WO2011132048A1 - Heteroaryl compounds as pde10a inhibitors - Google Patents

Heteroaryl compounds as pde10a inhibitors Download PDF

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Publication number
WO2011132048A1
WO2011132048A1 PCT/IB2011/000842 IB2011000842W WO2011132048A1 WO 2011132048 A1 WO2011132048 A1 WO 2011132048A1 IB 2011000842 W IB2011000842 W IB 2011000842W WO 2011132048 A1 WO2011132048 A1 WO 2011132048A1
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phenyl
pyridin
ylmethoxy
quinolin
substituted
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PCT/IB2011/000842
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French (fr)
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Laxmikant Atmaram Gharat
Lakshminarayana Narayana
Pravin Sabhajit Yadav
Neelima Khairatkar-Joshi
Malini Bajpai
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Glenmark Pharmaceutical S.A.
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Publication of WO2011132048A1 publication Critical patent/WO2011132048A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to heteroaryl compounds and their use in treating or preventing diseases, conditions and/or disorders by inhibiting phosphodiesterase 10A (PDE 10 A) enzyme.
  • PDE 10 A phosphodiesterase 10A
  • Phosphodiesterases are a class of intracellular enzymes involved in the hydrolysis of the nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphates (cGMP) into their respective nucleotide monophosphates.
  • the cyclic nucleotides cAMP and cGMP are synthesized by adenylyl and guanylyl cyclases, respectively and serve as secondary messengers in several cellular pathways.
  • a principal mechanism for regulating cyclic nucleotide signaling is by phosphodiesterase-catalyzed cyclic nucleotide catabolism.
  • PDE's encoded by 21 different genes. Each gene typically yields multiple splice variants that further contribute to the isozyme diversity.
  • the PDE families are distinguished functionally based on cyclic nucleotide substrate specificity, mechanism(s) of regulation and sensitivity to inhibitors.
  • PDE's are differentially expressed throughout the body, including in the central nervous system. As a result of these distinct enzymatic activities and localization, different PDE's isozymes can serve distinct physiological functions.
  • the murine homologue has also been cloned [Soderling, S. et al., Proc. Natl. Acad. Sci. USA vol. 96 p. 7071 -7076, ( 1999)] and N-terminal splice variants of both the rat and human genes have been identified [ otera, J. et al., Biochem. Biophys. Res. Comm. vol. 261 , p. 551 -557, (1999); Fujishige, K. et al., Eur. J. Biochem. vol. 266, p. 1 1 1 8- 1 127, ( 1 999)]. There is a high degree of homology across species.
  • the mouse PDE 10A 1 is a 779 amino acid protein that hydrolyzes both cAMP and cGMP to AMP and GMP, respectively.
  • the affinity of PDE10 for cAMP is higher than for cGMP.
  • approximately 5-fold greater Vmax for cGMP over cAMP has lead to the suggestion that PDE10 is a unique cAMP-inhibited cGMPase [Fujishige et al., J. Biol. Chem. vol. 274, p. 18438-18445, (1999)].
  • the PDE10 family of polypeptides shows a lower degree of sequence homology to previously identified PDE families. These low degrees of sequence homology of PDE10 family of polypeptide make them insensitive to certain inhibitors that are known to be specific for other known PDE families (US 6,350,603, incorporated herein by reference).
  • PDEI OA which is one of the PDE subtypes
  • the expression of its mRNA has been identified in many tissues and organs such as striatum, testis, kidney, thyroid gland, pituitary gland, thalamus, cerebellum, heart, lungs and placenta, cells such as aortic smooth muscle cells and aortic endothelial cells, cells of cancers such as lung small cell carcinoma, breast cancer and large bowel cancer. Accordingly, the possibility that PDEI OA is involved in diseases related to these cells, tissues and organs has been demonstrated [J. Biol. Chem. vol. 274, p. 1 8438 ( 1999); Gene, vol. 234, p. 109 ( 1999) and WO 01 /29199].
  • PDEI OA is selectively expressed in dopamine receptive medium spiny neurons, and considerable data suggests that cAMP and cGMP signalling pathways play significant roles in the regulation of medium spiny neuron excitability. Additional studies with papaverine, a potent inhibitor of PDEI OA, confirm that PDEI OA regulates both cAMP and cGMP in vivo in rats [J. A. Siuciak, et al. Neuropharmacology, vol. 5 1 , p. 386- 396, (2006)].
  • PDE I OA inhibitors are useful for treating and/or preventing various diseases caused by enhanced activity of PDEI OA, possibly with reduced side effects (for example, a neural disease such as Parkinson's disease, Huntington disease or Alzheimer's disease, dyskinesia, hypogonadism, diabetes, an ischemic heart disease, hypertension, an inflammatory disease, a disease of the digestive system, an allergic disease, osteoporosis, pain or a malignant tumor).
  • a neural disease such as Parkinson's disease, Huntington disease or Alzheimer's disease, dyskinesia, hypogonadism, diabetes, an ischemic heart disease, hypertension, an inflammatory disease, a disease of the digestive system, an allergic disease, osteoporosis, pain or a malignant tumor.
  • WO 2003/000269, WO 2003/0141 15, WO 2003/0141 16, WO 2003/0141 17, WO 2003/051877, WO 2006/034491 and WO 2006/034512 describe PDE10 inhibitors for treatment of neurodegenerative diseases, cancer, diabetes and its related disorders.
  • WO 2006/072828, WO 2008/084299, WO 2003/093499, WO 2005/082883, WO 2005/120514, WO 2006/01 1040, WO 2006/070284, WO 2007/077490, WO 2007/085954, WO 2007/096743, WO 2007/129183, WO 2008/001 182, WO 2008/0041 17, WO 2008/020302, WO 2009/070584, WO 2009/068320, WO 2009/068246 and WO 2009/036766 describe PDE10 inhibitors for treatment of obesity, diabetes, certain central nervous system disorders, neurodegenerative and psychiatric disorders.
  • WO 2009/029214, WO 2009/025839 and WO 2009/025823 describe PDE 10 inhibitors for treatment of obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder and obsessive-compulsive disorder.
  • WO 2009/1431 78, WO 2009/152825, WO 2009/158393, WO 2009/158467, WO 2009/158473, WO 2010/006130, WO 2010/017236, WO 2010/027097 and WO 2010/030027 describe PDE 10 inhibitors for treatment of anxiety, schizophrenia, drug addiction, movement disorder, certain central nervous system disorders, neurodegenerative and psychiatric disorders.
  • the present invention relates to compounds of formula (1):
  • ring Ar 1 and Ar 2 are independently selected from aryl, heteroaryl and heterocyclyi;
  • R 1 , R 8 and R 9 which may be the same or different, are independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalky!oxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryloxy, aralkyl, arylalkyloxy, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -OR a , -OC(0)R a , -OC(0)NR a R b , -C(0)R a , -C(0)OR a , - C(0)NR a R b , -CR a R b NR a R c , -NR a R b ,
  • R 2 , R 3 , R 10 and R 1 1 are independently selected from hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C(0)OR a and -NR a R b ; or R 2 and R 3 or R 10 and R n , together with the carbon atom to which they are attached may form cyclic ring, which may be monocyclic, bicyclic or tricyclic rings; substituted or unsubstituted; saturated, unsaturated or partially saturated; the cyclic ring may optionally contain one or more heteroatoms selected from O, N or S;
  • R 4 , R 7 and R 12 which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)R a , -C(0)OR a , -C(0)NR a R b , -S(0)NR a R b , -S0 2 NR a R b , - S(0)R a and -S0 2 R a ;
  • R 3 and R 6 which may be the same or different, are independently selected from hydrogen, halogen, haloalkyl, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cyanoalkyl, cyanoalkyloxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)R , -C(0)NR a R b , -C(0)OR a , -CR'R'WR', -NR a R b , - NR a CONR b R c , -NR a C(0)OR b , -N(R a )SOR b , -N(R a )S0 2 R b , -NR a C(0)R b , -NR a C(S)R b , - -
  • R 4 and R 5 together with the atoms to which they are attached may form cyclic ring, which may be monocyclic, bicyclic or tricyclic rings; substituted or unsubstituted; saturated, unsaturated or partially saturated; the cyclic ring may optionally include one or more heteroatoms selected from O, N, or S;
  • R a , R b and R c which may be the same or different, are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;
  • 'm' is an integer ranging from 0 to 4, both inclusive;
  • 'n' is an integer ranging from 1 to 3, both inclusive;
  • 'p' is an integer ranging from 0 to 4, both inclusive
  • 'q' is an integer ranging from 0 to 4, both inclusive
  • 'r is an integer ranging from 1 to 3, both inclusive.
  • the compounds of formula (I) 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.
  • ring Ar 3 and Ar 4 are independently selected from aryl, heteroaryl and heterocyclyl;
  • R 1 , R 9 , R 13 and R 14 which may be the same or different, are independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkyloxy, cycloalkyl, cycloalkylalkyi, cycloalkenyl, aryl, aryloxy, aralkyl, arylalkyloxy, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -OR a , -OC(0)R a , -OC(0)NR a R b , -C(0)R ⁇ -C(0)OR a , - C(0)NR a R , -CR'R'WR 0 , -NR a R b , -NR a C(0)
  • R 10 and R" which may be the same or different, are independently selected from hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C(0)OR a and -NR a R b ; or R 10 and R 1 1 , together with the carbon atom to which they are attached may form cyclic ring, which may be monocyclic, bicyclic or tricyclic rings; substituted or unsubstituted; saturated, unsaturated or partially saturated; the cyclic ring may optionally contain one or more heteroatoms selected from O, N or S; R 12 is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloa!kyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)R a ,
  • R a , R b and R c which may be the same or different, are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;
  • m ' is an integer ranging from 0 to 4, both inclusive;
  • 'q' is an integer ranging from 0 to 4, both inclusive;
  • 'r' is an integer ranging from 1 to 3, both inclusive;
  • 't' is an integer ranging from 0 to 4, both inclusive;
  • 'u' is an integer ranging from 0 to 4, both inclusive.
  • R 9 is halogen (e.g., fluorine) and 'q' is 1.
  • ring Ar 3 is aryl, preferably phenyl.
  • R 13 is halogen (e.g., fluorine), substituted or unsubstituted alkyl (preferably unsubstituted alkyl, more preferably methyl) or OR a ; wherein R a is substituted or unsubstituted alkyl, preferably unsubstituted alkyl, more preferably methyl.
  • 't' is 1 or 2.
  • compounds of the formula (II) in which A is -(C O)-(CR l 0 R") r -, wherein both R 10 and R n are hydrogen and 'r' is 1.
  • ring Ar 4 is aryl, preferably phenyl.
  • R 14 is halogen (e.g., fluorine or chlorine), substituted or unsubstituted alkyl (preferably unsubstituted alkyl, more preferably methyl, ethyl or r-butyl), haloalkyl (e.g., trifluoromethyl), cycloalkyl (e.g., cyclopropyl) or OR a ; wherein R a is substituted or unsubstituted alkyl, preferably unsubstituted alkyl, more preferably methyl.
  • 'u' is 1 , 2 or 3.
  • B is selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, aryl, heteroaryl and heterocyclyl;
  • R 1 , R 9 and R 13 which may be the same or different, are independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkyloxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryloxy, aralkyi, arylalkyloxy, heteroaryl, heteroaralkyi, heterocyclyl, heterocyclylalkyl, -OR a , -OC(0)R a , -OC(0)NR a R b , -C(0)R a , -C(0)OR a , - C(0)NR a R b , -CR a R b NR a R c , -NR a R b ,
  • R l 0 and R 1 ' which may be the same or different, are independently selected from hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C(0)OR a and -NR a R b ; or R 10 and R n , together with the carbon atom to which they are attached may form cyclic ring, which may be monocyclic, bicyclic or tricyclic rings; substituted or unsubstituted; saturated, unsaturated or partially saturated; the cyclic ring may optionally contain one or more heteroatoms selected from O, N or S;
  • R 12 is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)R a , -C(0)OR a , -C(0)NR a R b , - S(0)NR a R , -S0 2 NR a R b , -S(0)R a and -S0 2 R a ;
  • R a , R b and R c which may be the same or different, are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;
  • 'm' is an integer ranging from 0 to 4, both inclusive;
  • 'q' is an integer ranging from 0 to 4, both inclusive;
  • 'r' is an integer ranging from 1 to 3, both inclusive;
  • 't' is an integer ranging from 0 to 4, both inclusive.
  • specifically provided are compounds of the formula (III) in which A is -(CO)-. According to another embodiment, specifically provided are compounds of the formula (III) in which A is -(C 0)-(CH 2 ) , wherein 'r' is 1 , 2 or 3.
  • B is substituted or unsubstituted alkyl (preferably unsubstituted alkyl, more preferably methyl, ethyl, propyl or butyl) or substituted or unsubstituted haloalkyl (preferably trifluoromethyl).
  • D is selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, aryl, heteroaryl and heterocyclyl;
  • R 1 , R 9 and R 14 which may be the same or different, are independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkyloxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryloxy, aralkyi, arylalkyloxy, heteroaryl, heteroaralkyi, heterocyclyl, heterocyclylalkyl, -OR a , -OC(0)R a , -OC(0)NR a R b , -C(0)R a , -C(0)OR a , - C(0)NR a R , -CR a R b NR a R c , -NR a R b , -C(0)OR a
  • 'm' is an integer ranging from 0 to 4, both inclusive;
  • 'q' is an integer ranging from 0 to 4, both inclusive;
  • 'u' is an integer ranging from 0 to 4, both inclusive.
  • R 1 is r unsubstituted heteroaryl, preferably unsubstituted heteroaryl, more prefera and 'm' is 1.
  • R 14 is halogen, preferably fluorine and 'u' is 2.
  • D is hydrogen or substituted or unsubstituted alkyl (preferably unsubstituted alkyl, more preferably methyl).
  • ring Ar 1 is selected from aryl, heteroaryl and heterocyclyl
  • R 1 and R 8 are independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkyloxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryloxy, aralkyl, arylalkyloxy, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -OR A , -OC(0)R A , -
  • R 6 is selected from hydrogen, halogen, haloalkyl, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cyanoalkyl, cyanoalkyloxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)R a , -C(0)NR a R b , -C(0)OR a , - CR ⁇ 'WR 0 , -NR a R b , -NR a CONR b R c , -NR a C(0)OR b , -N(R a )SOR b , -N(R a )S0 2 R b , - NR a C(0)R b , -NR a C(S)R b , -NR a C(S)NR b
  • R 7 is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl. alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)R a , -C(0)OR a , -C(0)NR a R ⁇ - S(0)NR a R b , -S0 2 NR a R b , -S(0)R a and -S0 2 R a ;
  • R a , R b and R c which may be the same or different, are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;
  • 'm' is an integer ranging from 0 to 4, both inclusive;
  • 'p' is an integer ranging from 0 to 4, both inclusive.
  • R 6 is substituted or unsubstituted aryl, preferably substituted aryl, more preferably substituted phenyl; wherein the substituent is halogen preferably chlorine.
  • R 7 is hydrogen or substituted or unsubstituted alkyl (preferably unsubstituted alkyl, more preferably methyl).
  • ring Ar' is aryl, preferably phenyl.
  • ring Ar 1 is selected from aryl, heteroaryl and heterocyclyl
  • R 6 is selected from hydrogen, halogen, haloalkyl, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cyanoalkyl, cyanoalkyloxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)R A , -C(0)NR A R B , -C(0)OR A , - CR WR 0 , -NR A R B , -NR A CONR B R°, -NR A C(0)OR B , -N(R A )SOR B , -N(R a )S0 2 R B , - NR A C(0)R B , -NR A C(S)R B , -NR A C(S)NR B R C , -SONR A R B , -S0 2 NR A R
  • R 7 is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)R , -C(0)OR A , -C(0)NR A R B , - S(0)NR A R B , -S0 2 NR A R , -S(0)R A and -S0 2 R A ;
  • R 9 is independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkyloxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryloxy, aralkyl, arylalkyloxy, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -OR A , -OC(0)R A , - OC(0)N R A R B , -C(0)R A , -C(0)OR A , -C(0)NR A R B , -CR'R'WR", -NR A R B , -NR A C(0)NR B R C , - NR A C(0)OR B , -N(R A )S(0)R
  • R 16 and R 1 7 which may be the same or different, are independently selected from hydrogen and substituted or unsubstituted alkyl;
  • 'q' is an integer ranging from 0 to 4, both inclusive.
  • R 6 is substituted or unsubstituted aryl, preferably substituted aryl, more preferably substituted phenyl; wherein the substituent is halogen preferably chlorine.
  • R 7 is substituted or unsubstituted alkyl, preferably unsubstituted alkyl, more preferably methyl or ethyl.
  • ring Ar 1 is aryl, preferably phenyl.
  • R 16 is hydrogen or substituted or unsubstituted alkyl (preferably unsubstituted alkyl, more preferably methyl).
  • R 17 is hydrogen or substituted or unsubstituted alkyl (preferably unsubstituted alkyl, more preferably methyl).
  • the present invention 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 in the present patent application 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 capsule, sachet, paper or other container.
  • the compounds and pharmaceutical compositions of the present invention are useful for inhibiting PDE10A, which is related to a variety of disease states.
  • the present invention further provides a method of inhibiting PDE 10A in a subject in need thereof by administering to the subject one or more compounds described herein in an amount effective to cause inhibition of such receptor.
  • halogen or halo means fluorine, chlorine, bromine or iodine.
  • 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, 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). Unless set forth or recited to the contrary, all alkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • alkenyl refers to a hydrocarbon chain containing from 2 to 10 carbon atoms and including at least one carbon-carbon double bond. Examples of such alkenyl moiety include, but are not limited to, ethenyl, 1 -propenyl, 2-propenyl (allyl), wo-propenyl, ' 2-methyl- l -propenyl, 1 -butenyl and 2-butenyl. Unless set forth or recited to the contrary, all alkenyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • 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). Examples of such alkynyl moiety include, but are not limited to, ethynyl, propynyl and butynyl. Unless set forth or recited to the contrary, al l alkynyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • alkoxy refers an alkyl group attached via an oxygen linkage to the rest of the molecule. Examples of such alkoxy moiety include, but are not limited to, -OCH 3 and - OC 2 H 5 . Unless set forth or recited to the contrary, all alkoxy groups described herein may be straight chain or branched, substituted or unsubstituted.
  • alkoxyalkyl or “alkyloxyalkyl” refers to an alkoxy or alkyloxy group as defined above directly bonded to an alkyl group as defined above.
  • Example of such alkoxyalkyl moiety includes, but are not limited to, -CH 2 OCH 3 and -CH 2 OC 2 H 5 .
  • all alkoxyalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • haloalkyl refers to at least one halo group (selected from F, CI. Br or I), linked to an alkyl group as defined above.
  • haloalkyl moiety include, but are not l im ited 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, substituted or unsubstituted.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms.
  • 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, substituted or unsubstituted.
  • hydroxyalkyl refers to an alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups.
  • Examples of hydroxyalkyl moiety include, but are not limited to -CH2OH and -C2H 4 OH .
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or sprirobicyclic groups, e.g., sprio(4,4)non-2-yl, spiro[3,3]heptanyl, spiro[3,4]octanyl and spiro[4,4]heptanyl. Unless set forth or recited to the contrary, all cycloalkyl groups described herein may be substituted or unsubstituted.
  • cycloalkylalkyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms directly attached to an alkyl group.
  • 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.
  • Examples of cycloalkylalkyl moiety include, but are not limited to cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl. Unless set forth or recited to the contrary, all cycloalkylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • cycloalkenyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl. Unless set forth or recited to the contrary, all cycloalkenyl groups described or claimed herein may be substituted or unsubstituted.
  • aryl refers to an aromatic radical having 6 to 14 carbon atoms, including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl and biphenyl. Unless set forth or recited to the contrary, all aryl groups described herein may be substituted or unsubstituted.
  • aryloxy refers to an aryl group as defined above attached via an oxygen linkage to the rest of the molecule.
  • Examples of aryloxy moiety include, but are not limited to phenoxy and naphthoxy. Unless set forth or recited to the contrary, all aryloxy groups described herein may be substituted or unsubstituted.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above.
  • Examples of arylalkyl moiety include, but are not limited to - CH 2 C6H 5 and -C2H4C6H5. Unless set forth or recited to the contrary, all arylalkyl groups described herein may be substituted or unsubstituted.
  • arylalkyloxy refers to an arylalkyl group attached via an oxygen linkage to the rest of the molecule.
  • arylalkyloxy moiety include, but are not limited to - OCH2C6H5 and -OC2H4C6H5. Unless set forth or recited to the contrary, all arylalkyloxy groups described herein may be substituted or unsubstituted.
  • heterocyclic ring or “heterocyclyl” unless otherwise specified refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms 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, oxadiazolyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl,
  • 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. Unless set forth or recited to the contrary, all heterocyclyl groups described herein may be substituted or unsubstituted.
  • heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group.
  • 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. Unless set forth or recited to the contrary, all heterocyclylalkyl groups described herein may be substituted or unsubstituted.
  • heteroaryl refers to substituted or unsubstituted 5 to 14 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S.
  • the heteroaryl may be a mono-, bi- or tricyclic ring system.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indoli
  • heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group.
  • 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. Unless set forth or recited to the contrary, all heteroarylalkyi groups described herein may be substituted or unsubstituted.
  • 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). Other mammals include 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.
  • salts forming part of this patent application include salts derived from inorganic bases (such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn), salts of organic bases (such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, and thiamine), salts of chiral bases (such as alkylphenylamine, glycinol, and phenyl glycinol), salts of natural amino acids (such as glycine, alanine, valine, leucine, isoleucine, norleucine.
  • inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn
  • organic bases such as N,N'-diacetylethylenediamine, glucamine, triethylamine, cho
  • tyrosine cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, and serine
  • salts of non-natural amino acids such as D-isomers or substituted amino acids
  • salts of guanidine salts of substituted guanidine (wherein the substituents are selected from nitro, amino, alkyl, alkenyl or alkynyl), ammonium salts, substituted ammonium salts and aluminum salts.
  • salts include acid addition salts (where appropriate) such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates (such as trifluoroacetate), tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates and ketoglutarates.
  • acid addition salts such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates (such as trifluoroacetate), tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates and ketoglutarates.
  • Compounds described herein can comprise one or more asymmetric carbon atoms and thus can occur as racemic mixtures, enantiomers and diastereomers. These compounds can also exist as conformers/rotamers. All such isomeric forms of these compounds are expressly included in the present patent application. Although the specific compounds exemplified in this application may be depicted in a particular stereochemical configuration, compounds having either the opposite stereochemistry at any given chiral centre are envisioned as a part thereof. In addition, compounds of Formula I can exist in different geometrical isomeric forms. Unless otherwise stated a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. The various isomeric forms of the compounds of the present invention may be separated from one another by methods known in the art or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated.
  • the pharmaceutical composition of the present patent application comprises one or more compounds described herein and one or more pharmaceutically acceptable excipients, carriers, diluents or mixture thereof.
  • the compounds described herein may be associated with one or more pharmaceutically acceptable excipients, carriers, diluents or mixture thereof in the form of capsule, sachet, paper or other container.
  • suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethyl cellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmetic pressure, buffers, sweetening agents, flavoring agents, colorants or any combination of the foregoing.
  • the pharmaceutical composition of the patent application may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing methods known in the art.
  • compositions of the present patent application 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).
  • the active compound is mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid or liquid material that acts as a vehicle, excipient or medium for the active compound.
  • the active compound is adsorbed on a granular solid container, for example, in a sachet.
  • compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.
  • 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, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).
  • the oral route is preferred.
  • 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. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, cornstarch and/or potato starch. A syrup or elixir is used in cases where a sweetened vehicle is employed.
  • Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • 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.
  • the daily dosage of the PDEI OA inhibitors can range from about 0.1 to about 30.0 mg/Kg.
  • Mode of administration, dosage forms, suitable pharmaceutical excipients, diluents or carriers 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 patent application provides a method of treating a disease, condition or disorder modulated by a PDEI OA, in a subject by administering to the subject in need thereof a therapeutically effective amount of a compound or a pharmaceutical composition described herein.
  • the present patent application further provides a method of treating diseases, disorders or conditions, modulated by a PDE10A in mammals including human, of neuropsychiatric, neurodegenerative, neurological, neuroendocrinological nature such as, but not limiting to, schizophrenia, psychoses, schizoaffective disorders, positive symptoms of schizophrenia including delusions, disordered thoughts and speech, and tactile, auditory, visual, olfactory and gustatory hallucinations, paranoia, paranormal behaviors, negative symptoms of schizophrenia like deficits of normal emotional responses or of other thought processes including flat or blunted affect and emotion, poverty of speech (alogia), inability to experience pleasure (anhedonia), lack of desire to form relationships (asociality), and lack of motivation (avolition) leading to poor quality of life, functional disabilities typically regarded as manifestations of psychosis and other comorbidities like cognitive, executive, attention, learning, memory, spatial memory and social cognitive functions, Tic disorders like Tourette's syndrome, autism, autism spectrum disorders, attention deficit hyperactivity disorders (ADHD), pediatric
  • This patent application also provides a method of treating a disorder or condition comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in treating said disorder or condition.
  • the phrase "deficiency in attention and/or cognition” as used in the phrase “disorder comprising as a symptom a deficiency in attention and/or cognition” refers to a subnormal functioning in one or more cognitive aspects such as memory, intellect, or learning and logic ability, in a particular individual relative to other individuals within the same general age population.
  • "Deficiency in attention and/or cognition” also refers to a reduction in any particular individual's functioning in one or more cognitive aspects, for example as occur in age-related cognitive decline.
  • disorders that comprise as a symptom a deficiency in attention and/or cognition that can be treated according to the present patent application are dementia, for example, Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug- related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, Multiple sclerosis, Amyotrophic lateral sclerosis, Down's syndrome or AIDS-related dementia; delirium, amnestic disorder, post-traumatic stress disorder, mental retardation, a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression, attention- deficit/hyperactivity disorder and age-related cognitive decline.
  • dementia for example, Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug- related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, Multiple sclerosis, Amyotrophic lateral sclerosis, Down's syndrome or AIDS-related dementia
  • delirium amnes
  • This patent application also provides a method of treating a mood disorder or mood episode in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula I effective in treating said disorder or episode.
  • This patent application also provides a method of treating a mood disorder or mood episode in a mammal, including a human, comprising administering to said mammal a therapeutically effective amount of a compound of formula I in inhibiting PDE1 OA.
  • mood disorders and mood episodes that can be treated according to the present patent application include, but are not limited to, major depressive episode of the mild, moderate or severe type, a manic or mixed mood episode, a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post- stroke depression; major depressive disorder; dysthymic disorder; minor depressive disorder; premenstrual dysphoric disorder; post-psychotic depressive disorder of schizophrenia; a major depressive disorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia; a bipolar disorder, for example bipolar ] disorder, bipolar 11 disorder and cyclothymic disorder.
  • This patent application further provides a method of treating a neurodegenerative disorder or condition in a mammal, including a human, which method comprises administering to said mammal a therapeutically effective amount of a compound of the present invention in treating said disorder or condition.
  • a neurodegenerative disorder or condition refers to a disorder or condition that is caused by the dysfunction and/or death of neurons in the central nervous system.
  • the treatment of these disorders and conditions can be facilitated by administration of an agent which prevents the dysfunction or death of neurons at risk in these disorders or conditions and/or enhances the function of damaged or healthy neurons in such a way as to compensate for the loss of function caused by the dysfunction or death of at-risk neurons.
  • neurotrophic agent refers to a substance or agent that has some or all of these properties.
  • neurodegenerative disorders and conditions that can be treated according to the present patent application include, but are not limited to, Parkinson's disease; Huntington's disease; dementia, for example Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, and Fronto temperal Dementia; neurodegeneration associated with cerebral trauma; neurodegeneration associated with stroke, neurodegeneration associated with cerebral infarct; hypoglycemia-induced neurodegeneration; neurodegeneration associated with epileptic seizure; neurodegeneration associated with neurotoxin poisoning; and multi-system atrophy.
  • Parkinson's disease Huntington's disease
  • dementia for example Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, and Fronto temperal Dementia
  • neurodegeneration associated with cerebral trauma neurodegeneration associated with stroke, neurodegeneration associated with cerebral infarct
  • hypoglycemia-induced neurodegeneration neurodegeneration associated with epileptic seizure
  • neurodegeneration associated with neurotoxin poisoning and multi-system atrophy.
  • the neurodegenerative disorder or condition comprises neurodegeneration of striatal medium spiny neurons in a mammal, including a human.
  • this patent application provides a pharmaceutical composition for treating psychotic disorders, delusional disorders and drug induced psychosis, anxiety disorders, movement disorders, mood disorders, neurodegenerative disorders or drug addiction, comprising a therapeutically effective amount of a compound of the present invention in treating said disorder or condition.
  • this patent application provides a method of treating a disorder selected from psychotic disorders, delusional disorders and drug induced psychosis, anxiety disorders, movement disorders, mood disorders, and neurodegenerative disorders, which method comprises administering a therapeutically effective amount of a compound of the present invention in treating said disorder.
  • this patent application provides a method of treating the disorders above, where the disorders are selected from the group consisting of: dementia, Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; posttraumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention- deficit/hyperactivity disorder; age-related cognitive decline, major depressive episode of the mild, moderate or severe type; a manic or mixed mood episode; a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post- stroke depression; major depressive disorder; dysthymic disorder; minor depressive disorder; premenstrual dysphoric disorder; post-psychotic depressive disorder of schizophrenia
  • a disease or condition selected from obesity or related diseases, conditions; diabetes (including Type I and Type II diabetes); diabetic complications; glucose
  • the compound of formula (l a) is converted into compound of formula (2) by reacting with a substituted alkyl halide at a temperature range of 0-100°C using a suitable solvent (for e.g., acetonitrile, dimethylformamide, dimethylsulphoxide, tetrahydrofuran etc.) in the presence of suitable base such as alkali metal carbonate (for e.g., potassium carbonate etc.), alkali metal hydride (for e.g., sodium hydride etc.) or alkali metal hydroxide (for e.g., sodium hydroxide etc.) and the like following procedures known in the art of organic synthesis.
  • a suitable solvent for e.g., acetonitrile, dimethylformamide, dimethylsulphoxide, tetrahydrofuran etc.
  • suitable base such as alkali metal carbonate (for e.g., potassium carbonate etc.), alkali metal hydride (for e.g.,
  • a compound of formula (2) can also be prepared by the reaction of a compound of formula (l a) with a substituted hydroxy compound under Mitsunobu conditions.
  • Compound of formula (2) can also be prepared by the reaction of a compound of formula ( l b) with an appropriately substituted hydroxy compound in the presence of a base such as alkali metal carbonate (for e.g., potassium carbonate etc.), alkali metal hydride (for e.g., sodium hydride etc.) or alkali metal hydroxide (for e.g., sodium hydroxide etc.) and the like using a suitable solvent (for e.g., acetonitrile, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran etc.).
  • a base such as alkali metal carbonate (for e.g., potassium carbonate etc.), alkali metal hydride (for e.g., sodium hydride etc.) or alkali metal hydroxide (for
  • Compound of formula (2) is converted into compound of formula (3) under reductive conditions utilizing iron or tin metal in a mineral acid like hydrochloric acid or catalytic reduction condition utilizing palladium or platinum on carbon in presence of hydrogen gas and the like.
  • Compound of formula (3) can be converted to a compound of formula (4) by reacting with a substituted halide compound at a temperature (0-100°C) using an appropriate solvent (for e.g., acetonitrile, dimethylformamide, dimethylsulphoxide, tetrahydrofuran etc.) in the presence of suitable base such as alkali metal carbonate (for e.g., potassium carbonate etc.), alkali metal hydride (for e.g., sodium hydride etc.) or alkali metal hydroxide (for e.g., sodium hydroxide etc.) and the like following procedures known in the art of organic synthesis.
  • an appropriate solvent for e.g., acetonitrile, dimethylformamide, di
  • compound of formula (4) can be prepared by reacting the compound of formula (3) with an aldehyde under reductive amination conditions utilizing sodium borohydride, sodium triacetoxyborohydride and the like in an appropriate solvent (for e.g., dichloromethane, dichloroethane etc.) at a temperature range of 0-50°C.
  • an appropriate solvent for e.g., dichloromethane, dichloroethane etc.
  • Compound of formula (4) can also be prepared by reacting compound of formula (3) with an acid chloride or substituted carbamate derivative in the presence of a base (for e.g.
  • Compound of formula (4) can be converted to a compound of formula (IA) by reacting with a carboxylic acid derivative under standard amidation conditions utilizing a coupling agent (for e.g., carbodiimide, benzotriazol-l -yloxytris(dimethylamino) phosphoniumhexafluorophosphate (BOP reagent) etc.) in the presence of a base (for e.g., triethylamine, diisopropylethylamine etc.) in an appropriate solvent (for e.g., dichloromethane, tetrahydrofuran, dimethylformamide etc.).
  • a coupling agent for e.g., carbodiimide, benzotriazol-l -yloxytris(dimethylamino) phosphoniumhexafluorophosphate (BOP reagent) etc.
  • BOP reagent benzotriazol-l -yloxytris(
  • compound of formula (1A) can also be prepared by reacting a compound of formula (4) with an acid chloride, substituted isothiocyanate derivative or substituted carbamate derivative in the presence of a base (for e.g., triethylamine, diisopropylethylamine etc.) in an appropriate solvent (for e.g., dichloromethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide etc.).
  • a base for e.g., triethylamine, diisopropylethylamine etc.
  • an appropriate solvent for e.g., dichloromethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide etc.
  • Compound of formula (3) can be converted to a compound of formula (5) by reacting with carboxylic acid compounds under standard amidation conditions utilizing a coupling agent (for e.g., carbodiimide, BOP reagent etc.) in the presence of a base (for e.g., triethylamine, diisopropylethylamine etc.) in an appropriate solvent (for e.g., dichloromethane, tetrahydrofuran, dimethylformamide etc.).
  • a coupling agent for e.g., carbodiimide, BOP reagent etc.
  • a base for e.g., triethylamine, diisopropylethylamine etc.
  • an appropriate solvent for e.g., dichloromethane, tetrahydrofuran, dimethylformamide etc.
  • compound of formula (5) can also be prepared by reacting a compound of formula (3) with an acid chloride, substituted isothiocyanate derivative or substituted carbamate derivative in the presence of a base (for e.g., triethylamine, diisopropylethylamine etc.) in an appropriate solvent (for e.g., dichloromethane, tetrahydrofuran, dimethylformamide etc.).
  • a base for e.g., triethylamine, diisopropylethylamine etc.
  • an appropriate solvent for e.g., dichloromethane, tetrahydrofuran, dimethylformamide etc.
  • Compound of formula (5) can be converted to a compound of formula (IA) by reacting with a substituted alkyl halide or acyl halide at 0-100°C using an appropriate solvent (for e.g., acetonitrile, dimethylformamide, dimethylsulphoxide, tetrahydrofuran etc.) in the presence of suitable base such as alkali metal carbonate (for e.g., potassium carbonate etc.), alkali metal hydride (for e.g., sodium hydride etc.) or alkali metal hydroxide (for e.g., sodium hydroxide etc.) and the like.
  • an appropriate solvent for e.g., acetonitrile, dimethylformamide, dimethylsulphoxide, tetrahydrofuran etc.
  • suitable base such as alkali metal carbonate (for e.g., potassium carbonate etc.), alkali metal hydride (for e.g., sodium hydride etc.)
  • Compound of formula (IA) can also be prepared by reacting compound of formula (5) with an acid chloride or substituted carbamate derivative in a presence of a suitable base (for e.g. triethylamine, diisopropylethylamine etc.) in an appropriate solvent (for e.g., dichloromethane, tetrahydrofuran, dimethylformam ide, dimethyl sulfoxide etc.).
  • a suitable base for e.g. triethylamine, diisopropylethylamine etc.
  • an appropriate solvent for e.g., dichloromethane, tetrahydrofuran, dimethylformam ide, dimethyl sulfoxide etc.
  • X is O or S
  • Y is -(CR 10 R 1 1 ) r - or -NR 12 -
  • Compound of formula ( l a) is converted into compound of formula (6) by reacting with a substituted 2-chloromethylquinoline at a temperature range of 0- 100°C using an appropriate solvent (for e.g., acetonitrile, dimethylformamide, dimethylsulphoxide, tetrahydrofuran etc.) in the presence of suitable base such as alkali metal carbonate (for e.g., potassium carbonate etc.), alkali metal hydride (for e.g., sodium hydride etc.) or alkali metal hydroxide (for e.g., sodium hydroxide etc.).
  • an appropriate solvent for e.g., acetonitrile, dimethylformamide, dimethylsulphoxide, tetrahydrofuran etc.
  • suitable base such as alkali metal carbonate (for e.g., potassium carbonate etc.), alkali metal hydride (for e.g., sodium hydride etc.) or alkali metal hydro
  • compound of formula (6) can also be prepared by reacting compound of formula ( l a) with a substituted hydroxy 1 compound of quinoline derivative under Mitsunobu conditions.
  • Compound of formula (6) is converted to a compound of formula (7) under reductive conditions utilizing iron or tin metal in a mineral acid like hydrochloric acid or catalytic reduction condition utilizing palladium or platinum on carbon in presence of hydrogen gas and the like.
  • Compound of formula (7) can be converted to a compound of formula (8) by reacting with an substituted alkyl halide at 0-100°C using an appropriate solvent (for e.g.
  • alkali metal carbonate for e.g. potassium carbonate etc.
  • alkali metal hydride for e.g., sodium hydride etc.
  • alkali metal hydroxide for e.g., sodium hydroxide etc.
  • formula (8) could also be prepared by reacting a compound of formula (7) with an aldehyde compound under reductive amination conditions utilizing sodium borohydride, sodium triacetoxyborohydride and the like in an appropriate solvent (for e.g., dichloromethane, dichloroethane etc.) at a temperature range of 0-50°C.
  • an appropriate solvent for e.g., dichloromethane, dichloroethane etc.
  • Compound of formula (8) can be converted to a compound of formula (IIA) by reacting with a carboxylic acid derivative under standard amidation conditions utilizing a coupling agent (for e.g., carbodiimide, benzotriazol-l -yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) etc.) in the presence of suitable base (for e.g., triethylamine, diisopropylethylamine etc.) in an appropriate solvent (for e.g., dichloromethane, tetrahydrofuran, dimethylformamide etc.).
  • a coupling agent for e.g., carbodiimide, benzotriazol-l -yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) etc.
  • suitable base for e.g., triethylamine, diisoprop
  • formula (IIA) can also be prepared by reacting a compound of formula (8) with an acid chloride, substituted carbamate derivative or substituted isothiocyanate derivative in the presence of a base (for e.g., triethylamine, diisopropylethylamine etc.) in an appropriate solvent (for e.g., dichloromethane. tetrahydrofuran, dimethylformamide, dimethyl sulfoxide etc.).
  • a base for e.g., triethylamine, diisopropylethylamine etc.
  • an appropriate solvent for e.g., dichloromethane. tetrahydrofuran, dimethylformamide, dimethyl sulfoxide etc.
  • a compound of formula ( 10) is converted to a compound of formula (1 1) by reacting with a substituted 2- chloromethylquinoline at a temperature range of 0-100°C using an appropriate solvent (for e.g., acetonitrile, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran etc.) in the presence of a suitable base such as alkali metal carbonate (for e.g., potassium carbonate), alkali metal hydride (for e.g., sodium hydride) or alkali metal hydroxide (for e.g., sodium hydroxide) and the like by following procedure known in the art of organic synthesis.
  • an appropriate solvent for e.g., acetonitrile, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran etc.
  • a suitable base such as alkali metal carbonate (for e.g., potassium carbonate), alkali metal hydride (for e.g., sodium
  • Compound of formula (1 1 ) is converted to a compound of formula (7) under deprotection conditions utilizing a deprotecting reagent (for e.g., Cone. HCI, saturated ethyl acetate in HCI gas, methanol saturated with HCI gas, p-toluenesulphonic acid etc.) and the like by following procedure known in the art of organic synthesis.
  • a deprotecting reagent for e.g., Cone. HCI, saturated ethyl acetate in HCI gas, methanol saturated with HCI gas, p-toluenesulphonic acid etc.
  • compound of formula (12) is converted to a compound of formula (13), by reacting it with an appropriate substituted or unsubstituted acyl halide at elevated temperature (60°C to 120°C) in a suitable solvent (for e.g., acetonitrile, dimethylformamide, ethanol, dimethoxyethane, dioxane, dimethylsulphoxide etc.) by following procedures known in the art.
  • a suitable solvent for e.g., acetonitrile, dimethylformamide, ethanol, dimethoxyethane, dioxane, dimethylsulphoxide etc.
  • Compound of formula (13) is converted to a compound of formula (14) where Hal is halogen, by reacting it with halogenating agents such as N-bromosuccinimide or N-iodosuccinimide at -20°C to 100°C, in a suitable solvent such as diethylether, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylsulphoxide or the like by following procedure known in the art.
  • halogenating agents such as N-bromosuccinimide or N-iodosuccinimide at -20°C to 100°C
  • Compound of formula (14) is converted to a compound of formula (15) by reacting with 4-hydroxyphenylboronic acid in presence of palladium metal or palladium complex such as dichlorobis(triphenylphosphine)palladium(ll), tetrakis(triphenylphosphine) palladium(O), dichlorobis(diphenylphosphinopropane)palladium, tris(dibenzylideneacetone) dipalladium or the like as a catalyst, in a suitable solvent such as dioxane, toluene, ethanol, dimethylformamide, dimethylsulphoxide or water or a mixture of them in the temperature range of 25°C to 100°C.
  • palladium metal or palladium complex such as dichlorobis(triphenylphosphine)palladium(ll), tetrakis(triphenylphosphine) palladium(O), dichlorobis(diphenylphosphinopropan
  • Compound of formula (15) is converted to a compound of formula (16) by reacting with an a-haloester derivative in presence of a base such as alkali metal carbonate, alkali metal hydroxide or alkali metal hydride in a solvent such as acetonitrile, dimethylformamide or dimethylsulphoxide in the temperature range of 25°C to 100°C.
  • a base such as alkali metal carbonate, alkali metal hydroxide or alkali metal hydride in a solvent such as acetonitrile, methanol, ethanol, tetrahydrofuran or the like in presence of water in the temperature range of 25°C to 100°C.
  • Compound of formula (17) is converted to a compound of formula ( 18) (where Ar is aryl, heteroaryl or heterocyclyl ring), by reacting it with a phenol containing an electron withdrawing group especially a nitro group, by activating the acid, as acidchloride by reacting it with thionyl chloride or oxalyl chloride, using EDCI .HCI or t BOP reagent, in the presence of a base such as triethylamine, diisopropylethylamine or the like in a solvent such as dichloromethane, dimethylformamide, tetrahydrofuran or the like in the temperature range of 25°C to 100°C.
  • a base such as triethylamine, diisopropylethylamine or the like
  • a solvent such as dichloromethane, dimethylformamide, tetrahydrofuran or the like in the temperature range of 25°C to 100°C.
  • Compound of formula (18) is converted to a compound of formula (IB) by reacting with a compound of formula (19) in the presence of a base such as triethylamine, diisopropeylethylamine or an alkalimetal hydride in a solvent such as tetrahydrofuran, dimethylformamide or the like in the temperature range of 25°C to 100°C.
  • a base such as triethylamine, diisopropeylethylamine or an alkalimetal hydride
  • a solvent such as tetrahydrofuran, dimethylformamide or the like in the temperature range of 25°C to 100°C.
  • compound of formula (17) can also be converted to a compound of formula (IB) by activating it as an acidchloride and reacting it with the compound of formula (19) in the presence of a suitable base such as triethylamine, diisopropeylethylamine or an alkalimetal hydride in a appropriate solvent such as dichloromethane, tetrahydrofuran, dimethylformamide or the like in the temperature range of 25°C to 100°C.
  • a suitable base such as triethylamine, diisopropeylethylamine or an alkalimetal hydride
  • a suitable solvent such as dichloromethane, tetrahydrofuran, dimethylformamide or the like in the temperature range of 25°C to 100°C.
  • Compound of formula ( 17) can also be converted to a compound of formula (IB) by activating it in the presence of a substituted carbodiimide or BOP reagent and reacting it with a compound of formula (19) in the presence of a suitable base such as triethylamine, diisopropeylethylamine or an alkalimetal hydride in a suitable solvent such as dichloromethane, tetrahydrofuran, dimethylformamide or the like in the temperature range of 25°C to 100°C.
  • a suitable base such as triethylamine, diisopropeylethylamine or an alkalimetal hydride
  • a suitable solvent such as dichloromethane, tetrahydrofuran, dimethylformamide or the like in the temperature range of 25°C to 100°C.
  • compound of formula (19a) can optionally be converted to a compound of formula (19) (where R is alkyl), by reacting with an alkyl halide in the presence of a base such as triethylamine, diisopropylethylamine or an alkali metal hydride in a solvent such as tetrahydrofuran, dimethylformamide, dimethylsulphoxide etc., at 0°C to 100°C.
  • a base such as triethylamine, diisopropylethylamine or an alkali metal hydride
  • a solvent such as tetrahydrofuran, dimethylformamide, dimethylsulphoxide etc.
  • Compound of formula (19) and (19a) are converted to compound of formula (20) (where Hal is halogen), by reacting with a substituted a-halo acylhalide derivatives in the presence of a suitable base such as triethylamine, diisopropylethylamine or alkalimetal hydride in an appropriate solvent such as dichloromethane, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylsulphoxide etc., at 0°C to 100°C.
  • a suitable base such as triethylamine, diisopropylethylamine or alkalimetal hydride
  • an appropriate solvent such as dichloromethane, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylsulphoxide etc.
  • Compound of formula (20) is further reacted with compound of formula- (15) in presence of a suitable base such as alkali metal carbonate, alkali metal hydroxide or alkali metal hydride in a solvent such as acetonitrile, dimethylformamide, tetrahydrofuran or dimethylsulphoxide at 25°C to 100°C to obtain a compound of the general formula (IB).
  • a suitable base such as alkali metal carbonate, alkali metal hydroxide or alkali metal hydride
  • a solvent such as acetonitrile, dimethylformamide, tetrahydrofuran or dimethylsulphoxide
  • 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 sodium sulphate, filtration and evaporation of the solvent.
  • Purification includes purification by silica gel chromatographic techniques, in suitable solvents of a suitable polarity as the mobile phase.
  • the following abbreviations are used in the text: DMSO-efc: hexadeuterodimethyl sulfoxide; CDCI 3 - deuterated chloroform; J: coupling constant in units of Hz; RT or rt: room temperature (22- 26°C).
  • aq. aqueous; equiv. or eq.: equivalents.
  • Step 1 Preparation of 6-fluoro-quinoline-2-carbaldehyde To a freshly prepared solution of Se0 2 (0.690 g, 6.21 mmol) in 10% water in dioxane (20 mL) at 40-45°C was added 2-methyl-6-fluoro quinoline (0.500 g, 3.1 0 mmol) and the reaction mixture was stirred at 40-45°C for 3-4 hours. The reaction mass was fi ltered through celite bed, filtrate was di luted with water and extracted with dichloromethane.
  • Step 4 Preparation of tert-butyl ⁇ 4-[(6-fluoroquinolin-2-yl)methoxyl]phenyl ⁇ carbamate
  • a suspension of ter/-butyl (4-hydroxyphenyl)carbamate (0.282 g, 1 .35 mmol) and potassium carbonate (0.3 10 g, 2.24 mmol) in tetrahydrofuran at 80-90°C was added 2- chloromethyl-6-fluoro-quinoline, obtained in Step 3 (0.220 g, 1 .12 mmol) and the reaction mixture was stirred at 90- 100°C for 2-3 hours.
  • the reaction mixture was cooled to room temperature and was added aq 10% NaOH solution; a product precipitated.
  • Step 5 Preparation of 4-(6-fluoro-quinolin-2-ylmethoxy)-phenyl amine
  • Step 6 Preparation of [4-(6-fluoro-quinolin-2-ylmethoxy)-phenyl]-pyridin-3-ylmethylamine
  • 4-(6-fluoro-quinolin-2-ylmethoxy)-phenyl amine, obtained in Step 5 0.1 50 g. 0.559 mmol
  • ethylene dichloride 5 mL
  • 3-pyridine carbaldehyde 0.071 g, 0.663 mmol
  • Step 2 Preparation of (4-methyl-thiazol-5-ylmethyl)-[4-(quinolin-2-ylmethoxy)-phenyl]- amine
  • Step 4 Preparation of 2-pyridin-4-yl-4-(quinolin-2-ylmethoxy)-phenyl amine
  • Step 1 Preparation of 2-(4-chlorophenyl)imidazo[2, 1 -b][ 1 ,3]benzothiazole
  • 2-aminobenzothiazole 2.000 g, 13.33 mmol
  • 4-chlorophenacyl bromide 3.4 g, 14.66 mmol
  • Step 2 Preparation of 2-(4-chlorophenyl)-3-iodoimidazo[2, l -6][l ,3]benzothiazole
  • Step 3 Preparation of 2-(4-chlorophenyl)-3-(4-hydroxyphenyl)benzo[i ]imidazo[2, l-Z>][l ,3] thiazole
  • Step 1 Preparation of ethyl ⁇ 4-[2-(4-Chlorophenyl)imidazo[2,l-»][l,3]benzothiazol-3-yl] phenoxy ⁇ acetate
  • 2-(4-chlorophenyl)-3-(4-hydroxyphenyl)benzo[i ]imidazo[2, l - >][ l ,3] thiazole (0.150 g, 0.398 mmol) in dry DMF (3.0 mL) was added ethylbromoacetate (0.080 g, 0.479 mmol) followed by K 2 C0 3 (0.166 g, 1.200 mmol) and the reaction mixture was stirred at room temperature for 12 hours.
  • Step 2 Preparation of ⁇ 4-[2-(4-chlorophenyl)imidazo[2, l -&][l ,3]benzothiazole-3-yl] phenoxy ⁇ acetic acid
  • Step 1 Preparation of ⁇ 4-[2-(4-chlorophenyl)imidazo[2, l - >][ l ,3]benzothiazol-3-yl]phenoxy ⁇ acetyl chloride
  • Step 2 Preparation of 4-nitrophenyl ⁇ 4-[2-(4-chlorophenylimidazo[2, l -6][l ,3]benzothiazoI- 3-yl]phenoxyl ⁇ acetate
  • Step 1 Preparation of 2-(4-chlorophenyl)imidazo[l,2- ]pyrimidine
  • Step 2 Preparation of 3-bromo-2-(4-chIorophenyl)imidazo[ l ,2-a]pyrimidine
  • Examples 2-45 mentioned in Table 5 below were prepared using appropriate starting material and phenylacetic acid derivatives, by following the procedure as described for the preparation of Example 1 .
  • Examples 57-59 mentioned in Table 6 below were prepared using Intermediate 26 and appropriate amine derivatives, by following the procedure as described for the preparation of Example 56.
  • Table 6 Structure, starting material and characterization data for Examples 57-59
  • Examples 61 -68 mentioned in Table 7 below were prepared using appropriate starting material, by following the procedure as described for the preparation of Example 60.
  • Examples 70-72 mentioned in Table 8 below were prepared using appropriate starting material, by following the procedure as described for the preparation of Example 69.
  • Table 8 Structure, starting material and characterization data for Examples 70-72
  • the illustrative examples of the present invention are screened for PDE 10A activity according to a modified procedure described in Sette, C, lona, S. and Conti, M., J. Biol. Chem. 269 ( 12), pp. 9245-9252, 1994.
  • PDE10 enzyme hydrolyses cAMP / cGMP to metabolically inactive 5'-AMP / 5 '- GMP. Inhibition of PDE10 enzyme activity can be quantitated by using a two step radiometric assay. In this assay, PDE10 enzyme converts 3 H-cAMP/ 3 H-cGMP to 3 H-AMP/ 3 H-GMP which is then converted to 3 H-adenosine / 3 H-guanosine using snake venom nucleotidase. The radioactivity released in the supernatant is quantitated as an indicator of PDE 10 enzyme activity.
  • Test compounds or reference compounds such as dipyridamole, IBMX (Calbiochem) and papaverine (Sigma) were dissolved in dimethylsulfoxide (DMSO) to prepare 1 .0 mM stock solution and diluted suitably to get the desired concentration. Final concentration of DMSO in the reaction was 3 % (v/v).
  • Substrate mixture was prepared by mixing H-cAMP (GE Healthcare) and 1 .0 mM cold cAMP (Sigma) in order to get 0.5 ⁇ and 1 .0 ⁇ final concentrations of each respectively in the assay buffer.
  • 1 .0 mg/mL of snake venom nucleotidase (Sigma) was prepared in D/w.
  • PDE10A assay was carried out in 200 ⁇ _. reaction volume by addition of assay buffer containing 10 mM Tris-HCl (pH 7.4), 0.2 mM MgCl 2 , . test compound at required concentration and diluted enzyme. Reaction mixture was incubated at 30 °C for 30 min. The reaction was stopped by heating the plate in boiling water bath for 5 min and then cooling on an ice bath for 1 5 min. This was followed by addition of 50 ⁇ , of Crotalus atrox snake venom 5'-nucleotidase and incubation at 30 °C for 30 min. Thereafter, 400 ⁇ of Dowex was added and incubated on an ice bath for 1 5 min.
  • Reaction mixture was centrifuged and supernatant was used for quantifying radioactivity in the samples. Reaction was measured as counts per minute (cpm) using Packard Biosciences plate reader. An enzyme control without test compounds was run to quantitate maximum PDEI OA reaction. Inhibition of enzyme activity was calculated as a percent of control reaction. IC50 values were calculated from dose response curve by nonlinear regression analysis using GraphPad Prism software.

Abstract

The present invention provides heteroaryl compounds as Phosphodiesterase 10A (PDE I OA) inhibitors. In particular, compounds described herein are useful for treating or preventing diseases, conditions and/or disorders by inhibiting Phosphodiesterase 10A enzyme. Also provided herein are processes for preparing compounds described herein, Formula (I), intermediates used in their synthesis, pharmaceutical compositions thereof.

Description

HETEROARYL COMPOUNDS AS PDE10A INHIBITORS
Related applications
This application claims the benefit of Indian Provisional Application Nos. 1274/MUM/2010 filed on April 19, 2010; 2447/MUM/2010 filed on September 3, 2010; and US Provisional Application Nos. 61/329,305 filed on April 29, 2010 and all of which are hereby incorporated by reference.
Technical Field
The present invention relates to heteroaryl compounds and their use in treating or preventing diseases, conditions and/or disorders by inhibiting phosphodiesterase 10A (PDE 10 A) enzyme.
Background of the Invention
Phosphodiesterases (PDEs) are a class of intracellular enzymes involved in the hydrolysis of the nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphates (cGMP) into their respective nucleotide monophosphates. The cyclic nucleotides cAMP and cGMP are synthesized by adenylyl and guanylyl cyclases, respectively and serve as secondary messengers in several cellular pathways.
In tissues of vertebrates, various PDE subtypes have been found that hydrolyze cyclic nucleotides [Trend. Pharmacol. Sci. vol. 1 1 , p.150, (1990), Physiol. Rev. vol. 75, p.725, (1 995), Arch. Biochem. Biophys. vol. 322, p. l , (1995) and Kidney International, vol. 55, p.29, ( 1999)]. These have been classified into 1 1 families (PDE1 to PDE 1 1 ) according to biochemical characteristics, enzymological characteristics, homology of amino acid sequences by cloning of corresponding cDNAs, sensitivity to inhibitors and the like.
A principal mechanism for regulating cyclic nucleotide signaling is by phosphodiesterase-catalyzed cyclic nucleotide catabolism. There are 1 1 known families of PDE's encoded by 21 different genes. Each gene typically yields multiple splice variants that further contribute to the isozyme diversity. The PDE families are distinguished functionally based on cyclic nucleotide substrate specificity, mechanism(s) of regulation and sensitivity to inhibitors. Furthermore, PDE's are differentially expressed throughout the body, including in the central nervous system. As a result of these distinct enzymatic activities and localization, different PDE's isozymes can serve distinct physiological functions. Human PDEI O was identified by identification of cDNA fragments published in the National Center for Biotechnology Information (NCBI) Expressed Sequence Tags (EST) database (Loughney et al., W099/42596). While PDE 10 was found to share homology with known PDE's, no function could be identified for PDE10. PDE10 has been identified as a unique family based on primary amino acid sequence and distinct enzymatic activity. Homology screening of EST databases revealed mouse PDEI OA as the first member of the PDE10 family of PDE's [Fujishige et al., J. Biol. Chem. vol. 274, p. l 8438-18445, (1999); Loughney, K. et al., Gene vol. 234, p. 109-1 17, ( 1999)]. The murine homologue has also been cloned [Soderling, S. et al., Proc. Natl. Acad. Sci. USA vol. 96 p. 7071 -7076, ( 1999)] and N-terminal splice variants of both the rat and human genes have been identified [ otera, J. et al., Biochem. Biophys. Res. Comm. vol. 261 , p. 551 -557, (1999); Fujishige, K. et al., Eur. J. Biochem. vol. 266, p. 1 1 1 8- 1 127, ( 1 999)]. There is a high degree of homology across species. The mouse PDE 10A 1 is a 779 amino acid protein that hydrolyzes both cAMP and cGMP to AMP and GMP, respectively. The affinity of PDE10 for cAMP is higher than for cGMP. However, approximately 5-fold greater Vmax for cGMP over cAMP has lead to the suggestion that PDE10 is a unique cAMP-inhibited cGMPase [Fujishige et al., J. Biol. Chem. vol. 274, p. 18438-18445, (1999)].
The PDE10 family of polypeptides shows a lower degree of sequence homology to previously identified PDE families. These low degrees of sequence homology of PDE10 family of polypeptide make them insensitive to certain inhibitors that are known to be specific for other known PDE families (US 6,350,603, incorporated herein by reference).
Regarding PDEI OA which is one of the PDE subtypes, the expression of its mRNA has been identified in many tissues and organs such as striatum, testis, kidney, thyroid gland, pituitary gland, thalamus, cerebellum, heart, lungs and placenta, cells such as aortic smooth muscle cells and aortic endothelial cells, cells of cancers such as lung small cell carcinoma, breast cancer and large bowel cancer. Accordingly, the possibility that PDEI OA is involved in diseases related to these cells, tissues and organs has been demonstrated [J. Biol. Chem. vol. 274, p. 1 8438 ( 1999); Gene, vol. 234, p. 109 ( 1999) and WO 01 /29199].
From the view points of strong expression of mRNA of PDEI OA and its enzymatic activity in the striatum, this enzyme is suggested to be involved in, for example, onset or progression of Parkinson's disease, Huntington disease and dyskinesia caused by long-term administration of L-DOPA (L-3,4-dihydroxyphenylalanine). It has been reported that PDEI OA mRNA expression in the striatum of Huntington disease mouse model is different from that in the striatum of normal mice (WO 01/24781). There are very few effective treatments for neurological disorders characterized by progressive cell loss, known as neurodegenerative diseases, as well as those involving acute cell loss, such as stroke and trauma. In addition, few effective treatments exist for neurological disorders such as psychosis which has been linked to altered striatal function relating to changes in expression of the enzyme PDEI OA [J. A. Siuciak, et al. Neuropharmacology, vol. 51 , p. 374-385, (2006)]. Striatal dysfunction is implicated in a number of CNS disorders including psychosis, schizophrenia, obsessive-compulsive disorders, Parkinson's disease and Huntington's disease. The results with PDEI OA knock-out mice provide evidence that PDEI OA functions to inhibit striatal output by reducing spiny medium neuron excitability. PDEI OA is selectively expressed in dopamine receptive medium spiny neurons, and considerable data suggests that cAMP and cGMP signalling pathways play significant roles in the regulation of medium spiny neuron excitability. Additional studies with papaverine, a potent inhibitor of PDEI OA, confirm that PDEI OA regulates both cAMP and cGMP in vivo in rats [J. A. Siuciak, et al. Neuropharmacology, vol. 5 1 , p. 386- 396, (2006)].
In view of the foregoing, PDE I OA inhibitors are useful for treating and/or preventing various diseases caused by enhanced activity of PDEI OA, possibly with reduced side effects (for example, a neural disease such as Parkinson's disease, Huntington disease or Alzheimer's disease, dyskinesia, hypogonadism, diabetes, an ischemic heart disease, hypertension, an inflammatory disease, a disease of the digestive system, an allergic disease, osteoporosis, pain or a malignant tumor).
WO 2003/000269, WO 2003/0141 15, WO 2003/0141 16, WO 2003/0141 17, WO 2003/051877, WO 2006/034491 and WO 2006/034512 describe PDE10 inhibitors for treatment of neurodegenerative diseases, cancer, diabetes and its related disorders. WO 2006/072828, WO 2008/084299, WO 2003/093499, WO 2005/082883, WO 2005/120514, WO 2006/01 1040, WO 2006/070284, WO 2007/077490, WO 2007/085954, WO 2007/096743, WO 2007/129183, WO 2008/001 182, WO 2008/0041 17, WO 2008/020302, WO 2009/070584, WO 2009/068320, WO 2009/068246 and WO 2009/036766 describe PDE10 inhibitors for treatment of obesity, diabetes, certain central nervous system disorders, neurodegenerative and psychiatric disorders. WO 2009/029214, WO 2009/025839 and WO 2009/025823 describe PDE 10 inhibitors for treatment of obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder and obsessive-compulsive disorder. WO 2009/1431 78, WO 2009/152825, WO 2009/158393, WO 2009/158467, WO 2009/158473, WO 2010/006130, WO 2010/017236, WO 2010/027097 and WO 2010/030027 describe PDE 10 inhibitors for treatment of anxiety, schizophrenia, drug addiction, movement disorder, certain central nervous system disorders, neurodegenerative and psychiatric disorders.
Summary of the Invention
The present invention relates to compounds of formula (1):
Figure imgf000005_0001
(I)
or a pharmaceutically acceptable salt thereof,
wherein,
G] is
Figure imgf000005_0002
Figure imgf000005_0003
with the proviso that
Figure imgf000005_0004
ring Ar1 and Ar2 are independently selected from aryl, heteroaryl and heterocyclyi; L is a bond, or is selected from -(CRl0Rn)r-, -(C=0)- and -(C=0)-NR12-;
A is selected from -(C=0)-, -(C=S)-, -(C=O)-(CRl0Rn) , -(C=0)-NR12- and -(C=S)-
NR' 2-
B and D, which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, aryl, heteroaryl and heterocyclyi; with the proviso that when D is phenyl and A is -(C=0)- or -(C=0)-(CH2)r- then B is not hydrogen or substituted or unsubstituted alkyl;
at each occurrence, R 1 , R8 and R9, which may be the same or different, are independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalky!oxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryloxy, aralkyl, arylalkyloxy, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -ORa, -OC(0)Ra, -OC(0)NRaRb, -C(0)Ra, -C(0)ORa, - C(0)NRaRb, -CRaRbNRaRc, -NRaRb, -NRaC(0)NRbRc, -NRaC(0)ORb, -N(Ra)S(0)Rb, - N(Ra)S02Rb, -NRaC(0)Rb, -NRaC(S)Rb, -NRaC(S)NRbRc, -S(0)NRaRb, -S02NRaRb, -SRa, - S(0)Ra, -S02Ra and -C(S)Ra;
at each occurrence, R2, R3, R10 and R1 1, which may be the same or different, are independently selected from hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C(0)ORa and -NRaRb; or R2 and R3 or R10 and Rn, together with the carbon atom to which they are attached may form cyclic ring, which may be monocyclic, bicyclic or tricyclic rings; substituted or unsubstituted; saturated, unsaturated or partially saturated; the cyclic ring may optionally contain one or more heteroatoms selected from O, N or S;
R4, R7 and R12, which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)Ra, -C(0)ORa, -C(0)NRaRb, -S(0)NRaRb, -S02NRaRb, - S(0)Ra and -S02Ra;
R3 and R6, which may be the same or different, are independently selected from hydrogen, halogen, haloalkyl, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cyanoalkyl, cyanoalkyloxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)R , -C(0)NRaRb, -C(0)ORa, -CR'R'WR', -NRaRb, - NRaCONRbRc, -NRaC(0)ORb, -N(Ra)SORb, -N(Ra)S02Rb, -NRaC(0)Rb, -NRaC(S)Rb, - NRaC(S)NRbRc, -SONRaRb, -S02NRaRb, -OC(0)Ra, -OC(0)NRaRb, -SRa, -SORa, -S02Ra and -C(S)Ra ;
or R4 and R5 together with the atoms to which they are attached may form cyclic ring, which may be monocyclic, bicyclic or tricyclic rings; substituted or unsubstituted; saturated, unsaturated or partially saturated; the cyclic ring may optionally include one or more heteroatoms selected from O, N, or S;
Ra, Rb and Rc, which may be the same or different, are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;
'm' is an integer ranging from 0 to 4, both inclusive;
'n' is an integer ranging from 1 to 3, both inclusive;
'p' is an integer ranging from 0 to 4, both inclusive; 'q' is an integer ranging from 0 to 4, both inclusive; and
'r is an integer ranging from 1 to 3, both inclusive.
The compounds of formula (I) 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.
According to one e ula (II):
Figure imgf000007_0001
or a pharmaceutically acceptable salt thereof,
wherein,
ring Ar3 and Ar4 are independently selected from aryl, heteroaryl and heterocyclyl; A is selected from -(C=0)-, -(C=S)-, -(C=O)-(CRl 0R")r-, -(C=0)-NR12- and -(C=S)-
NR1 2-;
at each occurrence, R1 , R9, R13 and R14, which may be the same or different, are independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkyloxy, cycloalkyl, cycloalkylalkyi, cycloalkenyl, aryl, aryloxy, aralkyl, arylalkyloxy, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -ORa, -OC(0)Ra, -OC(0)NRaRb, -C(0)R\ -C(0)ORa, - C(0)NRaR , -CR'R'WR0, -NRaRb, -NRaC(0)NRbRc, -NRaC(0)ORb, -N(Ra)S(0)Rb, - N(Ra)S02Rb, -NRaC(0)Rb, -NRaC(S)Rb, -NRaC(S)NRbRc, -S(0)NRaRb, -S02NRaR , -SRa, - S(0)Ra, -S02Ra and -C(S)Ra;
at each occurrence, R10 and R" , which may be the same or different, are independently selected from hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C(0)ORa and -NRaRb; or R10 and R1 1 , together with the carbon atom to which they are attached may form cyclic ring, which may be monocyclic, bicyclic or tricyclic rings; substituted or unsubstituted; saturated, unsaturated or partially saturated; the cyclic ring may optionally contain one or more heteroatoms selected from O, N or S; R12 is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloa!kyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)Ra, -C(0)ORa, -C(0)NRaRb, - S(0)NRaRb, -S02NRaRb, -S(0)Ra and -S02Ra;
Ra, Rb and Rc, which may be the same or different, are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;
:m ' is an integer ranging from 0 to 4, both inclusive;
'q' is an integer ranging from 0 to 4, both inclusive;
'r' is an integer ranging from 1 to 3, both inclusive;
't' is an integer ranging from 0 to 4, both inclusive; and
'u' is an integer ranging from 0 to 4, both inclusive.
The embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified.
According to one embodiment, specifically provided are compounds of the formula (II) in which R9 is halogen (e.g., fluorine) and 'q' is 1.
According to another embodiment, specifically provided are compounds of the formula (II) in which 'q' is 0.
According to yet another embodiment, specifically provided are compounds of the formula (II) in which 'm' is 0.
According to yet another embodiment, specifically provided are compounds of the formula (II) in which ring Ar3 is aryl, preferably phenyl.
According to yet another embodiment, specifically provided are compounds of the formula (II) in which ring Ar3 is heteroaryl, referabl
Figure imgf000008_0001
According to yet another embodiment, specifically provided are compounds of the formula (II) in which 't' is 0.
According to yet another embodiment, specifically provided are compounds of the formula (II) in which R13 is halogen (e.g., fluorine), substituted or unsubstituted alkyl (preferably unsubstituted alkyl, more preferably methyl) or ORa; wherein Ra is substituted or unsubstituted alkyl, preferably unsubstituted alkyl, more preferably methyl. In this embodiment 't' is 1 or 2. According to yet another embodiment, specifically provided are compounds of the formula (II) in which A is -(C=O)-(CRl 0R")r-, wherein both R10 and Rn are hydrogen and 'r' is 1.
According to yet another embodiment, specifically provided are compounds of the formula (II) in which A is -(C=O)-(CR10R")r-, wherein R!0 and R1 1 combine together with the carbon atom to which they are attached to form cyclopropyl ring and 'r' is 1.
According to yet another embodiment, specifically provided are compounds of the formula (Π) in which A is -(C=0)-NR12-, wherein R12 is hydrogen.
According to yet another embodiment, specifically provided are compounds of the formula (II) in which ring Ar4 is aryl, preferably phenyl.
According to yet another embodiment, specifically provided are compounds of the formula (11) in which ring Ar4 is heteroaryl, preferably
Figure imgf000009_0001
According to yet another embodiment, specifically provided are compounds of the formula (II) in which 'u' is 0.
According to yet another embodiment, specifically provided are compounds of the formula (II) in which R14 is halogen (e.g., fluorine or chlorine), substituted or unsubstituted alkyl (preferably unsubstituted alkyl, more preferably methyl, ethyl or r-butyl), haloalkyl (e.g., trifluoromethyl), cycloalkyl (e.g., cyclopropyl) or ORa; wherein Ra is substituted or unsubstituted alkyl, preferably unsubstituted alkyl, more preferably methyl. In this embodiment 'u' is 1 , 2 or 3.
According to one embodiment, there is provided a compound of formula (111):
Figure imgf000009_0002
(III)
or a pharmaceutically acceptable salt thereof,
wherein, A is selected from -(CO)-, -(C=S)-, -(C=O)-(CRl 0R")r-, -(CO)-NR12- and -(C=S)-
NR12-;
B is selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, aryl, heteroaryl and heterocyclyl;
at each occurrence, R1 , R9 and R13, which may be the same or different, are independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkyloxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryloxy, aralkyi, arylalkyloxy, heteroaryl, heteroaralkyi, heterocyclyl, heterocyclylalkyl, -ORa, -OC(0)Ra, -OC(0)NRaRb, -C(0)Ra, -C(0)ORa, - C(0)NRaRb, -CRaRbNRaRc, -NRaRb, -NRaC(0)NRbRc, -NRaC(0)ORb, -N(Ra)S(0)Rb, - N(Ra)S02Rb, -NRaC(0)Rb, -NRaC(S)Rb, -NRaC(S)NRbRc, -S(0)NRaRb, -S02NRaRb, -SRa, - S(0)Ra, -S02Ra and -C(S)Ra;
at each occurrence, Rl 0 and R1 ' , which may be the same or different, are independently selected from hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C(0)ORa and -NRaRb; or R10 and Rn , together with the carbon atom to which they are attached may form cyclic ring, which may be monocyclic, bicyclic or tricyclic rings; substituted or unsubstituted; saturated, unsaturated or partially saturated; the cyclic ring may optionally contain one or more heteroatoms selected from O, N or S;
R12 is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)Ra, -C(0)ORa, -C(0)NRaRb, - S(0)NRaR , -S02NRaRb, -S(0)Ra and -S02Ra;
Ra, Rb and Rc, which may be the same or different, are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;
'm' is an integer ranging from 0 to 4, both inclusive;
'q' is an integer ranging from 0 to 4, both inclusive;
'r' is an integer ranging from 1 to 3, both inclusive; and
't' is an integer ranging from 0 to 4, both inclusive.
The embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified.
According to one embodiment, specifically provided are compounds of the formula (III) in which A is -(CO)-. According to another embodiment, specifically provided are compounds of the formula (III) in which A is -(C=0)-(CH2) , wherein 'r' is 1 , 2 or 3.
According to yet another embodiment, specifically provided are compounds of the formula (III) in which A is -(OS)-NH-.
According to yet another embodiment, specifically provided are compounds of the formula (111) in which B is substituted or unsubstituted alkyl (preferably unsubstituted alkyl, more preferably methyl, ethyl, propyl or butyl) or substituted or unsubstituted haloalkyl (preferably trifluoromethyl).
According to yet another embodiment, specifically provided are compounds of the formula (III) in which 'm' is 0.
According to yet another embodiment, specifically provided are compounds of the formula (III) in which 'q' is 0.
According to yet another embodiment, specifically provided are compounds of the formula (III) in which 't' is 0.
According to one embodiment, there is provided a compound of formula (IV):
Figure imgf000011_0001
(IV)
or a pharmaceutically acceptable salt thereof,
wherein,
D is selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, aryl, heteroaryl and heterocyclyl;
at each occurrence, R1, R9 and R14, which may be the same or different, are independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkyloxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryloxy, aralkyi, arylalkyloxy, heteroaryl, heteroaralkyi, heterocyclyl, heterocyclylalkyl, -ORa, -OC(0)Ra, -OC(0)NRaRb, -C(0)Ra, -C(0)ORa, - C(0)NRaR , -CRaRbNRaRc, -NRaRb, -NRaC(0)NRbRc, -NRaC(0)ORb, -N(Ra)S(0)Rb, - N(Ra)S02Rb, -NRaC(0)Rb, -NRaC(S)R , -NRaC(S)NRbRc, -S(0)NRaRb, -S02NRaR , -SRa, - S(0)Ra, -S02Ra and -C(S)Ra; RA, RB and RC, which may be the same or different, are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;
'm' is an integer ranging from 0 to 4, both inclusive;
'q' is an integer ranging from 0 to 4, both inclusive; and
'u' is an integer ranging from 0 to 4, both inclusive.
The embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified.
According to one embodiment, specifically provided are compounds of the formula (IV) in which R1 is r unsubstituted heteroaryl, preferably unsubstituted heteroaryl, more prefera
Figure imgf000012_0001
and 'm' is 1.
According to another embodiment, specifically provided are compounds of the formula (IV) in which R14 is halogen, preferably fluorine and 'u' is 2.
According to yet another embodiment, specifically provided are compounds of the formula (IV) in which D is hydrogen or substituted or unsubstituted alkyl (preferably unsubstituted alkyl, more preferably methyl).
According to yet another embodiment, specifically provided are compounds of the formula (IV) in which 'q' is 0.
According to one embodiment, there is provided a compound of formula (V):
Figure imgf000012_0002
(V)
or a pharmaceutically acceptable salt thereof,
wherein,
ring Ar1 is selected from aryl, heteroaryl and heterocyclyl;
at each occurrence, R1 and R8 are independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkyloxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryloxy, aralkyl, arylalkyloxy, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -ORA, -OC(0)RA, -
OC(0)NRARB, -C(0)RA, -C(0)ORA, -C(0)NRARB, -CRVWR', -NRARB, -NRAC(0)NRBRC, - NRaC(0)ORb, -N(Ra)S(0)Rb, -N(Ra)S02Rb, -NRaC(0)Rb, -NRaC(S)Rb, -NRaC(S)NRbRc, - S(0)NRaRb, -S02NRaRb, -SRa, -S(0)Ra, -S02Ra and -C(S)Ra;
R6 is selected from hydrogen, halogen, haloalkyl, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cyanoalkyl, cyanoalkyloxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)Ra, -C(0)NRaRb, -C(0)ORa, - CR^'WR0, -NRaRb, -NRaCONRbRc, -NRaC(0)ORb, -N(Ra)SORb, -N(Ra)S02Rb, - NRaC(0)Rb, -NRaC(S)Rb, -NRaC(S)NRbRc, -SONRaRb, -S02NRaRb, -OC(0)Ra, - OC(0)NRaRb, -SRa, -SORa, -S02Ra and -C(S)Ra ;
R7 is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl. alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)Ra, -C(0)ORa, -C(0)NRaR\ - S(0)NRaRb, -S02NRaRb, -S(0)Ra and -S02Ra;
Ra, Rb and Rc, which may be the same or different, are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;
'm' is an integer ranging from 0 to 4, both inclusive; and
'p' is an integer ranging from 0 to 4, both inclusive.
The embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified.
According to one embodiment, specifically provided are compounds of the formula (V) in which R6 is substituted or unsubstituted aryl, preferably substituted aryl, more preferably substituted phenyl; wherein the substituent is halogen preferably chlorine.
According to another embodiment, specifically provided are compounds of the formula (V) in which R7 is hydrogen or substituted or unsubstituted alkyl (preferably unsubstituted alkyl, more preferably methyl).
According to yet another embodiment, specifically provided are compounds of the formula (V) in which ring Ar' is aryl, preferably phenyl.
According to yet another embodiment, specifically provided are compounds of the formula (V) in which ring Ar' is heteroaryl, preferably
Figure imgf000013_0001
According to yet another embodiment, specifically provided are compounds of the formula (V) in which 'p' is 0. According to yet another embodiment, specifically provided are compounds of the formula (V) in which R8 is halogen (e.g., chlorine), cyano, substituted or unsubstituted alkyl (e.g.. methyl) or haloalkyl (e.g., trifluoromethyl); and 'p' is 1 or 2.
According to yet another embodiment, specifically provided are compounds of the formula (V) in which 'm' is 0.
According to one embodiment, there is provided a compound of formula (VI):
Figure imgf000014_0001
(VI)
or a pharmaceutically acceptable salt thereof,
wherein,
A is -S- or -N=CH-;
ring Ar1 is selected from aryl, heteroaryl and heterocyclyl;
R6 is selected from hydrogen, halogen, haloalkyl, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cyanoalkyl, cyanoalkyloxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)RA, -C(0)NRARB, -C(0)ORA, - CR WR0, -NRARB, -NRACONRBR°, -NRAC(0)ORB, -N(RA)SORB, -N(Ra)S02RB, - NRAC(0)RB, -NRAC(S)RB, -NRAC(S)NRBRC, -SONRARB, -S02NRARB, -OC(0)RA, - OC(0)NRAR , -SRA, -SOR , -S02RA and -C(S)RA ;
R7 is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)R , -C(0)ORA, -C(0)NRARB, - S(0)NRARB, -S02NRAR , -S(0)RA and -S02RA;
at each occurrence, R9 is independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkyloxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryloxy, aralkyl, arylalkyloxy, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -ORA, -OC(0)RA, - OC(0)N RARB, -C(0)RA, -C(0)ORA, -C(0)NRARB, -CR'R'WR", -NRARB, -NRAC(0)NRBRC, - NRAC(0)ORB, -N(RA)S(0)RB, -N(Ra)S02R , -NRAC(0)RB, -NRAC(S)RB, -NRAC(S)NRBRC, - S(0)NRARB, -S02NRARB, -SRA, -S(0)RA, -S02RA and -C(S)RA; Ra, Rb and Rc, which may be the same or different, are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and
R16 and R1 7, which may be the same or different, are independently selected from hydrogen and substituted or unsubstituted alkyl; and
'q' is an integer ranging from 0 to 4, both inclusive.
The embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified.
According to one embodiment, specifically provided are compounds of the formula (VI) in which R6 is substituted or unsubstituted aryl, preferably substituted aryl, more preferably substituted phenyl; wherein the substituent is halogen preferably chlorine.
According to another embodiment, specifically provided are compounds of the formula (VI) in which R7 is substituted or unsubstituted alkyl, preferably unsubstituted alkyl, more preferably methyl or ethyl.
According to yet another embodiment, specifically provided are compounds of the formula (VI) in which ring Ar1 is aryl, preferably phenyl.
According to yet another embodiment, specifically provided are compounds of the formula (VI) in which ring Ar' is heteroaryl, preferably
Figure imgf000015_0001
,
According to yet another embodiment, specifically provided are compounds of the formula (VI) in which A is -S-.
According to yet another embodiment, specifically provided are compounds of the formula (VI) in which A is -N=CH-
According to yet another embodiment, specifically provided are compounds of the formula (VI) in which R16 is hydrogen or substituted or unsubstituted alkyl (preferably unsubstituted alkyl, more preferably methyl).
According to yet another embodiment, specifically provided are compounds of the formula (VI) in which R17 is hydrogen or substituted or unsubstituted alkyl (preferably unsubstituted alkyl, more preferably methyl).
According to yet another embodiment, specifically provided are compounds of the formula (VI) in which 'q' is 0.
It should be understood that the formula (I-VI) structurally encompasses all stereoisomer, including enantiomer and diastereomer, N-oxide, deuterated compound, and pharmaceutically acceptable salt that may be contemplated from the chemical structure of the genus described herein.
The present invention 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 in the present patent application 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 capsule, sachet, paper or other container.
The compounds and pharmaceutical compositions of the present invention are useful for inhibiting PDE10A, which is related to a variety of disease states.
The present invention further provides a method of inhibiting PDE 10A in a subject in need thereof by administering to the subject one or more compounds described herein in an amount effective to cause inhibition of such receptor.
Detailed Description of the Invention
Definitions
The terms "halogen" or "halo" means fluorine, chlorine, bromine or iodine.
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, 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). Unless set forth or recited to the contrary, all alkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
The term "alkenyl" refers to a hydrocarbon chain containing from 2 to 10 carbon atoms and including at least one carbon-carbon double bond. Examples of such alkenyl moiety include, but are not limited to, ethenyl, 1 -propenyl, 2-propenyl (allyl), wo-propenyl, ' 2-methyl- l -propenyl, 1 -butenyl and 2-butenyl. Unless set forth or recited to the contrary, all alkenyl groups described herein may be straight chain or branched, substituted or unsubstituted.
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). Examples of such alkynyl moiety include, but are not limited to, ethynyl, propynyl and butynyl. Unless set forth or recited to the contrary, al l alkynyl groups described herein may be straight chain or branched, substituted or unsubstituted.
The term "alkoxy" refers an alkyl group attached via an oxygen linkage to the rest of the molecule. Examples of such alkoxy moiety include, but are not limited to, -OCH3 and - OC2H5. Unless set forth or recited to the contrary, all alkoxy groups described herein may be straight chain or branched, substituted or unsubstituted.
The term "alkoxyalkyl" or "alkyloxyalkyl" refers to an alkoxy or alkyloxy group as defined above directly bonded to an alkyl group as defined above. 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, substituted or unsubstituted.
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. Examples of such haloalkyl moiety include, but are not l im ited 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, substituted or unsubstituted.
The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms. 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, substituted or unsubstituted.
The term "hydroxyalkyl" refers to an alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups. Examples of hydroxyalkyl moiety include, but are not limited to -CH2OH and -C2H4OH .
The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or sprirobicyclic groups, e.g., sprio(4,4)non-2-yl, spiro[3,3]heptanyl, spiro[3,4]octanyl and spiro[4,4]heptanyl. Unless set forth or recited to the contrary, all cycloalkyl groups described herein may be substituted or unsubstituted.
The term "cycloalkylalkyl" refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms directly attached to an alkyl group. 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. Examples of cycloalkylalkyl moiety include, but are not limited to cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl. Unless set forth or recited to the contrary, all cycloalkylalkyl groups described or claimed herein may be substituted or unsubstituted.
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, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl. Unless set forth or recited to the contrary, all cycloalkenyl groups described or claimed herein may be substituted or unsubstituted.
The term "aryl" refers to an aromatic radical having 6 to 14 carbon atoms, including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl and biphenyl. Unless set forth or recited to the contrary, all aryl groups described herein may be substituted or unsubstituted.
The term "aryloxy" refers to an aryl group as defined above attached via an oxygen linkage to the rest of the molecule. Examples of aryloxy moiety include, but are not limited to phenoxy and naphthoxy. Unless set forth or recited to the contrary, all aryloxy groups described herein may be substituted or unsubstituted.
The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above. Examples of arylalkyl moiety include, but are not limited to - CH2C6H5 and -C2H4C6H5. Unless set forth or recited to the contrary, all arylalkyl groups described herein may be substituted or unsubstituted.
The term "arylalkyloxy" refers to an arylalkyl group attached via an oxygen linkage to the rest of the molecule. Examples of arylalkyloxy moiety include, but are not limited to - OCH2C6H5 and -OC2H4C6H5. Unless set forth or recited to the contrary, all arylalkyloxy groups described herein may be substituted or unsubstituted.
The term "heterocyclic ring" or "heterocyclyl" unless otherwise specified refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms 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, oxadiazolyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 7-aza-spiro[3,3]heptanyl, 7-spiro[3,4]octanyl, and 7-aza- spiro[3,4]octanyI. 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. Unless set forth or recited to the contrary, all heterocyclyl groups described herein may be substituted or unsubstituted.
The term "heterocyclylalkyl" refers to a heterocyclic ring radical directly bonded to an alkyl group. 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. Unless set forth or recited to the contrary, all heterocyclylalkyl groups described herein may be substituted or unsubstituted.
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. 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, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl and phthalazinyl. Unless set forth or recited to the contrary, all heteroaryl groups described herein may be substituted or unsubstituted.
The term "heteroarylalkyl" refers to a heteroaryl ring radical directly bonded to an alkyl group. 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. Unless set forth or recited to the contrary, all heteroarylalkyi groups described herein may be substituted or unsubstituted.
Unless otherwise specified, the term "substituted" as used herein refers to a group or moiety having one or more of the substituents attached to the structural skeleton of the group or moiety, including, but not limited to such substituents as hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkeny!, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyi, substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine, -COORx, -C(0)Rx, -C(S)RX, -C(0)NRxRy, - C(0)ONRxRv, -NR CONRyRz, -N(Rx)SORy, -N(Rx)S02Ry, -(=N-N(Rx)Ry), -NRxC(0)ORy, - NR Ry, -NRxC(0)Ry, -NRxC(S)Ry, -NRxC(S)NRyR7, -SONRxRy, -S02NRxRy, -ORx, - OC(0)Rx, -OC(0)NRxRy, -SRX, -SORx, -S02Rx, and -ON02, wherein Rx, Ry and Rz are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyi, or substituted or unsubstituted heterocyclic ring. The substituents in the aforementioned "substituted" groups cannot be further substituted. For example, when the substituent on "substituted alkyl" is "substituted aryl", the substituent on "substituted aryl" cannot be "substituted alkenyl".
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). Other mammals include 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.
Pharmaceutically acceptable salts forming part of this patent application include salts derived from inorganic bases (such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn), salts of organic bases (such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, and thiamine), salts of chiral bases (such as alkylphenylamine, glycinol, and phenyl glycinol), salts of natural amino acids (such as glycine, alanine, valine, leucine, isoleucine, norleucine. tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, and serine), salts of non-natural amino acids (such as D-isomers or substituted amino acids), salts of guanidine, salts of substituted guanidine (wherein the substituents are selected from nitro, amino, alkyl, alkenyl or alkynyl), ammonium salts, substituted ammonium salts and aluminum salts. Other pharmaceutically acceptable salts include acid addition salts (where appropriate) such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates (such as trifluoroacetate), tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates and ketoglutarates. Yet other pharmaceutically acceptable salts include, but are not limited to, quaternary ammonium salts of the compounds of invention with alkyl halides or alkyl sulphates (such as Mel or Me2S04).
Compounds described herein can comprise one or more asymmetric carbon atoms and thus can occur as racemic mixtures, enantiomers and diastereomers. These compounds can also exist as conformers/rotamers. All such isomeric forms of these compounds are expressly included in the present patent application. Although the specific compounds exemplified in this application may be depicted in a particular stereochemical configuration, compounds having either the opposite stereochemistry at any given chiral centre are envisioned as a part thereof. In addition, compounds of Formula I can exist in different geometrical isomeric forms. Unless otherwise stated a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. The various isomeric forms of the compounds of the present invention may be separated from one another by methods known in the art or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated.
Pharmaceutical Compositions
The pharmaceutical composition of the present patent application comprises one or more compounds described herein and one or more pharmaceutically acceptable excipients, carriers, diluents or mixture thereof. The compounds described herein may be associated with one or more pharmaceutically acceptable excipients, carriers, diluents or mixture thereof in the form of capsule, sachet, paper or other container.
Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethyl cellulose and polyvinylpyrrolidone.
The carrier or diluent may include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmetic pressure, buffers, sweetening agents, flavoring agents, colorants or any combination of the foregoing. The pharmaceutical composition of the patent application may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing methods known in the art.
The pharmaceutical compositions of the present patent application may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20th Ed., 2003 (Lippincott Williams & Wilkins). For example, the active compound is mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material that acts as a vehicle, excipient or medium for the active compound. The active compound is adsorbed on a granular solid container, for example, in a sachet.
The pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.
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, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment). The oral route is preferred.
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. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, cornstarch and/or potato starch. A syrup or elixir is used in cases where a sweetened vehicle is employed.
Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.
For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
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. For example, the daily dosage of the PDEI OA inhibitors can range from about 0.1 to about 30.0 mg/Kg. Mode of administration, dosage forms, suitable pharmaceutical excipients, diluents or carriers 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 patent application provides a method of treating a disease, condition or disorder modulated by a PDEI OA, in a subject by administering to the subject in need thereof a therapeutically effective amount of a compound or a pharmaceutical composition described herein.
The present patent application further provides a method of treating diseases, disorders or conditions, modulated by a PDE10A in mammals including human, of neuropsychiatric, neurodegenerative, neurological, neuroendocrinological nature such as, but not limiting to, schizophrenia, psychoses, schizoaffective disorders, positive symptoms of schizophrenia including delusions, disordered thoughts and speech, and tactile, auditory, visual, olfactory and gustatory hallucinations, paranoia, paranormal behaviors, negative symptoms of schizophrenia like deficits of normal emotional responses or of other thought processes including flat or blunted affect and emotion, poverty of speech (alogia), inability to experience pleasure (anhedonia), lack of desire to form relationships (asociality), and lack of motivation (avolition) leading to poor quality of life, functional disabilities typically regarded as manifestations of psychosis and other comorbidities like cognitive, executive, attention, learning, memory, spatial memory and social cognitive functions, Tic disorders like Tourette's syndrome, autism, autism spectrum disorders, attention deficit hyperactivity disorders (ADHD), pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), mood disorders, anxiety, depression, major depressive disorders, bipolar disorders, manias, aggression, obsessive compulsive disorders, Huntington's disease, Alzheimer's disease, Parkinsons disease, rest-less leg syndrome, various other neurological disorders consisting of movement disorders, ataxias, sensation disorders, cognitive disorders related to multiple sclerosis, amyotrophic lateral sclerosis, abnormalities of brain, spinal cord, nerves leading to symptoms such as paralysis, seizures, catatonias, catalepsies, muscle rigidities, muscle weakness, poor coordination, loss of sensation, confusion, mental suffering, pain and altered levels of consciousness and various other diseases, disorders or conditions related to neuroendocrinological and metabolic manifestations like change of circardian rhythms, sleep disorders, insomnia, jet lags, eating disorders like anorexia nervosa, bulimia nervosa, exercise bulimia or binge eating disorder, aggressive behaviours, obsessive compulsive personality disorders, narcissistic personality disorders, sexual and gender identity disorders and diseases related to brain, spinal cord regions, glands and hormones located in the central and peripheral nervous systems related to basal ganglia, limbic system, neostriatum, caudate putamen, striatum, striatal medium spiny neurons, globus pallidus, thalamus, prefrontal cortex, cortex, nucleus accumbens, ventral tegmental area, corpus striatum, substantia nigra, optic chiasm, vomeronasal organ, suprachiasmatic nucleus, hippocampus, amygdala, cerebellum, pineal gland, pituitary gland, hypothalamus, hypothalamo-pituitary-adrenal axis, thyroid, gonads and trinucleotide repeat expansion diseases of polyglutamine and non-polyglutamine nature.
This patent application also provides a method of treating a disorder or condition comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in treating said disorder or condition. The phrase "deficiency in attention and/or cognition" as used in the phrase "disorder comprising as a symptom a deficiency in attention and/or cognition" refers to a subnormal functioning in one or more cognitive aspects such as memory, intellect, or learning and logic ability, in a particular individual relative to other individuals within the same general age population. "Deficiency in attention and/or cognition" also refers to a reduction in any particular individual's functioning in one or more cognitive aspects, for example as occur in age-related cognitive decline.
Examples of disorders that comprise as a symptom a deficiency in attention and/or cognition that can be treated according to the present patent application are dementia, for example, Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug- related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, Multiple sclerosis, Amyotrophic lateral sclerosis, Down's syndrome or AIDS-related dementia; delirium, amnestic disorder, post-traumatic stress disorder, mental retardation, a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression, attention- deficit/hyperactivity disorder and age-related cognitive decline. This patent application also provides a method of treating a mood disorder or mood episode in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula I effective in treating said disorder or episode. This patent application also provides a method of treating a mood disorder or mood episode in a mammal, including a human, comprising administering to said mammal a therapeutically effective amount of a compound of formula I in inhibiting PDE1 OA.
Examples of mood disorders and mood episodes that can be treated according to the present patent application include, but are not limited to, major depressive episode of the mild, moderate or severe type, a manic or mixed mood episode, a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post- stroke depression; major depressive disorder; dysthymic disorder; minor depressive disorder; premenstrual dysphoric disorder; post-psychotic depressive disorder of schizophrenia; a major depressive disorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia; a bipolar disorder, for example bipolar ] disorder, bipolar 11 disorder and cyclothymic disorder.
This patent application further provides a method of treating a neurodegenerative disorder or condition in a mammal, including a human, which method comprises administering to said mammal a therapeutically effective amount of a compound of the present invention in treating said disorder or condition.
This patent application further provides a method of treating a neurodegenerative disorder or condition in a mammal, including a human, which method comprises administering to said mammal a therapeutically effective amount of a compound of formula (1) in inhibiting PDE 10A. As used herein and unless otherwise indicated, a "neurodegenerative disorder or condition" refers to a disorder or condition that is caused by the dysfunction and/or death of neurons in the central nervous system. The treatment of these disorders and conditions can be facilitated by administration of an agent which prevents the dysfunction or death of neurons at risk in these disorders or conditions and/or enhances the function of damaged or healthy neurons in such a way as to compensate for the loss of function caused by the dysfunction or death of at-risk neurons. The term "neurotrophic agent" as used herein refers to a substance or agent that has some or all of these properties.
Examples of neurodegenerative disorders and conditions that can be treated according to the present patent application include, but are not limited to, Parkinson's disease; Huntington's disease; dementia, for example Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, and Fronto temperal Dementia; neurodegeneration associated with cerebral trauma; neurodegeneration associated with stroke, neurodegeneration associated with cerebral infarct; hypoglycemia-induced neurodegeneration; neurodegeneration associated with epileptic seizure; neurodegeneration associated with neurotoxin poisoning; and multi-system atrophy.
In one aspect of the present patent application, the neurodegenerative disorder or condition comprises neurodegeneration of striatal medium spiny neurons in a mammal, including a human.
In another aspect, this patent application provides a pharmaceutical composition for treating psychotic disorders, delusional disorders and drug induced psychosis, anxiety disorders, movement disorders, mood disorders, neurodegenerative disorders or drug addiction, comprising a therapeutically effective amount of a compound of the present invention in treating said disorder or condition. In another aspect, this patent application provides a method of treating a disorder selected from psychotic disorders, delusional disorders and drug induced psychosis, anxiety disorders, movement disorders, mood disorders, and neurodegenerative disorders, which method comprises administering a therapeutically effective amount of a compound of the present invention in treating said disorder.
In another aspect, this patent application provides a method of treating the disorders above, where the disorders are selected from the group consisting of: dementia, Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; posttraumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention- deficit/hyperactivity disorder; age-related cognitive decline, major depressive episode of the mild, moderate or severe type; a manic or mixed mood episode; a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post- stroke depression; major depressive disorder; dysthymic disorder; minor depressive disorder; premenstrual dysphoric disorder; post-psychotic depressive disorder of schizophrenia; a major depressive disorder superimposed on a psychotic disorder comprising a delusional disorder or schizophrenia; a bipolar disorder comprising bipolar I disorder, bipolar II disorder, cyclothymic disorder, Parkinson's disease; Huntington's disease; dementia, Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, Fronto temperal Dementia; neurodegeneration associated with cerebral trauma; neurodegeneration associated with stroke; neurodegeneration associated with cerebral infarct; hypoglycemia-induced neurodegeneration; neurodegeneration associated with epileptic seizure; neurodegeneration associated with neurotoxin poisoning; multi-system atrophy, paranoid, disorganized, catatonic, undifferentiated or residual type; schizophreniform disorder; schizoaffective disorder of the delusional type or the depressive type; delusional disorder; substance-induced psychotic disorder, psychosis induced by alcohol, amphetamine, cannabis, ***e, hallucinogens, inhalants, opioids, or phencyciidine; personality disorder of the paranoid type; personality disorder of the schizoid type.
In another aspect, there is provided a method for preventing, ameliorating or treating a disease or condition selected from obesity or related diseases, conditions; diabetes (including Type I and Type II diabetes); diabetic complications; glucose tolerance; hyperinsulinemia; insulin sensitivity or resistance; metabolic syndromes; cardiovascular diseases including, for example, atherosclerosis, lipidemia, dyslipidemia, elevated blood pressure, microalbuminemia, hyperuricaemia, hypercholesterolemia, hyperlipidemias, hypertriglyceridemias, arteriosclerosis or combination thereof; respiratory diseases or disorders including, for example, sinusitis, asthma, bronchitis or combination thereof; or any combination these diseases, disorders, conditions and/or syndromes thereof; the disease or condition related to serum levels of triglyceride, LDL, HDL, VLDL, total chlolesterol, which method comprises administering to said mammal a therapeutically effective amount of a compound of formula (1) in treating said disorder or condition.
General Methods of Preparation
The compounds described herein, including compounds of general formula (l)-(VI) and specific examples are prepared using techniques known to one skilled in the art through the reaction sequences depicted in Schemes 1 -5 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 etc. may be used and are included within the scope of the present invention. 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 by using the general reaction sequences may be of insufficient purity. These compounds can be purified by 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 stereoisomers are envisioned within the scope of this invention.
The starting materials for the below reaction schemes are commercially available or can be prepared according to methods known to one skilled in the art or by methods disclosed herein. In general, the compounds according to the present invention may be prepared through the reaction scheme as follows.
Synthetic scheme 1
Figure imgf000029_0001
(ΙΑ)
A general approach for the synthesis of compounds of the general formula (IA), wherein R , R2, R3, R9, A, B, D, L, Ar2, ' m', 'n' and 'q' are as defined in the description is described in Synthetic scheme 1 .
The compound of formula (l a) is converted into compound of formula (2) by reacting with a substituted alkyl halide at a temperature range of 0-100°C using a suitable solvent (for e.g., acetonitrile, dimethylformamide, dimethylsulphoxide, tetrahydrofuran etc.) in the presence of suitable base such as alkali metal carbonate (for e.g., potassium carbonate etc.), alkali metal hydride (for e.g., sodium hydride etc.) or alkali metal hydroxide (for e.g., sodium hydroxide etc.) and the like following procedures known in the art of organic synthesis. Alternatively a compound of formula (2) can also be prepared by the reaction of a compound of formula (l a) with a substituted hydroxy compound under Mitsunobu conditions. Compound of formula (2) can also be prepared by the reaction of a compound of formula ( l b) with an appropriately substituted hydroxy compound in the presence of a base such as alkali metal carbonate (for e.g., potassium carbonate etc.), alkali metal hydride (for e.g., sodium hydride etc.) or alkali metal hydroxide (for e.g., sodium hydroxide etc.) and the like using a suitable solvent (for e.g., acetonitrile, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran etc.). Compound of formula (2) is converted into compound of formula (3) under reductive conditions utilizing iron or tin metal in a mineral acid like hydrochloric acid or catalytic reduction condition utilizing palladium or platinum on carbon in presence of hydrogen gas and the like. Compound of formula (3) can be converted to a compound of formula (4) by reacting with a substituted halide compound at a temperature (0-100°C) using an appropriate solvent (for e.g., acetonitrile, dimethylformamide, dimethylsulphoxide, tetrahydrofuran etc.) in the presence of suitable base such as alkali metal carbonate (for e.g., potassium carbonate etc.), alkali metal hydride (for e.g., sodium hydride etc.) or alkali metal hydroxide (for e.g., sodium hydroxide etc.) and the like following procedures known in the art of organic synthesis. Alternatively compound of formula (4) can be prepared by reacting the compound of formula (3) with an aldehyde under reductive amination conditions utilizing sodium borohydride, sodium triacetoxyborohydride and the like in an appropriate solvent (for e.g., dichloromethane, dichloroethane etc.) at a temperature range of 0-50°C. Compound of formula (4) can also be prepared by reacting compound of formula (3) with an acid chloride or substituted carbamate derivative in the presence of a base (for e.g. triethylamine, diisopropylethylamine etc.) in an appropriate solvent (for e.g., dichloromethane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide etc.) under standard coupling conditions. Compound of formula (4) can be converted to a compound of formula (IA) by reacting with a carboxylic acid derivative under standard amidation conditions utilizing a coupling agent (for e.g., carbodiimide, benzotriazol-l -yloxytris(dimethylamino) phosphoniumhexafluorophosphate (BOP reagent) etc.) in the presence of a base (for e.g., triethylamine, diisopropylethylamine etc.) in an appropriate solvent (for e.g., dichloromethane, tetrahydrofuran, dimethylformamide etc.). Alternatively, compound of formula (1A) can also be prepared by reacting a compound of formula (4) with an acid chloride, substituted isothiocyanate derivative or substituted carbamate derivative in the presence of a base (for e.g., triethylamine, diisopropylethylamine etc.) in an appropriate solvent (for e.g., dichloromethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide etc.). Alternatively, Compound of formula (3) can be converted to a compound of formula (5) by reacting with carboxylic acid compounds under standard amidation conditions utilizing a coupling agent (for e.g., carbodiimide, BOP reagent etc.) in the presence of a base (for e.g., triethylamine, diisopropylethylamine etc.) in an appropriate solvent (for e.g., dichloromethane, tetrahydrofuran, dimethylformamide etc.). Alternatively, compound of formula (5) can also be prepared by reacting a compound of formula (3) with an acid chloride, substituted isothiocyanate derivative or substituted carbamate derivative in the presence of a base (for e.g., triethylamine, diisopropylethylamine etc.) in an appropriate solvent (for e.g., dichloromethane, tetrahydrofuran, dimethylformamide etc.). Compound of formula (5) can be converted to a compound of formula (IA) by reacting with a substituted alkyl halide or acyl halide at 0-100°C using an appropriate solvent (for e.g., acetonitrile, dimethylformamide, dimethylsulphoxide, tetrahydrofuran etc.) in the presence of suitable base such as alkali metal carbonate (for e.g., potassium carbonate etc.), alkali metal hydride (for e.g., sodium hydride etc.) or alkali metal hydroxide (for e.g., sodium hydroxide etc.) and the like. Compound of formula (IA) can also be prepared by reacting compound of formula (5) with an acid chloride or substituted carbamate derivative in a presence of a suitable base (for e.g. triethylamine, diisopropylethylamine etc.) in an appropriate solvent (for e.g., dichloromethane, tetrahydrofuran, dimethylformam ide, dimethyl sulfoxide etc.).
Synthetic scheme 2
Figure imgf000031_0001
X is O or S
Y is -(CR10R1 1)r- or -NR12-
A general approach for the synthesis of compounds of the general formula (I I A), wherein R 1 . R9, R 1 0, R " , R 1 2, R 1 3, B, Ar3, 'm\ 'q ', V and 't' are as defined in description is descri bed in Synthetic scheme 2.
Compound of formula ( l a) is converted into compound of formula (6) by reacting with a substituted 2-chloromethylquinoline at a temperature range of 0- 100°C using an appropriate solvent (for e.g., acetonitrile, dimethylformamide, dimethylsulphoxide, tetrahydrofuran etc.) in the presence of suitable base such as alkali metal carbonate (for e.g., potassium carbonate etc.), alkali metal hydride (for e.g., sodium hydride etc.) or alkali metal hydroxide (for e.g., sodium hydroxide etc.). Alternatively compound of formula (6) can also be prepared by reacting compound of formula ( l a) with a substituted hydroxy 1 compound of quinoline derivative under Mitsunobu conditions. Compound of formula (6) is converted to a compound of formula (7) under reductive conditions utilizing iron or tin metal in a mineral acid like hydrochloric acid or catalytic reduction condition utilizing palladium or platinum on carbon in presence of hydrogen gas and the like. Compound of formula (7) can be converted to a compound of formula (8) by reacting with an substituted alkyl halide at 0-100°C using an appropriate solvent (for e.g. acetonitrile, dimethylformamide, dimethylsulphoxide, tetrahydrofuran etc.) in the presence of suitable base such as alkali metal carbonate (for e.g. potassium carbonate etc.), alkali metal hydride (for e.g., sodium hydride etc.) or alkali metal hydroxide (for e.g., sodium hydroxide etc.) and the like following procedure known in the art of organic synthesis. Alternatively formula (8) could also be prepared by reacting a compound of formula (7) with an aldehyde compound under reductive amination conditions utilizing sodium borohydride, sodium triacetoxyborohydride and the like in an appropriate solvent (for e.g., dichloromethane, dichloroethane etc.) at a temperature range of 0-50°C. Compound of formula (8) can be converted to a compound of formula (IIA) by reacting with a carboxylic acid derivative under standard amidation conditions utilizing a coupling agent (for e.g., carbodiimide, benzotriazol-l -yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) etc.) in the presence of suitable base (for e.g., triethylamine, diisopropylethylamine etc.) in an appropriate solvent (for e.g., dichloromethane, tetrahydrofuran, dimethylformamide etc.). Alternatively formula (IIA) can also be prepared by reacting a compound of formula (8) with an acid chloride, substituted carbamate derivative or substituted isothiocyanate derivative in the presence of a base (for e.g., triethylamine, diisopropylethylamine etc.) in an appropriate solvent (for e.g., dichloromethane. tetrahydrofuran, dimethylformamide, dimethyl sulfoxide etc.).
Synthetic scheme 3
Figure imgf000032_0001
(9) (10) (1 1 ) (7)
A general approach for the synthesis of compound of formula (7) wherein R1, R9, 'm' and 'q' are as defined in the description is described in Synthetic scheme 3. In this scheme, a compound of formula (9) is converted into compound of formula ( 10) (wherein, PG is protecting group) by reacting with a suitable protecting group (for e.g., BOC anhydride) in the presence of suitable base (for e.g., triethylamine, diisopropylethylamine, sodium hydroxide etc.) and the like in a appropriate solvent (for e.g., dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, DMSO, water etc.) and the like at a temperature range of 0-80°C following procedures known in the art of organic synthesis. A compound of formula ( 10) is converted to a compound of formula (1 1) by reacting with a substituted 2- chloromethylquinoline at a temperature range of 0-100°C using an appropriate solvent (for e.g., acetonitrile, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran etc.) in the presence of a suitable base such as alkali metal carbonate (for e.g., potassium carbonate), alkali metal hydride (for e.g., sodium hydride) or alkali metal hydroxide (for e.g., sodium hydroxide) and the like by following procedure known in the art of organic synthesis. Compound of formula (1 1 ) is converted to a compound of formula (7) under deprotection conditions utilizing a deprotecting reagent (for e.g., Cone. HCI, saturated ethyl acetate in HCI gas, methanol saturated with HCI gas, p-toluenesulphonic acid etc.) and the like by following procedure known in the art of organic synthesis.
Synthetic scheme 4
Figure imgf000033_0001
A general approach for the synthesis of compounds of the general formula (IB), wherein R1 , R2, R3, R4, R5, R6, R7, R8, Ar1, 'm', 'n' and 'p' are as defined above in the description is illustrated in Synthetic scheme 4. In this synthetic scheme, compound of formula (12) is converted to a compound of formula (13), by reacting it with an appropriate substituted or unsubstituted acyl halide at elevated temperature (60°C to 120°C) in a suitable solvent (for e.g., acetonitrile, dimethylformamide, ethanol, dimethoxyethane, dioxane, dimethylsulphoxide etc.) by following procedures known in the art. Compound of formula (13) is converted to a compound of formula (14) where Hal is halogen, by reacting it with halogenating agents such as N-bromosuccinimide or N-iodosuccinimide at -20°C to 100°C, in a suitable solvent such as diethylether, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylsulphoxide or the like by following procedure known in the art. Compound of formula (14) is converted to a compound of formula (15) by reacting with 4-hydroxyphenylboronic acid in presence of palladium metal or palladium complex such as dichlorobis(triphenylphosphine)palladium(ll), tetrakis(triphenylphosphine) palladium(O), dichlorobis(diphenylphosphinopropane)palladium, tris(dibenzylideneacetone) dipalladium or the like as a catalyst, in a suitable solvent such as dioxane, toluene, ethanol, dimethylformamide, dimethylsulphoxide or water or a mixture of them in the temperature range of 25°C to 100°C. Compound of formula (15) is converted to a compound of formula (16) by reacting with an a-haloester derivative in presence of a base such as alkali metal carbonate, alkali metal hydroxide or alkali metal hydride in a solvent such as acetonitrile, dimethylformamide or dimethylsulphoxide in the temperature range of 25°C to 100°C. Compound of formula (16) is converted to a compound of formula (17) in presence of a base such as alkali metal carbonate or alkali metal hydroxide in a solvent such as acetonitrile, methanol, ethanol, tetrahydrofuran or the like in presence of water in the temperature range of 25°C to 100°C. Compound of formula (17) is converted to a compound of formula ( 18) (where Ar is aryl, heteroaryl or heterocyclyl ring), by reacting it with a phenol containing an electron withdrawing group especially a nitro group, by activating the acid, as acidchloride by reacting it with thionyl chloride or oxalyl chloride, using EDCI .HCI or tBOP reagent, in the presence of a base such as triethylamine, diisopropylethylamine or the like in a solvent such as dichloromethane, dimethylformamide, tetrahydrofuran or the like in the temperature range of 25°C to 100°C. Compound of formula (18) is converted to a compound of formula (IB) by reacting with a compound of formula (19) in the presence of a base such as triethylamine, diisopropeylethylamine or an alkalimetal hydride in a solvent such as tetrahydrofuran, dimethylformamide or the like in the temperature range of 25°C to 100°C. Alternatively compound of formula (17) can also be converted to a compound of formula (IB) by activating it as an acidchloride and reacting it with the compound of formula (19) in the presence of a suitable base such as triethylamine, diisopropeylethylamine or an alkalimetal hydride in a appropriate solvent such as dichloromethane, tetrahydrofuran, dimethylformamide or the like in the temperature range of 25°C to 100°C. Compound of formula ( 17) can also be converted to a compound of formula (IB) by activating it in the presence of a substituted carbodiimide or BOP reagent and reacting it with a compound of formula (19) in the presence of a suitable base such as triethylamine, diisopropeylethylamine or an alkalimetal hydride in a suitable solvent such as dichloromethane, tetrahydrofuran, dimethylformamide or the like in the temperature range of 25°C to 100°C.
Synthetic scheme 5
Figure imgf000035_0001
(IB)
An alternative approach for the synthesis of compounds of the general formula (IB), wherein R1, R2, R3, R4, R5, R6, R7, R8, Ar1 , 'm', 'n' and 'p' are as defined above in the description is described in Synthetic Scheme 5.
In this synthetic scheme, compound of formula (19a) can optionally be converted to a compound of formula (19) (where R is alkyl), by reacting with an alkyl halide in the presence of a base such as triethylamine, diisopropylethylamine or an alkali metal hydride in a solvent such as tetrahydrofuran, dimethylformamide, dimethylsulphoxide etc., at 0°C to 100°C. Compound of formula (19) and (19a) are converted to compound of formula (20) (where Hal is halogen), by reacting with a substituted a-halo acylhalide derivatives in the presence of a suitable base such as triethylamine, diisopropylethylamine or alkalimetal hydride in an appropriate solvent such as dichloromethane, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylsulphoxide etc., at 0°C to 100°C. Compound of formula (20) is further reacted with compound of formula- (15) in presence of a suitable base such as alkali metal carbonate, alkali metal hydroxide or alkali metal hydride in a solvent such as acetonitrile, dimethylformamide, tetrahydrofuran or dimethylsulphoxide at 25°C to 100°C to obtain a compound of the general formula (IB).
Experimental
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 sodium sulphate, filtration and evaporation of the solvent. Purification, unless otherwise mentioned, includes purification by silica gel chromatographic techniques, in suitable solvents of a suitable polarity as the mobile phase. The following abbreviations are used in the text: DMSO-efc: hexadeuterodimethyl sulfoxide; CDCI3- deuterated chloroform; J: coupling constant in units of Hz; RT or rt: room temperature (22- 26°C). aq.: aqueous; equiv. or eq.: equivalents.
Preparation of Intermediates
Intermediate 1
2-[(4-Nitrophenoxy)methyl]quinoline
Figure imgf000036_0001
To a solution of 2-chloromethyl quinoline (0.5 g, 2.33 mmol) in NN-dimethylformamide (5 mL) was added potassium carbonate (0.97 g, 7.00 mmol) and p-nitro phenol (0.357 g, 2.5 mmol). The reaction mixture was heated at 80°C for 1 hour. The reaction mixture was poured in ice water; a product precipitated. The precipitate was filtered off and dried under vacuum to afford 0.700 g of the product; Ή NMR (300 MHz, DMSO-<¾: δ 8.40 (d, J = 8.4 Hz, 1 H), 8. 1 8 (d, J = 9.3 Hz, 2H), 7.97 (m, 2H), 7.74 (t, J= 15.0 Hz, IH), 7.67-7.58 (m, 2H), 7.25 (d, J = 9.3 Hz, 2H), 5.52 (s, 2H).
Intermediate 2
4-(Quinolin-2-ylmethoxy)anilin
Figure imgf000036_0002
To a solution of 2-[(4-nitrophenoxy)methyl]quinoline (Intermediate 1 , 0.7 g, 2.8 mmol) in methanol ( 1 0 mL) was added iron powder (0.40 g) followed by cone. HC1 ( 1 .0 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through celite bed. The filtrate was concentrated, diluted with water, neutralized with Na2C03 and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.33 g of the desired product; Ή NMR (300 MHz,
DMSC s): δ 8.34 (d, J = 8.4 Hz, 1 H), 7.94 (d, J = 14.1 Hz, 2H), 7.72 (t, J = 15.0 Hz, 2H), 7.63-7.55 (m, 2H), 6.73 (d, J = 6.3 Hz, 2H), 6.46 (d, J = 6.9 Hz, 2H), 5.19 (s, 2H), 4.66 (br s,
2H).
Intermediate 3
N-Benzyl-4-(quinolin-2-ylmethoxy)aniline
Figure imgf000037_0001
To a solution of 4-(quinolin-2-ylmethoxy)aniline (Intermediate 2, 0.15 g, 0.6 mmol) in 1 ,2- dichloroethane (10 mL) was added benzaldehyde (0.074 g, 0.66 mmol) followed by sodium triacetoxyborohydride (0.25 g, 1.18 mmol) and the reaction mixture was stirred for 30 min. To this mixture was added acetic acid and stirred at room temperature for 4 hours. The reaction mixture was poured in water and extracted with 1 ,2-dichloroethane. The organic layer was dried over anhydrous Na2S04, concentrated and purified by column chromatography to afford 0.100 g of the desired product; Ή NMR (300 MHz, DMSO-i¾: δ 8.34 (d, J = 8.4 Hz, 1 H), 7.97-7.95 (m, 2H), 7.71 (t, J = 1 5.6 Hz, 2H), 7.59-7.54 (m, 2H), 7.32-7.1 7 (m, 5H), 6.76 (d, J = 9.0 Hz, 2H), 6.47 (d, J = 8.7 Hz, 2H), 5.86 (m, 1 H), 5.1 8 (s, l H), 4.16 (d, J = 5.4 Hz, 2H); MS (m/z): 341 .16 (M+H)+.
Intermediates 4 to 9 mentioned in Table 1 below were prepared using Intermediate 2 and appropriate starting material, by following the procedure as described for the preparation of Intermediate 3.
Figure imgf000037_0002
Table 1 : Structure, starting material and characterization data for Intermediates 4-9
Figure imgf000038_0001
carbaldehyde
Intermediate 10
4-(6-Fluoro-quinolin-2-ylmethoxy)-pheny!]-pyridin-3-ylmethylamine
Figure imgf000038_0002
Step 1 : Preparation of 6-fluoro-quinoline-2-carbaldehyde To a freshly prepared solution of Se02 (0.690 g, 6.21 mmol) in 10% water in dioxane (20 mL) at 40-45°C was added 2-methyl-6-fluoro quinoline (0.500 g, 3.1 0 mmol) and the reaction mixture was stirred at 40-45°C for 3-4 hours. The reaction mass was fi ltered through celite bed, filtrate was di luted with water and extracted with dichloromethane. The organic layer was dried and concentrated to afford 0.550 g of the desired product; Ή NMR (300 MHz, DMSO-iVe): δ 10.07 (s, 1 H), 8.56 (d, J - 8.4 Hz, 1 H), 8.3 1 -8.26 (m, 1 H), 7.86-7.79 (m, 3H); MS (m/z): 1 76.30 (M+H)+.
Step 2: Preparation of (6-fluoro-quinolin-2-yl)-methanol
To a solution of 6-fluoro-quinoline-2-carbaldehyde, obtained in Step 1 (0.540 g, 3.08 mmol) in tetrahydrofuran was added NaBRi at 10-15°C and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water, extracted with ethyl acetate. The organic layer was dried and concentrated to afford 0.500 g of the desired product.
Step 3 : Preparation of 2-chloromethyl-6-fluoro-quinoline
To a solution of (6-fluoro-quinolin-2-yl)-methanol, obtained in Step 2 (0.550 g, 3. 10 mmol) in dichloromethane was added thionyl chloride (0.739 g, 6.21 mmol) and the reaction mixture was refluxed for 2 hours. The reaction mass was quenched with water, basified with Na2C03 and extracted with dichloromethane. The organic layer was dried and concentrated to afford 0.220 g of the desired product; Ή NMR (300 MHz, DMSO-i/6): δ 8.43 (d, J = 8. 1 Hz, 1 H), 8.08 (m, I H), 7.83 (d, ./ = 9.3 Hz, 1 H), 7.72 (d, J = 8. 1 Hz, 2H), 4.95 (s, 2H); MS (m/z): 1 96.23 (M+H)+.
Step 4: Preparation of tert-butyl {4-[(6-fluoroquinolin-2-yl)methoxyl]phenyl}carbamate To a suspension of ter/-butyl (4-hydroxyphenyl)carbamate (0.282 g, 1 .35 mmol) and potassium carbonate (0.3 10 g, 2.24 mmol) in tetrahydrofuran at 80-90°C was added 2- chloromethyl-6-fluoro-quinoline, obtained in Step 3 (0.220 g, 1 .12 mmol) and the reaction mixture was stirred at 90- 100°C for 2-3 hours. The reaction mixture was cooled to room temperature and was added aq 10% NaOH solution; a product precipitated. The precipitate was filtered off and dried under vacuum to afford 0.210 g of the desired product; Ή NMR (300 MHz, DMSO-fl¾): 5 9.1 7 (s, 1 H), 8.41 (d, J= 8.7 Hz, I H), 8.07 (t, J = 9.3 Hz. 1 H), 8.81 (d, J = 9.3 Hz, I H), 7.70 (d, J = 7.8 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.7 Hz, 2H), 5.29 (s, 2H), 1 .45 (s, 9H).
Step 5 : Preparation of 4-(6-fluoro-quinolin-2-ylmethoxy)-phenyl amine
A saturated solution of ethyl acetate with HC1 was added in the stirred solution of tert-butyl
{4-[(6-fluoroquinol in-2-yl)methoxyl]phenyl}carbamate, obtained in Step 4 and m ixture was stirred at room temperature for 2-3 hours. The reaction mass was quenched with water, basified with Na2C03 and extracted with dichloromethane. The organic layer was dried and concentrated to afford 0.200 g of the desired product.
Step 6: Preparation of [4-(6-fluoro-quinolin-2-ylmethoxy)-phenyl]-pyridin-3-ylmethylamine To a solution of 4-(6-fluoro-quinolin-2-ylmethoxy)-phenyl amine, obtained in Step 5 (0.1 50 g. 0.559 mmol) in ethylene dichloride (5 mL) was added 3-pyridine carbaldehyde (0.071 g, 0.663 mmol) and the reaction mixture was stirred for 30 mins. To this mixture was added acetic acid (0.033 g, 0.550 mmol) followed by sodium triacetoxyborohydride (0.235 g, 1 .1 1 mmol) and stirred for 1 8 hours at room temperature. The reaction mass was neutralized with Na2C03i extracted with dichloromethane and the resultant organic layer was concentrated to afford 0.100 g of the desired product; Ή NMR (300 MHz, DMSO-i/6): δ 8.71 (s, 1 H), 8.55- 8.37 (m, 2H), 8.06 (m, 1 H), 7.81-7.66 (m, 4H), 7.32 (br s, 1H), 6.81 (d, J = 7.5 Hz, 2H), 6.53 (d, ,/ = 7.8 Hz, 2H), 5.93 (br s, 1H), 5.19 (s, 2H), 4.21 (br s, 2H).
Intermediate 1 1
(4-Methyl-thiazol-5-ylmethyl)- -(quinolin-2-ylmethoxy)-phenyl]amine
Figure imgf000040_0001
Step 1 : Preparation of 4-methyl-thiazole-5-carbaldehyde
To a solution of 2-(4-methyl-thiazol-5-yl)ethanol (0.500 g, 3.496 mmol) in ethylene dichloride (8.0 mL) was added pyridinium chlorochromate (PCC) (1.127 g, 5.244 mmol) and the reaction mixture was stirred at room temperature for 2 hours. Ether was added to the reaction mass, filtered off and resultant organic layer was concentrated to afford 0.150 g of the desired product; Ή NMR (300 MHz, DMSO-a¾: δ 10.14 (s, 1H), 9.39 (s, 1H), 2.72 (s,
3H).
Step 2: Preparation of (4-methyl-thiazol-5-ylmethyl)-[4-(quinolin-2-ylmethoxy)-phenyl]- amine
The title compound was prepared following the procedure described for Intermediate 3, but starting from 4-(quinolin-2-ylmethoxy)aniIine (0.300 g, 1.195 mmol), 4-methyl-thiazole-5- carbaldehyde, obtained in Step 1 (0.1 1 g, 1.195 mmol) and sodium triacetoxyborohydride (0.378 g, 1 .79 mmol) in ethylene dichloride (15 mL) to afford 0.160 g of the desired product: Ή NMR (300 MHz, OMSO-d6): δ 8.80 (s, 1 H), 8.39 (d, J = 8.1 Hz, -I H), 8.01 -7.97 (m, 2H), 7.77 (t, J = 7.2 Hz, 1 H), 7.66-7.58 (m, 2H), 6.85 (d, ,/ = 8.7 Hz, 2H), 6.55 (d, J = 8.7 Hz, 2H), 5.76 (s, 1 H), 5.22 (s, 2H), 4.31 (s, 2H), 2.37 (s, 3H).
Intermediate 12
3-Iodomethyl-5-methyl-isoxazole
Figure imgf000041_0001
Step 1 : Preparation of (5-methyl-isoxazol-3-yl)-methanol
To a solution of 5-methyl-isoxazole-3-carboxylic acid (0.700 g, 5.51 1 mmol) in tetrahydrofuran ( 10 mL) was added lithium aluminium hydride (LAH) (0.203 g, 5.5 1 1 mmol) at 0°C and the reaction mixture stirred for 2 hours at room temperature. The reaction mixture was quenched with brine solution and acidified with acetic acid. The resultant residue was filtered off, washed with chloroform and methanol, and dried to afford 0. 140 g of the desired product; Ή NMR (300 MHz, DMSO-<fc): δ 6.19 (s, 1 H), 5.43 (br s, 1 H), 4.43 (s, 2H), 2.38 (s,
3H).
Step 2: Preparation of 3-iodomethyl-5-methyl-isoxazole
To a solution of triphenyl phosphine (2.216 g, 8.460 mmol) and imidazole (0.575 g, 8.460 mmol) was added iodine (2.247 g, 8.883 mmol) and the reaction mass was stirred for 10 mins followed by the addition of (5-methyl-isoxazol-3-yl)-methanol, obtained in step I (0.478 g, 4.230 mmol). The reaction mixture was stirred for 2 ½ hours at room temperature, quenched the reaction mass with water and extracted with dichloromethane. The organic layer was washed with 5% sodium sulphite solution and concentrated to afford 0.375 g of the desired product; Ή NMR (300 MHz, DMSO-<¾: δ 6.26 (s, 1 H), 4.37 (s, 2H), 2.36 (s, 3H).
Intermediate 13
(5-Methyl-isoxazol-3-ylmeth -[4-(quinolin-2-ylmethoxy)-phenyl]amine
Figure imgf000041_0002
To a solution of 4-(quinolin-2-ylmethoxy)aniline (Intermediate 2, 0.150 g, 0.597 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (0.164 g, 1.194 mmol) and 3-iodomethyl-5-methyl-isoxazole (Intermediate 12, 0.132 g, 0.597 mmol) and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was poured in ice water, extracted with ethyl acetate and concentrated the organic layer to afford 0.1 16 g of the desired product; Ή NMR (300 MHz, OMSO-d6): δ 8.39 (d, J = 8.4 Hz, 1 H), 7.99 (m, 2H), 7.77-7.75 (br t, 1 H), 7.66-7.60 (m, 2H), 6.84 (d, J = 8.7 Hz, 2H), 6.55 (d, J = 8.4 Hz, 2H), 6. 10 (s, l H), 5.81 (br s, 1 H), 5.21 (s, 2H), 4.17 (d, J = 5.7 Hz, 2H), 2.33 (s, 3H).
Intermediate 14
Phenyl (5-ter?-butyl-l ,3,4-thi
Figure imgf000042_0001
To a solution of 5-ier/-butyl-l ,3,4-thiadiazol-2 -amine (1 g) in dichloromethane (20 mL) was added triethylamine (3 eq) followed by phenylchloroformate ( 1 eq) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane and water. The organic layer was washed with water, dried over Na2S04, concentrated and purified by column chromatography to afford 1 .3 g of the desired product;
Ή NMR (DMSO-4s): δ 12.60 (br s, 1 H), 7.42 (t, J = 15.6 Hz, 3H), 7.28 (d, J = 7.2 Hz, 1 H), 7.22 (d, .7 = 7.8 Hz, 1 H), 1.38 (s, 9H).
Intermediates 15 to 1 7 mentioned in Table 2 below were prepared using phenylchloroformate and appropriate starting material, by following the procedure as described for the preparation of Intermediate 14.
Figure imgf000042_0002
Table 2: Structure, starting material and characterization data for Intermediates 15-17
Figure imgf000042_0003
Figure imgf000043_0001
Intermediate 18
2-Pyridin-4-yl-4-(quinolin-2-ylm
Figure imgf000043_0002
Step 1 : Preparation of 3-iodo-4-nitrophenol
To a solution of 3-iodophenol (1 .5 g) in acetic acid (10 mL) was added cone, nitric acid (0.03 mL) and the reaction mixture was stirred at room temperature for ½ hour. The reaction mixture was diluted with water, filtered off the reaction mass and the filtrate was extracted with ethyl acetate. The organic layer was concentrated to afford 1 .37 g of the desired product; Ή NMR (300 MHz, DMSO-<¾): δ 1 1 .07 (br s, 1 H), 7.96 (d, J = 9.3 Hz, 1 H), 7.46 (s, 1 H), 7.93 (d, J = 8.7 Hz, 1 H).
Step 2: Preparation of 4-nitro-3-pyridin-4-yl-phenol
To a solution of 3-iodo-4-nitrophenol, obtained in Step 1 ( 1 .36 g, 5.15 mmol) in dimethyl sulfoxide ( 10 mL) was added 4-pyridineboronic acid (0.63 g, 5.15 mmol) followed by potassium carbonate (2.13 g, 15.44 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.178 g, 0.154 mmol) and the reaction mixture was stirred at 80°C for 4 hours. Water was added to the reaction mixture, extracted with ethyl acetate and the organic layer was concentrated to afford 1.0 g of the desired product; Ή NMR (300 MHz, DMSO-i¾: δ 8.61 - 8.60 (br d, 2H), 8.05 (d, J = 9.3 Hz, 1H), 7.34-7.033 (br d, 2H), 6.93 (d, J= 8.7 Hz, 1 H), 6.70 (s, 1 H); MS (m/z): 215.41(M-H)\
Step 3: Preparation of 2-[(4-nitro-3-pyridin-4-ylphenoxy)methyl]quinoline
The title compound was prepared following the procedure described for Intermediate 1 , but starting from 4-nitro-3-pyridin-4-yl-phenol, obtained in Step 2 (1 .0 g, 4.629 mmol), potassium carbonate ( 1 .27 g, 9.20 mmol) and 2-chloromethyl quinoline hydrochloride ( 1 .08 g. 5.04 mmol) to afford 0.90 g of the desired product; Ή NMR (300 MHz, DMSO-i 6): δ 8.63 (br s, 2H), 8.45 (d, J = 7.8 Hz, 1 H), 8.17 (d, J = 9.3 Hz, 1H), 8.03-7.95 (br d, 2H), 7.80-7.54 (m, 4H), 7.39-7.33 (m, 2H), 7.24 (s, 1H), 5.57 (s, 2H).
Step 4: Preparation of 2-pyridin-4-yl-4-(quinolin-2-ylmethoxy)-phenyl amine
To a solution of 2-[(4-nitro-3-pyridin-4-ylphenoxy)methyl]quinoline, obtained in Step 3 (0.900 g, 2.520 mmol) in methanol (3 mL) was added iron powder (2.0 g) and HCl (3 mL) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mass was filtered off, removed methanol under vacuum and water was added to the residue. The aqueous layer was neutralized with potassium carbonate, extracted with ethyl acetate and concentrated to afford 0.400 g of the desired product; Ή NMR (300 MHz, DMSO-</6): δ 8.60-8.58 (br d, 2H), 8.41 (d, J = 8.1 Hz, 1 H), 7.99 (m, 2H), 7.80-7.61 (m, 5H), 6.91 -6.86 (m, 2H), 6.75 (d, J = 8.7 Hz, 1 H), 5.28 (s, 2H), 4.68 (br s, 2H).
Intermediate 19
4,4,4-Trifluoro-N-[4-(quinolin-2-ylmethoxy)-phenyl]-butyramide
Figure imgf000044_0001
To a solution of 4,4,4-trifluoro butyric acid (0.100 g, 0.704 mmol) in tetrahydrofuran (10 mL) was added l -(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.204 g, 1 .067 mmol), followed by hydroxybenzotriazole (HOBT) (0.142 g, 1 .05 mmol), N,N-diisopropyIethylamine (DIPEA) (0.1 83 g, 1 .41 mmol) and 4-(quinolin-2-ylmethoxy)anil ine (Intermediate 2. 0.300 g. 1 .2 mmol). The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was cooled to room temperature, quenched in water, extracted with ethyl acetate and concentrated the organic layer to afford 0.075 g of the desired product; Ή NMR (300 MHz, OMSO-d6): δ 9.96 (s, 1 H), 8.41 (d, J = 8.4 Hz, 1 H), 8.03-7.93 (m, 2H), 7.78 (d, J = 7.5 Hz, 1 H), 7.67-7.59 (m, 2H), 7.49 (d, J = 8.7 Hz, 2H), 7.02 (d, J= 8.7 Hz, 2H), 5.32 (s, 2H), 2.57-2.55 (m, 4H).
Intermediate 20
2-(4-Chlorophenyl)-3-(4-hydroxyphenyl)benzo[i/|imidazo[2, l - >][l ,3]thiazole
Figure imgf000044_0002
Step 1 : Preparation of 2-(4-chlorophenyl)imidazo[2, 1 -b][ 1 ,3]benzothiazole To a solution of 2-aminobenzothiazole (2.000 g, 13.33 mmol) in dry DMF (15 mL) was added 4-chlorophenacyl bromide (3.4 g, 14.66 mmol) and the reaction mixture was stirred at 90°C for 5 hours. The reaction mixture was allowed to cool to room temperature, poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous Na2SC>4, concentrated and purified by column chromatography to afford 2.5 g of the desired product; Ή NMR (300 MHz, DMSO-flfe): δ 8.82 (s, 1H), 8.02 (d, J = 8.1 Hz, 1 H), 7.95 (d, J = 7.8 Hz, 1 H), 7.85 (d, J = 8.4 Hz, 2H), 7.56 (t, J = 7.5 Hz, 1 H), 7.48 (d, J = 9.0 Hz, 2H), 7.44-7.40 (m, 1 H); MS (m/z): 285.52 (M+H)+.
Step 2: Preparation of 2-(4-chlorophenyl)-3-iodoimidazo[2, l -6][l ,3]benzothiazole
To a solution of 2-(4-chlorophenyl)imidazo[2, l -6][ l ,3]benzothiazole (1 .39 g, 4.90 mmol.) in dry THF (25 mL) was added N-iodosuccinimide (1.10 g, 4.90 mmol) and the reaction mixture was stirred at room temperature for 12 hours. The solvent was evaporated from the reaction mixture on rotavapor and obtained residue was diluted with water. The precipitated solid was filtered. Stirred the solid in diethyl ether and filtered followed by drying under vacuum to afford 1 .7 g of the desired product; Ή NMR (300 MHz, DMSO-d6): δ 8.66 (d, J = 7.8 Hz, 1 H), 8.07 (d, ./ = 7.8 Hz, 1 H), 7.94 (d, J = 8.4 Hz, 2H), 7.63-7.58 (br t, 1 H), 7.54 (d, J = 9.0 Hz, 2H), 7.54-7.48 (m, 1 H); MS (m/z): 41 1 .12 (M+H)+.
Step 3: Preparation of 2-(4-chlorophenyl)-3-(4-hydroxyphenyl)benzo[i ]imidazo[2, l-Z>][l ,3] thiazole
To a solution of 2-(4-chlorophenyl)-3-iodoimidazo[2,l-6][l ,3]benzothiazole (1.400 g, 3.41 mmol) and 4-hydroxyphenylboronic acid (0.941 g, 6.82 mmol) in DMSO (15 mL) was added K2CO3 (1 .41 g, 7.52 mmol) followed by tetrakistriphenylphosphine palladium (0.1 1 8 g, 0.102 mmol.) and the reaction mixture was stirred at 90°C for 3 hours under nitrogen atmosphere. The reaction mixture was quenched in water, neutralized with dilute HC1 and the obtained solid was filtered and purified by column chromatography to afford 1 .1 g of the desired product; Ή NMR (300 MHz, OMSO-d6): δ 10.02 (s, 1 H), 8.66 (d, ./ = 8.1 Hz, 1 H), 8.07 (d, J = 6.0 Hz, 1 H), 7.95 (d, J = 8.4 Hz, 2H), 7.61 (t, J = 7.5 Hz, 1 H), 7.60-7.45 (m, 5H), 7.32 (d, J = 8.7 Hz, 2H); MS (m/z): 377.54 (M+H)+.
Intermediates 21 to 24 mentioned in Table 3 below were prepared in three steps using appropriate amino thiazole compounds, 4-chlorophenacyl bromide and 4- hydroxyphenylboronic acid, by following the procedure as described for the preparation of Intermediate 20. Table 3: Structure, starting material and characterization data for Intermediates 21-24
Figure imgf000046_0002
Intermediate 25
{4-[2-(4-Chlorophenyl)imidazo[2,l-¾][l,3]benzothiazol-3-yl]phenoxy}acetic acid
Figure imgf000046_0001
Step 1 : Preparation of ethyl {4-[2-(4-Chlorophenyl)imidazo[2,l-»][l,3]benzothiazol-3-yl] phenoxy} acetate To a solution of 2-(4-chlorophenyl)-3-(4-hydroxyphenyl)benzo[i ]imidazo[2, l - >][ l ,3] thiazole (Intermediate 20) (0.150 g, 0.398 mmol) in dry DMF (3.0 mL) was added ethylbromoacetate (0.080 g, 0.479 mmol) followed by K2C03 (0.166 g, 1.200 mmol) and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was poured in water and extracted with ethyl acetate. The organic layer was washed with water and concentrated. The obtained residue was washed with «-pentane and purified by column chromatography to afford 0.190 g of the desired product; Ή NMR (300 MHz, DMSO-c¾: δ 8.00 (d, J = 7.8 Hz, 1 H), 7.54 (dd, ,/ = 8.4 Hz & 8.4 Hz, 4H), 7.32-7.23 (m, 4H), 7. 16 (d, J = 9.0 Hz, 2H), 6.68 (d, J = 6.0 Hz, 1 H), 4.92 (s, 2H), 4.19 (q, .7 = 34.8 Hz, 2H), 1 .23 (t, J = 14.1 Hz, 3H); MS (m/z): 463.49 (M+H)+.
Step 2: Preparation of {4-[2-(4-chlorophenyl)imidazo[2, l -&][l ,3]benzothiazole-3-yl] phenoxy} acetic acid
To a solution of ethyl {4-[2-(4-chlorophenyl)imidazo[2, l-0][l,3]benzothiazol-3-yl]phenoxy} acetate (0.180 g, 0.389 mmol) in THF (4 mL) was added aqeous LiOH.H20 (0.033 g, 0.786 mmol) and MeOH and it was stirred at room temperature for 3 hours. The solvent was evaporated from the reaction mixture and cold water was added and neutralized with acetic acid. The precipitated solid was filtered, washed with diethyl ether and dried to afford 0.140 g of the desired product; Ή NMR (300 MHz, DMSO-i¾: δ 13.00 (br s, 1 H), 8.00 (d, J = 6.9 Hz, 1 H), 7.54-7.47 (m, 4H), 7.36-7.24 (m, 3H), 7.14 (d, J = 7.8 Hz, 3H), 6.70 (d, J = 8.4 Hz, l H), 4.80 (s, 2H); MS (m/z): 435.60(M+H)+.
Intermediate 26
4-Nitrophenyl {4-[2-(4-chlorophenylimidazo[2, l -0][ l ,3]benzothiazol-3-yl]phenoxy I } acetate
Figure imgf000047_0001
Step 1 : Preparation of {4-[2-(4-chlorophenyl)imidazo[2, l - >][ l ,3]benzothiazol-3-yl]phenoxy} acetyl chloride
To the solution of {4-[2-(4-chlorophenyl)imidazo[2, l- >][l ,3]benzothiazol-3-yl]phenoxy} acetic acid (Intermediate 25, 0.480 g, 1.10 mmol) in DCM (10 mL) was added thionyl chloride (0.262 g, 2.2 mmol) and catalytic amount of DMF at room temperature. The reaction mixture was stirred for 2 hours. The reaction mixture was concentrated under vacuum to remove excess of thionyl chloride and taken for next step.
Step 2: Preparation of 4-nitrophenyl {4-[2-(4-chlorophenylimidazo[2, l -6][l ,3]benzothiazoI- 3-yl]phenoxyl}acetate
To the solution of {4-[2-(4-chlorophenyl)imidazo[2, l -6][l ,3]benzothiazol-3-yl]phenoxy} acetyl chloride in DCM was added 7-nitro phenol (0.183 g, 1 .31 mmol) and the reaction mixture was cooled at 10-1 5°C. Triethylamine (0.0337 g, 3.33 mmol) was added into stirring mixture and resultant mixtrure was stirred for 3 hours. The reaction mixture was quenched in ice water, filtered the solid and purified by column chromatography to afford 0.540 g of the desired product; Ή NMR (300 MHz, OMSO-d6): δ 8.37 (d, J = 9.0 Hz, 2H), 8.13 (d, J = 9.0 Hz, 3H), 8.04 (d, J = 7.8 'Hz, 1 H), 7.62-7.33 (m, 2H), 7.31 -7.17 (m, 2H), 6.94 (d, J = 9.0 Hz, 4H), 6.73 (d, J = 7.5 Hz, 2H), 5.31 (s, 2H); MS (m/z): 556.99 (M+H)+.
Intermediate 27
2-Chloro-N-(4-methylpyridin-2-yl)acetamide
Figure imgf000048_0001
To the solution of 2-amino-4-methylpyridine (0.500 g, 4.629 mmol) and Ν,Ν- diisopropylethylamine (DIPEA) (0.587 g, 4.629 mmol) in DCM was added chloroacetyl chloride (0.209 g, 1 .849 mmol) at 0-5°C and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified the crude •product by column chromatography to afford 0.255 g of the desired product; Ή NMR (300 MHz, DMSO-flfe): δ 10.73 (s, 1 H), 8.18 (d, J = 4.8 Hz, 1 H), 7.90 (s, 1 H), 6.98 (d, J = 4.5 Hz, 1 H), 4.33 (s, 2H), 2.34 (s, 3H); MS (m/z): 185.62 (M+H)+.
Intermediates 28-30 mentioned in Table 4 below were prepared using appropriate starting material and chloroacetyl chloride, by following the procedure as described for the preparation of Intermediate 27.
Table 4: Structure, starting material and characterization data for Intermediates 28-30
Intermediate Molecular Structure and Starting material Spectral data
No. chemical name
Figure imgf000049_0001
Intermediate 31
4-[2-(4-Chlorophenyl)imidazo[l ,2-a]pyrimidin-3-yl]phenol
Figure imgf000049_0002
Step 1 : Preparation of 2-(4-chlorophenyl)imidazo[l,2- ]pyrimidine
The title compound was prepared following the procedure described for Step 1 of Intermediate 20, but starting from 2-amino pyrimidine (1 .0 g, 10.5 mmol) and 4- chorophenacyl bromide (2.47 g, 10.5 mmol) to afford 1 .55 g of the desired product; Ή NMR (300 MHz, DMSO-</6): δ 8.96 (d, ./ = 6.0 Hz, 1 H), 8.55 (br s, 1 H), 8.42 (s, 1 H), 8.01 (d, ./ = 8.1 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.08 (br s, 1 H); MS (m/z): 230.49 (M+H)+.
Step 2: Preparation of 3-bromo-2-(4-chIorophenyl)imidazo[ l ,2-a]pyrimidine
The title compound was prepared following the procedure described for Step 2 of Intermediate 20, but starting from 2-(4-chlorophenyl)imidazo[ l ,2-o]pyrimidine ( 1 .5 g, 6.7 mmol) and N-bromosuccinimide (1.29 g, 7.3 mmol) to afford 1.9 g of the desired product; Ή NMR (300 MHz, DMSO-<¾): δ 8.83 (d, J = 6.6 Hz, 1 H), 8.62 (m, 1 H), 8. 13 (d, J = 8.1 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.22-7.20 (m, 1 H); MS (m/z): 309.20 (M+H)+.
Step 3: Preparation of 4-[2-(4-chlorophenyl)imidazo[l ,2-o]pyrimidin-3-yl]phenol
To a solution of 3-bromo-2-(4-chlorophenyl)imidazo[l ,2-a]pyrimidine (0.490 g, 1 .588 mmol) in degassed 1 ,4-dioxane (5 mL) was added 4-hydroxyphenylboronic acid (0.219 g, 1 .588 mmol) followed by 3M aqueous Na2C03 solution (0.505 g, 4.76 mmol) and PdCl2(PPh3)2 (0.055 g, 0.079 mmol) and the reaction mixture was refluxed for 3 hours. The solvent was evaporated from the reaction mixture on rotavapor, the residue was diluted with ethyl acetate and was washed with water. The organic layer was dried over anhydrous Na2SC>4, concentrated and purified by column chromatography to afford 0.32 g of the desired product; Ή NMR (300 MHz, DMSO-<¾): δ 9.94 (s, 1H), 8.55 (br s, 1 H), 8.40 (d, J = 6.9 Hz, 1 H), 7.70-7.65 (br d, 2H), 7.39 (d, J = 6.9 Hz, 2H), 7.30 (d, J = 7.2 Hz, 2H), 7.00-6.90 (m, 3H); MS (m/z): 322.47 (M+H)+.
Intermediate 32
2-Chloro-N-ethyl-N-pyridin-2-ylacetamide
Figure imgf000050_0001
Step 1 : Preparation of N-ethylpyridin-2-amine
To the solution of 2-aminopyridine (1.0 g, 10.06 mmol) in DMF was added NaH (0.386 g) at room temperature followed by ethyl iodide (1.570 g, 10.06 mmol). The reaction mixture was stirred at room temperature for 10 hours. The reaction mixture was quenched in water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate and concentrated. The residue was purified by column chromatography to afford 0.42 g of the desired product; Ή NMR (300 MHz, DMSO-<¾): δ 7.95 (s, 1H), 7.33 (t, J = 6.9 Hz, 1 H), 6.40 (d, J= 8.4 Hz, 3H), 3.24-3.17 (q, J= 6.9 Hz & 6.6 Hz, 2H), 1 .10 (t, J = 6.9 Hz, 3H); MS (m/z): 123.14 (M+H)+.
Step 2: Preparation of 2-chloro-N-ethyl-N-pyridin-2-ylacetamide
The title compound was prepared following the procedure described for Intermediate 27, but starting from 2-ethylamino pyridine (0.4 g, 3.27 mmol) and chloroacetyl chloride (0.37 g, 3.27 mmol) to afford 0.25 g of the desired product; Ή NMR (300 MHz, DMSO-i 6): δ 9.82 (d, .7 = 6.3 Hz, l H), 7.88 (t, J = 8.4 Hz, 1 H), 7.73 (d, J = 8.1 Hz, 1 H), 7.37 (t, J = 6.9 Hz, 1 H), 4.79 (s, 2H), 4.02-4.00 (q, J = 6.9 Hz & 6.6 Hz, 2H), 1.21 (t, J = 6.9 Hz, 3H); MS (m/z): 199.14 (M+H)+.
Examples
Example 1
2-(3-Methoxyphenyl)-N-(py lmethoxy)phenyl]acetami
Figure imgf000051_0001
To the solution of N-(pyridin-3-yImethyl)-4-(quinolin-2-ylmethoxy)aniline (Intermediate 4, 0.1 g, 0.294 mmol) in dichioromethane (5 mL) was added 3-methoxyphenylacetic acid (0.049 g, 0.294 mmol) followed by diisopropylethylamine (2 eq) and bezotriazol-l -yloxy tris(dimethylamino)phosphonium hexafluorophosphate (0.39 g, 0.88 mmol) and reaction mixture was refluxed for 12 hours. The reaction mixture was poured in water and extracted with dichioromethane. The organic layer was dried over anhydrous Na2S04, concentrated and purified by column chromatography to afford 0.036 g of the product as a pale yellow sticky solid; Ή NMR (300 MHz,
Figure imgf000051_0002
δ 8.44 (d, J = 7.8 Hz, 2H), 8.32 (d, 2H), 7.99 (m, 2H), 7.77 (t, 1 H), 7.69-7.50 (m, 3H), 7.18 (m, I H), 7.01 (m, 4H), 6.70 (d, 1 H), 6.57 (m, 2H), 5.35 (s, 2H), 4.84 (s, 2H), 3.67 (s, 3H), 3.41 (s, 2H); MS (m/z): 490.24(M+H)"\
Examples 2-45 mentioned in Table 5 below were prepared using appropriate starting material and phenylacetic acid derivatives, by following the procedure as described for the preparation of Example 1 .
Table 5: Structure, starting material and characterization data for Examples 2-45
Exam. Molecular structure and Chemical Starting Spectral data No. name material
2 Intermediate 4 Ή NMR (300 MHz, and
DMSO-i¾: δ 8.44 (d, J =
4-Fluorophenyl
7.8 Hz, 2H), 8.34 (s, 1 H), acetic acid
7.99 (m, 2H), 7.60-7.80 (m, 4H), 7.12 (m, 1 H), 7.02 (m,
2-(4-Fluorophenyl)-N-(pyridin-3-yl 8H), 5.36 (s, 2H), 4.84 (s, methyl)-N-[4-(quinolin-2-yl 2H), 3.42 (s, 2H).
methoxy)phenyl]acetamide
Figure imgf000052_0001
acetamide Exam. Molecular structure and Chemical Starting Spectral data No. name material
8 Intermediate 3 Ή NMR (300 MHz, and DMSO-i¾: δ 8.32 (d, J =
4-Fluorophenyl 8.10 Hz, 1 H), 8.00 (m, 2H), acetic acid 7.76 (t, J = 7.8 Hz, 1 H), 7.62
(m, 2H), 7.27-6.96 (m, 13H), 5.35 (s, 2H), 4.81 (s, 2H),
N-Benzyl-2-(4-fluorophenyl)-N-[4- 3.42 (s, 2H).
(quinolin-2-ylmethoxy)phenyl]
acetamide
9 a, Intermediate 3 Ή NMR (300 MHz, and DMSO-<¾: δ 8.41 (d, J = 2,3- 8.40 Hz, 1 H), 7.99 (m, 2H), Difluorophenyl 7.78 (t, 1 H), 7.62 (m, 2H), acetic acid 7.29-7.09 (m, 12H), 5.34 (s,
2H), 4.83 (s, 2H), 3.52 (s, 2H).
N-Benzyl-2-(2,3-difluorophenyl)- N-[4-(quinolin-2- ylmethoxy)phenyl] acetamide
10 Intermediate 3 Ή NMR (300 MHz, and DMSO-i/6): δ 8.41 (d, J = 4- 8.70 Hz, 1 H), 7.99 (m, 2H),
Chlorophenyl 7.76 (t, 1 H), 7.68 (m, 2H), acetic acid 7.27-7.05 (m, 13H), 5.35 (s,
2H), 4.81 (s, 2H), 3.42 (s,
N-Benzyl-2-(4-chlorophenyl)-N-[4- 2H).
(quinolin-2-ylmethoxy)phenyl]
acetamide
1 1 Intermediate 5 Ή NMR (300 MHz, and DMSO-i¾: δ 8.42 (d, J =
4-Fluorophenyl 8.10 Hz, 1H), 7.99 (m, 2H), acetic acid 7.79 (t, 1H), 7.62 (m, 2H),
7.18-7.02 (m, 12H), 5.35 (s, 2H), 4.78 (s, 2H), 3.40 (s,
N-(4-FIuorobenzyl)-2-(4- 2H).
fluorophenyl)-N-[4-(quinolin-2- ylmethoxy)phenyl]acetamide
12 Intermediate 5 Ή NMR (300 MHz, and DMSC s): δ 8.41 (d, J =
2-Fluorophenyl 8.1 Hz, 1 H), 8.00 (m, 2H), acetic acid 7.79 (t, 1 H), 7.62-7.66 (m,
2H), 7.20-7.09 (m, 12H), 5.35 (s, 2H), 4.80 (s, 2H), 3.44 (s, 2H); MS (m/z):
N-(4-Fluorobenzyl-2-(2- 495.27(M+H)+.
fluorophenyl)-N-[4-(quinolin-2- ylmethoxy)phenyl]acetamide
Figure imgf000054_0001
Figure imgf000055_0001
Exam. Molecular structure and Chemical Starting Spectral data No. name material
22 Intermediate 7 Ή NMR (300 MHz,
a, and DMSO-i/6): δ 8.50-8.35 (m,
2,4- 2H), 8.05-7.90 (m, 2H), Difluorophenyl 7.80-7.55 (m, 4H), 7.40-7.15 acetic acid (m, 5H), 7.15-6.95 (m, 4H),
5.36 (s, 2H), 4.90 (s, 2H),
2-(2,4-Difluorophenyl)-N-(2- 3.48 (s, 2H).
pyridylmethyl)-N-[4-(quinolin-2- ylmethoxy)-phenyl]acetamide
23 Intermediate 4 Ή NMR (300 MHz, and DMSO-<¾: δ 8.44-8.42 (m,
2,4,6-Trifluoro 2H), 8.36 (s, 1 H), 8.00 (m, phenylacetic 3H), 7.79 (t, J = 7.2 Hz, l H), acid 7.70-7.62 (m, 3H), 7.33 (t, J
= 6.9 Hz, l H), 7.23-7.1 3 (m,
N-Pyridin-3-ylmethyl-N-[4- 5H), 5.36 (s, 2H), 4.85 (s, (quinolin-2-ylmethoxy)-phenyl]-2- 2H), 3.42 (s, 2H).
(2,4,6-trifluoro-phenyl) acetamide
24 Intermediate 4 Ή NMR (300 MHz, and CDC13): δ 8.44-8.41 (br d,
2,3,4-Trifluoro 2H), 8.36 (s, 1 H), 8.01 -8.00 phenylacetic (br d, 2H), 7.79 (t, J = 7.2 acid Hz, 1H), 7.69-7.62 (m, 3H),
7.35-7.33 (m, 2H), 7.19 (d, J
N-Pyridin-3-ylmethyl-N-[4- = 8.7 Hz, 2H), 7.1 1 (d, J = (quinolin-2-ylmethoxy)-phenyl]-2- 8.4 Hz, 3H), 5.36 (s, 2H), (2,3,4-trifluoro-phenyl) acetamide 4.85 (s, 2H), 3.51 (s, 2H).
25 Intermediate 4 Ή NMR (300 MHz, and CDCI3): δ 8.44-8.42 (br d, 2-Fluoro-4- 2H), 8.36 (s, 1 H), 8.00 (m, chloro 2H), 7.79-7.76 (br t, 1 H), phenylacetic 7.69-7.62 (m, 3H), 7.33-7.21 acid (m, 3H), 7.18-7.1 1 (m, 4H),
2-(4-Chloro-2-fluoro-phenyl)-N- 6.96 (s, 1 H), 5.36 (s, 2H), pyridin-3-ylmethyl-N-[4-(quinolin- 4.85 (s, 2H), 3.46 (s, 2H). 2-ylmethoxy)-phenyl] acetamide
26 Intermediate 4 Ή NMR (300 MHz, and DMSO- i): δ 8.44-8.36 (m,
2,4,5-Trifluoro 2H), 8.00 (m, 2H), 7.79 (m, phenylacetic 1 H), 7.69-7.61 (m, 3H), acid 7.44-7.35 (m, 4H), 7.16-7.12
(m, 4H), 5.35 (s, 2H), 4.85
N-Pyridin-3-ylmethyl-N-[4- (s, 2H), 3.44 (s, 2H).
(quinolin-2-ylmethoxy)-phenyl]-2- (2,4,5-trifluoro-phenyl) acetamide
Figure imgf000057_0001
Exam. Molecular structure and Chemical Starting Spectral data No. name material
pyridin-3-ylmethyl-N-[4-(quinolin- 3H).
2-ylmethoxy)-phenyl] acetamide
32 Intermediate Ή NMR (300 MHz,
11 DMSO-<¾: δ 8.86 (s, 1H), and 8.43 (d, ./ = 8.4 Hz, ΓΗ), 2,4- 8.02-8.00 (m, 2H), 7.97 (t, ./ Difluorophenyl = 7.2 Hz, 1H), 7.70-7.60 (m, acetic acid 2H), 7.28-7.20 (m, 1H),
2-(2,4-Difluoro-phenyl)-N-(4- 7.10-7.06 (m, 5H), 7.01-6.96 methyl-thiazol-5-ylmethyl)-N-[4- (m, 1H), 5.39 (s, 2H), 4.94
(quinolin-2- (s, 2H), 3.37 (s, 2H), 1.97 (s, ylmethoxy)-phenyl]acetamide 3H).
33 Intermediate 4 Ή NMR (300 MHz, and DMSO- e): δ 8.46-8.41 (m, 1-Phenyl- 2H), 8.27 (s, 1H), 8.02 (d, J cyclopropane = 8.4 Hz, 2H), 7.79 (t, J = carboxylic acid 7.8 Hz, 1H), 7.61 (d, J= 8.1
Hz, 2H), 7.54 (m, 1H), 7.28 (m, 2H), 6.91 (m, 3H), 6.69
1 -Phenyl-cyclopropanecarboxylic (m, 3H), 6.54 (m, 2H), 5.27 acid pyridin-3-ylmethyl-[4- (s, 2H), 4.79 (s, 2H), 3.09 (quinolin-2-ylmethoxy)-phenyl] (m, 1H), 1.17-1.06 (m, 4H). amide
34 ocH3 Intermediate 8 Ή NMR (300 MHz, and DMSO-45): δ 8.42 (d, J =
2,4- 8.4 Hz, 1H), 8.00-7.79 (m, Difluorophenyl 2H), 7.76-7.68 (br t, 1H), acetic acid 7.65-7.63 (m, 3H), 7.35-7.28
(m, 3H), 7.10 (d, J = 7.8 Hz, 2H), 6.98-6.90 (m, 2H), 6.64
2-(2,4-Difluoro-phenyl)-N-(6- (d, J= 7.8 Hz, 2H), 5.37 (s, methoxy-pyridin-2-ylmethyl)-N-[4- 2H), 4.81 (s, 2H), 3.76 (s, (quinolin-2-ylmethoxy)-phenyl] 3H), 3.47 (s, 2H).
acetamide
35 Intermediate 9 Ή NMR (300 MHz, and DMSO-£¾: δ 8.42 (d, J = jaHro-> 2,4- 8.4 Hz, 1H), 8.01-7.99 (br d,
Difluorophenyl 2H), 7.79 (t,J=6.9Hz, 1H), acetic acid 7.68-7.62 (m, 2H), 7.25-7.10
(m, 1H), 7.08-6.98 (m, 5H),
2-(2,4-Difluoro-phenyl)-N-(3,5- 7.00-6.90 (m, 1H), 5.39 (s, dimethyI-isoxazol-4-ylmethyl)-N- 2H), 4.63 (s, 2H), 3.33 (s,
[4-(quinolin-2-ylmethoxy)-phenyl] 2H), 1.91-1.88 (brs, 6H). acetamide
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Example 46
2-(2,4-Difluorophenyl)-N-(pyridin-3-ylmethyl)-N-[4-(quinolin-2-ylmethoxy)
phenyl]acetamide succinate salt
Figure imgf000061_0002
To a solution of 2-(2,4-difluorophenyl)-N-(pyridin-3-ylmethyl)-N-[4-(quinolin-2- ylmethoxy)phenyl]acetamide (Example 15, 0.1 10 g, 0.222 mmol) in acetonitrile (5 ttiL) was added succinic acid (0.026 g, 0.222 mmol) and the reaction mass was stirred for 12 hours at room temperature. The excess of solvent was removed under vacuum and resultant residue was washed with pentane to afford 0.07 g of the desired product; Ή NMR (300 MHz, DMSO-i 6): δ 12.17 (br s, 2H), 8.44-8.36 (m, 3H), 8.00 (m 2H), 7.81 -7.76 (br t, I H), 7.81 - 7.62 (m, 3H), 7.32 (m, I H), 7.14-7.1 1 (m, 6H), 7.01 -6.99 (m, I H), 5.36 (s, 2H), 4.85 (s, 21 1), 3.44 (s, 2H), 2.41 (s, 4H).
Example 47 N-Pyridin-3-ylmethyl-N-[4-(quinolin-2-ylmethoxy)-phenyl]-acetamide
Figure imgf000062_0001
To the solution of N-(pyridin-3-ylmethyl)-4-(quinolin-2-ylmethoxy) aniline (Intermediate 4, 0.050 g, 0.147 mmol) in tetrahydrofuran was added sodium hydride (0.010 g, 0. 141 mmol) at 10- 1 5°C followed by addition of acetyl chloride and the reaction mixture was stirred at room temperature for 1 8 hours. The reaction mixture was quenched in water, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, concentrated to afford 0.025 g of the desired product; Ή NMR (300 MHz, OMSO-d6): δ 1.80 (s, 3H), 4.83 (s, 2H), 5.34 (s, 2H), 7.06 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 9.0 Hz, 2H), 7.31 (m, 1 H), 7.59-7.69 (m, 3H), 7.79 (t, J= 7.2 Hz, 1H), 7.99-8.01 (m, 2H), 8.41-8.43 (m, 3H).
Example 48
3-Butyl- l -pyridin-3-ylmeth - l -[4-(quinolin-2-ylmethoxy)-phenyl]thiourea
Figure imgf000062_0002
To a solution of N-(pyridin-3-ylmethyl)-4-(quinolin-2-ylmethoxy) aniline (Intermediate 4, 0.050 g, 0.147 mmol) in dimethyl sulfoxide (5 mL) was added triethylamine (1 mL) followed by n-butyl isothiocyanate (0.016 g, 0.140 mmol) and was stirred at room temperature for 6 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous a2S04, concentrated and purified by column chromatography to afford 0.030 g of the desired product; Ή NMR (300 MHz, DMSO-i/6): δ
0.83 (t, J = 7.2 Hz, 3H), 1.15-1.21 (m, 4H), 1.41-1.49 (m, 2H), 5.33 (s, 2H), 5.41 (s, 2H), 6.94 (s, 1H), 7.01 (d, J = 8.7 Hz, 2H), 7.09 (d, J = 8.7 Hz, 2H), 7.31 -7.32 (m, 1H), 7.62-7.71 (m, 3H), 7.79 (t, J = 7.8 Hz, 1 H), 8.01 (d, J = 8.1 Hz, 2H), 8.39-8.44 (m, 3H).
Example 49
l -Benzyl-3-(5-tertbutyl- l ,3,4-thiadiazol-2-yl)-l -[4-(quinoline-2-ylmethoxy)phenyl]urea
Figure imgf000063_0001
To a solution of N-benzyl-4-(quinolin-2-ylmethoxy)aniline (Intermediate 3, 0.080 g, 0.235 mmol)) in dimethyl sulfoxide (2 mL) was added triethylamine (1 mL) and phenyl (5-tert butyl- l ,3,4-thiadiazol-2-yl)carbamate (Intermediate 14, 0.071 g, 0.256 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured in water and extracted with ethyl acetate. The organic layer was dried over Na2S04, concentrated and purified by column chromatography to afford 0.030 g of the desired product; Ή NMR (300 MHz, DMSO-i¾: δ 8.40 (d, J = 8.4 Hz, 1 H), 7.97 (m, 2H), 7.76 (t, 1 H), 7.59-7.66 (m, 2H), 7.19-7.23 (m, 5H), 6.92-7.1 8 (m, 5H), 5.32 (s, 2H), 4.87 (br s, 2 H), 1 .33 (s, 9H).
Example 50
2-(2,4-Difluoro-phenyl)-N-[2-pyridin-4-yl-4-(quinolin-2-ylmethoxy)-phenyl]acetamide
Figure imgf000063_0002
The title compound was prepared following the procedure described for Example 1 , but starting from 2-pyridin-4-yl-4-(quinolin-2-ylmethoxy)-phenyl amine (Intermediate 18, 0.131 g, 0.400 mmol), benzotriazol-l -yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.442 g, 1.0 mmol), N,N-diisopropylethylamine (2 mL) and 2,4-difluorophenyl acetic acid (0.075 g, 0.428 mmol) to afford 0.040 g of the desired product; Ή NMR (300 MHz, CDC13): δ 8.57 (br s, 2H), 8.38 (d, J = 7.2 Hz, 1 H), 8.30 (d, J = 7.2 Hz, I H), 7.93-7.53 (m, 7H), 7.26- 7.16 (m, 2H), 7.03 (br s, 1 H), 6.84-6.81 (m, 2H), 5.57 (s, 2H), 3.61 (s, 2H).
Example 51
2-(2,4 Difluorophenyl)-N-methyl-N-[2-pyridin-4-yl-4-(quinolin-2-ylmethoxy)- phenyljacetamide
Figure imgf000064_0001
To a solution of 2-(2,4-difluoro-phenyl)-N-[2-pyridin-4-yl-4-(quinolin-2-ylmethoxy)- phenyl]acetamide (Example 50, 0.040 g, 0.083 mmol) in tetrahydrofuran was added (60%) sodium hydride (0.004 g, 0.1 mmol) at 10-15°C and stirred for 30 min. To this mixture was added methyl iodide (0.013 g, 0.091 mmol) and stirred for 12 hours. The reaction mixture was quenched in water and extracted with ethyl acetate. The organic layer was concentrated to afford 0.03 g of the desired product; Ή NMR (300 MHz, DMSO-<¾): '6 8.66-8.65 (br d, 1 H), 8.47-8.44 (br d, 1 H), 8.02-8.00 (br d, 2H), 7.82-7.72 (m, 2H), 7.62 (t, J = 7.8 Hz, 1 H), 7.48-7.41 (m, 3H), 7.28 (s, 2H), 7.13-7.04 (m, 3H), 6.95-6.93 (m, 1 H), 5.48 (s, 2H), 3.39 (m, 2H), 2.97 (s, 3H).
Example 52
4,4,4-Trifluoro-N-pyridin-3-ylmethyl-N-[4-(quinolin-2-ylmethoxy)-phenyl]-butyramide
Figure imgf000064_0002
To a solution of 4,4,4-trifluoro-N-[4-(quinolin-2-ylmethoxy)-phenyl]-butyramide (Intermediate 19, 0.075 g, 0.200 mmol) in N,N-dimethylformamide under nitrogen atmosphere, was added suspension of sodium hydride (0.024 g, 0.588 mmol) in NN- dimethylformamide (5 ml) and the mixture was stirred at room temperature for 30 min. To this mixture was added 3-chloromethyl pyridine (0.030 g, 0.218 mmol) at -20°C and stirred at room temperature for 24 hours. The reaction mixture was quenched in ice cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, concentrated and purified by column chromatography to afford 0.025 g of the desired product as pale yellow liquid; Ή NMR (DMSO-i/6): δ 8.44-8.32 (m, 3H), 8.02-7.99 (m, 2H), 7.95 (t, J = 6.9 Hz, 1 H), 7.75-7.59 (m, 3H), 7.33-7.29 (m, 1 H), 7.17 (d, J = 8.7 Hz, 2H), 7.10 (d, ./ = 9.6 Hz, 2H), 5.35 (s, 2H), 4.85 (s, 2H), 2.49 (m, 2H), 2.30 (t, J = 8.1 Hz, 2H); MS (m/z): 466.35 (M+H)+.
Example 53 2-{4-[2-(4-Chlorophenyl)imidazo[2,l-0][l,3]benzothiazol-3-yI]phenoxy}-N-(5-methyl pyridin-2-yl)acetamide
Figure imgf000065_0001
Prepared the solution of {4-[2-(4-chlorophenyl)imidazo[2,l-&][l,3]benzothiazol-3- yl]phenoxy}acetic acid (Intermediate 25) (0.050 g, 0.110 mmol) and 2-amino-5-methyl pyridine (0.037 g, 0.330 mmol) in DCM. The reaction mixture was cooled to 10-15°C and was added thionyl chloride (0.027 g, 0.229 mmol) drop wise followed by catalytic amount of DMF. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with ice water and extracted the organic mass with DCM. The organic layer was concentrated and purified the crude compound by column chromatography to afford 0.012 g of the desired product; Ή NMR (300 MHz, DMSO-<¾): δ 10.54 (s, 1H), 8.19 (s, 1H), 8.02 (t, J =7.8 Hz, 2H), 7.65 (d, J= 7.8 Hz, 5H), 7.57 (d, J= 8.1 Hz, 2H), 7.51 (d, ./= 8.4 Hz, 2H), 7.34 (d, J= 8.7 Hz, 1H), 7.23 (d, J= 8.7 Hz, 1H), 6.73 (d, J= 7.8 Hz, 1 H ), 4.92 (s, 2H), 2.26 (s, 3H); MS (m/z): 526.02 (M+H)+.
Example 54
2-{4-[2-(4-Chlorophenyl)imidazo[2,l-Z)][l,3]benzothiazol-3-yl]phenoxy}-N-(5-chloro pyridin-2-yl)acetamide
Figure imgf000065_0002
The title compound was prepared following the procedure described for Example 53, but starting from {4-[2-(4-chlorophenyl)imidazo[2,I->][l,3]benzothiazol-3-yl]phenoxy}acetic. acid (Intermediate 25) (0.080 g, 0.188 mmol), thionyl chloride (0.043 g, 0.369 mmol) and 2- amino-5-chloropyridine (0.070 g, 0.550 mmol) to afford 0.025 g of the desired product; Ή NMR (300 MHz, DMSO-i6): δ 10.87 (s, 1H), 8.42 (s, 1H), 8.14 (d, J = 8.7 Hz, 1H), 8.03 (d, J=7.8 Hz, 1H), 7.95 (d,j=9.0 Hz, 1H), 7.57 (d,J= 8.1 Hz, 2H), 7.51 (d,J=8.4 Hz, 2H), 7.33 (d, J = 9.0 Hz, 4H), 7.22 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 7.8 Hz, 1 H), 4.95 (s, 2H); MS (m/z): 546.1 1 (M+H)+.
Example 55
2-{4-[2-(4-Chlorophenyl)imidazo[2, l - »][l,3]benzothiazol-3-yl]phenoxy}-N-(6-chloropyridin -2-yl)acetamide
Figure imgf000066_0001
The title compound was prepared following the procedure described for Example 55, but starting from 2-(4-chlorophenyl)-3-(4-hydroxyphenyl)benzo[i ]imidazo[2, l - >][ ] ,3]thiazole (Intermediate 20) (0.080 g, 0.21 1 mmol) and 2-chloro-N-(6-chIoro-pyridin-2-yI)acetamide (Intermediate 28) (0.065 g, 0.317 mmol) to afford 0.022 g of the desired product; Ή NMR (300 MHz, DMSO-<¾): δ 1 1 .05 (s, 1 H), 8.09 (d, J = 7.8 Hz, 1 H), 8.04 (d, J = 7.2 Hz, 1 H), 7.90 (t, J = 8.4 Hz, 1H), 7.58 (d, J =8.1 Hz, 2H), 7.51 (d, J= 8.1 Hz, 3H), 7.34 (d, J = 7.8 Hz, 2H), 7.30-7.21 (m, 4H), 6.72 (d, J = 7.8 Hz, 1H), 4.94 (s, 2H); MS (m/z): 546.44 (M+H)+.
Example 56
2-{4-[2-(4-Chlorophenyl)imidazo[2, l -¾][l ,3]benzothiazol-3-yl]phenoxy}-N-[3-chloro-5- (trifluoromethyl)pyridin-2-yl]acetamide
Figure imgf000066_0002
To the suspension of 4-nitrophenyl-[4-(2-chlorophenyl)imidazo[2, l -6][l ,3]benzothiazol-3-yl] phenoxy]acetate (Intermediate 26) (0.080 g, 0.143 mmol) and 2-amino-3-chloro-5- (trifluoromethyl)pyridine (0.042 g 0.215 mmol) in DMF (1.0 mL) was added sodium hydride (0.014 g, 0.357 mmol) at -10 to 0°C under nitrogen atmosphere and stirred the reaction mixture at room temperature for 2-3 hours. The reaction mixture was quenched in ice water, acidified with dilute HCl. The resultant precipitate was filtered off and purified by column chromatography to afford 0.034 g of the desired product; Ή NMR (300 MHz, DMSO-< 6): δ 10.82 (s, l H), 8.87 (s, 1 H), 8.59 (s, 1 H), 8.04 (d, J = 7.8 Hz, 1 H), 7.60 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 3H), 7.26 (d, J = 7.8 Hz, 3H), 6.74 (d, J = 8.4 Hz, 1 H), 5.02 (s, 2H); MS (m/z): 614.44 (M+H)+.
Examples 57-59 mentioned in Table 6 below were prepared using Intermediate 26 and appropriate amine derivatives, by following the procedure as described for the preparation of Example 56.
Table 6: Structure, starting material and characterization data for Examples 57-59
Figure imgf000067_0001
Example 60 2-{4-[2-(4-Chlorophenyl)imidazo[2, l -0][l ,3]benzothiazol-3-yl]phenoxy} -N-(4-methyl pyridin-2-yl)acetamide
Figure imgf000068_0001
To the suspension of 2-(4-chlorophenyl)-3-(4-hydroxyphenyl)benzo[i/]imidazo[2, ] - )] [l ,3] thiazole (Intermediate 25) (0.080 g, 0.21 1 mmol) and 2-chloro-N-(4-methylpyridin-2-yl) acetamide (Intermediate 27) (0.058 g, 0.317 mmol) in DMF (1 .0 mL) was added potassium carbonate (0.058 g 0.423 mmol) and it was stirred at 90-100 °C for 5 hours. The reaction mixture was cooled at room temperature and quenched in ice water, acidified with di lute HC1. Resultant solid was filtered off and purified by column chromatography to afford 0.01 9 g of the desired product; Ή NMR (300 MHz, DMSO-<¾: δ 10.55 (s, 1 H), 8.21 (d, ./ = 4.8 Hz, 1 H), 8.03 (d, J = 7.2 Hz, 1 H), 7.96 (s, 1 H), 7.57 (d, J = 7.8 Hz, 2H), 7.5 1 (d, J = 8.4 Hz, 3H), 7.33 (d, ./ = 9.0 Hz, 2H), 7.23 (d, J = 8.4 Hz, 3H), 7.00 (d, J = 8.4 Hz, 1 H ), 6.73 (d, J = 8. 1 Hz, 1 H), 4.93 (s, 2H), 2.33 (s, 3H); MS (m/z): 526.02 (M+H)+.
Examples 61 -68 mentioned in Table 7 below were prepared using appropriate starting material, by following the procedure as described for the preparation of Example 60.
Table 7: Molecular structure, starting material and characterization data for Examples 61 -69
Figure imgf000068_0002
Figure imgf000069_0001
acetamide
Figure imgf000070_0001
ethyl-N-pyridin-2-ylacetamide
Example 69
-{4-[2-(4-Chlorophenyl)imidazo[2, l -¾][l ,3]benzothiazol-3-yl]phenoxy}-N-methyl- V-phenylacetamide
Figure imgf000070_0002
The mixture of {4-[2-(4-chlorophenyl)imidazo[2, l -6][l ,3]benzothiazol-3-yl]phenoxy}acetic acid (Intermediate 25, 0.050 g, 0.1 14 mmol), BOP (0.060 g, 0.137 mmol) and DIPEA (0.028 g, 0.229 mmol) was stirred at room temperature for 15-20 mins. To this mixture, N- methylaniline (0.015 g, 1.2 mmol) was added and stirred the reaction mixture at room temperature for 14 hours under nitrogen atmosphere. The reaction mixture was quenched in ice water, acidified with dilute HC1, filtered off the solid and purified by column chromatography to afford 0.012 g of the desired product; Ή NMR (300 MHz, DMSO-c¼): δ 8.03 (d, ,/ = 7.8 Hz, 1 H), 7.50 (d, J = 6.3 Hz, 8H), 7.33 (m, 5H), 7.02 (s, 2H), 6.69 (d, J = 9.0 Hz, 1 H), 4.59 (s, 2H), 3.25 (s, 3H); MS (m/z): 525.03 (M+H)+.
Examples 70-72 mentioned in Table 8 below were prepared using appropriate starting material, by following the procedure as described for the preparation of Example 69.
Table 8: Structure, starting material and characterization data for Examples 70-72
Figure imgf000071_0001
Exam. Molecular structure and Starting Spectral data
No. chemical name material
2-{4-[2-(4-Chlorophenyl) (t, J = 34.8 Hz, 1 H), 6.70 (d, J imidazo[2, l -Z>][l ,3] = 7.8 Hz, 1 H), 4.84 (s, 2H); benzothiazol-3-yl]phenoxy} MS (m/z): 51 1.72 (M+H)+. N-phenylacetamide
Pharmacological activity
The illustrative examples of the present invention are screened for PDE 10A activity according to a modified procedure described in Sette, C, lona, S. and Conti, M., J. Biol. Chem. 269 ( 12), pp. 9245-9252, 1994.
ln-vitro screening assay for PDE10A inhibitors:
PDE10 enzyme hydrolyses cAMP / cGMP to metabolically inactive 5'-AMP / 5 '- GMP. Inhibition of PDE10 enzyme activity can be quantitated by using a two step radiometric assay. In this assay, PDE10 enzyme converts 3H-cAMP/3H-cGMP to 3H-AMP/ 3H-GMP which is then converted to 3H-adenosine / 3H-guanosine using snake venom nucleotidase. The radioactivity released in the supernatant is quantitated as an indicator of PDE 10 enzyme activity.
Test compounds or reference compounds such as dipyridamole, IBMX (Calbiochem) and papaverine (Sigma) were dissolved in dimethylsulfoxide (DMSO) to prepare 1 .0 mM stock solution and diluted suitably to get the desired concentration. Final concentration of DMSO in the reaction was 3 % (v/v). Substrate mixture was prepared by mixing H-cAMP (GE Healthcare) and 1 .0 mM cold cAMP (Sigma) in order to get 0.5 μθί and 1 .0 μΜ final concentrations of each respectively in the assay buffer. 1 .0 mg/mL of snake venom nucleotidase (Sigma) was prepared in D/w. Dowex (AG1 -X8 from Biorad) slurry was mixed with water and ethanol at 1 : 1 : 1 ratio. The assay was carried out using suitably diluted PDE10A enzyme preparation (BPS Biosciences) to get around 1 -20 % substrate hydrolysis to ensure linear reaction kinetics.
PDE10A assay was carried out in 200 μΙ_. reaction volume by addition of assay buffer containing 10 mM Tris-HCl (pH 7.4), 0.2 mM MgCl2, . test compound at required concentration and diluted enzyme. Reaction mixture was incubated at 30 °C for 30 min. The reaction was stopped by heating the plate in boiling water bath for 5 min and then cooling on an ice bath for 1 5 min. This was followed by addition of 50 μΐ, of Crotalus atrox snake venom 5'-nucleotidase and incubation at 30 °C for 30 min. Thereafter, 400 μΕ of Dowex was added and incubated on an ice bath for 1 5 min. Reaction mixture was centrifuged and supernatant was used for quantifying radioactivity in the samples. Reaction was measured as counts per minute (cpm) using Packard Biosciences plate reader. An enzyme control without test compounds was run to quantitate maximum PDEI OA reaction. Inhibition of enzyme activity was calculated as a percent of control reaction. IC50 values were calculated from dose response curve by nonlinear regression analysis using GraphPad Prism software.
The compounds of the present invention were screened using the above assay procedure and the results obtained are given in Table 9. Percentage inhibition of human - PDEI OA enzyme at 1 .0 μΜ and 10.0 μΜ concentrations are given in Table 1 along with IC50 (nM), wherein "A" refers to an IC50 value of less than 100 nM, "B" refers to an IC50 value in range of 100.01 -250 nM, "C" refers to an IC50 value in range of 250.01 -500 nM and "D" refers to an IC50 value of greater than 500 nM.
Table 9: In-vitro screening results of compounds of present invention
Example No. percentage inhibition at IC50 (nM)
1 μΜ 10 μΜ
1 58.54 93.35 D
2 66.03 95.24 D
3 31.55 77.79 ~
4 72.44 92.16 C
5 88.73 96.29 A
6 36.80 64.61 -
7 18.72 47.53 ~
8 19.34 39.00 ~
9 17.42 37.09 -
10 1 1.60 21 .76 -
12 32.68 56.88
13 74.1 5 86.79 B
14 82.96 97.20 A
1 5 91 .10 97.53 A
16 83.07 96.40 B
17 65.83 90.99 D
18 84.84 96.88 B
19 76.62 96.39 B
20 40.60 72.63 — Example No. percentage inhibition at 1C50 (nM)
1 μΜ 10 μΜ
21 43.45 85.94 ~
22 22.17 66.40 ~
23 91.46 98.87 A
24 80.24 96.42 C
25 80.71 97.35 A
26 63.86 95.09 C
27 85.28 98.67 A
28 21.17 69.96 ~
29 68.07 94.90 B
30 68.75 96.3 1 C
3 1 36.22 86.98 -
32 75.53 99.75 B
33 29.07 80.69 —
34 36.46 73.41 -
35 73.35 95.44 C
36 78.59 99.04 B
37 36.81 56.92 ~
38 86.94 98.47 A
39 88.77 98.64 A
40 89.19 96.34 A
41 87.12 99.29 A
42 43.99 44.62 ~
43 58.13 81 .30 D
44 50.90 73.25 -
45 46.75 88.14 —
46 96.06 100.30 A
47 14.36 73.13 —
48 16.01 71 .59 -
49 34.07 39.88
50 04.78 07.98 - Example No. percentage inhibition at IC50 (nM)
1 μΜ 10 μΜ
51 06.91 43.63 -
52 80.81 96.71 B
53 20.39 48.90 ~
54 12.39 24.61 ~
55 0.00 3.35 ~
56 00 00 ~
57 16.99 19.96 —
58 1 8.03 26.53 -
59 1 1 .72 26.62 —
60 3 1 .89 32.42 -
61 84.32 88.81 B
62 17.40 41.41 ~
63 82.40 97.75 A
64 58.16 82.10 ~
65 76.78 94.56 A
66 78.32 89.21 B
67 83.63 95.45 A
68 76.6 91.50 B
69 09.19 27.73 -
70 57.57 58.83 -
71 14.15 32.30 -
72 43.91 46.19 ~

Claims

WE CLAIM:
A compound of the formula (I):
Figure imgf000076_0001
or a pharmaceutically acceptable salt thereof,
wherein,
G, is
Figure imgf000076_0002
is
7 ( )p ( )q
O R7
-C-N -© or Hg) .
with the proviso that
Figure imgf000076_0003
ring Ar1 and Ar2 are independently selected from aryl, heteroaryl and heterocyclyl; L is a bond, or is selected from -(CR10RU)R-, -(C=0)- and -(C=0)-NR12-;
A is selected from -(C=0)-, -(C=S)-,
Figure imgf000076_0004
2- and -(C=S)-
NR12-
B and D, which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, aryl, heteroaryl and heterocyclyl; with the proviso that when D is phenyl and A is -(C=0)- or -(C=0)-(CH2)r- then B is not hydrogen or substituted or unsubstituted alkyl;
at each occurrence, R1, R8 and R9, which may be the same or different, are independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkyloxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryloxy, aralkyl, arylalkyloxy, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -ORa, -OC(0)Ra, -OC(0)NRaRb, -C(0)Ra, -C(0)ORa, - C(0)NRaRb, -CR'^R'R', -NRaRb, -NRaC(0)NRbRc, -NRaC(0)ORb, -N(Ra)S(0)Rb, - N(Ra)S02R , -NRaC(0)Rb, -NRaC(S)Rb, -NRaC(S)NRbRc, -S(0)NRaRb, -S02NRaRh, -SRa, - S(0)Ra, -S02Ra and -C(S)Ra;
at each occurrence, R2, R3, R10 and R1 ', which may be the same or different, are independently selected from hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C(0)ORa and -NRaRb; or R2 and R3 or R10 and R", together with the carbon atom to which they are attached may form cyclic ring, which may be monocyclic, bicyclic or tricyclic rings; substituted or unsubstituted; saturated, unsaturated or partially saturated; the cyclic ring may optionally contain one or more heteroatoms selected from O, N or S;
R4, R7 and R12, which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)Ra, -C(0)ORa, -C(0)NRaRb, -S(0)NRaRb, -S02NRaRb, - S(0)Ra and -S02Ra;
R5 and R6, which may be the same or different, are independently selected from hydrogen, halogen, haloalkyl, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cyanoalkyl, cyanoalkyloxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)Ra, -C(0)NRaRb, -C(0)ORa, -CR'R^R'R', -NRaRb, - NRaCONRbRc, -NRaC(0)ORb, -N(Ra)SORb, -N(Ra)S02Rb, -NRaC(0)Rb, -NRaC(S)Rb, - NRaC(S)NR R°, -SONRaRb, -S02NRaRb, -OC(0)Ra, -OC(0)NRaRb, -SRa, -SORa, -S02Ra and -C(S)Ra ;
or R4 and R5 together with the atoms to which they are attached may form cyclic ring, which may be monocyclic, bicyclic or tricyclic rings; substituted or unsubstituted; saturated, unsaturated or partially saturated; the cyclic ring may optionally include one or more heteroatoms selected from O, N, or S;
Ra, R and Rc, which may be the same or different, are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;
'm' is an integer ranging from 0 to 4, both inclusive;
'n' is an integer ranging from 1 to 3, both inclusive;
'p' is an integer ranging from 0 to 4, both inclusive;
'q' is an integer ranging from 0 to 4, both inclusive; and
V is an integer ranging from 1 to 3, both inclusive.
2. The compound of claim 1 having the formula (II):
Figure imgf000078_0001
or a pharmaceutically acceptable salt thereof,
wherein,
ring Ar3 and Ar4 are independently selected from aryl, heteroaryl and heterocyclyl; A is selected from -(C=0)-, -(C=S)-, -(C=O)-(CR,0Rn)r-, -(C=0)-NR12- and -(C=S)-
NR12-;
at each occurrence, R1 , R9, R13 and R14, which may be the same or different, are independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkyloxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryloxy, aralkyl, arylalkyloxy, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -ORa, -OC(0)Ra, -OC(0)NRaRb, -C(0)Ra, -C(0)ORa, - C(0)NRaRb, -CR RbNRaRc, -NRaRb, -NRaC(0)NRbRc, -NRaC(0)ORb, -N(Ra)S(0)Rb, - N(Ra)S02Rb, -NRaC(0)Rb, -NRaC(S)Rb, -NRaC(S)NRbRc, -S(0)NRaRb, -S02NRaRb, -SRa, - S(0)Ra, -S02Ra and -C(S)Ra;
at each occurrence, R10 and R1 1 , which may be the same or different, are independently selected from hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C(0)ORa and -NRaRb; or R10 and Rn, together with the carbon atom to which they are attached may form cyclic ring, which may be monocyclic, bicyclic or tricyclic rings; substituted or unsubstituted; saturated, unsaturated or partially saturated; the cyclic ring may optionally contain one or more heteroatoms selected from O, N or S;
R12 is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)Ra, -C(0)ORa, -C(0)NRaRb, - S(0)NRaRb, -S02NRaRb, -S(0)Ra and -S02Ra;
Ra, Rb and Rc, which may be the same or different, are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; 'm' is an integer ranging from 0 to 4, both inclusive;
'q' is an integer ranging from 0 to 4, both inclusive;
'r' is an integer ranging from 1 to 3, both inclusive;
't' is an integer ranging from 0 to 4, both inclusive; and
'u' is an integer ranging from 0 to 4, both inclusive.
The compound of claim 2, wherein ring Ar3 is,
Figure imgf000079_0001
The compound of claim 2, wherein R1 is selected from fluorine, methyl and
The compound of claim 2, wherein ring Ar4 is,
Figure imgf000079_0002
The compound of claim 2, wherein R14 is fluorine, chlorine, methyl, ethyl, /-butyl, trifluoromethyl, cyclopropyl or -OCH3
The compound of claim 1 having the formula (III):
Figure imgf000079_0003
(III)
or a pharmaceutically acceptable salt thereof,
wherein,
A is selected from -(C=0)-, -(C=S)-, -(C=O)-(CRL 0R" )R-, -(C=0)-NR1 2- and -(C=S)-
NR12-;
B is selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, aryl, heteroaryl and heterocyclyl;
at each occurrence, R1 , R9 and R1 3, which may be the same or different, are independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkyloxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryloxy, aralkyl, arylalkyloxy, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -ORA, -OC(0)RA, -OC(0)NRARB, -C(0)RA, -C(0)ORA, - C(0)NRARB, -CRARBNRARC, -NRARB, -NRAC(0)NRBRC, -NRAC(0)ORB, -N(RA)S(0)RB, - N(Ra)S02Rb, -NRaC(0)Rb, -NRaC(S)Rb, -NRaC(S)NRbRc, -S(0)NRaRb, -S02NRaRb, -SRa, - S(0)Ra, -S02Ra and -C(S)Ra;
at each occurrence, Rl 0 and Rn, which may be the same or different, are independently selected from hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C(0)ORa and -NRaRb; or R10 and Rn, together with the carbon atom to which they are attached may form cyclic ring, which may be monocyclic, bicyclic or tricyclic rings; substituted or unsubstituted; saturated, unsaturated or partially saturated; the cyclic ring may optionally contain one or more heteroatoms selected from O, N or S;
R12 is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)Ra, -C(0)ORa, -C(0)NR R , - S(0)NRaRb, -S02NRaRb, -S(0)Ra and -S02Ra;
Ra, Rb and Rc, which may be the same or different, are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;
'm' is an integer ranging from 0 to 4, both inclusive;
'q' is an integer ranging from 0 to 4, both inclusive;
V is an integer ranging from 1 to 3, both inclusive; and
't' is an integer ranging from 0 to 4, both inclusive.
8. The compound of claim 7, wherein A is -(C=0)-.
9. The compound of claim 7, wherein A is -(C=0)-(CH2)r-,.
10. The compound of claim 9, wherein 'r' is 1, 2 or 3.
1 1 . The compound of claim 7, wherein A is -(C=S)-NH-.
12. The compound of claim 7, wherein B is methyl, ethyl, propyl, butyl or trifluoromethyl.
13. The compound of claim 1 hav
or a pharmaceutically acceptable salt thereof,
wherein, D is selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, aryl, heteroaryl and heterocyclyl;
at each occurrence, R1, R9 and R14, which may be the same or different, are independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkyloxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryloxy, aralkyl, arylalkyloxy, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -ORa, -OC(0)Ra, -OC(0)NRaRb, -C(0)Ra, -C(0)ORa, - C(0)NRaRb, -CR^^R^, -NRaRb, -NRaC(0)NRbRc, -NRaC(0)ORb, -N(Ra)S(0)Rb, - N(Ra)S02Rb, -NRaC(0)Rb, -NRaC(S)Rb, -NRaC(S)NRbRc, -S(0)NRaRb, -S02NRaRb, -SRa, - S(0)Ra, -S02Ra and -C(S)Ra;
Ra, Rb and Rc, which may be the same or different, are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;
'm' is an integer ranging from 0 to 4, both inclusive;
'q' is an integer ranging from 0 to 4, both inclusive; and
'u' is an integer ranging from 0 to 4, both inclusive.
14. The compound of claim 13, wherein R1 is pyridyl.
15. The compound of claim 13, wherein R14 is fluoro.
16. The compound of claim 13, wherein D is hydrogen or methyl.
17. The compound of claim 1 having the formula (V):
Figure imgf000081_0001
substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkyloxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryloxy, aralkyk arylalkyloxy, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -ORa, -OC(0)Ra, - OC(0)NRaRb, -C(0)Ra, -C(0)ORa, -C(0)NRaRb, -CRaRbNRaRc, -NRaRb, -NRaC(0)NRbRc, - NRaC(0)ORb, -N(Ra)S(0)R , -N(Ra)S02Rb, -NRaC(0)Rb, -NRaC(S)Rb, -NRaC(S)NRbRc, - S(0)NRaRb, -S02NRaRb, -SRa, -S(0)Ra, -S02Ra and -C(S)Ra;
R6 is selected from hydrogen, halogen, haloalkyl, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cyanoalkyi, cyanoalkyloxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)Ra, -C(0)NRaRb, -C(0)ORa, - CR'R^R^, -NRaRb, -NRaCONRbRc, -NRaC(0)ORb, -N(Ra)SORb, -N(Ra)S02Rb, - NRaC(0)Rb, -NRaC(S)Rb, -NRaC(S)NR Rc, -SONRaR , -S02NRaRb, -OC(0)Ra, - OC(0)NRaRb, -SRa, -SORa, -S02Ra and -C(S)Ra ;
R7 is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)Ra, -C(0)ORa, -C(0)NRaRb, - S(0)NRaRb, -S02NRaRb, -S(0)Ra and -S02Ra;
Ra, Rb and Rc, which may be the same or different, are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;
'm' is an integer ranging from 0 to 4, both inclusive; and
'p' is an integer ranging from 0 to 4, both inclusive.
18. The compound of claim 17, wherein Ar1 is
Figure imgf000082_0001
19. The compound of claim 1 7, wherein R is chloro, cyano, methyl or trifluoromethyl.
20. The compound of claim 1 havin
Figure imgf000082_0002
(VI)
or a pharmaceutically acceptable salt thereof,
wherein,
A is -S- or -N=CH-;
ring Ar1 is selected from aryl, heteroaryl and heterocyclyl;
R6 is selected from hydrogen, halogen, haloalkyl, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cyanoalkyi, cyanoalkyloxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)Ra, -C(0)NRaRb, -C(0)ORa, - CR^'WR0, -NRaRb, -NRaCONRbR°, -NRaC(0)ORb, -N(Ra)SORb, -N(Ra)S02Rb, - NRaC(0)Rb, -NRaC(S)Rb, -NRaC(S)NRbRc, -SONRaRb, -S02NRaRb, -OC(0)Ra, - OC(0)NRaRb, -SRa, -SORa, -S02Ra and -C(S)Ra ;
R7 is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)Ra, -C(0)ORa, -C(0)NRaRb, - S(0)NRaRb, -S02NRaRb, -S(0)Ra and -S02Ra;
at each occurrence, R9 is independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkyloxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryloxy, aralkyl, arylalkyloxy, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -ORa, -OC(0)Ra, - OC(0)NRaRb, -C(0)Ra, -C(0)ORa, -C(0)NRaRb, -CR'R^R'R^ -NRaR , -NRaC(0)NR Rc, - NRaC(0)ORb, -N(Ra)S(0)Rb, -N(Ra)S02Rb, -NRaC(0)Rb, -NRaC(S)Rb, -NRaC(S)NRbRc, - S(0)N RaRb, -S02NRaRb, -SRa, -S(0)Ra, -S02Ra and -C(S)Ra;
Ra, Rb and Rc, which may be the same or different, are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and
R16 and R17, which may be the same or different, are independently selected from hydrogen and substituted or unsubstituted alkyl; and
'q' is an integer ranging from 0 to 4, both inclusive.
21 . The compound of claim 20, wherein A is -S-.
22. The compound of claim 20, wherein A is -N=CH-
23. The compound of claim 17 or 20, wherein R6 is substituted aryl.
24. The compound of claim 23, wherein R6 is para-substituted phenyl, in which substitutent is chlorine.
25. The compound of claim 1 7 or 20, wherein R7 is hydrogen, methyl or ethyl.
26. The compound of claim 20, wherein Ar' is phenyl or pyridyl.
27. The compound of claim 20, wherein R16 and R17 are independently hydrogen or methyl .
28. The compound selected from :
2-(3-methoxyphenyl)-N-(pyridin-3-ylmethyl)-N-[4-(quinolin-2-ylmethoxy)phenyl] acetamide;
2-(4-fluorophenyl)-N-(pyridin-3-ylmethyl)-N-[4-(quinolin-2-ylmethoxy)phenyl] acetamide;
2-(2-methoxyphenyl)-N-(pyridin-3-ylmethyl)-N-[4-(quinolin-2-ylmethoxy)phenyl] acetamide; 2-(2-fluorophenyl)-N-(pyridin-3-ylmethyl)-N-[4-(quinolin-2-ylmethoxy)phenyl] acetam ide;
2-(4-chlorophenyl)-N-(pyridin-3-ylmethyl)-N-[4-(quinolin-2-ylmethoxy)phenyl] acetamide;
2-(4-chlorophenyl)-N-(pyridin-3-ylmethyl)-N-[4-(quinolin-2-ylmethoxy)phenyl] acetamide;
2-(2,3-difluorophenyl)-N-(pyridin-3-ylmethyl)-N-[4-(quinolin-2-ylmethoxy) phenyl] acetamide;
2-(3-trifluoromethylphenyl)-N-(pyridin-3-ylmethyl)-N-[4-(quinolin-2-ylmethoxy) phenyl] acetamide;
N-benzyl-2-(2-fluorophenyl)-N-[4-(quinolin-2-ylmethoxy)phenyl]acetamide;
N-benzyl-2-(2-methoxyphenyl)-N-[4-(quinolin-2-ylmethoxy)pheny]]acetam ide;
N-benzyl-2-(4-fluorophenyl)-N-[4-(quinolin-2-ylmethoxy)phenyl]acetam ide;
N-benzyl-2-(2,3-difluorophenyl)-N-[4-(quinolin-2-ylmethoxy)phenyl]acetamide; N-benzyl-2-(2-chlorophenyl)-N-[4-(quinol in-2-ylmethoxy)phenyl]acetamide;
/V-(4-fluorobenzyl)-2-(4-fluorophenyl)-N-[4-(quinolin-2-ylmethoxy)phenyl] acetam ide;
/V-(4-fluorobenzyl-2-(2-fluorophenyl)-N-[4-(quinolin-2-ylmethoxy)phenyl] acetamide;
N-benzyl -2-(2,6-difluorophenyl)-N-[4-(quinolin-2-ylmethoxy)phenyl]acetamide; , N-benzyl -2-(3-methoxyphenyl)-N-[4-(quinolin-2-ylmethoxy)phenyl]acetamide;
2-(2,4-difluorophenyl)-N-(4-Pyridylmethyl)-N-[4-(quinolin-2-ylmethoxy)-phenyl] acetamide;
2-(2,4-difluorophenyl)-N-(2-Pyridylmethyl)-N-[4-(quinolin-2-ylmethoxy)-phenyl] acetam ide;
N-pyridin-3-ylmethyl-N-[4-(quinolin-2-ylmeth0xy)-phenyl]-2-(2,3,4-trifluoro-phenyl) acetamide;
2-(2,4-difluoro-phenyl)-N-[4-(6-fluoro-quinolin-2-ylmethoxy)-phenyI]-/V-pyridin-3- ylmethylacetamide;
/V-pyridin-3-ylmethyl-N-[4-(quinolin-2-ylmethoxy)-phenyl]-2-(2,4,5-trifluoro-phenyl) acetam ide;
2-pyridin-2-yl-N-pyridin-3-ylmethyl-N-[4-(quinolin-2-yimethoxy)-phenyl]acetamide; 2-pyridin-3-yl-N-pyridin-3-ylmethyl-N-[4-(quinolin-2-ylmethoxy)-phenyl]acetamide; 2-pyridin-4-yl-N-pyridin-3-ylmethyl-N-[4-(quinolin-2-ylmethoxy)-phenyl]acetamide; 2-(3-methyl-isoxazol-5-yl)-N-pyridin-3-ylmethyl-N-[4-(quinolin-2-ylmethoxy)- phenyljacetamide;
2-(2,4-difluoro-p enyl)-N-(4-methyl-thiazol-5-ylmethyl)-N-[4-(quinolin-2- ylmethoxy)-phenyl]acetamide;
1 -phenyl-cyclopropanecarboxylic acid pyridin-3-ylmethyl-[4-(quinolin-2-ylmethoxy) -phenyl]amide;
2-(2,4-difluoro-phenyl)-N-(6-methoxy-pyridin-2-ylmethyl)-N-[4-(quinolin-2- ylmethoxy)-phenyl]acetamide;
2-(2,4-difluoro-phenyl)-N-(3,5-dimethyl-isoxazol-4-ylmethyl)-N-[4-(quinolin-2- ylmethoxy)-phenyl]acetamide;
2- (2,4-difluoro-phenyl)-N-(5-methyl-isoxazol-3-ylmethyl)-N-[4-(quinolin-2- ylmethoxy)-phenyl]acetamide;
l -benzyl-3-(5-tertbutyl-l ,3,4-thiadiazol-2-yl)-l -[4-(quinoline-2-ylmethoxy)phenyl] urea;
1 - benzyl-3-(5-tertbutyl-l ,3,4-thiadiazol-2-yl)-l -[4-(quinoline-2-ylmethoxy)phenyl urea;
1 -benzyI-3-(5-ethyl- 1 ,3,4-thiadiazol-2-yl)- 1 -[4-(quinoline-2-ylmethoxy)phenyl]urea; l -benzyl-3-(5-ethyl- l ,3,4-thiazol-2-yl)- l -[4-(quinoline-2-ylmethoxy)phenyl jurea; N-pyridin-3-ylmethyl-N-[4-(quinolin-2-ylrnethoxy)-phenyl]propionarnide;
N-pyridin-3-ylrnethyl-N-[4-(quinolin-2-ylrnethoxy)-phenyl]acetamide;
3- butyl-l ^yridin-3-ylrnethyl-l -[4-(quinolin-2-ylmethoxy)-phenyl]thiourea;
4,4,4-trifluoro-N-pyridin-3-ylrnethyl-N-[4-(quinolin-2-ylrnethoxy)-phenyl]- butyramide;
2- (2,4-difluorophenyl)-N-[2-pyridin-4-yl-4-(quinolin-2-ylmethoxy)-phenyl] acetamide;
2-(2,4-difluorophenyl)-N-methyl-N-[2-pyridin-4-yl-4-(quinoIin-2-ylrnethoxy)- phenyl]acetamide;
2-{4-[2-(4-chlorophenyl)irnidazo[2, l -6][l ,3]benzothiazol-3-yl]phenoxy}-N-(5-methyl pyridin-2-yl)acetamide;
2-{4-[2-(4-chlorophenyl)imidazo[2, l -¾][l ,3]benzothiazol-3-yl]phenoxy} -N-(5-chloro pyridin-2-yl)acetamide;
2-{4-[2-(4-chlorophenyl)imidazo[2, l - )][l ,3]benzothiazol-3-yl]phenoxy}-N-(4-methyl pyridin-2-yl)acetamide; 2-{4-[2-(4-chlorophenyl)imidazo[2, l-0][l ,3]benzothiazol-3-yl]phenoxy}-N-(6- chloropyridin -2-yl)acetamide;
2-{4-[2-(4-chlorophenyl)imidazo[2, l - >][l,3]benzothiazol-3-yl]phenoxy}-N-[3- chloro-5-(trifluoromethyl)pyridin-2-yl]acetamide;
2-{4-[2-(4-chlorophenyl)imidazo[2, l - >][l,3]benzothiazol-3-yl]phenoxy}N-(5-cyano pyridin-2-yl)acetamide;
2-{4-[2-(4-chlorophenyl)imidazo[2, l - >][l ,3]benzothiazol-3-yl]phenoxy}N-pyrazin-2- ylacetamide;
2-{4-[2-(4-chlorophenyl)imidazo[2, l -6][l ,3]benzothiazol-3-yl]phenoxy}-N- pyrimidin-2-yl acetamide;
2-{4-[2-(4-chlorophenyl)imidazo[2, l - )][l ,3]benzothiazol-3-yl]phenoxy}-N-methyl- N-pyridin-2-ylacetamide;
2-{4-[2-(4-chlorophenyl)imidazo[2, l - )][l ,3]benzothiazol-3-yl]phenoxy}-N-methyl- N-phenylacetamide;
2-{4-[2-(4-chlorophenyl)imidazo[2, l-0][l,3]benzothiazol-3-yl]phenoxy}N-pyridin-2- yi acetamide;
2- {4-[2-(4-chlorophenyl)imidazo[2, 1 -b][ 1 ,3]benzothiazol-3-yl]phenoxy } -N-(2- chlorophenyl) acetamide;
2-{4-[2-(4-chlorophenyl)imidazo[2, l- )][l ,3]benzothiazol-3-yl]phenoxy}N- phenylacetamide;
2-{4-[6-(4-(chlorophenyl)-3-methylimidazo[2, l -b][ \ , 3]thiazol-5-yl)phenoxy}-N- methyl-N-phenylacetamide;
2-{4-[2-(4-(chlorophenyl)-imidazo[ l ,2-a]pyrimidin-3-yl])phenoxy} -iV-methyl-N- pyridin-2-ylacetamide;
2-{4-[6-(4-(chlorophenyl)-2,3-dimethylimidazo[2, l -6]tl ,3]thiazol-5-yl)phenoxy}-N- methyl-N-pyridin-2-ylacetamide; and
2-{4-[6-(4-(chlorophenyl)-3-methylimidazo[2, l - >][l ,3]thiazol-5-yl)phenoxy}-N- ethyl-N-pyridin-2-ylacetamide;
or pharmaceutically acceptable salts thereof.
29. The compound selected from:
2-(2,6-difluorophenyl)-N-(pyridin-3-ylmethyl)-N-[4-(quinolin-2-ylmethoxy)phenyl] acetamide;
2-(phenyl)-N-(pyridin-3-ylmethyl)-N-[4-(quinolin-2-ylmethoxy)phenyl]acetamide; 2-(2,4-difluorophenyl)-N-(pyridin-3-ylmethyl)-N-[4-(quino!in-2-ylmethoxy acetamide;
N-pyridin-3-ylmethyl-N-[4-(quinolin-2-ylmethoxy)-phenyl]-2-(2,4,6-trifluoro-phenyl) acetamide;
2-(4-chloro-2-fluoro-phenyl)-N-pyridin-3-ylmethyl-N-[4-(quinolin-2-ylmethoxy)- phenyl] acetamide;
2-(4-chloro-2,6-difluoro-phenyl)-N-pyridin-3-yImethyl-N-[4-(quinolin-2-ylmethoxy)- phenyljacetamide;
N-pyridin-3-ylmethyl-N-[4-(quinolin-2-ylmethoxy)-phenyl]-butyramide; pentanoic acid pyridin-3-ylmethyl-[4-(quinolin-2-ylmethoxy)-phenyl]amide; heptanoic acid pyridin-3-ylmethyl-[4-(quinolin-2-ylmethoxy)-phenyl]amide; hexanoic acid pyridin-3-ylmethyl-[4-(quinolin-2-ylmethoxy)-phenyl]amide;
2-{4-[6-(4-(chlorophenyl)-3-methylimidazo[2, l -0][ l ,3]thiazol-5-yl)phenoxy}-N- methyl-N-pyridin-2-ylacetamide;
2-{4-[6-(4-(chlorophenyl)-2-methylimidazo[2, l -0][l ,3]thiazol-5-yl)phenoxy}-N- methyl-N-pyridin-2-ylacetamide; and
2-{4-[6-(4-(chlorophenyl)-imidazo[2, l -¾][l,3]thiazol-5-yl)phenoxy} -N-methyl-N- pyridin-2-ylacetamide;
or pharmaceutically acceptable salts thereof.
30. A pharmaceutical composition comprising a compound according to claims 1 to 29 either as a free base or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, carriers, diluents or mixture thereof.
31 . A method for preventing, ameliorating or treating a disease, disorder or syndrome modulated by PDE 10A in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 29.
32. A method of treating schizophrenia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 29.
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