WO2014071044A1 - Substituted 6,7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (pde10a) - Google Patents

Substituted 6,7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (pde10a) Download PDF

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Publication number
WO2014071044A1
WO2014071044A1 PCT/US2013/067821 US2013067821W WO2014071044A1 WO 2014071044 A1 WO2014071044 A1 WO 2014071044A1 US 2013067821 W US2013067821 W US 2013067821W WO 2014071044 A1 WO2014071044 A1 WO 2014071044A1
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Prior art keywords
methyl
dimethoxyisoquinolin
disorder
quinolin
dimethoxy
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PCT/US2013/067821
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French (fr)
Inventor
Bertrand Leblond
Eric Beausoleil
Anne-Sophie Casagrande
Laurent J.R. DESIRE
Matthew P. Pando
John E. Donello
Rong Yang
Thierry Taverne
Cedric Chauvignac
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Allergan, Inc.
Exonhit Therapeutics Sa
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Application filed by Allergan, Inc., Exonhit Therapeutics Sa filed Critical Allergan, Inc.
Publication of WO2014071044A1 publication Critical patent/WO2014071044A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D215/00Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D215/20Oxygen atoms
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/02Heterocyclic 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
    • C07D401/06Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic 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
    • C07D405/02Heterocyclic 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
    • C07D405/06Heterocyclic 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 carbon chain containing only aliphatic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D407/00Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic 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
    • C07D491/02Heterocyclic 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
    • C07D491/04Ortho-condensed systems

Definitions

  • Phosphodiesterases are a class of intracellular enzymes involved in the hydrolysis of the nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphates (cGMP) into their respective nucleotide monophosphates.
  • the cyclic nucleotides cAMP and cGMP are synthesized by adenylyl and guanylyl cyclases, respectively.
  • cAMP and cGMP function as intracellular second messengers regulating a vast array of intracellular processes particularly in neurons of the central nervous system. In neurons, this includes the activation of cAMP and cGMP-dependent kinases and subsequent phosphorylation of proteins involved in acute regulation of synaptic transmission as well as in neuronal
  • cyclic nucleotide signaling is indicated by the molecular diversity of the enzymes involved in the synthesis and degradation of cAMP and cGMP.
  • a principal mechanism for regulating cyclic nucleotide signaling is by phosphodiesterase-catalyzed cyclic nucleotide catabolism.
  • the PDE families are distinguished functionally based on cyclic nucleotide substrate specificity, mechanism(s) of regulation, and sensitivity to inhibitors.
  • PDEs are differentially expressed throughout the organism, including in the central nervous system. As a result of these distinct enzymatic activities and localization, different PDEs' isozymes can serve distinct physiological functions. Furthermore, compounds that can selectively inhibit distinct PDE families or isozymes may offer particular therapeutic effects, fewer side effects, or both.
  • PDE10 is identified as a unique family based on primary amino acid sequence and distinct enzymatic activity. Homology screening of EST databases revealed human PDE10A as the first member of the PDE10 family of PDEs (Fujishige et al., J. Biol. Chem. , 274, 18438- 18445, 1999; Loughney, K. et al., Gene, 234, 109-1 17, 1999). The murine homologue has also been cloned (Soderling, S. et al., Proc. Natl. Acad. Sci. USA, 96, 7071 -7076, 1999) and N- terminal splice variants of both the rat and human genes have been identified (Kotera, J.
  • the mouse PDE10A1 is a 779 amino acid protein that hydrolyzes both cAMP and cGMP to AMP and GMP, respectively.
  • PDE10A also is uniquely localized in mammals relative to other PDE families. mRNA for PDE10 is highly expressed only in testis and brain
  • PDE10 protein (Menniti, F.S., Stick, CA Seeger, T.F., and Ryan, A.M., Immunohistochemical localization of PDE10 in the rat brain, William Harvey Research Conference 'Phosphodiesterase in Health and Disease', Porto, Portugal, Dec. 5-7, 2001 ).
  • PDE10A was shown to be highly expressed in retinal neurons including photoreceptors.
  • the levels of PDE10A transcript and protein display daily rhythms which could be seen in preparations of the whole retina (Wolloscheck T. et al, Brain Res. , 201 1 ,1376, 42-50. Epub 2010 Dec 29).
  • the tissue distribution of PDE10A indicates that PDE10A inhibitors can be used to raise levels of cAMP and/or cGMP within cells that express the PDE10 enzyme, especially neurons that comprise the basal ganglia, and the PDE10A inhibitors of the present invention would therefore be useful in treating a variety of associated neuropsychiatric conditions involving the basal ganglia such as neurological and psychiatric disorders, schizophrenia, bipolar disorder, obsessive compulsive disorder, and the like, and may have the benefit of not possessing unwanted side effects, which are associated with the current therapies on the market.
  • US 2003/0032579 discloses a method for treating certain neurologic and psychiatric disorders with the PDE10A inhibitor papaverine.
  • the method relates to psychotic disorders such as schizophrenia, delusional disorders and drug-induced psychosis; to anxiety disorders such as panic and obsessive-compulsive disorder; and to movement disorders including
  • Parkinson's disease and Huntington's disease Other indications which may be treated using a PDE10A inhibitor are described in WO 20055120514.
  • PDE inhibitors A variety of therapeutic uses for PDE inhibitors has been reported including obtrusive lung disease, allergies, hypertension, angina, congestive heart failure, depression and erectile dysfunction (WO 2001041807, incorporated herein by reference). Furthermore, publications (WO 2005120514, WO 2005012485, Cantin et al., Bioorg. & Med. Chem. Lett, 17, 2869-2873, 2007) suggest that PDE1 OA inhibitors may be useful for treatment of obesity and non-insulin dependent diabetes.
  • WO2012/1 12946 discloses substituted 6,7-dialkoxy-3-isoquinolinol derivatives as inhibitors of phosphodiesterase 10 (PDE10A).
  • WO 201 1 1 10545, WO 201 1051342 disclose respectively imidazo[1 ,2-a]pyrazine derivatives, imidazo[1 ,2- b]pyridazine derivatives PDE10A inhibitors useful for the treatment or prevention of neurological, psychiatric and metabolic disorders in which the PDE10 enzyme is involved.
  • WO 2012007006, WO 2012000519, WO 201 1072695, WO 201 1072697, WO 201 1072694, WO 201 1072696, WO 2010145668 disclose respectively triazolo- and pyrazoloquinazoline derivatives, aryl- and heteroarylamide derivatives, phenylimidazole derivatives comprising an ethynylene linker, heteroaromatic aryl triazole derivatives, heteroaromatic phenylimidazole derivatives, 2-arylimidazole derivatives, novel phenylimidazole derivatives as PDE10A inhibitors reported to be useful for the treatment of psychiatric and neurodegenerative disorders including schizophrenia as well as bipolar disorders, anxiety, stress disorders and Alzheimer's, Parkinson's and Huntington's disease, dementia and attention deficit/hyperactivity disorder.
  • WO 201 1 150156 discloses heteroaryl compounds as PDE10A inhibitors useful for the treatment, prevention, and/or management of various disorders, such as CNS disorders and metabolic disorders, including, but not limited to, e.g., neurological disorders, psychosis, schizophrenia, obesity, and diabetes.
  • PDE10A inhibitors useful in treating central nervous system diseases such as psychosis and also in treating, for example, obesity, type 2 diabetes, metabolic syndrome, glucose intolerance, and pain.
  • WO 201 1053559 or WO 201 1022213 or WO 2010138430 and WO 2010138585 or WO 2010138430 disclose respectively aryl or amino or alkoxy tetrahydro-pyridopyrimidine derivatives or pyrimidinones as PDE10A inhibitors useful for the treatment of neurological and psychiatric disorders including schizophrenia, delusional disorders, drug induced psychosis, anxiety, movement, mood and neurodegenerative disorders.
  • WO 2010138577 discloses radiolabeled pyrimidinone compounds which are useful as radiotracers for quantitative imaging of PDE10A in mammals.
  • Pharmaceuticals SA disclose respectively aryl substituted olefinic compounds, tricyclic compounds, and heteroaryl compounds as PDE10A inhibitors reported to be useful for the treatment of schizophrenia.
  • WO 201 1 163355 & WO 2010090737 disclose respectively fused heterocyclic compounds and pyridazinone compounds as PDE1 OA inhibitors useful for the treatment of schizophrenia.
  • phenoxymethyl heterocyclic compounds as PDE10A inhibitors useful for the treatment of schizophrenia, bipolar disorder, Huntington's disease, obesity and metabolic syndrome, among other disorders.
  • WO 20101 17926 discloses substituted triazolopyridines and analogs thereof as PDE10A inhibitors reported to be useful for the treatment of schizophrenia, psychosis, Alzheimer's disease, bipolar disorder, depression, obesity, diabetes and metabolic syndrome.
  • WO 201 1051324 and WO 2010097367 disclose radiolabeled fluorinated azole PDE10A ligands reported to be useful in positron emission tomography imaging and quantification of PDE10A enzymes.
  • PDE10A inhibitors reported to be useful for the treatment of schizophrenia, cognitive disorders, anxiety, substance abuse and dependence, Parkinson's disease, mood disorders, neurodegenerative disorders, stroke, diabetes and cancer, among other disorders.
  • WO 201 1 143366, WO 201 1 143365, WO 201 1 143495, WO 2010077992, and WO 2010057126 disclose respectively
  • heteroaryloxycarbocyclyl compounds nitrogen heterocyclic compounds, heteroaryloxyheterocyclyl compounds, aminopyridine and carboxypyridine compounds, and pyridine and pyrimidine derivatives as PDE10A inhibitors that are considered to have potential in the treatment of psychiatric disorders such as schizophrenia, bipolar disorder, obsessive-compulsive disorder, obesity, non-insulin dependent diabetes.
  • Therapies GmbH - Wyeth disclose respectively substituted imidazo[1 ,5- a]quinoxalines and triazine derivatives as inhibitors of phosphodiesterases, particularly PDE10A and PDE2A, described as useful for the treatment of pain, cognitive disorders, diabetes, obesity, extrapyramidal disorders, epilepsy and psychiatric disorders such as depression, anxiety, schizophrenia and attention deficit/hyperactivity disorders.
  • JP 201 1201873, WO 201 1 105628, and WO 2010027097 disclose respectively trisubstituted pyrimidine compounds, pyrazolopyrimidine compounds, and tri-substituted pyrimidine compounds and their use as PDE10A inhibitors reported to be useful for the treatment of schizophrenia, anxiety, drug addiction, cognitive and mood disorders.
  • PDE10A inhibitors described as useful for the treatment of neurological and psychiatric disorders such as schizophrenia and post-traumatic stress disorder as well as Parkinson's disease, Huntington's disease, Alzheimer's disease, encephalitis, phobias, epilepsy, pain, sleep disorders, bipolar disorder and multiple sclerosis.
  • US 2010016303 & WO 2009152825 disclose novel phenylimidazole derivatives as PDE10A enzyme inhibitors to be useful in the treatment of psychiatric and neurological disorders such as schizophrenia, cognition deficits, Parkinson's disease, Alzheimer's disease, Huntington's disease and substance abuse, among others.
  • WO 2010006130 discloses vicinal substituted cyclopropyl compounds as PDE10A inhibitors.
  • WO 2009070583 discloses pyrido(3,2-e)pyrazines as inhibitors of PDE10A that are considered to have potential in the treatment of psychosis, mood diseases, anxiety, neurodegenerative disorders, obesity, diabetes, metabolic diseases, pain.
  • WO 2009068320 & WO 2009070584 disclose aryl and heteroaryl fused imidazo(1 ,5-a)pyrazines as inhibitors of PDE1 OA that are active compounds for treating central nervous system diseases of mammals, including humans.
  • WO 2009152825 & WO 2009036766 disclose respectively novel phenylimidazole derivatives and cyanoisoquinoline derivatives as PDE10A inhibitors.
  • WO 2009143178, WO 2008064342 & US 2008300240 disclose quinoline derivatives as PDE10A inhibitors active in psychotic, anxiety, movement disorders and/or neurological disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, encephalitis, phobias, epilepsy, aphasia, Bell's palsy, cerebral palsy, sleep disorders, pain, Tourette syndrome, schizophrenia, delusional disorders, drug-induced psychosis and panic and obsessive-compulsive disorders.
  • WO 2009025839 & WO 2009025823 disclose cinnoline derivatives as PDE10A inhibitors that are considered to have potential in the treatment of psychiatric disorders such as schizophrenia, bipolar disorder and obsessive-compulsive disorder.
  • WO 2009029214 (Amgen Inc. - Memory Pharmaceuticals Corp.) discloses isoquinolone derivatives as PDE10A inhibitors that are considered to have potential in the treatment of schizophrenia, bipolar disorder, obsessive- compulsive disorder, obesity and diabetes.
  • WO 2008032171 discloses dibenzofuran as inhibitors of PDE4 and PDE1 OA with potential utility in the treatment of asthma, chronic obstructive pulmonary disease, allergic rhinitis, atopic dermatitis, multiple sclerosis, Huntington disease, Alzheimer's disease, Parkinson's disease, schizophrenia and depression, among other disorders.
  • WO 2008020302 discloses heteroaromatic quinoline-based compounds as selective PDE10A inhibitors.
  • WO 2008006372 discloses 6,7-dialkoxyquinazoline and 6,7-dialkoxyisoquinoline derivatives as PDE10A inhibitors that are considered to have potential in the treatment of psychiatric and neurological disorders such as schizophrenia, cognition deficits, Parkinson's disease, Alzheimer's disease, dementia, epilepsy, multiple sclerosis and Huntington's diseases.
  • WO 20080041 17 & WO 2006072828 disclose respectively selective azole compounds and heteroaromatic quinoline compounds as PDE10A inhibitors that are considered to have potential in the treatment of psychotic, anxiety, movement, mood and neurodegenerative disorders and obesity.
  • WO 2007137819 & WO 2007137820 disclose respectively 4-amino-pyrido(3,2-e)pyrazines and pyrido(3,2-e)pyrazines as PDE10A inhibitors. More particularly, the inventions relate to the treatment of neurologic and psychiatric disorders, for example psychosis and disorders comprising cognitive deficits as symptoms.
  • WO 2007103554, WO 2007098214 & WO 2007098169 disclose cinnoline derivatives as PDE10A inhibitors that are considered to have potential in the treatment psychiatric disorders such as schizophrenia, bipolar disorders and obsessive-compulsive disorder.
  • WO 2007096743 & WO 2007085954 disclose respectively substituted quinazolines and aminophthalazine compounds as PDE10A inhibitors that are considered to have potential in the treatment of psychotic disorders, anxiety disorders, movement disorders such as Parkinson and Huntington diseases, mood disorders, obesity and drug addiction.
  • WO 2006089815 & WO 2006075012 disclose novel pyrrolodihydroisoquinolines as PDE10A inhibitors with potential utility in the treatment of neurological and psychiatric disorders, in diabetes therapy and in the regulation of fertility.
  • WO 2006071988 & WO 2006028957 disclose respectively thienopyrimidine derivatives and 4-substituted-4,6- dialkoxy-cinnoline derivatives as PDE1 OA inhibitors that are considered to have potential in the treatment of psychosis, including schizophrenia, bipolar disorder and obsessive-compulsive disorder, Alzheimer's disease and movement disorders such as Parkinson's disease.
  • Other conditions include epilepsy, multiple sclerosis, Huntington's disease, disorders relating to the basal ganglia, diabetes and obesity.
  • WO 2006070284 & WO 200601 1040 disclose respectively pyrrolidyl derivatives of heteroaromatic compounds, and quinazolin-4-yl-piperidine and cinnolin-4-yl derivatives as PDE10A inhibitors that are considered to have potential in the treatment of CNS disorders, including schizophrenia, delusional disorders, drug-induced psychosis, anxiety, mood and movement disorders, neurodegenerative disorders and drug addiction.
  • WO 2005082883 discloses tetrahydroisoquinolinyl derivatives of quinazoline and isoquinoline as PDE10A inhibitors that are claimed for use in the treatment of psychotic disorders, anxiety and movement disorders including Parkinson's disease and Huntington's disease, among other conditions.
  • WO 2006034512 & WO 2006034491 disclose PDE1 OA inhibitors described as useful for the treatment of diabetes and related disorders. Pyrrolodihydroisoquinolines and variants thereof are disclosed as inhibitors of PDE10A in WO 2005003129 and WO 2005002579 (Nycomed GmbH).
  • WO 2004005291 & WO 2004005290 (Bayer Healthcare AG) disclose hetero-cyclically substituted imidazotriazines as PDE10A inhibitors described as useful for the treatment of neurodegenerative conditions, particularly
  • Parkinson's disease and schizophrenia and cancer.
  • WO 2004002484 discloses quinoline derivatives as PDE10A inhibitors with potential in the treatment of Parkinson's disease, dyskinesia, anxiety, stress, mood and cognitive disorders, drug abuse, schizophrenia, cerebrovascular disorders, erectile dysfunction, diabetes, ischemic cardiopathies, renal disorders, peripheral vascular disease, hypertension, urinary incontinence, autoimmune diseases, respiratory disorders, allergies, pain, osteoporosis, cancer.
  • WO 20030141 16 (Bayer Healthcare AG) discloses pyrrolo[2.1 - a]isoquinoline derivatives as PDE10A inhibitors with potential in the treatment of cancer.
  • WO 2003000693 (Bayer Healthcare AG) discloses imidazotriazines for use as PDE1 OA inhibitors considered to have potential in the treatment of Parkinson's disease. All the above-mentioned publications are incorporated herein by reference.
  • the compounds of the invention offer alternatives to current marketed treatments for neurodegenerative and/or psychiatric disorders, which are not efficacious in all patients.
  • the present invention provides compounds that are PDE10A enzyme inhibitors, in particular selective PDE10A enzyme inhibitors.
  • the present invention further provides compounds which have such activity.
  • the invention also provides an effective treatment, in particular long-term treatment, of a human patient, without causing the side effects typically associated with current therapies for neurological and psychiatric disorders. Further aspects of the invention will become apparent upon reading the present specification.
  • the present invention relates to compounds of Formula (I):
  • R 1 is selected from the group of H, optionally substituted (CrC 6 )alkyl, optionally substituted (C3-C6)cycloalkyl and optionally substituted aryl;
  • R 2 is H
  • R 3 and R independently represent a (CrC 3 )alkyl group;
  • R 5 is H;
  • R6 and R 7 are independently H;
  • R' is H or (CrC 6 )alkyl
  • Ar is selected from the group consisting of: an optionally substituted fused nine- to ten-membered heteroaryl, optionally substituted benzo-fused aryl, optionally substituted benzo-fused heteroaryl, optionally substituted benzo-fused hetorocyclyl, and optionally substituted benzo-fused cycloalkyl, wherein two optional substituents at adjacent positions of each of said optionally substituted fused nine- to ten-membered heteroaryl, optionally substituted benzo-fused aryl, optionally substituted benzo-fused heteroaryl, optionally substituted benzo-fused hetorocyclyl, and optionally substituted benzo-fused cycloalkyl can be taken together with the atoms to which they are attached to form an aryl.
  • the present invention relates to compounds of Formula (IA):
  • R 1 is selected from the group of H, (CrC 6 )alkyl, (C 3 -C 6 )cycloalkyl and aryl;
  • R 2 is H
  • R 3 and R independently represent a (CrC 3 )alkyl group
  • R 5 is H
  • R6 and R 7 are independently H;
  • R' is H or (Ci-C 6 )alkyl
  • Ar is selected from the group consisting of: an optionally substituted fused nine- to ten-membered heteroaryl, optionally substituted benzo-fused aryl, optionally substituted benzo-fused heteroaryl, optionally substituted benzo-fused hetorocyclyl, and optionally substituted benzo-fused cycloalkyl, wherein two optional substituents at adjacent positions of each of said optionally substituted fused nine- to ten-membered heteroaryl, optionally substituted benzo-fused aryl, optionally substituted benzo-fused heteroaryl, optionally substituted benzo-fused hetorocyclyl, and optionally substituted benzo-fused cycloalkyl can be taken together with the atoms to which they are attached to form an aryl; and pharmaceutically acceptable salts, tautomer forms, solvates and esters thereof.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of Formula (I) or Formula (IA) as set forth above, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the present invention provides a method for inhibiting PDE10A in a mammal, comprising administering to said mammal in need thereof, a therapeutically effective amount of at least one compound of Formula (I) or (IA) as set forth above or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for treating a disease in a mammal modulated by PDE10A, comprising administering to said mammal in need thereof, a therapeutically effective amount of at least one compound of Formula (I) or (IA) as set forth above or a pharmaceutically acceptable salt thereof.
  • alkyl alone or in combination with other groups, denotes linear or branched saturated
  • alkyl groups having from 1 to 6 carbon atoms inclusive are methyl, ethyl, propyl (e.g., n-propyl, iso-propyl), butyl (e.g., ferf-butyl, sec-butyl, n-butyl), pentyl (e.g., neo-pentyl), hexyl (e.g., n-hexyl), 2- methylbutyl, 2-methylpentyl and the other isomeric forms thereof.
  • "Alkyl” may be unsubstituted or optionally substituted by one or more "ring system substituents" as defined herein below.
  • halogen denotes a chlorine, bromine, iodine or fluorine atom.
  • acetylaminoalkyl denotes a CH 3 CONH-alkyl group.
  • alkoxy denotes an alkyl-O- group, with alkyl as defined above.
  • alkoxy groups are methoxy, ethoxy, n-propyloxy, isopropyloxy and sec-butyloxy.
  • Cycloalkyl means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms.
  • the cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
  • suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • suitable multicyclic cycloalkyls include 1 -decalinyl, norbornyl, adamantyl and the like.
  • Heterocyclyl means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclyls contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), - N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention.
  • the heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like.
  • Example of such moiety is pyrrolidone, having the structure :
  • aryl refers to monocyclic or polycyclic (e.g. having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, antracenyl, phenanthrenyl and the like.
  • an aryl group has from 5 to 20 carbons, in particular from 6 to 14 carbon atoms.
  • Most preferred aryl groups are mono- or bi-cyclic and comprises from 6 to 14 carbon atoms, such as phenyl, a-naphthyl, ⁇ -naphthyl, antracenyl.
  • the aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • aryloxy denotes an aryl-O- group, with aryl as defined above.
  • heteroaryl means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen, phosphorus or sulfur, alone or in combination.
  • Preferred heteroaryls contain about 5 to about 6 ring atoms.
  • the "heteroaryl” can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
  • heteroaryl may also include a heteroaryl as defined above fused to an aryl as defined above.
  • suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4-thiadiazolyl, pyrazinyl, pyridazinyl,
  • heteroaryl also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
  • Ring system substituent means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system.
  • Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl,
  • alkoxycarbonyl aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio,
  • Ring system substituent may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system.
  • Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CH 3 ) 2 - and the like which form moieties such as, for example:
  • optionally substituted means optional substitution (i.e., unsubstituted or substituted) with the specified groups, radicals or moieties.
  • R 3 and R 4 are both methyl.
  • the optionally substituted (Ci- C 6 )alkyl of Ri is selected from the group consisting of ethyl, n-propyl, n-butyl, and isobutyl; the optionally substituted aryl is optionally substituted phenyl; and the optionally substituted (C 3 -C 6 )cycloalkyl is selected from the group consisting of cyclopropyl and cyclohexyl.
  • Ri is selected from the group consisting of ethyl, n-propyl, n-butyl, isobutyl, phenyl, cyclopropyl, and cyclohexyl.
  • R' is selected from the group consisting of H and methyl.
  • Ar is a fused nine to ten- membered heteroaryl and is an optionally substituted pyrazolo-pyridyl (e.g., that is attached to the carbon bearing the R 6 and R 7 groups through a carbon atom of the pyridyl ring.
  • Ar is an optionally substituted benzo-fused aryl and is napthyl, wherein said naphthyl is
  • Ar is an optionally substituted benzo-fused heteroaryl, which is attached to the carbon bearing the R 6 and R 7 groups either through a carbon atom of the benzene ring or through a carbon atom of the heteroaryl ring, and wherein two optional substituents at adjacent positions of said benzofused heteroaryl can be taken together with the atoms to which they are attached to form an aryl.
  • Ar is an optionally substituted said benzo-fused heteroaryl is selected from the group consisting of quinolinyl, benzofuranyl, benzopyrrolyl, benzothiophenyl, benzimidazolyl,
  • Ar is an optionally substituted said benzo-fused heteroaryl is selected from the group consisting of quinolinyl, benzofuranyl, benzopyrrolyl, benzothiophenyl, benzimidazolyl,
  • Ar is a benzo-fused hetorocyclyl, which is attached to the carbon bearing the R 6 and R 7 groups through a carbon atom of the benzene ring of said benzo-fused heterocyclyl.
  • Ar is a benzo-fused hetorocyclyl, which is attached to the carbon bearing the R 6 and R 7 groups through a carbon atom of the benzene ring of said benzo-fused heterocyclyl, wherein said benzo-fused heterocyclyl is selected from the group consisting of indolinyl, chrom including alkylchromanyl and dialkyl chromanyl (e.g., tionally substituted dihydro-2H-
  • benzo[6][1 ,4]oxazinyl e.g., each of which is unsubstituted or substituted at a nitrogen or carbon atom with at least one -(Ci-C6)alkyl.
  • Ar is a benzo-fused cycloalkyl, which is attached to the carbon bearing the R 6 and R 7 groups through a carbon atom of the benzene ring of said benzo-fused cycloalkyl.
  • Ar is a benzo-fused cycloalkyl, which is attached to the carbon bearing the R 6 and R 7 groups through a carbon atom of the benzene ring of said benzo-fused cycloalkyl, wherein said benzo-fused cycloalkyl is fluorenyl.
  • the compounds according to the present invention may be prepared by various methods known to those skilled in the art. General and specific methods for the preparation of compounds of formula (I) and (IA) are described herein below.
  • SSA 48072, SSA 48066, SSA 40084 and SSA 48100 were prepared in three synthetic steps from veratrole: a Friedel and Craft acylation of veratrole in anhydrous CH2CI2 with the desired commercially available acid chloride in presence of aluminium trichloride followed by an amination of the obtained ketone with aminoacetaldehyde diethyl acetal, preferentially at reflux in toluene (150°C for 4 h), using a Dean Stark apparatus and finally the reduction of the obtained iminoacetal using sodium borohydride in ethanol at reflux (100°C) (Reaction scheme 1 ).
  • Reaction Scheme 1 Synthetic routes used for the preparation of intermediary compounds TTA 24128B, SSA 39098, SSA 39102, SSA 48060, SSA 48072, SSA 48066, SSA 40084, SSA 48100, TTA 46082B, LPO 22102, ECO 33100, ECO 33118, ECO 33124, ECO 33138, TTA 24150B, TTA 24156B and ANP 31060A.
  • TTA 46082B was prepared in three synthetic steps from 1 -(3,4- dimethoxyphenyl)-2-hydroxyethanone (CAS#37803-48-8): a methylation of 1 - (3,4-dimethoxyphenyl)-2-hydroxyethanone in anhydrous CH 2 CI 2 in presence of silver (I) oxide and iodomethane at RT for 48 h gave 2-methoxy-1 -(3,4- dimethoxyphenyl)ethanone ECO 59016.
  • the intermediates LPO 22102, ECO 33100, ECO 33118, ECO 33124, ECO 33138, TTA 24150B and TTA 24156B were prepared in two synthetic steps by amination of the corresponding commercially available aldehydes with aminoacetaldehyde diethyl acetal, preferentially under reflux in toluene at 1 10°C for 4 hours using a Dean Stark apparatus, followed by a subsequent reduction of the obtained iminoacetals using sodium borohydride in refluxing ethanol (78°C) (reaction scheme 1 ).
  • the intermediary compound ANP 31060A was prepared in two steps by amination of (3,4-dimethoxyphenyl)methanamine with 1 ,1 -dimethoxypropan-2-one, preferentially in refluxing toluene (1 10°C for 4 h) and using a Dean Stark apparatus, followed by a subsequent reduction of the obtained (£)-1 -(3,4-dimethoxyphenyl)-A/-(1 ,1 -dimethoxypropan-2- ylidene)methanamine using sodium borohydride in refluxing ethanol (78°C) (reaction scheme 1 ).
  • the aldehydes LPO 43162A and ANP 49046 were prepared following the procedure described by Sing, Mrityunjay et al. , Tetrahedron letters, 48(34), 5987-90, 2007 and the aldehyde LPO 43136A from the procedure described by Kalluraya, Balakhrishna et al. , Indian Journal of Chemistry, 42B(1 ), 21 1 -214, 2003.
  • the 7-methoxy- and 7-methyl-quinoline-3-carbaldehydes were prepared following the procedure described by Tom, Norma J. et al., Synthesis, (9), 1351 -1355, 2001 .
  • the masked aldehyde 3-(1 ,3-dioxolan-2-yl)-7-methylquinoline SSA 48104 was prepared in two steps from 2-chloro-7-methylquinoline-3- carbaldehyde by treatment with ethane-1 ,2-diol in presence of p- toluenesulfonic acid (PTSA) in toluene followed by a reduction of the chlorine atom of the obtained 2-chloro-3-(1 ,3-dioxolan-2-yl)-7-methylquinoline SSA 48098 by hydrogenation catalyzed by Pd/C 10% in presence of K 2 C0 3 as base and MeOH as solvent.
  • PTSA p- toluenesulfonic acid
  • the masked aldehyde 3-(1 ,3-dioxolan-2-yl)-quinolin-6-ol LPO 55016 was obtained via a similar method as for SSA 48104 from 2-chloro-6- hydroxyquinoline-3-carbaldehyde LPO 50188A.
  • LPO 50188A itself was prepared by treatment of 2-chloro-6-methoxyquinoline-3-carbaldehyde by boron tribromide (BBr 3 ) in dichloromethane.
  • quinolin-6-ol LPO 55016 was O-alkylated by treatment with ethyl 2-bromoacetate and cesium carbonate as a base in acetone for 2 hours at 85°C to yield ethyl 2-((3-(1 ,3-dioxolan-2- yl)quinolin-6-yl)oxy)acetate LPO 55070A (reaction scheme 2).
  • Reaction Scheme 2 Preparation of non-commercially available aldehydes The masked aldehyde 3-(1 ,3-dioxolan-2-yl)-8-(trifluoromethyl)quinolin-5- ol LPO 50180C was prepared by radical trifluoromethylation of dioxolane TTA 46034 using a methodology developed by Langlois B. et al., Tetrahedron Lett., (32), 51 , 7525-7528, 1991 and modified by Baran P. et al., PNAS, 108, 35, 1441 1 -14415, 201 1 (reaction scheme 2).
  • the masked aldehyde 3-(dimethoxymethyl)-5-(trifluoromethyl)quinolin-6- ol ECO 55152 was prepared by radical trifluoromethylation via photoredox catalysis of dimethylacetal ECO 55108C using a methodology developed by MacMillan D. et ai, Nature, 480, 224-228, 201 1 (reaction scheme 2).
  • the 4-chloro-1 -ethyl-1 H-pyrazolo[3,4-6]pyridine-5-carbaldehyde SAO 33058 was obtained in two steps from ethyl 4-chloro-1 -ethyl-1 /-/-pyrazolo[3, 4- 0]pyridine-5-carboxylate (described by Hamblin, J. Nicole et al., Bioorg. Med. Chem. Lett., 18(14), 4237-41 , 2008).
  • Reduction of 4-chloro-1 -ethyl-1 /-/-pyrazolo[3,4-0]pyridine-5-carboxylate by LiBH 4 in THF provided the alcohol SAO 33034 that was oxidized in aldehyde SAO 33058 using Dess-Martin periodinane reagent in dichloromethane for 1 hour at 4°C then overnight at RT (reaction scheme 2).
  • the products obtained by following the reaction scheme 1 may be further modified, for example, by manipulation of substituents.
  • the compounds 42 and 75 were prepared respectively from the compounds 41 and ANP 49102A by reduction of the ester function using sodium borohydride in a mixture of ferf-butanol/MeOH at 140°C for 2 hours in an ace pressure tube (reaction Scheme 3).
  • the compounds 55, 56 and 76 were prepared from the free base of compound 49.
  • the compound 55 can be hydrogenated in presence of hydrogen and 10% Pd/C as catalyst in methanol at room temperature to yield compound LPO 43180.
  • the compound LPO 43180 was acetylated for 2 hours at 4°C in tetrahydrofuran with acetic anhydride, in presence of triethylamine as base, to give the free base of compound 56 that was subsequently transformed in its dihydrochloride salt by treatment with a 1 .75 N HCI solution in methanol at room temperature (reaction scheme 4).
  • the treatment of compound 49 with phosphorus oxychloride for 2 hours at 100°C gave the aryl chloro derivative LPO 50012.
  • the compound LPO 50016 was prepared by a Buchwald-Hartwig reaction of the compound LPO 50012 preferentially at 100°C for 8 hours in toluene with ethylenediamine, in presence of palladium(ll) acetate as catalyst, 2-(di-ferf-butylphosphino)biphenyl (JohnPhos) as ligand, and potassium ferf-butoxide as base.
  • Reaction Scheme 5 Preparation of compounds 77, 113 and 129.
  • the compounds 77 and 113 were preferentially respectively prepared from the aryl chloro derivative LPO 50012 and LPO50042C by a Buchwald- Hartwig reaction, at 170°C for 5 hours (77) or 100°C for 6 hours (113) in toluene with a 2 N solution of diethylamine in tetrahydrofuran, in presence of palladium(ll) acetate as catalyst, JohnPhos as ligand, and potassium tert- butoxide as base.
  • the obtained free bases were transformed into their corresponding dihydrochloride salt 77 and 113 by treatment with a 1 .76 N hydrochloride solution in methanol for 15 minutes at 4°C (reaction scheme 5).
  • the compound 129 was preferentially obtained from LPO 50012 by a Buchwald-Hartwig reaction at 145°C for 25 min in toluene with a 2 N solution of diethylamine in tetrahydrofuran, in presence of palladium(ll) acetate as catalyst, 2-(di-ferf-butylphosphinobiphenyl) as ligand, and potassium ferf-butoxide as base.
  • the A/-oxide derivative 35 was prepared from the free base of compound 10 by oxidation using preferentially mefa-chloroperbenzoic acid in dichloromethane for 24 hours (reaction scheme 6).
  • R ethyl: 83
  • R ethyl: RBO 51116 80%
  • R ethyl: RBO 51118B 80%
  • R n-propyl: 45
  • R n-propyl: LPO 55036C 72%
  • R n-propyl: LPO 55056D 65%
  • R MeOCH,: 163
  • R MeOCH,: 167 20%
  • Reaction Scheme 7 Preparation of compounds 84, 85, 119, 152, 156, 157, 159 and 167.
  • the sulfamide derivatives 159, 156, 84, 85 and 1 19 were prepared respectively from phenols 7, 131 , 83, 45 and 163 in three steps (reaction scheme 7).
  • the phenols 7, 131 , 83, 45 and 163 were treated in DMF with N- phenyl-bis(trifluoromethanesulfonimide) in presence of triethylamine at RT or 40°C to give, respectively, the triflates ANP 57032A, ANP 53184A, RBO 51 116, LPO 55036C and ECO 59060.
  • Reaction Scheme 8 Preparation of compounds 86-89 and 93.
  • the compounds 86-89 and 93 were prepared from aniline RBO 51118B as described in reaction scheme 8.
  • Reaction Scheme 9 Preparation of compounds 90-92 and 94.
  • the amide 91 was prepared by basic hydrolysis of the nitrile 90 that was prepared from inflate RBO 51116 as described in reaction scheme 9.
  • the compounds 92 and 94 were also prepared from triflate RBO 511 16 as described in reaction scheme 9.
  • Reaction Scheme 10 Preparation of compounds 96 to 101 .
  • the compounds 96 to 101 were prepared as described in reaction scheme 10.
  • LPO 55056D 158 160 i) Acetoxyacetylchloride, pyridine, dry THF, 0°C to RT, 1 h, 95%. ii) 2 M LiOH in THF, 70°C, THF, 2 h, 73%.
  • Reaction Scheme 11 Preparation of compounds 158 and 160.
  • the compounds 158 and 160 were prepared as described in reaction scheme 1 1 .
  • Reaction Scheme 12 Preparation of compounds 106, 107, 114, 115, 142, 145, 146, 149, 151 , 153 and 154.
  • the compounds 111 , 112 and 170 were prepared as described in reaction Scheme 13.
  • the compounds 147 and 148 were prepared as described in reaction scheme 14.
  • Reaction Scheme 15 Preparation of compounds 41 , 42, 46, 108, 116, 118, 120, 122, 128, 130, 135, 139,148, 164, 165 and 166.
  • the compounds 41 , 42, 46, 108, 116, 118, 120, 122, 128, 130, 135, 139,148, 164, 165 and 166 were prepared as described in reaction scheme 15.
  • Reaction Scheme 16 Preparation of compounds 125 and 126.
  • the compounds 165 and 166 were prepared as described in reaction scheme 16.
  • Reaction Scheme 17 Preparation of compounds 45, 134, 136 and 140.
  • Reaction Scheme 18 Preparation of compounds 138, 141 and 144.
  • the compounds 138, 141 and 144 were prepared as described in reaction schem
  • Reaction Scheme 19 Preparation of compound 171 .
  • the compound 171 was prepared as described in reaction scheme 19.
  • Another object of the present invention is the intermediate compounds used for the preparation of compounds of formula (I) or (IA).
  • the present invention relates to the intermediate compounds herein below mentioned in the examples.
  • the compounds according to the invention can be in the form of salts, particularly acid or base salts, preferably compatible with pharmaceutical use (i.e. pharmaceutically acceptable salts of the compounds of the invention). It will be appreciated by those skilled in the art that non-pharmaceutically acceptable salts of compounds of formula (I) or (IA) are also part of the present invention, since such non-pharmaceutically acceptable salts can be useful as intermediates in the preparation of pharmaceutically acceptable salts.
  • Salts of compounds of the invention include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium, and alkylated ammonium salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include
  • hydrochloric hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p- toluenesulfonic acids, sulphates, nitrates, phosphates, perchlorates,
  • metal salts include lithium, sodium, potassium, magnesium salts and the like.
  • Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium.
  • ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium,
  • organic bases include lysine, arginine, guanidine, diethanolamine, choline and the like.
  • the pharmaceutically acceptable salts can in particular be prepared by reacting the compound of formula (I) or (IA) with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p- toluenesulphonic acid, methanesulfonic acid, fonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane, etc. Mixture of solvents may also be used.
  • acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p- toluenesulphonic acid, methanesulfonic acid, fonic acid, acetic
  • Compounds of Formula (I) or (IA) may have optical centers and therefore may occur in different enantiomeric and diastereomeric
  • the present invention includes all enantiomers, diastereomers, and other stereoisomers of such compounds of Formula (I) or (IA), as well as racemic compounds and racemic mixtures and other mixtures of stereoisomers thereof.
  • the compounds according to the present invention may be prepared by various methods known to those skilled in the art. General and specific methods for the preparation of compounds of formula (I) or (IA) are described herein below.
  • the compounds of the invention can be administered alone, but are generally administered with a pharmaceutical carrier, with respect to standard pharmaceutical practice (such as described in Remington's Pharmaceutical Sciences, Mack Publishing), in either single or multiple doses.
  • a pharmaceutical carrier with respect to standard pharmaceutical practice (such as described in Remington's Pharmaceutical Sciences, Mack Publishing), in either single or multiple doses.
  • the invention thus also includes a pharmaceutical composition comprising, in a
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • the pharmaceutical compositions formed thereby can then be readily administered in a variety of dosage forms such as tablets, powders, lozenges, liquid preparations, syrups, injectable solutions and the like.
  • These pharmaceutical compositions can optionally contain additional ingredients such as flavorings, binders, excipients and the like.
  • the compound of the invention may be formulated for oral, ocular, buccal, intranasal, parenteral (e.g. intravenous, intramuscular or subcutaneous), transdermal (e.g. patch) or rectal administration, or in a form suitable for administration by inhalation or insufflation.
  • the pharmaceutical compositions of the invention can be formulated either as solid or liquid compositions.
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g.
  • pregelatinized maize starch polyvinylpyrrolidone or hydroxypropyl
  • methylcellulose methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium starch glycolate
  • wetting agents e.g. sodium lauryl sulphate
  • the tablets may be coated by methods well known in the art.
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g.
  • sorbitol syrup methyl cellulose or hydrogenated edible fats
  • emulsifying agents e.g. lecithin or acacia
  • non-aqueous vehicles e.g. almond oil, oily esters or ethyl alcohol
  • preservatives e.g. methyl or propyl p-hydroxybenzoates or sorbic acid
  • the composition may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in ampoules or in multi-dose containers, with an added preservative. They may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • a product solution When a product solution is required, it can be made by dissolving the isolated inclusion complex in water (or other aqueous medium) in an amount sufficient to generate a solution of the required strength for oral or parenteral administration to patients.
  • the compounds may be formulated for fast dispersing dosage forms, which are designed to release the active ingredient in the oral cavity. These have often been formulated using rapidly soluble gelatin-based matrices. These dosage forms are well known and can be used to deliver a wide range of drugs. Most fast dispersing dosage forms utilize gelatin as a carrier or structure-forming agent. Typically, gelatin is used to give sufficient strength to the dosage form to prevent breakage during removal from packaging, but once placed in the mouth, the gelatin allows immediate dissolution of the dosage form.
  • the compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the dosages and dosage regimen in which the compounds of formula (I) are administered will vary according to the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired.
  • the compounds according to the invention can be used enterally or parenterally. Orally, the compounds according to the invention are suitably administered in the amount from about 0.1 mg per day to 1 ,000 mg per day. For parenteral, sublingual, intranasal, or intrathecal administration, the compounds according to the invention are suitably used in the amount from about 0.5 to about 100 mg/day; for depo administration and implants from about 0.5 mg/day to about 50 mg/day; for topical administration from about 0.5 mg/day to about 200 mg/day; for rectal administration from about 0.5 mg to about 500 mg. In a preferred aspect, the therapeutically effective amounts for oral administration is from about 1 mg/day to about 100 mg/day; and for parenteral administration from about 5 to about 50 mg daily. In a more preferred aspect, the therapeutically effective amounts for oral administration are from about 5 mg/day to about 50 mg/day.
  • the compounds of the present invention can also be administered intraocularly (e.g., intravitreally (e.g., through injection) subconjunctival ⁇ , or injection into subtenon space).
  • intraocularly e.g., intravitreally (e.g., through injection) subconjunctival ⁇ , or injection into subtenon space.
  • the weight of the device i.e., drug plus carrier/vehicle/excipinent
  • the drug load is normally 10-50%.
  • the drug dose range for intravitreal administration is normally about 100-500 ⁇ g.
  • the drug load can be stretched to 2-65%, i.e., a drug dose range of 20-650 ⁇ g can be used.
  • the device weight may be 1 .5 mg, and for this a drug dose range of 20-975 ⁇ g can be used.
  • Another way of intravitreal delivery is by injecting drug suspension formulation. For this, the dose range is 10-600 ug.
  • An intraocular implant comprising a therapeutically effective amount of a compound of Formula (I) or (IA) (the therapeutic component; the active pharmaceutical ingredient (API)), and a drug release sustaining polymer component associated with the therapeutic compound can also be
  • an "intraocular implant” refers to a device or element that is structured, sized, or otherwise configured to be place in an eye. Intraocular implants are generally biocompatible with physiological conditions of an eye and do not cause adverse side effects.
  • Intraocular implants may be place in an eye without disrupting vision of the eye.
  • the implant may be solid, semisolid, or viscoelastic.
  • the drug release sustaining component is associated with the therapeutic component to sustain release of an amount of the therapeutic component into an eye in which the implant is placed.
  • the therapeutic component may be released from the implant by diffusion, erosion, dissolution or osmosis.
  • the drug release sustaining component may comprise one or more biodegradable polymers or one or more non-biodegradable polymers.
  • biodegradable polymers of the present implants may include poly-lactide-co-glycolide (PLGA and PLA), polyesters, poly (ortho ester), poly(phosphazine), polyphosphate ester), polycaprolactone, natural polymers such as gelatin or collagen, or polymeric blends.
  • the amount of the therapeutic component is released into the eye for a period of time greater than about one week after the implant is placed in the eye and is effective in reducing or treating an ocular condition.
  • the intraocular implant comprises a therapeutic component and a biodegradable polymer matrix.
  • the therapeutic component is associated with a biodegradable polymer matrix that degrades at a rate effective to sustain release of an amount of the therapeutic component from the implant effective to treat an ocular condition.
  • the intraocular implant is biodegradable or bioerodible and provides a sustained release of the therapeutic component in an eye for extended periods of time, such as for more than one week, for example for about one month or more and up to 5 about six months or more.
  • the implant may be configured to provide release of the therapeutic component in substantially one direction, or the implant may provide release of the therapeutic component from all surfaces of the implant.
  • the biodegradable polymer matrix of the foregoing implant may be a mixture of biodegradable polymers or the matrix may comprise a single type of biodegradable polymer.
  • the matrix may comprise a polymer selected from the group consisting of polylactides, poly(lactide-co-glycolides), polycaprolactones, and combinations thereof.
  • the intraocular implant comprises the therapeutic component and a polymeric outer layer covering the therapeutic component.
  • the polymeric outer layer includes one or more orifices or openings or holes that are effective to allow a liquid to pass into the implant, and to allow the therapeutic component to pass out of the implant.
  • the therapeutic component is provided in a core or interior portion of the implant, and the polymeric outer layer covers or coats the core.
  • the polymeric outer layer may include one or more non-biodegradable portions.
  • the implant can provide an extended release of the therapeutic component for more than about two months, and for more than about one year, and even for more than about five or about ten years.
  • One example of such a polymeric outer layer covering is disclosed in U.S. Pat. No. 6,331 ,313.
  • the present implant provides a sustained or controlled delivery of the therapeutic component at a maintained level despite the rapid elimination of the therapeutic component from the eye.
  • the present implant is capable of delivering therapeutically effective amounts of the therapeutic component for a period of at least about 30 days to about a year despite the short intraocular half-lives that may be associated with the therapeutic component.
  • Plasma levels of the therapeutic component obtained after implantation may be extremely low, thereby reducing issues or risks of systemic toxicity.
  • the controlled delivery of the therapeutic component from the present implants would permit the therapeutic component to be administered into an eye with reduced toxicity or deterioration of the blood-aqueous and blood-retinal barriers, which may be associated with intraocular injection of liquid formulations containing the therapeutic component.
  • a method of making the present implant involves combining or mixing the therapeutic component with a biodegradable polymer or polymers. The mixture may then be extruded or compressed to form a single composition. The single composition may then be processed to form individual implants suitable for placement in an eye of a patient.
  • Another method of making the present implant involves providing a polymeric coating around a core portion containing the therapeutic component, wherein the polymeric coating has one or more holes.
  • the implant may be placed in an ocular region to treat a variety of ocular conditions, such as treating, preventing, or reducing at least one symptom associated with nonexudative age related macular degeneration (ARMD), exudative age related macular degeneration, choroidal neovascularization, acute macular
  • ARMD nonexudative age related macular degeneration
  • exudative age related macular degeneration choroidal neovascularization
  • the daily dose may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.
  • the present invention also relates to a compound of formula (I) or (IA), or a composition comprising a compound of formula (I) or (IA), for use as a medicament.
  • the compounds according to the invention have been found to have pharmacologically important properties which can be used therapeutically.
  • the compounds of the invention can be used alone, in combination with each other or in combination with other active compounds.
  • the compounds of the invention are inhibitors selective for PDE10A.
  • the invention thus also relates to a compound of formula (I) or (IA) or a
  • the present invention also pertains to a pharmaceutical composition for use in the potential treatment of certain psychotic disorders and conditions such as schizophrenia, delusional disorders and drug induced psychosis; to anxiety disorders such as panic and obsessive-compulsive disorder; and to movement disorders including Parkinson's disease and Huntington's disease, comprising an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A.
  • the invention relates to a pharmaceutical composition for potentially treating psychotic disorders and condition such as schizophrenia, delusional disorders and drug induced psychosis; anxiety disorders such as panic and obsessive-compulsive disorder; and movement disorders including Parkinson's disease and Huntington's disease, comprising an amount of a compound of formula (I) effective in treating said disorder or condition.
  • psychotic disorders and condition such as schizophrenia, delusional disorders and drug induced psychosis
  • anxiety disorders such as panic and obsessive-compulsive disorder
  • movement disorders including Parkinson's disease and Huntington's disease
  • the invention also relates to a compound of formula (I) or (IA), for use in the potential treatment of certain psychotic disorders and conditions such as schizophrenia, delusional disorders and drug induced psychosis; to anxiety disorders such as panic and obsessive-compulsive disorder; and to movement disorders including Parkinson's disease and Huntington's disease.
  • certain psychotic disorders and conditions such as schizophrenia, delusional disorders and drug induced psychosis
  • anxiety disorders such as panic and obsessive-compulsive disorder
  • movement disorders including Parkinson's disease and Huntington's disease.
  • Examples of psychotic disorders that can potentially be treated according to the present invention include, but are not limited to, schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; delusional disorder; substance- induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type.
  • Examples of movement disorders that can potentially be treated according to the present invention include but are not limited to Huntington's disease and dyskinesia associated with dopamine agonist therapy, Parkinson's disease, restless leg syndrome, and essential tremor.
  • Other disorders that can potentially be treated according to the present invention are obsessive/compulsive disorders, Tourette's syndrome and other tic disorders.
  • the invention in another embodiment, relates to a method for potentially treating an anxiety disorder or condition in a mammal which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A.
  • the invention also provides a method for potentially treating an anxiety disorder or condition in a mammal which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in treating said disorder or condition.
  • the invention also relates to a compound of formula (I) or (IA), for use in the potential treatment of an anxiety disorder or condition in a mammal.
  • anxiety disorders that can potentially be treated according to the present invention include, but are not limited to, panic disorder;
  • agoraphobia a specific phobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; acute stress disorder; and generalized anxiety disorder.
  • the invention further provides a method of potentially treating a drug addiction, for example an alcohol, amphetamine, cocaine, or opiate addiction, in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in treating drug addiction.
  • a drug addiction for example an alcohol, amphetamine, cocaine, or opiate addiction
  • the invention also provides a method of treating a drug addiction, for example an alcohol, amphetamine, cocaine, or opiate addiction, in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A.
  • the invention also relates to a compound of formula (I) or (IA), for use in the treatment of a drug addiction, for example an alcohol, amphetamine, cocaine, or opiate addiction, in a mammal, including a human.
  • a drug addiction for example an alcohol, amphetamine, cocaine, or opiate addiction
  • a "drug addiction”, as used herein, means an abnormal desire for a drug and is generally characterized by motivational disturbances such a compulsion to take the desired drug and episodes of intense drug craving.
  • the invention further provides a method of potentially treating a disorder comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in treating said disorder.
  • the invention also provides a method of potentially treating a disorder or condition comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A.
  • the invention also provides a method of potentially treating a disorder or condition comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in treating said disorder or condition.
  • the invention also relates to a compound of formula (I) or (IA), for use in the potential treatment of a disorder or condition comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human.
  • deficiency in attention and/or cognition refers to a subnormal functioning in one or more cognitive aspects such as memory, intellect, or learning and logic ability, in a particular individual relative to other individuals within the same general age population.
  • Deficiency in attention and/or cognition also refers to a reduction in any particular individual's functioning in one or more cognitive aspects, for example as it occurs in age-related cognitive decline.
  • disorders that comprise as a symptom a deficiency in attention and/or cognition are dementia, for example Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention- deficit/hyperactivity disorder; and age-related cognitive decline.
  • dementia for example Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia
  • delirium amnestic disorder
  • post-traumatic stress disorder mental retardation
  • a learning disorder for example reading disorder, mathematics disorder, or a disorder of written expression
  • attention- deficit/hyperactivity disorder and age-related cognitive decline
  • the invention also provides a method of potentially treating a mood disorder or mood episode in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula (I) or (IA) effective in treating said disorder or episode.
  • the invention also provides a method of potentially treating a mood disorder or mood episode in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A.
  • the invention also relates to a compound of formula (I) or (IA), for use in the treatment of a mood disorder or mood episode in a mammal, including a human
  • mood disorders and mood episodes that can be treated according to the present invention include, but are not limited to, major depressive episode of the mild, moderate or severe type, a manic or mixed mood episode, a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post- stroke depression; major depressive disorder; dysthymic disorder; minor depressive disorder; premenstrual dysphoric disorder; post-psychotic depressive disorder of schizophrenia; a major depressive disorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia; a bipolar disorder, for example bipolar I disorder, bipolar II disorder, and cyclothymic disorder.
  • the invention further provides a method of potentially treating a neurodegenerative disorder or condition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in treating said disorder or condition.
  • the invention further provides a method of potentially treating a neurodegenerative disorder or condition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A.
  • the invention also provides to a compound of formula (I) or (IA), for use in the treatment of a neurodegenerative disorder or condition in a mammal, including a human.
  • a “neurodegenerative disorder or condition” refers to a disorder or condition that is caused by the dysfunction and/or death of neurons in the central nervous system.
  • the treatment of these disorders and conditions can be facilitated by administration of an agent which prevents the dysfunction or death of neurons at risk in these disorders or conditions and/or enhances the function of damaged or healthy neurons in such a way as to compensate for the loss of function caused by the dysfunction or death of at-risk neurons.
  • neurotrophic agent refers to a substance or agent that has some or all of these properties.
  • neurodegenerative disorders and conditions that can potentially be treated according to the present invention include, but are not limited to, Parkinson's disease; Huntington's disease; dementia, for example Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, and Fronto temperal Dementia; neurodegeneration associated with cerebral trauma;
  • neurodegeneration associated with stroke neurodegeneration associated with cerebral infarct; hypoglycemia-induced neurodegeneration; neurodegeneration associated with epileptic seizure; neurodegeneration associated with neurotoxin poisoning; and multi-system atrophy.
  • the neurodegenerative disorder is Parkinson's disease or Alzheimer's disease.
  • the neurodegenerative disorder or condition comprises neurodegeneration of striatal medium spiny neurons in a mammal, including a human.
  • the neurodegenerative disorder or condition is Huntington's disease.
  • the invention also provides a pharmaceutical composition for potentially treating psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, mood disorders, neurodegenerative disorders, obesity, and drug addiction, comprising an amount of a compound of formula (I) or (IA) effective in treating said disorder or condition.
  • the invention also provides a method of potentially treating a disorder selected from psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, obesity, mood disorders, and neurodegenerative disorders, which method comprises administering an amount of a compound of formula (I) or (IA) effective in treating said disorder.
  • the invention also provides to a compound of formula (I) or (IA), for use in the potential treatment of a disorder selected from psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, obesity, mood disorders, and neurodegenerative disorders.
  • a disorder selected from psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, obesity, mood disorders, and neurodegenerative disorders.
  • the invention also provides a method of potentially treating disorders selected from the group consisting of: dementia, Alzheimer's disease, multi- infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder; age- related cognitive decline, major depressive episode of the mild, moderate or severe type; a manic or mixed mood episode; a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post-stroke depression; major depressive disorder; dysthymic disorder; minor depressive disorder; premenstrual dysphoric disorder; post-psychotic depressive disorder of schizophrenia; a major depressive
  • Huntington's disease Fronto temperal Dementia; neurodegeneration associated with cerebral trauma; neurodegeneration associated with stroke; neurodegeneration associated with cerebral infarct; hypoglycemia- induced neurodegeneration; neurodegeneration associated with epileptic seizure;
  • neurodegeneration associated with neurotoxin poisoning multi-system atrophy, paranoid, disorganized, catatonic, undifferentiated or residual type;
  • schizophreniform disorder schizoaffective disorder of the delusional type or the depressive type; delusional disorder; substance-induced psychotic disorder, psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, obesity, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type, which method comprises administering an amount of a compound of Formula (I) or (IA) effective in treating said disorders.
  • the invention thus also provides a compound of formula (I) or (IA), for use in the treatment of the diseases mentioned in the previous sentence.
  • the invention also provides a method for the potential treatment of psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, mood disorders, neurodegenerative disorders, obesity, and drug addiction which method comprises administering an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A.
  • the invention also provides a method for the potential treatment of diseases of the retina, which method comprises administering an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A.
  • diseases of the retina the applicants mean any condition of the retina which impairs the normal functioning of the retina, its surrounding tissues, or the eye. These include macular degeneration, myopic retinal degeneration, diabetic
  • retinopathy choroidal neovascularization
  • macular edema also referred to as cystoid macular edema and macular swelling
  • epiretinal membrane macular pucker
  • macular hole retinitis (such as retinitis pigmentosa)
  • macular dystrophies such as Stargardt's juvenile macular degeneration, Best's vitelliform dystrophy, cone dystrophies, and pattern dystrophy of the retinal pigmented epithelium
  • retinal detachment retinal trauma, retinal tumors and retinal diseases associated with them, congenital hypertrophy of the retinal pigmented epithelium, acute posterior multifocal placoid pigment epitheliopathy, acute retinal pigment epithelitis, and uveitis (including crizis, pars planitis, choroiditis, retinitis, and chorioretinitis).
  • the invention relates to a compound of formula (I) or a composition comprising a compound of formula (I) or (IA), for use in a method for the potential treatment of type I or type II diabetes, impaired glucose tolerance, impaired fasting glucose, metabolic syndrome, metabolism related disorders including excess of body weight or excess of body fat in obese patients, psychotic disorders, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, delusional disorder, substance-induced psychotic disorder, anxiety disorders, panic disorder, obsessive/compulsive disorders, acute stress disorder, generalized anxiety disorder, drug addictions, movement disorders, Parkinson's disease, restless leg syndrome, cognition deficiency disorders, Alzheimer's disease, multi-infarct dementia, mood disorders, depression, bipolar disorders, neuropsychiatric conditions, psychosis, attention- deficit/hyperactivity disorder, attention disorders, diabetes and related disorders, type 2 diabetes mellitus, neurodegenerative disorders, Huntington's disease, multiple sclerosis, stroke, spinal cord injury, solid tumors, hemat
  • ARMD retinitis pigmentosa
  • choroidal ARMD dry ARMD
  • retinitis pigmentosa retinitis pigmentosa
  • neovascularization vascular diseases/exudative diseases, retinopathy, including diabetic retinopathy, uveitis/retinitis/choroiditis, Stargard's disease, macular edema, retinal detachment, trauma, systemic disorders with associated retinal dystrophies, cone dystrophies, dystrophy of the retinal pigmented epithelium, myopic retinal degeneration, acute retinal pigment epithelitis, retinal tumors, retinal disease associated with tumors.
  • the invention further relates to a method for the potential treatment of type I or type II diabetes, impaired glucose tolerance, impaired fasting glucose, metabolic syndrome, metabolism related disorders including excess of body weight or excess of body fat in obese patients, psychotic disorders,
  • schizophrenia positive, negative and/or cognitive symptoms associated with schizophrenia, delusional disorder, substance-induced psychotic disorder, anxiety disorders, panic disorder, obsessive/compulsive disorders, acute stress disorder, generalized anxiety disorder, drug addictions, movement disorders, Parkinson's disease, restless leg syndrome, cognition deficiency disorders, Alzheimer's disease, multi-infarct dementia, mood disorders, depression, bipolar disorders, neuropsychiatric conditions, psychosis, attention- deficit/hyperactivity disorder, attention disorders, diabetes and related disorders, type 2 diabetes mellitus, neurodegenerative disorders, Huntington's disease, multiple sclerosis, stroke, spinal cord injury, solid tumors,
  • ophthalmic diseases such as macular degeneration/retinal degeneration, including wet Age Related Macular Degeneration (ARMD), dry ARMD, geographic atrophy, retinitis pigmentosa, choroidal neovascularization, vascular diseases/exudative diseases, retinopathy, including diabetic retinopathy, uveitis/retinitis/choroiditis, Stargard's disease, macular edema, retinal detachment, trauma, systemic disorders with associated retinal dystrophies, cone dystrophies, dystrophy of the retinal pigmented epithelium, myopic retinal degeneration, acute retinal pigment epithelitis, retinal tumors, retinal disease associated with tumors, which method comprises administering an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A.
  • the invention further relates to a method for the potential treatment of type I or type II diabetes, impaired glucose tolerance, impaired fasting glucose, metabolic syndrome, metabolism related disorders including excess of body weight or excess of body fat in obese patients, psychotic disorders,
  • schizophrenia positive, negative and/or cognitive symptoms associated with schizophrenia, delusional disorder, substance-induced psychotic disorder, anxiety disorders, panic disorder, obsessive/compulsive disorders, acute stress disorder, generalized anxiety disorder, drug addictions, movement disorders, Parkinson's disease, restless leg syndrome, cognition deficiency disorders, Alzheimer's disease, multi-infarct dementia, mood disorders, depression, bipolar disorders, neuropsychiatric conditions, psychosis, attention- deficit/hyperactivity disorder, attention disorders, diabetes and related disorders, type 2 diabetes mellitus, neurodegenerative disorders, Huntington's disease, multiple sclerosis, stroke, spinal cord injury, solid tumors,
  • ophthalmic diseases such as macular degeneration/retinal degeneration, including wet Age Related Macular Degeneration, dry ARMD, geographic atrophy, retinitis pigmentosa, choroidal neovascularization, vascular diseases/exudative diseases, retinopathy, including diabetic retinopathy, uveitis/retinitis/choroiditis, Stargard's disease, macular edema, retinal detachment, trauma, systemic disorders with associated retinal dystrophies, cone dystrophies, dystrophy of the retinal pigmented epithelium, myopic retinal degeneration, acute retinal pigment epithelitis, retinal tumors, retinal disease associated with tumors, which method comprises administering an amount of a compound of Formula (I) or (IA) effective in treating said disorders.
  • macular degeneration/retinal degeneration including wet Age Related Macular Degeneration, dry ARMD, geographic atrophy, retinitis pigmentosa, choroidal neovascular
  • treating refers to reversing, alleviating, or inhibiting the progress of the disorder to which such term applies, or one or more symptoms of the disorder.
  • the term also encompasses, depending on the condition of the patient, preventing the disorder, including preventing onset of the disorder or of any symptoms associated therewith, as well as reducing the severity of the disorder or any of its symptoms prior to onset.
  • Treating refers also to preventing a recurrence of a disorder.
  • Example 1 preparation of compounds according to the invention
  • the compounds were analyzed by reverse phase high performance liquid chromatography (HPLC) using a Waters Autopurification System equipped with a Waters 2525 Pump, a Waters 2696 photodiode array detector.
  • HPLC reverse phase high performance liquid chromatography
  • the Method A (10 min) was performed with an XTerraTM column (5 ⁇ , C18, 4.5 x 50 mm, Model # 186000482) or an XBridgeTM column (5 ⁇ , C18, 4.5 50 mm, Model # 1860031 13).
  • Solvent A was H 2 0 with 0.05% TFA and solvent B was CH 3 CN with 0.05% TFA.
  • the 10 min gradient run was realized using 1 .0 ml.
  • the reaction mixture was stirred at 0°C for 1 h (see conditions in table 1 a) and was poured into a 3 N HCI solution (typically 15 mL) and CH2CI2 (typically 180 mL) was added. After extraction, the combined separated organic layers were washed with brine (typically 50 mL), dried over MgS0 4 , filtered and evaporated to give after further drying the desired acylated compound. When necessary, the acylated compound was purified by column chromatography (S1O2, see conditions in table 1 a).
  • the aromatic aldehyde or ketone and aminoacetaldehyde diethyl acetal were placed in a 500 mL round-bottom flask and toluene was added (see conditions in table 1 b). The mixture was heated under reflux in a Dean-Stark apparatus (around 4 h, see conditions in table 1 b) until complete separation of water was achieved. Toluene was then evaporated to give after drying the desired iminoacetal in almost quantitative yield.
  • the iminoacetal ANP 31058A was prepared from 3,4-dimethoxybenzylamine (23.2 mmol) and pyruvic aldehyde dimethyl acetal (35.5 mmol) using the same general procedure (see conditions in table 1 b).
  • the desired iminoacetal was dissolved in EtOH and NaBH 4 was added portion wise over a 0.5 h period and the reaction mixture was refluxed for 1 h (see conditions in table 2).
  • the reaction mixture was concentrated under reduced pressure and the obtained residue was poured into water (typically 250 mL).
  • This mixture was extracted using CH2CI2 (typically 3x100 mL) and the combined organic layers were washed with H 2 0 (typically 2x150 mL), brine (typically 50 mL), dried over Mg 2 S0 4 and evaporated to give the desired aminoacetal.
  • Procedures F for preparation of compounds 108, 1 18, 122, 145, 146, 150 and 160 a) Preparation of compounds 108, 118, 122, 145, 146 and 160 (saponification of esters using of KOH, NaOH or LiOH)
  • the derivative LPO 55070A (120 mg, 0.28 mmol) was dissolved in a 37% aqueous HCI solution (1 mL) and AcOH (1 mL). The reaction mixture was stirred at 1 10°C for 4 h. After cooling, the solvents were evaporated and the residue was poured in n-BuOH (60 mL) and a 1 M K 2 C0 3 solution (30 mL) was added. The separated organic layer was washed with brine (20 mL), dried over MgS0 4 , filtered and evaporated. The crude product was purified by column chromatography (Si0 2 , see exact conditions in table 7) to give after evaporation and further drying to the vacuum pump the acid 150.
  • the 2-hydroxyquinoline derivative (free base of 49 or SSA 48042) was stirred in phosphoryl trichloride in an ace pressure tube (Aldrich) at 100-1 10°C for 2 h (see conditions in table 5). After cooling, the mixture was pourred in ice (10 g) and a 1 M aqueous K 2 C0 3 solution (5 mL) and EtOAc (150 mL) were added. The separated organic layer was washed with brine (20 mL), dried over MgS0 4 , filtered and evaporated.
  • the obtained ferf-butyl carbamate was then deprotected by stirring with a solution of TFA (1 mL) in CH 2 CI 2 (10 mL) for 1 h at RT. After concentration to dryness, the residue was taken back in EtOAc (150 mL) and a 1 M K 2 CO 3 solution (50 mL) was added. The separated organic layer was washed with H 2 0 (3x20 mL), brine (3x20 mL), dried over Na 2 S0 4 , filtered and evaporated to provide a residue. This residue was purified by flash chromatography (Si0 2 , see exact conditions in table 7) to give, after evaporation after further drying under vacuum, the aminoquinoline 92, 96 or 97.
  • 2-(1 ,3-Dioxolan-2-yl)quinolin-8-ol TTA 46034 500 mg, 2.30 mmol
  • ierf-butyl hydroperoxide 70% solution in water, 1 .5 mL, 16.1 1 mmol
  • sodium trifluoromethanesulfinate (1 .8 g, 1 1 .51 mmol) were dissolved in CH 3 CN (5 mL) and H 2 0 (2.5 mL) in a round bottom flask.
  • Phthalamide derivative LPO 50192C (58 mg, 0.103 mmol) was dissolved in EtOH (1 mL) and hydrazine hydrate (100 ⁇ , 2.06 mmol) was added. The reaction mixture was stirred under N 2 atmosphere at 80°C for 2 h. Phthalhydrazine was filtered off, the filtrate was evaporated, H 2 0 (10 mL) was added and the resulting solution was extracted with CH 2 CI 2 (3x30 mL).
  • the assay utilizes the IMAP technology, which is based on the high affinity binding of phosphate by immobilized metal coordination complexes on nanoparticles.
  • the binding reagent complexes with phosphate groups on nucleotide monophosphate generated from cyclic nucleotides (cAMP/cGMP) through phosphodiesterases.
  • cAMP/cGMP cyclic nucleotides
  • fluorescence polarization detection binding causes a change in the rate of the molecular motion of the phosphate bearing molecule, and results in an increase in the fluorescence polarization value observed for the fluorescent label attached to the substrate.
  • the PDE assay is based on the homogenous time-resolved fluorescence resonance energy transfer (TR-FRET) technology (LANCE ® from Perkin Elmer).
  • TR-FRET fluorescence resonance energy transfer
  • This competition based assay is formatted using a cAMP specific antibody labeled with the dye, Alexa Fluor ® 647, biotin-cAMP and streptavidin labeled with Europium (Eu- SA).
  • Eu- SA Europium
  • PDE activity resulting in the degradation of the cyclic nucleotide, the complex is not formed and a decrease in signal is observed.
  • the phosphodiesterase assay was developed using the LANCE ® cAMP kit
  • the assay buffer contained HBSS with 5 mM HEPES, 0.1 % BSA, and 1 .5 mM MgCI 2 , pH 7.4.
  • PDE1 OA BPS Bioscience was used at 200 pg/well (with a specific activity of 3200 pmole/min ⁇ g with assay conditions: 10 mM Tris-HCI, pH 7.4, 10 mM MgCI 2 , 1 mM MnCI 2 , 200 ⁇ cAMP, 2.5 kU 5' nucleotidase, 37°C, 20 min) and PDE4D3 (BPS Bioscience) was used at 100 pg/well (with a specific activity of 32713 pmole/min ⁇ g with assay conditions: 10 mM Tris-HCI, pH 7.4, 10 mM MgCI 2 , 1 mM MnCI 2 , 200 ⁇ cAMP, 2.5 kU 5' nucleotidase, 37°C, 20 min).
  • Biotin-cAMP tracer supplied in 10 mmol/L Tris-HCI buffered (pH 8.0) salt solution with 1 mmol/L ethylenediaminetetraacetic acid (EDTA), 0.1 % bovine serum albumin (BSA), and 0.05% sodium azide, is used at a dilution of 1 /375.
  • the assay detection mixture contained the LANCE Eu-W8044 labeled streptavidin 1/2250 (supplied in 50 mmol/L Tris-HCI buffered (pH 7.8) salt solution with 0.9% sodium chloride (NaCI), 0.1 % BSA, and 0.05% sodium azide) and the Alexa Fluor ® 647-anti cAMP antibody 1/200 (supplied in 50 mmol/L Tris-HCI buffered (pH 7.8) salt solution with 0.9% NaCI, 0.1 % BSA, and 0.05% sodium azide). Chemical compounds were dissolved in DMSO (final concentration 2% (v/v)).
  • the compounds of the present invention have PDE10A inhibitory activities generally less than 10,000 nM ( ⁇ 10,000 nM). In one embodiment, they have activities less than 1000 nM ( ⁇ 1000 nM); in another embodiment less than 500 nM ( ⁇ 500 nM); in another embodiment less than 100 nM ( ⁇ 100 nM); in another embodiment less than 50 nM ( ⁇ 50 nM); and in another embodiment less than 20 nM ( ⁇ 20 nM)
  • the compounds have also been tested for their activities on PDEs1 -9 and PDE1 1 .
  • the most active PDE10A inhibitors ( ⁇ 20 nM) are all selective (at least 120 to 10000-fold) vs PDEs1 -3, PDEs5-9 and PDE1 1 .

Abstract

The invention relates to compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R', R1 through R7 and Ar are as defined herein. These compounds are useful as inhibitors of phosphodiesterase 10 (PDE10A) which are useful in treating central nervous system diseases such as psychosis and also in treating, for example, obesity, type II diabetes, metabolic syndrome, glucose intolerance, pain and ophthalmic diseases.

Description

SUBSTITUTED 6,7-DIALKOXY-3-ISOQUINOLINE DERIVATIVES AS INHIBITORS OF PHOSPHODIESTERASE 10 (PDE10A) By Inventors: Bertrand Leblond, Thierry Taverne, Cedric Chauvignac Eric Beausoleil, Anne-Sophie Casagrande, Laurent Desire,
Matthew P. Pando, John E. Donello and Rong Yang
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application Ser. No. 61 /721 ,260 filed on November 1 , 2012, which is incorporated by reference herein in its entirety.
BACKGROUND OF THE INVENTION
Phosphodiesterases (PDEs) are a class of intracellular enzymes involved in the hydrolysis of the nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphates (cGMP) into their respective nucleotide monophosphates. The cyclic nucleotides cAMP and cGMP are synthesized by adenylyl and guanylyl cyclases, respectively.
The cAMP and cGMP function as intracellular second messengers regulating a vast array of intracellular processes particularly in neurons of the central nervous system. In neurons, this includes the activation of cAMP and cGMP-dependent kinases and subsequent phosphorylation of proteins involved in acute regulation of synaptic transmission as well as in neuronal
differentiation and survival. The complexity of cyclic nucleotide signaling is indicated by the molecular diversity of the enzymes involved in the synthesis and degradation of cAMP and cGMP.
There are at least ten families of adenylyl cyclases, two of guanylyl cyclases, and eleven of phosphodiesterases. Furthermore, different types of neurons are known to express multiple isozymes of each of these classes, and there is good evidence for compartmentalization and specificity of function for different isozymes within a given neuron.
A principal mechanism for regulating cyclic nucleotide signaling is by phosphodiesterase-catalyzed cyclic nucleotide catabolism. There are 1 1 known families of PDEs encoded by 21 different genes. Each gene typically yields multiple splice variants that further contribute to the isozyme diversity. The PDE families are distinguished functionally based on cyclic nucleotide substrate specificity, mechanism(s) of regulation, and sensitivity to inhibitors.
Furthermore, PDEs are differentially expressed throughout the organism, including in the central nervous system. As a result of these distinct enzymatic activities and localization, different PDEs' isozymes can serve distinct physiological functions. Furthermore, compounds that can selectively inhibit distinct PDE families or isozymes may offer particular therapeutic effects, fewer side effects, or both.
PDE10 is identified as a unique family based on primary amino acid sequence and distinct enzymatic activity. Homology screening of EST databases revealed human PDE10A as the first member of the PDE10 family of PDEs (Fujishige et al., J. Biol. Chem. , 274, 18438- 18445, 1999; Loughney, K. et al., Gene, 234, 109-1 17, 1999). The murine homologue has also been cloned (Soderling, S. et al., Proc. Natl. Acad. Sci. USA, 96, 7071 -7076, 1999) and N- terminal splice variants of both the rat and human genes have been identified (Kotera, J. et al., Biochem. Biophys. Res. Comm., 261 , 551 -557, 1999; Fujishige, K. et al., Eur. J. Biochem., 266, 1 1 18-1 127, 1999). There is a high degree of homology across species. The mouse PDE10A1 is a 779 amino acid protein that hydrolyzes both cAMP and cGMP to AMP and GMP, respectively. The affinity of PDE10 for cAMP (Km = 0.05 μΜ) is higher than for cGMP (Km = 3 μΜ). However, the approximately 5-fold greater Vmax for cGMP over cAMP has lead to the suggestion that PDE10 is a unique cAMP-inhibited cGMPase (Fujishige et al., J. Biol. Chem., 274, 18438-18445, 1999).
PDE10A also is uniquely localized in mammals relative to other PDE families. mRNA for PDE10 is highly expressed only in testis and brain
(Fujishige, K. et al., Eur J Biochem., 266, 1 1 18-1 127, 1999; Soderling, S. et al., Proc. Natl. Acad. Sci., 96, 7071 -7076, 1999; Loughney, K. et al., Gene, 234, 109-1 17, 1999).
These initial studies indicated that within the brain PDE10A expression is highest in the striatum (caudate and putamen), n. accumbens, and olfactory tubercle. More recently, a detailed analysis has been made of the expression pattern in rodent brain of PDE10 mRNA (Seeger, T.F. et al., Abst. Soc.
Neurosci., 26, 345.10, 2000) and PDE10 protein (Menniti, F.S., Stick, CA Seeger, T.F., and Ryan, A.M., Immunohistochemical localization of PDE10 in the rat brain, William Harvey Research Conference 'Phosphodiesterase in Health and Disease', Porto, Portugal, Dec. 5-7, 2001 ).
PDE10A was shown to be highly expressed in retinal neurons including photoreceptors. The levels of PDE10A transcript and protein display daily rhythms which could be seen in preparations of the whole retina (Wolloscheck T. et al, Brain Res. , 201 1 ,1376, 42-50. Epub 2010 Dec 29). These findings place PDE10A in the context of the visual system and suggest an important role of PDE10A in the adaptation of cyclic nucleotide signaling to daily changes in light intensity in retinal neurons including photoreceptors.
The tissue distribution of PDE10A indicates that PDE10A inhibitors can be used to raise levels of cAMP and/or cGMP within cells that express the PDE10 enzyme, especially neurons that comprise the basal ganglia, and the PDE10A inhibitors of the present invention would therefore be useful in treating a variety of associated neuropsychiatric conditions involving the basal ganglia such as neurological and psychiatric disorders, schizophrenia, bipolar disorder, obsessive compulsive disorder, and the like, and may have the benefit of not possessing unwanted side effects, which are associated with the current therapies on the market.
US 2003/0032579 discloses a method for treating certain neurologic and psychiatric disorders with the PDE10A inhibitor papaverine. In particular, the method relates to psychotic disorders such as schizophrenia, delusional disorders and drug-induced psychosis; to anxiety disorders such as panic and obsessive-compulsive disorder; and to movement disorders including
Parkinson's disease and Huntington's disease. Other indications which may be treated using a PDE10A inhibitor are described in WO 20055120514.
A variety of therapeutic uses for PDE inhibitors has been reported including obtrusive lung disease, allergies, hypertension, angina, congestive heart failure, depression and erectile dysfunction (WO 2001041807, incorporated herein by reference). Furthermore, publications (WO 2005120514, WO 2005012485, Cantin et al., Bioorg. & Med. Chem. Lett, 17, 2869-2873, 2007) suggest that PDE1 OA inhibitors may be useful for treatment of obesity and non-insulin dependent diabetes.
WO2012/1 12946 discloses substituted 6,7-dialkoxy-3-isoquinolinol derivatives as inhibitors of phosphodiesterase 10 (PDE10A).
WO 201 1 1 10545, WO 201 1051342 (Janssen Pharmaceutica NV) disclose respectively imidazo[1 ,2-a]pyrazine derivatives, imidazo[1 ,2- b]pyridazine derivatives PDE10A inhibitors useful for the treatment or prevention of neurological, psychiatric and metabolic disorders in which the PDE10 enzyme is involved.
WO 2012007006, WO 2012000519, WO 201 1072695, WO 201 1072697, WO 201 1072694, WO 201 1072696, WO 2010145668 (H. Lundbeck A/S) disclose respectively triazolo- and pyrazoloquinazoline derivatives, aryl- and heteroarylamide derivatives, phenylimidazole derivatives comprising an ethynylene linker, heteroaromatic aryl triazole derivatives, heteroaromatic phenylimidazole derivatives, 2-arylimidazole derivatives, novel phenylimidazole derivatives as PDE10A inhibitors reported to be useful for the treatment of psychiatric and neurodegenerative disorders including schizophrenia as well as bipolar disorders, anxiety, stress disorders and Alzheimer's, Parkinson's and Huntington's disease, dementia and attention deficit/hyperactivity disorder.
WO 201 1 150156 (Sunovion Pharmaceuticals Inc.) discloses heteroaryl compounds as PDE10A inhibitors useful for the treatment, prevention, and/or management of various disorders, such as CNS disorders and metabolic disorders, including, but not limited to, e.g., neurological disorders, psychosis, schizophrenia, obesity, and diabetes.
WO 2010138833 (Biotie Therapies GmbH - Wyeth) discloses
substituted imidazo[1 ,5-a]quinoxalines as PDE10A inhibitors useful in treating central nervous system diseases such as psychosis and also in treating, for example, obesity, type 2 diabetes, metabolic syndrome, glucose intolerance, and pain. WO 201 1053559 or WO 201 1022213 or WO 2010138430 and WO 2010138585 or WO 2010138430 (Merck & Co., Inc.) disclose respectively aryl or amino or alkoxy tetrahydro-pyridopyrimidine derivatives or pyrimidinones as PDE10A inhibitors useful for the treatment of neurological and psychiatric disorders including schizophrenia, delusional disorders, drug induced psychosis, anxiety, movement, mood and neurodegenerative disorders.
WO 2010138577 (Merck & Co., Inc.) discloses radiolabeled pyrimidinone compounds which are useful as radiotracers for quantitative imaging of PDE10A in mammals.
WO 201 1 138657, WO 201 1 132051 , and WO 201 1 132048 (Glenmark
Pharmaceuticals SA) disclose respectively aryl substituted olefinic compounds, tricyclic compounds, and heteroaryl compounds as PDE10A inhibitors reported to be useful for the treatment of schizophrenia.
WO 201 1 163355 & WO 2010090737 (Takeda Pharmaceutical Co., Ltd.) disclose respectively fused heterocyclic compounds and pyridazinone compounds as PDE1 OA inhibitors useful for the treatment of schizophrenia.
WO 2010128995 (EnVivo Pharmaceuticals, Inc.) discloses
phenoxymethyl heterocyclic compounds as PDE10A inhibitors useful for the treatment of schizophrenia, bipolar disorder, Huntington's disease, obesity and metabolic syndrome, among other disorders.
WO 20101 17926 (Schering Corp.) discloses substituted triazolopyridines and analogs thereof as PDE10A inhibitors reported to be useful for the treatment of schizophrenia, psychosis, Alzheimer's disease, bipolar disorder, depression, obesity, diabetes and metabolic syndrome.
WO 201 1051324 and WO 2010097367 (Janssen Pharmaceutica NV) disclose radiolabeled fluorinated azole PDE10A ligands reported to be useful in positron emission tomography imaging and quantification of PDE10A enzymes.
WO 201 1 1 17264, WO 201 1089132 & WO 201 1 154327, WO
201 1036127, and WO 2010094762 & WO 2010063610 (F. Hoffmann-La Roche AG) disclose respectively A/-(imidazopyrimidin-7-yl)-heteroarylamide
derivatives, nitrogen-containing heteroaryl derivatives, novel imidazopyridines, and heteroaryl substituted pyridazinone derivatives as PDE10A inhibitors reported to be useful for the treatment of schizophrenia, cognitive disorders, anxiety, substance abuse and dependence, Parkinson's disease, mood disorders, neurodegenerative disorders, stroke, diabetes and cancer, among other disorders.
WO 201 1 143366, WO 201 1 143365, WO 201 1 143495, WO 2010077992, and WO 2010057126 (Amgen Inc.) disclose respectively
heteroaryloxycarbocyclyl compounds, nitrogen heterocyclic compounds, heteroaryloxyheterocyclyl compounds, aminopyridine and carboxypyridine compounds, and pyridine and pyrimidine derivatives as PDE10A inhibitors that are considered to have potential in the treatment of psychiatric disorders such as schizophrenia, bipolar disorder, obsessive-compulsive disorder, obesity, non-insulin dependent diabetes.
WO 2010062559 (Schering Corp.) discloses substituted
pyrazoloquinolines and derivatives thereof as PDE1 OA inhibitors for the treatment of PDE10-modulated disorders.
WO 2010138833, WO 2010054253 & WO 2010054260 (Biotie
Therapies GmbH - Wyeth) disclose respectively substituted imidazo[1 ,5- a]quinoxalines and triazine derivatives as inhibitors of phosphodiesterases, particularly PDE10A and PDE2A, described as useful for the treatment of pain, cognitive disorders, diabetes, obesity, extrapyramidal disorders, epilepsy and psychiatric disorders such as depression, anxiety, schizophrenia and attention deficit/hyperactivity disorders.
JP 201 1201873, WO 201 1 105628, and WO 2010027097 (Mitsubishi Tanabe Pharma Corp.) disclose respectively trisubstituted pyrimidine compounds, pyrazolopyrimidine compounds, and tri-substituted pyrimidine compounds and their use as PDE10A inhibitors reported to be useful for the treatment of schizophrenia, anxiety, drug addiction, cognitive and mood disorders.
WO 201 1 1 12828 and WO 2010017236 (Omeros Corp.) disclose
PDE10A inhibitors described as useful for the treatment of neurological and psychiatric disorders such as schizophrenia and post-traumatic stress disorder as well as Parkinson's disease, Huntington's disease, Alzheimer's disease, encephalitis, phobias, epilepsy, pain, sleep disorders, bipolar disorder and multiple sclerosis.
US 2010016303 & WO 2009152825 (H. Lundbeck A/S) disclose novel phenylimidazole derivatives as PDE10A enzyme inhibitors to be useful in the treatment of psychiatric and neurological disorders such as schizophrenia, cognition deficits, Parkinson's disease, Alzheimer's disease, Huntington's disease and substance abuse, among others.
WO 2010006130 (EnVivo Pharmaceuticals, Inc.) discloses vicinal substituted cyclopropyl compounds as PDE10A inhibitors.
WO 2009158473, WO 2009158467 & WO 2009158393 (EnVivo
Pharmaceuticals, Inc.) disclose respectively 5- and 6 membered heterocyclic compounds, disubstituted phenyls compounds and 1 ,2-disubstituted
heterocyclic compounds as PDE10A inhibitors described as useful for the treatment of schizophrenia, Huntington's disease, obesity and metabolic syndrome.
WO 2009070583 (Wyeth) discloses pyrido(3,2-e)pyrazines as inhibitors of PDE10A that are considered to have potential in the treatment of psychosis, mood diseases, anxiety, neurodegenerative disorders, obesity, diabetes, metabolic diseases, pain.
WO 2009068320 & WO 2009070584 (Biotie Therapies GmbH) disclose aryl and heteroaryl fused imidazo(1 ,5-a)pyrazines as inhibitors of PDE1 OA that are active compounds for treating central nervous system diseases of mammals, including humans.
WO 2009152825 & WO 2009036766 (H. Lundbeck A/S) disclose respectively novel phenylimidazole derivatives and cyanoisoquinoline derivatives as PDE10A inhibitors.
WO 2009143178, WO 2008064342 & US 2008300240 (Omeros Corp.) disclose quinoline derivatives as PDE10A inhibitors active in psychotic, anxiety, movement disorders and/or neurological disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, encephalitis, phobias, epilepsy, aphasia, Bell's palsy, cerebral palsy, sleep disorders, pain, Tourette syndrome, schizophrenia, delusional disorders, drug-induced psychosis and panic and obsessive-compulsive disorders.
WO 2009025839 & WO 2009025823 (Amgen Inc.) disclose cinnoline derivatives as PDE10A inhibitors that are considered to have potential in the treatment of psychiatric disorders such as schizophrenia, bipolar disorder and obsessive-compulsive disorder.
WO 2009029214 (Amgen Inc. - Memory Pharmaceuticals Corp.) discloses isoquinolone derivatives as PDE10A inhibitors that are considered to have potential in the treatment of schizophrenia, bipolar disorder, obsessive- compulsive disorder, obesity and diabetes.
WO 2008032171 (Matrix Laboratories Ltd.) discloses dibenzofuran as inhibitors of PDE4 and PDE1 OA with potential utility in the treatment of asthma, chronic obstructive pulmonary disease, allergic rhinitis, atopic dermatitis, multiple sclerosis, Huntington disease, Alzheimer's disease, Parkinson's disease, schizophrenia and depression, among other disorders.
WO 2008020302 (Pfizer Products Inc.) discloses heteroaromatic quinoline-based compounds as selective PDE10A inhibitors.
WO 2008006372 (H. Lundbeck A/S) discloses 6,7-dialkoxyquinazoline and 6,7-dialkoxyisoquinoline derivatives as PDE10A inhibitors that are considered to have potential in the treatment of psychiatric and neurological disorders such as schizophrenia, cognition deficits, Parkinson's disease, Alzheimer's disease, dementia, epilepsy, multiple sclerosis and Huntington's diseases.
WO 20080041 17 & WO 2006072828 (Pfizer Products Inc.) disclose respectively selective azole compounds and heteroaromatic quinoline compounds as PDE10A inhibitors that are considered to have potential in the treatment of psychotic, anxiety, movement, mood and neurodegenerative disorders and obesity.
WO 2007137819 & WO 2007137820 (Biotie Therapies GmbH) disclose respectively 4-amino-pyrido(3,2-e)pyrazines and pyrido(3,2-e)pyrazines as PDE10A inhibitors. More particularly, the inventions relate to the treatment of neurologic and psychiatric disorders, for example psychosis and disorders comprising cognitive deficits as symptoms.
WO 2007103370, WO 2007103260, WO 2007100880 & WO
2007022280 (Amgen Inc. - Memory Pharmaceuticals Corp.) disclose quinazoline derivatives as PDE10A inhibitors that are considered to have potential in the treatment of schizophrenia, bipolar disorder and obsessive- compulsive disorder. Further applications include obesity and non-insulin diabetes.
WO 2007103554, WO 2007098214 & WO 2007098169 (Amgen Inc. - Memory Pharmaceuticals Corp.) disclose cinnoline derivatives as PDE10A inhibitors that are considered to have potential in the treatment psychiatric disorders such as schizophrenia, bipolar disorders and obsessive-compulsive disorder.
WO 2007096743 & WO 2007085954 (Pfizer Products Inc.) disclose respectively substituted quinazolines and aminophthalazine compounds as PDE10A inhibitors that are considered to have potential in the treatment of psychotic disorders, anxiety disorders, movement disorders such as Parkinson and Huntington diseases, mood disorders, obesity and drug addiction.
WO 2006089815 & WO 2006075012 (Nycomed GmbH) disclose novel pyrrolodihydroisoquinolines as PDE10A inhibitors with potential utility in the treatment of neurological and psychiatric disorders, in diabetes therapy and in the regulation of fertility.
WO 2006071988 & WO 2006028957 (Memory Pharmaceuticals Corp.) disclose respectively thienopyrimidine derivatives and 4-substituted-4,6- dialkoxy-cinnoline derivatives as PDE1 OA inhibitors that are considered to have potential in the treatment of psychosis, including schizophrenia, bipolar disorder and obsessive-compulsive disorder, Alzheimer's disease and movement disorders such as Parkinson's disease. Other conditions include epilepsy, multiple sclerosis, Huntington's disease, disorders relating to the basal ganglia, diabetes and obesity.
WO 2006070284 & WO 200601 1040 (Pfizer Products Inc.) disclose respectively pyrrolidyl derivatives of heteroaromatic compounds, and quinazolin-4-yl-piperidine and cinnolin-4-yl derivatives as PDE10A inhibitors that are considered to have potential in the treatment of CNS disorders, including schizophrenia, delusional disorders, drug-induced psychosis, anxiety, mood and movement disorders, neurodegenerative disorders and drug addiction.
WO 2005082883 (Pfizer Products Inc.) discloses tetrahydroisoquinolinyl derivatives of quinazoline and isoquinoline as PDE10A inhibitors that are claimed for use in the treatment of psychotic disorders, anxiety and movement disorders including Parkinson's disease and Huntington's disease, among other conditions.
WO 2006034512 & WO 2006034491 (Bayer Pharmaceuticals Corp.) disclose PDE1 OA inhibitors described as useful for the treatment of diabetes and related disorders. Pyrrolodihydroisoquinolines and variants thereof are disclosed as inhibitors of PDE10A in WO 2005003129 and WO 2005002579 (Nycomed GmbH).
WO 2004005291 & WO 2004005290 (Bayer Healthcare AG) disclose hetero-cyclically substituted imidazotriazines as PDE10A inhibitors described as useful for the treatment of neurodegenerative conditions, particularly
Parkinson's disease and schizophrenia, and cancer.
WO 2004002484 (Kyowa Hakko Kirin Co., Ltd.) discloses quinoline derivatives as PDE10A inhibitors with potential in the treatment of Parkinson's disease, dyskinesia, anxiety, stress, mood and cognitive disorders, drug abuse, schizophrenia, cerebrovascular disorders, erectile dysfunction, diabetes, ischemic cardiopathies, renal disorders, peripheral vascular disease, hypertension, urinary incontinence, autoimmune diseases, respiratory disorders, allergies, pain, osteoporosis, cancer.
WO 20030141 16 (Bayer Healthcare AG) discloses pyrrolo[2.1 - a]isoquinoline derivatives as PDE10A inhibitors with potential in the treatment of cancer. WO 2003000693 (Bayer Healthcare AG) discloses imidazotriazines for use as PDE1 OA inhibitors considered to have potential in the treatment of Parkinson's disease. All the above-mentioned publications are incorporated herein by reference.
However, these disclosures do not pertain to the compounds of the invention, which are structurally unrelated to any of the known PDE10A inhibitors (Kehler, J. et al., Expert Opin. Ther. Patents, 17, 147-158, 2007 and above cited patent literature), and which have now been found by the inventors to be highly active and selective PDE10A enzyme inhibitors.
The compounds of the invention offer alternatives to current marketed treatments for neurodegenerative and/or psychiatric disorders, which are not efficacious in all patients.
SUMMARY OF THE INVENTION
The present invention provides compounds that are PDE10A enzyme inhibitors, in particular selective PDE10A enzyme inhibitors. The present invention further provides compounds which have such activity. The invention also provides an effective treatment, in particular long-term treatment, of a human patient, without causing the side effects typically associated with current therapies for neurological and psychiatric disorders. Further aspects of the invention will become apparent upon reading the present specification.
In one aspect, the present invention relates to compounds of Formula (I):
Figure imgf000012_0001
Formula (I)
or a pharmaceutically acceptable salt, thereof, wherein:
R1 is selected from the group of H, optionally substituted (CrC6)alkyl, optionally substituted (C3-C6)cycloalkyl and optionally substituted aryl;
R2 is H;
R3 and R independently represent a (CrC3)alkyl group; R5 is H;
R6 and R7 are independently H;
R' is H or (CrC6)alkyl;
Ar is selected from the group consisting of: an optionally substituted fused nine- to ten-membered heteroaryl, optionally substituted benzo-fused aryl, optionally substituted benzo-fused heteroaryl, optionally substituted benzo-fused hetorocyclyl, and optionally substituted benzo-fused cycloalkyl, wherein two optional substituents at adjacent positions of each of said optionally substituted fused nine- to ten-membered heteroaryl, optionally substituted benzo-fused aryl, optionally substituted benzo-fused heteroaryl, optionally substituted benzo-fused hetorocyclyl, and optionally substituted benzo-fused cycloalkyl can be taken together with the atoms to which they are attached to form an aryl.
In another aspect, the present invention relates to compounds of Formula (IA):
Figure imgf000013_0001
Formula (IA)
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from the group of H, (CrC6)alkyl, (C3-C6)cycloalkyl and aryl;
R2 is H;
R3 and R independently represent a (CrC3)alkyl group;
R5 is H;
R6 and R7 are independently H;
R' is H or (Ci-C6)alkyl; and
Ar is selected from the group consisting of: an optionally substituted fused nine- to ten-membered heteroaryl, optionally substituted benzo-fused aryl, optionally substituted benzo-fused heteroaryl, optionally substituted benzo-fused hetorocyclyl, and optionally substituted benzo-fused cycloalkyl, wherein two optional substituents at adjacent positions of each of said optionally substituted fused nine- to ten-membered heteroaryl, optionally substituted benzo-fused aryl, optionally substituted benzo-fused heteroaryl, optionally substituted benzo-fused hetorocyclyl, and optionally substituted benzo-fused cycloalkyl can be taken together with the atoms to which they are attached to form an aryl; and pharmaceutically acceptable salts, tautomer forms, solvates and esters thereof.
In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound of Formula (I) or Formula (IA) as set forth above, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
In another aspect, the present invention provides a method for inhibiting PDE10A in a mammal, comprising administering to said mammal in need thereof, a therapeutically effective amount of at least one compound of Formula (I) or (IA) as set forth above or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a method for treating a disease in a mammal modulated by PDE10A, comprising administering to said mammal in need thereof, a therapeutically effective amount of at least one compound of Formula (I) or (IA) as set forth above or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
Within the context of the present application, the term "alkyl", alone or in combination with other groups, denotes linear or branched saturated
hydrocarbon radical containing preferably from 1 to 10 carbon atoms, in particular from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms, unless otherwise indicated. Examples of alkyl groups having from 1 to 6 carbon atoms inclusive are methyl, ethyl, propyl (e.g., n-propyl, iso-propyl), butyl (e.g., ferf-butyl, sec-butyl, n-butyl), pentyl (e.g., neo-pentyl), hexyl (e.g., n-hexyl), 2- methylbutyl, 2-methylpentyl and the other isomeric forms thereof. "Alkyl" may be unsubstituted or optionally substituted by one or more "ring system substituents" as defined herein below.
The term "halogen" denotes a chlorine, bromine, iodine or fluorine atom.
The term "acetylaminoalkyl" denotes a CH3CONH-alkyl group.
The term "alkoxy" denotes an alkyl-O- group, with alkyl as defined above. Examples of alkoxy groups are methoxy, ethoxy, n-propyloxy, isopropyloxy and sec-butyloxy.
"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1 -decalinyl, norbornyl, adamantyl and the like.
"Heterocyclyl" means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), - N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention. The heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like.
"Heterocyclyl" also includes heterocyclyl rings as described above wherein =0 replaces two available hydrogens on the same ring carbon atom. Example of such moiety is pyrrolidone, having the structure :
Figure imgf000016_0001
The term "aryl" refers to monocyclic or polycyclic (e.g. having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, antracenyl, phenanthrenyl and the like. In some embodiments, an aryl group has from 5 to 20 carbons, in particular from 6 to 14 carbon atoms. Most preferred aryl groups are mono- or bi-cyclic and comprises from 6 to 14 carbon atoms, such as phenyl, a-naphthyl, β-naphthyl, antracenyl. The aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.
The term "aryloxy" denotes an aryl-O- group, with aryl as defined above.
The term "heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen, phosphorus or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. "Heteroaryl" may also include a heteroaryl as defined above fused to an aryl as defined above. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4-thiadiazolyl, pyrazinyl, pyridazinyl,
quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1 ,2-a]pyridinyl, imidazo[2,1 - b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyndyl, quinazolinyl, thienopyrimidyl, pyrrolopyndyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1 ,2,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
"Ring system substituent" means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl,
heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy,
alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio,
heteroaralkylthio, cycloalkyl, heterocyclyl, -SF5, -OSF5 (for aryl), -0-C(0)-alkyl, -0-C(0)-aryl, -0-C(0)-cycloalkyl,
Figure imgf000017_0001
-C(=N-CN)-NH2, - C(=NH)-NH2, -C(=NH)-NH(alkyl), oxime (e.g., =N-OH), -NY^, -alkyl-NY^, - C(0)NY1Y2, -S02NY1Y2 and -S02NY1Y2, wherein Yi and Y2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring system substituent" may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CH3)2- and the like which form moieties such as, for example:
Figure imgf000017_0002
The term "optionally substituted" means optional substitution (i.e., unsubstituted or substituted) with the specified groups, radicals or moieties.
In one embodiment, in Formula (I) or (IA), R3 and R4 are both methyl. In another embodiment, in Formula (I) or (IA), the optionally substituted (Ci- C6)alkyl of Ri is selected from the group consisting of ethyl, n-propyl, n-butyl, and isobutyl; the optionally substituted aryl is optionally substituted phenyl; and the optionally substituted (C3-C6)cycloalkyl is selected from the group consisting of cyclopropyl and cyclohexyl.
In another embodiment, in Formula (I) or (IA), Ri is selected from the group consisting of ethyl, n-propyl, n-butyl, isobutyl, phenyl, cyclopropyl, and cyclohexyl.
In another embodiment, in Formula (I) or (IA), R' is selected from the group consisting of H and methyl.
In another embodiment, in Formula (I) or (IA), Ar is a fused nine to ten- membered heteroaryl and is an optionally substituted pyrazolo-pyridyl (e.g.,
Figure imgf000018_0001
that is attached to the carbon bearing the R6 and R7 groups through a carbon atom of the pyridyl ring.
In another embodiment, in Formula (I) or (IA), Ar is an optionally substituted benzo-fused aryl and is napthyl, wherein said naphthyl is
unsubstituted or substituted with a (C-i-C6)alkoxy.
In another embodiment, in Formula (I) or (IA), Ar is an optionally substituted benzo-fused heteroaryl, which is attached to the carbon bearing the R6 and R7 groups either through a carbon atom of the benzene ring or through a carbon atom of the heteroaryl ring, and wherein two optional substituents at adjacent positions of said benzofused heteroaryl can be taken together with the atoms to which they are attached to form an aryl.
In another embodiment, in Formula (I) or (IA), Ar is an optionally substituted said benzo-fused heteroaryl is selected from the group consisting of quinolinyl, benzofuranyl, benzopyrrolyl, benzothiophenyl, benzimidazolyl,
Figure imgf000018_0002
(e.g.,
Figure imgf000019_0001
each of which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, haloalkyl, cyano, optionally substituted aryl, -aryl-(C C6)alkyl-OH, -aryl-C(=0)-OH, -aryl-CN, - aryl-OH, -NH2, -NH(C C6)alkyl, N((C C6)alkyl))2, hydroxy, hydroxy-(C
C6)alkyl, -0-(d-C6)alkyl-tetrazolyl (e.g., -0-(C C6)alkyl-(1 H-tetrazol-5-yl), -O- (CrC6)alkyl-NH-C(=0)-(Ci-C6)alkyl, -0-(C C6)alkyl-N((Ci-C6)alkyl)-C(=0)-(Ci- C6)alkyl, -C(=0)-(C C6)alkyl (C C6)alkoxy, (C C6)alkyl, -0-(C C6)alkyl- pyridyl, -0-(C C6)alkyl-C(=0)-0-(Ci-C6)alkyl, -0-(C C6)alkyl-OH, -0-(C C6)alkyl-C(=0)-NH2, -0-(Ci-C6)alkyl-C(=0)-OH,
Figure imgf000019_0002
C6)alkyl), -0-(C C6)alkyl-C(=0)-NH-((Ci-C6)cycloalkyl), -NH-(C C6)alkyl, - NHS(=0)2NH2, -NHS(=0)2NH-(CrC6)alkyl, -NHS(=0)2-(C C6)alkyl, -N((C C6)alkyl)-S(=0)2-(CrC6)alkyl, -NH-C(=0)-(CrC6)alkyl-OH, -NH-C(=0)-C(=0)- 0-(CrC6)alkyl, -NH-C(=0)-C(=0)-NH2, -NH-C(=0)-NH2, -NH-C(=0)-(C
C6)alkyl-0-C(=0)-(Ci-C6)alkyl, -NH-C(=0)-(Ci-C6)alkyl, -P(=0)(OH)2, -N- pyrrolidin-2-one, and -NH-(Ci-C6)alkyl-NH-C(=0)-(Ci-C6)alkyl.
In another embodiment, in Formula (I) or (IA), Ar is an optionally substituted said benzo-fused heteroaryl is selected from the group consisting of quinolinyl, benzofuranyl, benzopyrrolyl, benzothiophenyl, benzimidazolyl,
dibenzofuranyl, carbazolyl, 4/-/-c benzo[d]oxazol-2(3H)-onyl (e.g.,
Figure imgf000019_0003
substituted or substituted with at least one substituent selected from the group consisting of halogen, hydroxy, (CrC6)alkoxy, (CrC6)alkyl, -0-(Ci-C6)alkyl-pyhdyl, -O- (Ci-C6)alkyl-C(=0)-0-(CrC6)alkyl, -0-(Ci-C6)alkyl-OH, -0-(C C6)alkyl-C(=0)- 0-NH2, -NH-(Ci-C6)alkyl, -NHS02NH2, and -NH-(Ci-C6)alkyl-NH-C(=0)-(Ci- C6)alkyl.
In another embodiment, in Formula (I) or (IA), Ar is a benzo-fused hetorocyclyl, which is attached to the carbon bearing the R6 and R7 groups through a carbon atom of the benzene ring of said benzo-fused heterocyclyl. In another embodiment, in Formula (I) or (IA), Ar is a benzo-fused hetorocyclyl, which is attached to the carbon bearing the R6 and R7 groups through a carbon atom of the benzene ring of said benzo-fused heterocyclyl, wherein said benzo-fused heterocyclyl is selected from the group consisting of indolinyl, chrom including alkylchromanyl and dialkyl chromanyl (e.g.,
Figure imgf000020_0001
tionally substituted dihydro-2H-
benzo[6][1 ,4]oxazinyl (e.g.,
Figure imgf000020_0002
each of which is unsubstituted or substituted at a nitrogen or carbon atom with at least one -(Ci-C6)alkyl.
In another embodiment, in Formula (I) or (IA), Ar is a benzo-fused cycloalkyl, which is attached to the carbon bearing the R6 and R7 groups through a carbon atom of the benzene ring of said benzo-fused cycloalkyl.
In another embodiment, in Formula (I) or (IA), Ar is a benzo-fused cycloalkyl, which is attached to the carbon bearing the R6 and R7 groups through a carbon atom of the benzene ring of said benzo-fused cycloalkyl, wherein said benzo-fused cycloalkyl is fluorenyl.
Specific compounds of formula (I) or (IA) which fall within the scope of the present invention include each of compounds 1 to 171 presented in the following "Examples" part. The invention thus relates to a compound of formula (I), selected in the group consisting of compounds 1 to 171 or a
pharmaceutically acceptable salt thereof:
6,7-dimethoxy-4-(naphthalen-2-ylmethyl)isoquinoline hydrochloride 1 ;
3- ((6,7-dimethoxyisoquinolin-4-yl)methyl)quinoline dihydrochloride 2;
4- (benzo[0]thiophen-5-ylmethyl)-6,7-dimethoxyisoquinoline hydrochloride 3; 4-((9H-fluoren-2-yl)methyl)-6,7-dimethoxyisoquinoline hydrochloride 4;
2-((6,7-dimethoxyisoquinolin-4-yl)methyl)quinoline dihydrochloride 5;
6-((6,7-dimethoxyisoquinolin-4-yl)methyl)quinoline dihydrochloride 6,
2-((6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-ol dihydrochloride 7, 3-((6 J-dimethoxyisoquinolin-4-yl)methyl)-7-methoxyquinoline dihydrochloride 8,
6 J-dimethoxy-4-((6-methoxynaphthalen-2-yl)methyl)isoquinoline hydrochloride 9,
4-(dibenzo[0,c/]furan-2-ylmethyl)-6,7-dimethoxyisoquinoline hydrochloride 10, 6,7-dimethoxy-4-((1 -methylindolin-5-yl)methyl)isoquinoline hydrochloride 11 , 7-((6 J-dimethoxyisoquinolin-4-yl)methyl)-4-methyl-3,4-dihydro-2/-/- benzo[6][1 ,4]oxazine hydrochloride 12,
3-((6,7-dimethoxyisoquinolin-4-yl)methyl)-A/,A/-dimethylquinolin-2-amine dihydrochloride 13,
3- ((6,7-dimethoxyisoquinolin-4-yl)methyl)-9-ethyl-9/-/-carbazole hydrochloride 14,
4- ((1 H-benzo[<^imidazol-5-yl)methyl)-6,7-dimethoxyisoquinoline dihydrochloride 15,
4-((4-chloro-1 -ethyl-1 H-pyrazolo[3,4-0]pyridin-5-yl)methyl)-6,7- dimethoxyisoquinoline dihydrochloride 16,
4- ((4-ethoxy-1 -ethyl-1 /-/-pyrazolo[3,4-0]pyridin-5-yl)methyl)-6,7- dimethoxyisoquinoline dihydrochloride 17,
5- ((6,7-dimethoxyisoquinolin-4-yl)methyl)-1 -ethyl-1 /-/-pyrazolo[3,4-0]pyridin-4-ol dihydrochloride 18,
2- chloro-3-((6,7-dimethoxyisoquinolin-4-yl)methyl)quinoline dihydrochloride 19,
3- ((6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-2-ol hydrochloride 20,
2-((6,7-dimethoxyisoquinolin-4-yl)methyl)-8-methoxyquinoline dihydrochloride 21 ,
6,7-dimethoxy-3-methyl-4-(naphthalen-2-ylmethyl)isoquinoline hydrochloride 22,
2-((6,7-dimethoxyisoquinolin-4-yl)methyl)-8-(pyridin-4-ylmethoxy)quinoline trihydrochloride 23,
2-((6,7-dimethoxyisoquinolin-4-yl)methyl)-8-(pyridin-3-ylmethoxy)quinoline trihydrochloride 24,
6,7-dimethoxy-1 -methyl-4-(naphthalen-2-ylmethyl)isoquinoline hydrochloride 25, 3-((6,7-dimethoxy-1 -methylisoquinolin-4-yl)methyl)quinoline dihydrochloride 26,
2- ((6,7-dimethoxyisoquinolin-4-yl)methyl)-8-ethoxyquinoline dihydrochloride 27,
3- ((6,7-diethoxyisoquinolin-4-yl)methyl)quinoline dihydrochloride 28,
3- ((6-ethoxy-7-methoxyisoquinolin-4-yl)methyl)quinoline dihydrochloride 31 , 2-((6,7-dimethoxyisoquinolin-4-yl)methyl)-8-propoxyquinoline dihydrochloride
32,
4- (dibenzo[0,<^furan-2-ylmethyl)-6,7-dimethoxy-1 -methylisoquinoline
hydrochloride 33,
4-((2,2-dimethylchroman-6-yl)methyl)-6,7-dimethoxyisoquinoline hydrochloride 34,
4-(dibenzo[0,c/]furan-2-ylmethyl)-6,7-dimethoxyisoquinoline 2-oxide 35,
4-(dibenzo[0,rf]furan-2-ylmethyl)-6-ethoxy-7-methoxyisoquinoline hydrochloride 37,
4-(dibenzo[0,<^furan-2-ylmethyl)-1 -ethyl-6,7-dimethoxyisoquinoline
hydrochloride 39,
4-(dibenzo[0,<^furan-2-ylmethyl)-6,7-dimethoxy-1 -propylisoquinoline
hydrochloride 40,
ethyl 2-((2-((6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-yl)oxy)acetate dihydrochloride 41 ,
2-((2-((6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-yl)oxy)ethanol dihydrochloride 42,
3-((6,7-dimethoxy-3-methylisoquinolin-4-yl)methyl)quinoline dihydrocloride 43, 3-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinoline dihydrochloride 44, 2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-8-ol dihydrochloride 45,
2- ((2-((6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-yl)oxy)acetamide 46,
3- ((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-2-ol dihydrochloride 47,
6-((6,7-dimethoxyisoquinolin-4-yl)methyl)-2-methylquinoline dihydrochloride 48, 3-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-6-methoxyquinolin-2-ol dihydrochloride 49,
3-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinoline dihydrochloride 50, 3-((1 -ethyl-6 J-dimethoxyisoquinolin-4-yl)methyl)-6-methoxyquinolin-2-ol dihydrochloride 51 ,
3-((6 J-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-6-ethoxyquinolin-2-ol dihydrochloride 52,
3-((6 J-dimethoxyisoquinolin-4-yl)methyl)-6-methoxyquinolin-2-ol
dihydrochloride 53,
3-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-6-methylquinolin-2-ol dihydrochloride 54,
2- ((3-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-6-methoxyquinolin-2- yl)oxy)acetonitrile 55,
A/-(2-((3-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-6-methoxyquinolin-2- yl)oxy)ethyl)acetamide dihydrochloride 56,
6-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-2-methylquinoline
dihydrochloride 57,
6-((1 -ethyl-6, 7-dimethoxyisoquinolin-4-yl)methyl)-2-methylquinoline
dihydrochloride 58,
6-((6,7-dimethoxy-1 -phenylisoquinolin-4-yl)methyl)-2-methylquinoline dihydrochloride 59,
6-((1 -cyclohexyl-6,7-dimethoxyisoquinolin-4-yl)methyl)-2-methylquinoline dihydrochloride 60,
3- ((1 -isobutyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinoline dihydrochloride 61 ,
3-((1 -cyclopropyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinoline
dihydrochloride 62,
3-((6,7-dimethoxy-1 -phenylisoquinolin-4-yl)methyl)quinoline dihydrochloride 63,
3- ((1 -butyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinoline dihydrochloride 64,
4- (isoquinolin-3-ylmethyl)-6,7-dimethoxy-1 -propylisoquinoline dihydrochloride 65,
4-(isoquinolin-3-ylmethyl)-6,7-dimethoxyisoquinoline dihydrochloride 66,
6-((1 -butyl-6,7-dimethoxyisoquinolin-4-yl)methyl)-2-methylquinoline
dihydrochloride 67, 6-((1 -isobutyl-6 J-dimethoxyisoquinolin-4-yl)methyl)-2-methylquinoline dihydrochloride 68,
3-((6 J-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-7-methylquinoline
dihydrochloride 69,
3-((1 -butyl-6,7-dimethoxyisoquinolin-4-yl)methyl)-7-methylquinoline 70,
1 -ethyl-4-(isoquinolin-3-ylmethyl)-6,7-dimethoxyisoquinoline dihydrochloride 72,
2- ((2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-8- yl)oxy)acetamide dihydrochloride 73,
3- ((6,7-dimethoxyisoquinolin-4-yl)methyl)-7-methylquinoline 74,
2-((2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-8-yl)oxy)ethanol 75,
A/-(2-((3-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-6-methoxyquinolin-2- yl)amino)ethyl)acetamide dihydrochloride 76,
3-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-A/-ethyl-6-methoxyquinolin- 2-amine dihydrochloride 77,
6-((1 -cyclopropyl-6,7-dimethoxyisoquinolin-4-yl)methyl)-2-methylquinoline dihydrochloride 78,
3-((6,7-dimethoxyisoquinolin-4-yl)methyl)-6-methyl-4/-/-chromen-4-one hydrochloride 79,
3-((6,7-dimethoxyisoquinolin-4-yl)methyl)-4/-/-chromen-4-one hydrochloride 80, 6-((6,7-dimethoxyisoquinolin-4-yl)methyl)-3-methylbenzo[c/]oxazol-2(3/-/)-one hydrochloride 81 ,
2-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-ol 82,
6-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-3-methylbenzo[c/]oxazol- 2(3H)-one dihydrochloride 82,
2-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-ol 83,
A/-(2-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-yl)sulfamide 84, A/-(2-((1 -propyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-yl)sulfamide 85, A/-(2-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8- yl)methanesulfonamide 86,
1 -(2-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-yl)urea 87,
A/-(2-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-yl)acetamide 88, A/-(2-((1 -ethyl-6 ,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8- yl)ethanesulfonamide 89,
2-((1 -ethyl-6 J-dimethoxyisoquinolin-4-yl)methyl)quinoline-8-carbonitrile 90, 2-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinoline-8-carboxamide 91 , ethyl 2-((2-((1 -ethyl-6, 7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-yl)amino)-
2- oxoacetate 92,
Λ/1-(2-((1 -ethyl-6, 7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-yl)oxalamide 93, Λ/-((2-((1 -ethyl-6, 7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8- yl)methyl)sulfamide 94,
3-((1 -ethyl-6, 7-dimethoxyisoquinolin-4-yl)methyl)quinolin-6-ol 95,
3- ((1 -ethyl-6, 7-dimethoxyisoquinolin-4-yl)methyl)quinolin-6-amine 96,
1 -(3-((1 -ethyl-6, 7-dimethoxyisoquinolin-4-yl)methyl)quinolin-6-yl)pyrrolidin-2- one 97,
Λ/1-(3-((1 -ethyl-6, 7-dimethoxyisoquinolin-4-yl)methyl)quinolin-6-yl)oxalamide 98, Λ/-(3-((1 -ethyl-6, 7-dimethoxyisoquinolin-4-yl)methyl)quinolin-6- yl)methanesulfonamide 99,
Λ/-(3-((1 -ethyl-6, 7-dimethoxyisoquinolin-4-yl)methyl)quinolin-6-yl)sulfamide 100, Λ/-(3-((1 -ethyl-6, 7-dimethoxyisoquinolin-4-yl)methyl)quinolin-6-yl)-/V- ethylmethanesulfonamide 101 ,
3-((6,7-dimethoxyisoquinolin-4-yl)methyl)-6-fluoro-4/-/-chromen-4-one hydrochloride 102,
6-chloro-3-((6,7-dimethoxyisoquinolin-4-yl)methyl)-4/-/-chromen-4-one hydrochloride 103,
6,8-dichloro-3-((6,7-dimethoxyisoquinolin-4-yl)methyl)-4/-/-chromen-4-one hydrochloride 104,
6-((6,7-dimethoxy-1 -methylisoquinolin-4-yl)methyl)-2-methylquinoline dihydrochloride 105,
5-((6,7-dimethoxyisoquinolin-4-yl)methyl)benzo[c/]oxazol-2(3/-/)-one
hydrochloride 106,
5-((6,7-dimethoxyisoquinolin-4-yl)methyl)-3-ethylbenzo[d]oxazol-2(3/-/)-one hydrochloride 107, 2- ((2-((6 J-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-8-yl)oxy)acetic acid dihydrochloride 108,
3- ((6 J-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-6-fluoro-4H-chromen-4-one hydrochloride 109,
3-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-6-methyl-4H-chromen-4-one hydrochloride 1 10,
6-((6,7-dimethoxyisoquinolin-4-yl)methyl)benzo[c/]oxazol-2(3/-/)-one
hydrochloride 111 ,
6-((6,7-dimethoxyisoquinolin-4-yl)methyl)-3-ethylbenzo[d]oxazol-2(3/-/)-one hydrochloride 112,
3-((6,7-dimethoxyisoquinolin-4-yl)methyl)-A/-ethyl-6-methoxyquinolin-2-amine dihydrochloride 113,
5-((6,7-dimethoxyisoquinolin-4-yl)methyl)-2-phenylbenzo[c/]oxazole 114, methyl 4-(5-((6,7-dimethoxyisoquinolin-4-yl)methyl)benzo[c/]oxazol-2- yl)benzoate 1 15,
2- ((2-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8- yl)oxy)acetamide 116,
3- ((6,7-dimethoxy-1 -methylisoquinolin-4-yl)methyl)-7-methylquinoline 117, sodium 3-((2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-8- yl)oxy)propanoate 118,
2-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-ol 119,
2-((2-((6,7-dimethoxy-1 -methylisoquinolin-4-yl)methyl)quinolin-8- yl)oxy)acetamide 120,
8-((1 /-/-tetrazol-5-yl)methoxy)-2-((6,7-dimethoxy-1 -propylisoquinolin-4- yl)methyl)quinoline 121 ,
sodium 3-((2-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8- yl)oxy)propanoate 122,
2-((1 -cyclopropyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-ol 123,
2-((6,7-dimethoxy-3-methylisoquinolin-4-yl)methyl)quinolin-8-ol 124,
2-((2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-8-yl)oxy)-/V- methylacetamide 125, A/-cyclopropyl-2-((2-((6 ,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-8- yl)oxy)acetamide 126,
8-((1 H-tetrazol-5-yl)methoxy)-2-((1 -ethyl-6,7-dimethoxyisoquinolin-4- yl)methyl)quinoline 127,
ethyl 2-((2-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8- yl)oxy)acetate 128,
3-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-6-methoxy-A/-methylquinolin 2-amine 129,
2-((2-((1 -cyclopropyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8- yl)oxy)acetamide 130,
2-((6,7-dimethoxy-1 -methylisoquinolin-4-yl)methyl)quinolin-8-ol 131 ,
2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-5-(trifluoromethyl)quinolin ol 132,
2-((2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-5- (trifluoromethyl)quinolin-8-yl)oxy)acetamide 133,
2-((2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-8-yl)oxy)-2- methylpropanamide 134,
2- ((2-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-yl)oxy)ethanol 135,
A/-(2-((2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-8- yl)oxy)ethyl)acetamide 136,
3- ((6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-6-ol 137,
2-((3-((6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-6-yl)oxy)acetamide 138, 2-((2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-8- yl)oxy)acetamide 139,
2- ((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-8-yl acetate 140, (4-(5-((6,7-dimethoxyisoquinolin-4-yl)methyl)benzo[c/]oxazol-2- yl)phenyl)methanol 141 ,
(4-(5-((6,7-dimethoxyisoquinolin-4-yl)methyl)benzo[c/]oxazol-2- yl)phenyl)methanol 142,
3- ((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-6-ol 143, 2-((3-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-6- yl)oxy)acetamide 144,
potassium 4-(5-((6 ,7-dimethoxyisoquinolin-4-yl)methyl)benzo[d]oxazol-2- yl)benzoate 145,
4-(5-((6,7-dimethoxyisoquinolin-4-yl)methyl)benzo[c/]oxazol-2-yl)benzoic acid 146,
5-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)benzo[c/]oxazol-2(3/-/)-one 147,
2-(5-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-2-oxobenzo[c/]oxazol- 3(2H)-yl)acetamide 148,
4-(5-((6,7-dimethoxyisoquinolin-4-yl)methyl)benzo[c/]oxazol-2-yl)aniline 149,
2-((3-((6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-6-yl)oxy)acetic acid 150,
(3-(5-((6,7-dimethoxyisoquinolin-4-yl)methyl)benzo[c/]oxazol-2- yl)phenyl)methanol 151 ,
2-((6,7-dimethoxy-1 -methylisoquinolin-4-yl)methyl)quinolin-8-amine 152,
4-(5-((6,7-dimethoxyisoquinolin-4-yl)methyl)benzo[c/]oxazol-2-yl)benzonitnle
153,
(2-(5-((6,7-dimethoxyisoquinolin-4-yl)methyl)benzo[c/]oxazol-2- yl)phenyl)methanol 154,
3-((6,7-dimethoxy-1 -methylisoquinolin-4-yl)methyl)quinolin-6-ol 155,
(2-(6,7-dimethoxy-1 -methyl-isoquinolin-4-ylmethyl)-quinolin-8-yl)-sulfamide 156, 2-((6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-amine 157,
2- ((2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-8-yl)amino)-2- oxoethyl acetate 158,
(2-(6,7-dimethoxy-1 -methyl-isoquinolin-4-ylmethyl)-quinolin-8-yl)-sulfamide 159, A/-(2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-8-yl)-2- hydroxyacetamide 160,
3- ((6,7-dimethoxyisoquinolin-4-yl)methyl)-5-(trifluoromethyl)quinolin-6-ol 161 , 3-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-5-(trifluoromethyl)quinolin 01 162,
2-((6,7-dimethoxy-1 -(methoxymethyl)isoquinolin-4-yl)methyl)quinolin-8-ol 163, 2-((2-((6 J-dimethoxy-1 -(methoxymethyl)isoquinolin-4-yl)methyl)quinolin-8 yl)oxy)acetamide 164,
Ethyl 2-((2-((6 J-dimethoxy-1 -(methoxymethyl)isoquinolin-4-yl)methyl)quinolin- 8-yl)oxy)acetate 165,
2-((2-((6,7-dimethoxy-1 -(methoxymethyl)isoquinolin-4-yl)methyl)quinolin-8- yl)oxy)ethanol 166,
2- ((6,7-dimethoxy-1 -(methoxymethyl)isoquinolin-4-yl)methyl)quinolin-8-ami 167,
3- ((6,7-dimethoxy-1 -(methoxymethyl)isoquinolin-4-yl)methyl)quinolin-6-ol 168, 3-((6,7-dimethoxy-1 -(methoxymethyl)isoquinolin-4-yl)methyl)-5-
(trifluoromethyl)quinolin-6-ol 169,
(4-(6-((6,7-dimethoxyisoquinolin-4-yl)methyl)benzo[c/]oxazol-2- yl)phenyl)methanol 170,
and sodium 3-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-6-yl phosphate 171 ; or a pharmaceutically acceptable salt thereof.
The compounds according to the present invention may be prepared by various methods known to those skilled in the art. General and specific methods for the preparation of compounds of formula (I) and (IA) are described herein below.
The intermediary compounds TTA 24128B, SSA 39098, SSA 39102,
SSA 48072, SSA 48066, SSA 40084 and SSA 48100 were prepared in three synthetic steps from veratrole: a Friedel and Craft acylation of veratrole in anhydrous CH2CI2 with the desired commercially available acid chloride in presence of aluminium trichloride followed by an amination of the obtained ketone with aminoacetaldehyde diethyl acetal, preferentially at reflux in toluene (150°C for 4 h), using a Dean Stark apparatus and finally the reduction of the obtained iminoacetal using sodium borohydride in ethanol at reflux (100°C) (Reaction scheme 1 ).
Figure imgf000030_0001
Reaction Scheme 1 : Synthetic routes used for the preparation of intermediary compounds TTA 24128B, SSA 39098, SSA 39102, SSA 48060, SSA 48072, SSA 48066, SSA 40084, SSA 48100, TTA 46082B, LPO 22102, ECO 33100, ECO 33118, ECO 33124, ECO 33138, TTA 24150B, TTA 24156B and ANP 31060A.
TTA 46082B was prepared in three synthetic steps from 1 -(3,4- dimethoxyphenyl)-2-hydroxyethanone (CAS#37803-48-8): a methylation of 1 - (3,4-dimethoxyphenyl)-2-hydroxyethanone in anhydrous CH2CI2 in presence of silver (I) oxide and iodomethane at RT for 48 h gave 2-methoxy-1 -(3,4- dimethoxyphenyl)ethanone ECO 59016. ECO 59016 was then treated with aminoacetaldehyde diethyl acetal, preferentially under reflux in toluene (1 10°C for 4 h), using a Dean Stark apparatus followed by a subsequent reduction of the obtained iminoacetal TTA 46082A using sodium borohydride in refluxing at reflux (78°C) to give TTA 46082B (Reaction scheme 1 ).
The intermediates LPO 22102, ECO 33100, ECO 33118, ECO 33124, ECO 33138, TTA 24150B and TTA 24156B were prepared in two synthetic steps by amination of the corresponding commercially available aldehydes with aminoacetaldehyde diethyl acetal, preferentially under reflux in toluene at 1 10°C for 4 hours using a Dean Stark apparatus, followed by a subsequent reduction of the obtained iminoacetals using sodium borohydride in refluxing ethanol (78°C) (reaction scheme 1 ). The intermediary compound ANP 31060A was prepared in two steps by amination of (3,4-dimethoxyphenyl)methanamine with 1 ,1 -dimethoxypropan-2-one, preferentially in refluxing toluene (1 10°C for 4 h) and using a Dean Stark apparatus, followed by a subsequent reduction of the obtained (£)-1 -(3,4-dimethoxyphenyl)-A/-(1 ,1 -dimethoxypropan-2- ylidene)methanamine using sodium borohydride in refluxing ethanol (78°C) (reaction scheme 1 ).
The compounds 1-20, 22, 25, 26, 28-31 , 33, 34, 36-40, 43-45, 47-54, 57- 72, 74, 78-83, 95, 102-105, 109, 110, 117, 1 19, 123, 124, 131 , 132, 137, 143, 155, 161 -163, 168, 169 and intermediates SSA 48042, LPO 55070B, ANP 49174B, ANP 53134 and ANP 53006A were prepared from the corresponding aromatic aldehydes (1 equivalent) and the corresponding aminoacetaldehyde diethyl or dimethyl acetals (1 equivalent) in a one to one mixture of absolute EtOH and a 37% HCI solution, preferentially at 90-1 10°C for 15-30 min and in an ace pressure tube (Aldrich). After neutralization and purification of the obtained free base by column chromatography (Si02), when needed, the free base (1 equivalent) was dissolved in MeOH and a 1 .75 N HCI solution in MeOH (2.1 eq x number of basic nitrogen) was added and all the volatiles were evaporated to give the desired isoquinolines as hydrochloride salts (reaction scheme 1 ).
The aromatic aldehydes used to obtain the compounds of the invention were commercially available or can be prepared following the synthetic routes described in reaction scheme 2.
The aldehydes LPO 43162A and ANP 49046 were prepared following the procedure described by Sing, Mrityunjay et al. , Tetrahedron letters, 48(34), 5987-90, 2007 and the aldehyde LPO 43136A from the procedure described by Kalluraya, Balakhrishna et al. , Indian Journal of Chemistry, 42B(1 ), 21 1 -214, 2003. The 7-methoxy- and 7-methyl-quinoline-3-carbaldehydes were prepared following the procedure described by Tom, Norma J. et al., Synthesis, (9), 1351 -1355, 2001 .
The masked aldehyde 3-(1 ,3-dioxolan-2-yl)-7-methylquinoline SSA 48104 was prepared in two steps from 2-chloro-7-methylquinoline-3- carbaldehyde by treatment with ethane-1 ,2-diol in presence of p- toluenesulfonic acid (PTSA) in toluene followed by a reduction of the chlorine atom of the obtained 2-chloro-3-(1 ,3-dioxolan-2-yl)-7-methylquinoline SSA 48098 by hydrogenation catalyzed by Pd/C 10% in presence of K2C03 as base and MeOH as solvent.
The masked aldehyde 3-(1 ,3-dioxolan-2-yl)-quinolin-6-ol LPO 55016 was obtained via a similar method as for SSA 48104 from 2-chloro-6- hydroxyquinoline-3-carbaldehyde LPO 50188A. LPO 50188A itself was prepared by treatment of 2-chloro-6-methoxyquinoline-3-carbaldehyde by boron tribromide (BBr3) in dichloromethane. Finally quinolin-6-ol LPO 55016 was O-alkylated by treatment with ethyl 2-bromoacetate and cesium carbonate as a base in acetone for 2 hours at 85°C to yield ethyl 2-((3-(1 ,3-dioxolan-2- yl)quinolin-6-yl)oxy)acetate LPO 55070A (reaction scheme 2).
Figure imgf000033_0001
Figure imgf000033_0002
Reaction Scheme 2: Preparation of non-commercially available aldehydes The masked aldehyde 3-(1 ,3-dioxolan-2-yl)-8-(trifluoromethyl)quinolin-5- ol LPO 50180C was prepared by radical trifluoromethylation of dioxolane TTA 46034 using a methodology developed by Langlois B. et al., Tetrahedron Lett., (32), 51 , 7525-7528, 1991 and modified by Baran P. et al., PNAS, 108, 35, 1441 1 -14415, 201 1 (reaction scheme 2).
The masked aldehyde 3-(dimethoxymethyl)-5-(trifluoromethyl)quinolin-6- ol ECO 55152 was prepared by radical trifluoromethylation via photoredox catalysis of dimethylacetal ECO 55108C using a methodology developed by MacMillan D. et ai, Nature, 480, 224-228, 201 1 (reaction scheme 2). The 4-chloro-1 -ethyl-1 H-pyrazolo[3,4-6]pyridine-5-carbaldehyde SAO 33058 was obtained in two steps from ethyl 4-chloro-1 -ethyl-1 /-/-pyrazolo[3, 4- 0]pyridine-5-carboxylate (described by Hamblin, J. Nicole et al., Bioorg. Med. Chem. Lett., 18(14), 4237-41 , 2008).
Reduction of 4-chloro-1 -ethyl-1 /-/-pyrazolo[3,4-0]pyridine-5-carboxylate by LiBH4 in THF provided the alcohol SAO 33034 that was oxidized in aldehyde SAO 33058 using Dess-Martin periodinane reagent in dichloromethane for 1 hour at 4°C then overnight at RT (reaction scheme 2).
In some cases the products obtained by following the reaction scheme 1 may be further modified, for example, by manipulation of substituents.
Figure imgf000034_0001
Reaction Scheme 3: Preparation of compounds 21 , 23, 24, 27, 32, 41 , 42, 46, 73 and 75
The compounds 21 , 23, 24, 27, 32, 41 and 46 were prepared from the free base of 7 (Ri = H) by O-alkylation using the corresponding halogenoalkyl (Reaction Scheme 3). The compounds ANP 49102A and 73 were prepared from SSA 48106 (Ri = n-propyl) by O-alkylation using the corresponding halogenoalkyl. The compounds 42 and 75 were prepared respectively from the compounds 41 and ANP 49102A by reduction of the ester function using sodium borohydride in a mixture of ferf-butanol/MeOH at 140°C for 2 hours in an ace pressure tube (reaction Scheme 3).
The compounds 55, 56 and 76 were prepared from the free base of compound 49.
The reaction of compound 49 in dimethylformamide at 90°C for 1 hour with 2-chloroacetonitrile, in presence of cesium carbonate as a base, led to compound 55.
The compound 55 can be hydrogenated in presence of hydrogen and 10% Pd/C as catalyst in methanol at room temperature to yield compound LPO 43180. The compound LPO 43180 was acetylated for 2 hours at 4°C in tetrahydrofuran with acetic anhydride, in presence of triethylamine as base, to give the free base of compound 56 that was subsequently transformed in its dihydrochloride salt by treatment with a 1 .75 N HCI solution in methanol at room temperature (reaction scheme 4).
Figure imgf000035_0001
i) POCI3 2 h at 100°C; ii) Pd(OAc)2 fBuXPhos, tBuOK, NH2CH2CH2NH2i toluene, 8 h at 100°C; iii) Ac20, Et3N, THF, 4°C for 2 h then 1.75 N HCI solution in MeOH, MeOH, RT; iv) 2-chloroacetonitrile, Cs2C03, D F, 90°C for 1 h; v) H2/Pd/C, MeOH, HCI.
Reaction Scheme 4: Preparation of compounds 55, 56 and 76
The treatment of compound 49 with phosphorus oxychloride for 2 hours at 100°C gave the aryl chloro derivative LPO 50012. The compound LPO 50016 was prepared by a Buchwald-Hartwig reaction of the compound LPO 50012 preferentially at 100°C for 8 hours in toluene with ethylenediamine, in presence of palladium(ll) acetate as catalyst, 2-(di-ferf-butylphosphino)biphenyl (JohnPhos) as ligand, and potassium ferf-butoxide as base. The acetylation of compound LPO 50016 for 2 hours at 4°C in tetrahydrofuran with acetic anhydride, in presence of triethylamine as base, gave the free base of compound 76 that was subsequently transformed in its dihydrochloride salt by treatment with a 1 .75 N hydrochloride solution in methanol at room temperature (reaction scheme 4).
Figure imgf000036_0001
R = n-propyl: 129
i) 2-(di-ierf-butylphosphino)biphenyl, 2 N EtNH2 in THF, Pd(OAc)2, fBuOK, toluene; 170°C for 5 h (R = H); 100°C for 6 h (R = n-propyl) then 1.76 N HCI solution in MeOH, MeOH, 4 °C for 15 min.
ii) Dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2 N MeNH2 in THF, Pd(OAc)2, fBuOK, toluene;
145°C for 25 min.
Reaction Scheme 5: Preparation of compounds 77, 113 and 129.
The compounds 77 and 113 were preferentially respectively prepared from the aryl chloro derivative LPO 50012 and LPO50042C by a Buchwald- Hartwig reaction, at 170°C for 5 hours (77) or 100°C for 6 hours (113) in toluene with a 2 N solution of diethylamine in tetrahydrofuran, in presence of palladium(ll) acetate as catalyst, JohnPhos as ligand, and potassium tert- butoxide as base. The obtained free bases were transformed into their corresponding dihydrochloride salt 77 and 113 by treatment with a 1 .76 N hydrochloride solution in methanol for 15 minutes at 4°C (reaction scheme 5). The compound 129 was preferentially obtained from LPO 50012 by a Buchwald-Hartwig reaction at 145°C for 25 min in toluene with a 2 N solution of diethylamine in tetrahydrofuran, in presence of palladium(ll) acetate as catalyst, 2-(di-ferf-butylphosphinobiphenyl) as ligand, and potassium ferf-butoxide as base.
Figure imgf000037_0001
Free base of 10 35
Reaction Scheme 6: Preparation of compound 35
The A/-oxide derivative 35 was prepared from the free base of compound 10 by oxidation using preferentially mefa-chloroperbenzoic acid in dichloromethane for 24 hours (reaction scheme 6).
Figure imgf000037_0002
R = H: 7 R = H: ANP 57032A 53% R = H: 157 60% R H: 1592%
R = Me: 131 R = Me: ANP 53184A 52% R = Me: 152 16% R Me: 156 22%
R = ethyl: 83 R = ethyl: RBO 51116 80% R = ethyl: RBO 51118B 80% R ethyl: 8447% (recryst. in CH3CN: 27%) R = n-propyl: 45 R = n-propyl: LPO 55036C 72% R = n-propyl: LPO 55056D 65% R n-propyl: 85 53%
R = MeOCH,: 163 R = MeOCH,: ECO 59060 47% R = MeOCH,: 167 20% R MeOCH,: 119 10% i) W-phenyl-bis(trifluoromethanesulfonimide), Et3N, DMF, RT or 40°C, 16 h. ii) i. Benzophenone imine, Cs2C03 BINAP, Pd2(dba)3,
anh. toluene, reflux, overnight, ii. THF, 5 N or 3 N HCI , RT, 1-4 h. iii. NaHC03 to reach pH = 7. iii) Sulfamide, 1,4-dioxane, reflux, 15-16 h.
Reaction Scheme 7: Preparation of compounds 84, 85, 119, 152, 156, 157, 159 and 167. The sulfamide derivatives 159, 156, 84, 85 and 1 19 were prepared respectively from phenols 7, 131 , 83, 45 and 163 in three steps (reaction scheme 7). The phenols 7, 131 , 83, 45 and 163 were treated in DMF with N- phenyl-bis(trifluoromethanesulfonimide) in presence of triethylamine at RT or 40°C to give, respectively, the triflates ANP 57032A, ANP 53184A, RBO 51 116, LPO 55036C and ECO 59060. Palladium-catalyzed amination (Buchwald-Hartwig reaction) overnight at reflux between the triflates ANP 57032A, ANP 53184A, RBO 51116, LPO 55036C and ECO 59060 and benzophenone imine, using a catalyst consisting of a combination of tris(dibenzylideneacetone)dipalladium(0) and BINAP in presence of cesium carbonate in dry toluene, afforded respectively, after HCI hydrolysis in tetrahydrofuran at RT for 1 to 4 hours, anilines 157, 152, RBO 51 118B, LPO 55056D and 167. A final treatment of anilines 157, 152, RBO 511 18B, LPO 55056D and 167 with sulfamide for 15-16 hours reflux in refluxing 1 ,4-dioxane gave respectively, after purification, sulfamides 159, 156, 84, 85 and 119 (reaction scheme 7).
Figure imgf000038_0001
RB0 51118B i) R - S02CH3, 86 (83%) ii) R = S02C2H5, 89 (40%) iii) R = COCH3, 88 (60%) iv) R = CONH2, 87 (43%) v) R = COCONH2, 93 (61 %) i) Methane sulfonyl chloride, pyridine, CH2CI2, MW at 70°C, 30 min, 83%. ii) Ethane sulfonyl chloride, pyridine, CH2CI2, MW at 70°C, 3 h, 40%. iii) Ac20, pyridine, NMP, THF, RT, 15 h, 60%. iv) KOCN, AcOH, Water, 40°C, 3 h, 43%. v) 2-amino-2-oxoacetyl chloride, Et3N, THF, RT, 15 h, 30%.
Reaction Scheme 8: Preparation of compounds 86-89 and 93.
The compounds 86-89 and 93 were prepared from aniline RBO 51118B as described in reaction scheme 8.
Figure imgf000038_0002
Reaction Scheme 9: Preparation of compounds 90-92 and 94.
The amide 91 was prepared by basic hydrolysis of the nitrile 90 that was prepared from inflate RBO 51116 as described in reaction scheme 9. The compounds 92 and 94 were also prepared from triflate RBO 511 16 as described in reaction scheme 9.
Figure imgf000039_0001
Reaction Scheme 10: Preparation of compounds 96 to 101 . The compounds 96 to 101 were prepared as described in reaction scheme 10.
Figure imgf000040_0001
LPO 55056D 158 160 i) Acetoxyacetylchloride, pyridine, dry THF, 0°C to RT, 1 h, 95%. ii) 2 M LiOH in THF, 70°C, THF, 2 h, 73%.
Reaction Scheme 11 : Preparation of compounds 158 and 160. The compounds 158 and 160 were prepared as described in reaction scheme 1 1 .
Figure imgf000041_0001
Reaction Scheme 12: Preparation of compounds 106, 107, 114, 115, 142, 145, 146, 149, 151 , 153 and 154.
The compounds 106, 107, 114, 115, 142, 145, 146, 149, 151 , 153 and
154 were prepared as described in Reaction Scheme 12.
Figure imgf000042_0001
Reaction Scheme 13: Preparation of compounds 106, 111 and 112.
The compounds 111 , 112 and 170 were prepared as described in reaction Scheme 13.
Figure imgf000042_0002
Reaction Scheme 14: Preparation of compounds 147 and 148.
The compounds 147 and 148 were prepared as described in reaction scheme 14.
Figure imgf000043_0001
Figure imgf000043_0002
Reaction Scheme 15: Preparation of compounds 41 , 42, 46, 108, 116, 118, 120, 122, 128, 130, 135, 139,148, 164, 165 and 166.
The compounds 41 , 42, 46, 108, 116, 118, 120, 122, 128, 130, 135, 139,148, 164, 165 and 166 were prepared as described in reaction scheme 15.
Figure imgf000043_0003
Reaction Scheme 16: Preparation of compounds 125 and 126. The compounds 165 and 166 were prepared as described in reaction scheme 16.
Reaction Scheme 17: Preparation of compounds 45, 134, 136 and 140.
The compounds 45, 134, 136 and 140 were prepared as described in reaction sche
Figure imgf000044_0002
i) 2-Bromoacetamide, Cs2C03, acetone, reflux, 1 h, 44-73%. ii) Ac20, 130°C, 15 h, 41 %.
Reaction Scheme 18: Preparation of compounds 138, 141 and 144. The compounds 138, 141 and 144 were prepared as described in reaction schem
Figure imgf000045_0001
i) i. POCI3, Et3N, THF, 30 min, 4°C. ii. 5 N NaOH, 15 min, RT, 48%.
Reaction Scheme 19: Preparation of compound 171 .
The compound 171 was prepared as described in reaction scheme 19.
It should be understood that other ways of producing these compounds may be designed by the skilled person, based on common general knowledge and following guidance contained in this application.
Another object of the present invention is the intermediate compounds used for the preparation of compounds of formula (I) or (IA). In particular, the present invention relates to the intermediate compounds herein below mentioned in the examples.
Included within the scope of the invention are all stereoisomers, tautomeric forms, salts and solvates of the compound of formula (I) or (IA).
The compounds according to the invention can be in the form of salts, particularly acid or base salts, preferably compatible with pharmaceutical use (i.e. pharmaceutically acceptable salts of the compounds of the invention). It will be appreciated by those skilled in the art that non-pharmaceutically acceptable salts of compounds of formula (I) or (IA) are also part of the present invention, since such non-pharmaceutically acceptable salts can be useful as intermediates in the preparation of pharmaceutically acceptable salts.
Salts of compounds of the invention include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium, and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include
hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p- toluenesulfonic acids, sulphates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaphthoates, glycerophosphates, ketoglutarates and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci., 66, 2, 1977 which is incorporated herein by reference.
Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like. Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium,
hydroxyethylammonium, diethylammonium, butylammonium,
tetramethylammonium salts and the like. Other examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline and the like.
The pharmaceutically acceptable salts can in particular be prepared by reacting the compound of formula (I) or (IA) with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p- toluenesulphonic acid, methanesulfonic acid, fonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane, etc. Mixture of solvents may also be used.
Compounds of Formula (I) or (IA) may have optical centers and therefore may occur in different enantiomeric and diastereomeric
configurations. The present invention includes all enantiomers, diastereomers, and other stereoisomers of such compounds of Formula (I) or (IA), as well as racemic compounds and racemic mixtures and other mixtures of stereoisomers thereof.
The compounds according to the present invention may be prepared by various methods known to those skilled in the art. General and specific methods for the preparation of compounds of formula (I) or (IA) are described herein below.
The compounds of the invention can be administered alone, but are generally administered with a pharmaceutical carrier, with respect to standard pharmaceutical practice (such as described in Remington's Pharmaceutical Sciences, Mack Publishing), in either single or multiple doses. The invention thus also includes a pharmaceutical composition comprising, in a
pharmaceutically acceptable carrier, a compound of formula (I) or (IA).
Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed thereby can then be readily administered in a variety of dosage forms such as tablets, powders, lozenges, liquid preparations, syrups, injectable solutions and the like. These pharmaceutical compositions can optionally contain additional ingredients such as flavorings, binders, excipients and the like. Thus, the compound of the invention may be formulated for oral, ocular, buccal, intranasal, parenteral (e.g. intravenous, intramuscular or subcutaneous), transdermal (e.g. patch) or rectal administration, or in a form suitable for administration by inhalation or insufflation. The pharmaceutical compositions of the invention can be formulated either as solid or liquid compositions.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g.
pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl
methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycolate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).
For buccal administration, the composition may take the form of tablets or lozenges formulated in conventional manner.
The compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g. in ampoules or in multi-dose containers, with an added preservative. They may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use. When a product solution is required, it can be made by dissolving the isolated inclusion complex in water (or other aqueous medium) in an amount sufficient to generate a solution of the required strength for oral or parenteral administration to patients. The compounds may be formulated for fast dispersing dosage forms, which are designed to release the active ingredient in the oral cavity. These have often been formulated using rapidly soluble gelatin-based matrices. These dosage forms are well known and can be used to deliver a wide range of drugs. Most fast dispersing dosage forms utilize gelatin as a carrier or structure-forming agent. Typically, gelatin is used to give sufficient strength to the dosage form to prevent breakage during removal from packaging, but once placed in the mouth, the gelatin allows immediate dissolution of the dosage form.
Alternatively, various starches are used to the same effect. The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
The dosages and dosage regimen in which the compounds of formula (I) are administered will vary according to the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired.
Accordingly, optimal therapeutic concentrations will be best determined at the time and place through routine experimentation.
The compounds according to the invention can be used enterally or parenterally. Orally, the compounds according to the invention are suitably administered in the amount from about 0.1 mg per day to 1 ,000 mg per day. For parenteral, sublingual, intranasal, or intrathecal administration, the compounds according to the invention are suitably used in the amount from about 0.5 to about 100 mg/day; for depo administration and implants from about 0.5 mg/day to about 50 mg/day; for topical administration from about 0.5 mg/day to about 200 mg/day; for rectal administration from about 0.5 mg to about 500 mg. In a preferred aspect, the therapeutically effective amounts for oral administration is from about 1 mg/day to about 100 mg/day; and for parenteral administration from about 5 to about 50 mg daily. In a more preferred aspect, the therapeutically effective amounts for oral administration are from about 5 mg/day to about 50 mg/day.
The compounds of the present invention can also be administered intraocularly (e.g., intravitreally (e.g., through injection) subconjunctival^, or injection into subtenon space).
For intravitreal administration, the weight of the device (i.e., drug plus carrier/vehicle/excipinent) is typically 1 mg (which for example may be administered with a 22 G needle) and the drug load is normally 10-50%. The drug dose range for intravitreal administration is normally about 100-500 μg. However, the drug load can be stretched to 2-65%, i.e., a drug dose range of 20-650 μg can be used. However, the device weight may be 1 .5 mg, and for this a drug dose range of 20-975 μg can be used. Another way of intravitreal delivery is by injecting drug suspension formulation. For this, the dose range is 10-600 ug.
An intraocular implant comprising a therapeutically effective amount of a compound of Formula (I) or (IA) (the therapeutic component; the active pharmaceutical ingredient (API)), and a drug release sustaining polymer component associated with the therapeutic compound can also be
administered by intraocular means. As used herein, an "intraocular implant" refers to a device or element that is structured, sized, or otherwise configured to be place in an eye. Intraocular implants are generally biocompatible with physiological conditions of an eye and do not cause adverse side effects.
Intraocular implants may be place in an eye without disrupting vision of the eye.
The implant may be solid, semisolid, or viscoelastic. The drug release sustaining component is associated with the therapeutic component to sustain release of an amount of the therapeutic component into an eye in which the implant is placed.
The therapeutic component may be released from the implant by diffusion, erosion, dissolution or osmosis. The drug release sustaining component may comprise one or more biodegradable polymers or one or more non-biodegradable polymers. Examples of biodegradable polymers of the present implants may include poly-lactide-co-glycolide (PLGA and PLA), polyesters, poly (ortho ester), poly(phosphazine), polyphosphate ester), polycaprolactone, natural polymers such as gelatin or collagen, or polymeric blends. The amount of the therapeutic component is released into the eye for a period of time greater than about one week after the implant is placed in the eye and is effective in reducing or treating an ocular condition.
In one embodiment, the intraocular implant comprises a therapeutic component and a biodegradable polymer matrix. The therapeutic component is associated with a biodegradable polymer matrix that degrades at a rate effective to sustain release of an amount of the therapeutic component from the implant effective to treat an ocular condition. The intraocular implant is biodegradable or bioerodible and provides a sustained release of the therapeutic component in an eye for extended periods of time, such as for more than one week, for example for about one month or more and up to 5 about six months or more. The implant may be configured to provide release of the therapeutic component in substantially one direction, or the implant may provide release of the therapeutic component from all surfaces of the implant.
The biodegradable polymer matrix of the foregoing implant may be a mixture of biodegradable polymers or the matrix may comprise a single type of biodegradable polymer. For example, the matrix may comprise a polymer selected from the group consisting of polylactides, poly(lactide-co-glycolides), polycaprolactones, and combinations thereof.
In another embodiment, the intraocular implant comprises the therapeutic component and a polymeric outer layer covering the therapeutic component. The polymeric outer layer includes one or more orifices or openings or holes that are effective to allow a liquid to pass into the implant, and to allow the therapeutic component to pass out of the implant.
The therapeutic component is provided in a core or interior portion of the implant, and the polymeric outer layer covers or coats the core. The polymeric outer layer may include one or more non-biodegradable portions. The implant can provide an extended release of the therapeutic component for more than about two months, and for more than about one year, and even for more than about five or about ten years. One example of such a polymeric outer layer covering is disclosed in U.S. Pat. No. 6,331 ,313.
In one embodiment, the present implant provides a sustained or controlled delivery of the therapeutic component at a maintained level despite the rapid elimination of the therapeutic component from the eye. For example, the present implant is capable of delivering therapeutically effective amounts of the therapeutic component for a period of at least about 30 days to about a year despite the short intraocular half-lives that may be associated with the therapeutic component. Plasma levels of the therapeutic component obtained after implantation may be extremely low, thereby reducing issues or risks of systemic toxicity. The controlled delivery of the therapeutic component from the present implants would permit the therapeutic component to be administered into an eye with reduced toxicity or deterioration of the blood-aqueous and blood-retinal barriers, which may be associated with intraocular injection of liquid formulations containing the therapeutic component.
A method of making the present implant involves combining or mixing the therapeutic component with a biodegradable polymer or polymers. The mixture may then be extruded or compressed to form a single composition. The single composition may then be processed to form individual implants suitable for placement in an eye of a patient.
Another method of making the present implant involves providing a polymeric coating around a core portion containing the therapeutic component, wherein the polymeric coating has one or more holes. The implant may be placed in an ocular region to treat a variety of ocular conditions, such as treating, preventing, or reducing at least one symptom associated with nonexudative age related macular degeneration (ARMD), exudative age related macular degeneration, choroidal neovascularization, acute macular
neuroretinopathy, cystoid macular edema, diabetic macular edema, Behcet's disease, diabetic retinopathy, retinal arterial occlusive
The daily dose may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.
The present invention also relates to a compound of formula (I) or (IA), or a composition comprising a compound of formula (I) or (IA), for use as a medicament. Indeed, the compounds according to the invention have been found to have pharmacologically important properties which can be used therapeutically. The compounds of the invention can be used alone, in combination with each other or in combination with other active compounds.
The compounds of the invention are inhibitors selective for PDE10A. The invention thus also relates to a compound of formula (I) or (IA) or a
pharmaceutical composition comprising the same, for use in a method for the treatment of a disease selected in the group consisting of the diseases or groups of diseases described below, where inhibition of PDE10 would be efficient in the treatment of said diseases. The present invention also pertains to a pharmaceutical composition for use in the potential treatment of certain psychotic disorders and conditions such as schizophrenia, delusional disorders and drug induced psychosis; to anxiety disorders such as panic and obsessive-compulsive disorder; and to movement disorders including Parkinson's disease and Huntington's disease, comprising an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A.
In another embodiment, the invention relates to a pharmaceutical composition for potentially treating psychotic disorders and condition such as schizophrenia, delusional disorders and drug induced psychosis; anxiety disorders such as panic and obsessive-compulsive disorder; and movement disorders including Parkinson's disease and Huntington's disease, comprising an amount of a compound of formula (I) effective in treating said disorder or condition.
The invention also relates to a compound of formula (I) or (IA), for use in the potential treatment of certain psychotic disorders and conditions such as schizophrenia, delusional disorders and drug induced psychosis; to anxiety disorders such as panic and obsessive-compulsive disorder; and to movement disorders including Parkinson's disease and Huntington's disease.
Examples of psychotic disorders that can potentially be treated according to the present invention include, but are not limited to, schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; delusional disorder; substance- induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type. Examples of movement disorders that can potentially be treated according to the present invention include but are not limited to Huntington's disease and dyskinesia associated with dopamine agonist therapy, Parkinson's disease, restless leg syndrome, and essential tremor. Other disorders that can potentially be treated according to the present invention are obsessive/compulsive disorders, Tourette's syndrome and other tic disorders.
In another embodiment, the invention relates to a method for potentially treating an anxiety disorder or condition in a mammal which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A.
The invention also provides a method for potentially treating an anxiety disorder or condition in a mammal which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in treating said disorder or condition.
The invention also relates to a compound of formula (I) or (IA), for use in the potential treatment of an anxiety disorder or condition in a mammal.
Examples of anxiety disorders that can potentially be treated according to the present invention include, but are not limited to, panic disorder;
agoraphobia; a specific phobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; acute stress disorder; and generalized anxiety disorder.
The invention further provides a method of potentially treating a drug addiction, for example an alcohol, amphetamine, cocaine, or opiate addiction, in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in treating drug addiction. The invention also provides a method of treating a drug addiction, for example an alcohol, amphetamine, cocaine, or opiate addiction, in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A.
The invention also relates to a compound of formula (I) or (IA), for use in the treatment of a drug addiction, for example an alcohol, amphetamine, cocaine, or opiate addiction, in a mammal, including a human. A "drug addiction", as used herein, means an abnormal desire for a drug and is generally characterized by motivational disturbances such a compulsion to take the desired drug and episodes of intense drug craving.
The invention further provides a method of potentially treating a disorder comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in treating said disorder. The invention also provides a method of potentially treating a disorder or condition comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A.
The invention also provides a method of potentially treating a disorder or condition comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in treating said disorder or condition.
The invention also relates to a compound of formula (I) or (IA), for use in the potential treatment of a disorder or condition comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human.
The phrase "deficiency in attention and/or cognition" as used herein in "disorder comprising as a symptom a deficiency in attention and/or cognition" refers to a subnormal functioning in one or more cognitive aspects such as memory, intellect, or learning and logic ability, in a particular individual relative to other individuals within the same general age population. "Deficiency in attention and/or cognition" also refers to a reduction in any particular individual's functioning in one or more cognitive aspects, for example as it occurs in age-related cognitive decline. Examples of disorders that comprise as a symptom a deficiency in attention and/or cognition that can be treated according to the present invention are dementia, for example Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention- deficit/hyperactivity disorder; and age-related cognitive decline.
The invention also provides a method of potentially treating a mood disorder or mood episode in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula (I) or (IA) effective in treating said disorder or episode.
The invention also provides a method of potentially treating a mood disorder or mood episode in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A.
The invention also relates to a compound of formula (I) or (IA), for use in the treatment of a mood disorder or mood episode in a mammal, including a human
Examples of mood disorders and mood episodes that can be treated according to the present invention include, but are not limited to, major depressive episode of the mild, moderate or severe type, a manic or mixed mood episode, a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post- stroke depression; major depressive disorder; dysthymic disorder; minor depressive disorder; premenstrual dysphoric disorder; post-psychotic depressive disorder of schizophrenia; a major depressive disorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia; a bipolar disorder, for example bipolar I disorder, bipolar II disorder, and cyclothymic disorder.
The invention further provides a method of potentially treating a neurodegenerative disorder or condition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in treating said disorder or condition. The invention further provides a method of potentially treating a neurodegenerative disorder or condition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A. The invention also provides to a compound of formula (I) or (IA), for use in the treatment of a neurodegenerative disorder or condition in a mammal, including a human.
As used herein, and unless otherwise indicated, a "neurodegenerative disorder or condition" refers to a disorder or condition that is caused by the dysfunction and/or death of neurons in the central nervous system. The treatment of these disorders and conditions can be facilitated by administration of an agent which prevents the dysfunction or death of neurons at risk in these disorders or conditions and/or enhances the function of damaged or healthy neurons in such a way as to compensate for the loss of function caused by the dysfunction or death of at-risk neurons. The term "neurotrophic agent" as used herein refers to a substance or agent that has some or all of these properties.
Examples of neurodegenerative disorders and conditions that can potentially be treated according to the present invention include, but are not limited to, Parkinson's disease; Huntington's disease; dementia, for example Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, and Fronto temperal Dementia; neurodegeneration associated with cerebral trauma;
neurodegeneration associated with stroke, neurodegeneration associated with cerebral infarct; hypoglycemia-induced neurodegeneration; neurodegeneration associated with epileptic seizure; neurodegeneration associated with neurotoxin poisoning; and multi-system atrophy.
In one embodiment of the invention, the neurodegenerative disorder is Parkinson's disease or Alzheimer's disease.
In one embodiment of the present invention, the neurodegenerative disorder or condition comprises neurodegeneration of striatal medium spiny neurons in a mammal, including a human.
In a further embodiment of the present invention, the neurodegenerative disorder or condition is Huntington's disease.
The invention also provides a pharmaceutical composition for potentially treating psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, mood disorders, neurodegenerative disorders, obesity, and drug addiction, comprising an amount of a compound of formula (I) or (IA) effective in treating said disorder or condition.
The invention also provides a method of potentially treating a disorder selected from psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, obesity, mood disorders, and neurodegenerative disorders, which method comprises administering an amount of a compound of formula (I) or (IA) effective in treating said disorder.
The invention also provides to a compound of formula (I) or (IA), for use in the potential treatment of a disorder selected from psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, obesity, mood disorders, and neurodegenerative disorders.
The invention also provides a method of potentially treating disorders selected from the group consisting of: dementia, Alzheimer's disease, multi- infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder; age- related cognitive decline, major depressive episode of the mild, moderate or severe type; a manic or mixed mood episode; a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post-stroke depression; major depressive disorder; dysthymic disorder; minor depressive disorder; premenstrual dysphoric disorder; post-psychotic depressive disorder of schizophrenia; a major depressive disorder superimposed on a psychotic disorder comprising a delusional disorder or schizophrenia; a bipolar disorder comprising bipolar I disorder, bipolar II disorder, cyclothymic disorder, Parkinson's disease;
Huntington's disease; Fronto temperal Dementia; neurodegeneration associated with cerebral trauma; neurodegeneration associated with stroke; neurodegeneration associated with cerebral infarct; hypoglycemia- induced neurodegeneration; neurodegeneration associated with epileptic seizure;
neurodegeneration associated with neurotoxin poisoning; multi-system atrophy, paranoid, disorganized, catatonic, undifferentiated or residual type;
schizophreniform disorder; schizoaffective disorder of the delusional type or the depressive type; delusional disorder; substance-induced psychotic disorder, psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, obesity, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type, which method comprises administering an amount of a compound of Formula (I) or (IA) effective in treating said disorders. The invention thus also provides a compound of formula (I) or (IA), for use in the treatment of the diseases mentioned in the previous sentence.
The invention also provides a method for the potential treatment of psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, mood disorders, neurodegenerative disorders, obesity, and drug addiction which method comprises administering an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A.
The invention also provides a method for the potential treatment of diseases of the retina, which method comprises administering an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A. By "diseases of the retina," the applicants mean any condition of the retina which impairs the normal functioning of the retina, its surrounding tissues, or the eye. These include macular degeneration, myopic retinal degeneration, diabetic
retinopathy, choroidal neovascularization, macular edema (also referred to as cystoid macular edema and macular swelling), epiretinal membrane (macular pucker), macular hole, retinitis (such as retinitis pigmentosa), macular dystrophies (such as Stargardt's juvenile macular degeneration, Best's vitelliform dystrophy, cone dystrophies, and pattern dystrophy of the retinal pigmented epithelium), retinal detachment, retinal trauma, retinal tumors and retinal diseases associated with them, congenital hypertrophy of the retinal pigmented epithelium, acute posterior multifocal placoid pigment epitheliopathy, acute retinal pigment epithelitis, and uveitis (including iritis, pars planitis, choroiditis, retinitis, and chorioretinitis).
According to a particular aspect, the invention relates to a compound of formula (I) or a composition comprising a compound of formula (I) or (IA), for use in a method for the potential treatment of type I or type II diabetes, impaired glucose tolerance, impaired fasting glucose, metabolic syndrome, metabolism related disorders including excess of body weight or excess of body fat in obese patients, psychotic disorders, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, delusional disorder, substance-induced psychotic disorder, anxiety disorders, panic disorder, obsessive/compulsive disorders, acute stress disorder, generalized anxiety disorder, drug addictions, movement disorders, Parkinson's disease, restless leg syndrome, cognition deficiency disorders, Alzheimer's disease, multi-infarct dementia, mood disorders, depression, bipolar disorders, neuropsychiatric conditions, psychosis, attention- deficit/hyperactivity disorder, attention disorders, diabetes and related disorders, type 2 diabetes mellitus, neurodegenerative disorders, Huntington's disease, multiple sclerosis, stroke, spinal cord injury, solid tumors, hematological malignancies, renal cell carcinoma and breast cancer, pain, ophthalmic diseases such as macular degeneration/retinal degeneration, including wet Age Related Macular
Degeneration (ARMD), dry ARMD, retinitis pigmentosa, choroidal
neovascularization, vascular diseases/exudative diseases, retinopathy, including diabetic retinopathy, uveitis/retinitis/choroiditis, Stargard's disease, macular edema, retinal detachment, trauma, systemic disorders with associated retinal dystrophies, cone dystrophies, dystrophy of the retinal pigmented epithelium, myopic retinal degeneration, acute retinal pigment epithelitis, retinal tumors, retinal disease associated with tumors.
The invention further relates to a method for the potential treatment of type I or type II diabetes, impaired glucose tolerance, impaired fasting glucose, metabolic syndrome, metabolism related disorders including excess of body weight or excess of body fat in obese patients, psychotic disorders,
schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, delusional disorder, substance-induced psychotic disorder, anxiety disorders, panic disorder, obsessive/compulsive disorders, acute stress disorder, generalized anxiety disorder, drug addictions, movement disorders, Parkinson's disease, restless leg syndrome, cognition deficiency disorders, Alzheimer's disease, multi-infarct dementia, mood disorders, depression, bipolar disorders, neuropsychiatric conditions, psychosis, attention- deficit/hyperactivity disorder, attention disorders, diabetes and related disorders, type 2 diabetes mellitus, neurodegenerative disorders, Huntington's disease, multiple sclerosis, stroke, spinal cord injury, solid tumors,
hematological malignancies, renal cell carcinoma and breast cancer, pain, ophthalmic diseases such as macular degeneration/retinal degeneration, including wet Age Related Macular Degeneration (ARMD), dry ARMD, geographic atrophy, retinitis pigmentosa, choroidal neovascularization, vascular diseases/exudative diseases, retinopathy, including diabetic retinopathy, uveitis/retinitis/choroiditis, Stargard's disease, macular edema, retinal detachment, trauma, systemic disorders with associated retinal dystrophies, cone dystrophies, dystrophy of the retinal pigmented epithelium, myopic retinal degeneration, acute retinal pigment epithelitis, retinal tumors, retinal disease associated with tumors, which method comprises administering an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A.
The invention further relates to a method for the potential treatment of type I or type II diabetes, impaired glucose tolerance, impaired fasting glucose, metabolic syndrome, metabolism related disorders including excess of body weight or excess of body fat in obese patients, psychotic disorders,
schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, delusional disorder, substance-induced psychotic disorder, anxiety disorders, panic disorder, obsessive/compulsive disorders, acute stress disorder, generalized anxiety disorder, drug addictions, movement disorders, Parkinson's disease, restless leg syndrome, cognition deficiency disorders, Alzheimer's disease, multi-infarct dementia, mood disorders, depression, bipolar disorders, neuropsychiatric conditions, psychosis, attention- deficit/hyperactivity disorder, attention disorders, diabetes and related disorders, type 2 diabetes mellitus, neurodegenerative disorders, Huntington's disease, multiple sclerosis, stroke, spinal cord injury, solid tumors,
hematological malignancies, renal cell carcinoma and breast cancer, pain, ophthalmic diseases such as macular degeneration/retinal degeneration, including wet Age Related Macular Degeneration, dry ARMD, geographic atrophy, retinitis pigmentosa, choroidal neovascularization, vascular diseases/exudative diseases, retinopathy, including diabetic retinopathy, uveitis/retinitis/choroiditis, Stargard's disease, macular edema, retinal detachment, trauma, systemic disorders with associated retinal dystrophies, cone dystrophies, dystrophy of the retinal pigmented epithelium, myopic retinal degeneration, acute retinal pigment epithelitis, retinal tumors, retinal disease associated with tumors, which method comprises administering an amount of a compound of Formula (I) or (IA) effective in treating said disorders.
The term "treating", as in "a method of treating a disorder", refers to reversing, alleviating, or inhibiting the progress of the disorder to which such term applies, or one or more symptoms of the disorder. As used herein, the term also encompasses, depending on the condition of the patient, preventing the disorder, including preventing onset of the disorder or of any symptoms associated therewith, as well as reducing the severity of the disorder or any of its symptoms prior to onset. "Treating" as used herein refers also to preventing a recurrence of a disorder.
The following examples illustrate the invention. However, it is to be understood that the invention is not limited to the details provided in these examples.
EXAMPLES
Example 1 : preparation of compounds according to the invention
General
1H-NMR and 13C-NMR spectra were recorded at ambient temperature with an Advance 300 (Bruker) spectrometer.
The compounds were analyzed by reverse phase high performance liquid chromatography (HPLC) using a Waters Autopurification System equipped with a Waters 2525 Pump, a Waters 2696 photodiode array detector. The Method A (10 min) was performed with an XTerra™ column (5 μιη, C18, 4.5 x 50 mm, Model # 186000482) or an XBridge™ column (5 μιη, C18, 4.5 50 mm, Model # 1860031 13). Solvent A was H20 with 0.05% TFA and solvent B was CH3CN with 0.05% TFA. The 10 min gradient run was realized using 1 .0 ml. min"1 with 5% B in A (0.0-1 .0 min), 5% to 100% B in A (1 .0-7.0 min), 100% to 5% B in A (7.0-7.5 min), 5 B in A (7.5-10.0 min). The 5 min gradient run was realized using 1 .0 mL min"1 with 5% B in A (0.0-0.25 min), 5% to 100% B in A (0.25-3.0 min), 100% to 5% B in A (3.0-4.0 min), 5% B in A (4.0-5.0 min).
Melting points were measured with a Buchi B-545 melting point apparatus and were uncorrected. Microwave reactions were performed in a Biotage Initiator 60 EXP microwave reactor.
To isolate reaction products the solvent were removed by evaporation using a vacuum rotatory evaporator, unless otherwise indicated, the water bath temperature did not exceed 40°C.
General procedure for Friedel-Crafts acylation of 1 ,2-dimethoxybenzene
(veratrole): preparation of compounds TTA 24178A, TTA 24178B, SSA 48078, SSA 48050. SSA 48090. SSA 48054. and SSA 48046 In a 100 mL round bottom flask at -4°C, AICI3 was dissolved in anhydrous CH2CI2 and the desired acyl chloride was added portion wise (see conditions in table 1 a). After complete addition, the mixture was stirred at -4°C for 5 min under a nitrogen atmosphere and a solution of veratrole in anhydrous CH2CI2 was slowly added drop wise over 15 min (see conditions in table 1 a). The reaction mixture was stirred at 0°C for 1 h (see conditions in table 1 a) and was poured into a 3 N HCI solution (typically 15 mL) and CH2CI2 (typically 180 mL) was added. After extraction, the combined separated organic layers were washed with brine (typically 50 mL), dried over MgS04, filtered and evaporated to give after further drying the desired acylated compound. When necessary, the acylated compound was purified by column chromatography (S1O2, see conditions in table 1 a).
General Procedure for preparation of iminoacetals: preparation of compounds LPO 22100. ANP 31058A. TTA 24128A. SSA 39096. SSA 39100. SSA 48080. SSA 48058. SSA 48092. SSA 48064. SSA 48052. ECO 33094. ECO 33114. ECO 33122. ECO 33134. TTA 24150A. TTA 24156A and TTA 46082A
The aromatic aldehyde or ketone and aminoacetaldehyde diethyl acetal were placed in a 500 mL round-bottom flask and toluene was added (see conditions in table 1 b). The mixture was heated under reflux in a Dean-Stark apparatus (around 4 h, see conditions in table 1 b) until complete separation of water was achieved. Toluene was then evaporated to give after drying the desired iminoacetal in almost quantitative yield. The iminoacetal ANP 31058A was prepared from 3,4-dimethoxybenzylamine (23.2 mmol) and pyruvic aldehyde dimethyl acetal (35.5 mmol) using the same general procedure (see conditions in table 1 b).
General procedure for reduction of iminoacetals to aminoacetals: preparation of compounds LPO 22102. ANP 31060A. TTA 24128B. SSA 39098. SSA 39102. SSA 48084. SSA 48066. SSA 48100. SSA 48072. SSA 48060. ECO 33100. ECO 33118. ECO 33124. ECO 33138. TTA 24150B. TTA 24156B and TTA
46082B
The desired iminoacetal was dissolved in EtOH and NaBH4 was added portion wise over a 0.5 h period and the reaction mixture was refluxed for 1 h (see conditions in table 2). The reaction mixture was concentrated under reduced pressure and the obtained residue was poured into water (typically 250 mL). This mixture was extracted using CH2CI2 (typically 3x100 mL) and the combined organic layers were washed with H20 (typically 2x150 mL), brine (typically 50 mL), dried over Mg2S04 and evaporated to give the desired aminoacetal.
TABLE 1
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
TABLE 2
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Preparation of compounds 1 -169
General procedure A for preparation of compounds 1-20, 22, 25, 26, 28-31 , 33, 34, 36-40, 43-45, 47-54, 57-72, 74. 78-83, 95, 102-105, 109, 110, 117, 1 19, 123, 124, 131 , 132, 137, 143, 155, 161-163, 168, 169 and compounds SSA 48042, LPO 55070B, ANP 49174B, ANP 53134 and ANP 53006A
A solution of 37% aqueous HCI was added to a mixture of the corresponding aromatic aldehyde (or masked aldehyde) and aminoacetaldehyde diethyl acetal (in absolute EtOH (see conditions in tables 3 and 7). The reaction mixture was stirred in an ace pressure tube (Aldrich) according to the conditions described in tables 3 and 7. The reaction mixture was immediately cooled at 4°C and concentrated to dryness under reduced pressure. EtOAc (typically 200 mL) was added to the residue and this mixture was poured into a 1 M aqueous K2CO3 solution (typically 50 mL). The separated organic layer was washed with brine (typically 20 mL), dried over MgS04, filtered and evaporated to give a residue. This residue was purified by column chromatography (S1O2, see exact conditions in tables 3 and 7). After evaporation, if the hydrochloride salt was needed, the obtained free base (1 eq.) was dissolved in MeOH (2 mL) and a 1 .75 N HCI solution in MeOH (2.1 eq. x number of basic nitrogen) was added (see conditions in tables 3 and 7). The desired isoquinoline, either as a free base or a hydrochloride salt, was obtained after further drying under vacuum pump.
Table 3
Figure imgf000074_0001
General procedures B for preparation of compounds 21 , 23, 24, 27, 32, 41 , 46, 55, 73, 107, 112, 116, 120, 125, 126, 128, 130, 133, 134, 135, 138, 139, 143, 148, 164 & 165 and compounds LPO 55070A, LPO 50156C, LPO 50172C, LPO 50040C, LPO 50164C, ANP 49102A & LPO 50192C.
a) O-Alkylation using Cs?CO^ or K?CO^ (compounds 23, 27, 32, 41 , 46, 55, 73,
107, 112, 116, 120, 125, 126, 128, 130, 133, 134, 135, 138, 139, 143, 148, 164 & 165) and compounds LPO 55070A, LPO 50156C, LPO 50172C, LPO 50040C, LPO 50164C, ANP 49102A & LPO 50192C.
To a stirred mixture of the hydroxyquinoline derivative, CS2CO3 or K2CO3 as base, and acetone, acetonitrile or DMF as solvent was added the desired halogeno- derivative (see tables 4 and 7 for conditions). The resulting mixture was stirred between 1 h to 40 h at RT to 90°C or heated under microwave irradiation (see tables 4 and 7 for conditions). After cooling, the reaction mixture was partitioned between EtOAc (typically 200 mL) and a 1 M K2C03 solution (typically 30 mL). The organic layer was separated, washed with H20 (typically 30 mL), brine (typically 30 mL), dried over MgS04, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (Si02, see tables 4 and 7 for conditions). After evaporation of the solvents, if a hydrochloride salt was needed, the obtained free base (1 eq) was dissolved in MeOH (1 mL) and a 1 .75 N HCI solution in MeOH (2.1 eq x number of basic nitrogen) was added. The desired O-alkylated isoquinoline derivative was obtained as a free base or hydrochloride salt after further drying under vacuum pump. b) O-Alkylation using KOH in HpO/DME (compounds 21 and 24)
To a stirred mixture of the hydroxyquinoline derivative and KOH in a mixture of H20 and DME was added the desired halogeno-derivative (see conditions in table 7). The resulting mixture was stirred between 24 h to 55 h at RT then partitioned between EtOAc (200 mL) and a 1 M K2CO3 solution (30 mL). The organic layer was separated, washed with H20 (30 mL), brine (30 mL), dried over MgS04, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (Si02, see conditions in table 7). After evaporation of the solvents, the obtained free base (1 eq) was dissolved in MeOH (1 mL) and a 1 .75 N HCI solution in MeOH (2.1 eq x number of basic nitrogen) was was added. All the volatiles were evaporated to give the desired O-alkylated isoquinoline derivative as a hydrochloride salt (see table 7) after further drying under vacuum pump.
TABLE 4
Figure imgf000077_0001
Figure imgf000078_0001
General procedures C to prepare compounds 56, 76, 136, 140, 141 , 158, 93, 106, 11 1 , 147.
a) Acylation using acetic anhydride or an acyl chloride (56, 76, 136, 140, 141 , 158)
The amine derivative and triethylamine, DMAP or pyridine were dissolved in anhydrous THF or in CH2CI2 and acetic anhydride (or acetoxyacetyl chloride for 158) was slowly added (see conditions in table 7). After complete addition, the reaction mixture was stirred under a nitrogen atmosphere (see conditions in table 7). The reaction mixture was poured in 1 M aqueous K2CO3 (typically 10 mL) and dichloromethane (typically 100 mL) was added. The separated organic layer was washed with brine (typically 20 mL), dried over MgS04, filtered and evaporated to give a crude A/-acetylated amine derivative. This crude compound was purified by column chromatography (Si02, see conditions in table 7) and solvents were evaporated. If a hydrochloride salt was needed, the obtained free base (1 eq) was dissolved in MeOH (1 mL) and a 1 .75 N HCI solution in MeOH (2.1 eq x number of basic nitrogen) was added. The A/-acetylated amine derivative was obtained, as a free base or a dihydrochloride salt, after further drying under vacuum pump. b) Preparation of oxalamides 93 and 98
2-Amino-2-oxoacetyl chloride RBO 56082
To a solution of oxamic acid (500 mg, 5.61 mmol) in dry CH2CI2 (20 mL) in a 50 mL round bottom flask equipped with a magnetic stirrer was added SOCI2 (4.07 mL, 56.10 mmol) followed by 1 drop of DMF and the mixture was stirred under reflux for 3 h then cooled to 25°C. After concentration to dryness at 40°C under vacuum, the residue was diluted with CH2CI2 (20 mL) before concentration back to dryness (done twice), giving 633 mg of a pale yellow solid 2-amino-2-oxoacetyl chloride RBO 56082 that was used in the next step whitout further purification (quant, crude yield). Oxalamides 93 and 98
To a solution of aminoquinoline RBO 51118B or 86 in THF in a 50 mL round bottom flask equipped with a magnetic stirrer was added Et3N followed by 2-amino- 2-oxoacetyl chloride RBO 56082 (see conditions table 7). The mixture was stirred overnight at 25°C. All the volatiles were evaporated at 40°C under vacuum and the residue was taken back in CH2CI2 (30 mL) and the solution was washed with H20 (3x5 mL), brine (5 mL), dried over Na2S04, filtered and concentrated at 40°C under vacuum. Purification by column chromatography (Si02, see conditions in table 7) gave after evaporation and drying the oxalamide 93 or 98. c) Preparation of benzoxazolinones 106, 111 and 147 using 1 , 1 '-carbonyl diimidazole
To a solution of 2-aminophenol derivative (ANP 49188A, ANP49184A or ANP
53156A) in anhydrous CH2CI2 were added triethylamine and 1 ,1 '-carbonyl diimidazole in anhydrous CH2CI2 at 0-4°C under nitrogen (see conditions table 7). The reaction mixture was stirred at 0-4°C and then abandoned to RT 5 h or overnight (see conditions table 7). The precipitate that appeared was filtered and dried to give the desired benzoxazolinone 106. In case no precipitate was observed, the reaction mixture was evaporated and the residue was purified by column chromatography (Si02, see conditions table 7) to give the benzoxazolinone 11 1 or 147. d) Preparation of sulfonamides 86 and 99 using alkyl sulfonyl chloride
To a solution of RBO 51118B in CH2CI2 in a 20 mL microwave vial equipped with a magnetic stirrer was added pyridine followed by methane- or ethane-sulfonyl chloride (see conditions table 7). The mixture was heated under microwave irradiation at 70°C (see conditions table 7). After cooling to RT, the mixture was then washed with water (3x5 mL), brine (5 mL), dried over Na2S04, filtered and concentrated at 40°C under vacuum. Purification by column chromatography (Si02, see exact conditions table 7) gave after evaporation and drying the sulfonamide 86 or 99. e) Preparation of urea 87
To a solution of RBO 5111 SB (100 mg, 0.27 mmol) in AcOH (10 mL) in a 50 mL round bottom flask equipped with a magnetic stirrer was added a solution of potassium cyanate (21 .9 mg, 0.27 mmol) in H20 (1 mL) and the mixture was stirred for 3 h at 40°C. AcOH was then removed at 40°C under reduced pressure and the residue was taken up in CH2CI2 (20 mL) before neutralisation with a saturated aqueous NaHCOrj solution. The precipitate that formed was isolated by filtration and further washed with pentane (2x10 mL). After drying under vacuum, 48 mg of 1 -(2-((1 - ethyl-6 J-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-yl)urea 87 (see table 7) were obtained as a white solid (43%).
General procedures D to prepare compounds TTA 46118B, 42, 75, 142, 149, 151 , 154 and 166. a) Preparation of compounds TTA 46118B. 42, 75, 142, 151 , 154, 166
The corresponding ester derivative TTA 46118A, 41 (free base), ANP 49102A, 115, ANP 53192A, ANP 53174B or 165 was dissolved in MeOH or fBuOH or THF and NaBH4 or a solution of LiAIH4 in THF was added at RT (see conditions in tables 5 and 7). The reaction mixture was stirred at 0°C to RT or 140°C (see conditions in tables 5 and 7). After cooling to RT, the reaction mixture was concentrated under reduced pressure and the residue was poured into water (typically 100 mL) and extracted with CH2CI2 (typically 200 mL). The separated organic layer was washed with water (typically 2x30 mL), brine (typically 30 mL), dried over Mg2S04, filtered and evaporated to give a crude compound. This crude compound was purified by column chromatography (Si02, see conditions tables 5 and 7). After evaporation of the solvents, if a hydrochloride salt was needed, the obtained free base (1 eq.) was dissolved in MeOH (1 mL) and a 1 .75 N HCI solution in MeOH (2.1 eq x number of basic nitrogen) was added. The alcohol derivative TTA 46118B, 42, 75, 142, 151 , 154 or 166 was obtained as a free base or a dihydrochloride salt after further drying under vacuum pump. b) Preparation of compound 149 and LPO 43180
To a solution of ANP 53142B or 55 in MeOH was added 10% Pd/C at RT under a hydrogen atmosphere (see conditions in table 7 and 5). The reaction mixture was stirred according to the conditions described in table 7 or 5. The mixture was filtered on celite and the filtrate was concentrated to dryness.
For reaction involving 55, crude LPO 43180 (see table 5) was obtained after further drying and was used without further purification in the next step.
For reaction involving ANP 53142B, the residue was purified by column chromatography (Si02, see conditions in table 7) to give, after evaporation and further drying, the aminophenyl derivative 149. c) Preparation of compounds SSA 48104, LPO 55016 and ECO 55108C
In a 100 mL round bottom flask, 2-chloro-3-[1 ,3]dioxolan-2-yl-7-methyl- quinoline, LPO 55012B or ECO 55098, 10% Pd/C and K2C03 were dissolved in MeOH (see conditions in table 5). The reaction mixture was stirred under a hydrogen atmosphere according to the conditions described in table 5. The reaction mixture was filtered on celite and the celite cake was further washed with MeOH (5 mL). The obtained filtrate was evaporated to give a crude product. This crude product was purified by column chromatography (see conditions in table 5) to give, after evaporation and further drying, compounds SSA 48104, LPO 55016 or ECO 55108C. d) Preparation of compound RBO 51 194
To a solution of compound 90 (872 mg, 2.27 mmol) in THF (20 mL) in a 50 mL round bottom flask equipped with a magnetic stirrer at -7S°C was added dropwise D!BAL-H (10 M solution in THF, 9.00 mL, 9.00 mmol). After complete addition, the mixture was stirred for 20 min at -78°C, then for 30 min at -40°C and then for 1 h at RT. Another portion of DIBAL-H (1 .0 M solution in THF, 6.80 mL, 6.80 mmol) was then added at -78°C and the mixture was further stirred for 3 h allowing the medium to slowly reach RT. After cooling to 0°C, the mixture was carefully hydrolysed with H2Q (6 mL) and a saturated aqueous NH4CI solution (10 mL) before stirring for 3 days at RT. The solid that had formed was filtered-off and the filtrate was concentrated to dryness at 40°C under vacuum. The residue was taken up in CH2CI2 (60 mL) and washed with H20 (3x15 mL), brine (15 mL), dried over Na2S04, filtered and concentrated at 40°C under vacuum. Purification by column chromatography (Si02 e!uent CH2CI2:MeOH = 100:0 to 90:10) gave after evaporation and further drying RBO 51 194 as a yellow solid (see table 5).
Procedures E to prepare compounds 35, 91 and SAO 33058 a) Preparation of compound 35
To a solution of 4-(dibenzo[0,d]furan-2-ylmethyl)-6,7-dimethoxyisoquinoline 10 (600 mg, 1 .62 mmol) in CH2CI2 (40 mL) was added mCPBA (336 mg, 1 .95 mmol) at RT under a nitrogen atmosphere. The reaction mixture was stirred at RT overnight and then this mixture was partitioned between CH2CI2 (200 mL) and a 1 M K2C03 aqueous solution (50 ml_). The separated organic layer was washed with brine (50 ml_), dried over MgS04, filtered and evaporated to give 4-dibenzofuran-2-ylmethyl- 6,7-dimethoxy-isoquinoline 2-oxide 35 (see table 7) as yellow solid (645 mg, quant, yield).
b) Preparation of compound 91
To a solution of quinolinecarbonitri!e 90 (0.78 mmol) in EtOH (10 mL) in a 25 mL round bottom flask equipped with a magnetic stirrer was added 35% H202 (236 μ!_, 2.74 mmol) followed by a 0.5 M aqueous solution of NaOH (1 .57 mL, 0.78 mmol). The mixture was heated at reflux for 3 days, then cooled to RT. After evaporation of the vo!atiles, the residue was taken back in ΟΗ2(¾ (20 mL) and washed with water (3x5 mL), brine (5 mL), dried over Na2SC¼, filtered and concentrated at 40°C under vacuum. Purification by column chromatography (SiC^, see exact conditions in table 7) gave after evaporation and further drying the desirated quinolinecarboxamide 91.
c) Preparation of compound SAO 33058
(4-Chloro-1 -ethyl-1 H-pyrazolo[3,4-0]pyridin-5-yl)-methanol SAO 33034 (359 mg, 1 .70 mmol) was dissolved in anhydrous CH2CI2 (50 mL) at RT under nitrogen. Dess Martin Periodinane (755 mg, 1 .78 mmol) was slowly added portionwise at 4°C. The reaction mixture was stirred for 1 h at 4°C then overnight at RT. The solid was filtered off and CH2CI2 (200 mL) was added to the mixture. After separation, the organic layer was washed with brine (20 mL), dried over MgS04, filtered and evaporated to give 4-chloro-1 -ethyl-1 /-/-pyrazolo[3,4-0]pyridine-5-carbaldehyde SAO 33058 (see table 5) as an off-white solid (71 1 mg, 100%).
Procedures F for preparation of compounds 108, 1 18, 122, 145, 146, 150 and 160) a) Preparation of compounds 108, 118, 122, 145, 146 and 160 (saponification of esters using of KOH, NaOH or LiOH)
To a solution of KOH, NaOH or LiOH in MeOH:H20 or THF:H20 (1 :1 ) was added a solution of the ester derivative in MeOH or THF at RT (see conditions in table 7). The reaction mixture was stirred according to the conditions described in table 7.
To obtain a sodium (118, 122) or a potassium (145) carboxylate: the solvent was evaporated and the residue was purified by column chromatography (RP 18; gradient H20:CH3CN = 10:0 to 7:3) to give after evaporation and further drying the desired salt 118, 122 or 145. To obtain a carboxylic acid 108 or 146 or the 2-hydroxyacetamide 160: the solvent was evaporated and the residue was dissolved in CH2CI2 (75 mL) and a 2 N HCI solution was added until pH = 7-8. The organic layer was then washed with brine (20 mL), dried over MgS04, filtered and evaporated. The residue was purified by column chromatography (Si02, see exact conditions in table 7) to give after evaporation and further drying the desired compound (free base of 108, 146 or 160). To obtain the dihydrochloride salt 108, the free base of 108 (0.08 mmol) was dissolved in MeOH and a 1 .76 N HCI methanolic solution (100 μί, 0.17 mmol) was added at 4°C. This solution was stirred at 4°C for 10 min and then concentrated. The dihydrochloride salt 108 was obtained after further drying to vacuum pump.
b) Preparation of compound 150
The derivative LPO 55070A (120 mg, 0.28 mmol) was dissolved in a 37% aqueous HCI solution (1 mL) and AcOH (1 mL). The reaction mixture was stirred at 1 10°C for 4 h. After cooling, the solvents were evaporated and the residue was poured in n-BuOH (60 mL) and a 1 M K2C03 solution (30 mL) was added. The separated organic layer was washed with brine (20 mL), dried over MgS04, filtered and evaporated. The crude product was purified by column chromatography (Si02, see exact conditions in table 7) to give after evaporation and further drying to the vacuum pump the acid 150.
Procedures G for preparation of compounds ANP 57032A, ANP 53184A, RBO 51 116. LPO 55036C. ECO 59060. RBO 56020. LPO 50012 and LPO 50042C
a) Preparation of triflates ANP 57032A. ANP 53184A. RBO 51116. LPO 55036C, ECO 59060 and RBO 56020
To a solution of the corresponding hydroxyquinoline derivative 7 free base, 131 , 83, 45, 163 or 95 in DMF (20 mL) were added A/-phenyl bis-trifluoromethane sulfonimide and triethylamine (see conditions described in table 5). The reaction mixture was stirred according to the conditions described in table 5. DMF was removed under vacuum at 70°C. The residue was diluted in CH2CI2 (typically 100 mL), washed with H20 (typically 3x30 mL), brine (typically 20 mL), dried over Na2S0 , filtered and concentrated at 40°C under reduced pressure. The crude product was purified by column chromatography (Si02, see conditions in table 5) to give, after evaporation and further drying under vacuum, the triflates ANP 57032A, ANP 53184A, RBO 51116, LPO 55036C, ECO 59060 or RBO 56020. b) Preparation of compounds LPO 50012 and LPO 50042C
The 2-hydroxyquinoline derivative (free base of 49 or SSA 48042) was stirred in phosphoryl trichloride in an ace pressure tube (Aldrich) at 100-1 10°C for 2 h (see conditions in table 5). After cooling, the mixture was pourred in ice (10 g) and a 1 M aqueous K2C03 solution (5 mL) and EtOAc (150 mL) were added. The separated organic layer was washed with brine (20 mL), dried over MgS04, filtered and evaporated. The crude product was purified by column chromatography (Si02, eluent cyclohexane: EtOAc = 70:30 to 50:50) to give, after evaporation and further drying to the vacuum pump, the 2-chloroquinoline derivative LPO 50012 or LPO 50042C.
Table 5
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Procedures H for preparation of compounds 77, 113, 129, RBO 51 118B, LPO 55056D, 152, 157, 167, 92, 96, 97 and 90 (using palladium) a) Preparation of compounds LPO 50016, 77, 113 and 129
A mixture of 2-chloroquinoline LPO 50012 or LPO 50042C, 2-(di-terf- butylphosphinobiphenyl), ethane-1 ,2-diamine or a 2 N EtNH2 or MeNH2 solution in THF, palladium (II) acetate, and fBuOK was dissolved in anhydrous toluene (see conditions in tables 6 and 7). The reaction mixture was stirred according the conditions described in tables 6 and 7. The solvent was evaporated and the residue was partitioned between CH2CI2 (typically 175 mL) and a 1 M K2CO3 solution (typically 5 mL). The separated organic layer was washed with brine (20 mL), dried over MgS04, filtered and evaporated. The crude product was purified by column chromatography (Si02, see conditions in tables 6 and 7) to give, after evaporation and further drying under vacuum, the amino derivative LPO 50016, 77, 113 or 129. b) Preparation of compounds RBO 51118B, LPO 55056D, 152, 157 and 167
To a solution of the corresponding triflate RBO 511 16, LPO 55036C, ANP 53184A, ANP 57032A or ECO 59060 in toluene were added Pd2(dba)3, (+/-)-2,2- bis(diphenylphosphino)-1 ,1 -binaphthyl (BINAP), benzophenone imine and CS2CO3 (see conditions in tables 6 and 7). The mixture was stirred according to the conditions described in tables 6 and 7. After cooling, the mixture was filtered through celite and the obtained cake was washed with EtOAc (typically 20 mL). After evaporation of all the volatiles, the residue was diluted with EtOAc (typically 30 mL), washed with brine (typically 3x10 mL), dried over Na2S04, filtered and evaporated at 40°C under vacuum. The obtained crude product was treated with a 5 N HCI solution (typically 2 mL) in THF (typically 20 mL) and stirred at RT for 4 h, then the reaction mixture was neutralized with a saturated aqueous NaHC03 solution to reach pH = 7. The solvent were removed under reduced pressure and the resulting aqueous layer was extracted using CH2CI2 (typically 3x75 mL). The organics layers were combined then washed with H20 (typically 3x20 mL), brine (typically 3x20 mL), dried over Na2S04, filtered and evaporated. The obtained residue was purified by flash chromatography (Si02, see conditions in tables 6 and 7) to give the aminoquinoline RBO 51 118B, LPO 55056D, 152, 157 or 167 after further drying under vacuum pump.
c) Preparation of compounds 92, 96, 97, and 152
To a solution of the corresponding triflate RBO 511 16, RBO 56020 or ANP 53184A in 1 ,4-dioxane was added ferf-butyl carbamate or pyrolidinone, cesium carbonate, Xantphos and Pd2dba3 at RT under nitrogen flux (see conditions in table 7). The reaction mixture was stirred according to the conditions described in table 7. After cooling, the reaction mixture was filtrated on celite and the solvent was removed to give a residue. This residue was purified by column chromatography to give, after evaporation and drying, a ferf-butyl carbamate intermediate (Si02, eluent: CH2CI2:MeOH = 100:0 to 98:2) or the pyrrolidinone 152 (Si02, eluent: CH2CI2: EtOAc = 100:0 to 0:100).
The obtained ferf-butyl carbamate was then deprotected by stirring with a solution of TFA (1 mL) in CH2CI2 (10 mL) for 1 h at RT. After concentration to dryness, the residue was taken back in EtOAc (150 mL) and a 1 M K2CO3 solution (50 mL) was added. The separated organic layer was washed with H20 (3x20 mL), brine (3x20 mL), dried over Na2S04, filtered and evaporated to provide a residue. This residue was purified by flash chromatography (Si02, see exact conditions in table 7) to give, after evaporation after further drying under vacuum, the aminoquinoline 92, 96 or 97.
d) Preparation of nitrile 90
To a solution of the triflate RBO 51116 in DMF in a 20 mL microwave vial equipped with a magnetic stirrer was added Zn(CN)2 followed by Pd(PPh3)4 (see exact conditions in table 7). The mixture was heated under microwave irradiation at 180°C for 15 min then cooled to 25°C. The reaction mixture was then hydrolysed with a 2 M aq. H2S04 solution (10 mL) at RT for 20 min. The mixture was filtered through celite and the cake was washed with CH2CI2 (3x50 mL). After concentration to dryness, the residue was taken back in CH2CI2 (50 mL) and neutralized with a saturated aqueous NaHC03 solution (until pH = 9). The separated organic layer was washed with water (3x10 mL), brine (10 mL), dried over Na2S04 filtered and concentrated. Purification by flash chromatography (Si02, see exact conditions in table 7) gave, after evaporation and further drying to the vacuum, the nitrile 90. Procedure I for preparation of sulfamides 84, 85, 94, 100, 119, 156, 159
To a solution of the corresponding amino derivative RBO 51118B, LPO 55056D, RBO 51194, 96, 167, 152 or 157 in 1 ,4-dioxane (20 ml.) was added sulfamide. The mixture was heated according to the conditions described in the table 7. After cooling to RT, the volatiles were removed at 50°C under reduced pressure to provide a residue that was purified by flash chromatography (Si02, see exact conditions in table 7) to give, after evaporation and further drying under vacuum pump, the sulfamide 84, 85, 94, 100, 119, 156 or 159. Procedure J for preparation of benzoxazoles LPO 55056D, ANP 53142B, ANP 53192A. 114. 115. 153 and 170
To a solution of ANP 49184A or ECO 59064 in MeOH was added the corresponding aldehyde at RT in an ace pressure tube (see aldehyde and exact conditions in tables 6 and 7). The reaction mixture was stirred according to the conditions described in tables 6 and 7. After cooling to RT, the solvent was evaporated and the residue was dissolved in CH2CI2 and DDQ was added (see exact conditions in table 7). This reaction mixture was stirred at RT for 30 min and CH2CI2 (100 mL) and a 1 M K2C03 aqueous solution (20 mL) were added. The separated organic layer was washed with brine (50 mL), dried over MgS04, filtered and evaporated. The residue was purified by column chromatography (S1O2, see exact conditions in tables 6 and 7) to give, after evaporation and further drying under vacuum, the benzoxazole LPO 55056D, ANP 53142B, ANP 53192A, 114, 115, 153 or 170. Procedure K for preparation of tetrazoles 121 and 127
To a solution of the nitrile LPO 50040C or LPO 50172C in DMF were added ammonium chloride and sodium azide at RT in ace pressure tube (see conditions in table 7). The reaction mixture was stirred according to the conditions described in table 7. After cooling to RT, the solvent was evaporated and a 2 N HCI solution (2.5 mL) was added. This solution was stirred RT for 30 min, neutralized by a 1 M K2CO3 aqueous solution (35 mL) and extracted with n-butanol (70 mL). The separated organic layer was washed with brine (20 mL), dried over MgS04, filtered and evaporated. The residue was purified by column chromatography (S1O2, see Table 6
Figure imgf000092_0001
Figure imgf000093_0001
Yield : 91%, brown solid.
5.67 (s, 1 H, CHO), 7.20 (d, 1 H, ArH), 7.36-7.45 (dd, 1 MS-ESI m/z (% rel. Int.): 254.1/256.1 ([MH , TR = 4.72 min, peak area 99.1%. mg); MW: 285.22; Yield: 6 = 5:5); H-NMR (CDCI3, 6): 4.10-4.28 = 8.1 Hz), 7.79 (d, 1H, ArH, J = 8.9 Hz), ArH, J = 1.8 Hz, J = 8.9 Hz); 3C-NMR (C 31.3 Hz), 120.28, 124.4 (q, CF3, J = 272.2 Hz 137.22, 155.52, 156.02; MS-ESI m/z (% rel. Int
= 5.54 min, peak area 98.2%. mg); MW: 287.23; Yield: 40%;
5.67 (s, 1H, CHO), 7.46 ArH), 8.77 (s, 1 H, ArH); 124.3, 126.5 (q, J = 274 m/z (% rel. Int.): 288.0 ([MHf peak area 99.5%.
239.66; Yield: 71 %; Yello 7.31 (td, 2H, J = 8.8 Hz & 10.24 (s, 1 H, CHO), 12.15 (signal Method A, detection UV 254 n Yield: 79%; White Solid; (t, 1H, J = 5.11 Hz, OH), 4.63 ( 2H, J = 8.20 Hz, ArH), 10. (2xC), 135.53, 148.04, 192.25; detection UV 254 nm, RT = 3
Figure imgf000094_0001
Figure imgf000095_0001
conditions in table 7) to give, after evaporation and further drying under vacuum, the tetrazole 121 or 127.
Procedure L for preparation of acetals LPO 55012B, TTA 46034 and TTA 46118A
A solution of the aldehyde (LPO 50188A, 8-hydroxyquinoline-2-carbaldehyde or methyl 4-formylbenzoate) in ethylene glycol and p-toluenesulfonic acid monohydrate (PTSA) were placed in a 250 mL round-bottom flask and toluene was added (see exact conditions in table 6). The mixture was heated under reflux in a Dean-Stark apparatus (according to the conditions described in table 6) until complete separation of water was effected. Toluene was evaporated then EtOAc (300 mL) and a 1 M aqueous NaHC03 solution (20 mL) were added. The separated organic layer was washed with brine (20 mL), dried over MgS04, filtered and evaporated. After further drying under vacuum, the acetal LPO 55012B, TTA 46034 or TTA 461 18A was obtained. Procedure M for preparation of compounds LPO 50188A and ECO 55098
To a solution of 2-chloro-6-methoxyquinoline-3-carbaldehyde in CH2CI2 was added drop wise at -78 °C a 1 M BBr3 solution in CH2CI2 (see conditions in table 6). The reaction mixture was stirred at -78°C to RT (see conditions in table 6). The reaction mixture was quenched with ice and stirred at RT for another 30 min then a saturated NaHC03 solution (400 mL) was slowly added and the aqueous layer was extracted with CH2CI2 (3x350 mL). The combined organic layers were washed with brine (30 mL), dried over MgS04, filtered and solvent was evaporated to give crude LPO 50188A. The crude product was purified by column chromatography (S1O2, see conditions in table 6) to give after evaporation and further drying under vacuum pump, LPO 50188A as a yellow solid.
Crude LPO 50188A was dissolved in a 0.78 N HCI solution in MeOH (26 mL). This reaction mixture was stirred at RT for 1 h. At 0°C, a 7 N NH4OH solution in MeOH (3.7 mL) was slowly added (until pH = 7) and the solvent was evaporated. A mixture of CH2Cl2:MeOH = 9:1 (30 mL) was added and the precipitate was filtered off and washed with a mixture of CH2Cl2:MeOH = 9:1 (70 mL). The filtrate was evaporated and dried under vacuum to give crude ECO 55098 (see table 6). Procedures N for preparation of compounds LPO 50180C and ECO 55152
a) Preparation of compound LPO 50180C
2-(1 ,3-Dioxolan-2-yl)quinolin-8-ol TTA 46034 (500 mg, 2.30 mmol), ierf-butyl hydroperoxide (70% solution in water, 1 .5 mL, 16.1 1 mmol) and sodium trifluoromethanesulfinate (1 .8 g, 1 1 .51 mmol) were dissolved in CH3CN (5 mL) and H20 (2.5 mL) in a round bottom flask. This reaction mixture was stirred at RT for 1 .5 h then H20 (10 mL) and a 1 M aqueous NaHC03 solution (5 mL) were added and this mixture was extracted with CH2CI2 (3X70 mL). The combined organic layers were washed with brine (10 mL), dried over MgS04, filtered and evaporated. The crude product was purified by two successive column chromatography (Si02, eluent cyclohexane:EtOAc = 100:0 to 50:50 then RP18 CH3CN:H20 = 100:0 to 50:50) to give, after evaporation and further drying under vacuum in presence of P2O5, 2-(1 ,3-dioxolan-2-yl)-5-(trifluoromethyl)quinolin-8-ol LPO 50180C (see table 6). b) Preparation of compound ECO 55152
8 Wheaton vials were charged with lr(dF.ppy)3 (7.3 mg, 9.56 μιηοΙ) and K2HP04 (250 mg, 1 .44 mmol) and 3-(dimethoxymethyl)quinolin-6-ol ECO 55108C (105 mg, 0.48 mmol) in CH3CN (4.5 mL). This reaction mixture was cooled at -78°C and degassed under vacuum then flushed at RT with argon (3 folds). Triflyl chloride (203 μί, 1 .91 mmol) was added and the vials were sealed and exposed to light (28W compact fluorescent light bulb (1746 lumens)). The reaction mixture was stirred 20 h at 34°C then was quenched with H20 (80 mL) and extracted with CH2CI2 (3x70 mL). The combined organic layers were washed with brine (80 mL), dried over MgS04, filtered and evaporated. The crude product was purified by column chromatography (Si02, cyclohexane:EtOAc = 100:0 to 50:50) to give, after evaporation and further drying, ECO 55152 (see table 6).
Procedure O for preparation of compounds SSA 48036 and TTA 461 18C
2-Chloro-6-methoxy-quinoline-3-carbaldehyde or TTA 46118B was dissolved in H20 or MeOH then an HCI solution was added (see exact conditions table 6). The reaction mixture was stirred according to the conditions described in table 6. For the reaction involving 2-chloro-6-methoxy-quinoline-3-carbaldehyde, a precipitate appeared that was filtered and washed with a minimum amount of water, to give, after further drying in presence of P205, LPO 43136A (see table 6). For the reaction involving TTA 461 18B, the reaction mixture was evaporated. The obtained colorless oil was taken back in CH2CI2 (180 mL) and the resulting solution was washed with H20 (2x40mL), brine (30 mL), dried over MgS04, filtered and concentrated to dryness to give crude TTA 461 18C that was used in the next step without further purification.
Procedure P for preparation of compound LPO 55010B
Phthalamide derivative LPO 50192C (58 mg, 0.103 mmol) was dissolved in EtOH (1 mL) and hydrazine hydrate (100 μί, 2.06 mmol) was added. The reaction mixture was stirred under N2 atmosphere at 80°C for 2 h. Phthalhydrazine was filtered off, the filtrate was evaporated, H20 (10 mL) was added and the resulting solution was extracted with CH2CI2 (3x30 mL). The combined organic layers were washed with brine (10 mL), dried over MgS0 , evaporated to give, after further drying in presence of P205, 2-((2-((6,7- dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-8-yl)oxy)ethanamine LPO 55010B (see table 6) as a yellow solid (50.8 mg, quantitative crude yield).
Procedure Q for preparation of compound 171
To a mixture of POCI3 (252 μί, 2.70 mmol) and Et3N (1 13 yiL, 0.81 mmol) in dry THF (2.5 mL) at 4 °C in a 10 mL round-bottomed flask equipped with a magnetic stirrer was added drop wise a suspension of 3-((6,7-dimethoxy-1 -propylisoquinolin-4- yl)methyl)quinolin-6-ol 143 (210 mg, 0.54 mmol) in dry THF (5 mL). The mixture was stirred for 30 min at 4°C, and concentrated to dryness under vacuum. The residue was taken up in a 5 N aq. NaOH solution (1 .8 mL) and stirred for 1 5 min at RT before concentration to a volume of around 1 mL. This residue was purified by reversed phase flash chromatography (RP18, 1 1 .0 g, 25-40 μιη, eluent H20:CH3CN = 1 00:0 to 90: 10) to give, after concentration and drying under vacuum, sodium 3-((6,7-dimethoxy-1 -propylisoquinolin-4- yl)methyl)quinolin-6-yl phosphate 171 (see table 7) as a white solid (87 mg, 48% yield).
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
o •J\
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
2-((2-((6,7-dimethoxy-1-propylisoquinolin-4-yl)methyl)quinolin-8-yl)oxy)acetamide (146 mg); MW: 445.51; Yi
B (a) 25%; White Solid; Mp (°C): 226.9; Rf: 0.25 (CH2CI2:MeOH = 96:4); H-NMR (CDCI3, 6): 1.08 (t, 3H, CH3,
Free base of 45 (700 mg, 7.35 Hz), 1.92 (m, 2H, CH2, J = 7.68 Hz), 3.18 (t, 2H, CH2, J = 7.66 Hz), 3.86 (s, 3H, OCH3), 3.99 (s, 1.80 mmol); DMF (9 mL); Chromatography Si02, OCH3), 4.63 (s, 2H, CH2), 4.75 (s, 2H, CH2), 5.58 (s, 1H, NH2), 7.16-7.19 (dd, 1H, ArH, J = 2.76 Hz, J =
Cs2C03 (1.76 g, 5.41 CH2CI2:MeOH = 100:0 Hz), 7.32-7.37 (m, 2H, 2xArH), 7.40-7.45 (m, 3H, 3xArH), 8.02 (d, 1 H, ArH, J = 8.49 Hz), 8.22 (s, 1H, N mmol); 2-bromoacetamide to 96:4 8.39 (s, 1H, ArH); 13C-NMR (CDCI3, 6): 14.38, 22.57, 37.51 , 41.08, 55.89, 55.92, 70.71 , 103.25, 104 (398 mg, 2.58 mmol); 80°C 113.98, 121.93, 122.08, 122.82, 125.47, 126.34, 128.11, 132.07, 136.84, 140.08, 141.77, 149.53, 152. overnight. 154.07, 159.30, 160.18, 171.62; MS-ESI m/z (% rel. Int.): 446.3 ([MH]*1, 100); HPLC: Method A, detection
254 nm, RT = 3.63 min, peak area 99.9%.
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Scottish Biomedical Phosphodiesterase Assay (PDEs1 -3, PDEs5-9 and PDE1 1 )
The assay utilizes the IMAP technology, which is based on the high affinity binding of phosphate by immobilized metal coordination complexes on nanoparticles. The binding reagent complexes with phosphate groups on nucleotide monophosphate generated from cyclic nucleotides (cAMP/cGMP) through phosphodiesterases. With fluorescence polarization detection, binding causes a change in the rate of the molecular motion of the phosphate bearing molecule, and results in an increase in the fluorescence polarization value observed for the fluorescent label attached to the substrate.
Previously prepared stocks of the compounds in 100% DMSO were used at a concentration of 30 mM and all assays were performed in 3% DMSO (final). The compounds were tested at a concentration of 10 μΜ in duplicate against each phosphodiesterase. The percentage inhibition values were calculated based on the two data points.
Diaxonhit Phosphodiesterase Assay (PDE10A and PDE4D3)
The PDE assay is based on the homogenous time-resolved fluorescence resonance energy transfer (TR-FRET) technology (LANCE® from Perkin Elmer). This competition based assay is formatted using a cAMP specific antibody labeled with the dye, Alexa Fluor® 647, biotin-cAMP and streptavidin labeled with Europium (Eu- SA). As the complex of Eu-SA / biotin-cAMP / Alexa Fluor 647 labeled antibody is formed, an increase in signal is generated. When there is PDE activity, resulting in the degradation of the cyclic nucleotide, the complex is not formed and a decrease in signal is observed.
The phosphodiesterase assay was developed using the LANCE® cAMP kit
(PerkinElmer). The assay buffer contained HBSS with 5 mM HEPES, 0.1 % BSA, and 1 .5 mM MgCI2, pH 7.4. PDE1 OA (BPS Bioscience) was used at 200 pg/well (with a specific activity of 3200 pmole/min^g with assay conditions: 10 mM Tris-HCI, pH 7.4, 10 mM MgCI2, 1 mM MnCI2, 200 μΜ cAMP, 2.5 kU 5' nucleotidase, 37°C, 20 min) and PDE4D3 (BPS Bioscience) was used at 100 pg/well (with a specific activity of 32713 pmole/min^g with assay conditions: 10 mM Tris-HCI, pH 7.4, 10 mM MgCI2, 1 mM MnCI2, 200 μΜ cAMP, 2.5 kU 5' nucleotidase, 37°C, 20 min). The Biotin-cAMP tracer, supplied in 10 mmol/L Tris-HCI buffered (pH 8.0) salt solution with 1 mmol/L ethylenediaminetetraacetic acid (EDTA), 0.1 % bovine serum albumin (BSA), and 0.05% sodium azide, is used at a dilution of 1 /375. The assay detection mixture contained the LANCE Eu-W8044 labeled streptavidin 1/2250 (supplied in 50 mmol/L Tris-HCI buffered (pH 7.8) salt solution with 0.9% sodium chloride (NaCI), 0.1 % BSA, and 0.05% sodium azide) and the Alexa Fluor® 647-anti cAMP antibody 1/200 (supplied in 50 mmol/L Tris-HCI buffered (pH 7.8) salt solution with 0.9% NaCI, 0.1 % BSA, and 0.05% sodium azide). Chemical compounds were dissolved in DMSO (final concentration 2% (v/v)).
In a 384-well plate, 2 μί of the inhibitor and 3 μί PDE were added to the well, followed by the addition of 5 μΙ substrate biotinylated cAMP (1 :5). After 60 min incubation at room temperature, 10 μί of assay detection mixture was added to the assay plate. After 1 h at room temperature, the signal was measured on EnVision™ (PerkinElmer).
The compounds of the present invention have PDE10A inhibitory activities generally less than 10,000 nM (<10,000 nM). In one embodiment, they have activities less than 1000 nM (<1000 nM); in another embodiment less than 500 nM (<500 nM); in another embodiment less than 100 nM (<100 nM); in another embodiment less than 50 nM (<50 nM); and in another embodiment less than 20 nM (<20 nM)
The activities of specific compounds are shown in Table 8 below.
Table 8
Figure imgf000136_0001
12 70 nM 97 15 nM
13 142 nM 98 3.5 nM
14 26 nM 99 16 nM
15 74 nM 100 4.6 nM
16 330 nM 101 43 nM
17 3556 nM 102 38 nM
18 238 nM 103 20 nM
19 95 nM 104 27 nM
20 - 105 4.3 nM
21 46 nM 106 28 nM
22 1069 nM 107 7.8 nM
23 213 nM 108 4.9 nM
24 90 nM 109 54 nM
25 194 nM 110 31 nM
26 49 nM 11 1 34 nM
27 49 nM 112 32 nM
28 168 nM 113 32 nM
29 > 10000 114 189 nM
30 > 10000 115 61 nM
31 92 nM 116 20 nM
32 315 nM 117 7.1 nM
33 184 nM 118 2.3 nM
34 81 nM 119 0.18 nM
35 31 nM 120 64 nM
36 7558 nM 121 4.7 nM
37 287 nM 122 5.0 nM
38 3174 nM 123 151 nM
39 339 nM 124 41 nM
40 278 nM 125 51 nM
41 51 nM 126 71 nM
42 42 nM 127 31 nM
43 39 nM 128 59 nM
44 11 nM 129 9.5 nM
45 20 nM 130 67 nM
46 21 nM 131 42 nM
47 36 nM 132 491 nM
48 6.5 nM 133 102 nM
49 63 nM 134 59 nM
50 19 nM 135 192 nM
51 44 nM 136 58 nM
52 99 nM 137 2.9 nM
53 25 nM 138 2.5 nM 54 151 nM 139 5.3 nM
55 158 nM 140 109 nM
56 65 nM 141 3107 nM
57 20 nM 142 19 nM
58 28 nM 143 9.4 nM
59 148 nM 144 6.5 nM
60 368 nM 145 1.6 nM
61 20 nM 146 4.7 nM
62 42 nM 147 64 nM
63 - 148 87 nM
64 92 nM 149 49 nM
65 159 nM 150 7.9 nM
66 30 nM 151 28 nM
67 154 nM 152 13 nM
68 31 nM 153 148 nM
69 5.2 nM 154 95 nM
70 946 nM 155 18 nM
71 >10000 nM 156 0.71 nM
72 32 nM 157 13 nM
73 1.4 nM 158 204 nM
74 1.2 nM 159 0.42 nM
75 6.6 nM 160 15 nM
76 11 nM 161 6.0 nM
77 9.7 nM 162 13 nM
78 25 nM 163 19 nM
79 5.1 nM 164 21 nM
80 41 nM 165 71 nM
81 3.6 nM 166 28 nM
82 4.4 nM 167 8.6 nM
83 11 nM 168 5.6 nM
84 0.53 nM 169 4.5 nM
85 0.82 nM 170 20 nM
171 62 nM
The compounds have also been tested for their activities on PDEs1 -9 and PDE1 1 . The most active PDE10A inhibitors (< 20 nM) are all selective (at least 120 to 10000-fold) vs PDEs1 -3, PDEs5-9 and PDE1 1 . They are also selective (at least 55 to 3000-fold) for PDE10A vs PDE4D3 (excepted the compound 162 that inhibits PDE4D3 with an IC50 of 232 nM, compound 93 that inhibits PDE4D3 with an IC50 of 398 nM, compound 83 that inhibits PDE4D3 with an IC50 of 439 nM) and compound 169 that inhibits PDE4D3 with an IC50 of 194 nM. Each and every reference (whether patent publication or a scientific/journal publication) disclosed herein is incorporated by reference herein for all purposes.
The details of specific embodiments described in this invention are not be construed as limitations. Various equivalents and modifications may be made without departure from the essence and scope of this invention, and it is understood that such equivalent embodiments are part of this invention.

Claims

What is claimed is:
1. A compound of Formula (I)
Figure imgf000140_0001
Formula (I)
or a pharmaceutically acceptable salt, thereof, wherein:
R1 is selected from the group of H, optionally substituted (CrC6)alkyl, optionally substituted (C3-C6)cycloalkyl and optionally substituted aryl;
R2 is H;
R3 and R independently represent a (CrC3)alkyl group;
R5 is H;
R6 and R7 are independently H;
R' is H or (CrC6)alkyl;
Ar is selected from the group consisting of: an optionally substituted fused nine- to ten-membered heteroaryl, optionally substituted benzo-fused aryl, optionally substituted benzo-fused heteroaryl, optionally substituted benzo-fused hetorocyclyl, and optionally substituted benzo-fused cycloalkyl, wherein two optional substituents at adjacent positions of each of said optionally substituted fused nine- to ten- membered heteroaryl, optionally substituted benzo-fused aryl, optionally substituted benzo-fused heteroaryl, optionally substituted benzo-fused hetorocyclyl, and optionally substituted benzo-fused cycloalkyl can be taken together with the atoms to which they are attached to form an aryl.
2. The compound according to claim 1 , wherein R3 and R4 are both methyl.
3. The compound according to claim 1 , wherein the optionally substituted (d- C6)alkyl of Ri is selected from the group consisting of ethyl, n-propyl, n-butyl, and isobutyl; the optionally substituted aryl is optionally substituted phenyl; and the optionally substituted (C3-C6)cycloalkyl is selected from the group consisting of cyclopropyl and cyclohexyl.
4. The compound according to claim 1 , wherein R' is selected from the group consisting of H and methyl.
5. The compound according to claim 1 , wherein Ar is a fused nine to ten- membered heteroaryl and is an optionally substituted pyrazolo-pyridyl that is attached to the carbon bearing the R6 and R7 groups through a carbon atom of the pyridine ring of said pyrazolo-pyridyl.
6. The compound according to claim 1 , wherein Ar is an optionally substituted benzo-fused aryl and is napthyl, wherein said naphthyl is unsubstituted or substituted with a (Ci-C6)alkoxy.
7. The compound according to claim 1 , wherein Ar is an optionally substituted benzo-fused heteroaryl, which is attached to the carbon bearing the R6 and R7 groups either through a carbon atom of the benzene ring or through a carbon atom of the heteroaryl ring, and wherein two optional substituents at adjacent positions of said benzofused heteroaryl can be taken together with the atoms to which they are attached to form an aryl.
8. The compound according to claim 7, wherein said benzo-fused heteroaryl is selected from the group consisting of quinolinyl, benzofuranyl, benzopyrrolyl, benzothiophenyl, benzimidazolyl, dibenzofuranyl, carbazolyl, 4/-/-chromen-4-onyl, benzo[c/]oxazolyl, and benzo[c/]oxazol-2(3/-/)-onyl, each of which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, haloalkyl, cyano, optionally substituted aryl, -aryl-(CrC6)alkyl-OH, -aryl- C(=0)-OH, -aryl-CN, -aryl-OH, -NH2, -NH(C C6)alkyl, N((C C6)alkyl))2, hydroxy, hydroxy-(C C6)alkyl, -0-(C C6)alkyl-tetrazole,
Figure imgf000141_0001
C6)alkyl, -0-(CrC6)alkyl-N((Ci-C6)alkyl)-C(=0)-(Ci-C6)alkyl, -C(=0)-(C C6)alkyl (C C6)alkoxy, (Ci-C6)alkyl, -0-(Ci-C6)alkyl-pyhdyl, -0-(Ci-C6)alkyl-C(=0)-0-(Ci-C6)alkyl, -0-(CrC6)alkyl-OH, -0-(C C6)alkyl-C(=0)-NH2, -0-(C C6)alkyl-C(=0)-OH, -0-(C C6)alkyl-C(=0)-NH-((CrC6)alkyl), -0-(C C6)alkyl-C(=0)-NH-((Ci-C6)cycloalkyl), - NH-(CrC6)alkyl, -NHS(=0)2NH2, -NHS(=0)2NH-(C C6)alkyl, -NHS(=0)2-(C C6)alkyl, -N((C C6)alkyl)-S(=0)2-(Ci-C6)alkyl, -NH-C(=0)-(C C6)alkyl-OH, -NH- C(=0)-C(=0)-0-(CrC6)alkyl, -NH-C(=0)-C(=0)-NH2, -NH-C(=0)-NH2, -NH-C(=0)- (Ci-C6)alkyl-0-C(=0)-(CrC6)alkyl, -NH-C(=0)-(C C6)alkyl, -P(=0)(OH)2, -N- pyrrolidin-2-one, and -NH-(Ci-C6)alkyl-NH-C(=0)-(Ci-C6)alkyl.
9. The compound of claim 1 , wherein Ar is a benzo-fused hetorocyclyl, which is attached to the carbon bearing the R6 and R7 groups through a carbon atom of the benzene ring of said benzo-fused heterocyclyl.
10. The compound of claim 9, wherein said benzo-fused heterocyclyl is selected from the group consisting of indolinyl, chromanyl, and dihydro-2/-/- benzo[6][1 ,4]oxazinyl, each of which is unsubstituted or substituted at a nitrogen or carbon atom with at least one -(Ci-C6)alkyl.
1 1. The compound according to claim 1 , wherein Ar is a benzo-fused cycloalkyl, which is attached to the carbon bearing the R6 and R7 groups through a carbon atom of the benzene ring of said benzo-fused cycloalkyl.
12. The compound according to claim 1 1 , wherein said benzo-fused cycloalkyl is fluorenyl.
13. The compound according to claim 1 , selected from the group consisting of:
6,7-dimethoxy-4-(naphthalen-2-ylmethyl)isoquinoline hydrochloride 1 ;
3- ((6,7-dimethoxyisoquinolin-4-yl)methyl)quinoline dihydrochloride 2;
4- (benzo[0]thiophen-5-ylmethyl)-6,7-dimethoxyisoquinoline hydrochloride 3; 4-((9/-/-fluoren-2-yl)methyl)-6,7-dimethoxyisoquinoline hydrochloride 4;
2-((6,7-dimethoxyisoquinolin-4-yl)methyl)quinoline dihydrochloride 5;
6-((6,7-dimethoxyisoquinolin-4-yl)methyl)quinoline dihydrochloride 6,
2-((6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-ol dihydrochloride 7, 3- ((6 J-dimethoxyisoquinolin-4-yl)methyl)-7-methoxyquinoline dihydrochlonde
8,
6,7-dimethoxy-4-((6-methoxynaphthalen-2-yl)methyl)isoquinoline
hydrochloride 9,
4- (dibenzo[0,d]furan-2-ylmethyl)-6,7-dimethoxyisoquinoline hydrochloride 10, 6,7-dimethoxy-4-((1 -methylindolin-5-yl)methyl)isoquinoline hydrochloride 11 , 7-((6,7-dimethoxyisoquinolin-4-yl)methyl)-4-methyl-3,4-dihydro-2/-/- benzo[0][1 ,4]oxazine hydrochloride 12,
3-((6,7-dimethoxyisoquinolin-4-yl)methyl)-A/,A/-dimethylquinolin-2-amine dihydrochlonde 13,
3- ((6,7-dimethoxyisoquinolin-4-yl)methyl)-9-ethyl-9/-/-carbazole hydrochloride
14,
4- ((1 H-benzo[c/]imidazol-5-yl)methyl)-6,7-dimethoxyisoquinoline
dihydrochlonde 15,
4-((4-chloro-1 -ethyl-1 /-/-pyrazolo[3,4-0]pyridin-5-yl)methyl)-6,7- dimethoxyisoquinoline dihydrochlonde 16,
4- ((4-ethoxy-1 -ethyl-1 /-/-pyrazolo[3,4-0]pyridin-5-yl)methyl)-6,7- dimethoxyisoquinoline dihydrochlonde 17,
5- ((6,7-dimethoxyisoquinolin-4-yl)methyl)-1 -ethyl-1 /-/-pyrazolo[3,4-0]pyridin-4- ol dihydrochlonde 18,
2- chloro-3-((6,7-dimethoxyisoquinolin-4-yl)methyl)quinoline dihydrochloride
19,
3- ((6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-2-ol hydrochloride 20, 2-((6,7-dimethoxyisoquinolin-4-yl)methyl)-8-methoxyquinoline dihydrochloride
21 ,
6,7-dimethoxy-3-methyl-4-(naphthalen-2-ylmethyl)isoquinoline hydrochloride
22,
2-((6,7-dimethoxyisoquinolin-4-yl)methyl)-8-(pyridin-4-ylmethoxy)quinoline trihydrochloride 23,
2-((6,7-dimethoxyisoquinolin-4-yl)methyl)-8-(pyridin-3-ylmethoxy)quinoline trihydrochloride 24,
6,7-dimethoxy-1 -methyl-4-(naphthalen-2-ylmethyl)isoquinoline hydrochloride
25, 3-((6 J-dimethoxy-1 -methylisoquinolin-4-yl)methyl)quinoline dihydrochloride
26,
2- ((6,7-dimethoxyisoquinolin-4-yl)methyl)-8-ethoxyquinoline dihydrochloride
27,
3- ((6,7-diethoxyisoquinolin-4-yl)methyl)quinoline dihydrochloride 28,
3- ((6-ethoxy-7-methoxyisoquinolin-4-yl)methyl)quinoline dihydrochloride 31 , 2-((6,7-dimethoxyisoquinolin-4-yl)methyl)-8-propoxyquinoline dihydrochloride
32,
4- (dibenzo[0,<^furan-2-ylmethyl)-6,7-dimethoxy-1 -methylisoquinoline hydrochloride 33,
4-((2,2-dimethylchroman-6-yl)methyl)-6,7-dimethoxyisoquinoline
hydrochloride 34,
4-(dibenzo[0,d]furan-2-ylmethyl)-6,7-dimethoxyisoquinoline 2-oxide 35,
4-(dibenzo[0,rf|furan-2-ylmethyl)-6-ethoxy-7-methoxyisoquinoline
hydrochloride 37,
4-(dibenzo[0,<^furan-2-ylmethyl)-1 -ethyl-6,7-dimethoxyisoquinoline
hydrochloride 39,
4-(dibenzo[0,<^furan-2-ylmethyl)-6,7-dimethoxy-1 -propylisoquinoline hydrochloride 40,
ethyl 2-((2-((6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-yl)oxy)acetate dihydrochloride 41 ,
2- ((2-((6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-yl)oxy)ethanol dihydrochloride 42,
3- ((6,7-dimethoxy-3-methylisoquinolin-4-yl)methyl)quinoline dihydrocloride 43, 3-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinoline dihydrochloride
44,
2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-8-ol dihydrochloride
45,
2- ((2-((6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-yl)oxy)acetamide 46,
3- ((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-2-ol dihydrochloride
47,
6-((6,7-dimethoxyisoquinolin-4-yl)methyl)-2-methylquinoline dihydrochloride
48, 3-((6 J-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-6-methoxyquinolin-2-ol dihydrochlonde 49,
3-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinoline dihydrochlonde 50,
3-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)-6-methoxyquinolin-2-ol dihydrochlonde 51 ,
3-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-6-ethoxyquinolin-2-ol dihydrochlonde 52,
3-((6,7-dimethoxyisoquinolin-4-yl)methyl)-6-methoxyquinolin-2-ol
dihydrochlonde 53,
3-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-6-methylquinolin-2-ol dihydrochlonde 54,
2- ((3-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-6-methoxyquinolin-2- yl)oxy)acetonitrile 55,
A/-(2-((3-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-6-methoxyquinolin- 2-yl)oxy)ethyl)acetamide dihydrochlonde 56,
6-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-2-methylquinoline dihydrochlonde 57,
6-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)-2-methylquinoline dihydrochlonde 58,
6-((6,7-dimethoxy-1 -phenylisoquinolin-4-yl)methyl)-2-methylquinoline dihydrochlonde 59,
6-((1 -cyclohexyl-6,7-dimethoxyisoquinolin-4-yl)methyl)-2-methylquinoline dihydrochlonde 60,
3- ((1 -isobutyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinoline dihydrochlonde
61 ,
3-((1 -cyclopropyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinoline
dihydrochlonde 62,
3-((6,7-dimethoxy-1 -phenylisoquinolin-4-yl)methyl)quinoline dihydrochlonde
63,
3- ((1 -butyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinoline dihydrochlonde 64,
4- (isoquinolin-3-ylmethyl)-6,7-dimethoxy-1 -propylisoquinoline dihydrochlonde
65,
4-(isoquinolin-3-ylmethyl)-6,7-dimethoxyisoquinoline dihydrochloride 66, 6-((1 -butyl-6 J-dimethoxyisoquinolin-4-yl)methyl)-2-methylquinoline
dihydrochloride 67,
6-((1 -isobutyl-6 J-dimethoxyisoquinolin-4-yl)methyl)-2-methylquinoline dihydrochloride 68,
3-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-7-methylquinoline dihydrochloride 69,
3-((1 -butyl-6, 7-dimethoxyisoquinolin-4-yl)methyl)-7-methylquinoline 70,
1 - ethyl-4-(isoquinolin-3-ylmethyl)-6,7-dimethoxyisoquinoline dihydrochloride
72,
2- ((2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-8- yl)oxy)acetamide dihydrochloride 73,
3- ((6,7-dimethoxyisoquinolin-4-yl)methyl)-7-methylquinoline 74,
2- ((2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-8-yl)oxy)ethanol
75,
A/-(2-((3-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-6-methoxyquinolin- 2-yl)amino)ethyl)acetamide dihydrochloride 76,
3- ((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-A/-ethyl-6-methoxyquinolin- 2-amine dihydrochloride 77,
6-((1 -cyclopropyl-6,7-dimethoxyisoquinolin-4-yl)methyl)-2-methylquinoline dihydrochloride 78,
3-((6,7-dimethoxyisoquinolin-4-yl)methyl)-6-methyl-4/-/-chromen-4-one hydrochloride 79,
3-((6,7-dimethoxyisoquinolin-4-yl)methyl)-4/-/-chromen-4-one hydrochloride
80,
6-((6,7-dimethoxyisoquinolin-4-yl)methyl)-3-methylbenzo[d]oxazol-2(3/-/)-one hydrochloride 81 , and
6-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-3-methylbenzo[c/]oxazol-
2(3/-/)-one dihydrochloride 82,
2-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-ol 83,
A/-(2-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-yl)sulfamide 84, A/-(2-((1 -propyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-yl)sulfamide
85, A/-(2-((1 -ethyl-6 ,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8- yl)methanesulfonamide 86,
1 -(2-((1 -ethyl-67-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-yl)urea 87, A/-(2-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-yl)acetamide
88,
A/-(2-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8- yl)ethanesulfonamide 89,
2-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinoline-8-carbonitrile 90,
2- ((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinoline-8-carboxamide 91 , ethyl 2-((2-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-yl)amino)-
2-oxoacetate 92,
A/1-(2-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-yl)oxalamide
93,
A/-((2-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8- yl)methyl)sulfamide 94,
3- ((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-6-ol 95,
3-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-6-amine 96,
1 -(3-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-6-yl)pyrrolidin-2- one 97,
A/1-(3-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-6-yl)oxalamide
98,
A/-(3-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-6- yl)methanesulfonamide 99,
A/-(3-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-6-yl)sulfamide
100,
A/-(3-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-6-yl)-/V- ethylmethanesulfonamide 101 ,
3-((6,7-dimethoxyisoquinolin-4-yl)methyl)-6-fluoro-4/-/-chromen-4-one hydrochloride 102,
6-chloro-3-((6,7-dimethoxyisoquinolin-4-yl)methyl)-4/-/-chromen-4-one hydrochloride 103,
6,8-dichloro-3-((6,7-dimethoxyisoquinolin-4-yl)methyl)-4/-/-chromen-4-one hydrochloride 104, 6-((6 J-dimethoxy-1 -methylisoquinolin-4-yl)methyl)-2-methylquinoline dihydrochloride 105,
5-((6 ,7-dimethoxyisoquinolin-4-yl)methyl)benzo[c/]oxazol-2(3/-/)-one hydrochloride 106,
5- ((6,7-dimethoxyisoquinolin-4-yl)methyl)-3-ethylbenzo[c/]oxazol-2(3/-/)-one hydrochloride 107,
2- ((2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-8-yl)oxy)acetic acid dihydrochloride 108,
3- ((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-6-fluoro-4H-chromen-4-one hydrochloride 109,
3-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-6-methyl-4/-/-chromen-4- one hydrochloride 110,
6- ((6,7-dimethoxyisoquinolin-4-yl)methyl)benzo[d]oxazol-2(3/-/)-one hydrochloride 11 1 ,
6-((6,7-dimethoxyisoquinolin-4-yl)methyl)-3-ethylbenzo[d]oxazol-2(3/-/)-one hydrochloride 112,
3-((6,7-dimethoxyisoquinolin-4-yl)methyl)-A/-ethyl-6-methoxyquinolin-2-amine dihydrochloride 113,
5-((6,7-dimethoxyisoquinolin-4-yl)methyl)-2-phenylbenzo[d]oxazole 114, methyl 4-(5-((6,7-dimethoxyisoquinolin-4-yl)methyl)benzo[d]oxazol-2- yl)benzoate 115,
2- ((2-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8- yl)oxy)acetamide 1 16,
3- ((6,7-dimethoxy-1 -methylisoquinolin-4-yl)methyl)-7-methylquinoline 1 17, sodium 3-((2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-8- yl)oxy)propanoate 118,
2-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-ol 119,
2-((2-((6,7-dimethoxy-1 -methylisoquinolin-4-yl)methyl)quinolin-8- yl)oxy)acetamide 120,
8-((1 /-/-tetrazol-5-yl)methoxy)-2-((6,7-dimethoxy-1 -propylisoquinolin-4- yl)methyl)quinoline 121 ,
sodium 3-((2-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8- yl)oxy)propanoate 122, 2-((1 -cyclopropyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-ol 123, 2-((6 J-dimethoxy-3-methylisoquinolin-4-yl)methyl)quinolin-8-ol 124,
2- ((2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-8-yl)oxy)-/V- methylacetamide 125,
A/-cyclopropyl-2-((2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin- 8-yl)oxy)acetamide 126,
8-((1 H-tetrazol-5-yl)methoxy)-2-((1 -ethyl-6,7-dimethoxyisoquinolin-4- yl)methyl)quinoline 127,
ethyl 2-((2-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8- yl)oxy)acetate 128,
3- ((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-6-methoxy-/V- methylquinolin-2-amine 129,
2-((2-((1 -cyclopropyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8- yl)oxy)acetamide 130,
2-((6,7-dimethoxy-1 -methylisoquinolin-4-yl)methyl)quinolin-8-ol 131 ,
2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-5-(trifluoromethyl)quinolin-
8-ol 132,
2-((2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-5- (trifluoromethyl)quinolin-8-yl)oxy)acetamide 133,
2-((2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-8-yl)oxy)-2- methylpropanamide 134,
2- ((2-((1 -ethyl-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-yl)oxy)ethanol
135,
A/-(2-((2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-8- yl)oxy)ethyl)acetamide 136,
3- ((6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-6-ol 137,
2-((3-((6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-6-yl)oxy)acetamide 138, 2-((2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-8- yl)oxy)acetamide 139,
2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-8-yl acetate 140, (4-(5-((6,7-dimethoxyisoquinolin-4-yl)methyl)benzo[d]oxazol-2- yl)phenyl)methanol 141 , (4-(5-((6 ,7-dimethoxyisoquinolin-4-yl)methyl)benzo[d]oxazol-2- yl)phenyl)methanol 142,
3- ((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-6-ol 143,
2-((3-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-6- yl)oxy)acetamide 144,
potassium 4-(5-((6,7-dimethoxyisoquinolin-4-yl)methyl)benzo[c/]oxazol-2- yl)benzoate 145,
4- (5-((6,7-dimethoxyisoquinolin-4-yl)methyl)benzo[c/]oxazol-2-yl)benzoic acid
146,
5- ((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)benzo[c/]oxazol-2(3/-/)-one
147,
2-(5-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-2-oxobenzo[c/]oxazol-
3(2H)-yl)acetamide 148,
4-(5-((6,7-dimethoxyisoquinolin-4-yl)methyl)benzo[c/]oxazol-2-yl)aniline 149, 2-((3-((6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-6-yl)oxy)acetic acid 150, (3-(5-((6,7-dimethoxyisoquinolin-4-yl)methyl)benzo[d]oxazol-2- yl)phenyl)methanol 151 ,
2- ((6,7-dimethoxy-1 -methylisoquinolin-4-yl)methyl)quinolin-8-amine 152, 4-(5-((6,7-dimethoxyisoquinolin-4-yl)methyl)benzo[c/]oxazol-2-yl)benzonitnle
153,
(2-(5-((6,7-dimethoxyisoquinolin-4-yl)methyl)benzo[d]oxazol-2- yl)phenyl)methanol 154,
3- ((6,7-dimethoxy-1 -methylisoquinolin-4-yl)methyl)quinolin-6-ol 155,
(2-(6,7-dimethoxy-1 -methyl-isoquinolin-4-ylmethyl)-quinolin-8-yl)-sulfamide
156,
2-((6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-8-amine 157,
2- ((2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-8-yl)amino)-2- oxoethyl acetate 158,
(2-(6,7-dimethoxy-1 -methyl-isoquinolin-4-ylmethyl)-quinolin-8-yl)-sulfamide
159,
A/-(2-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-8-yl)-2- hydroxyacetamide 160,
3- ((6,7-dimethoxyisoquinolin-4-yl)methyl)-5-(trifluoromethyl)quinolin-6-ol 161 , 3-((6 J-dimethoxy-1 -propylisoquinolin-4-yl)methyl)-5-(trifluoromethyl)quino 6-ol 162,
2-((6,7-dimethoxy-1 -(methoxymethyl)isoquinolin-4-yl)methyl)quinolin-8-ol 163,
2-((2-((6,7-dimethoxy-1 -(methoxymethyl)isoquinolin-4-yl)methyl)quinol^ yl)oxy)acetamide 164,
Ethyl 2-((2-((6,7-dimethoxy-1 -(methoxymethyl)isoquinolin-4-yl)methyl)quinolin- 8-yl)oxy)acetate 165,
2-((2-((6,7-dimethoxy-1 -(methoxymethyl)isoquinolin-4-yl)methyl)quinolin-8- yl)oxy)ethanol 166,
2- ((6,7-dimethoxy-1 -(methoxymethyl)isoquinolin-4-yl)methyl)quinolin-8-amin
167,
3- ((6,7-dimethoxy-1 -(methoxymethyl)isoquinolin-4-yl)methyl)quinolin-6-ol 168, 3-((6,7-dimethoxy-1 -(methoxymethyl)isoquinolin-4-yl)methyl)-5-
(trifluoromethyl)quinolin-6-ol 169,
(4-(6-((6,7-dimethoxyisoquinolin-4-yl)methyl)benzo[d]oxazol-2- yl)phenyl)methanol 170,
and sodium 3-((6,7-dimethoxy-1 -propylisoquinolin-4-yl)methyl)quinolin-6-yl phosphate 171 ; or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
15. A method for inhibiting PDE10A in a mammal, comprising administering to said mammal in need thereof, a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt thereof.
16. A method for treating a disease in a mammal modulated by PDE10A, comprising administering to said mammal in need thereof, a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt thereof.
17. The method of claim 16, wherein said disease is selected from the group consisting of: type I or type II diabetes, impaired glucose tolerance, impaired fasting glucose, metabolic syndrome, metabolism related disorders, psychotic disorders, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, delusional disorder, substance-induced psychotic disorder, anxiety disorders, panic disorder, obsessive/compulsive disorders, acute stress disorder, generalized anxiety disorder, drug addictions, movement disorders, Parkinson's disease, restless leg syndrome, cognition deficiency disorders, Alzheimer's disease, multi-infarct dementia, mood disorders, depression, bipolar disorders, neuropsychiatric conditions, psychosis, attention- deficit/hyperactivity disorder, attentional disorders, diabetes and related disorders, type 2 diabetes mellitus, neurodegenerative disorders, Huntington's disease, multiple sclerosis, stroke, spinal cord injury, solid tumors, hematological malignancies, renal cell carcinoma and breast cancer, pain, macular degeneration/retinal degeneration, wet Age Related Macular Degeneration (ARMD), dry ARMD, geographic atrophy, retinitis pigmentosa, choroidal neovascularization, vascular diseases/exudative diseases, retinopathy, diabetic retinopathy, uveitis/retinitis/choroiditis, Stargard's disease, macular edema, retinal detachment, trauma, systemic disorders with associated retinal dystrophies, cone dystrophies, dystrophy of the retinal pigmented epithelium, myopic retinal degeneration, acute retinal pigment epithelitis, retinal tumors, and retinal disease associated with tumors.
18. The method of claim 16, wherein said disease is selected from the group consisting of: dementia, Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; posttraumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder; age-related cognitive decline, major depressive episode of the mild, moderate or severe type; a manic or mixed mood episode; a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post-stroke depression; major depressive disorder; dysthymic disorder; minor depressive disorder; premenstrual dysphoric disorder; post-psychotic depressive disorder of schizophrenia; a major depressive disorder superimposed on a psychotic disorder comprising a delusional disorder or schizophrenia; a bipolar disorder comprising bipolar I disorder, bipolar II disorder, cyclothymic disorder, Parkinson's disease; Huntington's disease; Fronto temperal Dementia; neurodegeneration associated with cerebral trauma; neurodegeneration associated with stroke; neurodegeneration associated with cerebral infarct; hypoglycemia- induced neurodegeneration; neurodegeneration associated with epileptic seizure; neurodegeneration associated with neurotoxin poisoning; multi-system atrophy, paranoid, disorganized, catatonic, undifferentiated or residual type; schizophreniform disorder; schizoaffective disorder of the delusional type or the depressive type; delusional disorder; substance-induced psychotic disorder, psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, obesity, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type.
19. A method of treating a disorder in a mammal, said disorder being selected from the group consisting of: dementia, Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder; age-related cognitive decline, major depressive episode of the mild, moderate or severe type; a manic or mixed mood episode; a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post-stroke depression; major depressive disorder; dysthymic disorder; minor depressive disorder; premenstrual dysphoric disorder; post-psychotic depressive disorder of schizophrenia; a major depressive disorder superimposed on a psychotic disorder comprising a delusional disorder or schizophrenia; a bipolar disorder comprising bipolar I disorder, bipolar II disorder, cyclothymic disorder, Parkinson's disease; Huntington's disease; Fronto temperal Dementia; neurodegeneration associated with cerebral trauma; neurodegeneration associated with stroke; neurodegeneration associated with cerebral infarct; hypoglycemia- induced neurodegeneration; neurodegeneration associated with epileptic seizure; neurodegeneration associated with neurotoxin poisoning; multi-system atrophy, paranoid, disorganized, catatonic, undifferentiated or residual type; schizophreniform disorder; schizoaffective disorder of the delusional type or the depressive type; delusional disorder; substance-induced psychotic disorder, psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, obesity, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type, said method comprising administering to said mammal in need thereof, a therapeutically effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof.
20. A method of treating a disorder in a mammal, said disorder being selected from the group consisting of: dementia, Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder; age-related cognitive decline, major depressive episode of the mild, moderate or severe type; a manic or mixed mood episode; a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post-stroke depression; major depressive disorder; dysthymic disorder; minor depressive disorder; premenstrual dysphoric disorder; post-psychotic depressive disorder of schizophrenia; a major depressive disorder superimposed on a psychotic disorder comprising a delusional disorder or schizophrenia; a bipolar disorder comprising bipolar I disorder, bipolar II disorder, cyclothymic disorder, Parkinson's disease; Huntington's disease; Fronto temperal Dementia; neurodegeneration associated with cerebral trauma; neurodegeneration associated with stroke; neurodegeneration associated with cerebral infarct; hypoglycemia- induced neurodegeneration; neurodegeneration associated with epileptic seizure; neurodegeneration associated with neurotoxin poisoning; multi-system atrophy, paranoid, disorganized, catatonic, undifferentiated or residual type; schizophreniform disorder; schizoaffective disorder of the delusional type or the depressive type; delusional disorder; substance-induced psychotic disorder, psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, obesity, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type, said method comprising administering to said mammal in need thereof, a therapeutically effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof.
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