mmol) in DMSO (2.0 mL) to afford 30 mg of the title product H NMR (300 MHz, DMSO- 6): δ 7.90 (s, 1H), 7.85-7.82 (d, = 7.8 Hz, 1H), 7.55-7.53 (d, = 6.0 Hz, 2H), 7.17 (s, 1H), 7.0-6.97 (d, = 9.0 Hz, 1H), 4.34- 4.29 (t, J = 6.9 Hz, 2H), 3.48-3.45 (m, 4H), 2.91-2.88 (m, 2H), 1.75 (m, 6H), 1.44-1.35 (m, 6H), 1.25 (s, 1H), 1.20-1.16 (t, / = 7.5 Hz, 2H), 0.91 (t, 3H); MS [M+H]+: 491 .
Example- 85
2-(Dimethylamino)-2-oxoethyl 3-(6-carbamoylpyridin-3-yl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoate
Figure imgf000211_0001
Step 1: Preparation of 2-(dimethylamino)-2-oxoethyl 3-(6-carbamoylpyridin-3-yl)-4-((4- ((methylsulfonyl)oxy)-2-(trifluoromethyl)phenyl)ethynyl)benzoate
Figure imgf000211_0002
The title compound was prepared following the procedure described in step-3, Intermediate- 1 using 2-(dimethylamino)-2-oxoethyl 3-(6-carbamoylpyridin-3-yl)-4-iodobenzoate (Intermediate- 83, 200 mg, 0.44 mmol), 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 116 mg, 0.44 mmol), Et3N (66.8 mg, 0.662 mmol), PdCl2(PPh3)2 (6.16 mg, 0.008 mmol), Cul (1.67 mg, 0.008 mmol) in DMSO (3.0 mL) to afford 100 mg of the title product.1!! NMR (300 MHz, DMSO-d6): δ 8.86 (s, 1H), 8.23-8.18 (m, 2H), 8.15-8.11 (m, 3H), 7.95-7.74 (m, 3H), 5.09 (s, 2H), 3.49 (s, 3H), 2.99 (s, 3H), 2.84 (s, 3H); MS [M+H]+: 590. Step 2: Preparation of 2-(dimethylamino)-2-oxoethyl 3-(6-carbamoylpyridin-3-yl)-4-((4- hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoate
To a solution of 2-(dimethylamino)-2-oxoethyl 3-(6-carbamoylpyridin-3-yl)-4-((4- ((methylsulfonyl)oxy)-2-(trifluoromethyl)phenyl)ethynyl)benzoate (90 mg, 0.15 mmol) in THF (2.0 mL) was added 1M TBAF solution in THF (1.0 mL). The reaction mixture was stirred at rt for 2 h. The reaction mixture was quenched in water and extracted with DCM. The organic layers were concentrated to afford 39 mg of title compound. 1H NMR (300 MHz, DMSO-d6): δ 10.74 (s, 1H), 8.84 (s, 1H), 8.26 (m, 2H), 8.23-8.07 (m, 3H), 7.85-7.82 (d, J = 8.4 Hz, 1H), 7.72 (s, 1H), 7.45-7.42 (d, 7 = 8.1 Hz, 1H), 7.10 (s, 1H), 7.06-7.04 (d, J = 7.8 Hz, 1H), 5.08 (s, 2H), 2.98 (s, 3H), 2.84 (s, 3H); MS [M+H]+: 512.
Example- 86
Hexyl 3-(3-ethoxypropyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoate
Figure imgf000212_0001
The title compound was prepared following the procedure described in in step-3, Intermediate- 1 using 4-ethynyl-3-(trifluoromethyl)phenol (Intermediate-43, 60 mg, 0.32 mmol), hexyl 3-(3-ethoxypropyl)-4-iodobenzoate (Intermediate-84, 130 mg, 0.32 mmol), TBAF (88 mg, 0.34 mmol), PdCl2(PPh3)2 (5.0 mg, 0.007 mmol) in DMSO (2.0 mL) to afford 20 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 7.92 (s, 1H), 7.86-7.83 (d, = 8.4Hz, 1H), 7.56-7.53 (t, J = 7.8 Hz, 1H), 7.46 (m, 1H), 7.26 (s, 1H), 7.17 (s, 1H), 7.00 (t, 1H), 4.34-4.29 (t, 2H), 3.52-3.47 (m, 4H), 2.97-2.95 (t, J = 7.8 Hz, 2H), 1.98 (m, 2H), 1.79- 1.77 (m, 2H), 1.44- 1.35 (m, 6H), 1.25 (s, 1H), 1.23-1.18 (t, J = 6.6 Hz, 2H), 0.91 (s, 3H); MS [M-H]": 475.
Example- 87
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(3-methyl- lH-pyrazol-l- yl)propyl)benzoic acid
Figure imgf000212_0002
Step 1 : Preparation of 4-((4-cyano-2-(3-(3-methyl- lH-pyrazol- l-yl)propyl)phenyl)ethynyl)-3- (trifluoromethyl)phenyl methanesulfonate
Figure imgf000212_0003
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using 4-iodo-3-(3-(3-methyl-lH-pyrazol-l-yl)propyl)benzonitrile (Intermediate-85, 110 mg, 0.31 mmol), 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 76 mg, 0.31 mmol), Et3N (46 mg, 0.46 mmol), PdCl2(PPh3)2 (4.3 mg, 0.006 mmol), Cul (1.17 mg, 0.006 mmol) in DMSO (3.0 mL) at rt for 16 h to afford 40 mg of the title product.1H NMR (300 MHz, DMSO-d6): δ 7.95-7.93 (d, = 7.8 Hz, 2H), 7.50-7.44 (m,3H), 7.18-7.15 (d, = 7.8 Hz, 2H), 6.13 (m, 1H), 4.23 (br s, 2H), 2.77 (m, 2H), 2.35 (s, 3H), 2.19 (m, 2H), 1.88 (m, 3H).
Step 2: Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(3-methyl- lH- pyrazol- 1 -yl)propyl)benzonitril
Figure imgf000213_0001
The title compound was prepared following the procedure described in step-2 of Example-85 by using 4-((4-cyano-2-(3-(3-methyl- lH-pyrazol-l-yl)propyl)phenyl)ethynyl)-3-
(trifluoromethyl)phenyl methanesulfonate (70 mg), 1M TBAF solution in THF (1.0 mL) in THF (2.0 mL) to afford 35 mg of title compound.
Step 3: Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(3-methyl- lH- pyrazol- l-yl)propyl)benzoic acid
The title compound was prepared following the procedure described in Example- 1 using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(3-methyl- lH-pyrazol-l- yl)propyl)benzonitrile (50 mg), EtOH (3.0 mL), 2N NaOH (3.0 mL) to afford 20 mg of title product. 1H NMR (300 MHz, DMSO- 6): δ 13- 12 (br s, 1H), 10.71 (s, 1H), 7.83 (m, 2H), 7.59 (m, 3H), 7.17 (m, 2H), 5.95 (d, 1H), 4.04 (d, 1H), 2.81 (s, 1H), 2.10 (m, 3H), 1.22 (m, 2H); MS [M+H]+: 429.
Example- 88
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(4-methyl- lH-pyrazol-l- yl)propyl)benzoic acid
Figure imgf000213_0002
Step 1 : Preparation of 4-((4-cyano-2-(3-(4-methyl- lH-pyrazol- l-yl)propyl)phenyl)ethynyl)-3- (trifluoromethyl)phenyl methanesulfonate
Figure imgf000214_0001
The title compound was prepared following the procedure described in step-3, Intermediate- 1 using 4-iodo-3-(3-(4-methyl-lH-pyrazol-l-yl)propyl)benzonitrile (Intermediate- 86, 110 mg, 0.31 mmol), 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 76 mg, 0.31 mmol), Et3N (46 mg, 0.46 mmol), PdCl2(PPh3)2 (4.3 mg, 0.006 mmol), Cul (1.17 mg, 0.006 mmol) in DMSO (3.0 mL) at rt for 16 h to afford 20 mg of the title product.1H NMR (300 MHz, DMSO-d6): δ 7.98-7.95 (d, = 8.7 Hz, IH), 7.85-7.68 (m, 5H), 7.46 (s, IH), 7.17 (s, IH), 4.07 (m, 2H), 3.52 (s, 3H), 2.82 (t, 2H), 2.11 (m, 2H), 1.99 (s, 3H)
Step 2: Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(4-methyl- lH- pyrazol- l-yl)propyl)benzoic acid
The title compound was prepared following the procedure described in Example- 1 using 4- ((4-cyano-2-(3-(4-methyl- lH-pyrazol- l-yl)propyl)phenyl)ethynyl)-3-(trifluoromethyl)phenyl methanesulfonate (75 mg), EtOH (3.0 mL), 2N NaOH (3.0 mL) to afford 12 mg of title product.1!! NMR (300 MHz, DMSO- 6): δ 13-12 (s, IH), 10.73 (s, IH), 7.85-7.80 (m, 2H), 7.64-7.58 (m, 2H), 7.46 (s, IH), 7.20-7.12 (m, 3H), 4.07(t, 2H), 2.81 (t, 2H), 2.09 (m, 2H), 1.96 (s, 3H); MS [M+H]+: 429.
Example- 89
3-(3-(lH-pyrazol- l-yl)propyl -4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
Figure imgf000214_0002
Step 1 : Preparation 4-((2-(3-(lH-pyrazol- l-yl)propyl)-4-cyanophenyl)ethynyl)-3- (trifluoromethyl)phenyl methanesulfonate
Figure imgf000215_0001
The title compound was prepared following the procedure described in step-3, Intermediate- 1 using 3-(3-(lH-pyrazol-l-yl)propyl)-4-iodobenzonitrile (Intermediate-87, 110 mg, 0.31 mmol), 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 80 mg, 0.32 mmol), Et3N (48.5 mg, 0.48 mmol), PdCl2(PPh3)2 (4.59 mg, 0.006 mmol), Cul (1.21 mg, 0.006 mmol) in DMSO (3.0 mL) at rt for 16 h to afford 80 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 7.93 (m, IH), 7.75-7.72 (d, 7 = 8.1 Hz, IH), Ί .62-1.59 (d, 7 = 8.7 Hz, IH), 7.54-7.49 (t, 7 = 7.8 Hz, 2H), 7.43-7.38 (m, 2H), 7.16-7.14 (d, 7 = 6.3 Hz, IH), 6.24 (s, IH), 4.24-4.19 (t, 7 = 6.9 Hz, 2H), 3.26 (s, 3H), 2.90-2.84 (t, 7 = 8.4 Hz, 2H), 2.26 (m, 2H). Step 2: Preparation of 3-(3-(lH-pyrazol-l-yl)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoic acid
The title compound was prepared following the procedure described in Example- 1 using 4- ((2-(3-(lH-pyrazol-l-yl)propyl)-4-cyanophenyl)ethynyl)-3-(trifluoromethyl)phenyl methanesulfonate (60 mg), EtOH (3.0 mL), 2N NaOH (3.0 mL) to afford 15 mg of title product.1!! NMR (300 MHz, DMSO-d6): δ 13-12 (m, IH), 10.70 (s, IH), 7.84-7.79 (m, 2H), 7.71 (s, IH), 7.63-7.60 (d, 7 = 8.4 Hz, IH), 7.57-7.54 (d, 7 = 8.7 Hz, IH), 7.41 (s, IH), 7.16 (s, IH), 7.11 (m, IH), 6.21 (s, IH), 4.15 (t, 2H), 2.81 (t, 2H), 2.11 (t, 2H); MS [M+H]+: 415.
Example- 90
3-(3-(2,6-Dichlorophenoxy)propyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
Figure imgf000215_0002
Step 1: Preparation of 4-((4-cyano-2-(3-(2,6-dichlorophenoxy)propyl)phenyl)ethynyl)-3- (trifluoromethyl)phenyl methanesulfonate
Figure imgf000216_0001
The title compound was prepared following the procedure described in step-3, Intermediate- 1 using 3-(3-(2,6-dichlorophenoxy)propyl)-4-iodobenzonitrile (Intermediate-88, 141 mg, 0.32 mmol), 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 80 mg, 0.32 mmol), Et3N (48.5 mg, 0.48 mmol), PdCl2(PPh3)2 (4.59 mg, 0.006 mmol), Cul (1.21 mg, 0.006 mmol) in DMSO (3.0 mL) at rt for 16 h to afford 75 mg of the title product. 1H NMR (300 MHz, DMSO- 6): δ 7.81-7.78 (d, J = 8.4 Hz, 1H), 7.68-7.45 (m, 4H), 7.31-7.26 (m, 3H), 7.03-6.97 (t, = 7.8 Hz, 1H), 4.10-4.07 (t, = 8.4 Hz, 2H), 3.23-3.17 (m, 5H), 2.24-2.19 (m, 2H).
Step 2: Preparation of 3-(3-(2,6-dichlorophenoxy)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoic acid
The title compound was prepared following the procedure described in Example- 1 using 4- ((4-cyano-2-(3-(2,6-dichlorophenoxy)propyl)phenyl)ethynyl)-3-(trifluoromethyl)phenyl methanesulfonate (60 mg), EtOH (3.0 mL), 2N NaOH (3.0 mL) to afford 15 mg of title product. 1H NMR (300 MHz, DMSO- 6): δ 13.13 (br s, 1H), 10.70 (s, 1H), 7.95 (s, 1H), 7.83- 7.81 (d, = 7.8 Hz, 1H), 7.68-7.65 (d, = 8.4 Hz, 1H), 7.60-7.58 (d, = 7.8 Hz, 1H), 7.49- 7.46 (d, = 8.1 Hz, 2H), 7.16 (s, 2H), 7.06 (m, 1H), 4.03 (t, 2H), 3.06 (t, 2H), 2.13 (m 2H); MS [M+H]+: 507.
Example- 91
4-((2-Chloro-4-hydroxyphenyl)ethynyl)-3-(3-((2-methylpyridin-3-yl)oxy)propyl)benzoic acid
Figure imgf000216_0002
Step 1: Preparation of 4-((2-chloro-4-hydroxyphenyl)ethynyl)-3-(3-((2-methylpyridin-3- yl)oxy)propyl)benzonitrile
Figure imgf000217_0001
The title compound was prepared following the procedure described in step-3, Intermediate- 1 using 4-iodo-3-(3-((2-methylpyridin-3-yl)oxy)propyl)benzonitrile (Intermediate-78, 164 mg, 0.43 mmol), 3-chloro-4-ethynylphenyl methanesulfonate (Intermediate- 89, 100 mg, 0.43 mmol), TBAF (136 mg, 0.52 mmol), PdCl2(PPh3)2 (6.0 mg, 0.008 mmol) in DMSO (3.0 mL) at 90-100°C for 2 h to afford 80 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.54 (s, 1H), 7.96 (d, 1H), 7.85 (s, 1H), 7.70-7.58 (m, 2H), 7.50-7.47 (d, = 8.1 Hz, 1H), 7.28-7.25 (d, J = 8.1 Hz, 1H), 7.12 (m, 1H), 6.95(s, 1H), 6.81-6.78 (d, J = 8.1 Hz, 1H), 4.04 (t, 2H), 3.06 (t, 2H), 2.25 (s, 3H), 2.15 (m, 2H); MS [M+H]+: 403.
Step 2: Preparation of 4-((2-chloro-4-hydroxyphenyl)ethynyl)-3-(3-((2-methylpyridin-3- yl)oxy)propyl)benzoic acid
The title compound was prepared following the procedure described in Example- 1 using 4- ((2-chloro-4-hydroxyphenyl)ethynyl)-3-(3-((2-methylpyridin-3-yl)oxy)propyl)benzonitrile (70 mg, 0.17 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) to afford 40 mg of title product. 1H NMR (300 MHz, DMSO- 6): δ 10.59 (s, 1H), 8.25 (d, 1H), 7.95-7.90 (m, 2H), 7.81-7.79 (s, 1H), 7.68 (m, 1H), 7.61-7.59 (d, J = 7.8 Hz, 1H), 7.48-7.45 (d, J = 8.7 Hz, 1H), 6.96 (s, 1H), 6.82-6.79 (d, = 8.7 Hz, 1H), 4.22 (t, 2H), 2.18 (t, 2H), 2.49 (s, 3H), 2.18 (m, 2H); MS [M+H]+: 422.
Example- 92
3-(3-(lH- l,2,3-triazol- l-yl)propyl)-4-((2-chloro-4-hydroxyphenyl)ethynyl)benzoic acid
Figure imgf000217_0002
Step 1 : Preparation of 3-(3-(lH-l,2,3-triazol- l-yl)propyl)-4-((2-chloro-4- hydroxyphenyl)ethynyl)benzonitrile
Figure imgf000218_0001
The title compound was prepared following the procedure described in step-3, Intermediate- 1 using 3-(3-(lH-l,2,3-triazol-l-yl)propyl)-4-iodobenzonitrile (step-1, Intermediate-58, 147 mg, 0.43 mmol), 3-chloro-4-ethynylphenyl methanesulfonate (Intermediate- 89, 100 mg, 0.43 mmol), TBAF (136 mg, 0.52 mmol), PdCl2(PPh3)2 (6.0 mg, 0.008 mmol) in DMSO (3.0 mL) at 90-100°C for 2 h to afford 80 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.55 (s, 1H), 7.79-7.62 (m, 5H), 7.51-7.48 (d, J = 8.4 Hz, 1H), 6.94 (s, 1H), 6.84-6.81 (d, J = 8.4 Hz, 1H), 4.48-4.46 (t, J = 6.3 Hz, 2H), 2.85 (t, 2H), 2.24 (m, 2H); MS [M+H]+: 363.
Step 2: Preparation of 3-(3-(lH-l,2,3-triazol-l-yl)propyl)-4-((2-chloro-4- hydroxyphenyl)ethynyl)benzoic acid
The title compound was prepared following the procedure described in Example-1 using 3-(3- ( 1H- 1 ,2,3-triazol- 1 -yl)propyl)-4-((2-chloro-4-hydroxyphenyl)ethynyl)benzonitrile (80 mg, 0.22 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) to afford 35 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 13.09 (br s, 1H), 10.55 (br s, 1H), 7.87 (s, 1H), 7.82-7.79 (d, J = 8.4 Hz, 2H), 7.75 (s, 1H), Ί .60-1.51 (d, = 8.4 Hz, 1H), 7.50-7.48 (t, = 8.1 Hz, 1H), 6.98 (s, 1H), 6.84-6.81 (d, / = 8.4 Hz, 1H),4.48 (t, 2H), 2.87 (t, 2H), 2.24 (t, 2H); MS [M+H]+: 382.
Example-93
3-(3-(lH-l,2,4-triazol-l-yl)propyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
Figure imgf000218_0002
Step 1: Preparation of 3-(3-(lH-l,2,4-triazol-l-yl)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzonitrile
Figure imgf000218_0003
The title compound was prepared following the procedure described in step-3, Intermediate- 1 using 3-(3-(lH-l,2,4-triazol- l-yl)propyl)-4-iodobenzonitrile (Intermediate- 90, 90 mg, 0.26 mmol), 4-ethynyl-3-(trifluoromethyl)phenol (Intermediate-43 , 70 mg, 0.26 mmol), TBAF (83 mg, 0.31 mmol), PdCl2(PPh3)2 (4.0 mg, 0.0051 mmol) in DMSO (2.0 mL) in DMSO (2.0 ,L) to afford 70 mg title product. Η NMR (300 MHz, DMSO- 6): δ 10.77 (s, IH), 8.5 l(s, IH), 7.92 (s, IH), 7.82 (s, IH), 7.71 (d, IH), 7.63-7.62 (t, 2H), 7.17 (s, IH), 7.12 (d, 2H), 4.21 (t, 2H), 2.82 (t, 2H), 2.14 (t, 2H); MS [M-H]~: 395.
Step 2: Preparation of 3-(3-(lH-l,2,4-triazol- l-yl)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoic acid
The title compound was prepared following the procedure described in Example- 1 using 3- (3-( IH- 1 ,2,4-triazol- 1 -yl)propyl)-4-((4-hydroxy-2-
(trifluoromethyl)phenyl)ethynyl)benzonitrile (60 mg, 0.22 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) to afford 40 mg of title product.1H NMR (300 MHz, DMSO- 6): δ 14- 13 (s, IH), 10.71 (s, IH), 8.51 (s, IH), 7.93 (s, IH), 7.86 (s, IH), 7.82-7.79 (d, J = 7.8 Hz, IH), 7.63-7.55 (m, 2H), 7.16 (s, IH), 7.1 1 (d, IH), 4.22 (t, 2H), 2.83 (t, 2H), 2.14 (t, 2H); MS [M+H]+: 416.
Example- 94
4-((2-Chloro-4-hydroxyphenyl)ethynyl)-3-(3-(2-methyl- lH-imidazol- l-yl)propyl)benzoic acid
Figure imgf000219_0001
Step 1 : Preparation of 4-((2-chloro-4-hydroxyphenyl)ethynyl)-3-(3-(2-methyl-lH-imidazol-l- yl)propyl)benzonitrile
Figure imgf000219_0002
The title compound was prepared following the procedure described in step-3, Intermediate- 1 using 4-iodo-3-(3-(2-methyl-lH-imidazol- l-yl)propyl)benzonitrile (step- 1, Intermediate-62, 152 mg, 0.53 mmol), 3-chloro-4-ethynylphenyl methanesulfonate (Intermediate- 89 , 100 mg, 0.53 mmol), TBAF (136 mg, 0.52 mmol), PdCl2(PPh3)2 (6.0 mg, 0.0086 mmol) in DMSO (3.0 mL) at 90- 100°C for 2 h to afford 85 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.60 (br s, IH), 7.82 (s, IH), 7.70 (m, IH), 7.66 (m, IH), 7.50-7.47 (d, J = 8.1 Hz, IH), 7.06 (s, IH), 6.95 (s, IH), 6.84 (d, IH), 6.73 (s, IH), 3.93 (t, 2H), 2.87 (m, 2H), 2.22 (s, 3H), 2.04 (m, 2H); MS [M+H]+: 376.
Step 2: Preparation of 4-((2-chloro-4-hydroxyphenyl)ethynyl)-3-(3-(2-methyl-lH-imidazol-l- yl)propyl)benzoic acid
The title compound was prepared following the procedure described in Example- 1 using 4- ((2-chloro-4-hydroxyphenyl)ethynyl)-3-(3-(2-methyl- lH-imidazol- l-yl)propyl)benzonitrile (80 mg, 0.22 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) to afford 40 mg of title product. 1H NMR (300 MHz, DMSO- 6): δ 14-13 (br s, IH), 10.66 (s, IH), 7.90 (m, IH), 7.83-7.80 (d, = 7.8 Hz, IH), 7.66 (s, IH), 7.62-7.59(d, = 8.4 Hz, IH), 7.52-7.49 (m, 2H), 7.01 (s, IH), 6.87-6.84 (d, = 8.1 Hz, IH), 4.16 (t, 2H), 2.94 (t, 2H), 2.54 (s, 3H), 2.17 (m, 2H); MS [M+H]+: 396.
Example-95
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(pyridin-4-yloxy)propyl)benzoic acid
Figure imgf000220_0001
Step 1 : Preparation of 4-((4-cyano-2-(3-(pyridin-4-yloxy)propyl)phenyl)ethynyl)-3- (trifluoromethyl)phenyl methanesulfonate
Figure imgf000220_0002
The title compound was prepared following the procedure described in step-3, Intermediate- 1 using 4-iodo-3-(3-(pyridin-4-yloxy)propyl)benzonitrile (Intermediate-91, 1 16 mg, 0.32 mmol), 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 80 mg, 0.32 mmol), Et3N (48.5 mg, 0.48 mmol), PdCl2(PPh3)2 (4.59 mg, 0.006 mmol), Cul (1.21 mg, 0.006 mmol) in DMSO (3.0 mL) at rt for 16 h to afford 50 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 7.72-7.69(d, = 9.0 Hz, 1H), 7.65-7.48 (m, 7H), 6.49-6.47 (d, = 8.1 Hz, 2H), 4.03-3.99 (t, / = 6.6 Hz, 2H), 3.32 (s, 3H), 2.96-2.90 (t, / = 7.2 Hz, 2H), 2.17 (m, 2H).
Step 2: Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(pyridin-4- yloxy)propyl)benzoic acid
The title compound was prepared following the procedure described in Example- 1 using 4- ((4-cyano-2-(3-(pyridin-4-yloxy)propyl)phenyl)ethynyl)-3-(trifluoromethyl)phenyl methanesulfonate (87 mg, 0.22 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) to afford 30 mg of title product. 1H NMR (300 MHz, DMSO- 6): δ 7.85 (br s, 1H), 7.84 (m, 1H), 7.66-7.64 (d, = 7.2 Hz, 2H), 7.54 (t, 2H), 7.17 (m, 2H), 6.04 (m, 2H), 3.92 (t, 2H), 2.81 (m, 2H), 2.02 (m, 2H); MS [M+H]+: 442.
Example-96
3-(3-(2-Chlorophenoxy)propyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
Figure imgf000221_0001
Step 1: Preparation of 4-((2-(3-(2-chlorophenoxy)propyl)-4-cyanophenyl)ethynyl)-3- (trifluoromethyl)phenyl methanesulfonate
Figure imgf000221_0002
The title compound was prepared following the procedure described in step-3, Intermediate- 1 using 3-(3-(2-chlorophenoxy)propyl)-4-iodobenzonitrile (Intermediate-92, 100 mg, 0.25 mmol), 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 61 mg, 0.25 mmol), Et3N (48.5 mg, 0.48 mmol), PdCl2(PPh3)2 (3.5 mg, 0.005 mmol), Cul (0.95 mg, 0.005 mmol) in DMSO (3.0 mL) at rt for 16 h to afford 45 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 7.76-7.73 (d, = 9.0 Hz, 1H), 7.61 (s, 3H), 7.53-7.51 (t, = 7.8 Hz, 2H), 7.36-7.33 (d, = 8.4 Hz, 1H), 7.19 (t, 1H), 6.91-6.88 (m, 2H), 4.09-4.05 (t, = 5.4 Hz, 2H), 3.25 (s, 3H), 3.17-3.12 (t, = 7.8 Hz, 2H), 2.23 (m, 2H). Step 2: Preparation of 3-(3-(2-chlorophenoxy)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoic acid
The title compound was prepared following the procedure described in Example- 1
((2-(3-(2-chlorophenoxy)propyl)-4-cyanophenyl)ethynyl)-3-(trifluoromethyl)phenyl methanesulfonate (60 mg, 0.11 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) to afford 25 mg of title product. 1H NMR (300 MHz, DMSO- 6): δ 13.09 (s, 1H), 10.69 (s, 1H), 7.89 (s, 1H), 7.82-7.80 (d, = 7.8 Hz, 1H), 7.65-7.57 (m, 2H), 7.40-7.38 (d, = 7.8 Hz, 1H), 7.25 (t, 1H), 7.12-7.09 (m, 3H), 6.95-6.92 (t, J = 7.2 Hz, 1H), 4.09 (t, 2H), 3.04 (t, 2H), 2.11 (m, 2H); MS [M+H]+: 476.
Example-97
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(2-(pyridin-3-yl)ethyl)benzoic acid
Figure imgf000222_0001
The title compound was prepared following the procedure described in step-3, Intermediate- 1 using 4-iodo-3-(2-(pyridin-3-yl)ethyl)benzonitrile (Intermediate-93, 100 mg, 0.29 mmol), 4- ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 71 mg, 0.29 mmol), Et3N (44.0 mg, 0.43 mmol), PdCl2(PPh3)2 (4.0 mg, 0.005 mmol), Cul (0.95 mg, 0.005 mmol) in DMSO (3.0 mL) at rt for 16 h to afford 55 mg of the title product.1H NMR (300 MHz, DMSO- 6): δ 8.08-7.99 (m, 2H), 7.87-7.85 (d, = 6.3 Hz, 1H), 7.79-7.70 (m, 3H), 7.62-7.58 (m, 3H), 7.41-7.39 (d, J = 6.3 Hz, 1H), 3.33 (s, 3H), 3.17 (m, 2H), 2.99 (m, 2H); MS [M+H]+: 471.
Step 2: Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(2-(pyridin-3- yl)ethyl)benzoic acid The title compound was prepared following the procedure described in Example- 1 using 4- ((4-cyano-2-(2-(pyridin-3-yl)ethyl)phenyl)ethynyl)-3-(trifluoromethyl)phenyl
methanesulfonate (80 mg, 0.17 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) to afford 12 mg of title product. 1H NMR (300 MHz, DMSO- 6): δ 10.83 (s, 1H), 8.65 (s, 2H), 8.11 (d, 1H), 7.88 (s, 1H), 7.84-7.81 (d, = 7.8 Hz, 1H), 7.74 (t, 2H), 7.68-7.65 (d, = 8.4 Hz, 1H), 7.60- 7.57 (d, J = 7.8 Hz, 1H), 7.19 (s, 1H), 7.13 (d, 1H), 3.21 (m, 2H), 3.10 (m, 2H); MS [M+H]+: 412.
Example- 98
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(3-methoxyphenoxy)propyl)benzoic acid
Figure imgf000223_0001
Step 1: Preparation of 4-((4-cyano-2-(3-(3-methoxyphenoxy)propyl)phenyl)ethynyl)-3- (trifluoromethyl)phenyl methanesulfonate
Figure imgf000223_0002
The title compound was prepared following the procedure described in step-3, Intermediate- 1 using 4-iodo-3-(3-(3-methoxyphenoxy)propyl)benzonitrile (Intermediate-94, 130 mg, 0.33 mmol), 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 80 mg, 0.33 mmol), Et3N (50 mg, 0.43 mmol), PdCl2(PPh3)2 (4.6 mg, 0.006 mmol), Cul (1.2 mg, 0.006 mmol) in DMSO (3.0 mL) at rt for 16 h to afford 62 mg of the title product H NMR (300
MHz, DMSO-d6): δ 7.73-7.70 (d, J = 8.7 Hz, 1H), 7.63-7.58 (t, J = 7.8 Hz, 3H), 7.53-7.47 (d, = 7.8 Hz, 2H), 7.19-7.13 (t, = 7.8 Hz, 1H) 6.51-6.43 (m, 3H), 4.01-3.97 (t, = 6.0 Hz, 2H), 3.77 (s, 3H), 3.24 (s, 3H), 3.10-3.05 (t, = 7.2 Hz, 2H), 2.16 (m, 2H). Step 2: Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(3- methoxyphenoxy)propyl)benzoic acid
The title compound was prepared following the procedure described in Example- 1 using 4- ((4-cyano-2-(3-(3-methoxyphenoxy)propyl)phenyl)ethynyl)-3-(trifluoromethyl)phenyl methanesulfonate (80 mg, 0.15 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) to afford 15 mg of title product. 1H NMR (300 MHz, DMSO- 6): δ 13.0 (br s, 1H), 10.70 (s, 1H), 8.61 (s, 1H), 7.89 (s, 1H), 7.80 (d, 1H), 7.66-7.63 (d, = 8.7 Hz, 1H), 7.60-7.57 (d, = 8.1 Hz, 1H), 7.16- 7.05 (m, 2H), 6.54-6.42 (m, 3H), 3.98 (t, 2H), 3.69 (s, 3H), 3.00 (m, 2H), 2.06 (m, 2H); MS [M+H]+: 470.
Example-99
3-(3-(2,6-Difluorophenoxy)propyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
Figure imgf000224_0001
Step 1: Preparation of 4-((4-cyano-2-(3-(2,6-difluorophenoxy)propyl)phenyl)ethynyl)-3- (trifluoromethyl)phenyl methanesulfonate
Figure imgf000224_0002
The title compound was prepared following the procedure described in step-3, Intermediate- 1 using 3-(3-(2,6-difluorophenoxy)propyl)-4-iodobenzonitrile (Intermediate-95, 130 mg, 0.32 mmol), 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 80 mg, 0.32 mmol), Et3N (50 mg, 0.43 mmol), PdCl2(PPh3)2 (4.6 mg, 0.006 mmol), Cul (1.2 mg, 0.006 mmol) in DMSO (3.0 mL) at rt for 16 h to afford 56 mg of the title product. 1H NMR (300 MHz, DMSO- 6): δ 7.78-7.75 (d, = 8.1 Hz, 1H), 7.61 (m, 3H), 7.53-7.50 (m, 2H), 6.92-6.90 (m, 3H), 4.16 (t, 2H), 3.24 (s, 3H), 3.13 (t, 2H), 2.13 (m, 2H).
Step 2: Preparation of 3-(3-(2,6-difluorophenoxy)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoic acid The title compound was prepared following the procedure described in Example- 1 using 4- ((4-cyano-2-(3-(2,6-difluorophenoxy)propyl)phenyl)ethynyl)-3-(trifluoromethyl)phenyl methanesulfonate (65 mg, 0.12 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) to afford 18 mg of title product.1H NMR (300 MHz, DMSO- 6): δ 10.08 (br s,lH), 7.89 (s, 1H), 7.81 (br s, lH),7.60-7.57 (m, 3H), 7.18-7.10 (m, 4H), 4.13 (m, 2H), 3.00 (m, 2H), 2.04 (m, 2H); MS [M+H]+: 477.
Example- 100
3-(3-((5-Fluoropyridin-3-yl)oxy)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoic acid
Figure imgf000225_0001
Step 1: Preparation of 3-(3-((5-fluoropyridin-3-yl)oxy)propyl)-4-((4-hydroxy-2-
(trifluoromethyl)phenyl)ethynyl)benzonitrile
Figure imgf000225_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using 3-(3-((5-fluoropyridin-3-yl)oxy)propyl)-4-iodobenzonitrile (Intermediate-96, 230 mg, 0.53 mmol), 4-ethynyl-3-(trifluoromethyl)phenol (Intermediate-43 , 100 mg, 0.53 mmol), TBAF (180 mg, 0.68 mmol), PdCl2(PPh3)2 (7.4 mg, 0.01 mmol) in DMSO (3.0 mL) at 90- 100°C for 2 h to afford 75 mg of the title product. 1H NMR (300 MHz, DMSO- 6): δ 10.76 (s, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.6 (s, 1H), 7.75-7.72 (d, J = 7.8 Hz, 1H), 7 '.65-7 '.63 (m, 2H), 7.37-7.33 (d, = 10.8 Hz, 1H), 7.15 (s, 1H), 7.09-7.05 (d, = 9.9 Hz, 1H), 4.11-4.07 (t, = 6.3 Hz, 2H), 3.00 (t, 2H), 2.10 (m, 2H).
Step 2: Preparation of 3-(3-((5-fluoropyridin-3-yl)oxy)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoic acid The title compound was prepared following the procedure described in Example-1 using 3-(3- ((5-fluoropyridin-3-yl)oxy)propyl)-4-((4-hydroxy-2-
(trifluoromethyl)phenyl)ethynyl)benzonitrile (50 mg, 0.11 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) to afford 18 mg of title product.1H NMR (300 MHz, DMSO- 6): δ 10.78 (br s, 1H), 8.15-8.13 (d, J = 6.3 Hz, 2H), 7.89 (s, 1H), 7.83-7.80 (d, J = 8.4 Hz, 1H), 7.64-7.57 (m, 2H), 7.41-7.37 (d, / = 11.1 Hz, 1H), 7.17 (s, 1H), 7.10-7.07 (d, J = 9.0 Hz, 1H), 4.10 (t, 2H), 3.02 (t, 2H), 2.09 (m, 2H); MS [M+H]+: 460.
Example- 101
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-isobutyramidopropyl)benzoic acid
Figure imgf000226_0001
Step 1: Preparation of ethyl 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3- isobutyramidopropyl)benzoat
Figure imgf000226_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using ethyl 4-iodo-3-(3-isobutyramidopropyl)benzoate (Intermediate-97,100 mg, 0.24 mmol), 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30 , 60 mg, 0.24 mmol), TBAF (94 mg, 0.36 mmol), PdCl2(PPh3)2 (3.36 mg, 0.004 mmol) in DMSO (5.0 mL) at 90-100 °C for 2 h to afford 55 mg of the title product.
Step 2: Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3- isobutyramidopropyl)benzoic acid
The title compound was prepared following the procedure described in Example- 14 using ethyl 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-isobutyramidopropyl)benzoate (50 mg, 0.10 mmol) in THF+H20 (5.0+5.0 ml) and LiOH.H20 (26 mg, 0.61 mmol) to afford 55 mg of the title product.1!! NMR (300 MHz, DMSO- 6): δ 13.13 (br s, 1H), 10.73 (s, 1H), 7.87 (s, 1H), 7.78 (d, 1H), 7.70 (d, 1H) 7.58-7.55 (d, / = 9.0 Hz, 1H), 7.17 (s, 1H), 7.11 (d, 1H), 3.08 (m, 2H), 2.83 (m, 2H), 2.31 (m, 1H), 1.73 (m, 2H),0.97-0.95 (d, J = 6.3 Hz, 6H) ; MS [M+H]+: 434
Example- 102
Ethyl 4-((2-chloro-4-hydroxyphenyl)ethynyl)-3-(6-cyanopyridin-3-yl)benzoate
Figure imgf000227_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using ethyl 3-(6-cyanopyridin-3-yl)-4-iodobenzoate (step-3, Intermediate-53, 328 mg, 0.86 mmol), 3-chloro-4-ethynylphenyl methanesulfonate (Intermediate- 89 , 200 mg, 0.86 mmol), TBAF (273 mg, 1.04 mmol), PdCl2(PPh3)2 (12 mg, 0.017 mmol) in DMSO (5.0 mL) at 90- 100°C for 2 h to afford 150 mg of the title product.1H NMR (300 MHz, DMSO-d6): δ 10.55 (s, 1H), 9.02 (s, 1H), 8.36-8.34 (d, J = 8.1 Hz, 1H), 8.21-8.18 (d, J = 7.8 Hz, 1H), 8.08 (s, 2H), 7.86-7.84 (d, J = 7.8 Hz, 1H), 7.37-7.34 (d, J = 8.4 Hz, 1H), 6.90 (s, 1H), 6.79-6.76 (d, J = 8.7 Hz, 1H), 4.36-4.34 (q, = 6.9Hz, 2H), 1.35-1.31 (t, 7 = 6.9 Hz, 3H)
Example- 103
4-((2-Chloro-4-hydroxyphenyl)ethynyl)-3-(6-cyanopyridin-3-yl)benzoic acid
Figure imgf000227_0002
The title compound was prepared following the procedure described in Example- 14 using ethyl 4-((2-chloro-4-hydroxyphenyl)ethynyl)-3-(6-cyanopyridin-3-yl)benzoate (Example- 102, 60 mg, 0.14 mmol) in THF+H20 (5.0+5.0 ml) and LiOH.H20 (26 mg, 0.61 mmol) to afford 25 mg of the title product.1H NMR (300 MHz, DMSO-d6): δ 13.37 (s, 1H), 10.55 (s, 1H), 9.01 (s, 1H), 8.35-8.33 (d, J = 6.0 Hz, 1H), 8.19-8.17 (d, J = 8.7 Hz, 1H), 8.03 (m, 2H), 7.84- 7.81 (d, = 8.7 Hz, 1H), 7.36-7.33 (d, = 8.1 Hz, 1H), 6.88 (s, 1H), 6.78-6.75 (d, = 8.7 Hz, 1H)
Example- 104
3-(3-(lH-l,2,4-triazol-l-yl)propyl)-4-((2-chloro-4-hydroxyphenyl)ethynyl)benzoic acid
Figure imgf000228_0001
Step 1 : Preparation of 3-(3-(lH-l,2,4-triazol- l-yl)propyl)-4-((2-chloro-4- hydroxyphenyl)ethynyl)benzonitrile
Figure imgf000228_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using 3-(3-(lH- l,2,4-triazol- l-yl)propyl)-4-iodobenzonitrile (Intermediate-90, 88 mg, 0.26 mmol), 3-chloro-4-ethynylphenyl methanesulfonate (Intermediate- 89 , 60 mg, 0.26 mmol), TBAF (82 mg, 0.31 mmol), PdCl2(PPh3)2 (4.0 mg, 0.005 mmol) in DMSO (5.0 mL) at 90-100 °C for 2 h to afford 70 mg of the title product.1!! NMR (300 MHz, DMSO-d6): δ 10.57 (s, 1H), 8.52 (s, 1H), 7.92 (d, 1H), 7.82 (d, 1H), 7.75-7.70 (d, = 7.8 Hz, 1H), 7.66 (t, 1H), 7.51-7.48 (d, = 8.4 Hz, 1H), 6.96 (s, 1H), 6.83 (m, 1H), 4.25-4.23 (m, 2H), 2.85 (m, 2H), 2.17 (m, 2H) Step 2: Preparation of 3-(3-(lH-l,2,4-triazol- l-yl)propyl)-4-((2-chloro-4-hydroxyphenyl) ethynyl)benzoic acid
The title compound was prepared following the procedure described in Example-1 using 3-(3- (lH-l,2,4-triazol-l-yl)propyl)-4-((2-chloro-4-hydroxyphenyl)ethynyl)benzonitrile (70 mg, 0.19 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) to afford 30 mg of title product H NMR (300 MHz, DMSO- 6): δ 13.1 1 (s, 1H), 10.51 (s, 1H), 8.52 (s, 1H), 7.93 (s, 1H), 7.86 (s, 1H), 7.81-7.79 (d, = 7.8 Hz, 1H), 7.60-7.58 (d, = 8.1 Hz, 1H), 7.50-7.47 (d, = 8.7 Hz, 1H), 6.96 (s, 1H), 6.84-6.81 (d, = 9.0 Hz, 1H), 4.24-4.22 (t, = 6.9 Hz, 2H), 2.87-2.84 (m, 2H), 2.17 (m, 2H).
Example- 105
3-(3-Cyanopropyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
Figure imgf000229_0001
Step 1 : Preparation of ethyl 3-(3-cyanopropyl)-4-((4-hydroxy-2-
(trifluoromethyl)phenyl)ethynyl)benzoate
Figure imgf000229_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using ethyl 3-(3-cyanopropyl)-4-iodobenzoate (Intermediate-98, 100 mg, 0.29 mmol), 4- ethynyl-3-(trifluoromethyl)phenol (Intermediate-43 , 71 mg, 0.29 mmol), TBAF (98 mg, 0.37 mmol), PdCl2(PPh3)2 (4.0 mg, 0.005 mmol) in DMSO (5.0 mL) at 90- 100 °C for 2 h to afford 65 mg of the title product.1H NMR (300 MHz, DMSO-d6): δ 10.57 (s, IH), 8.52 (s, IH), 7.92 (d, IH), 7.82 (d, IH), 7.75-7.70 (d, J = 7.8 Hz, IH), 7.66 (t, IH), 7.51-7.48 (d, J = 8.4 Hz, IH), 6.96 (s, IH), 6.83 (m, IH), 4.25-4.23 (m, 2H), 2.85 (m, 2H), 2.17 (m, 2H)
Step 2: Preparation of 3-(3-cyanopropyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl) benzoic acid
The title compound was prepared following the procedure described in Example- 14 using ethyl 3-(3-cyanopropyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoate (60 mg, 0.14 mmol) in THF+H20 (5.0+5.0 ml) and LiOH.H20 (30 mg, 0.71 mmol) to afford 15 mg of the title product.1!! NMR (300 MHz, DMSO-d6): δ 1 1.95 (br s, IH), 10.69 (s, IH), 7.88- 7.84 (m, 2H), 7.71 (m, IH), 7.60 (m, IH), 7.17-7.10 (m, 2H), 2.93 (m, 2H), 2.50 (m, 2H), 1.94 (m, 2H); MS [M+H]+: 373.
Example- 106
3-(3-(lH-tetrazol-l-yl)propyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
Figure imgf000230_0001
Step 1 : Preparation of ethyl 3-(3-(lH-tetrazol-2-yl)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoate
Figure imgf000230_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using ethyl 3-(3-(lH-tetrazol-l-yl)propyl)-4-iodobenzoate (Intermediate-99, 100 mg, 0.25 mmol), 4-ethynyl-3-(trifluoromethyl)phenol (Intermediate-43 , 63 mg, 0.25 mmol), TBAF (85 mg, 0.32 mmol), PdCl2(PPh3)2 (3.5 mg, 0.004 mmol) in DMSO (5.0 mL) at 90-100 °C for 2 h to afford 55 mg of the title product.1!! NMR (300 MHz, DMSO-d6): δ 10.76 (br s, 1H), 9.42 (s, 1H), 7.91 (m, 2H), 7.62 (m, 2H), 7.17-7.11 (m, 2H), 4.52 (m, 2H), 4.34 (m, 2H), 2.89 (m, 2H), 2.25 (m, 2H), 1.33 (s, 3H).
Step 2: Preparation of 3-(3-(lH-tetrazol-l-yl)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoic acid
The title compound was prepared following the procedure described in Example- 14 using ethyl 3-(3-(lH-tetrazol- l-yl)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoate (50 mg, 0.11 mmol) in THF+H20 (5.0+5.0 ml) and LiOH.H20 (25 mg, 0.60 mmol) to afford 12 mg of the title product.1H NMR (300 MHz, DMSO-d6): δ 9.42 (s, 1H), 7.89 (m, 2H), 7.63 (m, 2H), 7.16 (m, 2H), 4.51 (m, 2H), 2.87 (t, 2H), 2.23 (m, 2H); MS [M-H]": 415.
Example- 107
3-(3-Aminopropyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid
hydrochloride
Figure imgf000231_0001
Step 1: Preparation of ethyl 3-(3-((ieri-butoxycarbonyl)amino)propyl)-4-((4-hydroxy-2-
(trifluoromethyl)phenyl)ethynyl)benzoate
Figure imgf000231_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using ethyl 3-(3-((ieri-butoxycarbonyl)amino)propyl)-4-iodobenzoate (step-3, Intermediate- 97, 100 mg, 0.23 mmol), 4-ethynyl-3-(trifluoromethyl)phenol (Intermediate-43 , 56 mg, 0.23 mmol), TBAF (78 mg, 0.29 mmol), PdCl2(PPh3)2 (3.2 mg, 0.004 mmol) in DMSO (5.0 mL) at 90-100 °C for 2 h to afford 65 mg of the title product.
Step 2: Preparation of 3-(3-((ieri-butoxycarbonyl)amino)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoic acid
Figure imgf000231_0003
The title compound was prepared following the procedure described in Example- 14 using ethyl 3-(3-((ieri-butoxycarbonyl)amino)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoate (65 mg, 0.13 mmol) in THF+H20 (5.0+5.0 ml) and LiOH.H20 (28 mg, 0.66 mmol) to afford 48 mg of the title product.1H NMR (300 MHz, DMSO-d6): δ 10.69 (s, 1H), 7.86 (s, 1H), 7.80-7.77 (d, J = 8.4 Hz, 1H), 7.69-7.66 (d, J = 7.8 Hz, IH), 7.56-7.53 (d, J = 7.8 Hz, IH), 7.15 (s, IH), 7.09-7.07 (d, J = 8.1 Hz, 1H),6.88 (br s, IH), 2.96 (m, 2H), 2.81 (m, 2H), 1.70 (m, 2H), 1.33 (s, 9H).
Step 3: Preparation of 3-(3-aminopropyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl) benzoic acid
The title compound was prepared following the procedure described in step-4, Intermediate - 97 using 3-(3-((ieri-butoxycarbonyl)amino)propyl)-4-((4-hydroxy-2-
(trifluoromethyl)phenyl)ethynyl)benzoic acid (45 mg, 0.09 mmol), HCl saturated in EtOAc (3.0 mL) to afford 14 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 13.13 (br s, 2H), 10.91 (s, IH), 7.97 (br s, 2H), 7.91 (s, IH), 7.184-7.81(d, = 7.2 Hz, IH), 7.72-7.69 (d, = 7.8 Hz, IH), 7.60-7.58 (d, = 7.8 Hz, IH), 7.23 (s, IH), 7.15-7.12 (d, = 9.0 Hz, IH), 2.91 (t, 2H), 2.78 (t, 2H), 1.91 (t, 2H); MS [M+H]+: 415.
Example- 108
3-(6-Carbamoylpyridin-3-yl)-4-((2-chloro-4-hydroxyphenyl)ethynyl)benzoic acid
Figure imgf000232_0001
Step 1 : Preparation of ethyl 3-(6-carbamoylpyridin-3-yl)-4-((2-chloro-4- hydroxyphenyl)ethynyl)benzoate
Figure imgf000232_0002
The title compound was prepared following the procedure described in step-5 of Intermediate- 46 by using ethyl 4-((2-chloro-4-hydroxyphenyl)ethynyl)-3-(6-cyanopyridin-3-yl)benzoate (Example- 102, 100 mg, 0.248 mmol), 50% H202 (2.5 mL), K2C03 (34 mg, 0.248 mmol) in in DMSO (5 mL) to afford 50 mg of the title product.1H NMR (300 MHz, DMSO-d6): δ 10.51 (s, IH), 8.84 (s, IH), 8.20 (m, 2H), 8.14 (d, IH), 8.03 (s, 2H), 7.84 (d, IH), 7.71 (s, IH), 7.30 (m, IH), 6.87 (s, IH), 6.76 (d, IH), 4.35 (q, 2H), 1.32 (t, 3H).
Step 2: Preparation of 3-(6-carbamoylpyridin-3-yl)-4-((2-chloro-4- hydroxyphenyl)ethynyl)benzoic acid The title compound was prepared following the procedure described in Example- 14 using ethyl 3-(6-carbamoylpyridin-3-yl)-4-((2-chloro-4-hydroxyphenyl)ethynyl)benzoate (50 mg, 0.11 mmol) in THF+H20 (5.0+5.0 ml) and LiOH.H20 (23 mg, 0.54 mmol) to afford 14 mg of the title product.1H NMR (300 MHz, DMSO-d6): δ 13.32 (br s, 1H), 10.49 (s, 1H), 8.85 (s, 1H), 8.24-8.14 (m, 3H), 8.02 (s, 2H), 7.83 (d, 1H), 7.69 (m, 1H), 7.33-7.30 (d, J = 8.1 Hz, 1H), 6.87 (s, 1H), 6.77 (d, 1H) ; MS [M+H]+: 393.
Example- 109
3-(3-((5-Cyanopyridin-3-yl)oxy)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoic acid
Figure imgf000233_0001
Step 1: Preparation of ethyl 3-(3-((5-cyanopyridin-3-yl)oxy)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoate
Figure imgf000233_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using ethyl 3-(3-((5-cyanopyridin-3-yl)oxy)propyl)-4-iodobenzoate (Intermediate- 100, 234 mg, 0.53 mmol), 4-ethynyl-3-(trifluoromethyl)phenol (Intermediate-43, 100 mg, 0.23 mmol), TBAF (180 mg, 0.68 mmol), PdCl2(PPh3)2 (7.0 mg, 0.01 mmol) in DMSO (2.0 mL) at 90- 100°C for 2 h to afford 65 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.72 (s, 1H), 8.55 (s, 1H), 8.48 (s, 1H), 7.89 (s, 1H), 7.84-7.82 (d, J = 6.6 Hz, 2H), 7.64-7.59 (t, J = 7.8 Hz, 2H), 7.15 (s, 1H), 7.08-7.05 (d, J = 8.7 Hz, 1H), 4.31-4.29 (q, J = 6.9 Hz, 2H), 4.13 (t, 2H), 3.03 (t, 2H), 2.11 (m, 2H), 1.32-1.27 (t, J = 6.6 Hz, 3H).
Step 2: Preparation of 3-(3-((5-cyanopyridin-3-yl)oxy)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoic acid The title compound was prepared following the procedure described in Example ethyl 3-(3-((5-cyanopyridin-3-yl)oxy)propyl)-4-((4-hydroxy-2-
(trifluoromethyl)phenyl)ethynyl)benzoate (40 mg, 0.11 mmol) in THF+H20 (3.0+3.0 ml) and LiOH.H20 (20 mg, 0.47 mmol) to afford 15 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.63 (s, 1H), 8.54-8.45 (d, 1H), 7.89 (s, 2H), 7.79 (d, 1H), 7.58 (m, 2H), 7.14 (s, 1H), 7.08 (d, 1H), 4.14 (t, 2H), 3.02 (m, 2H), 2.10 (t, 2H); MS [M-H]": 465.
Example-110
4- ((4-Hydroxy-2- (trifluoromethyl)phenyl)ethynyl) -3 - (3 - ( 1 - methylethylsulfonamido)propyl)benzoic acid
Figure imgf000234_0001
Step 1: Preparation of ethyl 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(l- methylethylsulfonamido)propyl)benzoate
Figure imgf000234_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using ethyl 4-iodo-3-(3-(l-methylethylsulfonamido)propyl)benzoate (Intermediate- 101, 175 mg, 0.40 mmol), 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 100 mg, 0.40 mmol), TBAF (136 mg, 0.52 mmol), PdCl2(PPh3)2 (6.0 mg, 0.008 mmol) in DMSO (3.0 mL) at 90-100°C for 2 h to afford 55 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.72 (s, 1H), 7.90 (s, 1H), 7.83 (d, 1H), 7.68 (d, 1H), 7.60 (d, 1H), 7.16-7.10 (m, 3H), 4.32 (m, 2H), 3.15 (m, 1H), 2.99 (m, 2H), 2.87 (m, 2H), 1.78 (m, 2H), 1.32 (t, 3H), 1.18-1.16 (d, 7 = 6.3 Hz, 6H).
Step 2: Preparation of 3-(3-((5-cyanopyridin-3-yl)oxy)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoic acid The title compound was prepared following the procedure described in Example- 14 using ethyl 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(l- methylethylsulfonamido)propyl)benzoate (40 mg, 0.11 mmol) in THF+H20 (3.0+3.0 ml) and LiOH.H20 (20 mg, 0.47 mmol) to afford 15 mg of the title product. 1H NMR (300 MHz, DMSO- 6): δ 13.11 (br s, 1H), 10.70 (s, 1H), 7.89 (s, 1H), 7.79 (d, 1H), 7.71-7.68 9 (d, J = 8.7 Hz, 1H), 7.58-7.55 (d, J = 8.4 Hz, 1H), 7.16 (s, 1H), 7.08 (d, 2H), 3.12 (m, 1H), 2.98 (m, 2H), 2.87 (m, 2H), 1.76 (m, 2H), 1.20-1.17 (d, J = 6.6 Hz, 6H); MS [M-H]": 469
Example-I l l
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-hydroxy-3-methylbutyl)benzoic acid
Figure imgf000235_0001
Step 1: Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-hydroxy-3- methylbutyl)benzonitrile
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using 3-(3-hydroxy-3-methylbutyl)-4-iodobenzonitrile (Intermediate- 102 126 mg, 0.40 mmol), 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 100 mg, 0.40 mmol), TBAF (136 mg, 0.45 mmol), PdCl2(PPh3)2 (6.0 mg, 0.008 mmol) in DMSO (5.0 mL) at 90-100 °C for 2 h to afford 60 mg of the title product.
Step 2: Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-hydroxy-3- methylbutyl)benzoic acid
The title compound was prepared following the procedure described in Example- 1 using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-hydroxy-3-methylbutyl)benzonitrile (60 mg, 0.16 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) to afford 30 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.70 (s, 1H), 7.85 (s, 1H), 7.76 (d, 1H), 7.67-7.64 (d, J = 7.8 Hz 1H), 7.55-7.52 (d, = 7.8 Hz 1H), 7.16 (s, 1H), 7.10 (d, 1H), 4.33 (s, 1H), 2.85 (m, 1.66 (m, 2H), 1.14 (s, 6H); MS [M-H]~: 391
Example- 112
3-(3-(lH-tetrazol-l-yl)propyl)-4-((2-chloro-4-hydroxyphenyl)ethynyl)benzoic acid
Figure imgf000236_0001
Step 1 : Preparation of ethyl 3-(3-(lH-tetrazol- l-yl)propyl)-4-((2-chloro-4- hydroxyphenyl)ethynyl)benzoate
Figure imgf000236_0002
The title compound was prepared following the procedure described in step-3, Intermediate- 1 using ethyl 3-(3-(lH-tetrazol-l-yl)propyl)-4-iodobenzoate (Intermediate-99, 254 mg, 0.65 mmol), 3-chloro-4-ethynylphenol (Intermediate- 103, 100 mg, 0.65 mmol), TBAF (220 mg, 0.84 mmol), PdCl2(PPh3)2 (91.0 mg, 0.13 mmol) in DMSO (3.0 mL) at 90- 100°C for 2 h to afford 105 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.63 (s, 1H), 7.91 (s, 2H), 7.60-7.57(d, J = 8.7 Hz, 1H), 7.50 (d, 1H), 7.40-7.37 (d, J = 8.1 Hz, 1H), 7.01 (s, 1H), 6.84-6.82 (d, J = 8.1 Hz, 1H), 4.49 (t, 2H), 4.43-4.38 (q, J = 3.6 Hz, 2H), 3.03 (t, 2H), 2.43 (t, 2H), 1.44- 1.39 (t, = 7.2Hz, 3H).
Step 2: Preparation of 3-(3-(lH-tetrazol-l-yl)propyl)-4-((2-chloro-4- hydroxyphenyl)ethynyl)benzoic acid
The title compound was prepared following the procedure described in Example- 14 using ethyl 3-(3-(lH-tetrazol- l-yl)propyl)-4-((2-chloro-4-hydroxyphenyl)ethynyl)benzoate (50 mg, 0.12 mmol) in THF+H20 (3.0+3.0 ml) and LiOH.H20 (20 mg, 0.47 mmol) to afford 15 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 13.13 (br s, 1H), 10.51(s, 1H), 9.42 (s, 1H), 7.89 (s, 1H), 7.82 (d, 1H), 7.61 (d, 1H), 7.50-7.47 (d, J = 8.4 Hz, 1H), 6.96 (s, 1H), 6.83 (d, 1H), 4.52 (t, 2H), 2.91 (m, 2H), 2.26 (m, 2H); MS [M-H]~: 381
Example- 113
4-((2-Chloro-4-hydroxyphenyl)ethynyl)-3-(3-isobutyramidopropyl)benzoic acid
Figure imgf000237_0001
Step 1: Preparation of ethyl 4-((2-chloro-4-hydroxyphenyl)ethynyl)-3-(3- isobutyramidopropyl)benzoate
Figure imgf000237_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using ethyl 4-iodo-3-(3-isobutyramidopropyl)benzoate (Intermediate-97, 50 mg, 0.21 mmol), 3-chloro-4-ethynylphenyl methanesulfonate (Intermediate-89 , 50 mg, 0.21 mmol), TBAF (68 mg, 0.26 mmol), PdCl2(PPh3)2 (4.0 mg, 0.004 mmol) in DMSO (5.0 mL) at 90-100 °C for 2 h to afford 55 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 7.91 (m, 2H), 7.59 (d, 1H), 7.46 (d, 1H), 7.14 (m, 1H), 6.98 (m, 1H), 6.80 (m, 1H), 5.36 (m, 1H), 4.40- 4.38 (d, = 6.3Hz, 2H), 3.73 (m, 2H), 3.00 (m, 2H), 1.95 (m, 2H), 1.41 (m, 3H), 1.23 (m, 6H); MS [M+H]+: 429
Step 2: Preparation of 4-((2-Chloro-4-hydroxyphenyl)ethynyl)-3-(3- isobutyramidopropyl)benzoic acid
The title compound was prepared following the procedure described in Example- 14 using ethyl 4-((2-chloro-4-hydroxyphenyl)ethynyl)-3-(3-isobutyramidopropyl)benzoate (20 mg, 0.04 mmol) in THF+H20 (3.0+3.0 ml) and LiOH.H20 (10 mg, 0.23 mmol) to afford 10 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 13.00 (br s, 1H), 10.51 (s, 1H), 7.87 (s, IH), 7.77 (s, 2H), 7.57 (m, 2H), 6.97 (s, IH), 6.83 (m, IH), 5.32 (m, IH), 3.07 (m, 2H), 2.88 (m, 2H), 1.76 (m, 2H), 1.23 (s, 6H); MS [M-H]~: 398
Example- 114
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(pyridin-4-yl)benzoic acid
Figure imgf000238_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using 4-iodo-3-(pyridin-4-yl)benzonitrile (Intermediate- 104, 126 mg, 0.40 mmol), 4- ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 100 mg, 0.40 mmol), TBAF (136 mg, 0.52 mmol), PdCl2(PPh3)2 (6.0 mg, 0.008 mmol) in DMSO (5.0 mL) at 90- 100 °C for 2 h to afford 45 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.79 (s, IH), 8.71 (d, IH), 8.06 (s, IH), 7.96 (d, IH), 7.83 (d, IH), 7.67 (m, 2H), 7.50 (m, 2H), 7.12 (m, 2H); MS [M-H]~: 363
Step 2: Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(pyridin-4- yl)benzoic acid
The title compound was prepared following the procedure described in Example- 1 using of 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(pyridin-4-yl)benzonitrile (60 mg, 0.16 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) to afford 30 mg of title product. 1H NMR (300 MHz, DMSO- 6): δ 10.87 (s, IH), 8.85-8.83 (d, = 5.7Hz, 2H), 8.09-8.05 (m, 2H), 7.92 (m, 2H), 7.82-7.79 (d, = 7.8Hz, IH), 7.50-7.47 (d, = 8.7Hz, IH), 7.15 (s, IH), 7.09-7.07 (d, = 8.4Hz, IH); MS [M+H]+: 384
Example- 115
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(2-(thiazol-2-yl)ethyl)benzoic acid
Figure imgf000239_0001
Step 1: Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(2-(thiazol-2- yl)ethyl)benzonitrile
Figure imgf000239_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using 4-iodo-3-(2-(thiazol-2-yl)ethyl)benzonitrile (Intermediate- 106, 70 mg, 0.28 mmol), 4- ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 97 mg, 0.28 mmol), TBAF (90 mg, 0.34 mmol), PdCl2(PPh3)2 (5.0 mg, 0.005 mmol) in DMSO (2.0 mL) at 90- 100°C for 2 h to afford 60 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.77 (s, 1H), 7.83 (s, 1H), 7.70-7.65 (m, 4H), 7.57 (d, 1H), 7.16 (s, 1H), 7.12-7.09 (d, = 8.7Hz, 1H), 3.33 (m, 4H).
Step 2: Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(2-(thiazol-2- yl)ethyl)benzoic acid
The title compound was prepared following the procedure described in Example- 1 using of 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(2-(thiazol-2-yl)ethyl)benzonitrile (60 mg, 0.15 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) to afford 20 mg of title product. 1H NMR (300 MHz, DMSO- 6): δ 10.73 (s, 1H), 7.86 (s, 1H), 7.83-7.81 (d, = 8.1Hz, 1H), 7.70-7.57 (m, 4H), 7.66 (s, 1H), 7.11-7.09 (d, = 8.1Hz, 1H), 3.34 (m, 4H); MS [M+H]+: 418
Example- 116
4-((2-Chloro-4-hydroxyphenyl)ethynyl)-3-(2-(thiazol-2-yl)ethyl)benzoic acid
Figure imgf000239_0003
4-((2-chloro-4-hydroxyphenyl)ethynyl)-3-(2-(thiazol-2-
Figure imgf000240_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using 4-iodo-3-(2-(thiazol-2-yl)ethyl)benzonitrile (Intermediate- 106, 88 mg, 0.26 mmol), 3- chloro-4-ethynylphenyl methanesulfonate (Intermediate- 89, 60 mg, 0.26 mmol), TBAF (81 mg, 0.31 mmol), PdCl2(PPh3)2 (4.0 mg, 0.005 mmol) in DMSO (2.0 mL) at 90-100°C for 2 h to afford 60 mg of the title product. 1H NMR (300 MHz, DMSO- 6): δ 10.56 (s, 1H), 7.85 (s, 1H), 7.72-7.69 (m, 3H), 7.58 (m, 2H), 6.95 (s, 1H), 6.83-6.80 (d, J = 8.1 Hz, 1H), 3.83 (m, 4H); MS [M+H]+: 365
Step 2: Preparation of 4-((2-chloro-4-hydroxyphenyl)ethynyl)-3-(2-(thiazol-2- yl)ethyl)benzoic acid
The title compound was prepared following the procedure described in Example- 1 using 4- ((2-chloro-4-hydroxyphenyl)ethynyl)-3-(2-(thiazol-2-yl)ethyl)benzonitrile (60 mg, 0.16 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) to afford 25 mg of title product. 1H NMR (300 MHz, DMSO- 6): δ 12.80 (s, 1H), 10.50 (s, 1H), 7.89 (s, 1H), 7.83-7.80 (d, J = 7.8 Hz, 1H), 7.70 (s, 1H), 7.63-7.60 (d, J = 8.4 Hz, 1Η),7.56-7.52 (m, 2H), 6.95 (s, 1H), 6.83-6.80 (d, J = 8.7 Hz, 1H), 3.37-3.34 (d, J = 9.0 Hz, 4H); MS [M+H]+: 384
Example- 117
4-((2-Chloro-4-hydroxyphenyl)ethynyl)-3-(3-(pyridin-4-yloxy)propyl)benzoic acid
Figure imgf000240_0002
Step 1: Preparation of 4-((2-chloro-4-hydroxyphenyl)ethynyl)-3-(3-(pyridin-4- yloxy)propyl)benzonitrile
Figure imgf000241_0001
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using 4-iodo-3-(3-(pyridin-4-yloxy)propyl)benzonitrile (Intermediate-91, 95 mg, 0.26 mmol), 3-chloro-4-ethynylphenyl methanesulfonate (Intermediate-89 , 60 mg, 0.26 mmol), TBAF (81 mg, 0.31 mmol), PdCl2(PPh3)2 (4.0 mg, 0.02 mmol) in DMSO (2.0 mL) at 90- 100 °C for 2 h to afford 60 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.56 (s, 1H), 8.41 (s, 2H), 7.85 (s, 1H), 7.71-7.67 (m, 2H), 7.49 (m, 2H), 7.0-6.96 (m, 2H), 6.79 (d, 1H), 4.15 (t, 2H), 3.04 (t, 2H), 2.14 (m, 2H); MS [M+H]+: 389
Step 2: Preparation of 4-((2-chloro-4-hydroxyphenyl)ethynyl)-3-(3-(pyridin-4- yloxy)propyl)benzoic acid
The title compound was prepared following the procedure described in Example- 1 using of 4- ((2-chloro-4-hydroxyphenyl)ethynyl)-3-(3-(pyridin-4-yloxy)propyl)benzonitrile (70 mg, 0.18 mmol), EtOH (5.0 mL), 2N NaOH (5.0 mL) to afford 30 mg of title product. 1H NMR (300 MHz, DMSO- 6): δ 10.38 (s, 1H), 8.70 (d, 2H), 7.90 (s, 1H), 7.80 (d, 1H), 7.62-7.59 (d, = 7.8 Hz, 1H), 7.48 (s, 3H), 6.99 ((s, 1H), 6.84-6.81 (d, = 9.3 Hz, 1H), 4.37 (t, 2H), 3.09 (t, 2H), 2.19 (t, 2H); MS [M+H]+: 408
Example-118
3-Chloro-4-((2-(3-(2-methyl- lH-imidazol- l-yl)propyl)-4-(lH-tetrazol-5- yl)phenyl)ethynyl)phenol
Figure imgf000241_0002
The title compound was prepared following the procedure described in Example-36 using of 4-((2-chloro-4-hydroxyphenyl)ethynyl)-3-(3-(2-methyl-lH-imidazol-l-yl)propyl)benzonitrile (step- 1, Example-94, 60 mg, 0.295 mmol), sodium azide (41.6 mg, 0.64 mmol) and triethyl ammonium chloride (41.6 mg, 0.64 mmol) in DMF (2.0 mL) to afford 15 mg of title product. 1H NMR (300 MHz, DMSO- 6): δ 14.24 (br s, 1H), 10.63 (s, 1H), 8.12 (s, 1H), 7.97-7.94 (d, = 7.5 Hz, 1H), 7.71-7.68 (d, = 8.21 Hz, 2H), 7.51-7.48 (d, = 8.7 Hz, 2H), 7.00 (s, 1H), 6.86-6.83 (d, J = 8.4 Hz, 1H), 4.20-4.18 (t, J = 6.3 Hz, 2H), 2.97 (t, 2H), 2.54 (s, 3H), 2.22 (t, 2H); MS [M+H]+: 419
Example- 119
N-(3-(2-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-5-(lH-tetrazol-5- yl)phenyl)propyl)isobutyramide
Figure imgf000242_0001
Step 1 : Preparation of N-(3-(5-cyano-2-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)phenyl)propyl)isobutyramide
Figure imgf000242_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using N-(3-(5-cyano-2-iodophenyl)propyl)isobutyramide (Intermediate- 107, 100 mg, 0.28 mmol), 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30 , 70 mg, 0.28 mmol), TBAF (90 mg, 0.34 mmol), PdCl2(PPh3)2 (5.0 mg, 0.005 mmol) in DMSO (5.0 mL) at 90- 100 °C for 2 h to afford 50 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.77 (s, 1H), 7.84-7.64 (m, 5H), 7.17 (s, 1H), 7.11 (d, 1H), 3.05 (m, 1H), 2.8 l(t, 1H), 2.31 (m, 1H), 1.73 (m, 2H), 0.97-0.95 (d, J = 6.3 Hz, 6H).
Step 2: Preparation of N-(3-(2-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-5-(lH- tetrazol-5-yl)phenyl)propyl)isobutyramide
The title compound was prepared following the procedure described in Example-36 using N- (3-(5-cyano-2-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)phenyl)propyl)isobutyramide (70 mg, 0.16 mmol), sodium azide (41.6 mg, 0.64 mmol) and triethyl ammonium chloride (41.6 mg, 0.64 mmol) in DMF (2.0 mL) to afford 15 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.71 (br s, 1H), 7.97 (s, 1H), 7.89-7.86 (d, = 7.8 Hz, 1H), 7.81 (t, 1H), 7.68- 7.65 (d, 7 = 8.4 Hz, 1H), 7.57-7.54 (d, J = 8.4 Hz, 1H), 7.17 (s, 1H), 7.11-7.08 (d, J = 8.4 Hz, 1H), 3.09-3.04 (m, 2H), 2.84 (t, 2H), 2.34-2.32 (m, 1H), 1.77 (m, 2H), 0.98-0.95 (d, 7 = 6.9 Hz, 6H); MS [M+H]+: 458.
Example- 120
4-((2-(pyridin-4-yl)-4-(l -tetrazol-5-yl)phenyl)ethynyl)-3-(trifluoromethyl)phenol
Figure imgf000243_0001
The title compound was prepared following the procedure described in Example-36 using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(pyridin-4-yl)benzonitrile (step- 1 ,
Example- 114, 70 mg, 0.19 mmol), sodium azide (62 mg, 0.96 mmol) and triethyl ammonium chloride (131 mg, 0.96 mmol) in DMF (5.0 mL) to afford 14 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.92 (s, 1H), 9.06 (br s, 2H), 8.38 (s, 1H), 8.29 (3H), 7.96-7.93 (d, 7 = 8.4 Hz, 1H), 7.57-7.54 (d, 7 = 8.4 Hz, 1H), 7.16 (s, 1H), 7.11-7.08 (d, 7 = 8.7 Hz, 1H); MS [M-H]": 405.6.
Example- 121
Ethyl 3-(6-carbamoylp yl)ethynyl)benzoate
Figure imgf000243_0002
The title compound was prepared following the procedure described in step-5 of Intermediate- 46 using ethyl 4-((2-chloro-4-hydroxyphenyl)ethynyl)-3-(6-cyanopyridin-3-yl)benzoate (Example-102, 200 mg, 0.49 mmol), 30% H202 (10 mL), K2C03 (48 mg, 0.34 mmol) in DMSO (10 mL) to afford 150 mg of title compound. 1H NMR (300 MHz, DMSO-d6): δ 10.54 (s, 1H), 8.85 (s, 1H), 8.27-8.22 ((m, (m, 2H), 8.15-8.13 (d, 7 = 8.4Hz, 1H), 8.06 (s, 2H), 7.86- 7.83 (d, 7 = 8.1 Hz, 1H), 7.73 (s, 1H), 7.35-7.32 (d, 7 = 8.7 Hz, 1H), 6.87 (s, 1H), 6.78-6.75 (d, 7 = 8.7 Hz, 1H), 4.39-4.32 (q, 7 = 6.6 Hz, 2H), 1.36-1.31 (t, 7 = 7.2 Hz, 3H); MS [M+H]+: 421.
Example- 122
4-((2-(3-(Pyridin-4-yloxy)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol
Figure imgf000244_0001
Step 1 : Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(pyridin-4- yloxy)propyl)benzonitrile
Figure imgf000244_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using 4-iodo-3-(3-(pyridin-4-yloxy)propyl)benzonitrile (Intermediate-91, 89 mg, 0.24 mmol), 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30 , 60 mg, 0.24 mmol), TBAF (77 mg, 0.29 mmol), PdCl2(PPh3)2 (4.0 mg, 0.004 mmol) in DMSO (2.0 mL) at 90- 100 °C for 2 h to afford 60 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.76 (s, 1H), 8.34 (br s, 2H), 7.84 (s, 2H), 7.71 (m, 1H), 7.14 (m, 3H), 6.90 (m, 2H), 4.09 (t, 2H), 2.97 (m, 2H), 2.08 (m, 2H); MS [M-H]": 421.
Step 2: Preparation of 4-((2-(3-(pyridin-4-yloxy)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)- 3 - (trifluoromethyl)phenol
The title compound was prepared following the procedure described in Example-36 using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(pyridin-4-yloxy)propyl)benzonitrile (60 mg, 0.19 mmol), sodium azide (46 mg, 0.71 mmol) and triethyl ammonium chloride (97 mg, 0.71 mmol) in DMF (5.0 mL) to afford 30 mg of title product. 1H NMR (300 MHz, DMSO- d6): δ 10.80 (br s, 1H), 8.33 (br s, 2H), 8.01 (s, 1H), 7.92-7.89 (d, J = 7.8Hz, 1H), 7.61-7.55 (m, 2H), 7.20 (s, 1H), 7.11-7.08 (d, = 8.1 Hz, 1H), 6.93 (s, 2H), 4.13 (t, 1H), 4.11 (t, 2H), 3.16 (t, 2H), 2.10 (br s, 2H); MS [M+H]+: 466.
Example- 123
3-Chloro-4-((2-(3-(pyridin-4-yloxy)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)phenol
Figure imgf000245_0001
Step 1 : Preparation of 4-((2-chloro-4-hydroxyphenyl)ethynyl)-3-(3-(pyridin-4- yloxy)propyl)benzonitrile
Figure imgf000245_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using 4-Iodo-3-(3-(pyridin-4-yloxy)propyl)benzonitrile (Intermediate-91, 95 mg, 0.26 mmol), 3-chloro-4-ethynylphenyl methanesulfonate (Intermediate- 89 , 60 mg, 0.26 mmol), TBAF (81 mg, 0.31 mmol), PdCl2(PPh3)2 (4.0 mg, 0.004 mmol) in DMSO (2.0 mL) at 90-100 °C for 2 h to afford 60 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.55 (br s, 1H), 8.43 (br s, 2H), 7.61-7.48 (m, 4H), 7.05 (m, 3H), 6.93 (m, 1H), 4.17 (m, 2H),3.14 (m,2H), 2.13 (m, 2H); MS [M+H]+: 432.
Step 2: Preparation of 3-chloro-4-((2-(3-(pyridin-4-yloxy)propyl)-4-(lH-tetrazol-5- yl)phenyl)ethynyl)phenol
The title compound was prepared following the procedure described in Example-36 using 4- ((2-chloro-4-hydroxyphenyl)ethynyl)-3-(3-(pyridin-4-yloxy)propyl)benzonitrile (60 mg, 0.15 mmol), sodium azide (50 mg, 0.77 mmol) and triethyl ammonium chloride (106 mg, 0.77 mmol) in DMF (5.0 mL) to afford 30 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.67 (br s, 1H), 8.34 (s, 2H), 8.07 (s, 1H), 7.93 (d, 1H), 7.62-7.34 (m, 3H), 7.01-6.94 (m, 1H), 6.82 (d, 1H), 4.15 (m, 2H), 3.07 (m, 2H), 2.17 (m, 2H); MS [M+H]+: 432.
Example- 124
4-((2-(2-(pyridin-4-yl)ethyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-(trifluoromethyl)phenol
Figure imgf000246_0001
Step 1 : Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(2-(pyridin-4- yl)ethyl)benzonitrile
Figure imgf000246_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 100 mg, 0.37 mmol), 4-iodo-3-(2-(pyridin-4-yl)ethyl)benzonitrile (Intermediate- 108, 126 mg, 0.37 mmol), TBAF (119 mg, 0.45 mmol), PdCl2(PPh3)2 (5.3 mg, 0.07 mmol) in DMSO (2.0 mL) at 70°C to afford 55 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.78 (s, 1H), 8.45 (br s, 2H), 7.83 (s, 1H), 7.73 (d, 1H), 7.66 (t, 2H), 7.22-7.10 (m, 4H), 3.15 (m, 2H), 2.96 (m, 2H). Step 2: Preparation of 4-((2-(2-(pyridin-4-yl)ethyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol
The title compound was prepared following the procedure described in Example-36 using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(2-(pyridin-4-yl)ethyl)benzonitrile (50 mg, 0.12 mmol), sodium azide (99 mg, 1.5 mmol) and triethyl ammonium chloride (198 mg, 1.5 mmol) in DMF (2.0 mL) to afford 20 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.73 (s, 1H), 8.43 (m, 2H), 8.03 (s, 1H), 7.95 (m, 1H), 7.68 (t, 2H), 7.26-7.11 (m, 3H), 6.94 (s, 1H), 3.34 (m, 2H), 3.01 (m, 2H); MS [M+H]+: 436.
Example- 125
4-((2-(3-(lH-l,2,4-triazol-l-yl)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-
(trifluoromethyl)phenol
Figure imgf000247_0001
Step 1 : Preparation of 3-(3-(lH-l,2,4-triazol- l-yl)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethyny
Figure imgf000247_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 60 mg, 0.24 mmol), 3-(3-(lH-l,2,4-triazol- l-yl)propyl)-4-iodobenzonitrile (Intermediate-90, 83 mg, 0.24 mmol), TBAF (77 mg, 0.29 mmol), PdCl2(PPh3)2 (4.0 mg, 0.005 mmol) in DMSO (2.0 mL) at 100°C to afford 50 mg of the title product.
Step 2: Preparation of 4-((2-(3-(lH-l,2,4-triazol- l-yl)propyl)-4-(lH-tetrazol-5- yl)phenyl)ethynyl)-3-(trifluoromethyl)phenol
The title compound was prepared following the procedure described in Example-36 using 3- (3-( IH- 1 ,2,4-triazol- 1 -yl)propyl)-4-((4-hydroxy-2-
(trifluoromethyl)phenyl)ethynyl)benzonitrile (60 mg, 0.15 mmol), sodium azide (49 mg, 0.75 mmol) and triethyl ammonium chloride (103 mg, 0.75 mmol) in DMF (5.0 mL) to afford 30 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.72 (br s, IH), 8.53 (s, IH), 7.93 (s, 2H), 7.89 (d, IH), 7.60-7.52 (m, 2H), 7.16 (s, IH), 7.10 (d, IH), 4.24 (t, 2H), 2.82 (m, 2H), 2.16 (m, 2H); MS [M+H]+: 438.
Example- 126
4-((2-(3-( IH- 1 ,2,4-triazol- 1 -yl)propyl)-4-( lH-tetrazol-5-yl)phenyl)ethynyl)-3-chlorophenol
Figure imgf000248_0001
Step 1 : Preparation of 3-(3-(lH-l,2,4-triazol- l-yl)propyl)-4-((2-chloro-4- hydroxyphenyl)ethynyl)benzonitrile
Figure imgf000248_0002
The title compound was prepared following the procedure described in step-3 Intermediate- 1 using 3-chloro-4-ethynylphenyl methanesulfonate (Intermediate-89, 60 mg, 0.26 mmol), 3- (3-(lH-l,2,4-triazol- l-yl)propyl)-4-iodobenzonitrile (Intermediate-90, 88 mg, 0.26 mmol), TBAF (82 mg, 0.31 mmol), PdCl2(PPh3)2 (4.0 mg, 0.005 mmol) in DMSO (2.0 mL) at 100°C to afford 60 mg of the title product. 1H NMR (300 MHz, DMSO- 6): δ 10.56 (s, 1H), 8.52 (s, 1H), 7.93 (s, 1H), 7.82 (s, 1H), 7.71 (d, 1H), 7.66 (d, 1H), 7.51-7.48 (d, = 8.7 Hz, 1H), 6.97 (s, 1H), 6.84 (d, 1H), 4.23 (m, 2H), 2.86 (m, 2H), 2.18 (m, 2H); MS [M+H]+: 361
Step 2: Preparation of 4-((2-(3-(lH-l,2,4-triazol- l-yl)propyl)-4-(lH-tetrazol-5- yl)phenyl)ethynyl)-3-chlorophenol
The title compound was prepared following the procedure described in Example-36 using 3- (3-(lH-l,2,4-triazol- l-yl)propyl)-4-((2-chloro-4-hydroxyphenyl)ethynyl)benzonitrile (60 mg, 0.16 mmol), sodium azide (53 mg, 0.82 mmol) and triethyl ammonium chloride (113 mg, 0.85 mmol) in DMF (5.0 mL) to afford 20 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.51 (br s, 1H), 8.54 (s, 1H), 7.95 (m, 2H), 7.47 (m, 2H), 7.30 (br s, 1H), 6.96 (s, 1H), 6.81 (m, 1H), 4.27 (m, 2H), 2.82 (m, 2H), 2.02 (m, 2H); MS [M+H]+: 361
Example- 127
4-((2-(6-chloropyridin-3-yl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-(trifluoromethyl)phenol
Figure imgf000249_0001
Step- 1 : Preparation of 3-(6-chloropyridin-3-yl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethyny
Figure imgf000249_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 77 mg, 0.29 mmol), 3-(6-chloropyridin-3-yl)-4-iodobenzonitrile (Intermediate- 109, 100 mg, 0.29 mmol), TBAF (91 mg, 0.34 mmol), PdCl2(PPh3)2 (41 mg, 0.05 mmol) in DMSO (2.0 mL) at 100°C to afford 52 mg of the title product.
Step-2: Preparation 4-((2-(6-chloropyridin-3-yl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol
The title compound was prepared following the procedure described in Example-36 using 3- (6-chloropyridin-3-yl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzonitrile (60 mg, 0.15 mmol), sodium azide (117 mg, 1.80 mmol) and triethyl ammonium chloride (248 mg, 1.80 mmol) in DMF (2.0 mL) to afford 18 mg of title product. 1H NMR (300 MHz, DMSO- d6): δ 8.66 (s, 1H), 8.12 (br s, 2H), 7.78 (d, 1H), 7.66 (d, 1H), 7.43 (d, 1H), 7.10-7.06 (m, 3H); MS [M+H]+: 440.
Example- 128
4-((2-(3-ethoxypropyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-(trifluoromethyl)phenol
Figure imgf000249_0003
The title compound was prepared following the procedure described in Example-36 using 3- (3-ethoxypropyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzonitrile
(Intermediate-38, 40 mg, 0.10 mmol), sodium azide (83 mg, 1.28 mmol) and triethyl ammonium chloride (165 mg, 1.28 mmol) in DMF (2.0 mL) to afford 12 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 7.83 (m, 2H), 7.55 (m, 1H), 7.44 (m, 1H), 7.10 (s, 1H), 6.94 (m, 1H), 3.45 (m, 2H), 3.14 (m, 2H), 2.91 (m, 2H), 1.93 (m, 2H), 1.31 (m, 3H); MS [M+H]+: 417.
Example- 129
4-((2-(3-morpholinopropyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-(trifluoromethyl)phenol
Figure imgf000250_0001
Step- 1 : Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3- morpholinopropyl)benzonitrile
Figure imgf000250_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using 4-ethynyl-3-(trifluoromethyl)phenol (Intermediate-43, 52 mg, 0.28 mmol), 4-iodo-3- (3-morpholinopropyl)benzonitrile (step-1, Intermediate-51, 100 mg, 0.28 mmol), TBAF (88 mg, 0.33 mmol), PdCl2(PPh3)2 (39 mg, 0.05 mmol) in DMSO (2.0 mL) at 100°C to afford 60 mg of the title product.
Step-2: Preparation 4-((2-(3-morpholinopropyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol
The title compound was prepared following the procedure described in Example-36 using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-morpholinopropyl)benzonitrile (40 mg, 0.10 mmol), sodium azide (125 mg, 1.92 mmol) and triethyl ammonium chloride (265 mg, 1.92 mmol) in DMF (2.0 mL) to afford 10 mg of title product. . 1H NMR (300 MHz, DMSO- d6): δ 10.76 (br s, 1H), 8.13 (m, 1H), 7.98 (m, 1H), 7.71 (m, 2H), 7.20 (m, 2H), 3.81 (m, 4H), 3.16 (m, 6H), 2.96 (m, 2H), 2.12 (m, 2H); MS [M+H]+: 458.
Example- 130
4-((2-((pyridin-3-yloxy)methyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-
(trifluoromethyl)phenol
Figure imgf000251_0001
Stepl : Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-((pyridin-3- yloxy)methyl)benzonitrile
Figure imgf000251_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 150 mg, 0.519 mmol), 4-bromo-3-((pyridin-3-yloxy)methyl)benzonitrile (Intermediate- 110, 96.53 mg, 0.519 mmol), TBAF (408 mg, 1.55 mmol), PdCl2(PPh3)2 (15 mg, 0.020 mmol) in DMSO (5.0 mL) at 80°C to afford 70 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.79 (s, 1H), 8.49 (s, 1H), 8.22 (s, 1H), 8.09 (s, 1H), 7.92-7.89 (d, = 7.8 Hz, 1H), 7.76-7.73 (d, = 7.8 Hz, 1H), 7.62-7.47 (m, 2H),7.39 (m, 1H), 7.14 (s, 1H), 7.07-7.04 (d, = 9.0 Hz, 1H), 5.33 (s, 2H).
Step 2: Preparation of 4-((2-((pyridin-3-yloxy)methyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol
The title compound was prepared following the procedure described in Example-36 using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-((pyridin-3-yloxy)methyl)benzonitrile (45 mg, 0.11 mmol), sodium azide (37.11 mg, 0.57 mmol) and triethyl ammonium chloride (79 mg, 0.57 mmol) in DMF (5.0 mL) to afford 11 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.80 (br s, 1H), 8.40 (s, 1H), 8.27 (s, 1H), 8.20 (s, 1H), 8.08-8.05 (d, = 6.6 Hz, IH), 7.76-7.73 (d, = 8.4 Hz, IH), 7.57-7.54 (d, = 7.8 Hz, IH), 7.46 (d, IH), 7.36 (m, IH), 7.13 (s, lH),7.06-7.03 (d, J = 7.8 Hz, IH), 5.39 (s, 2H); MS [M+H]+: 438.
Example- 131
4-((2-(3-(lH-l,2,3-triazol-l-yl)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol
Figure imgf000252_0001
Step- 1 : Preparation of 3-(3-(lH-l,2,3-triazol- l-yl)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzonitrile
Figure imgf000252_0002
The title compound was prepared following the procedure described in step-3 Intermediate- 1 by using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 60 mg, 0.24 mmol), 3-(3-(lH-l,2,3-triazol- l-yl)propyl)-4-iodobenzonitrile (step- 1, Intermediate-58, 83 mg, 0.24 mmol), TBAF (77 mg, 0.29 mmol), PdCl2(PPh3)2 (4.0 mg, 0.020 mmol) in DMSO (5.0 mL) at 80°C to afford 50 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.14 (s, IH), 7.82 (s, IH), 7.75-7.54 (m, IH), 7.12 (d, IH), 4.45-4.40 (t, 2H), 2.82-2.76 (t, 2H), 2.19 (t, 2H); MS [M+H]+: 397.
Step 2: Preparation of 4-((2-(3-(lH-l,2,3-triazol- l-yl)propyl)-4-(lH-tetrazol-5- yl)phenyl)ethynyl)-3-(trifluoromethyl)phenol
The title compound was prepared following the procedure described in Example-36 using 3- (3-(lH-l,2,3-triazol- l-yl)propyl)-4-((4-hydroxy-2-
(trifluoromethyl)phenyl)ethynyl)benzonitrile (60 mg, 0.15 mmol), sodium azide (49 mg, 0.75 mmol) and triethyl ammonium chloride (103 mg, 0.75 mmol) in DMF (5.0 mL) to afford 30 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.80 (br s, IH), 8.16 (s, IH), 7.95 (s, IH), 7.90-7.88 (d, = 8.4 Hz, IH), 7.70 (s, IH), 7.60-7.57 (d, = 8.7 Hz, IH), 7.58-7.52 (d, = 7.8 Hz, 1H), 7.17 (s, 1H), 7.11-7.09 (d, = 8.1 Hz, 1H), 4.93-4.44 (t, J = 7.5 Hz, 2H), 2.88- 2.84 (m, 2H), 2.21 (m, 2H); MS [M+H]+: 439.
Example- 132
4-((2-(6-methoxypyridin-3-yl -4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-(trifluoromethyl)phenol
Figure imgf000253_0001
Step- 1 : Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(6- methoxypyridin-3-yl)benzonitrile
Figure imgf000253_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 80 mg, 0.32 mmol), 4-iodo-3-(6-methoxypyridin-3-yl)benzonitrile (Intermediate-I l l, 110 mg, 0.32 mmol), TBAF (102 mg, 0.39 mmol), PdCl2(PPh3)2 (6.0 mg, 0.008 mmol) in DMSO (2.0 mL) at 80°C to afford 100 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.76 (s, 1H), 8.14 (s, 1H), 8.01 (s, 2H), 7.90-7.88 (d, = 8.7 Hz, 1H), 7.78-7.75 (d, = 7.8 Hz, 1H), 7.48- 7.45 (d, J = 8.4 Hz, 1H), 7.11 (s, 1H), 7.08-7.04 (m, 1H), 6.96-6.94 (d, J = 8.4 Hz, 1H), 3.91 (s, 3H).
Step 2: Preparation of 4-((2-(6-methoxypyridin-3-yl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol
The title compound was prepared following the procedure described in Example-36 using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(6-methoxypyridin-3-yl)benzonitrile (100 mg, 0.25 mmol), sodium azide (82 mg, 1.26 mmol) and triethyl ammonium chloride (173 mg, 1.26 mmol) in DMF (5.0 mL) to afford 40 mg of title product. 1H NMR (300 MHz, DMSO- d6): δ 8.39 (s, 1H), 8.08-8.0 (m, 3H), 7.82-7.79 (d, = 7.8 Hz, 2H), 7.48-7.42 (d, = 8.4 Hz, 1H), 7.10 (br s, 1H), 7.05-7.03 (d, J = 7.8 Hz, 1H), 6.97-6.94 (d, J = 8.7 Hz, 1H), 3.89 (s, 3H); MS [M+H]+: 438. Example- 133
2'-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-5'-(lH-tetrazol-5-yl)-[l,r-biphi
carboxamide
Figure imgf000254_0001
Step- 1 : Preparation of 5'-cyano-2'-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-[l, - biphenyl] -4-carboxamide
Figure imgf000254_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 70 mg, 0.28 mmol), 5'-cyano-2'-iodo-[l,l'-biphenyl] -4-carboxamide (Intermediate- 112, 100 mg, 0.28 mmol), TBAF (90 mg, 0.34 mmol), PdCl2(PPh3)2 (39 mg, 0.05 mmol) in DMSO (2.0 mL) at 80°C to afford 80 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.72 (s, 1H), 8.08 (s, 1H), 8.01-7.98 (d, = 8.7 Hz, 2H), 7.92-7.89 (d, = 7.8 Hz, 1H), 7.78-7.73 (t, = 9.3Hz, 2H), 7.46-7.40 (m, 2H), 7.11 (s, 1H), 7.06-7.03 (d, = 8.4 Hz, 1H).
Step 2: Preparation of 2'-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-5'-(lH-tetrazol-5- yl)- [ 1 , 1 '-biphenyl] -4-carboxamide
The title compound was prepared following the procedure described in Example-36 using 5'- cyano-2'-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-[l,r-biphenyl] -4-carboxamide (60 mg, 0.14 mmol), sodium azide (109 mg, 1.68 mmol) and triethyl ammonium chloride (232 mg, 1.68 mmol) in DMF (2.0 mL) at 65°C for 48 h to afford 20 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.67 (br s, 1H), 8.1 1-7.99 (m, 4H), 7.76-7.58 (m, 4H), 7.40 (m, 2H), 7.11 (s, 1H), 7.05 (d, 2H).
Example- 134
4-((2-(pyridin-3-yl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-(trifluoromethyl)phenol
Figure imgf000255_0001
Step- 1 : Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(pyridin-3- yl)benzonitrile
Figure imgf000255_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 70 mg, 0.28 mmol), 4-iodo-3-(pyridin-3-yl)benzonitrile (Intermediate- 113, 88 mg, 0.28 mmol), TBAF (90 mg, 0.34 mmol), PdCl2(PPh3)2 (4 mg, 0.005 mmol) in DMSO (2.0 mL) at 90- 100°C to afford 40 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.75 (s, 1H), 8.80 (s, 1H), 8.64-8.63 (d, 1H), 8.05 (br s, 2H), 7.94-7.91 (d, = 8.4 Hz, 1H), 7.79-7.77 (d, = 7.8 Hz, 1H), 7.60-7.50 (m, 1H), 7.41-7.38 (m, 1H), 7.08 (s, 1H), 7.05-7.02 (d, = 8.4 Hz, 1H); MS [M+H]+: 365.
Step 2: Preparation of 4-((2-(pyridin-3-yl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol
The title compound was prepared following the procedure described in Example-36 using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(pyridin-3-yl)benzonitrile (80 mg, 0.21 mmol), sodium azide (71 mg, 1.09 mmol) and triethyl ammonium chloride (150 mg, 1.09 mmol) in DMF (5.0 mL) at 65°C for 48-72 h to afford 40 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.72 (s, 1H), 8.87 (s, 1H), 8.68 (br s, 1H), 8.18-8.15 (m, 3H), 7.88-7.85 (d, = 7.5 Hz, 1H), 7.57 (t, 1H), 7.43-7.40 (d, = 7.8 Hz, 1H), 7.11-7.07 (m, 2H); MS [M+H]+: 405.
Example- 135
4-((2-(2-(pyridin-3-yl)ethyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-(trifluoromethyl)phenol
Figure imgf000256_0001
Step- 1 : Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(2-(pyridin-3- yl)ethyl)benzonitrile
Figure imgf000256_0002
The title compound was prepared following the procedure described in step-1 of Intermediate- 1 using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 80 mg, 0.32 mmol), 4-Iodo-3-(2-(pyridin-3-yl)ethyl)benzonitrile (Intermediate-93, 109 mg, 0.32 mmol), TBAF (102 mg, 0.39 mmol), PdCl2(PPh3)2 (5 mg, 0.006 mmol) in DMSO (2.0 mL) at 90- 100°C to afford 70 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.75 (br s, IH), 8.35 (s, 2H), 7.79 (s, IH), 7.72-7.55 (m, 4H), 7.28-7.24 (m, IH), 7.14 (s, IH), 7.10-7.07 (d, / = 8.4 Hz, IH), 3.15-3.10 (m, 2H), 2.52-2.48 (m, 2H); MS [M+H]+: 393.
Step 2: Preparation of 4-((2-(2-(pyridin-3-yl)ethyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol
The title compound was prepared following the procedure described in Example-36 using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(2-(pyridin-3-yl)ethyl)benzonitrile (70 mg, 0.17 mmol), sodium azide (58 mg, 0.89 mmol) and triethyl ammonium chloride (123 mg, 0.89 mmol) in DMF (5.0 mL) at 65°C for 48-72 h to afford 20 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.71 (br s, IH), 8.38 (s, 2H), 8.01 (s, IH), 7.90 (d, IH), 7.68-7.63 (m, 3H), 7.27 (br s, IH), 7.15 (s, IH), 7.10 (d, IH), 3.18 (m, 2H), 2.98 (m, 2H); MS [M+H]+: 436.
Example- 136
3-chloro-4-((2-(2-(pyridin-3-yl)ethyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)phenol
Figure imgf000257_0001
Step- 1 : Preparation of 4-((2-chloro-4-hydroxyphenyl)ethynyl)-3-(2-(pyridin-3- yl)ethyl)benzonitrile
Figure imgf000257_0002
The title compound was prepared following the procedure described in step-3 of Intermediate- 1 using 3-chloro-4-ethynylphenyl methanesulfonate (Intermediate-89, 80 mg, 0.34 mmol), 4- iodo-3-(2-(pyridin-3-yl)ethyl)benzonitrile (Intermediate-93, 116 mg, 0.34 mmol), TBAF (109 mg, 0.41 mmol), PdCl2(PPh3)2 (5 mg, 0.006 mmol) in DMSO (2.0 mL) at 90- 100°C to afford 70 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.55 (br s, 1H), 8.37 (s, 2H), 7.81 (s, 1H), 7.69-7.57 (m, 3H), 7.52-7.50 (d, J = 8.1 Hz, 1H), 7.28-7.26 (m, 1H), 6.94 (s, 1H), 6.82-6.79 (d, J = 8.4 Hz, 1H), 2.98-2.96 (m, 2H), 2.58 (m, 2H); MS [M+H]+: 359.
Step 2: Preparation of 3-chloro-4-((2-(2-(pyridin-3-yl)ethyl)-4-(lH-tetrazol-5- yl)phenyl)ethynyl)phenol
The title compound was prepared following the procedure described in Example-36 using 4- ((2-chloro-4-hydroxyphenyl)ethynyl)-3-(2-(pyridin-3-yl)ethyl)benzonitrile (70 mg, 0.19 mmol), sodium azide (64 mg, 0.97 mmol) and triethyl ammonium chloride (133 mg, 0.97 mmol) in DMF (5.0 mL) at 65°C for 48-72 h to afford 25 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.60 (br s, 1H), 8.75 (s, 1H), 8.71-8.70 (d, J = 5.4 Hz, 1H), 8.28 (d, 1H), 8.10 (s, 1H), 7.98-7.95 (d, J = 9.9 Hz, 1H), 7.85 (m, 1H), 7.72 (m, 1H), 7.54-7.51 (d, J = 8.7 Hz, 1H), 6.98 (s, 1H), 6.83 (d, 1H), 3.31 (m, 2H), 3.23 (m, 2H); MS [M+H]+: 402.
Example- 137
4-((2-(3-(2-methyl-lH-imidazol- l-yl)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-
(trifluoromethyl)phenol
Figure imgf000258_0001
Step- 1 : Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(2-methyl- lH- imidazol- 1 -yl)propyl)benzonitrile
Figure imgf000258_0002
The title compound was prepared following the procedure described in step-1 of Intermediate- 1 using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 70 mg, 0.28 mmol), 4-iodo-3-(3-(2-methyl-lH-imidazol- l-yl)propyl)benzonitrile (step-1, Intermediate-62, 100 mg, 0.28 mmol), TBAF (87 mg, 0.33 mmol), PdCl2(PPh3)2 (39 mg, 0.05 mmol) in DMSO (2.0 mL) at 90-100°C to afford 50 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.31 (s, 1H), 7.83 (s, 1H), 7.71 (d, 1H), 7.63-7.61 (d, = 8.4 Hz, 2H), 7.17-7.04 (m, 3H), 6.71 (s, 1H), 3.91(t, 2H), 2.83 (t, 2H), 2.22 (s, 3H), 2.01 (m, 2H).
Step 2: Preparation of 4-((2-(3-(2-methyl- lH-imidazol- l-yl)propyl)-4-(lH-tetrazol-5- yl)phenyl)ethynyl)-3-(trifluoromethyl)phenol
The title compound was prepared following the procedure described in Example-36 using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(2-methyl- lH-imidazol- 1- yl)propyl)benzonitrile (70 mg, 0.17 mmol), sodium azide (133 mg, 2.04 mmol) and triethyl ammonium chloride (281 mg, 1.80 mmol) in DMF (2.0 mL) at 65°C for 48-72 h to afford 28 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 8.30 (br s, 1H), 7.98-7.88 (m, 2H), 7.58 (br s, 2H), 7.36 (m, 1H), 7.17 (m, 2H), 4.10 (br , 1H), 2.88 (br s, 2H), 2.48 (s, 3H), 2.14 (m, 2H).
Example- 138
4-((2-(3-(lH-pyrazol-l-yl)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-
(trifluoromethyl)phenol
Figure imgf000259_0001
Step- 1 : Preparation of 3-(3-(lH-pyrazol-l-yl)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethyn
Figure imgf000259_0002
The title compound was prepared following the procedure described in step-1 of Intermediate- 1 using 4-ethynyl-3-(trifluoromethyl)phenol (Intermediate-43, 110 mg, 0.59 mmol), 3-(3-(lH- pyrazol- l-yl)propyl)-4-iodobenzonitrile (Intermediate-87, 144 mg, 0.59 mmol), Et3N (71 mg, 0.708 mmol), PdCl2(PPh3)2 (82 mg, 0.118 mmol), Cul (185 mg, 0.70 mmol) in DMSO (3.0 mL) at rt for 16 h to afford 50 mg of the title product.
Step 2: Preparation of 4-((2-(3-(lH-pyrazol-l-yl)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)- 3-(trifluoromethyl)phenol
The title compound was prepared following the procedure described in Example-36 using 3- (3-(lH-pyrazol-l-yl)propyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzonitrile (65 mg, 0.15 mmol), sodium azide (124 mg, 1.80 mmol) and triethyl ammonium chloride (248 mg, 1.80 mmol) in DMF (2.0 mL) at 65°C for 48-72 h to afford 18 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.67 (br s, 1H), 7.92-7.86 (m, 2H), 7.74 (s, 1H), 7.62- 7.59 (d, J = 8.4 Hz, 1H), 7.52-7.50 (d, J = 8.4 Hz, 1H),7.43 (s, 1H), 7.16 (s, 1H), 7.10 (d, 1H), 6.21 (s, 1H), 4.18 (t, 2H), 2.80 (t, 2H), 2.14 (t, 2H); MS [M+H]+: 439.
Example- 139
4-((2-(pyridin-3-ylmethoxy)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-(trifluoromethyl)phenol
Figure imgf000259_0003
Step- 1 : Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(pyridin-3- ylmethoxy)benzonitrile
Figure imgf000260_0001
The title compound was prepared following the procedure described in step-1 of Intermediate- 1 using 4-ethynyl-3-(trifluoromethyl)phenol (Intermediate-43, 124 mg, 0.66 mmol), 4-iodo- 3-(pyridin-3-ylmethoxy)benzonitrile (Intermediate- 114, 150 mg, 0.44 mmol), TBAF (350 mg, 1.33 mmol), PdCl2(PPh3)2 (12.5 mg, 0.01 mmol) in DMSO (5.0 mL) at 90- 100°C to afford 105 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.71 (s, 1H), 8.57 (s, 1H), 7.89 (s, 1H), 7.75 (t, 1H), 7.62-7.43 (m, 3H), 7.12-7.08 (m, 2H), 5.33 (s, 2H); MS [M+H]+: 395. Step 2: Preparation of 4-((2-(pyridin-3-ylmethoxy)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol
The title compound was prepared following the procedure described in Example-36 using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(pyridin-3-ylmethoxy)benzonitrile (100 mg, 0.25 mmol), sodium azide (99 mg, 1.52 mmol) and triethyl ammonium chloride (210 mg, 1.52 mmol) in DMF (2.0 mL) at 65°C for 48-72 h to afford 20 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.70 (br s, 1H), 8.71 (br s, 2H), 8.18 (d, 1H), 7.93 (s, 1H), 7.71 (m, 3H), 7.55 (d, 1H), 7.12 (s, 1H), 7.07 (d, 2H), 5.43 (s, 2H); MS [M+H]+: 438
Example- 140
4-((2-(3-(cyclopropylmethoxy)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-
(trifluoromethyl)phenol
Figure imgf000260_0002
Step- 1 : Preparation of 4-((4-cyano-2-(3-(cyclopropylmethoxy)propyl)phenyl)ethynyl)-3- (trifluoromethyl)phenyl methanesulfonate
Figure imgf000260_0003
The title compound was prepared following the procedure described in step-1 of Intermediate- 1 using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 70 mg, 0.20 mmol), 3-(3-(cyclopropylmethoxy)propyl)-4-iodobenzonitrile (step-1, Intermediate-54, 71 mg, 0.20 mmol), Et3N (60 mg, 0.59 mmol), PdCl2(PPh3)2 (28 mg, 0.03 mmol), Cul (10 mg, 0.03 mmol) in DMSO (3.0 mL) at rt for 16 h to afford 55 mg of the title product.
Step-2: Preparation of 3-(3-(cyclopropylmethoxy)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzonitrile
Figure imgf000261_0001
The title compound was prepared following the procedure described in step-1 of Intermediate- 1 using 4-((4-cyano-2-(3-(cyclopropylmethoxy)propyl)phenyl)ethynyl)-3-
(trifluoromethyl)phenyl methanesulfonate (100 mg), 1M TBAF solution in THF (0.5 mL) to afford 90 mg of title product..
Step 3: Preparation of 4-((2-(3-(cyclopropylmethoxy)propyl)-4-(lH-tetrazol-5- yl)phenyl)ethynyl)-3-(trifluoromethyl)phenol
The title compound was prepared following the procedure described in Example-36 using 3- (3-(cyclopropylmethoxy)propyl)-4-((4-hydroxy-2-
(trifluoromethyl)phenyl)ethynyl)benzonitrile (90 mg, 0.22 mmol), sodium azide (176 mg, 2.70 mmol) and triethyl ammonium chloride (364 mg, 2.70 mmol) in DMF (2.0 mL) at 65°C for 48-72 h to afford 15 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.72 (br s, 1H), 7.99-7.89 (m, 2H), 7.69-7.63 (m, 2H), 7.17 (s, 1H), 7.11 (d, 1H), 3.21 (m, 2H), 2.91 (m, 2H), 1.88 (m, 2H), 1.23 (m, 1H), 0.84 (d, 2H), 0.41 (d, 2H), 0.13 (s, 2H); MS [M+H]+: 443.
Example- 141
4-((2-(4-hydroxybutyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-(trifluoromethyl)phenol
Figure imgf000261_0002
The title compound was prepared following the procedure described in Example-36 using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(4-hydroxybutyl)benzonitrile (step- 1 , Example-83, 70 mg, 0.19 mmol), sodium azide (152 mg, 2.33 mmol) and triethyl ammonium chloride (314 mg, 2.33 mmol) in DMF (2.0 mL) at 65°C for 48-72 h to afford 17 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.78 (br s, 1H), 8.12 (s, 1H), 8.03-8.01 (d, = 7.8 Hz, 1H), 7.68-7.65 (d, J = 8.1 Hz„ 2H), 7.18 (s, 1H), 7.12-7.10 (d, J = 7.2 Hz, 1H), 4.97 (m, 1H), 3.63 (m, 2H), 2.66 (m, 2H), 2.50 (m, 2H), 1.22 (m, 2H); MS [M+H]+: 401.
Example- 142
-((2-(2-(pyridin-2-yl)ethyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-(trifluoromethyl)phenol
Figure imgf000262_0001
The title compound was prepared following the procedure described in step-1 of Intermediate- 1 using 4-ethynyl-3-(trifluoromethyl)phenol (Intermediate-43, 70 mg, 0.37 mmol), 4-iodo-3- (2-(pyridin-2-yl)ethyl)benzonitrile (Intermediate- 115, 125 mg, 0.37 mmol), TBAF (118 mg, 0.45 mmol), PdCl2(PPh3)2 (52 mg, 0.07 mmol) in DMSO (2.0 mL) at 100°C to afford 55 mg of the title product.
Step 2: Preparation of 4-((2-(2-(pyridin-2-yl)ethyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol
The title compound was prepared following the procedure described in Example-36 using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(2-(pyridin-2-yl)ethyl)benzonitrile (70 mg, 0.17 mmol), sodium azide (139 mg, 2.03 mmol) and triethyl ammonium chloride (281 mg, 2.03 mmol) in DMF (2.0 mL) at 65°C for 48-72 h to afford 12 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.68 (br s, 1H), 8.52 (s, 1H), 7.98 (s, 1H), 7.91 (d, 1H), 7.69 (m, 3H), 7.22-7.16 (m, 4H), 3.29 (m, 2H), 3.13 (m, 2H); MS (m z): 437 (M+H)+.
Example- 143
3-chloro-4-((2-(3-(pyridin-3-yloxy)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)phenol
Figure imgf000263_0001
Step l :Preperation of 4-((2-chloro-4-hydroxyphenyl)ethynyl)-3-(3-(pyridin-3- yloxy)propyl)benzonitrile
Figure imgf000263_0002
The title compound was prepared following the procedure described in step-1 of Intermediate- 1 using 3-chloro-4-ethynylphenyl methanesulfonate (Intermediate-89, 80 mg, 0.34 mmol), 4- iodo-3-(3-(pyridin-3-yloxy)propyl)benzonitrile (step-1, Intermediate-80, 126 mg, 0.34 mmol), TBAF (109 mg, 0.41 mmol), PdCl2(PPh3)2 (5 mg, 0.02 mmol) in DMSO (2.0 mL) at 100°C to afford 75 mg of the title product. 1H NMR (300 MHz, DMSO- ): δ 10.56 (s, 1H), 8.31 (s, 1H), 7.84 (s, 1H), 7.73-7.70 (d, = 6.6 Hz, 1H), 7.67-7.64 (d, = 8.4 Hz, 1H), 7.52-7.49 (d, 1H), 7.36 (m, 2H), 6.96 (s, 1H), 6.81-6.79 (d, = 6.3 Hz, 2H), 4.09 (t, 2H), 3.05 (t, 2H), 2.13 (t, 2H); MS [M+H]+: 389.
Step 2: Preparation of 3-chloro-4-((2-(3-(pyridin-3-yloxy)propyl)-4-(lH-tetrazol-5- yl)phenyl)ethynyl)phenol
The title compound was prepared following the procedure described in Example-36 using 4- ((2-chloro-4-hydroxyphenyl)ethynyl)-3-(3-(pyridin-3-yloxy)propyl)benzonitrile (70 mg, 0.18 mmol), sodium azide (58 mg, 0.90 mmol) and triethyl ammonium chloride (123 mg, 0.90 mmol) in DMF (10.0 mL) at 65°C for 48-72 h to afford 30 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.49 (br s, 1H), 8.25 (s, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.88-7.85 (d, = 8.1 Hz, 1H), 7.56-7.54 (d, = 8.4 Hz, 1H), 7.49-7.46 (d, = 8.4 Hz, 1H), 7.34 (d, 1H), 7.28 (d, 1H), 6.95 (s, 1H), 6.80-6.77 (d, = 8.4 Hz, 1H), 4.15 (t, 2H), 3.05-3.03 (t, 2H), 2.14 (m, 2H); MS [M+H]+: 432. Example- 144
4-((2-(3-(pyridin-3-yloxy)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-
(trifluoromethyl)phenol
Figure imgf000264_0001
Step l :Preperation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(pyridin-3- yloxy)propyl)benzonitrile
Figure imgf000264_0002
The title compound was prepared following the procedure described in step-1 of Intermediate- 1 using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 80 mg, 0.32 mmol), 4-iodo-3-(3-(pyridin-3-yloxy)propyl)benzonitrile (step- 1, Intermediate-80, 119 mg, 0.32 mmol), TBAF (102 mg, 0.39 mmol), PdCl2(PPh3)2 (5 mg, 0.006 mmol) in DMSO (2.0 mL) at 100°C to afford 75 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.75 (s, 1H), 8.23 (s, 1H), 7.74-7.65 (m, 4H), 7.50 (m, 1H), 7.37 (m, 2H), 7.09 (m, 2H), 4.07 (t, 2H), 3.00 (t, 1H), 2.10 (t, 2H); MS [M+H]+: 423.
Step 2: Preparation of 4-((2-(3-(pyridin-3-yloxy)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)- 3-(trifluoromethyl)phenol
The title compound was prepared following the procedure described in Example-36 using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(pyridin-3-yloxy)propyl)benzonitrile (70 mg, 0.16 mmol), sodium azide (54 mg, 0.82 mmol) and triethyl ammonium chloride (113 mg, 0.82 mmol) in DMF (10.0 mL) at 65°C for 48-72 h to afford 35 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.72 (br s, 1H), 8.23 (s, 1H), 8.1 1 (s, 1H), 8.07 (s, 1H), 7.91-7.88 (d, J = 7.5 Hz, 1H), 7.62-7.56 (d, J = 8.4 Hz, 2H), 7.31-7.04 (m, 4H), 4.09 (t, 2H), 3.02(t, 2H), 2.11 (m, 2H); MS [M+H]+: 466. Example- 145
4-((2-(3-(pyrazin-2-yloxy)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-
(trifluoromethyl)phenol
Figure imgf000265_0001
Step l :Preperation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(pyrazin-2- yloxy)propyl)benzonitrile
Figure imgf000265_0002
The title compound was prepared following the procedure described in step-1 of Intermediate- 1 using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 80 mg, 0.32 mmol), 4-iodo-3-(3-(pyrazin-2-yloxy)propyl)benzonitrile (ste-1 of Intermediate-67, 119 mg, 0.32 mmol), TBAF (102 mg, 0.39 mmol), PdCl2(PPh3)2 (5 mg, 0.006 mmol) in DMSO (2.0 mL) at 100°C to afford 70 mg of the title product.
Step 2: Preparation of 4-((2-(3-(pyridin-3-yloxy)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)- 3-(trifluoromethyl)phenol
The title compound was prepared following the procedure described in Example-36 using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(pyrazin-2-yloxy)propyl)benzonitrile (70 mg, 0.16 mmol), sodium azide (53 mg, 0.82 mmol) and triethyl ammonium chloride (113 mg, 0.82 mmol) in DMF (10.0 mL) at 65°C for 48-72 h to afford 25 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.73 (br s, IH), 8.23 (s, IH), 8.15 (s, IH), 7.96 (s, IH), 7.85 (d, IH), 7.58 (d, IH), 7.50 (d, IH), 7.16 (s, IH), 7.09 (d, IH), 4.35 (m, 2H), 2.99 (m, 2H), 2.13 (m, 2H); MS [M+H]+: 465. Example- 146
3-chloro-4-((2-(pyridin-3-yl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)phenol
Figure imgf000266_0001
Step- 1 : Preparation of 4-((2-chloro-4-hydroxyphenyl)ethynyl)-3-(pyridin-3-yl)benzonitrile
Figure imgf000266_0002
The title compound was prepared following the procedure described in step-1 of Intermediate- 1 using 3-chloro-4-ethynylphenyl methanesulfonate (Intermediate- 89, 80 mg, 0.34 mmol), 4- iodo-3-(pyridin-3-yl)benzonitrile (Intermediate- 1 13, 106 mg, 0.34 mmol), TBAF (109 mg, 0.41 mmol), PdCl2(PPh3)2 (5 mg, 0.006 mmol) in DMSO (2.0 mL) at 90- 100°C to afford 70 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.55 (s, 1H), 8.84 (s, 1H), 8.65 (s, 1H), 8.06 (m, 1H),7.92 (m, 1H), 7.86-7.83 (m, 1H), 7.54 (m, 2H), 7.33-7.30 (d, 1H), 6.89 (s, 1H), 6.78 (d, 1H); MS [M+H]+: 330.
Step 2: Preparation of 4-((2-(pyridin-3-yl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol
The title compound was prepared following the procedure described in Example-36 using 4- ((2-chloro-4-hydroxyphenyl)ethynyl)-3-(pyridin-3-yl)benzonitrile (70 mg, 0.21 mmol), sodium azide (69 mg, 1.06 mmol) and triethyl ammonium chloride (145 mg, 1.06 mmol) in DMF (5.0 mL) at 65°C for 48-72 h to afford 30 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.48 (s, 1H), 8.88 (s, 1H), 8.64 (s, 1H), 8.14 (m, 3H), 7.86-7.83 (d, J = 8.4 Hz, 1H), 7.55 (m, 1H), 7.32-7.30 (d, = 8.4 Hz, 1H), 6.89 (s, 1H), 6.78-6.75 (d, = 8.4 Hz, 1H).
Example- 147
4-((2-(pyrimidin-5-yl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-(trifluoromethyl)phenol
Figure imgf000266_0003
Figure imgf000267_0001
The title compound was prepared following the procedure described in step-1 of Intermediate- 1 using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 80 mg, 0.32 mmol), 4-iodo-3-(pyrimidin-5-yl)benzonitrile (Intermediate- 116, 100 mg, 0.32 mmol), TBAF (102 mg, 0.39 mmol), PdCl2(PPh3)2 (5 mg, 0.006 mmol) in DMSO (2.0 mL) at 100°C to afford 80 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.78 (br s, 1H), 9.27 (s, 1H), 9.07 (s, 2H), 8.17 (s, 1H), 8.01-7.98 (d, J = 8.4 Hz, 1H), 7.91-7.86 (d, 1H), 7.47-7.45 (d, = 8.1 Hz, 1H), 7.10-7.05 (m, 2H)
Step 2: Preparation of 4-((2-(pyrimidin-5-yl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol
The title compound was prepared following the procedure described in Example-36 using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(pyrimidin-5-yl)benzonitrile (80 mg, 0.21 mmol), sodium azide (71 mg, 1.09 mmol) and triethyl ammonium chloride (150 mg, 1.09 mmol) in DMF (5.0 mL) at 65°C for 48-72 h to afford 30 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.74 (s, 1H), 9.29 (s, 1H), 9.12 (s, 2H), 8.22-8.19 (m, 2H), 7.92-7.89 (d, = 8.4 Hz, 1H), 7.47-7.45 (d, = 7.2 Hz, 1H), 7.11-7.05 (m, 2H)
Example- 148
3-chloro-4-((2-(pyrimidin-5-yl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)phenol
Figure imgf000267_0002
Step- 1 : Preparation of 4-((2-chloro-4-hydroxyphenyl)ethynyl)-3-(pyrimidin-5-yl)benzonitrile
Figure imgf000267_0003
The title compound was prepared following the procedure described in step-1 of Intermediate- 1 using 3-chloro-4-ethynylphenyl methanesulfonate (Intermediate- 89, 80 mg, 0.34 mmol), 4- iodo-3-(pyrimidin-5-yl)benzonitrile (Intermediate- 116, 106 mg, 0.34 mmol), TBAF (109 mg, 0.41 mmol), PdCl2(PPh3)2 (5 mg, 0.006 mmol) in DMSO (2.0 mL) at 90- 100°C to afford 60 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.58 (s, 1H), 9.26 (s, 1H), 9.1 1 (s, 2H), 8.17 (s, 1H), 8.00-7.97 (m, 1H), 7.89-7.87 (d, = 7.8 Hz, 1H), 7.37-7.34 (d, = 8.7 Hz, 1H), 6.88 (s, 1H), 6.79-6.77 (d, = 6.6 Hz, 1H).
Step 2: Preparation of 3-chloro-4-((2-(pyrimidin-5-yl)-4-(lH-tetrazol-5- yl)phenyl)ethynyl)phenol
The title compound was prepared following the procedure described in Example-36 using 4- ((2-chloro-4-hydroxyphenyl)ethynyl)-3-(pyrimidin-5-yl)benzonitrile (80 mg, 0.24 mmol), sodium azide (79 mg, 1.20 mmol) and triethyl ammonium chloride (165 mg, 1.20 mmol) in DMF (5.0 mL) at 65°C for 48-72 h to afford 25 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.54 (s, 1H), 9.28 (s, 1H), 9.16 (s, 2H), 8.24 (s, 1H), 8.21-8.18 (d, = 8.1 Hz, 1H), 7.95-7.93 (d, = 8.1 Hz, 1H), 7.37-7.34 (d, = 8.1 Hz, 1H), 6.90 (s, 1H), 6.80-6.77 (m, 1H).
Example- 149
2'-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-5'-(lH-tetrazol-5-yl)-[l,r-biphenyl]-3- carboxamide
Figure imgf000268_0001
Step 1 : Preparation of 5'-cyano-2'-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-[l,r- biphenyl]-3-carboxamide
Figure imgf000268_0002
The title compound was prepared following the procedure described in step-1 of Intermediate- 1 using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 100 mg, 0.28 mmol), 5'-cyano-2'-iodo-[l, -biphenyl]-3-carboxamide (Intermediate- 117, 70 mg, 0.28 mmol), TBAF (90 mg, 0.34 mmol), PdCl2(PPh3)2 (39 mg, 0.05 mmol) in DMSO (2.0 mL) at 100°C to afford 70 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.12-8.10 (d, = 7.8 Hz, 1H), 8.02 (s, 1H), 7.92-7.90 (d, = 7.5 Hz, 1H), 7.81 (s, 1H), 7.67-7.49 (m, 5H), 7.33-7.30 (d, 7 = 8.4 Hz, 1H).
Step 2: Preparation of 2'-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-5'-(lH-tetrazol-5- yl)- [ 1 , 1 '-biphenyl] -3 -carboxamide
The title compound was prepared following the procedure described in Example-36 using 5'- cyano-2'-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-[l,r-biphenyl]-3-carboxamide (70 mg, 0.17 mmol), sodium azide (134 mg, 2.06 mmol) and triethyl ammonium chloride (285 mg, 2.06 mmol) in DMF (2.0 mL) at 65°C for 48-72 h to afford 20 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.66 (br s, 1H), 8.27 (m, 1H), 7.99-7.92 (m, 3H), 7.62 (m, 5H), 7.38 (m, 1H), 7.09 (m, 2H); MS [M+2H]+: 452.
Example- 150
N-ethyl-3-(2-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-5-(lH-tetrazol-5- yl)phenyl)propan amide
Figure imgf000269_0001
Step 1 : Preparation of 3-(5-cyano-2-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)phenyl)- N-ethylprop anamide
Figure imgf000269_0002
The title compound was prepared following the procedure described in step-1 of Intermediate- 1 using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 100 mg, 0.30 mmol), 3-(5-cyano-2-iodophenyl)-N-ethylpropanamide (Intermediate- 118, 100 mg, 0.30 mmol), TBAF (94 mg, 0.36 mmol), PdCl2(PPh3)2 (42 mg, 0.060 mmol) in DMSO (2.0 mL) at 100°C to afford 70 mg of the title product.1!! NMR (300 MHz, DMSO- 6): δ
Step 2: Preparation of N-ethyl-3-(2-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-5-(lH- tetrazol-5-yl)phenyl)propanamide
The title compound was prepared following the procedure described in Example-36 using 3- (5-cyano-2-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)phenyl)-N-ethylpropanamide (100 mg, 0.25 mmol), sodium azide (202 mg, 3.10 mmol) and triethyl ammonium chloride (414 mg, 3.0 mmol) in DMF (2.0 mL) at 65°C for 48-72 h to afford 20 mg of title product. 1H NMR (300 MHz, DMSO- 6): δ 8.0 (s, 1H), 7.89 (s, 1H), 7.63 (m, 2H), 7.16-7.11 (m, 2H), 3.23 (m, 2H), 3.09 (m, 2H), 2.65 (m, 2H), 0.96 (br s, 3H).
Example- 151
4-((2-(3-(lH-tetrazol-l-yl)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-
(trifluoromethyl)phenol
Figure imgf000270_0001
Step 1 : Preparation of 3-(3-(lH-tetrazol-l-yl)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethyny
Figure imgf000270_0002
The title compound was prepared following the procedure described in step-1 of Intermediate- 1 using 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30, 100 mg, 0.29 mmol), 3-(3-(lH-tetrazol-l-yl)propyl)-4-iodobenzonitrile (Intermediate- 119, 100 mg, 0.29 mmol), TBAF (91 mg, 0.34 mmol), PdCl2(PPh3)2 (41 mg, 0.058 mmol) in DMSO (2.0 mL) at 100°C to afford 60 mg of the title product.
Step 2: Preparation of 4-((2-(3-(lH-tetrazol-l-yl)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)- 3-(trifluoromethyl)phenol
The title compound was prepared following the procedure described in Example-36 using 3- (3-(lH-tetrazol-l-yl)propyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzonitrile (60 mg, 0.15 mmol), sodium azide (122 mg, 1.87 mmol) and triethyl ammonium chloride (248 mg, 1.80 mmol) in DMF (2.0 mL) at 65°C for 48-72 h to afford 20 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.73 (s, 1H), 9.44 (s, 1H), 8.01 (s, 1H), 7.93 (d, 1H), 7.69-7.58 (m, 2H), 7.17 (s, 1H), 7.12 (d, 1H), 4.55 (t, 2H), 2.91 (t, 2H), 2.27 (m, 2H).
Example- 152
3-(2-((2-chloro-4-hydroxyphenyl)ethynyl)-5-(lH-tetrazol-5-yl)phenyl)-N-ethylpropanamide
Figure imgf000271_0001
Step- 1 : Preparation of 3-(2-((2-chloro-4-hydroxyphenyl)ethynyl)-5-cyanophenyl)-N- ethylprop anamide
Figure imgf000271_0002
The title compound was prepared following the procedure described in step-1 of Intermediate- 1 using 3-chloro-4-ethynylphenyl methanesulfonate (Intermediate-89, 100 mg, 0.43 mmol), 3-(5-cyano-2-iodophenyl)-N-ethylpropanamide (Intermediate- 118, 141 mg, 0.43 mmol), TBAF (134 mg, 0.51 mmol), PdCl2(PPh3)2 (60 mg, 0.086 mmol) in DMSO (2.0 mL) at 90- 100°C to afford 45 mg of the title product.
Step 2: Preparation of 3-(2-((2-chloro-4-hydroxyphenyl)ethynyl)-5-(lH-tetrazol-5-yl)phenyl)- N-ethylprop anamide
The title compound was prepared following the procedure described in Example-36 using 3- (2-((2-chloro-4-hydroxyphenyl)ethynyl)-5-cyanophenyl)-N-ethylpropanamide (70 mg, 0.21 mmol), sodium azide (164 mg, 2.52 mmol) and triethyl ammonium chloride (347 mg, 2.52 mmol) in DMF (5.0 mL) at 65°C for 48-72 h to afford 10 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 8.01 (s, 1H), 7.89 (d, 1H), 7.73 (s, 1H), 7.65-7.63 (d, J = 7.8 Hz, 1H), 7.51-7.48 (d, J = 8.1 Hz, 1H), 6.96 (s, 1H), 6.83-6.80 (d, J = 7.8 Hz, 1H), 3.24 (t, 2H), 3.12 (t, 2H), 2.69 (t, 2H), 0.99-0.97 (m, 3H) Example- 153
3-(2-((2-chloro-4-hydroxyphenyl)ethynyl)-5-(lH-tetrazol-5-yl)phenyl)propanamide
Figure imgf000272_0001
Step- 1 : Preparation of 3-(2-((2-chloro-4-hydroxyphenyl)ethynyl)-5- cyanophenyl)propanamide
Figure imgf000272_0002
The title compound was prepared following the procedure described in step-1 of Intermediate- 1 using 3-chloro-4-ethynylphenyl methanesulfonate (Intermediate- 89, 80 mg, 0.34 mmol), 3- (5-cyano-2-iodophenyl)propanamide (Intermediate- 120, 100 mg, 0.34 mmol), TBAF (109 mg, 0.41 mmol), PdCl2(PPh3)2 (5 mg, 0.006 mmol) in DMSO (2.0 mL) at 90- 100°C to afford 65 mg of the title product.
Step 2: Preparation of 3-(2-((2-chloro-4-hydroxyphenyl)ethynyl)-5-(lH-tetrazol-5- yl)phenyl)propanamide
The title compound was prepared following the procedure described in Example-36 using 3- (2-((2-chloro-4-hydroxyphenyl)ethynyl)-5-cyanophenyl)propanamide (50 mg, 0.15 mmol), sodium azide (120 mg, 1.80 mmol) and triethyl ammonium chloride (248 mg, 1.80 mmol) in
DMF (5.0 mL) at 65°C for 48-72 h to afford 13 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.60 (br s, 1H), 8.00 (s, 1H), 7.90 (m, 1H), 7.64 (d, 1H), 7.51 (d, 1H), 7.32- 6.97 (m, 2H), 6.79 (m, 2H), 3.35 (m, 2H), 3.11(m, 2H); MS [M+H]+: 367.
Example- 154
N-(3-(2-((2-chloro-4-hydroxyphenyl)ethynyl)-5-(lH-tetrazol-5- yl)phenyl)propyl)isobutyramide
Figure imgf000273_0001
Step 1 : Preparation of N-(3-(2-((2-chloro-4-hydroxyphenyl)ethynyl)-5- cyanophenyl)propyl)isobutyramide
Figure imgf000273_0002
The title compound was prepared following the procedure described in step-1 of Intermediate- 1 using N-(3-(5-cyano-2-iodophenyl)propyl)isobutyramide (Intermediate- 107, 100 mg, 0.28 mmol), 3-chloro-4-ethynylphenyl methanesulfonate (Intermediate-89 , 65 mg, 0.28 mmol), TBAF (90 mg, 0.34 mmol), PdCl2(PPh3)2 (5.0 mg, 0.005 mmol) in DMSO (5.0 mL) at 90-100 °C for 2 h to afford 28 mg of the title product.
Step 2: Preparation of N-(3-(2-((2-chloro-4-hydroxyphenyl)ethynyl)-5-(lH-tetrazol-5- yl)phenyl)propyl)isobutyramide
The title compound was prepared following the procedure described in Example-36 using N- (3-(2-((2-chloro-4-hydroxyphenyl)ethynyl)-5-cyanophenyl)propyl)isobutyramide (60 mg, 0.16 mmol), sodium azide (41.6 mg, 0.64 mmol) and triethyl ammonium chloride (41.6 mg, 0.64 mmol) in DMF (2.0 mL) to afford 12 mg of title product. 1H NMR (300 MHz, DMSO- d6): δ 10.50 (br s, 1H), 7.96 (s, 1H), 7.87-7.85 (d, = 8.1 Hz, 1H), 7.78 (m, 1H), 7.58-7.56 (d, = 8.4 Hz, 1H), 7.51-7.48 (d, = 8.7 Hz, 1H), 6.96 (s, 1H), 6.81-6.79 (d, = 8.1 Hz, 1H), 3.11-3.09 (m, 2H), 2.87 (t, 2H), 2.32 (m, 1H), 1.78 (m, 2H), 0.96-0.94 (d, = 6.9 Hz, 6H); MS [M+H]+: 424.
Example- 155
N-(2-((2-chloro-4-hydroxyphenyl)ethynyl)-5-(lH-tetrazol-5-yl)phenethyl)isobutyramide
Figure imgf000274_0001
Step 1 : Preparation of N-(2-((2-chloro-4-hydroxyphenyl)ethynyl)-5- cyanophenethyl)isobutyramide
Figure imgf000274_0002
The title compound was prepared following the procedure described in step-1 of Intermediate- 1 using N-(5-cyano-2-iodophenethyl)isobutyramide (Intermediate- 121, 100 mg, 0.28 mmol), 3-chloro-4-ethynylphenyl methanesulfonate (Intermediate- 89 , 65 mg, 0.28 mmol), TBAF (90 mg, 0.34 mmol), PdCl2(PPh3)2 (5.0 mg, 0.005 mmol) in DMSO (5.0 mL) at 90-100 °C for 2 h to afford 22 mg of the title product.
Step 2: Preparation of N-(2-((2-chloro-4-hydroxyphenyl)ethynyl)-5-(lH-tetrazol-5- yl)phenethyl)isobutyramide
The title compound was prepared following the procedure described in Example-36 using N- (2-((2-chloro-4-hydroxyphenyl)ethynyl)-5-cyanophenethyl)isobutyramide (60 mg, 0.16 mmol), sodium azide (41.6 mg, 0.64 mmol) and triethyl ammonium chloride (41.6 mg, 0.64 mmol) in DMF (2.0 mL) to afford 10 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.48 (br s, 1H), 7.95-7.83 (m, 3H), 7.66-7.54 (m, 4H), 6.97 (s, 1H), 6.83 (d, 1H), 3.05 (m, 1H), 2.89 (m, 2H), 0.94-0.91 (d, J = 9.3 Hz, 6H).
Example- 156
3-chloro-4-((2-(l-methyl- -pyrazol-4-yl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)phenol
Figure imgf000274_0003
Step 1 : Preparation of 4-((2-chloro-4-hydroxyphenyl)ethynyl)-3-(l-methyl- lH-pyrazol-4- yl)benzonitrile
Figure imgf000275_0001
The title compound was prepared following the procedure described in step-1 of Intermediate- 1 using 4-iodo-3-(l-methyl-lH-pyrazol-4-yl)benzonitrile (Intermediate- 122, 107 mg, 0.34 mmol), 3-chloro-4-ethynylphenyl methanesulfonate (Intermediate-89 , 80 mg, 0.34 mmol), TBAF (109 mg, 0.41 mmol), PdCl2(PPh3)2 (5.0 mg, 0.005 mmol) in DMSO (5.0 mL) at 90- 100 °C for 2 h to afford 50 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.80 (br s, 1H), 8.45 (s, 1H), 8.13-8.10 (d, J = 8.7 Hz, 2H), 7.74-7.49 (m, 3H), 6.97 (s, 1H), 6.85- 6.82(d, = 7.8 Hz, 1H), 3.89 (s, 3H).
Step 2: Preparation of 3-chloro-4-((2-(l-methyl- lH-pyrazol-4-yl)-4-(lH-tetrazol-5- yl)phenyl)ethynyl)phenol
The title compound was prepared following the procedure described in Example-36 using 4- ((2-chloro-4-hydroxyphenyl)ethynyl)-3-(l-methyl- lH-pyrazol-4-yl)benzonitrile (70 mg, 0.21 mmol), sodium azide (68 mg, 1.05 mmol) and triethyl ammonium chloride (143 mg, 1.05 mmol) in DMF (2.0 mL) to afford 12 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 8.36 (s, 1H), 8.20 (s, 1H), 8.06 (s, 1H), 7.90-7.88 (d, = 6.9 Hz, 1H), 7.79-7.76 (d, = 7.8 Hz, 1H), 7.53-7.50 (d, = 8.7 Hz, 1H), 6.95 (s, 1H), 6.84-6.80 (d, = 10.5 Hz, 1H), 3.88 (s, 3H).
Example- 157
4-((2-(l-methyl-lH-pyrazol-4-yl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-
(trifluoromethyl)phenol
Figure imgf000275_0002
Step 1 : Preparation of 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(l-methyl-lH- pyrazol-4-yl)benzonitrile
Figure imgf000276_0001
The title compound was prepared following the procedure described in step- 1, Intemediate- 1 using 4-iodo-3-(l-methyl- lH-pyrazol-4-yl)benzonitrile (Intermediate- 122, 101 mg, 0.32 mmol), 4-ethynyl-3-(trifluoromethyl)phenyl methanesulfonate (Intermediate-30 , 80 mg, 0.32 mmol), TBAF (103 mg, 0.39 mmol), PdCl2(PPh3)2 (5.0 mg, 0.006 mmol) in DMSO (5.0 mL) at 90- 100 °C for 2 h to afford 45 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.75 (s, 1H), 8.33 (s, 1H), 8.09-8.06 (d, J = 9.3 Hz, 2H), 7.67-7.56 (m, 3H), 7.16 (s, 1H), 7.12-7.09 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H).
Step 2: Preparation of 4-((2-(l-methyl-lH-pyrazol-4-yl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)- 3-(trifluoromethyl)phenol
The title compound was prepared following the procedure described in Example-36 using 4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(l-methyl-lH-pyrazol-4-yl)benzonitrile (70 mg, 0.21 mmol), sodium azide (62 mg, 1.05 mmol) and triethyl ammonium chloride (130 mg, 1.05 mmol) in DMF (2.0 mL) to afford 10 mg of title product. 1H NMR (300 MHz, DMSO- d6): δ 8.26 (s, lH), 8.19 (s, 1H), 8.00 (s, 1H), 7.91 -7.89 (d, = 8.4 Hz, 1H), 7.73-7.71 (d, = 8.1 Hz, 1H), 7.65-7.62 (d, = 8.4 Hz, 1H), 7.16 (s, 1H), 7.12-7.09 (d, = 8.1 Hz, 1H), 3.89 (s, 3H); MS [M+H]+: 411.
Example- 158
l-(4-(2-((2-chloro-4-hydroxyphenyl)ethynyl)-5-(lH-tetrazol-5-yl)phenyl)piperidin- l- yl)ethanone
Figure imgf000276_0002
Step 1 : Preparation of 3-(l-acetylpiperidin-4-yl)-4-((2-chloro-4- hydroxyphenyl)ethynyl)benzonitrile
Figure imgf000277_0001
The title compound was prepared following the procedure described in step- 1, Intemediate- 1 using 3-(l-acetylpiperidin-4-yl)-4-iodobenzonitrile (Intermediate- 123, 100 mg, 0.28 mmol), 3-chloro-4-ethynylphenyl methanesulfonate (Intermediate-89, 42 mg, 0.28 mmol), TBAF (87 mg, 0.33 mmol), PdCl2(PPh3)2 (4.0 mg, 0.005 mmol) in DMSO (5.0 mL) at 90-100 °C for 2 h to afford 50 mg of the title product.
Step 2: Preparation of l-(4-(2-((2-chloro-4-hydroxyphenyl)ethynyl)-5-(lH-tetrazol-5- yl)phenyl)piperidin- 1 -yl)ethanone
The title compound was prepared following the procedure described in Example-36 using 3- (l-acetylpiperidin-4-yl)-4-((2-chloro-4-hydroxyphenyl)ethynyl)benzonitrile (50 mg, 0.13 mmol), sodium azide (103 mg, 1.58 mmol) and triethyl ammonium chloride (219 mg, 1.58 mmol) in DMF (2.0 mL) to afford 15 mg of title product. 1H NMR (300 MHz, DMSO-d6): δ 10.50 (s,lH), 7.99 (s, 1H), 7.91 (s, 1H), 7.72-7.69 (d, J = 8.4 Hz, 1H), 7.55-7.52 (d, J = 9.0 Hz, 1H), 6.96 (s, 1H), 6.83 (m, 1H), 4.57 (m, 2H), 3.97 (m, 2H), 2.03 (s, 3H), 1.89 (m, 2H), 1.56 (m, 2H); MS [M+H]+: 422.
Example- 159
4-(2-((2-chloro-4-hydroxyphenyl)ethynyl)-5-(lH-tetrazol-5-yl)phenyl)-N-ethylbutanamide
Figure imgf000277_0002
Step 1 : Preparation of 4-(2-((2-chloro-4-hydroxyphenyl)ethynyl)-5-cyanophi
ethylbutanamide
Figure imgf000278_0001
The title compound was prepared following the procedure described in step- 1, Intemediate- 1 using 4-(5-cyano-2-iodophenyl)-N-ethylbutanamide (Intermediate- 124, 100 mg, 0.29 mmol), 3-chloro-4-ethynylphenyl methanesulfonate (Intermediate- 89 , 44 mg, 0.29 mmol), TBAF (91 mg, 0.34 mmol), PdCl2(PPh3)2 (4.0 mg, 0.005 mmol) in DMSO (5.0 mL) at 90-100 °C for 2 h to afford 55 mg of the title product.
Step 2: Preparation of 4-(2-((2-chloro-4-hydroxyphenyl)ethynyl)-5-(lH-tetrazol-5-yl)phenyl)- N-ethylbutanamide
The title compound was prepared following the procedure described in Example-36 using 4- (2-((2-chloro-4-hydroxyphenyl)ethynyl)-5-cyanophenyl)-N-ethylbutanamide (45 mg, 0.13 mmol), sodium azide (106 mg, 1.60 mmol) and triethyl ammonium chloride (226 mg, 1.60 mmol) in DMF (2.0 mL) to afford 15 mg of title product. 1H NMR (300 MHz, DMSO- 6): δ 10.50 (s, lH), 7.97 (s, 1H), 7.87 (s, 1H), 7.60 (d, 1H), 7.53-7.50 (d, J = 9.0 Hz, 1H), 7.11 (s, 1H), 6.82 (d, 1H), 3.20 (m, 2H), 2.92 (t, 2H), 2.34 (t, 2H), 1.91 (m, 2H), 0.99-0.98 (m, 3H).
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 1. 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 1.
The IC50 (nM) values of the compounds are set forth in Table- 1 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 1: In-vitro screening results of compounds of the present invention
Example No. % Inhibition of GSNOR activity at ICso
1 μΜ 10 μΜ (nM)
1 78.03 85.97 C
2 14.52 56.32 D
3 79.68 84.07 C
4 62.46 80.14 D
5 80.9 85.8 B
6 84.3 84.3 B
7 78.9 79.32 A
8 84.45 88.56 A
9 80.4 85.06 A
10 81.24 85.22 B
11 79.11 83.18 B
13 78.06 81.74 B
14 70.22 68.07 C
22 90.67 95.14 B
23 89.9 96.9 A
24 68.46 88.70 C
25 68.34 91.66 C
26 93.83 95.32 A
27 92.5 95.58 A
28 96.16 97.6 A 29 98.13 99.15 A
30 93.33 97.84 A
31 94.16 96.63 A
32 86.01 93.9 A
33 85.59 90.38 C
34 92.77 95.92 A
35 93.45 95.73 A
36 89.2 95.65 A
40 72.6 74.1 B
42 92.26 96.08 A
43 86.04 93.54 A
44 85.69 93.65 A
45 87.7 91.86 A
46 91.91 94.81 A
47 91.73 91.46 A
48 86.03 95.42 A
49 86.24 93.24 B
50 86.94 91.23 A
51 85.88 89.6 A
52 86.58 89.31 A
53 86.52 89.3 A
55 93.87 93.91 A
56 93.38 92.32 A
57 88.12 91.82 A
59 86.16 92.05 A
60 88.83 93.72 A
61 94.03 92.76 A
62 89.37 92.86 A
64 90.66 95.29 A
65 94.37 94.37 A
66 94.9 95.17 A
67 90.79 94.08 A
68 87.81 93.07 A 69 91.44 93.73 A
70 87.15 89.72 B
71 87.5 89.3 A
72 93.84 91.88 A
75 81.58 86.55 B
76 85.27 90.73 B
77 89.31 92.63 A
79 91.21 93.81 A
80 93.99 94.39 A
82 89.51 92.58 A
83 87.19 91.65 A
87 89.88 96.37 A
88 90.2 96.12 A
89 94.24 95.26 A
90 89.41 95.41 B
91 95.55 96.81 A
92 89.14 94.96 A
93 90 93.52 A
94 91.2 92.27 A
95 92.39 93.4 A
96 92.22 94.23 A
97 91.14 93.83 A
98 87.7 94.92 A
99 87.17 90.55 B
100 90.03 94.11 A
101 92.01 92.73 A
103 87.87 93.18 A
104 88.58 92.63 A
105 89.92 94.09 A
106 87.92 91.34 A
107 82.29 94.47 B
108 93.22 96.18 A
109 86.08 93.54 A 110 90.05 94.33 A
111 91.21 94.34 A
112 94.2 94.54 A
113 90.01 94.07 A
114 91.19 93.67 A
115 86.8 92.93 A
116 88.92 96.13 A
117 92.89 94.38 A
118 87.31 86.32 A
119 86.17 91.68 A
120 89.74 93.38 A
122 90.63 91.35 A
123 91.52 95.23 A
124 87.84 - C
125 85.84 92.53 B
126 87.71 93.32 B
127 86.89 90.51 A
128 89.84 94.57 A
129 85.09 92.9 B
130 87.75 92.82 B
131 88.95 94.29 A
132 87.62 93.89 B
133 85.71 87.69 A
134 87.22 88.35 A
135 85.55 87.48 A
136 87.93 90.66 A
137 88.95 95.24 A
138 91.41 94.12 A
139 85.8 90.53 B
140 85.62 90.16 B
141 87.03 87.56 A
142 83.28 86.79 A
143 92.93 92.63 A 144 91.72 94.14 A
145 88.41 95 A
146 85.28 88.4 B
147 87.26 91.16 A
148 87.74 87.93 A
149 80.12 - C
150 86.57 89.85 A
151 87.48 87.6 A
152 84.74 88.85 A
153 83.86 89.25 B
154 81.83 86.25 B
155 81.03 83.91 B
156 84.95 89.54 A
157 87.16 86.74 A
158 83.14 89.26 A
159 84.19 88.39 B
(--): Not determined

Claims

WHAT IS CLAIMED IS:
1. A compound of formula (la)
Figure imgf000284_0001
(la)
or a pharmaceutically acceptable salt thereof,
wherein,
A is selected from
B is sele
OH and
Figure imgf000284_0002
-~^-¾b c ¾c
Ra is selected from hydrogen, Ci_8alkyl, -(CH2)xC(0)NRbRc and -(CH2)XN R R . at each occurrence, R1 is independently selected from halogen, Ci_8alkoxy, Ci_ 8alkoxyCi_8alkyl, hydroxyCi_8alkyl, haloCi_8alkyl, -(CH2)xNRbRc, -(CRbRc)xORb, - 0(CRbRc)xRb, -(CH2)XCN, -(CH2)xC(0)NRbRc, -(CH2)xNHC(0)Rb, -(CH2)xN(Rb)S02Rc, C6_ i4aryl, 3 to 15 membered heterocyclyl, 3 to 15 membered heterocyclylC i_8alkyl, 5 to 14 membered heteroaryl and 5 to 14 membered heteroarylCi_8alkyl, wherein C6-14aryl, 3 to 15 membered heterocyclyl, 3 to 15 membered heterocyclylC i_8alkyl, 5 to 14 membered heteroaryl and 5 to 14 membered heteroarylCi_8alkyl optionally substituted with one or more
R4;
at each occurrence, R is independently selected from halogen, Ci_8alkoxy, Ci_ 8alkoxyCi_8alkyl, haloCi_8alkyl, 3 to 15 membered heterocyclylC i_8alkyl and -(CRbRc)xORb;
R is selected from hydrogen and Ci_8alkyl;
at each occurrence, R4 is independently selected from halogen, hydroxyl, cyano, Ci_ 8alkyl, Ci_8alkoxy, 5 to 14 membered heteroaryl, -(CH2)xC(0)Rb and -(CH2)xC(0)NRbRc; at each occurrence, Rb and Rc which may be same or different, are independently selected from hydrogen, Ci_8alkyl, Ci_8alkoxyCi_8alkyl, C3_i2cycloalkylCi_8alkyl, C6-i4aryl optionally substituted with halogen or Ci_8alkoxy, C6 i4arylCi_8alkyl, 5 to 14 membered heteroaryl optionally substituted with halogen, CN or Ci-galkyl and 5 to 14 membered heteroarylCi-galkyl optionally substituted with Ci-galkyl;
m is selected from '0' to '4', both inclusive;
n is selected from '0' to '4' , both inclusive; and
x is selected from '0' to '4' , both inclusive.
2. The compound according to claim 1, wherein A is
Figure imgf000285_0001
The compound according to claim 1 or 2, wherein B
OH or
Figure imgf000285_0002
4. The compound according to any one of claims 1 to 3, wherein R1 is CI, F, trifluoromethyl, 3-fluoropropyl, methoxy, 3-ethoxypropyl, 3-methoxypropyl, 3- propoxypropyl, 4-ethoxybutyl, 3-hydroxypropyl, 4-hydroxybutyl, 3-hydroxy-3-methylbutyl, cyanomethyl, cyanoethyl, 3-Cyanopropyl, pyridin-3-ylmethoxy, 4-(N-ethylamino-4-oxo)butyl, 3-amino-3-oxopropyl, 3-(7V-ethyl-3-oxo)propyl, 3-(2-methoxyethoxy)propyl, 3-(2- ethoxyethoxy)propyl, 3-(cyclopropylmethoxy)propyl, 3-(benzyloxy)propyl, 4-(pyrazin-2- yloxy)butyl, 3-((6-chloropyridin-3-yl)oxy)propyl, 3-((6-methylpyridin-3-yl)oxy)propyl, 3-((2- methylpyridin-3-yl)oxy)propyl, 3-((4-methylthiazol-2-yl)methoxy)propyl, 3-(2,6-
Dichlorophenoxy)propyl, 3-((2-methylpyridin-3-yl)oxy)propyl, 3-(pyridin-4-yloxy)propyl, 3- (2-Chlorophenoxy)propyl, 3-(3-methoxyphenoxy)propyl, 3-(2,6-Difluorophenoxy)propyl, 3- ((5-Fluoropyridin-3-yl)oxy)propyl, 3-((5-Cyanopyridin-3-yl)oxy)propyl, (pyridin-3- yloxy)methyl, 3-(pyridin-3-yloxy)propyl, 3-(pyrazin-2-yloxy)propyl), 3-(diethylamino)propyl, 3-Aminopropyl, 3-isobutyramidopropyl, 2-isobutyramidoethyl, 3-(l- methylethylsulfonamido)propyl, 3-(l-H-imidazol-l-yl)propyl, 6-(propoxypyridin-3-yl)ethyl, 3-(lH- l,2,3-triazol-l-yl)propyl, 3-(2-methyl-lH-imidazol-l-yl)propyl, 4-(2-methyl- lH- imidazol-l-yl)butyl, 3-(3-methyl- lH-pyrazol- l-yl)propyl, 3-(4-methyl- lH-pyrazol-l- yl)propyl, 3-(lH-pyrazol- l-yl)propyl, 3-(lH-l,2,4-triazol- l-yl)propyl, 2-(pyridin-3-yl)ethyl,
2- (pyridin-4-yl)ethyl, 2-(pyridin-2-yl)ethyl, 3-(2H-tetrazol-2-yl)propyl, 2-(thiazol-2-yl)ethyl,
3- (lH-tetrazol- l-yl)propyl, 3-morpholinopropyl, 4-carbamoylpiperidin- l-ylpropyl, 4- ethoxypiperidin-l-ylpropyl, 1-acetyl piperidin-4-yl, 4-cyanophenyl, 4-Carbamoylphenyl, 3- Carbamoylphenyl, 4-Carbamoyl-3-fluorophenyl, 4-Carbamoyl-3,5-difluorophenyl, 4- Carbamoyl-3-chlorophenyl, 4-Carbamoyl-3-methylphenyl, 6-methoxypyridin-3-yl, 6- carbamoylpyridin-3-yl, 6-propoxypyridin-3-yl, 6-chloropyridin-3-yl, 6-hydroxypyridin-3-yl, 2-carbamoylpyrimidin-5-yl, 6-cyanopyridin-3-yl, pyridin-4-yl, pyridin-3-yl, pyrimidin-5-yl or 1 -methyl- lH-pyrazol-4-yl.
5. The compound according to any one of claims 1 to 4, wherein R is CI, F, methoxy, ethoxymethyl, propoxymethyl, CF3, fluoromethyl, difluoromethyl, pyrrolidin- l-ylmethyl, pyrrolidin- l-ylmethyl or 2-(methoxyethoxy)methyl.
6. The compound according to any one of claims 1 to 5, wherein R4 is cyano, CI, F, methyl, ethyl, hydroxyl, methoxy, ethoxy, propoxy, -CONH2 or acetyl.
7. The compound according to any one of claims 1 to 6, wherein m is 0, 1 or 2.
8. The compound according to any one of claims 1 to 7, wherein n is 0, 1 or 2.
9. The compound according to claim 1, wherein
A is
Figure imgf000286_0001
Figure imgf000286_0002
R1 is CI, F, trifluoromethyl, 3-fluoropropyl, methoxy, 3-ethoxypropyl, 3- methoxypropyl, 3-propoxypropyl, 4-ethoxybutyl, 3-hydroxypropyl, 4-hydroxybutyl, 3- hydroxy-3-methylbutyl, cyanomethyl, cyanoethyl, 3-Cyanopropyl, pyridin-3-ylmethoxy, 4- (N-ethylamino-4-oxo)butyl, 3-amino-3-oxopropyl, 3-(N-ethyl-3-oxo)propyl, 3-(2- methoxyethoxy)propyl, 3-(2-ethoxyethoxy)propyl, 3-(cyclopropylmethoxy)propyl, 3- (benzyloxy)propyl, 4-(pyrazin-2-yloxy)butyl, 3-((6-chloropyridin-3-yl)oxy)propyl, 3-((6- methylpyridin-3-yl)oxy)propyl, 3-((2-methylpyridin-3-yl)oxy)propyl, 3-((4-methylthiazol-2- yl)methoxy)propyl, 3-(2,6-Dichlorophenoxy)propyl, 3-((2-methylpyridin-3-yl)oxy)propyl, 3- (pyridin-4-yloxy)propyl, 3-(2-Chlorophenoxy)propyl, 3-(3-methoxyphenoxy)propyl, 3-(2,6- Difluorophenoxy)propyl, 3-((5-Fluoropyridin-3-yl)oxy)propyl, 3-((5-Cyanopyridin-3- yl)oxy)propyl, (pyridin-3-yloxy)methyl, 3-(pyridin-3-yloxy)propyl, 3-(pyrazin-2- yloxy)propyl), 3-(diethylamino)propyl, 3-Aminopropyl, 3-isobutyramidopropyl, 2- isobutyramidoethyl, 3-(l-methylethylsulfonamido)propyl, 3-(l-H-imidazol-l-yl)propyl, 6- (propoxypyridin-3-yl)ethyl, 3-(lH-l,2,3-triazol- l-yl)propyl, 3-(2-methyl-lH-imidazol- l- yl)propyl, 4-(2-methyl- lH-imidazol-l-yl)butyl, 3-(3-methyl- lH-pyrazol- l-yl)propyl, 3-(4- methyl-lH-pyrazol- l-yl)propyl, 3-(lH-pyrazol- l-yl)propyl, 3-(lH- l,2,4-triazol- l-yl)propyl, 2-(pyridin-3-yl)ethyl, 2-(pyridin-4-yl)ethyl, 2-(pyridin-2-yl)ethyl, 3-(2H-tetrazol-2-yl)propyl, 2-(thiazol-2-yl)ethyl, 3-(lH-tetrazol-l-yl)propyl, 3-morpholinopropyl, 4-carbamoylpiperidin- 1-ylpropyl, 4-ethoxypiperidin-l-ylpropyl, 1 -acetyl piperidin-4-yl, 4-cyanophenyl, 4- Carbamoylphenyl, 3-Carbamoylphenyl, 4-Carbamoyl-3 -fluorophenyl, 4-Carbamoyl-3,5- difluorophenyl, 4-Carbamoyl-3-chlorophenyl, 4-Carbamoyl-3-methylphenyl, 6- methoxypyridin-3-yl, 6-carbamoylpyridin-3-yl, 6-propoxypyridin-3-yl, 6-chloropyridin-3-yl, 6-hydroxypyridin-3-yl, 2-carbamoylpyrimidin-5-yl, 6-cyanopyridin-3-yl, pyridin-4-yl, pyridin-3-yl, pyrimidin-5-yl or 1 -methyl- lH-pyrazol-4-yl,
R is CI, F, methoxy, ethoxymethyl, propoxymethyl, CF3, fluoromethyl, difluoromethyl, pyrrolidin- l-ylmethyl or 2-(methoxyethoxy)methyl,
m is 0, 1 or 2, and
n is 0, 1 or 2.
10. A compound of formula (lb)
Figure imgf000287_0001
(lb)
or a pharmaceutically acceptable salt thereof,
wherein,
A is selected from
Figure imgf000287_0002
-"^-¾b
Ra is selected from hydrogen, Ci_8alkyl, -(CH2)xC(0)NRbRc and -(CH2)XNR . at each occurrence, R1 is independently selected from halogen, Ci_8alkoxy, Ci_ 8alkoxyCi_8alkyl, hydroxyCi_8alkyl, haloCi_8alkyl, -(CH2)xNRbRc, -(CRbRc)xORb, - 0(CRbRc)xRb, -(CH2)XCN, -(CH2)xC(0)NRbRc, -(CH2)xNHC(0)Rb, -(CH2)xN(Rb)S02Rc, C6_ i4aryl, 3 to 15 membered heterocyclyl, 3 to 15 membered heterocyclylCi_8alkyl, 5 to 14 membered heteroaryl and 5 to 14 membered heteroarylCi_8alkyl, wherein C6 i4aryl, 3 to 15 membered heterocyclyl, 3 to 15 membered heterocyclylCi_8alkyl, 5 to 14 membered heteroaryl and 5 to 14 membered heteroarylCi-8alkyl optionally substituted with one or more
R4;
at each occurrence, R is independently selected from halogen, Ci_8alkoxy, Ci_ galkoxyCi-galkyl, haloCi_8alkyl, 3 to 15 membered heterocyclylCi_8alkyl and -(CRbRc)xORb; at each occurrence, R4 is independently selected from halogen, hydroxyl, cyano, Ci_ salkyl, Ci_8alkoxy, 5 to 14 membered heteroaryl, -(CH2)xC(0)Rb and -(CH2)xC(0)NRbRc; at each occurrence, Rb and Rc which may be same or different, are independently selected from hydrogen, Ci_8alkyl, Ci_8alkoxyCi_8alkyl, C3_i2cycloalkylCi_8alkyl, C6-i4aryl optionally substituted with halogen or Ci_8alkoxy, C6-i4arylCi_8alkyl, 5 to 14 membered heteroaryl optionally substituted with halogen, CN or Ci_8alkyl and 5 to 14 membered heteroarylCi-8alkyl optionally substituted with Ci_8alkyl;
m is selected from '0' to '4', both inclusive;
n is selected from '0' to '4' , both inclusive; and
x is selected from '0' to '4' , both inclusive.
11. The compound according to claim 10, wherein A is
Figure imgf000288_0001
12. The compound according to claim 10 or 11, wherein R1 is CI, F, trifluoromethyl, 3- fluoropropyl, methoxy, 3-ethoxypropyl, 3-methoxypropyl, 3-propoxypropyl, 4-ethoxybutyl, 3-hydroxypropyl, 4-hydroxybutyl, 3-hydroxy-3-methylbutyl, cyanomethyl, cyanoethyl, 3- Cyanopropyl, pyridin-3-ylmethoxy, 4-(N-ethylamino-4-oxo)butyl, 3-amino-3-oxopropyl, 3- (N-ethyl-3-oxo)propyl, 3-(2-methoxyethoxy)propyl, 3-(2-ethoxyethoxy)propyl, 3- (cyclopropylmethoxy)propyl, 3-(benzyloxy)propyl, 4-(pyrazin-2-yloxy)butyl, 3-((6- chloropyridin-3-yl)oxy)propyl, 3-((6-methylpyridin-3-yl)oxy)propyl, 3-((2-methylpyridin-3- yl)oxy)propyl, 3-((4-methylthiazol-2-yl)methoxy)propyl, 3-(2,6-Dichlorophenoxy)propyl, 3- ((2-methylpyridin-3-yl)oxy)propyl, 3-(pyridin-4-yloxy)propyl, 3-(2-Chlorophenoxy)propyl, 3-(3-methoxyphenoxy)propyl, 3-(2,6-Difluorophenoxy)propyl, 3-((5-Fluoropyridin-3- yl)oxy)propyl, 3-((5-Cyanopyridin-3-yl)oxy)propyl, (pyridin-3-yloxy)methyl, 3-(pyridin-3- yloxy)propyl, 3-(pyrazin-2-yloxy)propyl), 3-(diethylamino)propyl, 3-Aminopropyl, 3- isobutyramidopropyl, 2-isobutyramidoethyl, 3-(l-methylethylsulfonamido)propyl, 3-(l-H- imidazol-l-yl)propyl, 6-(propoxypyridin-3-yl)ethyl, 3-(lH-l,2,3-triazol- l-yl)propyl, 3-(2- methyl- lH-imidazol- 1 -yl)propyl, 4-(2-methyl- lH-imidazol- 1 -yl)butyl, 3-(3-methyl- 1H- pyrazol- l-yl)propyl, 3-(4-methyl- lH-pyrazol- l-yl)propyl, 3-(lH-pyrazol- l-yl)propyl, 3-(lH- l,2,4-triazol-l-yl)propyl, 2-(pyridin-3-yl)ethyl, 2-(pyridin-4-yl)ethyl, 2-(pyridin-2-yl)ethyl, 3- (2H-tetrazol-2-yl)propyl, 2-(thiazol-2-yl)ethyl, 3-(lH-tetrazol-l-yl)propyl, 3- morpholinopropyl, 4-carbamoylpiperidin-l-ylpropyl, 4-ethoxypiperidin- l-ylpropyl, 1 -acetyl piperidin-4-yl, 4-cyanophenyl, 4-Carbamoylphenyl, 3-Carbamoylphenyl, 4-Carbamoyl-3- fluorophenyl, 4-Carbamoyl-3,5-difluorophenyl, 4-Carbamoyl-3-chlorophenyl, 4-Carbamoyl- 3-methylphenyl, 6-methoxypyridin-3-yl, 6-carbamoylpyridin-3-yl, 6-propoxypyridin-3-yl, 6- chloropyridin-3-yl, 6-hydroxypyridin-3-yl, 2-carbamoylpyrimidin-5-yl, 6-cyanopyridin-3-yl, pyridin-4-yl, pyridin-3-yl, pyrimidin-5-yl or 1 -methyl- lH-pyrazol-4-yl.
13. The compound according to any one of claims 10 to 12, wherein R is CI, F, methoxy, ethoxymethyl, propoxymethyl, CF3, fluoromethyl, difluoromethyl, pyrrolidin- l-ylmethyl, pyrrolidin- l-ylmethyl and 2-(methoxyethoxy)methyl.
14. The compound according to any one of claims 10 to 13, wherein R4 is cyano, CI, F, methyl, ethyl, hydroxyl, methoxy, ethoxy, propoxy, -CONH2 or acetyl.
15. The compound according to claim 10 to 14, wherein m is 0, 1 or 2.
16. The compound according to claim 10 to 15, wherein n is 0, 1 or 2.
17. The compound according to claim 10, wherein
Figure imgf000289_0001
R1 is CI, F, trifluoromethyl, 3-fluoropropyl, methoxy, 3-ethoxypropyl, 3- methoxypropyl, 3-propoxypropyl, 4-ethoxybutyl, 3-hydroxypropyl, 4-hydroxybutyl, 3- hydroxy-3-methylbutyl, cyanomethyl, cyanoethyl, 3-Cyanopropyl, pyridin-3-ylmethoxy, 4- (N-ethylamino-4-oxo)butyl, 3-amino-3-oxopropyl, 3-(V-ethyl-3-oxo)propyl, 3-(2- methoxyethoxy)propyl, 3-(2-ethoxyethoxy)propyl, 3-(cyclopropylmethoxy)propyl, 3- (benzyloxy)propyl, 4-(pyrazin-2-yloxy)butyl, 3-((6-chloropyridin-3-yl)oxy)propyl, 3-((6- methylpyridin-3-yl)oxy)propyl, 3-((2-methylpyridin-3-yl)oxy)propyl, 3-((4-methylthiazol-2- yl)methoxy)propyl, 3-(2,6-Dichlorophenoxy)propyl, 3-((2-methylpyridin-3-yl)oxy)propyl, 3- (pyridin-4-yloxy)propyl, 3-(2-Chlorophenoxy)propyl, 3-(3-methoxyphenoxy)propyl, 3-(2,6- Difluorophenoxy)propyl, 3-((5-Fluoropyridin-3-yl)oxy)propyl, 3-((5-Cyanopyridin-3- yl)oxy)propyl, (pyridin-3-yloxy)methyl, 3-(pyridin-3-yloxy)propyl, 3-(pyrazin-2- yloxy)propyl), 3-(diethylamino)propyl, 3-Aminopropyl, 3-isobutyramidopropyl, 2- isobutyramidoethyl, 3-(l-methylethylsulfonamido)propyl, 3-(l-H-imidazol-l-yl)propyl, 6- (propoxypyridin-3-yl)ethyl, 3-(lH-l,2,3-triazol- l-yl)propyl, 3-(2-methyl-lH-imidazol- l- yl)propyl, 4-(2-methyl- lH-imidazol-l-yl)butyl, 3-(3-methyl- lH-pyrazol- l-yl)propyl, 3-(4- methyl-lH-pyrazol- l-yl)propyl, 3-(lH-pyrazol- l-yl)propyl, 3-(lH- l,2,4-triazol- l-yl)propyl, 2-(pyridin-3-yl)ethyl, 2-(pyridin-4-yl)ethyl, 2-(pyridin-2-yl)ethyl, 3-(2H-tetrazol-2-yl)propyl, 2-(thiazol-2-yl)ethyl, 3-(lH-tetrazol-l-yl)propyl, 3-morpholinopropyl, 4-carbamoylpiperidin- 1-ylpropyl, 4-ethoxypiperidin-l-ylpropyl, 1 -acetyl piperidin-4-yl, 4-cyanophenyl, 4- Carbamoylphenyl, 3-Carbamoylphenyl, 4-Carbamoyl-3 -fluorophenyl, 4-Carbamoyl-3,5- difluorophenyl, 4-Carbamoyl-3-chlorophenyl, 4-Carbamoyl-3-methylphenyl, 6- methoxypyridin-3-yl, 6-carbamoylpyridin-3-yl, 6-propoxypyridin-3-yl, 6-chloropyridin-3-yl, 6-hydroxypyridin-3-yl, 2-carbamoylpyrimidin-5-yl, 6-cyanopyridin-3-yl, pyridin-4-yl, pyridin-3-yl, pyrimidin-5-yl or 1 -methyl- lH-pyrazol-4-yl,
R is CI, F, methoxy, ethoxymethyl, propoxymethyl, CF3, fluoromethyl, difluoromethyl, pyrrolidin- l-ylmethyl or 2-(methoxyethoxy)methyl,
m is 0, 1 or 2, and
n is 0, 1 or 2.
18. A compound selected from
3- Fluoro-4-((4-hydroxyphenyl)ethynyl)benzoic acid;
4- ((4-(lH-imidazol- l-yl)phenyl)ethynyl)-3-fluorobenzoic acid;
3- Chloro-4-((4-hydroxyphenyl)ethynyl)benzoic acid;
4- ((4-Hydroxyphenyl)ethynyl)-3-methoxybenzoic acid;
4-((2-Fluoro-4-hydroxyphenyl)ethynyl)benzoic acid;
3- Fluoro-4-((2-fluoro-4-hydroxyphenyl)ethynyl)benzoic acid;
4- ((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid;
3- Fluoro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid;
4- ((2-Chloro-4-hydroxyphenyl)ethynyl)-3-fluorobenzoic acid;
3-Chloro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid;
3-Chloro-4-((2-fluoro-4-hydroxyphenyl)ethynyl)benzoic acid;
3-Fluoro-4-((4-hydroxy-2-methoxyphenyl)ethynyl)benzoic acid;
3- Chloro-4-((2-chloro-4-hydroxyphenyl)ethynyl)benzoic acid;
4- ((2-fluoro-4-hydroxyphenyl)ethynyl)-3-(trifluoromethyl)benzoic acid;
4-((4-Hydroxy-2-(pyrrolidin- l-ylmethyl)phenyl)ethynyl)benzoic acid; 4-((2-(Ethoxymethyl)-4-hydroxyphenyl)ethynyl)benzoic acid;
4-((4-Hydroxy-2-((2-methoxyethoxy)methyl)phenyl)ethynyl)benzoic acid;
4-((4-Hydroxy-2-(propoxymethyl)phenyl)ethynyl)benzoic acid;
3-Fluoro-4-((4-hydroxy-2-(propoxymethyl)phenyl)ethynyl)benzoic acid;
3- Fluoro-4-((2-(fluoromethyl)-4-hydroxyphenyl)ethynyl)benzoic acid;
4- ((2-(Difluoromethyl)-4-hydroxyphenyl)ethynyl)-3-fluorobenzoic acid;
2- Fluoro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid;
3,5-Difluoro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid;
4-((2,6-Difluoro-4-hydroxyphenyl)ethynyl)benzoic acid;
4-((2,6-Difluoro-4-hydroxyphenyl)ethynyl)-3-fluorobenzoic acid;
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(trifluoromethyl)benzoic acid; 4'-Cyano-6-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-[l, -biphenyl]-3- carboxylic acid;
4'-Carbamoyl-6-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-[l, -biphenyl]-3- carboxylic acid;
4'-Carbamoyl-6-((2-chloro-4-hydroxyphenyl)ethynyl)-[l, -biphenyl]-3-carboxylic acid;
4'-Carbamoyl-3'-fluoro-6-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-[l, - biphenyl]-3-carboxylic acid;
4'-Carbamoyl-3\5'-difluoro-6-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-[l, - biphenyl]-3-carboxylic acid;
2,5-Difluoro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid;
4-((2,5-Difluoro-4-hydroxyphenyl)ethynyl)-3-(trifluoromethyl)benzoic acid;
3- (3-Ethoxypropyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid;
3- (3-Fluoropropyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid;
4- ((2-Fluoro-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-(trifluoromethyl)phenol;
Ethyl 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoate;
4- ((3-Fluoropyridin-4-yl-N-oxide)ethynyl)benzoic acid;
Ethyl 3-fluoro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoate;
5- ((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)thiophene-2-carboxylic acid; Ethyl 4'-carbamoyl-6-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-[l, -biphenyl] 3-carboxylate;
4'-Carbamoyl-3 '-chloro-6-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)- [ 1 , 1 '- biphenyl]-3-carboxylic acid; 4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-methoxypropyl)benzoic acid; 3-(2-Cyanoethyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid;
3- (3-Amino-3-oxopropyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl) benzoic acid;
4- ((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-propoxypropyl)
benzoic acid;
4'-Carbamoyl-6-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3'-methyl-[l, - biphenyl]-3-carboxylic acid;
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(2-methoxyethoxy)propyl) benzoic acid;
3- (3-(diethylamino)propyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl) benzoic acid;
4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(6-methoxypyridin-3-yl)benzoic acid;
3- (3-(lH-imidazol-l-yl)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoic acid;
4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-morpholinopropyl)benzoic acid;
4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-hydroxypropyl)benzoic acid; Ethyl 3-(6-carbamoylpyridin-3-yl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoate;
3-(6-carbamoylpyridin-3-yl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)
ethynyl)benzoic acid;
3-(3-(cyclopropylmethoxy)propyl)-4-((4-hydroxy-2-(trifluoromethyl)
phenyl)ethynyl)benzoic acid;
3- (4-ethoxybutyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid; Ethyl 4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(2-(6-propoxypyridin-3- yl)ethyl)benzoate;
4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(2-(6-propoxypyridin-3- yl)ethyl)benzoic acid;
3- (3-(lH-l,2,3-triazol-l-yl)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoic acid;
4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(pyridin-3- yloxy)propyl)benzoic acid; 3- (3-(2-ethoxyethoxy)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoic acid;
Ethyl 3-(3-(cyclopropylmethoxy)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoate;
4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(2-methyl- lH-imidazol-l- yl)propyl)benzoic acid;
3- (3-(benzyloxy)propyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid;
4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(6-propoxypyridin-3-yl)benzoic acid;
3- (6-chloropyridin-3-yl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl) benzoic acid;
4- ((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(6-hydroxypyridin-3-yl)benzoic acid;
4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(pyrazin-2- yloxy)propyl)benzoic acid;
3-(3-(4-carbamoylpiperidin-l-yl)propyl)-4-((4-hydroxy-2-(trifluoromethyl) phenyl)ethynyl)benzoic acid;
3-(3-(4-ethoxypiperidin- l-yl)propyl)-4-((4-hydroxy-2-(trifluoromethyl)
phenyl)ethynyl)benzoic acid;
3-(3-((6-chloropyridin-3-yl)oxy)propyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl) ethynyl)benzoic acid;
Hexyl 3-fluoro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoate;
2- (diethylamino)-2-oxoethyl 3-fluoro-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoate;
3- (2-carbamoylpyrimidin-5-yl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl) benzoic acid;
4- ((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(4-(2-methyl- lH-imidazol-l- yl)butyl)benzoic acid;
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(4-(pyrazin-2- yloxy)butyl)benzoic acid;
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-((6-methylpyridin-3- yl)oxy)propyl)benzoic acid; 4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-((2-methylpyridin-3- yl)oxy)propyl)benzoic acid;
3- (3-(Pyridin-3-yloxy)propyl)-4-((2-(trifluoromethyl)phenyl)ethynyl)benzoic acid;
4- ((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-((4-methylthiazol-2- yl)methoxy)propyl)benzoic acid;
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(4-hydroxybutyl)benzoic acid; Hexyl 3-(4-ethoxybutyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoate;
2- (Dimethylamino)-2-oxoethyl 3-(6-carbamoylpyridin-3-yl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoate;
Hexyl 3-(3-ethoxypropyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoate; 4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(3-methyl- lH-pyrazol-l- yl)propyl)benzoic acid;
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(4-methyl- lH-pyrazol-l- yl)propyl)benzoic acid;
3- (3-(lH-pyrazol- l-yl)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoic acid;
3- (3-(2,6-Dichlorophenoxy)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoic acid;
4- ((2-Chloro-4-hydroxyphenyl)ethynyl)-3-(3-((2-methylpyridin-3- yl)oxy)propyl)benzoic acid;
3-(3-(lH-l,2,3-triazol-l-yl)propyl)-4-((2-chloro-4-hydroxyphenyl)ethynyl)benzoic acid;
3- (3-(lH-l,2,4-triazol-l-yl)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoic acid;
4- ((2-Chloro-4-hydroxyphenyl)ethynyl)-3-(3-(2-methyl-lH-imidazol- l- yl)propyl)benzoic acid;
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(pyridin-4- yloxy)propyl)benzoic acid;
3- (3-(2-Chlorophenoxy)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoic acid;
4- ((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(2-(pyridin-3-yl)ethyl)benzoic acid;
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(3- methoxyphenoxy)propyl)benzoic acid; 3-(3-(2,6-Difluorophenoxy)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoic acid;
3- (3-((5-Fluoropyridin-3-yl)oxy)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoic acid;
4- ((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-isobutyramidopropyl)benzoic acid;
Ethyl 4-((2-chloro-4-hydroxyphenyl)ethynyl)-3-(6-cyanopyridin-3-yl)benzoate; 4-((2-Chloro-4-hydroxyphenyl)ethynyl)-3-(6-cyanopyridin-3-yl)benzoic acid;
3-(3-(lH-l,2,4-triazol-l-yl)propyl)-4-((2-chloro-4-hydroxyphenyl)ethynyl)benzoic acid;
3-(3-Cyanopropyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid; 3-(3-(lH-tetrazol- l-yl)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoic acid ;
3-(6-Carbamoylpyridin-3-yl)-4-((2-chloro-4-hydroxyphenyl)ethynyl)benzoic acid;
3- (3-((5-Cyanopyridin-3-yl)oxy)propyl)-4-((4-hydroxy-2- (trifluoromethyl)phenyl)ethynyl)benzoic acid;
4- ((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-(l- methylethylsulfonamido)propyl)benzoic acid;
4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(3-hydroxy-3- methylbutyl)benzoic acid;
3- (3-(lH-tetrazol- l-yl)propyl)-4-((2-chloro-4-hydroxyphenyl)ethynyl)benzoic acid;
4- ((2-Chloro-4-hydroxyphenyl)ethynyl)-3-(3-isobutyramidopropyl)benzoic acid; 4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(pyridin-4-yl)benzoic acid; 4-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-3-(2-(thiazol-2-yl)ethyl)benzoic acid;
4-((2-Chloro-4-hydroxyphenyl)ethynyl)-3-(2-(thiazol-2-yl)ethyl)benzoic acid;
4-((2-Chloro-4-hydroxyphenyl)ethynyl)-3-(3-(pyridin-4-yloxy)propyl)benzoic acid;
3- Chloro-4-((2-(3-(2-methyl-lH-imidazol-l-yl)propyl)-4-(lH-tetrazol-5- yl)phenyl)ethynyl)phenol ;
N-(3-(2-((4-Hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-5-(lH-tetrazol-5- yl)phenyl)propyl)isobutyramide;
4- ((2-(pyridin-4-yl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-(trifluoromethyl)phenol; Ethyl 3-(6-carbamoylpyridin-3-yl)-4-((2-chloro-4-hydroxyphenyl)ethynyl)benzoate; 4-((2-(3-(Pyridin-4-yloxy)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol ;
3- Chloro-4-((2-(3-(pyridin-4-yloxy)propyl)-4-(lH-tetrazol-5- yl)phenyl)ethynyl)phenol ;
4- ((2-(2-(pyridin-4-yl)ethyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol;
4-((2-(3-(lH-l,2,4-triazol-l-yl)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol;
4-((2-(3-(lH-l,2,4-triazol-l-yl)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- chlorophenol;
4-((2-(6-chloropyridin-3-yl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol;
4-((2-(3-ethoxypropyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-(trifluoromethyl)phenol;
4-((2-(3-morpholinopropyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-
(trifluoromethyl)phenol;
4-((2-((pyridin-3-yloxy)methyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol;
4-((2-(3-(lH-l,2,3-triazol-l-yl)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol;
4-((2-(6-methoxypyridin-3-yl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol;
2'-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-5'-(lH-tetrazol-5-yl)-[l,r- biphenyl] -4-carboxamide;
4-((2-(pyridin-3-yl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-(trifluoromethyl)phenol;
4-((2-(2-(pyridin-3-yl)ethyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-
(trifluoromethyl)phenol;
3- chloro-4-((2-(2-(pyridin-3-yl)ethyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)phenol;
4- ((2-(3-(2-methyl- lH midazol-l-yl)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol;
4-((2-(3-(lH-pyrazol- l-yl)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol;
4-((2-(pyridin-3-ylmethoxy)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol; 4-((2-(3-(cyclopropylmethoxy)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol;
4-((2-(4-hydroxybutyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-(trifluoromethyl)phenol;
4-((2-(2-(pyridin-2-yl)ethyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-
(trifluoromethyl)phenol;
3- chloro-4-((2-(3-(pyridin-3-yloxy)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)phenol;
4- ((2-(3-(pyridin-3-yloxy)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol;
4-((2-(3-(pyrazin-2-yloxy)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol;
3- chloro-4-((2-(pyridin-3-yl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)phenol;
4- ((2-(pyrimidin-5-yl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3-(trifluoromethyl)phenol;
3- chloro-4-((2-(pyrimidin-5-yl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)phenol;
2'-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-5'-(lH-tetrazol-5-yl)-[l,r- biphenyl]-3-carboxamide;
N-ethyl-3-(2-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)-5-(lH-tetrazol-5- yl)phenyl)propanamide;
4- ((2-(3-(lH-tetrazol- l-yl)propyl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol;
3-(2-((2-chloro-4-hydroxyphenyl)ethynyl)-5-(lH-tetrazol-5-yl)phenyl)-N- ethylprop anamide ;
3-(2-((2-chloro-4-hydroxyphenyl)ethynyl)-5-(lH-tetrazol-5-yl)phenyl)propanamide;
N-(3-(2-((2-chloro-4-hydroxyphenyl)ethynyl)-5-(lH-tetrazol-5- yl)phenyl)propyl)isobutyramide;
N-(2-((2-chloro-4-hydroxyphenyl)ethynyl)-5-(lH-tetrazol-5- yl)phenethyl)isobutyramide;
3- chloro-4-((2-(l-methyl-lH-pyrazol-4-yl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)phenol;
4- ((2-(l-methyl-lH-pyrazol-4-yl)-4-(lH-tetrazol-5-yl)phenyl)ethynyl)-3- (trifluoromethyl)phenol;
l-(4-(2-((2-chloro-4-hydroxyphenyl)ethynyl)-5-(lH-tetrazol-5-yl)phenyl)piperidin- l- yl)ethanone;
4-(2-((2-chloro-4-hydroxyphenyl)ethynyl)-5-(lH-tetrazol-5-yl)phenyl)-N- ethylbutanamide ;
and pharmaceutically acceptable salt thereof.
19. A compound selected from
2- ((3-Fluoro-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoyl)oxy)-N,N,N- trimethylethanaminium iodide; and
3- (3-Aminopropyl)-4-((4-hydroxy-2-(trifluoromethyl)phenyl)ethynyl)benzoic acid hydrochloride.
20. A compound of formula
Figure imgf000298_0001
or a pharmaceutically acceptable salt thereof.
21. A compound of formula
Figure imgf000298_0002
or a pharmaceutically acceptable salt thereof.
22. A compound of formula
Figure imgf000298_0003
or a pharmaceutically acceptable salt thereof.
23. A compound of formula
Figure imgf000298_0004
or a pharmaceutically acceptable salt thereof.
24. A compound of formula
Figure imgf000299_0001
or a pharmaceutically acceptable salt thereof.
A compound of formula
Figure imgf000299_0002
or a pharmaceutically acceptable salt thereof.
26. A compound of formula
Figure imgf000299_0003
or a pharmaceutically acceptable salt thereof.
27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 26 and a pharmaceutically acceptable excipient.
28. The pharmaceutical composition according to claim 27, wherein the pharmaceutically acceptable excipient is a carrier or diluent.
29. 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 26.
30. The method according to claim 29, wherein the disease is a respiratory disease.
31. The method according to claim 30, 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).
32. The method according to claim 30, wherein the respiratory disease is asthma, cystic fibrosis or chronic obstructive pulmonary disease (COPD).
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WO2018177995A1 (en) 2017-03-31 2018-10-04 Bayer Cropscience Aktiengesellschaft Tricyclic carboxamides for controlling arthropods
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CN113582847A (en) * 2021-07-16 2021-11-02 湖北工业大学 Method for preparing iodobenzoic acid (ester) by improving sandmeyer reaction
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