WO2012090179A2 - Isoquinoline derivatives as cannabinoid receptor modulators - Google Patents

Isoquinoline derivatives as cannabinoid receptor modulators Download PDF

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WO2012090179A2
WO2012090179A2 PCT/IB2011/056012 IB2011056012W WO2012090179A2 WO 2012090179 A2 WO2012090179 A2 WO 2012090179A2 IB 2011056012 W IB2011056012 W IB 2011056012W WO 2012090179 A2 WO2012090179 A2 WO 2012090179A2
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Prior art keywords
pain
isoquinolin
amino
methanone
disorders
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PCT/IB2011/056012
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French (fr)
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WO2012090179A3 (en
Inventor
Sanjeev Anant Kulkarni
Sachin MADAN
Nirmal Kumar JANA
Sachin Jaysing Mahangare
Prashant Vitthalrao TALE
Seema Prabhakar ZADE
Amolsing Dattu PATIL
Narasimha Murthy CHEEMALA
Venkata P. Palle
Rajender Kumar Kamboj
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Lupin Limited
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Publication of WO2012090179A2 publication Critical patent/WO2012090179A2/en
Publication of WO2012090179A3 publication Critical patent/WO2012090179A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D417/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems

Definitions

  • the present invention relates to compounds and pharmaceutically acceptable salts thereof and pharmaceutical compositions for the treatment, prevention, management, and/or lessening the severity of diseases, disorders, syndromes or conditions associated with the modulation of cannabinoid (CB) receptors.
  • the invention also relates to methods of treating, preventing, managing and/or lessening the severity of the diseases disorders, syndromes or conditions associated with the modulation of cannabinoid (CB) receptors.
  • the invention also relates to processes for the preparation of the compounds of the invention.
  • CX5 G-protein coupled receptor expressed in human promyelocytic leukemic cell line (HL60) was discovered in 1993. This was later identified as type II Cannabinoid receptor (Munro et al. Nature (1993), 365, 61 -65). CB 2 receptors are found to be expressed predominantly in immune cells. When activated they modulate immune cell migration and cytokine release outside and within the brain (Pertwee et al. Handb. Exp. Pharmacol. (2005), 168, 1-51 ). CB 2 activation affects a host of immune responses from inflammation to neuroprotection (Cabral et al. Handb. Exp. Pharmacol. (2005), 168, 385 ⁇ 123). The activation of CB 2 receptors is reported to have analgesic effect in many animal models of pain from acute pain to neuropathic pain (Anand et al. Pain. (2009), 138, 667-680).
  • CB 2 is an attractive therapeutic target for pain management and immune system modulation without overt psycho activity and substance abuse possibility, its presumed absence in the CNS was reviewed by many researchers. The findings of these recent investigations support the presence of CB 2 receptors in CNS.
  • the CB 2 mRNA and protein have been found in microglia (Beltramo et al. Eur. J. Neurosci. (2006), 23, 1530-1538; Carlisle et al. Int. Immuno Pharmacol. (2002), 2, 69-82; Klegeris et al. Br. J. Pharmacol. (2003), 139, 775-786; Maresz et al., Nat. Med. (2007), 13, 492-497; Walter et al. J. Neurosci.
  • CB 2 The expression levels of CB 2 are proportional to the activation extent of microglia (Cabral et al., Br. J. Pharmacol. (2008), 153, 240-251 ; Pietr et al. FEBS Lett. (2009), 583, 2071 -2076; Stella et al. Glia. (2004), 48, 267-277). Microglial migration and their infiltration into brain areas with active neuroinflammation and degeneration are modulated by CB 2 . In healthy brain microglia does not express CB 2 but they do in Alzheimer's brain tissue in the neuritic-plaque associated microglia (Benito et al. J Neurosci.
  • CB 2 mRNA is found to increase in association with activated microglia in the spinal cord (Zhang et al. Eur. J. Neurosci. (2003), 17, 2750-2754). Similarly in amyotrophic lateral sclerosis and multiple sclerosis, CB 2 microglial expression increases in spinal cord (Yiangou et al. BMC. Neurol. (2006), 6, 12).
  • CB 2 receptor distribution is also known in macrophages, CD4 T cells, CD8 T cells, B cells, natural killer cells, monocytes, and polymorphonuclear neutrophils (Dittel B N. et al. BJP. (2008), 153, (2), 271 -276; Maresz K. et al. Nature Medicine. (2007), 13, 492-497).
  • CB 2 receptor presence is also known in other brain areas like thalamus, straitum, hippocampus.
  • Peripheral neurons, nociceptive neurons and sensory neurons also are known to express CB 2 receptors.
  • CB 2 receptor is expressed in the bone cells and is reported to have anabolic effect on bones (Ofek et al. PNAS. (2006), 103, 696-701 ). Presence of CB 2 is also reported in the enteric nervous system, (Duncan M Mouihate et al, Am. J. Physiol. Gastrointest. Liver Physiol. 295, G78-G87). Similar anabolic effect is also reported through CB2 receptor mediation in neurogenesis (Molina-Holgado et al. Eur. J. Neurosci. (2007), 25, 629-634 & Palazuelos J. et al FASEB J. (2006), 20, 2405-2407).
  • CB1 in pain management is also well known. This receptor is known to exist majorly in the central nervous system. To a minor extent, CB1 is also reported to exist in the periphery (Pharmacology, Biochemistry and Behavior 90 (2008) 501-51 1 ). Therefore, along with compounds that are CB2 selective modulators, dual modulators working through CB1 and CB2 are also targeted.
  • WO 2002/042248, WO 2010/096371 , WO 2010/133973, WO 2006/129178, WO 2010/ 084767, WO 2009/053799, WO 2008/1 15672, WO 2008/027812, WO 2007/102059, WO 2007/091950 and WO 2002/42248 applications disclose compounds related to cannabinoid receptors for the treatment of various diseases mediated by cannabinoid receptors. Also, Bioorganic Medicinal Chemistry, (201 1 ), 19, 939-950, discloses the compounds related to cannabinoid receptors.
  • the invention provides compounds having the Formula (I):
  • X is selected from -NR a -, -O- and -S(O) n -;
  • Y is selected from -C(O)-, -S(O) 2 -, and -CR 5 R 6 -;
  • R 1 which may be same or different at each occurrence, is independently selected from halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkoxy, cycloalkoxy, -C(O)OH, -NR a R b and -C(O)NR a R b ;
  • R 2 is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyi, heteroaryl, heteroarylalkyi, heterocyclyl, and heterocyclylalkyi;
  • R 3 is selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyi, heteroaryl, heteroarylalkyi, heterocyclyl, and heterocyclylalkyi; or
  • R 2 and R 3 together with the nitrogen atom to which they are attached, may form a substituted or an unsubstituted 3 to 14 membered heterocyclic ring;
  • R 2 and R 3 together with the nitrogen atom to which they are attached, may form a substituted or an unsubstituted 5 to 14 membered heteroaryl ring;
  • R 4 is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl
  • R 5 and R 6 which may be same or different, are independently selected from hydrogen, alkyl, and haloalkyl;
  • R a and R b which may be same or different at each occurrence, are independently selected from hydrogen, alkyl, haloalkyl, acyl and cycloalkyl; or R a and R b, together with the nitrogen atom to which they are attached, may form a substituted or unsubstituted 3 to 14 membered heteroaryl or heterocyclic ring;
  • 'm' is an integer ranging from 0 to 3, both inclusive;
  • 'n' is an integer ranging from 0 to 2, both inclusive;
  • R 7 which may be same or different at each occurrence, is independently selected from halogen, cyano, nitro, hydroxy, alkyl, haloalkyi, hydroxyalkyl, cycloalkyi, alkoxy, haloalkoxy, cycloalkoxy, -C(0)OH, -NR a R b and -C(0)NR a R b ;
  • R 2 , R3, R a , and R b are as defined herein above;
  • 'p' is an integer ranging from 0 to 4, both inclusive;
  • R 7 which may be same or different at each occurrence, is independently selected from halogen, cyano, nitro, hydroxy, alkyl, haloalkyi, hydroxyalkyl, cycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, -C(0)OH, -NR a R b and -C(0)NR a R b ;
  • W is CR 8 R 9 , O, or S(0) 2 ;
  • R 8 and R 9 are independently selected from hydrogen, halogen, cyano, hydroxy, alkyl, haloalkyi, hydroxyalkyl, cycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, heteroaryl, heterocyclyl, -NR a Rb and -C(0)NR a Rb;
  • R 7 is not p-methyl or o-methoxy
  • R 7 is not p-methyl, o- methoxy, p-methoxy or p-halogen
  • R a and R b are as defined herein above;
  • 'p' is an integer ranging from 0 to 4, both inclusive;
  • R 3 is selected from alkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl.
  • substituent(s) on heterocyclic ring may be one or more, same or different and are independently selected from halogen, alkyl, haloalkyl, aryl or heteroaryl.
  • a compound of formula (I) useful in treating, preventing, managing and/or lessening the severity of diseases, disorders, syndromes or conditions associated with cannabinoid (CB) modulators.
  • the invention provides a pharmaceutical composition that includes at least one compound of formula (I) and at least one pharmaceutically acceptable excipient.
  • the invention provides a pharmaceutical composition of compound of formula (I) useful in treating, preventing, managing and/or lessening the severity of the diseases disorders or conditions associated with cannabinoid (CB) modulators in a subject, in need thereof by administering to the subject, one or more compounds described herein in a therapeutically effective amount to cause modulation of such receptor. Also provided herein are processes for preparing compounds described herein.
  • halogen or halo means fluorine, chlorine, bromine, or iodine.
  • alkyl refers to an alkane derived hydrocarbon radical that includes solely carbon and hydrogen atoms in the backbone, contains no unsaturation, has from one to six carbon atoms, and is attached to the remainder of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1 -methylethyl (isopropyl), n-butyl, n-pentyl, 1 ,1 - dimethylethyl (t-butyl) and the like. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkenyl refers to a hydrocarbon radical containing from 2 to 10 carbon atoms and including at least one carbon-carbon double bond.
  • alkenyl groups include ethenyl, 1 -propenyl, 2-propenyl (allyl), iso- propenyl, 2-methyl-l- propenyl, 1 -butenyl, 2-butenyl and the like. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkynyl refers to a hydrocarbon radical containing 2 to 10 carbon atoms and including at least one carbon- carbon triple bond.
  • Non- limiting examples of alkynyl groups include ethynyl, propynyl, butynyl and the like. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkoxy refers to an alkyl group attached via an oxygen linkage. Non- limiting examples of such groups are methoxy, ethoxy and propoxy and the like. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkenyloxy refers to an alkenyl group attached via an oxygen linkage.
  • Non-limiting examples of such groups are vinyloxy, allyloxy, 1 -butenyloxy, 2- butenyloxy, isobutenyloxy, 1 -pentenyloxy, 2-pentenyloxy, 3-methyl-1 -butenyloxy, 1 - methyl-2-butenyloxy, 2,3-dimethylbutenyloxy, 1 -hexenyloxy and the like.
  • all alkenyloxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkynyloxy refers to an alkynyl group attached via an oxygen linkage.
  • Non-limiting examples of such groups are acetylenyloxy, propynyloxy, 1 -butynyloxy, 2-butynyloxy, 1 -pentynyloxy, 2-pentynyloxy, 3-methyl-1 -butynyloxy, 1 -hexynyloxy, 2- hexynyloxy, and the like.
  • cycloalkyl refers to a non-aromatic mono or multicyclic ring system having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl and the like. Unless set forth or recited to the contrary, all cycloalkyi groups described or claimed herein may be substituted or unsubstituted.
  • cycloalkoxy refers to an cycloalkyi, defined herein, group attached via an oxygen linkage.
  • Non-limiting examples of such groups are cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy and the like. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • cycloalkenyl refers to a non-aromatic mono or multicyclic ring system having 3 to 12 carbon atoms and including at least one carbon-carbon double bond, such as cyclopentenyl, cyclohexenyl, cycloheptenyl and the like. Unless set forth or recited to the contrary, all cycloalkenyl groups described or claimed herein may be substituted or unsubstituted.
  • cycloalkylalkyl refers to a cycloalkyi group as defined above, directly bonded to an alkyl group as defined above, e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, etc. Unless set forth or recited to the contrary, all cycloalkylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • haloalkyi refers to an alkyl group as defined above that is substituted by one or more halogen atoms as defined above.
  • the haloalkyi may be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl.
  • a monohaloalkyl can have one iodine, bromine, chlorine or fluorine atom.
  • Dihaloalkyl and polyhaloalkyl groups can be substituted with two or more of the same halogen atoms or a combination of different halogen atoms.
  • a polyhaloalkyl is substituted with up to 12 halogen atoms.
  • Non-limiting examples of a haloalkyi include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl and the like.
  • a perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halogen atoms.
  • haloalkoxy refers to an haloalkyl, defined herein, group attached via an oxygen linkage.
  • Non-limiting examples of such groups are monohaloalkoxy, dihaloalkoxy or polyhaloalkoxy including perhaloalkoxy.
  • all haloalkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • hydroxyalkyl refers to an alkyl group, as defined above that is substituted by one or more hydroxy groups.
  • the hydroxyalkyl is monohydroxyalkyl or di hydroxyalkyl.
  • Non-limiting examples of a hydroxyalkyl include 2- hydroxyethyl, 3- hydroxypropyl, 2-hydroxypropyl, and the like.
  • aryl refers to an aromatic radical having 6- to 14- carbon atoms, including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl and the like. Unless set forth or recited to the contrary, all aryl groups described or claimed herein may be substituted or unsubstituted.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH 2 C 6 H 5 and -C 2 H 4 C 6 H 5 . Unless set forth or recited to the contrary, all arylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • heterocyclic ring or “heterocyclyl ring” or “heterocyclyl”, unless otherwise specified, refers to substituted or unsubstituted non-aromatic 3- to 15- membered ring which consists of carbon atoms and with one or more heteroatom(s) independently selected from N, O or S.
  • the heterocyclic ring may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems and the nitrogen, carbon, oxygen or sulfur atoms in the heterocyclic ring may be optionally oxidized to various oxidation states.
  • heterocyclic ring may also be fused with aromatic ring.
  • heterocyclic rings include azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, benzopyranyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidiny
  • heterocyclic ring 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 or claimed herein may be substituted or unsubstituted; substituents may be on same or different ring atom.
  • heteroaryl refers to a substituted or unsubstituted 5- to 14- membered aromatic heterocyclic ring 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 may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • Non-limiting examples of a heteroaryl ring include oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl
  • 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 or claimed herein may be substituted or unsubstituted.
  • heteroarylalkyi refers to a heteroaryl ring radical directly bonded to an alkyl group.
  • the heteroarylalkyi 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 or claimed herein may be substituted or unsubstituted.
  • substituted refers to a group or moiety having one or more substituents attached to the structural skeleton of the group or moiety.
  • the phrase "may optionally be substituted” refers to a moiety or group that may or may not be substituted.
  • optionally substituted aryl means that the aryl radical may or may not be substituted and that the description includes both substituted and unsubstituted aryl radicals.
  • a "stereoisomer” refers to a compound having the same atoms bonded through the same bonds but having different three-dimensional orientations, which are not interchangeable.
  • the invention contemplates various stereoisomers and mixtures thereof and includes enantiomers and diastereomers.
  • the invention also includes geometric isomers ⁇ " or "Z” or cis or trans configuration in a compound having either a double bond or having substituted cycloalkyl ring system.
  • a “tautomer” refers to a compound that undergoes rapid proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. The individual tautomers as well as mixture thereof are encompassed with compounds of formula (I).
  • treating or “treatment” of a state, disease, disorder, condition or syndrome includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disease, disorder, condition or syndrome developing in a subject that may be afflicted with or predisposed to the state, disease, disorder, condition or syndrome but does not yet experience or display clinical or subclinical symptoms of the state, disease, disorder, condition or syndrome; (b) inhibiting the state, disease, disorder, condition or syndrome, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; c) lessening the severity of a disease, disorder, syndrome or condition or at least one of its clinical or subclinical symptoms thereof; and/or (d) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • modulate refers to an increase or decrease in the amount, quality, or effect of a particular activity, function or molecule. By way of illustration and not limitation, it includes agonists, partial agonists, inverse agonists and antagonists of a cannabinoid (CB) receptor of the present invention.
  • CB cannabinoid
  • subject includes mammals, preferably humans and other animals, such as domestic animals; e.g., household pets including cats and dogs.
  • a “therapeutically effective amount” refers to the amount of a compound that, when administered to a subject in need thereof, is sufficient to cause a desired effect.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity, age, weight, physical condition and responsiveness of the subject to be treated.
  • the compounds of the invention may form salts.
  • administration of the compound as a pharmaceutically acceptable salt may be appropriate.
  • pharmaceutically acceptable salts are organic acid addition salts formed by addition of acids, which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, a-ketoglutarate, a-glycerophosphate, formate, fumarate, propionate, glycolate, lactate, pyruvate, oxalate, maleate, and salicylate.
  • Suitable inorganic salts may also be formed, including, sulfate, nitrate, bicarbonate, carbonate salts, hydrobromate and phosphoric acid.
  • salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • a sufficiently basic compound such as an amine
  • a suitable acid affording a physiologically acceptable anion.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • the invention extends to stereoisomeric forms and to mixtures thereof.
  • the different stereoisomeric forms of the invention may be separated from one another by the method 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. Screening of compounds of invention for cannabinoid receptor modulation activity can be achieved by using various in vitro and in vivo protocols mentioned herein below or methods known in the art.
  • the invention relates to pharmaceutical composition containing the compounds of the Formula (I) disclosed herein.
  • pharmaceutical compositions containing a therapeutically effective amount of at least one compound of formula (I) described herein and at least one pharmaceutically acceptable excipient (such as a carrier or diluent).
  • the contemplated pharmaceutical compositions include the compound(s) described herein in an amount sufficient to modulate cannabinoid receptor mediated diseases described herein when administered to a subject.
  • the subjects contemplated include, for example, a living cell and a mammal, including human mammal.
  • the compound of the invention 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.
  • a pharmaceutically acceptable excipient includes a pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity.
  • 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, silicylic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing.
  • the pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
  • the pharmaceutical compositions described herein may be prepared by conventional techniques known in the art.
  • the active compound can be 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 can be 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 invention 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).
  • 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.
  • 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 formulation.
  • Liquid formulations include, but are not limited to, syrups, emulsions, suspensions, solutions, 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.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as pocketed tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the total daily dose of the compounds of the invention depends, of course, on the mode of administration.
  • oral administration may require a higher total daily dose, than an intravenous (direct into blood).
  • the quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 10000 mg according to the potency of the active component or mode of administration.
  • 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 subject 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 the patient.
  • the daily dosage of the CB modulator 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 invention.
  • the invention provides compounds and pharmaceutical compositions thereof that are useful in treating, preventing, managing and/or lessening the severity of diseases, disorders, syndromes or conditions modulated by cannabinoid receptor.
  • the invention further provides method of treating diseases, disorders or conditions modulated by cannabinoid receptor in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the invention.
  • the methods provided are also useful for diagnosis of conditions that can be treated by acting on cannabinoid receptor for determining if a patient will be responsible to therapeutic agents.
  • the invention provides a method for the treatment of diseases, disorders or conditions through modulating cannabinoid receptor. In this method, a subject in need of such treatment is administered a therapeutically effective amount of a compound of formula (I) described herein.
  • the compound of formula (I), being modulators of cannabinoid receptor, is potentially useful in treating, preventing, managing and/or lessening the severity of diseases, disorders, syndromes or conditions include but are not limited to pain, inflammation, analgesic conditions, healing of wounds and burns, movement disorders, immune disorders (such as autoimmune disorders), respiratory disorders, lung diseases associated with inflammation, pruritis associated with inflammation, allergic diseases associated with inflammation, organ contraction, preanesthetic medication, pre operative medication, muscle spasm, locomotor activity disorders, bone disorders, multiple sclerosis, glaucoma and related intra ocular pressure, cell growth disorders, gastrointestinal disorders, diseases of central nervous system (CNS) erythromyalgia, neurological disorders, neurodegenerative disorders, neuromuscular conditions, neuroinflammatory pathologies and the like.
  • CNS central nervous system
  • Pain includes, but is not limited to, acute pain, chronic pain, musculoskeletal pain, post-operative pain, visceral pain, peripherally mediated pain, centrally mediated pain, inflammatory pain, neuropathic pain, nociceptive pain, and idiopathic pain.
  • the compounds, compositions and methods of the invention are of particular use in treating, preventing or lessening of pain includes but is not limited to acute pain, chronic pain, visceral pain, neuropathic pain, inflammatory pain or nociceptive pain or pain associated with, such as but are not limited to dental pain, eye pain, ear pain, perioperative, traumatic pain, muscle pain, pain in burned skin, sun burn, trigeminal neuralgia, spasm of the gastrointestinal tract or uterus, colics, back pain, chronic fatigue syndrome, clinical depression, complex regional pain syndrome, myofascial pain syndrome, post-vasectomy pain syndrome, restless leg syndrome, spinal stenosis, chronic pelvic pain, pancreatitis, peptic ulcer, interstitial cystitis, renal colic, angina, dysmenorrhoea, menstruation, gynaecological pain, irritable bowel syndrome (IBS), non-ulcer dyspepsia, non-cardiac chest pain, myocardial isch
  • the compounds of the invention may be useful for treating various types of inflammatory disease such as inflammations due to immune system, inflammations due to cancer, atherosclerosis, ischaemic heart diseases, pancreatitis, which includes but is not limited to acute pancreatitis and chronic pancreatitis, which is characterized by recurring or persistent abdominal pain with or without steatorrhea hereditary pancreatitis, pancreatic dysfunction.
  • inflammatory disease such as inflammations due to immune system, inflammations due to cancer, atherosclerosis, ischaemic heart diseases, pancreatitis, which includes but is not limited to acute pancreatitis and chronic pancreatitis, which is characterized by recurring or persistent abdominal pain with or without steatorrhea hereditary pancreatitis, pancreatic dysfunction.
  • Respiratory related syndromes, disorders or diseases include, but are not limited to, diseases of the respiratory tract or lung diseases such as asthma, bronchitis (acute or chronic), emphysema, allergic rhinitis, emphysema, adult respiratory distress syndrome (ARDS), pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease (COPD), asthma including allergic asthma (atopic or non-atopic) as well as exercise-induced bronchoconstriction, occupational asthma, viral- or bacterial exacerbation of asthma, other non-allergic asthmas and "whez- infant syndrome", pneumoconiosis, including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.
  • diseases of the respiratory tract or lung diseases such as asthma, bronchitis (acute or chronic), emphyse
  • the compounds of invention may be useful in the treatment of pruritus and related diseases including, but not limited to psoriatic pruritis, itch due to hemodyalisis, aguagenic pruritis, itching caused by skin disorders, allergic itch, insect bite itch, itch caused by hypersensitivity such as dry skin, acne, eczema, psoriasis or injury, itch caused by vulvar vestibulitis and the similar itch.
  • pruritus and related diseases including, but not limited to psoriatic pruritis, itch due to hemodyalisis, aguagenic pruritis, itching caused by skin disorders, allergic itch, insect bite itch, itch caused by hypersensitivity such as dry skin, acne, eczema, psoriasis or injury, itch caused by vulvar vestibulitis and the similar itch.
  • Allergic diseases all forms of allergic reactions include but are not limited to angioneurotic edema, hay fever, insect bites, viral or bacterial diseases, allergic reactions to drugs, blood derivatives, contrast agents, delayed or immediate hypersensitivity, allergic rhinitis, contact dermatitis, conjunctivitis, allergic reactions associated with inflammatory diseases such as diseases of the joints, spondylitis, gout, vasculitis, Crohn's disease, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) or osteoporosis.
  • inflammatory diseases such as diseases of the joints, spondylitis, gout, vasculitis, Crohn's disease, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) or osteoporosis.
  • Autoimmune or inflammation related syndromes, disorders or diseases include, but are not limited to, psoriasis, lupus erythematosus, diseases of the connective tissue, Sjogren's syndrome, ankylosing spondylarthritis, rheumatoid arthritis, reactional arthritis, undifferentiated spondylarthritis, Behcet's disease, autoimmune hemolytic anaemias, multiple sclerosis, amyotrophic lateral sclerosis, amyloses, graft rejection or diseases affecting the plasma cell line.
  • Gastrointestinal diseases including, but not limited to inflammatory bowel diseases, irritable bowel syndrome, regional enteritis (Crohns disease), colitis ulcerosa, gastritis, or aphthous.
  • the compounds described herein may be prepared by techniques known in the art.
  • the compounds described herein may be prepared by following the reaction sequence as depicted in Scheme-1 .
  • reaction sequence as depicted in Scheme-1 .
  • specific bases, acids, reagents, solvents, coupling agents, etc. are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the scope of the present invention.
  • Variations in reaction conditions, for example, temperature and/or duration of the reaction which may be used as known in the art are also within the scope of the present invention. All the isomers of the compounds in described in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.
  • the compound of formula (9) where X, R 1 ; R 2, R3, R 4 and 'm' are as described herein above, can be prepared by following the sequential transformations of isoquinoline as depicted in Scheme-1 .
  • the cyano compound of formula (2) undergoes hydrolysis in presence of KOH and the resultant acid compound (3) undergoes esterification to give compound of formula (4) in the presence of EDCI (1 -Ethyl-3-(3-dimethyl aminopropyl)carbodiimide), HOBt (hydroxybenzotriazole), DMAP (dimethyl aminopyridine) and in suitable solvent and this is further treated with mCPBA (m- chloroperbenzoic acid) to afford /V-oxide compound of formula (5).
  • This N-oxide compound of formula (5) is treated with POCI 3 to give chloro compound of formula (6) which is further reacted with compound R 4 -XH in the presence of Pd or Cu in suitable solvent to afford compound of formula (7).
  • Methyl 1 -chloroisoquinolin-4-carboxylate Methyl 2-oxideisoquinolin-4-carboxylate (lntermediate-5) (700 mg, 3.4 mmol) was dissolved in CHCI 3 (10 mL) and to this, POCI 3 (1 .1 mL, 12.1 mmol) was added at room temperature and the reaction mixture was refluxed for 1 h. It was then cooled to room temperature, concentrated, diluted with ice water, neutralized with K 2 C0 3 and extracted with EtOAc. The organic layer was separated, dried over Na 2 S0 4 , filtered and concentrated to give the crude product that was purified by flash column (10% EtOAC:Hexanes) to afford the title compound (380 mg, 50%) as a white solid.
  • the title compound was prepared by using methyl 1 -chloroisoquinolin-4- carboxylate (lntermediate-6) (1 equivalent) and 3-fluoroaniline (1 .5 equiv) by following a procedure similar to that described in lntermediate-7a.
  • the title compound was prepared by using methyl 1 -chloroisoquinolin-4- carboxylate (lntermediate-6) and 3,5-difluoroaniline by following a procedure similar to that described in lntermediate-7a.
  • the title compound was prepared by using methyl 1 -chloroisoquinolin-4- carboxylate (lntermediate-6) and 2,4-difluoroaniline by following a procedure similar to that described in lntermediate-7a.
  • the title compound was prepared by using methyl 1 -chloroisoquinolin-4- carboxylate (lntermediate-6) and 3,4-difluorophenol by following a procedure similar to that described in lntermediate-7e.
  • the title compound was prepared by using methyl 1 -chloroisoquinolin-4- carboxylate (lntermediate-6) and 2-methoxyaniline by following a procedure similar to that described in lntermediate-7a.
  • the title compound was prepared by using methyl 1 -chloroisoquinolin-4- carboxylate (lntermediate-6) and 4-methoxyaniline by following a procedure similar to that described in lntermediate-7a.
  • the title compound was prepared by using methyl 1 -chloroisoquinolin-4- carboxylate (lntermediate-6) and 3-chloro-4-methylaniline by following a procedure similar to that described in lntermediate-7a.
  • the title compound was prepared by using methyl 1 -chloroisoquinolin-4- carboxylate (lntermediate-6) and 2,3-difluoroaniline by following a procedure similar to that described in lntermediate-7a.
  • the title compound was prepared by using methyl 1 -chloroisoquinolin-4- carboxylate (lntermediate-6) and 3-(trifluoromethyl)aniline by following a procedure similar to that described in lntermediate-7a.
  • the title compound was prepared by using methyl 1 -chloroisoquinolin-4- carboxylate (lntermediate-6) and 3-chloro-2-fluoroaniline by following a procedure similar to that described in lntermediate-7a.
  • the title compound was prepared by using methyl 1 -chloroisoquinolin-4- carboxylate (lntermediate-6) and 2-fluoro-3-(trifluoromethyl)aniline by following a procedure similar to that described in lntermediate-7a.
  • Intermedite-8a 1 -((3-Chlorophenyl)amino)isoquinolin-4-carboxylic acid:
  • Intermedite-8c 1 -((3,5-Difluorophenyl)amino)isoquinolin-4-carboxylic acid:
  • lntermediate-8d 1 -((2,4-Difluorophenyl)amino)isoquinolin-4-carboxylic acid:
  • lntermediate-8h 1 -((4-Methoxyphenyl)amino)isoquinolin-4-carboxylic acid:
  • lntermediate-8i 1 -((3-Chloro-4-methylphenyl)amino)isoquinolin-4-carboxylic acid:
  • This compound was prepared by using lntermediate-81 and 1 ,1 -dioxidothio morpholine by following the similar procedure as described in Example-1 ;
  • Certain illustrative compounds within the scope of the invention are screened for CB 2 activity according to the procedure given below.
  • the screening of the compounds may also be carried by other methods and procedures known to skilled in the art.
  • In-vitro assay method for determination of cAMP in functional hCB?-CHO stable cells Recombinant CHO-hCB 2 cells (procured from Perkin Elmer Inc. USA) were propagated and maintained in Ham's F-12 complete medium containing 10% heat inactivated FBS (Sigma.UK) and 1 x penstrep. For assay, 0.1 x10 6 to 1 .0 x10 6 CHO- hCB 2 cells were seeded in T-25 flask and grown to mid-log phase in culture media without antibiotics for 2-3 days.
  • assay cell monolayer was washed twice with PBS (pH.7.4) and then cells were detached with PBS-EDTA, centrifuged and resuspended in assay buffer (KRBG containing: 1 15 mM NaCI, 5 mM KCI, 24 mM NaHCOs, 10 mM Glucose, 1 mM MgCI 2 , 2.5 mM CaCI 2 , 10 mM HEPES, 1 mM IBMX and 0.1 - 0.5 g/l BSA). The test is performed in 96 1 ⁇ 2 area black well plates.
  • cAMP calibrator/standards were added in the plate with range of 70 nM to 0.01 nM and 4-parameter curve fit (based on DF values) was used for calculation of cAMP concentration of sample wells.
  • vehicle control (0.4% v/v DMSO) was set to 0% and forskolin control wells as 100%.
  • the concentration of compound required to stimulate a half-maximal response (EC 5 o) was determined using the GraphPad Prism software (version 5).
  • the compounds prepared were tested using the above assay procedure and the results obtained are given below.
  • the EC 50 (nM) values of the compounds are set forth in Table-1 wherein "A” refers to an EC 50 value of less than 10 nM and "B” refers to an EC50 value in range of 10.01 to 1000 nM.
  • hCB1 -HEK cells (clone 8) were propagated and maintained in DMEM complete medium supplemented with 10% heat inactivated FBS (Sigma. U.S.A), 400 ⁇ 9/ ⁇ of G418 and 1 x penstrep.
  • FBS heat inactivated FBS
  • 0.6 - 1 .0 x10 6 hCB1 -HEK cells were seeded in T-25 flask and grown to mid-log phase in complete culture medium as mentioned above for 2-3 days.
  • cell monolayer was washed once with PBS (pH.7.4) and then serum starved for overnight in DMEM medium containing 0.2% bovine serum albumin (devoid of antibiotics, FBS and penstrep).
  • test On the day of assay, cells were trypsinized using 0.025% trypsin-EDTA, centrifuged and resuspended in assay buffer (KRBG containing: 1 15 mM NaCI, 5 mM KCI, 24 mM NaHCO3, 1 0 mM Glucose, 1 mM MgCI 2 , 2.5 mM CaCI2, 10 mM HEPES, 1 mM IBMX and 0.1 - 0.5 g/l BSA) at a concentration of 2.5 x 10 5 cells/ml. The test is performed in 96 1 ⁇ 2 area black well plates.
  • assay buffer KRBG containing: 1 15 mM NaCI, 5 mM KCI, 24 mM NaHCO3, 1 0 mM Glucose, 1 mM MgCI 2 , 2.5 mM CaCI2, 10 mM HEPES, 1 mM IBMX and 0.1 - 0.5 g/l BSA
  • cAMP calibrator/standards were added in the plate with range of 70 nM to 0.01 nM and 4-parameter curve fit (based on DF values) was used for calculation of cAMP concentration of sample wells.
  • vehicle control (0.4% v/v DMSO) was set to 0% and forskolin control wells were set as 100%.
  • Assay was validated using CP55940, WIN-55212-2 and SR144528 as reference compounds.
  • the compounds of the invention have EC 50 values in the nano molar (nM) to micro molar range ( ⁇ ).

Abstract

Compounds of Formula (I) along with processes for their preparation that are useful for treating, preventing and/or managing the diseases, disorders, syndromes or conditions associated with the modulation of cannabinoid (CB) receptors. Methods of treating, preventing managing and/or lessening the diseases, disorders, syndromes or conditions associated with the modulation of cannabinoid (CB) receptors of Formula (I).

Description

ISOQUINOLINE DERIVATIVES AS CANNABINOID RECEPTOR MODULATORS
Related Applications
This application claims the benefit of Indian patent application nos. 1477/KOL/2010 filed on Dec 30, 2010 and 909/KOL/201 1 filed on July 05, 201 1 , all of which are hereby incorporated by reference in their entirety.
Field of the Invention
The present invention relates to compounds and pharmaceutically acceptable salts thereof and pharmaceutical compositions for the treatment, prevention, management, and/or lessening the severity of diseases, disorders, syndromes or conditions associated with the modulation of cannabinoid (CB) receptors. The invention also relates to methods of treating, preventing, managing and/or lessening the severity of the diseases disorders, syndromes or conditions associated with the modulation of cannabinoid (CB) receptors. The invention also relates to processes for the preparation of the compounds of the invention.
Background of the Invention
A G-protein coupled receptor (CX5) expressed in human promyelocytic leukemic cell line (HL60) was discovered in 1993. This was later identified as type II Cannabinoid receptor (Munro et al. Nature (1993), 365, 61 -65). CB2 receptors are found to be expressed predominantly in immune cells. When activated they modulate immune cell migration and cytokine release outside and within the brain (Pertwee et al. Handb. Exp. Pharmacol. (2005), 168, 1-51 ). CB2 activation affects a host of immune responses from inflammation to neuroprotection (Cabral et al. Handb. Exp. Pharmacol. (2005), 168, 385^123). The activation of CB2 receptors is reported to have analgesic effect in many animal models of pain from acute pain to neuropathic pain (Anand et al. Pain. (2009), 138, 667-680).
Since CB2 is an attractive therapeutic target for pain management and immune system modulation without overt psycho activity and substance abuse possibility, its presumed absence in the CNS was reviewed by many researchers. The findings of these recent investigations support the presence of CB2 receptors in CNS. The CB2 mRNA and protein have been found in microglia (Beltramo et al. Eur. J. Neurosci. (2006), 23, 1530-1538; Carlisle et al. Int. Immuno Pharmacol. (2002), 2, 69-82; Klegeris et al. Br. J. Pharmacol. (2003), 139, 775-786; Maresz et al., Nat. Med. (2007), 13, 492-497; Walter et al. J. Neurosci. (2003), 23, 1 398-1405). The expression levels of CB2 are proportional to the activation extent of microglia (Cabral et al., Br. J. Pharmacol. (2008), 153, 240-251 ; Pietr et al. FEBS Lett. (2009), 583, 2071 -2076; Stella et al. Glia. (2004), 48, 267-277). Microglial migration and their infiltration into brain areas with active neuroinflammation and degeneration are modulated by CB2. In healthy brain microglia does not express CB2 but they do in Alzheimer's brain tissue in the neuritic-plaque associated microglia (Benito et al. J Neurosci. (2003), 23, 1 1 136-1 1 141 ). In the neuropathic pain models CB2 mRNA is found to increase in association with activated microglia in the spinal cord (Zhang et al. Eur. J. Neurosci. (2003), 17, 2750-2754). Similarly in amyotrophic lateral sclerosis and multiple sclerosis, CB2 microglial expression increases in spinal cord (Yiangou et al. BMC. Neurol. (2006), 6, 12).
As reported earlier highest CB2 receptor distribution is also known in macrophages, CD4 T cells, CD8 T cells, B cells, natural killer cells, monocytes, and polymorphonuclear neutrophils (Dittel B N. et al. BJP. (2008), 153, (2), 271 -276; Maresz K. et al. Nature Medicine. (2007), 13, 492-497). Similarly CB2 receptor presence is also known in other brain areas like thalamus, straitum, hippocampus. Peripheral neurons, nociceptive neurons and sensory neurons also are known to express CB2 receptors.
Apart from the relevance of CB2 in the area of pain management, this receptor is also known to be involved in other functions. For example CB2 receptor is expressed in the bone cells and is reported to have anabolic effect on bones (Ofek et al. PNAS. (2006), 103, 696-701 ). Presence of CB2 is also reported in the enteric nervous system, (Duncan M Mouihate et al, Am. J. Physiol. Gastrointest. Liver Physiol. 295, G78-G87). Similar anabolic effect is also reported through CB2 receptor mediation in neurogenesis (Molina-Holgado et al. Eur. J. Neurosci. (2007), 25, 629-634 & Palazuelos J. et al FASEB J. (2006), 20, 2405-2407).
Role of CB1 in pain management is also well known. This receptor is known to exist majorly in the central nervous system. To a minor extent, CB1 is also reported to exist in the periphery (Pharmacology, Biochemistry and Behavior 90 (2008) 501-51 1 ). Therefore, along with compounds that are CB2 selective modulators, dual modulators working through CB1 and CB2 are also targeted.
WO 2002/042248, WO 2010/096371 , WO 2010/133973, WO 2006/129178, WO 2010/ 084767, WO 2009/053799, WO 2008/1 15672, WO 2008/027812, WO 2007/102059, WO 2007/091950 and WO 2002/42248 applications disclose compounds related to cannabinoid receptors for the treatment of various diseases mediated by cannabinoid receptors. Also, Bioorganic Medicinal Chemistry, (201 1 ), 19, 939-950, discloses the compounds related to cannabinoid receptors.
Summary of the Invention
In accordance with one aspect, the invention provides compounds having the Formula (I):
Figure imgf000005_0001
wherein,
X is selected from -NRa-, -O- and -S(O)n-;
Y is selected from -C(O)-, -S(O)2-, and -CR5R6-;
R1 ; which may be same or different at each occurrence, is independently selected from halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkoxy, cycloalkoxy, -C(O)OH, -NRaRb and -C(O)NRaRb; R2 is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyi, heteroaryl, heteroarylalkyi, heterocyclyl, and heterocyclylalkyi;
R3 is selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyi, heteroaryl, heteroarylalkyi, heterocyclyl, and heterocyclylalkyi; or
R2 and R3, together with the nitrogen atom to which they are attached, may form a substituted or an unsubstituted 3 to 14 membered heterocyclic ring; or
R2 and R3, together with the nitrogen atom to which they are attached, may form a substituted or an unsubstituted 5 to 14 membered heteroaryl ring;
with the proviso that when X is NH and R is m-(trifluoromethyl)phenyl, R2 and R3 do not together form a morpholine ring;
R4 is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl;
R5 and R6, which may be same or different, are independently selected from hydrogen, alkyl, and haloalkyl;
Ra and Rb, which may be same or different at each occurrence, are independently selected from hydrogen, alkyl, haloalkyl, acyl and cycloalkyl; or Ra and Rb, together with the nitrogen atom to which they are attached, may form a substituted or unsubstituted 3 to 14 membered heteroaryl or heterocyclic ring;
'm' is an integer ranging from 0 to 3, both inclusive;
'n' is an integer ranging from 0 to 2, both inclusive; and
wherein alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, acyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkoxy, cycloalkylalkyl, aryl, arylalkyi, heteroaryl, heteroarylalkyi, heterocyclyl, (heterocyclic ring) heterocyclylalkyi wherever they occur may optionally be substituted with one or more substituents independently selected from hydroxy, halo, cyano, nitro, oxo (=0), thio (=S), alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyi, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyi, heteroarylalkyi, -C(0)ORx, -C(0)Rx, - C(S)RX, -C(0)NRxRy, -NRxC(0)NRyRz, -N(Rx)S(0)Ry, -N(Rx)S(0)2Ry, -NRxRy, - NRxC(0) Ry, -NRxC(S)Ry, -NRxC(S)NRyRz, -S(0)2NRxRy, -ORx, -OC(0)Rx, - OC(0)NRxRy, -RxC(0)ORy, -RxC(0)NRyRz, -RxC(0)Ry, -SRX, and -S(0)2Rx; and wherein at each occurrence, Rx, Ry and Rz are independently selected from hydrogen, alkyl, haloalkyi, alkenyl, alkynyl, aryl, arylalkyi, cycloalkyi, cydoalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl;
or a pharmaceutically acceptable salt thereof.
According to one embodiment, there is provided a compound of formula (II):
Figure imgf000007_0001
wherein,
Figure imgf000007_0002
R7, which may be same or different at each occurrence, is independently selected from halogen, cyano, nitro, hydroxy, alkyl, haloalkyi, hydroxyalkyl, cycloalkyi, alkoxy, haloalkoxy, cycloalkoxy, -C(0)OH, -NRaRb and -C(0)NRaRb;
R2, R3, Ra, and Rb are as defined herein above; and
'p' is an integer ranging from 0 to 4, both inclusive;
or its pharmaceutically acceptable salt thereof.
According to one embodiment, there is provided a compound of formula (III):
Figure imgf000007_0003
(III) wherein,
R7, which may be same or different at each occurrence, is independently selected from halogen, cyano, nitro, hydroxy, alkyl, haloalkyi, hydroxyalkyl, cycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, -C(0)OH, -NRaRb and -C(0)NRaRb;
W is CR8R9, O, or S(0)2;
R8 and R9 are independently selected from hydrogen, halogen, cyano, hydroxy, alkyl, haloalkyi, hydroxyalkyl, cycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, heteroaryl, heterocyclyl, -NRaRb and -C(0)NRaRb;
with the proviso that:
when W is O then R7 is not p-methoxy;
when W is CH2 then R7 is not p-methyl or o-methoxy;
when W is CH(alkyl) or CH(benzyl) then R7 is not p-methyl, o- methoxy, p-methoxy or p-halogen;
Ra and Rb are as defined herein above; and
'p' is an integer ranging from 0 to 4, both inclusive;
or its pharmaceutically acceptable salt thereof.
It should be understood that formulae (I), (I I) or (II I) structurally encompasses all tautomers, stereoisomers including isotopes wherever applicable and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the genera described herein.
According to one sub embodiment there is provided a compound of formula (I I) in which R7 is halogen, hydroxyl, alkyl, haloalkyi or alkoxy and 'p' is 0, 1 , 2 or 3.
According to another sub embodiment there is provided a compound of formula (I I) in which R2 is hydrogen or alkyl. According to another sub embodiment there is provided a compound of formula (I I) in which R3 is selected from alkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl.
According to another sub embodiment there is provided a compound of formula (II) in which R2 and R3 together with nitrogen atom to which they are attached, may form a substituted or an unsubstituted 3 to 12 membered heterocyclic ring which may be monocyclic, fused bicyclic, bridged bicyclic or spirocylcic; wherein the substituent(s) on heterocyclic ring may be one or more, same or different and are independently selected from halogen, alkyl, haloalkyl, aryl or heteroaryl. Below are the representative compounds, which are illustrative in nature only and are not intended to limit to the scope of the invention.
(1 -((3-Chlorophenyl)amino)isoquinolin-4-yl)(morpholino)methanone;
1 -((3-Chlorophenyl)amino)-/V-((tetrahydro-2 - -pyran-4-yl)methyl)isoquinolin-4- carboxamide;
/V-(ieri-Butyl)-1 -((3-chlorophenyl)amino)isoquinolin-4-carboxamide;
1 -((3-Chlorophenyl)amino)-/V-(pyridin-4-ylmethyl)isoquinolin-4-carboxamide;
(1 -((3-Fluorophenyl)amino)isoquinolin-4-yl)(morpholino)methanone;
(1 -((3-Fluorophenyl)amino)isoquinolin-4-yl)(piperidin-1 -yl)methanone;
Azetidin-1 -yl(1 -((3-fluorophenyl)amino)isoquinolin-4-yl)methanone;
1 -((3-Fluorophenyl)amino)-/V-(piperidin-1 -yl)isoquinolin-4-carboxamide;
(1 -((3,5-Difluorophenyl)amino)isoquinolin-4-yl)(morpholino)methanone;
(1 -((3,5-Difluorophenyl)amino)isoquinolin-4-yl)(piperidin-1 -yl)methanone;
Azetidin-1 -yl(1 -((3,5-difluorophenyl)amino)isoquinolin-4-yl)methanone;
1 -((3,5-Difluorophenyl)amino)-N-(piperidin-1 -yl)isoquinoline-4-carboxamide;
(1 -((2,4-Difluorophenyl)amino)isoquinolin-4-yl)(morpholino)methanone;
(1 -((2,4-Difluorophenyl)amino)isoquinolin-4-yl)(piperidin-1 -yl)methanone;
Azetidin-1 -yl(1 -((2,4-difluorophenyl)amino)isoquinolin-4-yl)methanone; 1 -((2,4-Difluorophenyl)amino)-A/-morpholinoisoquinolin-4-carboxamide;
(1 -(4-Fluorophenoxy)isoquinolin-4-yl)(morpholino)methanone;
(1 -(4-Fluorophenoxy)isoquinolin-4-yl)(piperidin-1 -yl)methanone;
(1 -(4-Fluorophenoxy)isoquinolin-4-yl)(4-phenylpiperidin-1 -yl)methanone;
(1 -(3,4-Difluorophenoxy)isoquinolin-4-yl)(morpholino)methanone;
(1 -(3,4-Difluorophenoxy)isoquinolin-4-yl)(piperidin-1 -yl)methanone;
(1 -(3,4-Difluorophenoxy)isoquinolin-4-yl)(4-phenylpiperidin-1 -yl)methanone;
(1 -((2,3-Difluorophenyl)amino)isoquinolin-4-yl)(1 , 1 - dioxidothiomorpholino)methanone;
(1 , 1 -Dioxidothiomorpholino)(1 -((3-(trifluoromethyl)ph
methanone;
(1 , 1 -Dioxidothiomorpholino)(1 -((2-fluoro-3-(trifluoromethyl)phenyl)amino)isoquinolin- 4-yl)methanone;
6-Oxa-3-azabicyclo[3.1 .1 ]heptan-3-yl(1 -((3- (trifluoromethyl)phenyl)amino)isoquinolin-4-yl) methanone;
6-Oxa-3-azabicyclo[3.1 .1 ]heptan-3-yl(1 -((3-chloro-2-fluorophenyl)amino)isoquinolin- 4-yl) methanone and
(1 , 1 -Dioxidothiomorpholino)(1 -((2-fluoro-3-chlorophenyl)amino)isoquinolin-4-yl) methanone
or pharmaceutically acceptable salt thereof.
In another aspect of the invention, there is provided a compound of formula (I) useful in treating, preventing, managing and/or lessening the severity of diseases, disorders, syndromes or conditions associated with cannabinoid (CB) modulators.
In another aspect, the invention provides a pharmaceutical composition that includes at least one compound of formula (I) and at least one pharmaceutically acceptable excipient.
In another aspect, the invention provides a pharmaceutical composition of compound of formula (I) useful in treating, preventing, managing and/or lessening the severity of the diseases disorders or conditions associated with cannabinoid (CB) modulators in a subject, in need thereof by administering to the subject, one or more compounds described herein in a therapeutically effective amount to cause modulation of such receptor. Also provided herein are processes for preparing compounds described herein.
The details of one or more embodiments of the invention set forth in the below are illustrative in nature only and not intended to limit to the scope of the invention. Other features, objects and advantages of the inventions will be apparent from the description and claims.
Detailed description of the invention
Definitions and Abbreviations:
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below.
For purposes of interpreting the specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa.
The terms "halogen" or "halo" means fluorine, chlorine, bromine, or iodine.
Unless otherwise stated, in the present application "oxo" means C(=O) group. Such an oxo group may be a part of either a cycle or a chain in the compounds of the present invention.
The term "alkyl" refers to an alkane derived hydrocarbon radical that includes solely carbon and hydrogen atoms in the backbone, contains no unsaturation, has from one to six carbon atoms, and is attached to the remainder of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1 -methylethyl (isopropyl), n-butyl, n-pentyl, 1 ,1 - dimethylethyl (t-butyl) and the like. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted. The term "alkenyl" refers to a hydrocarbon radical containing from 2 to 10 carbon atoms and including at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include ethenyl, 1 -propenyl, 2-propenyl (allyl), iso- propenyl, 2-methyl-l- propenyl, 1 -butenyl, 2-butenyl and the like. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
The term "alkynyl" refers to a hydrocarbon radical containing 2 to 10 carbon atoms and including at least one carbon- carbon triple bond. Non- limiting examples of alkynyl groups include ethynyl, propynyl, butynyl and the like. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
The term "alkoxy" refers to an alkyl group attached via an oxygen linkage. Non- limiting examples of such groups are methoxy, ethoxy and propoxy and the like. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
The term "alkenyloxy" refers to an alkenyl group attached via an oxygen linkage. Non-limiting examples of such groups are vinyloxy, allyloxy, 1 -butenyloxy, 2- butenyloxy, isobutenyloxy, 1 -pentenyloxy, 2-pentenyloxy, 3-methyl-1 -butenyloxy, 1 - methyl-2-butenyloxy, 2,3-dimethylbutenyloxy, 1 -hexenyloxy and the like. Unless set forth or recited to the contrary, all alkenyloxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
The term "alkynyloxy" refers to an alkynyl group attached via an oxygen linkage. Non-limiting examples of such groups are acetylenyloxy, propynyloxy, 1 -butynyloxy, 2-butynyloxy, 1 -pentynyloxy, 2-pentynyloxy, 3-methyl-1 -butynyloxy, 1 -hexynyloxy, 2- hexynyloxy, and the like.
The term "cycloalkyl" refers to a non-aromatic mono or multicyclic ring system having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl and the like. Unless set forth or recited to the contrary, all cycloalkyi groups described or claimed herein may be substituted or unsubstituted.
The term "cycloalkoxy" refers to an cycloalkyi, defined herein, group attached via an oxygen linkage. Non-limiting examples of such groups are cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy and the like. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
The term "cycloalkenyl" refers to a non-aromatic mono or multicyclic ring system having 3 to 12 carbon atoms and including at least one carbon-carbon double bond, such as cyclopentenyl, cyclohexenyl, cycloheptenyl and the like. Unless set forth or recited to the contrary, all cycloalkenyl groups described or claimed herein may be substituted or unsubstituted.
The term "cycloalkylalkyl" refers to a cycloalkyi group as defined above, directly bonded to an alkyl group as defined above, e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, etc. Unless set forth or recited to the contrary, all cycloalkylalkyl groups described or claimed herein may be substituted or unsubstituted.
The term "haloalkyi" refers to an alkyl group as defined above that is substituted by one or more halogen atoms as defined above. Preferably, the haloalkyi may be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodine, bromine, chlorine or fluorine atom. Dihaloalkyl and polyhaloalkyl groups can be substituted with two or more of the same halogen atoms or a combination of different halogen atoms. Preferably, a polyhaloalkyl is substituted with up to 12 halogen atoms. Non-limiting examples of a haloalkyi include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl and the like. A perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halogen atoms.
The term "haloalkoxy" refers to an haloalkyl, defined herein, group attached via an oxygen linkage. Non-limiting examples of such groups are monohaloalkoxy, dihaloalkoxy or polyhaloalkoxy including perhaloalkoxy. Unless set forth or recited to the contrary, all haloalkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
The term "hydroxyalkyl" refers to an alkyl group, as defined above that is substituted by one or more hydroxy groups. Preferably, the hydroxyalkyl is monohydroxyalkyl or di hydroxyalkyl. Non-limiting examples of a hydroxyalkyl include 2- hydroxyethyl, 3- hydroxypropyl, 2-hydroxypropyl, and the like.
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, tetrahydronaphthyl, indanyl, and biphenyl and the like. Unless set forth or recited to the contrary, all aryl groups described or claimed 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, e.g., -CH2C6H5 and -C2H4C6H5. Unless set forth or recited to the contrary, all arylalkyl groups described or claimed herein may be substituted or unsubstituted.
The term "heterocyclic ring" or "heterocyclyl ring" or "heterocyclyl", unless otherwise specified, refers to substituted or unsubstituted non-aromatic 3- to 15- membered ring which consists of carbon atoms and with one or more heteroatom(s) independently selected from N, O or S. The heterocyclic ring may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems and the nitrogen, carbon, oxygen or sulfur atoms in the heterocyclic ring may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized, the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s), and one or two carbon atoms(s) in the heterocyclic ring or heterocyclyl may be interrupted with -CF2-, -C(O)-, -S(O)-, S(0)2, -C(=N-alkyl)-, or - C(=N-cycloalkyl), etc. In addition heterocyclic ring may also be fused with aromatic ring. Non-limiting examples of heterocyclic rings include azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, benzopyranyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone indoline, tetrahydroquinoline, tetrahydrobenzopyran and the like. The heterocyclic ring 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 or claimed herein may be substituted or unsubstituted; substituents may be on same or different ring atom.
The term "heteroaryl" unless otherwise specified, refers to a substituted or unsubstituted 5- to 14- membered aromatic heterocyclic ring 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 may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Non-limiting examples of a heteroaryl ring include oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl, phthalazinyl and the like. Unless set forth or recited to the contrary, all heteroaryl groups described or claimed 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 or claimed herein may be substituted or unsubstituted.
The term "heteroarylalkyi" refers to a heteroaryl ring radical directly bonded to an alkyl group. The heteroarylalkyi 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 or claimed 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 substituents attached to the structural skeleton of the group or moiety. Such substituents include, but are not limited to hydroxy, halo, carboxyl, cyano, nitro, oxo (=0), thio (=S), alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, amino, heteroaryl, heterocyclic ring, heterocyclylalkyl, heteroarylalkyi, -C(0)ORx, -C(0)Rx, -C(S)RX, -C(0)NRxRy, - NRxC(0)NRyRz, -N(Rx)S(0)Ry, -N(Rx)S(0)2Ry, -NRxRy, -NRxC(0)Ry, -NRxC(S)Ry, - NRxC(S)NRyRz, - S(0)2NRxRy, -ORx, -OC(0)Rx, -OC(0)NRxRy, -RxC(0)ORy, - RxC(0)N RyRz, -RxC(0)Ry, -SRX, and -S(0)2Rx; wherein each occurrence of Rx, Ry and Rz are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl ring and heteroarylalkyi.
The phrase "may optionally be substituted" refers to a moiety or group that may or may not be substituted. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted and unsubstituted aryl radicals. A "stereoisomer" refers to a compound having the same atoms bonded through the same bonds but having different three-dimensional orientations, which are not interchangeable. The invention contemplates various stereoisomers and mixtures thereof and includes enantiomers and diastereomers. The invention also includes geometric isomers Έ" or "Z" or cis or trans configuration in a compound having either a double bond or having substituted cycloalkyl ring system.
A "tautomer" refers to a compound that undergoes rapid proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. The individual tautomers as well as mixture thereof are encompassed with compounds of formula (I).
The term "treating" or "treatment" of a state, disease, disorder, condition or syndrome includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disease, disorder, condition or syndrome developing in a subject that may be afflicted with or predisposed to the state, disease, disorder, condition or syndrome but does not yet experience or display clinical or subclinical symptoms of the state, disease, disorder, condition or syndrome; (b) inhibiting the state, disease, disorder, condition or syndrome, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; c) lessening the severity of a disease, disorder, syndrome or condition or at least one of its clinical or subclinical symptoms thereof; and/or (d) 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 "modulate" or "modulating" or "modulation" or "modulator" refers to an increase or decrease in the amount, quality, or effect of a particular activity, function or molecule. By way of illustration and not limitation, it includes agonists, partial agonists, inverse agonists and antagonists of a cannabinoid (CB) receptor of the present invention.
The term "subject" includes mammals, preferably humans and other animals, such as domestic animals; e.g., household pets including cats and dogs.
A "therapeutically effective amount" refers to the amount of a compound that, when administered to a subject in need thereof, is sufficient to cause a desired effect. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, age, weight, physical condition and responsiveness of the subject to be treated.
Pharmaceutically Acceptable Salts:
The compounds of the invention may form salts. In cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compound as a pharmaceutically acceptable salt may be appropriate. Non- limiting examples of pharmaceutically acceptable salts are organic acid addition salts formed by addition of acids, which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, a-ketoglutarate, a-glycerophosphate, formate, fumarate, propionate, glycolate, lactate, pyruvate, oxalate, maleate, and salicylate. Suitable inorganic salts may also be formed, including, sulfate, nitrate, bicarbonate, carbonate salts, hydrobromate and phosphoric acid.
Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
With respect to the overall compounds described by the Formula (I) the invention extends to stereoisomeric forms and to mixtures thereof. The different stereoisomeric forms of the invention may be separated from one another by the method 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. Screening of compounds of invention for cannabinoid receptor modulation activity can be achieved by using various in vitro and in vivo protocols mentioned herein below or methods known in the art.
Pharmaceutical Compositions
The invention relates to pharmaceutical composition containing the compounds of the Formula (I) disclosed herein. In particular, pharmaceutical compositions containing a therapeutically effective amount of at least one compound of formula (I) described herein and at least one pharmaceutically acceptable excipient (such as a carrier or diluent). Preferably, the contemplated pharmaceutical compositions include the compound(s) described herein in an amount sufficient to modulate cannabinoid receptor mediated diseases described herein when administered to a subject.
The subjects contemplated include, for example, a living cell and a mammal, including human mammal. The compound of the invention 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 pharmaceutically acceptable excipient includes a pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity. 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, silicylic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing. The pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
The pharmaceutical compositions described herein may be prepared by conventional techniques known in the art. For example, the active compound can be 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 can be 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 invention 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).
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. 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 formulation.
Liquid formulations include, but are not limited to, syrups, emulsions, suspensions, solutions, 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.
The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as pocketed tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
For administration to subject patients, the total daily dose of the compounds of the invention depends, of course, on the mode of administration. For example, oral administration may require a higher total daily dose, than an intravenous (direct into blood). The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 10000 mg according to the potency of the active component or mode of administration.
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 subject 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 the patient. For example, the daily dosage of the CB modulator 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 invention.
Methods of Treatment In an embodiment, the invention provides compounds and pharmaceutical compositions thereof that are useful in treating, preventing, managing and/or lessening the severity of diseases, disorders, syndromes or conditions modulated by cannabinoid receptor. The invention further provides method of treating diseases, disorders or conditions modulated by cannabinoid receptor in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the invention.
In another aspect of the invention, the methods provided are also useful for diagnosis of conditions that can be treated by acting on cannabinoid receptor for determining if a patient will be responsible to therapeutic agents. In still another aspect, the invention provides a method for the treatment of diseases, disorders or conditions through modulating cannabinoid receptor. In this method, a subject in need of such treatment is administered a therapeutically effective amount of a compound of formula (I) described herein.
The compound of formula (I), being modulators of cannabinoid receptor, is potentially useful in treating, preventing, managing and/or lessening the severity of diseases, disorders, syndromes or conditions include but are not limited to pain, inflammation, analgesic conditions, healing of wounds and burns, movement disorders, immune disorders (such as autoimmune disorders), respiratory disorders, lung diseases associated with inflammation, pruritis associated with inflammation, allergic diseases associated with inflammation, organ contraction, preanesthetic medication, pre operative medication, muscle spasm, locomotor activity disorders, bone disorders, multiple sclerosis, glaucoma and related intra ocular pressure, cell growth disorders, gastrointestinal disorders, diseases of central nervous system (CNS) erythromyalgia, neurological disorders, neurodegenerative disorders, neuromuscular conditions, neuroinflammatory pathologies and the like. Pain includes, but is not limited to, acute pain, chronic pain, musculoskeletal pain, post-operative pain, visceral pain, peripherally mediated pain, centrally mediated pain, inflammatory pain, neuropathic pain, nociceptive pain, and idiopathic pain.
The compounds, compositions and methods of the invention are of particular use in treating, preventing or lessening of pain includes but is not limited to acute pain, chronic pain, visceral pain, neuropathic pain, inflammatory pain or nociceptive pain or pain associated with, such as but are not limited to dental pain, eye pain, ear pain, perioperative, traumatic pain, muscle pain, pain in burned skin, sun burn, trigeminal neuralgia, spasm of the gastrointestinal tract or uterus, colics, back pain, chronic fatigue syndrome, clinical depression, complex regional pain syndrome, myofascial pain syndrome, post-vasectomy pain syndrome, restless leg syndrome, spinal stenosis, chronic pelvic pain, pancreatitis, peptic ulcer, interstitial cystitis, renal colic, angina, dysmenorrhoea, menstruation, gynaecological pain, irritable bowel syndrome (IBS), non-ulcer dyspepsia, non-cardiac chest pain, myocardial ischemia, non-herpetic neuralgia, post herpetic neuralgia, diabetic neuropathy, nerve injury, acquired immune deficiency syndrome (AIDS) related pain, herpes virus infection, head trauma, causalgia, plexus avulsion, neuroma, limb amputation, vasculitis, painful traumatic mononeuropathy, phantom limb pain, painful polyneuropathy, thalamic pain syndrome, post-stroke pain, central nervous system injury, stump pain, repetitive motion pain, pain induced by post mastectomy syndrome, multiple sclerosis, root avulsions, postthoracotomy syndrome, hyperalgesia, allodynia, nerve damage from chronic alcoholism, arthritis pain, osteoarthritis, rheumatoid arthritis, rheumatic disease, teno-synovitis, gout, vulvodynia, myofascial pain (muscular injury, fibromyalgia), tendonitis, juvenile arthritis, spondylitis, gouty arthritis, psoriatic arthritis, muscoskeletal pain, fibromyalgia, sprains and strains, sympathetically maintained pain, myositis, pain associated with migraine, dental pain, systemic lupus erythematosus, central and peripheral pathway mediated pain, bone and joint pain, pain associated with cancer including chemotherapy pain, orofacial pain, somatic pain, sciatica pain, intestinal obstruction pain, coliky pain, myofacial pain, trauma pain, labour pain, brachial plexus avulsion, reflex sympathetic dystrophy, fibromyalgia, phantom limb pain, pain following stroke, thalamic lesions, radiculopathy, migraine pain, menstrual cramps, dermatitis, immunodeficiency, HIV-related neuropathy; familial hemiplegic migraine, conditions associated with cephalic pain, headache (e.g., chronic headache, sinus headache, headache associated with stress, headache with different origins), cardiac pain arising from an ischemic myocardium, pain following stroke, neuropathy secondary to metastatic inflammation, pain due to connective tissue damage, and other forms of neuralgic, neuropathic, and idiopathic pain syndromes.
The compounds of the invention may be useful for treating various types of inflammatory disease such as inflammations due to immune system, inflammations due to cancer, atherosclerosis, ischaemic heart diseases, pancreatitis, which includes but is not limited to acute pancreatitis and chronic pancreatitis, which is characterized by recurring or persistent abdominal pain with or without steatorrhea hereditary pancreatitis, pancreatic dysfunction. Respiratory related syndromes, disorders or diseases include, but are not limited to, diseases of the respiratory tract or lung diseases such as asthma, bronchitis (acute or chronic), emphysema, allergic rhinitis, emphysema, adult respiratory distress syndrome (ARDS), pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease (COPD), asthma including allergic asthma (atopic or non-atopic) as well as exercise-induced bronchoconstriction, occupational asthma, viral- or bacterial exacerbation of asthma, other non-allergic asthmas and "wheezy- infant syndrome", pneumoconiosis, including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.
The compounds of invention may be useful in the treatment of pruritus and related diseases including, but not limited to psoriatic pruritis, itch due to hemodyalisis, aguagenic pruritis, itching caused by skin disorders, allergic itch, insect bite itch, itch caused by hypersensitivity such as dry skin, acne, eczema, psoriasis or injury, itch caused by vulvar vestibulitis and the similar itch.
Allergic diseases: all forms of allergic reactions include but are not limited to angioneurotic edema, hay fever, insect bites, viral or bacterial diseases, allergic reactions to drugs, blood derivatives, contrast agents, delayed or immediate hypersensitivity, allergic rhinitis, contact dermatitis, conjunctivitis, allergic reactions associated with inflammatory diseases such as diseases of the joints, spondylitis, gout, vasculitis, Crohn's disease, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) or osteoporosis.
Autoimmune or inflammation related syndromes, disorders or diseases include, but are not limited to, psoriasis, lupus erythematosus, diseases of the connective tissue, Sjogren's syndrome, ankylosing spondylarthritis, rheumatoid arthritis, reactional arthritis, undifferentiated spondylarthritis, Behcet's disease, autoimmune hemolytic anaemias, multiple sclerosis, amyotrophic lateral sclerosis, amyloses, graft rejection or diseases affecting the plasma cell line.
Gastrointestinal diseases including, but not limited to inflammatory bowel diseases, irritable bowel syndrome, regional enteritis (Crohns disease), colitis ulcerosa, gastritis, or aphthous.
General Methods of Preparation
The compounds described herein may be prepared by techniques known in the art. In addition, the compounds described herein may be prepared by following the reaction sequence as depicted in Scheme-1 . Further, in the following schemes, where specific bases, acids, reagents, solvents, coupling agents, etc. are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the scope of the present invention. Variations in reaction conditions, for example, temperature and/or duration of the reaction, which may be used as known in the art are also within the scope of the present invention. All the isomers of the compounds in described in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.
Scheme-1
Figure imgf000027_0001
The compound of formula (9) where X, R1 ; R2, R3, R4 and 'm' are as described herein above, can be prepared by following the sequential transformations of isoquinoline as depicted in Scheme-1 . First the compound of formula (1 ) is prepared by bromination of isoquinoline with NBS followed by reacting with Zinc cyanide in presence of palladium. The cyano compound of formula (2) undergoes hydrolysis in presence of KOH and the resultant acid compound (3) undergoes esterification to give compound of formula (4) in the presence of EDCI (1 -Ethyl-3-(3-dimethyl aminopropyl)carbodiimide), HOBt (hydroxybenzotriazole), DMAP (dimethyl aminopyridine) and in suitable solvent and this is further treated with mCPBA (m- chloroperbenzoic acid) to afford /V-oxide compound of formula (5). This N-oxide compound of formula (5) is treated with POCI3 to give chloro compound of formula (6) which is further reacted with compound R4-XH in the presence of Pd or Cu in suitable solvent to afford compound of formula (7). Compound of formula (7) undergoes hydrolysis to give acid compound of formula (8). Finally Compound of formula (9) is obtained by carrying amide coupling reaction in presence of EDCI, HOBt, and DIPEA (Ν,Ν-Diisopropylethylamine) and in suitable solvent.
Experimental
The invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. The examples set forth below demonstrate the synthetic procedures for the preparation of the representative compounds. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention. The aforementioned patents and patent applications are incorporated herein by reference. Intermediates lntermediate-1 : 3-Bromoisoquinoline:
To a stirred solution of isoquinoline (24 g, 186 mmol) in AcOH (50 ml_) was added NBS (36.2 g, 204.6 mmol) at room temperature and the reaction mixture was heated to 100 QC overnight. Then it was cooled to room temperature and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography (5% EtOAc:Hexanes) to furnish the title compound (9.2 g, 23.8%) as an oil.
lntermediate-2: lsoquinolin-4-carbonitrile:
To a stirred solution of 3-bromoisoquinoline (lntermediate-1 ) (9.2 g, 44.2 mmol) in DMF (1 5 ml_) were added, Pd(PPh3) (1 0.2 g, 8.84 mmol) and Zn(CN)2 (10.34 g, 88.44 mmol, 2.0 eq) and the solution was degassed with N2 for 20 min. It was then heated to 120 QC overnight. After the completion (TLC (thin layer chromatography)), reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography (10% EtOAc:Hexanes) to afford the title compound (3.4 g, 27.4%) as pale yellow solid.
lntermediate-3: lsoquinolin-4-carboxylic acid:
To a stirred solution of isoquinolin-4-carbonitrile (lntermediate-2) (3.0 g, 19.45 mmol) in EtOH (30 ml_) was added KOH (20 g in 20 ml_ water) and the mixture was refluxed overnight. It was then cooled to room temperature and concentrated under reduced pressure. The aqueous layer was washed with Et20 and neutralized using 1 N HCI. It was extracted with EtOAc and the organic layer was dried over Na2S04, filtered, and concentrated to give the title compound (2 g, 59.3%) as an off white solid.
lntermediate-4: Methyl isoquinolin-4-carboxylate:
To a stirred solution of isoquinolin-4-carboxylic acid (lntermediate-3) (1 .2 g, 6.9 mmol) in CH2CI2 (10 ml_) was added, EDCI (1 .3 g, 8.3 mmol), HOBt (1 .12 g, 8.3 mmol), DMAP (84 mg, 0.7 mmol) and the mixture was stirred at room temperature for 20 min. To this, MeOH (0.33 g, 10.4 mmol) was added and the reaction mixture was further stirred at room temperature for overnight. It was diluted with CH2CI2 (1 00 ml_) and washed with water. The organic layer was separated, dried over Na2SO4, filtered and concentrated to give crude product that was purified by flash column chromatography (10% EtOAc:Hexanes) to give the title compound (700 mg, 54%) as pale yellow solid.
lntermediate-5: Methyl 2-oxideisoquinolin-4-carboxylate:
To a well stirred solution of methyl isoquinolin-4-carboxylate (lntermediate-4) (700 mg, 3.74 mmol) in CH2CI2 (10 ml_) was added, mCPBA (1 .0 g, 4.1 1 mmol) portion wise at 0 QC and the reaction mixture was stirred overnight while allowing it to attain RT. After reaction completion (TLC), it was diluted with CH2CI2 (50 ml_) and washed with saturated NaHCO3 solution. The organic layer was separated, dried, filtered and concentrated to give the desired product (700 mg, 93.3%) as yellow solid.
lntermediate-6: Methyl 1 -chloroisoquinolin-4-carboxylate: Methyl 2-oxideisoquinolin-4-carboxylate (lntermediate-5) (700 mg, 3.4 mmol) was dissolved in CHCI3 (10 mL) and to this, POCI3 (1 .1 mL, 12.1 mmol) was added at room temperature and the reaction mixture was refluxed for 1 h. It was then cooled to room temperature, concentrated, diluted with ice water, neutralized with K2C03 and extracted with EtOAc. The organic layer was separated, dried over Na2S04, filtered and concentrated to give the crude product that was purified by flash column (10% EtOAC:Hexanes) to afford the title compound (380 mg, 50%) as a white solid.
Intermediate-7a: Methyl 1 -((3-chlorophenyl)amino)isoquinolin-4-carboxylate:
Figure imgf000030_0001
To a stirred solution of methyl 1 -chloroisoquinolin-4-carboxylate (lntermediate-6) (1 equiv) in toluene was added, BINAP (10 mol%), Cs2C03 (2 equiv), and 3-chloroaniline (1 .5 equiv) in a sealed tube. The mixture was degassed with N2 for 20 min and then added Pd(OAc)2 (20 mol%). It was again degassed for 20 min and heated to 100 QC overnight. It was cooled to room temperature, filtered and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography (15% EtOAc:Hexanes) to afford the title compound. Intermediate-7b: Methyl 1 -((3-fluorophenyl)amino)isoquinolin-4-carboxylate:
Figure imgf000030_0002
The title compound was prepared by using methyl 1 -chloroisoquinolin-4- carboxylate (lntermediate-6) (1 equivalent) and 3-fluoroaniline (1 .5 equiv) by following a procedure similar to that described in lntermediate-7a.
Intermediate-7c: Methyl 1 -((3,5-difluorophenyl)amino)isoquinolin-4-carboxylate:
Figure imgf000031_0001
The title compound was prepared by using methyl 1 -chloroisoquinolin-4- carboxylate (lntermediate-6) and 3,5-difluoroaniline by following a procedure similar to that described in lntermediate-7a.
Intermediate-7d: Methyl 1 -((2,4-difluorophenyl)amino)isoquinolin-4-carboxylate:
Figure imgf000031_0002
The title compound was prepared by using methyl 1 -chloroisoquinolin-4- carboxylate (lntermediate-6) and 2,4-difluoroaniline by following a procedure similar to that described in lntermediate-7a.
Intermediate-7e: Methyl 1 -(4-fluorophenoxy)isoquinolin-4-carboxylate:
Figure imgf000031_0003
To a stirred solution of methyl 1 -chloroisoquinolin-4-carboxylate (lntermediate-6) (1 mmol, 1 equiv) in dry DMF (5 ml_) was added, 4-fluorophenol (1 .1 equiv), Cul (1 .1 equiv) and K2C03 (2 equiv) in a sealed tube. The reaction mixture was degassed for 20 minutes and then stirred at 150 QC for 2 h. The reaction mixture was allowed to reach room temperature and then diluted with EtOAc. The slurry was filtered through celite, and then washed with EtOAc. The solvent was removed, and the residue was purified by column chromatography (15% EtOAc: Hexanes) to afford the desired compound.
Intermediate-7f: Methyl 1 -(3,4-difluorophenoxy)isoquinolin-4-carboxylate:
Figure imgf000032_0001
The title compound was prepared by using methyl 1 -chloroisoquinolin-4- carboxylate (lntermediate-6) and 3,4-difluorophenol by following a procedure similar to that described in lntermediate-7e.
Intermediate-7g: Methyl 1 -((2-methoxyphenyl)amino)isoquinolin-4-carboxylate:
Figure imgf000032_0002
The title compound was prepared by using methyl 1 -chloroisoquinolin-4- carboxylate (lntermediate-6) and 2-methoxyaniline by following a procedure similar to that described in lntermediate-7a.
Intermediate-7h: Methyl 1 -((4-methoxyphenyl)amino)isoquinolin-4-carboxylate:
Figure imgf000033_0001
The title compound was prepared by using methyl 1 -chloroisoquinolin-4- carboxylate (lntermediate-6) and 4-methoxyaniline by following a procedure similar to that described in lntermediate-7a.
Intermediate-7i: Methyl 1 -((3-chloro-4-methylphenyl)amino)isoquinolin-4-carboxylate:
Figure imgf000033_0002
The title compound was prepared by using methyl 1 -chloroisoquinolin-4- carboxylate (lntermediate-6) and 3-chloro-4-methylaniline by following a procedure similar to that described in lntermediate-7a.
Intermediate-7j: Methyl 1 -((2,3-difluorophenyl)amino)isoquinolin-4-carboxylate:
Figure imgf000033_0003
The title compound was prepared by using methyl 1 -chloroisoquinolin-4- carboxylate (lntermediate-6) and 2,3-difluoroaniline by following a procedure similar to that described in lntermediate-7a.
Intermediated: Methyl 1 -((3-(trifluoromethyl)phenyl)amino)isoquinolin-4- carboxylate:
Figure imgf000034_0001
The title compound was prepared by using methyl 1 -chloroisoquinolin-4- carboxylate (lntermediate-6) and 3-(trifluoromethyl)aniline by following a procedure similar to that described in lntermediate-7a.
lntermediate-7l: Methyl 1 -((3-chloro-2-fluorophenyl)amino)isoquinolin-4-carboxylate:
Figure imgf000034_0002
The title compound was prepared by using methyl 1 -chloroisoquinolin-4- carboxylate (lntermediate-6) and 3-chloro-2-fluoroaniline by following a procedure similar to that described in lntermediate-7a.
Intermediate-7m: Methyl 1 -((2-fluoro-3-(trifluoromethyl)phenyl)amino)isoquinolin-4- carboxylate:
Figure imgf000034_0003
The title compound was prepared by using methyl 1 -chloroisoquinolin-4- carboxylate (lntermediate-6) and 2-fluoro-3-(trifluoromethyl)aniline by following a procedure similar to that described in lntermediate-7a.
Intermedite-8a: 1 -((3-Chlorophenyl)amino)isoquinolin-4-carboxylic acid:
Figure imgf000035_0001
To a stirred solution of lntermediate-7a (1 equiv) in MeOH was added, aqueous KOH solution (2 equiv) and the reaction mixture was refluxed for 2 h. It was then cooled to room temperature and the solvent was removed. It was washed with Et2O followed by 1 N HCI and extracted with EtOAc. The organic layer was separated, dried over Na2SO4, filtered, and concentrated to give the title compound. Intermedite-8b: 1 -((3-Fluorophenyl)amino)isoquinolin-4-carboxylic acid:
The title compound was prepared by carrying out basic hydrolysis of lntermediate-7b by following a procedure similar to that described in Intermediate- 8a.
Intermedite-8c: 1 -((3,5-Difluorophenyl)amino)isoquinolin-4-carboxylic acid:
Figure imgf000035_0003
The title compound was prepared by carrying out basic hydrolysis of lntermediate-7c by following a procedure similar to that described in Intermediate- 8a. lntermediate-8d: 1 -((2,4-Difluorophenyl)amino)isoquinolin-4-carboxylic acid:
Figure imgf000036_0001
The title compound was prepared by carrying out basic hydrolysis of lntermediate-7d by following a procedure similar to that described in Intermediate- 8a.
Intermediate-8e: 1 -(4-Fluorophenoxy)isoquinolin-4-carboxylic acid:
Figure imgf000036_0002
The title compound was prepared by carrying out basic hydrolysis of lntermediate-7e by following a procedure similar to that described in Intermediate- 8a.
Intermediate-8f: 1 -(3,4-Difluorophenoxy)isoquinolin-4-carboxylic acid:
Figure imgf000036_0003
The title compound was prepared by carrying out basic hydrolysis of Intermediated by following a procedure similar to that described in lntermediate-8a. Intermediate-8g: 1 -((2-Methoxyphenyl)amino)isoquinolin-4-carboxylic acid:
Figure imgf000037_0001
The title compound was prepared by carrying out basic hydrolysis of lntermediate-7g by following a procedure similar to that described in Intermediate- 8a.
lntermediate-8h: 1 -((4-Methoxyphenyl)amino)isoquinolin-4-carboxylic acid:
Figure imgf000037_0002
The title compound was prepared by carrying out basic hydrolysis of lntermediate-6h by following a procedure similar to that described in Intermediate- 8a.
lntermediate-8i: 1 -((3-Chloro-4-methylphenyl)amino)isoquinolin-4-carboxylic acid:
Figure imgf000037_0003
The title compound was prepared by carrying out basic hydrolysis of lntermediate-7i by following a procedure similar to that described in lntermediate-8a. Intermediate-8j: 1 -((2,3-Difluorophenyl)amino)isoquinolin-4-carboxylic acid:
Figure imgf000038_0001
The title compound was prepared by carrying out basic hydrolysis of lntermediate-7j by following a procedure similar to that described in lntermediate-8a. Intermediate-8k: 1 -((3-(Trifluoromethyl)phenyl)amino)isoquinolin-4-carboxylic acid:
Figure imgf000038_0002
The title compound was prepared by carrying out basic hydrolysis of lntermediate-7k by following a procedure similar to that described in Intermediate- 8a.
Intermediate-8I: 1 -((3-Chloro-2-fluorophenyl)amino)isoquinolin-4-carboxylic acid:
Figure imgf000038_0003
The title compound was prepared by carrying out basic hydrolysis of lntermediate-71 by following a procedure similar to that described in lntermediate-8a. Intermediate-8m: 1 -((2-Fluoro-3-(trifluoromethyl)phenyl)amino)isoquinolin-4- carboxylic acid:
Figure imgf000039_0001
The title compound was prepared by carrying out basic hydrolysis of lntermediate-7m by following a procedure similar to that described in Intermediate- 8a.
Examples
The present invention is further illustrated by the following examples, which are not to be construed in any way as imposing limitations upon the scope of this disclosure, but rather are intended to be illustrative only.
Example-1
(1 -((3-Chlorophenyl)amino)isoquinolin-4-yl)(morpholino)methanone
Figure imgf000039_0002
1 -((3-Chlorophenyl)amino)isoquinolin-4-carboxylic acid lntermediate-8a (1 equiv) was dissolved in CH2CI2 and to this, EDCI (1 .5 equiv), HOBt (1 .5 equiv) and DIPEA (2 equiv) were added at room temperature under nitrogen atmosphere. The mixture was stirred for 10 min then morpholine (1 .5 equiv) was added to the reaction mixture and the reaction mixture was stirred at room temperature for overnight. After completion (TLC), it was diluted with CH2CI2 (100 ml_) and washed with water. The organic layer was then separated, dried over Na2S04, filtered, and concentrated. The crude product obtained was purified by flash column chromatography to give the title compound; 1H NMR (400 MHz, CDCI3)□ 3.4 (bs, 2H), 3.59 (bs, 2H), 3.83 (bs, 2H), 3.92 (bs, 2H), 7.06-7.09 (m, 1H), 7.28-7.32 (m, 2H), 7.50-7.53 (m, 1H), 7.6-7.64 (m, 1H), 7.71-7.75 (m, 1H), 7.86 (s, 1H), 7.88 (m, 1H), 7.95-7.97 (d, 1H, J= 8.4 Hz), 8.08 (s, 1H); MS m/z 368 (M+1)v
Example-2
1-((3-Chlorophenyl)amino)-/V-((tetrahydro-2--pyran-4-yl)methyl)isoquinolin-4- carboxamide
Figure imgf000040_0001
The title compound was prepared by using lntermediate-8a and (tetrahydro- 2H-pyran-4-yl)methanamine by following the similar procedure as described in Example-1; 1H NMR (400 MHz, CD3OD)□ 1.35-1.45 (m, 2H), 1.75-1.8 (m, 2H), 1.9- 2.0 (m, 1H), 3.36 (d, 2H, J= 7.2 Hz), 3.43-3.5 (m, 2H), 3.99-4.02 (m, 2H), 7.08-7.11 (m, 1H), 7.32-7.36 (t, 1H), 7.62-7.7 (m, 2H), 7.75-7.82 (m, 1H), 7.95 (s, 1H), 8.19 (s, 1H), 8.3 (d, 1H, J= 8.4 Hz), 8.42 (d, 1H, J= 8.4 Hz); MS m/z 396 (Μ+1)τ
Example-3
/V-(ieri-Butyl)-1-((3-chlorophenyl)amino)isoquinolin-4-carboxamide
Figure imgf000040_0002
The title compound was prepared by using lntermediate-8a and tert- butylamine by following the similar procedure as described in Example-1; 1H NMR (400 MHz, CDCI3) □ 1.52 (s, 9H), 5.86 (bs, 1H), 7.06-7.09 (m, 1H), 7.27-7.31 (m, 2H), 7.48-7.51 (m, 1H), 7.58-7.63 (m, 1H), 7.71-7.75 (m, 1H), 7.91 (s, 1H), 7.93 (m, 1H), 8.27 (s, 1H), 8.46 (d, 1H, J= 8.4 Hz); MS m/z 354 (M+1).
Example-4
1-((3-Chlorophenyl)amino)-A/-(pyridin-4-ylmethyl)isoquinolin-4-carboxamide
Figure imgf000041_0001
The title compound was prepared by using lntermediate-8a and pyridin-4- ylmethanamine by following the similar procedure as described in Example-1; 1H NMR (400 MHz, CD3OD)□ 4.71 (s, 2H), 7.1-7.12 (m, 1H), 7.35 (t, 1H), 7.51 (d, 2H, J= 6.0 Hz), 7.63-7.72 (m, 2H), 7.79-7.83 (m, 1H), 7.97 (s, 1H), 8.33 (s, 1H), 8.37 (d, 1H, J= 8.0 Hz), 8.45 (d, 1H, J= 8.4 Hz), 8.53-8.55 (m, 2H); MS m/z 389 (M+1),
Example-5
(1-((3-Fluorophenyl)amino)isoquinolin-4-yl)(morpholino)methanone
Figure imgf000041_0002
The title compound was prepared by using lntermediate-8b and morpholine by following the similar procedure as described in Example-1; 1H NMR (400 MHz, CDCI3) □ 3.41 (bs, 2H), 3.59 (bs, 2H), 3.83 (bs, 2H), 3.92 (bs, 2H), 6.77-6.82 (m, 1H), 7.28-7.35 (m, 3H), 7.61-7.65 (m, 1H), 7.71-7.78 (m, 2H), 7.88 (d, 1H, J Hz), 7.97 (d, 1H, J= 8.4 Hz), 8.09 (s, 1H); MS m/z352 (M+1).
Example-6
(1-((3-Fluorophenyl)amino)isoquinolin-4-yl)(piperidin-1-yl)methanone
Figure imgf000042_0001
The title compound was prepared by using lntermediate-8b and piperidine by following the similar procedure as described in Example-1 ; 1H NMR (400 MHz, CDCI3)□ 1.46 (bs, 2H), 1.71 (m, 4H), 3.3 (bs, 2H), 3.88 (bs, 2H), 6.75-6.79 (m, 1H), 7.29-7.31 (m, 2H), 7.34 (bs, 1H), 7.59-7.61 (m, 1H), 7.671-7.76 (m, 2H), 7.84 (d, 1H, J= 8.0 Hz), 7.95 (d, 1H, J= 8.4 Hz), 8.05 (s, 1H); MS m/z 350 (M+1).
Example-7
Azetidin-1-yl(1-((3-fluorophenyl)amino)isoquinolin-4-yl)methanone
Figure imgf000042_0002
The title compound was prepared by using lntermediate-8b and azetidine by following the similar procedure as described in Example-1; 1H NMR (400 MHz, CD3OD) □ 2.34-2.42 (m, 2H), 4.17 (t, 2H), 4.3 (t, 2H), 6.82-6.85 (m, 1H), 7.33-7.38 (m, 1H), 7.49-7.52 (m, 1H), 7.67-7.71 (m, 1H), 7.75-7.84 (m, 2H), 8.11-8.13 (m, 2H), 8.45 (d, 1H, J= 8.0 Hz); MS m/z 322 (M+1).
Example-8
1-((3-Fluorophenyl)amino)-/V-(piperidin-1-yl)isoquinolin-4-carboxamide
Figure imgf000043_0001
The title compound was prepared by using lntermediate-8b and 1- aminopiperidine by following the exact method as described in Example-1; 1H NMR (400 MHz, CD3OD) □ 1.5 (bs, 2H), 1.81 (m, 4H), 2.92 (bs, 4H), 6.81-6.85 (m, 1H), 7.33-7.39 (m, 1H), 7.48-7.51 (m, 1H), 7.67-7.82 (m, 3H), 8.16 (s, 1H), 8.27 (d, 1H, J = 8.8 Hz), 8.44 (d, 1H, J= 8.4 Hz); MS m/z 365 (M+1).
Example-9
(1-((3,5-Difluorophenyl)amino)isoquinolin-4-yl)(morpholino)methanone
Figure imgf000043_0002
The title compound was prepared by using lntermediate-8c and morpholine by following the similar procedure as described in Example-1; 1H NMR (400 MHz, CDCI3) □ 3.38 (bs, 2H), 3.59 (bs, 2H), 3.85 (bs, 2H), 3.953 (bs, 2H), 6.49-6.54 (m, 1H), 7.36-7.39 (m, 2H), 7.53-7.57 (m, 1H), 7.63-7.67 (m, 1H), 7.68 (bs, 1H), 7.76 (d, 1H, J= 7.6 Hz), 7.92 (d, 1H, J= 8.4 Hz), 7.98 (s, 1H); MS m/z370 (M+1).
Example-10
(1-((3,5-Difluorophenyl)amino)isoquinolin-4-yl)(piperidin-1-yl)methan
Figure imgf000044_0001
The title compound was prepared by using lntermediate-8c and piperidine by following the similar procedure as described in Example-1 ; 1H NMR (400 MHz, CDCI3)□ 1.45 (bs, 2H), 1.7-1.77 (m, 4H), 3.29 (bs, 2H), 3.89 (bs, 2H), 6.49-6.52 (m, 1H), 7.35-7.41 (m, 2H), 7.47-7.51 (m, 1H), 7.55-7.59 (m, 1H), 7.67 (d, 1H, J = 7.6 Hz), 7.89-7.91 (m, 3H); MS m/z368 (M+1).
Example-11
Azetidin-1-yl(1-((3,5-difluorophenyl)amino)isoquinolin-4-yl)methanone
Figure imgf000044_0002
The title compound was prepared by using lntermediate-8c and azetidine by following the similar procedure as described in Example-1; 1H NMR (400 MHz, CDCI3) □ 2.33-2.4 (m, 2H), 4.11 (t, 2H), 4.32 (t, 2H), 6.49-6.54 (m, 1H), 7.39-7.42 (m, 2H), 7.51-7.55 (m, 1H), 7.64-7.68 (m, 1H), 7.72 (bs, 1H), 7.92 (d, 1H, J= 8.4 Hz), 8.1 (s, 1H), 8.19 (d, 1H, J= 8.4 Hz); MS m/z 340 (M+1).
Example-12
1 -((3,5-Difluorophenyl)amino)-N-(piperidin-1 -yl)isoquinoline-4-carboxamide
Figure imgf000045_0001
The title compound was prepared by using lntermediate-8c and 1- aminopiperidine by following the similar procedure as described in Example-1; 1H NMR (400 MHz, CD3OD)□ 1.77-1.83 (m, 4H), 2.92 (bs, 4H), 4.64 (s, 1H), 5.79-5.86 (m, 1H), 6.59-6.64 (m, 1H), 7.58 (dd, 2H), 7.68-7.72 (m, 1H), 7.79-7.83 (m, 1H), 8.22 (s, 1H), 8.27 (d, 1H), 8.44 (d, 1H); MS m/z 383 (M+1).
Example-13
(1-((2,4-Difluorophenyl)amino)isoquinolin-4-yl)(morpholino)methanone
Figure imgf000045_0002
The title compound was prepared by using lntermediate-8d and morpholine by following the similar procedure as described in Example-1; 1H NMR (400 MHz, CDCI3) □ 3.39 (bs, 2H), 3.58 (bs, 2H), 3.83-3.92 (m, 4H), 6.93-6.97 (m, 2H), 7.34 (bs, 1H), 7.63-7.66 (m, 1H), 7.73-7.77 (m, 1H), 7.88 (d, 1H, J= 8.0 Hz), 7.99 (d, 1H, J= 8.4 Hz), 8.06 (s, 1H), 8.42-8.48 (m, 1H); MS m/z 370 (M+1).
Example-14
-((2,4-Difluorophenyl)amino)isoquinolin-4-yl)(piperidin-1-yl)methanon
Figure imgf000046_0001
The title compound was prepared by using lntermediate-8d and piperidine by following the similar procedure as described in Example-1 ; 1H NMR (400 MHz, CDCI3)□ 1.46 (bs, 2H), 1.69 (m, 4H), 3.3 (bs, 2H), 3.85 (bs, 2H), 6.93-6.97 (m, 2H), 7.31 (bs, 1H), 7.61-7.65 (m, 1H), 7.71-7.74 (m, 1H), 7.86 (d, 1H, J=8.0 Hz), 7.96 (d, 1H, J= 8.4 Hz), 8.05 (s, 1H), 8.44-8.49 (m, 1H); MS m/z 368 (M+1).
Example-15
Azetidin-1-yl(1-((2,4-difluorophenyl)amino)isoquinolin-4-yl)methanone
Figure imgf000046_0002
The title compound was prepared by using lntermediate-8d and azetidine by following the similar procedure as described in Example-1; 1H NMR (400 MHz, CDCI3) □ 2.29-2.39 (m, 2H), 4.11 (t, 2H), 4.3 (t, 2H), 6.92-6.97 (m, 2H), 7.37 (bs, 1H), 7.61-7.65 (m, 1H), 7.73-7.77 (m, 1H), 7.96 (d, 1H, J= 8.8 Hz), 8.15 (s, 1H), 8.29 (d, 1H, J= 8.4 Hz), 8.43-8.47 (m, 1H); MS m/z 340 (M+1).
Example-16
1-((2,4-Difluorophenyl)amino)-/V-morpholinoisoquinolin-4-carboxamide
Figure imgf000047_0001
The title compound was prepared by using lntermediate-8d and 4- aminomorpholine by following the similar procedure as described in Example-1; 1H NMR (400 MHz, CDCI3) □ 3.03 (bs, 4H), 3.97 (bs, 4H), 6.76 (bs, 1H), 6.95-7.02 (m, 2H), 7.44 (bs, 1H), 7.68 (t, 1H), 7.79 (t, 1H), 7.99 (d, 1H, J= 8.8 Hz), 8.27 (s, 1H), 8.42-8.49 (m, 2H); MS m/z 385 (M+1).
Example-17
(1-(4-Fluorophenoxy)isoquinolin- -yl)(morpholino)methanone
Figure imgf000047_0002
The title compound was prepared by using lntermediate-8e and morpholine by following the similar procedure as described in Example-1; 1H NMR (400 MHz, CDCI3) □ 3.33 (bs, 2H), 3.55 (bs, 2H), 3.82 (bs, 2H), 3.92 (bs, 2H), 7.14 -7.16 (m, 2H), 7.19-7.22 (m, 2H), 7.67-7.71 (m, 1H), 7.78-7.87 (m, 2H), 7.99 (s, 1H), 8.48 (d, 1H); MS m/z 353 (M+1).
Example-18
(1-(4-Fluorophenoxy)isoquinolin- -yl)(piperidin-1-yl)methanone
Figure imgf000048_0001
The title compound was prepared by using lntermediate-8e and piperidine by following the similar procedure as described in Example-1; 1H NMR (400 MHz, CDCI3) □ 1.40-1.44 (m, 2H), 1.60-1.73 (m, 4H), 3.26 (bs, 2H), 3.84 (bs, 2H), 7.13- 7.16 (m, 2H), 7.19-7.25 (m, 2H), 7.65-7.69 (m, 2H), 7.76-7.80 (m, 1H), 7.84-7.86 (m, 1H), 8.48 (d, 1H); MS m/z 351 (M+1).
Example-19
(1-(4-Fluorophenoxy)isoquinolin- -yl)(4-phenylpiperidin-1-yl)methanone
Figure imgf000048_0002
The title compound was prepared by using lntermediate-8e and 4- phenylpiperidine by following the similar procedure as described in Example-1; 1H NMR (400 MHz, CDCI3) □ 1.74-1.85 (m, 3H), 1.87-2.04 (m, 1H), 2.76-2.81 (m, 1H), 2.93-2.96 (m, 1H), 2.99-3.13 (m, 1H), 3.71 (d, 1H), 4.99-5.1 (m, 1H), 7.17-7.26 (m, 6H), 7.30-7.34 (m, 2H), 7.69 (t, 1H), 7.71-7.83 (m, 2H), 7.93-8.01 (m, 2H), 8.48 (d, 1H); MS m/z 427 (M+1).
Example-20
(1-(3,4-Difluorophenoxy)isoquinolin-4-yl)(morpholino)methanone
Figure imgf000049_0001
The title compound was prepared by using lntermediate-8f and morpholine by following the similar procedure as described in Example-1 ; 1H NMR (400 MHz, CDCI3)□ 3.3 (bs, 2H), 3.56 (bs, 2H), 3.84 (bs, 2H), 3.93 (bs, 2H), 6.98-7.02 (m,1H), 7.10-7.13 (m,1H), 7.14-7.28 (m,1H), 7.69-7.32 (m,1H), 7.80-7.84 (m,2H), 7.93 (s,1H), 8.45 (d, 1H); MS m/z 371 (M+1).
Example-21
(1-(3,4-Difluorophenoxy)isoquinolin-4-yl)(piperidin-1-yl)methanone
Figure imgf000049_0002
The title compound was prepared by using lntermediate-8f and piperidine by following the similar procedure as described in Example-1; 1H NMR (400 MHz, CDCI3)□ 1.45 (bs, 2H), 1.71-1.74 (m, 4H), 3.26 (bs, 2H), 3.85 (bs, 2H), 7.0-7.01 (m, 1H), 7.11-7.13 (m, 1H), 7.14 (s, 1H), 7.67-7.69 (m, 1H), 7.69-7.7 (m, 1H), 7.71 (d, 1H), 7.77 (d, 1H), 8.43 (s, 1H); MS m/z 369 (M+1).
Example-22
(1-(3,4-Difluorophenoxy)isoquinolin-4-yl)(4-phenylpiperidin-1-yl)methanon
Figure imgf000050_0001
The title compound was prepared by using lntermediate-8f and 4- phenylpiperidine by following the similar procedure as described in Example-1; 1H NMR (400 MHz, CDCI3)□ 1.74-1.77 (m, 3H), 2.05 (bs, 1H), 2.82 (t, 1H), 2.93 (t, 1H), 2.99-3.14 (m, 1H), 3.71 (d, 1H), 4.99-5.09 (m, 1H), 7.14-7.15 (m, 2H), 7.16-7.18 (m, 1H), 7.20-7.25 (m, 3H), 7.30-7.33 (m, 2H), 7.69 (t, 1H), 7.74-8.05 (m, 3H), 8.5 (s, 1H); MS m/z 445 (M+1).
Example-23
(1-((2,3-Difluorophenyl)amino)isoquinolin-4-yl)(1 ,1-
Figure imgf000050_0002
The title compound was prepared by using Intermediate-^ and 1,1- dioxidothio morpholine by following the similar procedure as described in Example-1 ; 1H NMR (400 MHz, CDCI3) □ 3.05-3.08 (m, 4H), 4.01-4.32 (m, 4H), 6.93-6.97 (m, 1H), 7.13-7.19 (m, 1H), 7.54-7.58 (m, 1H), 7.71-7.88 (m, 3H), 8.05-8.08 (m, 1H), 8.15 (s, 1H), 8.31-8.34 (m, 1H); MS m/z418 (M+1).
Example-24
(1 ,1-Dioxidothiomorpholino)(1-((3-(trifluoromethyl)phenyl)amino)isoquinolin-4-yl) methanone
Figure imgf000051_0001
The title compound was prepared by using lntermediate-8k and 1,1- dioxidothio morpholine by following the similar procedure as described in Example-1 ; 1H NMR (400 MHz, CDCI3)□ 3.09-3.19 (m, 4H), 4.04-4.17 (m, 4H), 7.40 (d, J = 8.0 Hz, 1H), 7.49 (s, 1H), 7.67-7.71 (m, 1H), 7.78-7.85 (m, 2H), 7.94-8.06 (m, 3H), 8.13 (s, 1H); MS m/z 450 (M+1).
Example-25
(1 ,1-Dioxidothiomorpholino)(1-((2-fluoro-3-(trifluoromethyl)phenyl)amino)isoquinolin- 4-yl)methanone
Figure imgf000052_0001
The title compound was prepared by using lntermediate-8m and 1,1- dioxidothio morpholine by following the similar procedure as described in Example-1 ; 1H NMR (400 MHz, CDCI3)□ 3.06-3.18 (brs, 4H), 4.0-4.36 (brs, 4H), 7.28-7.34 (m, 2H), 7.54-7.88 (m, 4H), 8.07 (d, J= 8.0 Hz, 1H), 8.15 (s, 1H), 8.86-8.9 (m, 1H); MS m/z 468 (M+1).
Example-26
6-Oxa-3-azabicyclo[3.1.1 ]heptan-3-yl(1 -((3- (trifluoromethyl)phenyl)amino)isoquinolin-4-yl) methanone
Figure imgf000052_0002
The title compound was prepared by using lntermediate-8k and 6-oxa-3- azabicyclo [3.1.1]heptane by following the similar procedure as described in Example-1; 1H NMR (400 MHz, CDCI3)□ 1.94-1.96 (m, 1H), 3.26-3.31 (m, 1H), 3.46- 3.50 (m, 1H), 3.76-3.79 (m, 1H), 3.96-4.0 (m, 1H), 4.31-4.34 (m, 1H), 4.47-4.48 (m, 1H), 4.79-4.8 (m, 1H), 7.35 (d, 1H, J= 8.0 Hz), 7.50 (t, 1H, J= 8.0 Hz), 7.58-7.62 (m, 2H), 7.67-7.71 (m, 1H), 7.78 (d, 1H, J= 8.0 Hz), 7.95-8.04 (m, 3H), 8.09 (s, 1H); MS m/z 414 (M+1).
Example-27
6-Oxa-3-azabicyclo[3.1.1 ]heptan-3-yl(1 -((3-chloro-2-fluorophenyl)amino)isoquinolin- 4-yl) methanone
Figure imgf000053_0001
The title compound was prepared by using lntermediate-8l and 6-oxa-3- azabicyclo[3.1.1] heptane by following the similar procedure as described in Example-1; 1H NMR (400 MHz, CDCI3) □ 1.94-1.96 (m, 1H), 3.26-3.31 (m, 1H), 3.44-3.52 (m, 1H), 3.76-3.79 (m, 1H), 3.96-3.99 (m, 1H), 4.31-4.34 (m, 1H), 4.47- 4.48 (m, 1H), 4.79-4.80 (m, 1H), 7.01-7.18 (m, 2H), 7.54-7.56 (brs, 1H), 7.70 (t, 1H, J= 8.0 Hz), 7.78 (t, 1H, J= 7.6 HzH), 7.87 (d, 1H, J= 8.0 Hz), 8.04 (d, 1H, J= 8.0 Hz), 8.17 (s, 1H), 8.53-8.56 (m, 1H); MS m/z 398 (M+1).
Example-28
(1 ,1-Dioxidothiomorpholino)(1-((2-fluoro-3-chlorophenyl)amino)isoquinolin-4-yl) methanone
Figure imgf000054_0001
This compound was prepared by using lntermediate-81 and 1 ,1 -dioxidothio morpholine by following the similar procedure as described in Example-1 ; 1 H NMR (400 MHz, CDCI3) D2.90-2.97 (brs, 4H), 4.03-4.15 (brs, 4H), 7.12-7.23 (m, 2H), 7.61 (brs, 1 H), 7.73 (t, 1 H, J = 6.8 Hz), 7.80-7.87 (m, 2H), 8.05 (d, 1 H, J = 8.0 Hz), 8.14 (s, 1 H), 8.50-8.53 (m, 1 H); MS m/z 434 (M+1 ).
Pharmacological activity
Certain illustrative compounds within the scope of the invention are screened for CB2 activity according to the procedure given below. The screening of the compounds may also be carried by other methods and procedures known to skilled in the art.
In-vitro assay method for determination of cAMP in functional hCB?-CHO stable cells: Recombinant CHO-hCB2 cells (procured from Perkin Elmer Inc. USA) were propagated and maintained in Ham's F-12 complete medium containing 10% heat inactivated FBS (Sigma.UK) and 1 x penstrep. For assay, 0.1 x106 to 1 .0 x106 CHO- hCB2 cells were seeded in T-25 flask and grown to mid-log phase in culture media without antibiotics for 2-3 days. On the day of assay cell monolayer was washed twice with PBS (pH.7.4) and then cells were detached with PBS-EDTA, centrifuged and resuspended in assay buffer (KRBG containing: 1 15 mM NaCI, 5 mM KCI, 24 mM NaHCOs, 10 mM Glucose, 1 mM MgCI2, 2.5 mM CaCI2, 10 mM HEPES, 1 mM IBMX and 0.1 - 0.5 g/l BSA). The test is performed in 96 ½ area black well plates. For agonist testing, 20 μΙ cells/well were mixed with 20 μΙ of sample and 10 μΙ of forskolin (with final concentration of 10 μΜ) and incubated for 20 to 40 min at room temperature in incubator. The plate was then processed for the cAMP determination using cAMP Femto-2 HTRF kit (Cisbio, Germany) as per the manual. 25 μΙ each of D2 and cryptate (prepared in lysis buffer) was added to the plate and incubated for additional 1 h followed by reading in FeraStar FS (BMG Labtech, Germany) with HTRF settings (Excitation/Emission filter: 665/620 nm). cAMP calibrator/standards were added in the plate with range of 70 nM to 0.01 nM and 4-parameter curve fit (based on DF values) was used for calculation of cAMP concentration of sample wells. For calculation of cAMP % activity, vehicle control (0.4% v/v DMSO) was set to 0% and forskolin control wells as 100%.
Through the use of the above described assays compounds were found to exhibit agonistic or antagonistic activity, to be particularly well suited for the treatment of the diseases or disorders as described herein above.
The concentration of compound required to stimulate a half-maximal response (EC5o) was determined using the GraphPad Prism software (version 5).
The compounds prepared were tested using the above assay procedure and the results obtained are given below. The EC50 (nM) values of the compounds are set forth in Table-1 wherein "A" refers to an EC50 value of less than 10 nM and "B" refers to an EC50 value in range of 10.01 to 1000 nM.
Activity data has been given in Table-1 for representative compounds. Table-1 :
Figure imgf000056_0001
Thus, certain compounds of the present invention are shown to have activity against CB2 receptors. ln-vitro assay method for determination of cAMP in functional hCB HEK stable cells: Recombinant hCB1 -HEK cells (clone 8) overexpressing human CBi was developed in-house by electroporation of hCB1 -pCI neo plasmid in HEK cells as per kits manual (Amaxa. Inc. U.S. A). hCB1 was cloned in pCI neo vector Promega Inc. USA) and sequenced for DNA sequence authenticity with NCBI reference sequence : NM_016083. hCB1 -HEK cells (clone 8) were propagated and maintained in DMEM complete medium supplemented with 10% heat inactivated FBS (Sigma. U.S.A), 400 μ9/ΓτιΙ of G418 and 1 x penstrep. For assay, 0.6 - 1 .0 x106 hCB1 -HEK cells were seeded in T-25 flask and grown to mid-log phase in complete culture medium as mentioned above for 2-3 days. One day prior to assay, cell monolayer was washed once with PBS (pH.7.4) and then serum starved for overnight in DMEM medium containing 0.2% bovine serum albumin (devoid of antibiotics, FBS and penstrep). On the day of assay, cells were trypsinized using 0.025% trypsin-EDTA, centrifuged and resuspended in assay buffer (KRBG containing: 1 15 mM NaCI, 5 mM KCI, 24 mM NaHCO3, 1 0 mM Glucose, 1 mM MgCI2, 2.5 mM CaCI2, 10 mM HEPES, 1 mM IBMX and 0.1 - 0.5 g/l BSA) at a concentration of 2.5 x 105 cells/ml. The test is performed in 96 ½ area black well plates. For agonist testing, 20 μΙ cells/well were mixed with 20 μΙ of compound and 10 μΙ of forskolin (with final concentration of 10 μΜ) and incubated for 40 min at 25°C incubator. The plates were then processed for cAMP determination using cAMP Femto-2 HTRF kit (Cisbio, Germany) as per the kit manual. 25 μΙ each of D2 and cryptate (prepared in lysis buffer) was added to the plate and incubated for additional 1 h followed by reading in FeraStar FS (BMG Labtech, Germany) with HTRF settings (Excitation/Emission filter: 665/620 nm). cAMP calibrator/standards were added in the plate with range of 70 nM to 0.01 nM and 4-parameter curve fit (based on DF values) was used for calculation of cAMP concentration of sample wells. For calculation of compound mediated inhibition of forskolin stimulated % cAMP activity, vehicle control (0.4% v/v DMSO) was set to 0% and forskolin control wells were set as 100%. Assay was validated using CP55940, WIN-55212-2 and SR144528 as reference compounds.
The compounds of the invention have EC50 values in the nano molar (nM) to micro molar range (μΜ).
All patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were so individually denoted.
Although certain embodiments and examples have been described in detail above, those having ordinary skill in the art will clearly understand that many modifications are possible in the embodiments and examples without departing from the teachings thereof. All such modifications are intended to be encompassed within the below claims of the invention.

Claims

1 . A method of treating, managing and/or lessening diseases or disorders, syndromes or conditions associated with the modulation of cannabinoid (CB) receptors in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
Figure imgf000058_0001
wherein,
X is selected from -NRa-, -O- and -S(0)n-;
Y is selected from -C(O)-, -S(0)2-, and -CR5R6-;
R1 ; which may be same or different at each occurrence, is independently selected from halogen, cyano, nitro, hydroxy, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkoxy, cycloalkoxy, -C(0)OH, -NRaRb and -C(0)NRaRb;
R2 is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
R3 is selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; or
R2 and R3, together with the nitrogen atom to which they are attached, may form a substituted or an unsubstituted 3 to 14 membered heterocyclic ring; or
R2 and R3, together with the nitrogen atom to which they are attached, may form a substituted or an unsubstituted 5 to 14 membered heteroaryl ring; with the proviso that when X is NH and R4 is m-(trifluoromethyl)phenyl, R2 and R3 do not together form a morpholine ring; R4 is selected from cycloalkyi, aryl, heteroaryl and heterocyclyl;
R5 and R6, which may be same or different, are independently selected from hydrogen, alkyl, and haloalkyi;
Ra and Rb, which may be same or different at each occurrence, are independently selected from hydrogen, alkyl, haloalkyi, acyl and cycloalkyi; or Ra and Rb, together with the nitrogen atom to which they are attached, may form a substituted or unsubstituted 3 to 14 membered heteroaryl or heterocyclic ring;
'm' is an integer ranging from 0 to 3, both inclusive;
'n' is an integer ranging from 0 to 2, both inclusive; and
wherein alkyl, haloalkyi, hydroxyalkyl, alkenyl, alkynyl, acyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, cycloalkyi, cycloalkoxy, cycloalkylalkyl, aryl, arylalkyi, heteroaryl, heteroarylalkyi, heterocyclyl, (heterocyclic ring) heterocyclylalkyi wherever they occur may optionally be substituted with one or more substituents independently selected from hydroxy, halo, cyano, nitro, oxo (=0), thio (=S), alkyl, haloalkyi, alkenyl, alkynyl, aryl, arylalkyi, cycloalkyi, cycloalkylalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyi, heteroarylalkyi, -C(0)ORx, -C(0)Rx, - C(S)RX, -C(0)NRxRy, -NRxC(0)NRyRz, -N(Rx)S(0)Ry, -N(Rx)S(0)2Ry, -NRxRy, - NRxC(0) Ry, -NRxC(S)Ry, -NRxC(S)NRyRz, -S(0)2NRxRy, -ORx, -OC(0)Rx, - OC(0)NRxRy, -RxC(0)ORy, -RxC(0)NRyRz, -RxC(0)Ry, -SRX, and -S(0)2Rx; and wherein at each occurrence, Rx, Ry and Rz are independently selected from hydrogen, alkyl, haloalkyi, alkenyl, alkynyl, aryl, arylalkyi, cycloalkyi, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyi ring and heteroarylalkyi;
or a pharmaceutically acceptable salt thereof.
2. The method of treating of claim 1 , comprises administering to the subject a therapeutically effective amount of a compound having the Formula (II):
Figure imgf000060_0001
wherein,
Figure imgf000060_0002
R7, which may be same or different at each occurrence, is independently selected from halogen, cyano, nitro, hydroxy, alkyl, haloalkyi, hydroxyalkyl, cycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, -C(0)OH, -NRaRb and -C(0)NRaRb;
R2, R3, Ra, and Rb are as defined in claim 1 ; and
'p' is an integer ranging from 0 to 4, both inclusive;
or its pharmaceutically acceptable salt thereof.
3. The method of treating of claim 1 , comprising administering to the subject a therapeutically effective amount of a compound having the Formula (III):
Figure imgf000060_0003
wherein,
R7, which may be same or different at each occurrence, is independently selected from halogen, cyano, nitro, hydroxy, alkyl, haloalkyi, hydroxyalkyl, cycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, -C(0)OH, -NRaRb and -C(0)NRaRb;
W is CR8R9, O, or S(0)2; R8 and R9 are independently selected from hydrogen, halogen, cyano, hydroxy, alkyl, haloalkyl, hydroxyalkyl, cycloalkyi, alkoxy, haloalkoxy, cycloalkoxy, aryl, heteroaryl, heterocyclyl, -C(0)OH, -NRaRb and - C(0)NRaRb;
Ra and Rb are as defined in claim 1 ; and
'p' is an integer ranging from 0 to 4, both inclusive;
or its pharmaceutically acceptable salt thereof.
4. The method of treating of claim 1 , comprising administering to the subject a therapeutically effective amount of the compound of Formula (I), wherein X of Formula (I) is -NRa- or -O- wherein Ra is hydrogen.
5. The method of treating of claim 1 , comprising administering to the subject a therapeutically effective amount of the compound of Formula (I), wherein R4 of Formula (I) is a substituted or an unsubstituted aryl, and wherein the substituents on aryl may be one or more, same or different and are independently selected from halogen, alkyl, haloalkyl, alkoxy and haloalkoxy.
6. The method of treating of claim 1 , comprising administering to the subject a therapeutically effective amount of the compound of Formula (I), wherein R2 in Formula (I) is hydrogen or alkyl.
7. The method of treating of claim 1 , comprising administering to the subject a therapeutically effective amount of the compound of Formula (I), wherein R3 of Formula (I) is selected from alkyl, cycloalkyi, heteroaryl, heteroarylalkyi, heterocyclyl and heterocyclylalkyl.
8. The method of treating of claim 1 , comprising administering to the subject a therapeutically effective amount of the compound of Formula (I), wherein R2 and R3 of Formula (I), together with the nitrogen atom to which they are attached, may form a substituted or an unsubstituted 3 to 12 membered heterocyclic ring.
9. A compound having the Formula (I I I):
Figure imgf000062_0001
wherein,
R7, which may be same or different at each occurrence, is independently selected from halogen, cyano, nitro, hydroxy, alkyl, haloalkyi, hydroxyalkyl, cycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, -C(0)OH, -NRaRb and -C(0)NRaRb;
W is CR8R9, O, or S(0)2;
R8 and R9 are independently selected from hydrogen, halogen, cyano, hydroxy, alkyl, haloalkyi, hydroxyalkyl, cycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, heteroaryl, heterocyclyl, -NRaRb and -C(0)NRaRb;
with the proviso that:
when W is O then R7 is not p-methoxy;
when W is CH2 then R7 is not p-methyl or o-methoxy;
when W is CH(alkyl) or CH(benzyl) then R7 is not p-methyl, o- methoxy, p-methoxy or p-halogen;
Ra and Rb are as defined in claim 1 ; and
'p' is an integer ranging from 0 to 4;
or its pharmaceutically acceptable salt thereof.
10. A compound selected from:
(1 -((3-Chlorophenyl)amino)isoquinolin-4-yl)(morpholino)methanone;
1 -((3-Chlorophenyl)amino)-/V-((tetrahydro-2 - -pyran-4-yl)methyl)isoquinolin-4- carboxamide;
/V-(ieri-Butyl)-1 -((3-chlorophenyl)amino)isoquinolin-4-carboxamide;
1 -((3-Chlorophenyl)amino)-/V-(pyridin-4-ylmethyl)isoquinolin-4-carboxamide; (1 -((3-Fluorophenyl)amino)isoquinolin-4-yl)(morpholino)methanone;
(1 -((3-Fluorophenyl)amino)isoquinolin-4-yl)(piperidin-1 -yl)methanone;
Azetidin-1 -yl(1 -((3-fluorophenyl)amino)isoquinolin-4-yl)methanone;
1 -((3-Fluorophenyl)amino)-A/-(piperidin-1 -yl)isoquinolin-4-carboxamide;
(1 -((3,5-Difluorophenyl)amino)isoquinolin-4-yl)(morpholino)methanone;
(1 -((3,5-Difluorophenyl)amino)isoquinolin-4-yl)(piperidin-1 -yl)methanone;
Azetidin-1 -yl(1 -((3,5-difluorophenyl)amino)isoquinolin-4-yl)methanone;
1 -((3,5-Difluorophenyl)amino)-A/-(piperidin-1 -yl)isoquinoline-4-carboxamide;
(1 -((2,4-Difluorophenyl)amino)isoquinolin-4-yl)(morpholino)methanone;
(1 -((2,4-Difluorophenyl)amino)isoquinolin-4-yl)(piperidin-1 -yl)methanone;
Azetidin-1 -yl(1 -((2,4-difluorophenyl)amino)isoquinolin-4-yl)methanone;
1 -((2,4-Difluorophenyl)amino)-A/-morpholinoisoquinolin-4-carboxamide;
(1 -(4-Fluorophenoxy)isoquinolin-4-yl)(morpholino)methanone;
(1 -(4-Fluorophenoxy)isoquinolin-4-yl)(piperidin-1 -yl)methanone;
(1 -(4-Fluorophenoxy)isoquinolin-4-yl)(4-phenylpiperidin-1 -yl)methanone;
(1 -(3,4-Difluorophenoxy)isoquinolin-4-yl)(morpholino)methanone;
(1 -(3,4-Difluorophenoxy)isoquinolin-4-yl)(piperidin-1 -yl)methanone;
(1 -(3,4-Difluorophenoxy)isoquinolin-4-yl)(4-phenylpiperidin-1 -yl)methanone;
(1 -((2,3-Difluorophenyl)amino)isoquinolin-4-yl)(1 , 1 - dioxidothiomorpholino)methanone;
(1 , 1 -Dioxidothiomorpholino)(1 -((3-(trifluoromethyl)phenyl)amino)isoquinolin-4-yl) methanone;
(1 , 1 -Dioxidothiomorpholino)(1 -((2-fluoro-3-(trifluoromethyl)phenyl)amino)isoquinolin- 4-yl)methanone;
6-Oxa-3-azabicyclo[3.1 .1 ]heptan-3-yl(1 -((3-
(trifluoromethyl)phenyl)amino)isoquinolin-4-yl) methanone;
6-Oxa-3-azabicyclo[3.1 .1 ]heptan-3-yl(1 -((3-chloro-2-fluorophenyl)amino)isoquinolin- 4-yl) methanone and (1 , 1 -Dioxidothiomorpholino)(1 -((2-fluoro-3-chlorophenyl)amino)isoquinolin-4-yl) methanone
or pharmaceutically acceptable salt thereof.
1 1 . A pharmaceutical composition comprising one or more compounds of
Formula (I)
according to claim 1 , and one or more pharmaceutically acceptable excipients.
12. A method of treating, managing and/or lessening diseases or disorders, syndromes or conditions associated with the modulation of cannabinoid (CB) receptors in a subject in need thereof wherein the method comprises administering to the subject a therapeutically effective amount of a compound of claim 9 or a pharmaceutically acceptable salt thereof.
13. The method of claim 1 , wherein the diseases, disorders, syndromes or conditions associated with the modulation of cannabinoid (CB) receptor are selected from the group consisting of pain or inflammation.
14. The method of claim 13, wherein the pain is neuropathic pain.
15. The method of claim 13, wherein the pain is inflammatory pain.
16. The method of claim 12, wherein the diseases, disorders, syndromes or
conditions
associated with the modulation of cannabinoid (CB) receptor are selected from the group consisting of pain or inflammation.
17. The method of claim 16, wherein the pain is neuropathic pain.
18. The method of claim 16, wherein the pain is inflammatory pain.
19. The method of claim 13, wherein the pain is selected from acute pain,
chronic pain,
visceral pain or nociceptive pain.
20. The method of claim 19, wherein the pain is associated with the group comprising of dental pain, eye pain, ear pain, perioperative, traumatic pain, muscle pain, pain in burned skin, sun burn, trigeminal neuralgia, spasm of the gastrointestinal tract or uterus, colics, back pain, chronic fatigue syndrome, clinical depression, complex regional pain syndrome, myofascial pain syndrome, post-vasectomy pain syndrome, restless leg syndrome, spinal stenosis, chronic pelvic pain, pancreatitis, peptic ulcer, interstitial cystitis, renal colic, angina, dysmenorrhoea, menstruation, gynaecological pain, irritable bowel syndrome (IBS), non-ulcer dyspepsia, non-cardiac chest pain, myocardial ischemia, non-herpetic neuralgia, post herpetic neuralgia, diabetic neuropathy, nerve injury, acquired immune deficiency syndrome (AIDS) related pain, herpes virus infection, head trauma, causalgia, plexus avulsion, neuroma, limb amputation, vasculitis, painful traumatic mononeuropathy, phantom limb pain, painful polyneuropathy, thalamic pain syndrome, post-stroke pain, central nervous system injury, stump pain, repetitive motion pain, pain induced by post mastectomy syndrome, multiple sclerosis, root avulsions, postthoracotomy syndrome, hyperalgesia, allodynia, nerve damage from chronic alcoholism, arthritis pain, osteoarthritis, rheumatoid arthritis, rheumatic disease, teno-synovitis, gout, vulvodynia, myofascial pain (muscular injury, fibromyalgia), tendonitis, juvenile arthritis, spondylitis, gouty arthritis, psoriatic arthritis, muscoskeletal pain, fibromyalgia, sprains and strains, sympathetically maintained pain, myositis, pain associated with migraine, dental pain, systemic lupus erythematosus, central and peripheral pathway mediated pain, bone and joint pain, pain associated with cancer including chemotherapy pain, orofacial pain, somatic pain, sciatica pain, intestinal obstruction pain, coliky pain, myofacial pain, trauma pain, labour pain, brachial plexus avulsion, reflex sympathetic dystrophy, fibromyalgia, phantom limb pain, pain following stroke, thalamic lesions, radiculopathy, migraine pain, menstrual cramps, dermatitis, immunodeficiency, HIV-related neuropathy; familial hemiplegic migraine, conditions associated with cephalic pain, headache (e.g., chronic headache, sinus headache, headache associated with stress, headache with different origins), cardiac pain arising from an ischemic myocardium, pain following stroke, neuropathy secondary to metastatic inflammation, pain due to connective tissue damage, and other forms of neuralgic, neuropathic, and idiopathic pain syndromes.
21 . The method of claim 1 , wherein the diseases, disorders, syndromes or conditions
associated with the modulation of CB receptors are selected from the group consisting of analgesic conditions, healing of wounds and burns, movement disorders, immune disorders (for example autoimmune disorders), respiratory disorders, lung diseases, pruritis, allergic diseases, lung diseases associated with inflammation, pruritis associated with inflammation, allergic diseases associated with inflammation, organ contraction, preanesthetic medication, preoperative medication, muscle spasm, locomotor activity disorders, bone disorders, multiple sclerosis, glaucoma and related intra ocular pressure, cell growth disorders, gastrointestinal disorders, diseases of central nervous system (CNS) erythromyalgia, neurological disorders, neurodegenerative disorders, neuromuscular conditions, and neuroinflammatory pathologies.
22. The method of claim 12, wherein the diseases, disorders, syndromes or conditions
associated with the modulation of CB receptors are selected from the group consisting of analgesic conditions, healing of wounds and burns, movement disorders, immune disorders (for example autoimmune disorders), respiratory disorders, lung diseases, pruritis, allergic diseases, lung diseases associated with inflammation, pruritis associated with inflammation, allergic diseases associated with inflammation, organ contraction, preanesthetic medication, preoperative medication, muscle spasm, locomotor activity disorders, bone disorders, multiple sclerosis, glaucoma and related intra ocular pressure, cell growth disorders, gastrointestinal disorders, diseases of central nervous system (CNS) erythromyalgia, neurological disorders, neurodegenerative disorders, neuromuscular conditions, and neuroinflammatory pathologies.
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