WO2012085167A1 - Metabotropic glutamate receptor modulators - Google Patents

Metabotropic glutamate receptor modulators Download PDF

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Publication number
WO2012085167A1
WO2012085167A1 PCT/EP2011/073712 EP2011073712W WO2012085167A1 WO 2012085167 A1 WO2012085167 A1 WO 2012085167A1 EP 2011073712 W EP2011073712 W EP 2011073712W WO 2012085167 A1 WO2012085167 A1 WO 2012085167A1
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amino
dihydropyrido
chlorophenyl
pyrimidin
alkyl
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PCT/EP2011/073712
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French (fr)
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Ulrich Abel
Bjoern Krueger
Holger Kubas
Udo Meyer
Ronalds Zemribo
Gints Smits
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Merz Pharma Gmbh & Co. Kgaa
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Publication of WO2012085167A1 publication Critical patent/WO2012085167A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic 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
    • C07D471/02—Heterocyclic 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
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/84—Nitrogen atoms

Definitions

  • the present invention relates to heterocyclic derivatives, which may act as novel metabotropic glutamate receptor (mGluR) modulators, methods for their synthesis and the treatment and/or prevention of various diseases and disorders, including neurological disorders, by administration of such derivatives.
  • mGluR metabotropic glutamate receptor
  • Neuronal stimuli are transmitted by the central nervous system (CNS) through the interaction of a neurotransmitter released by a neuron, which neurotransmitter has a specific effect on a neuroreceptor of another neuron.
  • L-glutamic acid is considered to be a major excitatory neurotransmitter in the mammalian CNS, consequently playing a critical role in a large number of physiological processes.
  • Glutamate-dependent stimulus receptors are divided into two main groups. The first group comprises ligand-controlled ion channels whereas the other comprises metabotropic glutamate receptors (mGluR). Metabotropic glutamate receptors are a subfamily of G-protein-coupled receptors (GPCR). There is increasing evidence for a peripheral role of both ionotropic and metabotropic glutamate receptors outside the CNS e.g, in chronic pain states.
  • mGluRI and mGluR5 belong to Group I which are positively coupled to phospholipase C and their activation leads to a mobilization of intracellular calcium ions.
  • mGluR2 and mGluR3 belong to Group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to Group III, both of which are negatively coupled to adenylyl cyclase, i.e., their activation causes a reduction in second messenger cAMP and thus a dampening of neuronal activity.
  • the mGluR5 modulators have been shown to modulate the effects of the presynaptically released neurotransmitter glutamate via postsynaptic mechanisms (receptors). Moreover, as these modulators may be both positive and/or negative mGluR5 modulators, such modulators may increase or inhibit the effects mediated through these metabotropic glutamate receptors.
  • Modulators which are negative mGluR5 modulators decrease the effects mediated through metabotropic glutamate receptors. Since a variety of pathophysiological processes and disease states affecting the CNS are thought to be related to abnormal glutamate neurotransmission, and mGluR5 receptors are shown to be expressed in many areas of the CNS and in PNS (peripheral nervous system), modulators of these receptors could be therapeutically beneficial in the treatment of diseases involving CNS and PNS.
  • mGluR5 positive or negative modulators may be administered to provide neuroprotection and/or disease modification in the following acute or chronic pathological conditions or to provide a symptomatological effect on the following conditions: Alzheimer's disease, Creutzfeld-Jakob ' s syndrome/disease, bovine spongiform encephalopathy (BSE), prion related infections, diseases involving mitochondrial dysfunction, diseases involving ⁇ -amyloid and/or tauopathy, Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, post-operative cognitive deficit (POCD), systemic lupus erythematosus, systemic sclerosis, Sjogren's syndrome, Neuronal Ceroid Lipofuscinosis, neurodegenerative cerebellar ataxias, Parkinson's disease, Parkinson's dementia, mild cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive impairment
  • mGluR5 negative or positive modulators may also be administered to provide inhibition of tumour cell growth, migration, invasion, adhesion and toxicity in the peripheral tissues, peripheral nervous system and CNS.
  • MGIuR5 modulators may be administered to provide therapeutic intervention in neoplasia, hyperplasia, dysplasia, cancer, carcinoma, sarcoma, oral cancer, squamous cell carcinoma (SCC), oral squamous cell carcinoma (SCC), lung cancer, lung adenocarcinoma, breast cancer, prostate cancer, gastric cancer, liver cancer, colon cancer, colorectal carcinoma, rhabdomyosarcoma, brain tumour, tumour of a nerve tissue, glioma, malignant glioma, astroglioma, neuroglioma, neuroblastoma, glioblastoma, medulloblastoma, cancer of skin cells, melanoma, malignant melanoma, epithelial neoplasm, lympho
  • mGluR5 positive or negative modulators may also be administered to provide disease modification and/or to provide a symptomatological effect on the following conditions: diabetes, hyperammonemia and liver failure.
  • mGluR5 negative or positive modulators include those indications wherein a particular condition does not necessarily exist but wherein a particular physiological parameter may be improved through administration of the instant compounds, for example cognitive enhancement, learning impairment and/or neuroprotection.
  • Positive modulators may be particularly useful in the treatment of positive and negative symptoms in schizophrenia and cognitive deficits in various forms of dementia and mild cognitive impairment.
  • mGluR modulators may have activity when administered in combination with other substances exhibiting neurological effects via different mechanisms.
  • Simultaneous administration of Group I mGluR modulators and NMDA receptor antagonists has also been shown to provide neuroprotection in animal models (Zieminska et al. Acta Neurobiol. Exp., 2006, 66, 301 -309; Zieminska et al. Neurochemistry International, 2003, 43, 481 -492; and Zieminska et al. Neurochemistry International, 2006, 48, 491 -497).
  • Group I mGluR modulators and compounds such as L-DOPA, dopaminomimetics, and/or neuroleptics may be useful in treating various conditions including drug induced dyskinesias, neuroleptic-induced dyskinesias, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias.
  • heterocyclic derivatives are potent mGluR5 modulators. Therefore, these substances may be therapeutically beneficial in the treatment of conditions which involve abnormal glutamate neurotransmission or in which modulation of mGluR5 receptors results in therapeutic benefit.
  • These substances may be administered in the form of a pharmaceutical composition, wherein they are present together with one or more pharmaceutically acceptable diluents, carriers, or excipients.
  • R 1 represents H, Ci -6 alkyl, or F;
  • R 2 represents H, C h alky!, or F; or
  • R 3 represents H, C h alky!, or F
  • R 4 represents H, C h alky!, or F
  • R 3 and R 4 together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci -6 alkyl, Ci -6 alkoxy, amino, hydroxy, cyano, acyl, Ci -6 alkylamino, di-(C-i -6 alkyl)amino, Ci- 6 alkylcarbonylamino, and oxo;
  • R 5 represents a monocyclic moiety selected from aryl, heteroaryl, cycloC 3-6 alkyl, and heterocyclyl;
  • R 6 represents H, C h alky! which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci -6 alkoxy, amino, hydroxy, C-i -6 alkylamino, and di-(Ci -6 alkyl)amino, or F;
  • R 7 represents C h alky!, which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci -6 alkoxy, amino, hydroxy, C-i -6 alkylamino, and di-(C-i -6 alkyl)amino, cycloC 3-6 alkyl, heterocyclyl, or NR 11 R 12 ; or R 6 and R 7 together with the carbon atoms to which they are attached form a 3- 7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci -6 alkyl, Ci -6 alkoxy, amino, hydroxy, cyano, acyl, Ci -6 alkylamino, di-(C-i -6 alkyl)amin
  • R 8 represents Ci -6 alkyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci -6 alkoxy, amino, hydroxy, Ci -6 alkylamino, and di-(Ci -6 alkyl)amino, cycloC 3-6 alkyl, heterocyclyl, aryl, heteroaryl, Ci- 6 alkylcarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci -6 alkoxy, amino, hydroxy, C-i -6 alkylamino, and di- (C-i -6 alkyl)amino, cycloC 3-6 alkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, heteroarylcarbonyl, Ci- 6 alkoxycarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl,
  • alkylaminosulfonyl wherein the alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci- 6 alkoxy, amino, hydroxy, C-i- 6 alkylamino, and di-(C-i- 6 alkyl)amino, or ⁇ /,/V-di- (Ci- 6 alkyl)aminosulfonyl, wherein the alkyl moieties may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci -6 alkoxy, amino, hydroxy, C-i -6 alkylamino, and di- (C-i -6 alkyl)amino;
  • R 9 represents H, C h alky!, or F;
  • R 10 represents H, Ci -6 alkyl, or F; or R 9 and R 10 together with the carbon atom to which they are attached form a 3-
  • R 11 represents H, C h alky!, or cycloC3-6alkyl
  • R 12 represents H, Ci -6 alkyl, or cycloC 3-6 alkyl; or R 11 and R 12 together with the nitrogen atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, C h alky!, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(Ci-6alkyl)amino, Ci -6 alkylcarbonylamino, and oxo; and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof; it being understood that: if R 1 and R 2 together with the carbon atom to which they are attached form a carbonyl group, then R 8 may also represent H
  • a further aspect of the invention relates to a compound of Formula I, wherein R 8 represents C h alky!
  • halogen trifluoromethyl, trifluoromethoxy, Ci- 6 alkoxy, amino, hydroxy, d- 6 alkylamino, and di-(C-i -6 alkyl)amino, cycloC 3-6 alkyl, heterocyclyl, aryl, heteroaryl, d- 6 alkylcarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci- 6 alkoxy, amino, hydroxy, d- 6 alkylamino, and di-(C-i- 6 alkyl)amino, cycloC 3 - 6 alkylcarbonyl, arylcarbonyl,
  • Ci -6 alkoxycarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci -6 alkoxy, amino, hydroxy, C-i -6 alkylamino, and di-(Ci -6 alkyl)amino, aminocarbonyl, N- C-i- 6 alkylaminocarbonyl, wherein the alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy,
  • alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, d -6 alkoxy, amino, hydroxy, d -6 alkylamino, and di-(d -6 alkyl)amino, or ⁇ /,/V-di- (Ci- 6 alkyl)aminosulfonyl, wherein the alkyl moieties may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy,
  • a further aspect of the invention relates to a compound of Formula I, wherein R 1 and R 2 together with the carbon atom to which they are attached form a carbonyl group, and X represents NR 8 , wherein R 8 represents H.
  • a further aspect of the invention relates to a compound of Formula I, wherein R 1 and R 2 represent H, and X represents NR 8 , wherein R 8 represents Ci -6 alkylcarbonyl, cycloC 3 - 6 alkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, Ci- 6 alkoxycarbonyl, /V-C-i- 6 alkylaminocarbonyl, /V./V-di ⁇ Ci-ealky aminocarbonyl, ⁇ /,/V-di-
  • R 8 represents C-i- 6 alkylcarbonyl, cycloC3-6alkylcarbonyl, arylcarbonyl, Ci-6alkoxycarbonyl, A/-Ci-6alkylaminocarbonyl, N,N- di-(Ci-6alkyl)aminocarbonyl, Ci-6alkylsulfonyl, cycloC3-6alkylsulfonyl, ⁇ /,/V-di- (Ci-6alkyl)aminosulfonyl, or heteroaryl.
  • Such a compound of Formula I wherein represents optionally substituted pyridyl or tetrazolyl.
  • a further aspect of the invention relates to a compound of Formula I, wherein R 5 represents phenyl optionally substituted by one or more substituents selected from halogen, Ci -6 alkyl, and cyano.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IA
  • R 3 -R 5 and R 8 -R 10 are as defined above for Formula I, and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
  • Such a compound of Formula IA wherein R 3 , R 4 , R 8 , R 9 , and R 10 each represent H and R 5 represents a monocyclic moiety selected from aryl and heteroaryl.
  • Such a compound of Formula IA wherein R 3 , R 4 , R 8 , R 9 , and R 10 each represent H and R 5 represents phenyl optionally substituted by one or more halogen atoms.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IB
  • R 1 -R 4 , R 9 -R 12 are as defined above for Formula I, and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
  • Such a compound of Formula IB wherein R 5 represents a monocyclic moiety selected from aryl and heteroaryl.
  • R 3 , R 4 , R 9 , and R 10 each represent H
  • R 11 and R 12 represent C h alky! (e.g., methyl or ethyl) or R 11 and R 12 together with the nitrogen atom to which they are attached combine to form a 3-7 membered saturated ring
  • R 5 represents a monocyclic moiety selected from aryl and heteroaryl.
  • Such a compound of Formula IB wherein R 3 , R 4 , R 9 , and R 10 each represent H, R 11 and R 12 together with the nitrogen atom to which they are attached combine to form piperidino, and R 5 represents phenyl optionally substituted by one or more halogen atoms.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IC
  • R 1 -R 5 and R 8 -R 10 are as defined above for Formula I, and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
  • Such a compound of Formula IC wherein R 5 represents a monocyclic moiety selected from aryl and heteroaryl.
  • Such a compound of Formula IC wherein R 1 -R 4 , R 9 , and R 10 each represent H; R 5 represents a monocyclic moiety selected from aryl and heteroaryl; and R 8 represents Ci -6 alkylcarbonyl, cycloC 3-6 alkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, d.
  • R 8 represents Ci- 6 alkylcarbonyl, cycloC 3 - 6 alkylcarbonyl, arylcarbonyl, Ci- 6 alkoxycarbonyl, /V-Ci- 6 alkylaminocarbonyl, N,N- di-(Ci- 6 alkyl)aminocarbonyl, Ci- 6 alkylsulfonyl, cycloC 3 - 6 alkylsulfonyl, ⁇ /,/V-di- (Ci- 6 alkyl)aminosulfonyl, or heteroaryl.
  • Such a compound of Formula IC wherein R 1 -R 4 , R 9 , and R 10 each represent H; R 5 represents phenyl optionally substituted by one or more substituents selected from halogen, C h alky!, and cyano; and R 8 represents Ci- 6 alkylcarbonyl, cycloC 3-6 alkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, Ci -6 alkoxycarbonyl, N-C ⁇ ⁇ . 6 alkylaminocarbonyl, /V,/V-di-(Ci- 6 alkyl)aminocarbonyl, ⁇ /,/V-di-
  • R 8 represents Ci -6 alkylcarbonyl, cycloC 3-6 alkylcarbonyl, arylcarbonyl, Ci -6 alkoxycarbonyl, /V-Ci -6 alkylaminocarbonyl, N,N- di-(Ci -6 alkyl)aminocarbonyl, Ci -6 alkylsulfonyl, cycloC 3-6 alkylsulfonyl, ⁇ /,/V-di- (Ci -6 alkyl)aminosulfonyl, or heteroaryl.
  • Such a compound of Formula IC wherein R 1 -R 4 , R 9 , and R 10 each represent H; R 5 represents phenyl optionally substituted by one or more substituents selected from halogen, Ci -6 alkyl, and cyano; and R 8 represents optionally substituted pyridyl, tetrazolyl, pyrimidyl, furyl, thiazolyl, or imidazolyl.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula ID
  • R 1 -R 5 and R 9 and R 10 are as defined above for Formula I and
  • R 13 represents Ci -6 alkyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci- 6 alkoxy, amino, hydroxy, Ci -6 alkylamino, and di-(Ci -6 alkyl)amino, cycloC 3-6 alkyl, heterocyclyl, aryl, heteroaryl, Ci- 6 alkoxy which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci- 6 alkoxy, amino, hydroxy, d- 6 alkylamino, and di-(C-i- 6 alkyl)amino, aminocarbonyl, /V-C-i- 6 alkylamino, wherein the alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci- 6 alkoxy, amino, hydroxy, C-
  • Such a compound of Formula ID wherein R 13 represents Ci -6 alkyl, cycloC 3- 6 alkyl, heterocyclyl, aryl, Ci- 6 alkoxy, /V-C-i- 6 alkylamino, /V,/V-di-(Ci- 6 alkyl)amino, N-C- ⁇ . 6 alkyl-/V-cycloC 3-6 alkylamino, or / -Ci-ealkyl-Z -cycloCs-ealkyl-d-ealkylamino.
  • Such a compound of Formula ID wherein R 1 -R 4 , R 9 , and R 10 each represent H and R 5 represents a monocyclic moiety selected from aryl and heteroaryl.
  • Such a compound of Formula ID wherein R 3 , R 4 , R 8 , R 9 , and R 10 each represent H and R 5 represents phenyl optionally substituted by one or more substituents selected from halogen, Ci -6 alkyl, and cyano.
  • the invention relates to a compound of Formula I as defined above or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for the treatment and/or prevention of a condition or disease associated with abnormal glutamate neurotransmission, including a condition or disease which is affected or facilitated by modulation of the mGluR5 receptor, including for the conditions or diseases selected from those described earlier in the description.
  • the invention relates to a compound of Formula I as defined above or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for the treatment and/or prevention of a CNS disorder.
  • the invention relates to a compound of Formula I as defined above or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for the treatment and/or prevention of abnormal glutamate neurotransmission.
  • the invention additionally relates to a compound of Formula I as defined above or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for modulation of the mGluR5 receptor.
  • the invention furthermore relates to such a compound for treatment, prevention and or modulation of a condition or disease selected from those described earlier in the description.
  • the invention still further relates to such a compound for treatment, prevention and or modulation of a a physiological parameter, such as cognitive disorder, whether or not a specific identifiable condition exists.
  • a further aspect of the invention relates to a compound of Formula I as defined above or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for the treatment and/or prevention of a condition associated with abnormal glutamate neurotransmission or in which modulation of mGluR5 receptors results in therapeutic benefit.
  • the conditions which may be treated have already been described above.
  • Such conditions and indications include: a) For mGluR5 modulators: chronic pain, neuropathic pain, diabetic neuropathic pain (DNP), cancer pain, pain related to rheumathic arthritis, inflammatory pain, L-dopa-induced dyskinesias, dopaminomimetic- induced dyskinesias, L-dopa-induced dyskinesias in Parkinson's disease therapy, dopaminomimetic-induced dyskinesias in Parkinson's disease therapy, tardive dyskinesias, Parkinson's disease, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), generalized anxiety disorder, substance-induced anxiety disorder, eating disorders, obesity, binge eating disorders, Huntington's chorea, epilepsy, Alzheimer's disease, positive and negative symptoms of schizophrenia, cognitive impairment, functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), migraine, irritable bowel syndrome (IBS), or for cognitive enhancement and/or neuroprotection.
  • Negative modulation of mGluR5 may be particularly useful for: chronic pain, neuropathic pain, diabetic neuropathic pain (DNP), cancer pain, pain related to rheumathic arthritis, inflammatory pain, L-dopa-induced dyskinesias, dopaminomimetic-induced dyskinesias, L-dopa-induced dyskinesias in Parkinson's disease therapy, dopaminomimetic-induced dyskinesias in Parkinson's disease therapy, tardive dyskinesias, Parkinson's disease, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), generalized anxiety disorder, substance-induced anxiety disorder, eating disorders, obesity, binge eating disorders, migraine, irritable bowel syndrome (IBS), functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), Huntington's chorea and/or epilepsy.
  • Positive modulation of mGluR5 may be particularly useful for: Alzheimer's disease, positive and/or negative symptoms of
  • a further aspect of the invention relates to a compound of Formula I as defined above or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for the treatment of binge eating disorders.
  • the invention relates to the use of a compound of Formula I as defined above or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for the preparation of a medicament for treating or preventing a condition or disease associated with abnormal glutamate neurotransmission.
  • a use includes the use of such a compound for the preparation of a medicament for the prevention and/or treatment of a condition or disease in an animal including a human being which condition or disease is affected or facilitated by modulation of the mGluR5 receptor.
  • the invention relates to a method for treating or preventing a condition associated or disease associated with abnormal glutamate neurotransmission, including a condition or disease which is affected or facilitated by modulation of the mGluR5 receptor, including for the conditions or diseases selected from those described earlier in the description.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient at least one compound of Formula I as defined above or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, together with one or more pharmaceutically acceptable excipients.
  • the mGluR modulators as described above are expected to have a high activity when administered in combination with other substances exhibiting neurological effects via different mechanisms.
  • the invention thus relates to a compound of Formula I as defined above or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for Neuroprotection and/or for cognitive enhancement in combination with at least one NMDA receptor antagonist such as Memantine.
  • a further aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least two different active ingredients, selected from least one compound of Formula I as defined above, and, additionally, at least one NMDA-antagonist, together with one or more pharmaceutically acceptable excipients.
  • These compositions may be used for the treatment of CNS-related diseases, cognitive enhancement and for neuro-protection.
  • the invention thus additionally provides a composition comprising at least two different active ingredients, selected from least one compound of Formula I as defined above, and, additionally, at least one NMDA-antagonist for the treatment of any of the conditions indicated herein, including CNS-related diseases, cognitive enhancement and for neuroprotection.
  • This invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of a compound of Formula I as described above and an NMDA receptor antagonist, including compositions wherein the NMDA receptor antagonist is e.g. Memantine and pharmaceutically acceptable salts, polymorphs, hydrates and solvates thereof.
  • the NMDA receptor antagonist is e.g. Memantine and pharmaceutically acceptable salts, polymorphs, hydrates and solvates thereof.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least two different active ingredients, selected from at least one compound of Formula I as defined above, and, additionally, at least one active ingredient selected from L-DOPA, other dopaminomimetics (such as antiparkinsonian dopaminomimetics, including bromocriptine, cabergolin, ropinirole, pramiperole, pergolide, rotigotine), and neuroleptics (such as classical neuroleptics, including haloperidol, perphenazin, chlorpromazine, metoclopramide).
  • dopaminomimetics such as antiparkinsonian dopaminomimetics, including bromocriptine, cabergolin, ropinirole, pramiperole, pergolide, rotigotine
  • neuroleptics such as classical neuroleptics, including haloperidol, perphenazin, chlorpromazine, metoclopramide.
  • the invention also relates to a method of providing neuroprotection in a living animal, including a human, comprising the step of administering to a living animal, including a human, a therapeutically effective amount of a composition as described above.
  • the invention relates to the use of a composition as described above for the manufacture of a medicament to provide neuroprotection in an animal, including a human.
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula ⁇ '
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula IB'
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula IB'
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula IC
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula IC
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula ID'
  • R 5 represents aryl or heteroaryl and R 13 is as defined above for Formula ID, wherein a com ound of Formula XIV
  • the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Cj. j indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive.
  • (d ⁇ alkyl refers to alkyl of one to three carbon atoms (i.e.
  • Ci -6 alkyl represents straight or branched chain alkyl groups. Examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert -butyl.
  • C 2 - 6 alkenyl represents straight or branched chain alkenyl groups.
  • Ci -6 alkoxy represents straight or branched chain -0-Ci -6 alkyl groups. Examples of such alkoxy groups include methoxy, ethoxy, n-propoxy, and isopropoxy, sec-butoxy, fe/f-butoxy.
  • acyl represents Ci -6 alkylcarbonyl, trifluoroacetyl, hydroxy- Ci -6 alkylcarbonyl, Ci -6 alkoxycarbonyl, /V-Ci -6 alkylaminocarbonyl, ⁇ /,/V-di- (C-i- 6 alkyl)aminocarbonyl, Ci- 6 alkoxy-Ci- 6 alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, cyclo-C 3- i 2 alkylcarbonyl, aryl-Ci -6 alkylcarbonyl, heteroaryl-Ci -6 alkylcarbonyl, arylamino- Ci -6 alkylcarbonyl, heteroarylamino-Ci -6 alkylcarbonyl, heterocyclylcarbonyl and heterocyclyl-Ci- 6 alkylcarbonyl.
  • cycloC 3- i 2 alkyl represents monocyclic or bicyclic, or tricyclic alkyl groups, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1 ]heptyl and adamantanyl, which may be optionally substituted by one or more (e.g., 1 , 2, 3, 4, or 5) substituents, which may be the same or different, selected independently from halogen, trifluoromethyl, trifluoromethoxy, Ci -6 alkyl, C 2-6 alkenyl, Ci -6 alkoxy, amino, hydroxy, cyano, Ci -6 alkoxycarbonyl, C-i -6 alkylamino, and di-(C-i -6 alkyl)amino, Ci -6 alkyl- carbonylamino, oxo, C-i -6 alkoxyimino, /V-Ci -6 alkylamin
  • cycloC 3-6 alkyl represents monocyclic alkyl groups, including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, which may be optionally substituted by one or more (e.g., 1 , 2, 3, 4, or 5) substituents, which may be the same or different, selected independently from halogen, trifluoromethyl, trifluoromethoxy, Ci -6 alkyl, C 2- 6 alkenyl, Ci -6 alkoxy, amino, hydroxy, cyano, Ci -6 alkoxycarbonyl, Ci -6 alkylamino, and di- (C-i -6 alkyl)amino, Ci -6 alkylcarbonylamino, oxo, C-i -6 alkoxyimino, /V-d. 6 alkylaminocarbonyl, /V,/V-di-(Ci -6 alkyl)aminocarbonyl, aryl
  • aryl represents phenyl or naphthyl, wherein the phenyl or naphthyl group is optionally substituted by one or more (e.g., 1 , 2, 3, 4, or 5) substituents, which may be the same or different, selected independently from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, d.
  • heteroaryl represents an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic group comprising a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl group may be optionally substituted by one or more (e.g., 1 , 2, 3, 4, or 5) substituents, which may be the same or different, selected independently from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, Ci -6 alkyl, hydroxyCi -6 alkyl, C 2-6 alkenyl, Ci -6 alkoxy, amino, hydroxy, nitro, cyano, Ci -6 alkylcarbonyl, Ci
  • heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, pyrazolyl, triazolyl, thiadiazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, purinyl, benzofuryl, benzothienyl, indolyl, indolizinyl, isoindolyl, indolinyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, isoquinolinyl, quinolizin
  • heterocyclyl represents a saturated or unsaturated non-aromatic 3 to 12 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, and a saturated or unsaturated non-aromatic bicyclic ring system having 3 to 12 members comprising one to six heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heterocyclic ring or ring system may be optionally substituted by one or more (e.g., 1 , 2, 3, 4, or 5) substituents, which may be the same or different, selected independently from halogen, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, C h alky!, C2- 6 alkenyl, amino, hydroxy, nitro, cyano, Ci- 6 alkoxycarbonyl, Ci- 6 alkylamino, and di-(Ci- 6 alkyl)amino, Ci- 6 alkylcarbonylamino, oxo, Ci- 6
  • halogen represents fluorine, chlorine, bromine and iodine.
  • the compounds of the present invention are usually named according to the lUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g. "Ph” for phenyl, “Me” for methyl, “Et” for ethyl, “min” for minute or minutes, “h” for hour or hours, and “rt” for room temperature).
  • Memantine also known as 1 -amino-3,5-dimethyladamantane, is disclosed, U.S. Patent Nos. 4, 122, 193; 4,273,774; and 5,061 ,703, the subject matter of which patents is hereby incorporated by reference.
  • Memantine is a system ically-active noncompetitive NMDA receptor antagonists having moderate affinity for the receptor. It exhibits strong voltage dependent characteristics and fast blocking/unblocking kinetics (see e.g. Gortelmeyer et al., Arzneim-Forsch/Drug Res., 1992, 42:904-913; Winblad et al., Int. J. Geriat. Psychiatry, 1999, 14: 135-146; Rogawski, Amino Acids, 2000, 19: 133-49; Danysz et al., Curr. Pharm. Des., 2002, 8:835-43; Jirgensons et. al. Eur. J. Med. Chem., 2000, 35: 555- 565).
  • analog or “derivative” is used herein in the conventional pharmaceutical sense, to refer to a molecule that structurally resembles a reference molecule, but has been modified in a targeted and controlled manner to replace one or more specific substituents of the reference molecule with an alternate substituent, thereby generating a molecule which is structurally similar to the reference molecule.
  • Synthesis and screening of analogs e.g., using structural and/or biochemical analysis, to identify slightly modified versions of a known compound which may have improved or biased traits (such as higher potency and/or selectivity at a specific targeted receptor type, greater ability to penetrate blood-brain barriers, fewer side effects, etc.) is a drug design approach that is well known in pharmaceutical chemistry.
  • analogs and derivatives of the compounds of the invention may be created which have improved therapeutic efficacy, i.e., higher potency and/or selectivity at a specific targeted receptor type, either greater or lower ability to penetrate mammalian blood-brain barriers (e.g., either higher or lower blood-brain barrier permeation rate), fewer side effects, etc.
  • prodrug is used herein in the conventional pharmaceutical sense, to refer to a molecule which undergoes a transformation in vivo (e.g., an enzymatic or chemical transformation) to release an active parent drug.
  • Prodrugs of the compounds of Formula I of the present invention may be prepared by chemically modifying a functional group present in the compound of Formula I such that the chemically modified compound may undergo a transformation in vivo (e.g., enzymatic hydrolysis) to provide the compound of Formula I.
  • Examples of functional groups present in the compounds of Formula I which may be modified to produce prodrugs include carboxy, hydroxy, amino, and thio groups.
  • Prodrugs of the compounds of Formula I of the present invention may be prepared according to conventional techniques which have been described in the art (see, for example, Stella V., et al., Prodrugs: Challenges and Rewards, AAPS Press/Springer, New York, 2007).
  • compositions of the invention refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g., human).
  • pharmaceutically acceptable may also mean approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.
  • Compounds of the present invention may be in the form of pharmaceutically acceptable salts.
  • “Pharmaceutically acceptable salts” refers to those salts which possess the biological effectiveness and properties of the parent compound and which are not biologically or otherwise undesirable. The nature of the salt is not critical, provided that it is non-toxic and does not substantially interfere with the desired pharmacological activity.
  • ⁇ -Alanine ester 1 is acylated with methylmalonylchloride (2).
  • the resulting diester 3 is cyclized to lactam 4, which is subsequently decarboxylated to piperidine-2,4-dione (5).
  • Treatment of intermediate 5 with dimethylformamide dimethyl acetal (DMF-DMA) at elevated temperature results in the formation of dimethylaminomethylene derivative 6, which is reacted with an appropriate guanidine 7 to provide a compound of Formula ⁇ '.
  • DMF-DMA dimethylformamide dimethyl acetal
  • the Boc group is cleaved with trifluoroacetic acid (TFA) to provide an amine 16, which is acylated using acyl chlorides, chloroformates, sulfonyl or carbamoyl chlorides, or alkylated with alkyl halides to provide compounds of Formula IC
  • Amine 16 may also be reacted with isocyanates or isothiocyanates to give ureas or thioureas, or it can be arylated to give the corresponding /V-aryl derivatives.
  • deprotected piperidone 17 may be directly reacted with an appropriate acylating or alkylating reagent to obtain ketone 18, which is subsequently converted to dimethylaminomethylene derivative 19 by means of DMF-DMA.
  • the final compound IC is formed analogously to the above described method using substituted guanidine 7 in the presence of triethylamine or another suitable base.
  • R 5' aryl or eteroaryl
  • BOC-protected intermediate 14 is reacted with methyl carbarn imidothioate (20) under acidic conditions at elevated temperature to form intermediate 21 , which is deprotected and converted to the corresponding acylated compound 23.
  • intermediate 21 is deprotected and converted to the corresponding acylated compound 23.
  • oxidizing reagent like mCPBA the mesylate group is substituted by an arylamine 25 to provide compounds of formula ID'.
  • stereoisomeric forms (including optical isomers) of the compounds and the intermediates of this invention may be obtained by the application of art-known procedures.
  • Diastereomers may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g. liquid chromatography using chiral stationary phases.
  • Enantiomers (optically active isomers) may be separated from each other by selective crystallization of their diastereomeric salts with optically active acids.
  • enantiomers may be separated by chromatographic techniques using chiral stationary phases.
  • stereoisomeric forms may also be derived from the corresponding pure stereoisomeric form of appropriate starting materials, provided that the reaction occur stereoselectively.
  • Stereoisomeric forms of Formula I are included within the scope of this invention.
  • Compounds of Formula I which are marked by radioactive atoms may be obtained using art-known procedures. Typical compounds include those where one or more hydrogens are substituted by tritium, where one or more 12 C are substituted by 14 C, where one or more fluor atoms are substituted by 18 F or other isotopes. These may be used for the treatment of diseases (e.g. cancer) but also for diagnostic purposes.
  • the radioactive atoms exchanged in the molecule are often isotopes of carbon, hydrogen, halogen, sulphur or phosphorus.
  • Compounds of the Formula I which are marked by radioactive atoms are included within the scope of this invention.
  • salts of the compounds of Formula I are those wherein the counterion is pharmaceutically acceptable.
  • salts of acids and bases which are non-pharmaceutically acceptable, may also find use, for example, in the preparation and purification of pharmaceutically acceptable compounds. All salts whether pharmaceutically acceptable or not are included within the ambit of the present invention.
  • the pharmaceutically acceptable salts as mentioned above are meant to comprise the therapeutically active non-toxic salt forms, which the compounds of Formula I are able to form. The latter may conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, e.g.
  • hydrohalic acids such as hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids such as acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1 ,2,3- propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4- methylbenzenesulfonic, cyclohexanesulfonic, 2-hydroxybenzoic, 4-amino-2- hydroxybenzoic and the like acids.
  • the salt form may be converted by treatment with alkali into the free base form.
  • the active ingredients of the compounds of the invention may be placed into the form of pharmaceutical compositions, unit dosages or dosage forms.
  • the pharmaceutical compositions may be employed as solid dosage forms, such as powders, granules, pellets, coated or uncoated tablets or filled capsules, or liquid dosage forms, such as solutions, suspensions, emulsions, or capsules filled with the same, or semi solid dosage forms, such as gels, creams and ointments.
  • the active ingredient(s) dissolution and release profiles of the pharmaceutical dosage forms may be varied from seconds to months.
  • compositions are designed for the use in animals and humans and may be applied via all application routes.
  • Preferred application routes will be the oral route, the dermal route, the pulmonary route, the nasal route, the rectal route, the parenteral route.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional or new ingredients in conventional or special proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • Tablets containing one (1 ) to one hundred (100) milligrams of active ingredient or, more broadly, zero point five (0.5) to five hundred (500) milligrams per tablet, are accordingly suitable representative unit dosage forms.
  • carrier applied to pharmaceutical compositions of the invention refers to a diluent, excipient, or vehicle with which an active compound is administered.
  • Such pharmaceutical carriers may be sterile liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • A.R. Gennaro, 20 th Edition describes suitable pharmaceutical carriers in "Remington: The Science and Practice of Pharmacy”. METHOD OF TREATING
  • the active principles of the invention may be administered to a subject, e.g., a living animal (including a human) body, in need thereof, for the treatment, alleviation, or amelioration, palliation, or elimination of an indication or condition which is susceptible thereto, or representatively of an indication or condition set forth elsewhere in this application, preferably concurrently, simultaneously, or together with one or more pharmaceutically-acceptable excipients, carriers, or diluents, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parental (including intravenous and subcutaneous) or in some cases even topical route, in an effective amount.
  • Suitable dosage ranges are 1 -1000 milligrams daily, optionally 10-500 milligrams daily, and optionally 50-500 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
  • treat is used herein to mean to relieve or alleviate at least one symptom of a disease in a subject.
  • the term “treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.
  • compositions comprising a compound of the present invention and a second active ingredient (e.g., an NMDA receptor antagonist, L-DOPA, a dopaminomimetic, or a neuroleptic), in a formulation known in the art, or two separate pharmaceutical compositions (formulations), one comprising a compound of the present invention as formulated above and one comprising a second active ingredient (e.g., an NMDA receptor antagonist, L-DOPA, a dopaminomimetic, or a neuroleptic) in a formulation known in the art, to be administered conjointly.
  • a second active ingredient e.g., an NMDA receptor antagonist, L-DOPA, a dopaminomimetic, or a neuroleptic
  • the term “conjoint administration” is used to refer to administration of a compound of the present invention and a second active ingredient (e.g., an NMDA receptor antagonist, L-DOPA, a dopaminomimetic, or a neuroleptic) in one composition, or simultaneously in different compositions, or sequentially.
  • a second active ingredient e.g., an NMDA receptor antagonist, L-DOPA, a dopaminomimetic, or a neuroleptic
  • the sequential administration to be considered “conjoint”
  • the compound of the present invention and the NMDA receptor antagonist must be administered separated by a time interval that still permits the resultant beneficial effect in a mammal.
  • the compound of the present invention and the NMDA receptor antagonist must be administered on the same day (e.g., each - once or twice daily), including within an hour of each other, and including simultaneously.
  • terapéuticaally effective applied to dose or amount refers to that quantity of a compound or pharmaceutical composition that is sufficient to result in a desired activity upon administration to a living animal body in need thereof.
  • Compounds of the present invention may be administered orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. It is usually desirable to use the oral route.
  • the active agents may be administered orally in the form of a capsule, a tablet, or the like (see Remington: The Science and Practice of Pharmacy, 20 th Edition).
  • the orally administered pharmaceutical compositions may be administered in the form of a time-controlled release vehicle, including diffusion- controlled systems, osmotic devices, dissolution-controlled matrices, and erodible/degradable matrices.
  • the active drug component of Formula I may be combined with non-toxic, pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, and the like); disintegrants (e.g., potato starch or sodium starch glycolate); and/or wetting agents (e.g., sodium lauryl sulphate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (
  • binding agents e.g., pregelatinized maize starch
  • the drug components may be combined with nontoxic, pharmaceutically acceptable inert carriers (e.g., ethanol, glycerol, water), suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid), and the like.
  • Stabilizing agents such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) may also be added to stabilize the dosage forms.
  • compositions of the invention containing as active compound a compound of Formula I may be also introduced in beads, microspheres or microcapsules, e.g., fabricated from polyglycolic acid/lactic acid (PGLA).
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups, emulsions or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Preparations for oral administration may be suitably formulated to give controlled or postponed release of the active compound.
  • Liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes may be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines, as is well known.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • Active drugs may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxy- propyl methacrylamide-phenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • active drug may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • the therapeutics according to the present invention containing as active compound a compound of Formula I may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. , dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant e.g. , dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane, carbon dioxide, or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • Formations comprising compounds of the present invention may be delivered parenterally, i.e., by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c), intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.), or intradermal (i.d.) administration, by direct injection, via, for example, bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • compositions may take such forms as excipients, suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory 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.
  • Compounds of the present invention may also be formulated for rectal administration, e.g., as suppositories or retention enemas (e.g., containing conventional suppository bases such as cocoa butter or other glycerides).
  • rectal administration e.g., as suppositories or retention enemas (e.g., containing conventional suppository bases such as cocoa butter or other glycerides).
  • compositions containing a compound of Formula I may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient and/or may contain different dosage levels to facilitate dosage titration.
  • the pack may, for example, comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • Compositions of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • the dose of the components in the compositions of the present invention is determined to ensure that the dose administered continuously or intermittently will not exceed an amount determined after consideration of the results in test animals and the individual conditions of a patient.
  • a specific dose naturally varies depending on the dosage procedure, the conditions of a patient or a subject animal such as age, body weight, sex, sensitivity, feed, dosage period, drugs used in combination, seriousness of the disease.
  • the appropriate dose and dosage times under certain conditions may be determined by the test based on the above-described indices but may be refined and ultimately decided according to the judgment of the practitioner and each patient's circumstances (age, general condition, severity of symptoms, sex, etc.) according to standard clinical techniques.
  • compositions of the invention may be determined by standard pharmaceutical procedures in experimental animals, e.g., by determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between therapeutic and toxic effects is the therapeutic index and it may be expressed as the ratio LD50/ED50.
  • Compositions that exhibit large therapeutic indices are preferred.
  • the instant compounds of Formula I represent a novel class of mGluR5 modulators. In view of their potency, they will be useful therapeutics in a wide range of disorders, in particular CNS disorders, which involve excessive glutamate induced excitation.
  • Neuroprotection as well as cognitive enhancement may also be achieved by administration of the instant compounds in combination with a NMDA receptor antagonist like Memantine.
  • the method-of-treating a living animal body with a compound of the invention, for the inhibition of progression or alleviation of the selected ailment therein, is as previously stated by any normally-accepted pharmaceutical route, employing the selected dosage which is effective in the alleviation of the particular ailment desired to be alleviated.
  • Use of the compounds of the present invention in the manufacture of a medicament for the treatment of a living animal for inhibition of progression or alleviation of selected ailments or conditions, particularly ailments or conditions susceptible to treatment with a Group I mGluR modulator is carried out in the usual manner comprising the step of admixing an effective amount of a compound of the invention with a pharmaceutically-acceptable diluent, excipient, or carrier, and the method-of- treating, pharmaceutical compositions, and use of a compound of the present invention in the manufacture of a medicament.
  • compositions prepared by admixing the active ingredient with a suitable pharmaceutically-acceptable excipient, diluent, or carrier include tablets, capsules, solutions for injection, liquid oral formulations, aerosol formulations, TDS formulations, and nanoparticle formulations, thus to produce medicaments for oral, injectable, or dermal use, also in accord with the foregoing.
  • ACN is defined as acetonitrile
  • Boc as fe/f-butyloxycarbonyl
  • DCM dichloromethane
  • DEE diethyl ether
  • DMAP as 4- dimethylaminopyridine
  • DIPEA N,N- diisopropylethylamine
  • DF-DMA N,N- dimethylformamide
  • EDC EDC
  • EDC EDC
  • EDC as 1 -ethyl-3-(3-dimethylaminopropyl) carbodiimide (/V 1 -((ethylimino)methylene)-/V 3 ,/V 3 - dimethylpropane-1 ,3-diamine
  • O-Dimethylhydroxylamine hydrochloride (0.13 g, 1 .28 mmol) is added to a solution of 2-((3-chlorophenyl)amino)-5,6,7,8-tetrahydroquinazoline-6-carboxylic acid 0.30 g, 0.98 mmol), HOBt hydrate (0.20 g, 1 .28 mmol), EDC (0.25 g, 1 .28 mmol) and DIPEA (0.56 mL ,3.26 mmol) in dry DMF (3 mL), and the resulting mixture is stirred at room temperature for 24 h.
  • the obtained residue is purified by column chromatography (silica gel, EtOAc/hexane, 1 :5) and washed with DEE/hexane mixture (1 : 1 ) to give an impure mixture of fe/f-butyl 2-((3-chlorophenyl)amino)-5-methyl-7,8-dihydropyrido[4,3- d]pyrimidine-6(5/-/)-carboxylate and fe/f-butyl 2-((3-chlorophenyl)amino)-7-methyl-7,8- dihydropyrido[4,3-d]pyrimidine-6(5/-/)-carboxylate (in total 369 mg).
  • the formed solid is collected by filtration, washed with acetone/DEE (1 :1 ) and air-dried to obtain a mixture of ⁇ /-(3- chlorophenyl)-5-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and ⁇ /-(3- chlorophenyl)-7-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (496 mg, 97%) as a white solid.
  • Example 75 the title compound (78 mg, 13%) is separated as a white solid.
  • compositions according to the present invention may be processed into tablets, coated tablets, capsules, drip solutions, suppositories, injection and infusion preparations, and the like and may be therapeutically applied by the oral, rectal, parenteral, and additional routes.
  • Representative pharmaceutical compositions according to the present invention follow:
  • Tablets suitable for oral administration which contain the active ingredient may be prepared by conventional tabletting techniques.
  • any usual suppository base may be employed for incorporation thereinto by usual procedure of the active ingredient, such as a polyethyleneglycol which is a solid at room temperature but which melts at or about body temperature.
  • a suitable formulation for a tablet containing 10 milligrams of active ingredient is as follows: mg
  • Another suitable formulation for a tablet containing 100 mg is as follows:
  • the film coating material consists of:
  • Capsule Formulation A suitable formulation for a capsule containing 50 milligrams of active ingredient is as follows:
  • a suitable formulation for an injectable solution is as follows:
  • a suitable formulation for 1 liter of a an oral solution containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows: mg
  • Another suitable formulation for 1 liter of a liquid mixture containing 20 milligrams of active ingredient in one milliliter of the mixture is as follows:
  • Active Ingredient 10 Oleic acid Ethanol Purified Water Tetrafluoroethane
  • Polybutylcyanoacrylate nanoparticles are prepared by emulsion polymerization in a water/0.1 N HCI/ethanol mixture as polymerizsation medium. The nanoparticles in the suspension are finally lyophilized under vacuum.
  • 1.0 g of the suspension contains the following:
  • Hypromellose is dispersed in water homogeneously with a high speed mixer/blender. After about one hour of hydration time of the hypromellose, the active ingredient is blended homogeneously into the hypromellose solution. The viscosity of the suspension may be adjusted by the amount of hypromellose, resulting in a very stable suspension with a very slow tendency of particle sedimentation and particle agglomeration.
  • the active ingredient is dissolved in DMSO by stirring and heating (solution 1 ).
  • the mannitol is dissolved in WFI (solution 2).
  • solution 1 After cooling down to room temperature solution 1 is mixed with solution 2 by continuous stirring.
  • the solution is sterilized by filtration of by autoclaving.
  • the supernatant and the buffy coat are centrifuged at 48,000 x g for 20 minutes in the presence of 50 m M Tris-HCI, pH 8.0.
  • the pellet is then re-suspended and centrifuged two to three more times at 48,000 x g for 20 minutes in the presence of 50 mM Tris-HCI, pH 8.0. All centrifugation steps are carried out at 4 °C. After resuspension in 5 volumes of 50 m M Tris-HCI, pH 8.0, the membrane suspension is frozen rapidly at -80 °C.
  • the membrane suspensions are thawed and washed four times by resuspension in 50 mM Tris-HCI, pH 8.0, and centrifugation at 48,000 x g for 20 minutes and finally re-suspended in 50 mM Tris-HCI, pH 7.4.
  • the amount of protein in the final membrane preparation (500-700 pg/ml) is determined according to the method of Lowry (Lowry O. H. et al. 1951 . J. Biol. Chem. 193, 256-275).
  • [00251 ]lncubations are started by adding [ 3 H]-MPEP (50.2 Ci/mmol, 5 nM, Tocris, GB) to vials with 125-250 g protein (total volume 0.25 ml) and various concentrations of the agents.
  • assays are performed with [ 3 H]-MMPEP (2-(3- methoxyphenylethynyl)-6-methylpyridine hydrochloride) as radioligand.
  • the incubations are continued at room temperature for 60 minutes (equilibrium is achieved under the conditions used).
  • Non-specific binding is defined by the addition of unlabeled MPEP (10 ⁇ ). Incubations are terminated using a Millipore filter system.
  • the samples are rinsed twice with 4 ml of ice-cold assay buffer over glass fibre filters (Schleicher & Schuell, Germany) under a constant vacuum. Following separation and rinse, the filters are placed into scintillation liquid (5 ml Ultima Gold, Perkin Elmer, Germany) and radioactivity retained on the filters is determined with a conventional liquid scintillation counter (Canberra Packard, Germany). Characterization
  • the Kd of [ 3 H]-MPEP of 13.6 nM is determined by Scatchard analysis and used according to the Cheng Prussoff relationship to calculate the affinity of displacers as Kd values (IC 50 of cold MPEP equates to a Kj of 8.2 nM).
  • B max is 0.56 pm / mg protein.
  • Ca-Kit is reconstituted in an assay buffer containing 20 rriM HEPES pH 7.4, glutamic-pyruvate transaminase, pyridoxal phosphate and sodium pyruvate in Hank's balanced salt solution (HBBS).
  • HBBS Hank's balanced salt solution
  • Agonistic compounds to the receptor elicit increases in cytosolic calcium which can be measured as increases in fluorescence signals by use of a fluorescence imaging plate reader (Molecular Devices).
  • a fluorescence imaging plate reader Molecular Devices.
  • To analyze their potency to modulate the Ca-response test compounds dissolved in a final DMSO concentration of 0.5%, are added on-line 5 minutes before the agonist to the receptor (L-quisqualic acid at a concentration giving ⁇ 80% of the maximal signal).
  • astrocyte cultures are prepared from cortices of newborn rats as described by Booher and Sensenbrenner (1972, Neurobiology 2(3):97-105). Briefly, Sprague-Dawley rat pups (2 - 4 d old) are decapitated and neocortices are dissected, disintegrated with a nylon filter (pore size 80 m) and carefully triturated.
  • the cell suspension is plated on poly-D-lysine pre-coated flasks (Costar, Netherlands) and cultivated in Dulbecco's Modified Eagle's Medium (DMEM, Invitrogen, Germany) supplemented with 10% foetal calf serum (FCS, Sigma, Germany), 4 rri M glutamine and 50 pg/ml gentamycin (both Biochrom, Germany) at 37 °C in a humidified atmosphere of 5% CO2 95% air for 7 days with exchanging the medium at day 2 and 6.
  • DMEM Dulbecco's Modified Eagle's Medium
  • FCS foetal calf serum
  • FCS foetal calf serum
  • 4 rri M glutamine 4 rri M glutamine
  • 50 pg/ml gentamycin both Biochrom, Germany
  • astrocytes are rinsed with PBS ++ (phosphate buffered saline, Biochrom, Germany) and fed with astrocyte-defined medium (ADM) consisting of DMEM containing 1x G5- supplement (Invitrogen, Germany), 0.5 pg/ml heparan sulfate, and 1 .5 pg/ml fibronectin (both Sigma, Germany) (Miller et al., (1993) Brain Res. 618(1 ): 175-8). 3 days later the medium is exchanged and the cells incubated for another 2-3 days, so that at the time of experiments astrocytes are 14-15 DIV.
  • ADM astrocyte-defined medium
  • the increase of cytosolic calcium after stimulation with the mGluR5 agonist L- quisqualate is measured using a fluorometric imaging plate reader (FLIPR) and the Ca- Kit (both Molecular Devices).
  • FLIPR fluorometric imaging plate reader
  • the medium Prior to addition of agonist or antagonist the medium is aspirated and cells are loaded for 2 h at RT with 150 ⁇ of loading buffer consisting of Ca-sensitive dye reconstituted in sodium chloride (123 rri M), potassium chloride (5.4 rriM), magnesium chloride (0.8 rri M), calcium chloride (1.8 rri M), D-glucose (15 rri M), and HEPES (20 m M), pH 7.3.
  • concentration-response curves for quisqualate are performed in the presence and absence of 10 ⁇ modulator to determine the extent of potentiation / agonist potency increase. Thereafter, concentration-response curves for the positive modulator are performed in the presence of a fixed concentration of quisqualate showing the biggest window for potentiation (normally 10-30 nM).
  • MaxMin maximum minus minimum
  • EC50 and IC50 are calculated according the logistic equation using GraFit 5.0 (Erithacus Software, GB) or Prism 4.0 (GraphPad Software, USA).
  • the compounds of the present invention have a potency (IC 50 ) within a range of about 0.5 nM to about 100 ⁇ .

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Abstract

The invention relates to heterocyclic derivatives as well as their pharmaceutically acceptable salts. The invention further relates to a process for the preparation of such compounds. The compounds of the invention are m GluR5 modulators and are therefore useful for the control and prevention of acute and/or chronic neurological disorders.

Description

METABOTROPIC GLUTAMATE RECEPTOR MODULATORS
FIELD OF THE INVENTION
[0001 ] The present invention relates to heterocyclic derivatives, which may act as novel metabotropic glutamate receptor (mGluR) modulators, methods for their synthesis and the treatment and/or prevention of various diseases and disorders, including neurological disorders, by administration of such derivatives.
BACKGROUND OF THE INVENTION
[0002] Neuronal stimuli are transmitted by the central nervous system (CNS) through the interaction of a neurotransmitter released by a neuron, which neurotransmitter has a specific effect on a neuroreceptor of another neuron. L-glutamic acid is considered to be a major excitatory neurotransmitter in the mammalian CNS, consequently playing a critical role in a large number of physiological processes. Glutamate-dependent stimulus receptors are divided into two main groups. The first group comprises ligand-controlled ion channels whereas the other comprises metabotropic glutamate receptors (mGluR). Metabotropic glutamate receptors are a subfamily of G-protein-coupled receptors (GPCR). There is increasing evidence for a peripheral role of both ionotropic and metabotropic glutamate receptors outside the CNS e.g, in chronic pain states.
[0003] At present, eight different members of these mGluRs are known. On the basis of structural parameters such as sequence homology, the second messenger system utilized by these receptors and their different affinity to low-molecular weight compounds, these eight receptors may be divided into three groups. mGluRI and mGluR5 belong to Group I which are positively coupled to phospholipase C and their activation leads to a mobilization of intracellular calcium ions. mGluR2 and mGluR3 belong to Group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to Group III, both of which are negatively coupled to adenylyl cyclase, i.e., their activation causes a reduction in second messenger cAMP and thus a dampening of neuronal activity. [0004] The mGluR5 modulators have been shown to modulate the effects of the presynaptically released neurotransmitter glutamate via postsynaptic mechanisms (receptors). Moreover, as these modulators may be both positive and/or negative mGluR5 modulators, such modulators may increase or inhibit the effects mediated through these metabotropic glutamate receptors.
[0005] Modulators which are negative mGluR5 modulators decrease the effects mediated through metabotropic glutamate receptors. Since a variety of pathophysiological processes and disease states affecting the CNS are thought to be related to abnormal glutamate neurotransmission, and mGluR5 receptors are shown to be expressed in many areas of the CNS and in PNS (peripheral nervous system), modulators of these receptors could be therapeutically beneficial in the treatment of diseases involving CNS and PNS.
[0006] Therefore, mGluR5 positive or negative modulators may be administered to provide neuroprotection and/or disease modification in the following acute or chronic pathological conditions or to provide a symptomatological effect on the following conditions: Alzheimer's disease, Creutzfeld-Jakob's syndrome/disease, bovine spongiform encephalopathy (BSE), prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tauopathy, Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, post-operative cognitive deficit (POCD), systemic lupus erythematosus, systemic sclerosis, Sjogren's syndrome, Neuronal Ceroid Lipofuscinosis, neurodegenerative cerebellar ataxias, Parkinson's disease, Parkinson's dementia, mild cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, macular degeneration, head or brain or spinal cord injuries, head or brain or spinal cord trauma, trauma, hypoglycaemia, hypoxia, perinatal hypoxia, ischaemia, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, myoclonic epilepsy, inner ear insult, inner ear insult in tinnitus, tinnitus, sound- or drug-induced inner ear insult, sound- or drug-induced tinnitus, hyperacusis, L-dopa-induced dyskinesias, L- dopa-induced dyskinesias in Parkinson's disease therapy, dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced dyskinesias, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, neuroleptics-induced dyskinesia, tic disorder, torticollis spasmodicus, blepharospasm, focal and generalized dystonia, nystagmus, hereditary cerebellar ataxias, corticobasal degeneration, tremor, essential tremor, abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, ***e addiction, ***e abuse, amphetamine addiction, amphetamine abuse, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), restless leg syndrome (RLS), hyperactivity in children, autism, dementia, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, Korsakoff syndrome, vascular dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, AIDS dementia complex, AIDS-related dementia, major depressive disorder, major depression, depression, depression resulting from Borna virus infection, major depression resulting from Borna virus infection, bipolar manic-depressive disorder, drug tolerance, drug tolerance to opioids, movement disorders, fragile-X syndrome, irritable bowel syndrome (IBS), migraine, multiple sclerosis (MS), muscle spasms, pain, chronic pain, acute pain, inflammatory pain, neuropathic pain, diabetic neuropathic pain (DNP), pain related to rheumatic arthritis, allodynia, hyperalgesia, nociceptive pain, cancer pain, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, spasticity, Tourette's syndrome, urinary incontinence, vomiting, pruritic conditions, pruritis, sleep disorders, micturition disorders, neuromuscular disorder in the lower urinary tract, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, regurgitation, respiratory tract infection, bulimia nervosa, chronic laryngitis, asthma, reflux-related asthma, lung disease, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, or delirium, diabetes, hyperammonemia and liver failure and sleep disturbances.
[0007] mGluR5 negative or positive modulators may also be administered to provide inhibition of tumour cell growth, migration, invasion, adhesion and toxicity in the peripheral tissues, peripheral nervous system and CNS. MGIuR5 modulators may be administered to provide therapeutic intervention in neoplasia, hyperplasia, dysplasia, cancer, carcinoma, sarcoma, oral cancer, squamous cell carcinoma (SCC), oral squamous cell carcinoma (SCC), lung cancer, lung adenocarcinoma, breast cancer, prostate cancer, gastric cancer, liver cancer, colon cancer, colorectal carcinoma, rhabdomyosarcoma, brain tumour, tumour of a nerve tissue, glioma, malignant glioma, astroglioma, neuroglioma, neuroblastoma, glioblastoma, medulloblastoma, cancer of skin cells, melanoma, malignant melanoma, epithelial neoplasm, lymphoma, myeloma, Hodgkin's disease, Burkitt's lymphoma, leukemia, thymoma, and other tumours.
[0008] mGluR5 positive or negative modulators may also be administered to provide disease modification and/or to provide a symptomatological effect on the following conditions: diabetes, hyperammonemia and liver failure.
[0009] Further indications for mGluR5 negative or positive modulators include those indications wherein a particular condition does not necessarily exist but wherein a particular physiological parameter may be improved through administration of the instant compounds, for example cognitive enhancement, learning impairment and/or neuroprotection.
[0010] Positive modulators may be particularly useful in the treatment of positive and negative symptoms in schizophrenia and cognitive deficits in various forms of dementia and mild cognitive impairment.
[001 1 ] Moreover, mGluR modulators may have activity when administered in combination with other substances exhibiting neurological effects via different mechanisms. [0012] Simultaneous administration of Group I mGluR modulators and NMDA receptor antagonists has also been shown to provide neuroprotection in animal models (Zieminska et al. Acta Neurobiol. Exp., 2006, 66, 301 -309; Zieminska et al. Neurochemistry International, 2003, 43, 481 -492; and Zieminska et al. Neurochemistry International, 2006, 48, 491 -497).
[0013] Simultaneous administration of Group I mGluR modulators and compounds such as L-DOPA, dopaminomimetics, and/or neuroleptics may be useful in treating various conditions including drug induced dyskinesias, neuroleptic-induced dyskinesias, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias.
[0014] In the literature, several types of modulators of mGluR5 have already been described.
THE PRESENT INVENTION
[0015] It now has been found that certain heterocyclic derivatives are potent mGluR5 modulators. Therefore, these substances may be therapeutically beneficial in the treatment of conditions which involve abnormal glutamate neurotransmission or in which modulation of mGluR5 receptors results in therapeutic benefit. These substances may be administered in the form of a pharmaceutical composition, wherein they are present together with one or more pharmaceutically acceptable diluents, carriers, or excipients.
OBJECTS OF THE INVENTION
[0016] It is an object of the present invention to provide novel pharmaceutical compounds which are mGluR5 modulators and pharmaceutical compositions thereof. It is a further object of the invention to provide a novel method of treating, eliminating, alleviating, palliating, modifying, or ameliorating undesirable CNS disorders which involve abnormal glutamate neurotransmission, and/or to provide symptomological effects, by employing a compound of the invention or a pharmaceutical composition containing the same. [0017] An additional object of the invention is the provision of processes for producing the heterocyclic derivatives.
SUMMARY OF THE INVENTION
[0018] What we therefore believe to be comprised by our invention may be summarized inter alia in the following words:
A compound selected from those of Formula I
Figure imgf000007_0001
wherein
X represents CR6(C=0)R7 or NR8; R1 represents H, Ci-6alkyl, or F; R2 represents H, Chalky!, or F; or R1 and R2 together with the carbon atom to which they are attached form a carbonyl group; or R1 and R2 together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Chalky!, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(C-i-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo;
R3 represents H, Chalky!, or F; R4 represents H, Chalky!, or F; or R3 and R4 together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(C-i-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo;
R5 represents a monocyclic moiety selected from aryl, heteroaryl, cycloC3-6alkyl, and heterocyclyl;
R6 represents H, Chalky! which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, C-i-6alkylamino, and di-(Ci-6alkyl)amino, or F;
R7 represents Chalky!, which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, C-i-6alkylamino, and di-(C-i-6alkyl)amino, cycloC3-6alkyl, heterocyclyl, or NR11 R12; or R6 and R7 together with the carbon atoms to which they are attached form a 3- 7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(C-i-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo;
R8 represents Ci-6alkyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, Ci-6alkylamino, and di-(Ci-6alkyl)amino, cycloC3-6alkyl, heterocyclyl, aryl, heteroaryl, Ci-6alkylcarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, C-i-6alkylamino, and di- (C-i-6alkyl)amino, cycloC3-6alkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, heteroarylcarbonyl, Ci-6alkoxycarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, Ci-6alkylamino, and di-(C-i-6alkyl)amino, aminocarbonyl, /V-Ci-6alkylaminocarbonyl, wherein the alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, Ci-6alkylamino, and di-(Ci-6alkyl)amino, /V,/V-di-(Ci-6alkyl)aminocarbonyl, wherein the alkyl moieties may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, Ci-6alkoxycarbonyl, cyano, amino, hydroxy, Ci-6alkylamino, and di-(C-i-6alkyl)amino, /V-Ci-6alkyl-/V- cycloC3-6alkylaminocarbonyl, /V-Ci-ealkyl-ZV-cycloCs-ealkyl-d-ealkylaminocarbonyl, aminothiocarbonyl, /V-Ci-6alkylaminothiocarbonyl, wherein the alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, C-i-6alkylamino, and di-(Ci-6alkyl)amino, /V,/V-di-(Ci-6alkyl)aminothiocarbonyl, wherein the alkyl moieties may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, d- 6alkylamino, and di-(C-i-6alkyl)amino, Ci-6alkylsulfonyl, wherein the alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, C-i-6alkylamino, and di-(Ci-6alkyl)amino, cycloC3-6alkylsulfonyl, aminosulfonyl, /V-d. 6alkylaminosulfonyl, wherein the alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, C-i-6alkylamino, and di-(C-i-6alkyl)amino, or Λ/,/V-di- (Ci-6alkyl)aminosulfonyl, wherein the alkyl moieties may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, C-i-6alkylamino, and di- (C-i-6alkyl)amino; R9 represents H, Chalky!, or F; R10 represents H, Ci-6alkyl, or F; or R9 and R10 together with the carbon atom to which they are attached form a 3- 7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(Ci-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo;
R11 represents H, Chalky!, or cycloC3-6alkyl;
R12 represents H, Ci-6alkyl, or cycloC3-6alkyl; or R11 and R12 together with the nitrogen atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Chalky!, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(Ci-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo; and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof; it being understood that: if R1 and R2 together with the carbon atom to which they are attached form a carbonyl group, then R8 may also represent H; R5 may not represent optionally substituted thiazolyl; if R8 represents unsubstituted Ci-6alkyl, then R5 does not represent optionally substituted phenyl; and the compound of formula (I) may not represent:
/V-(2,4-Difluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine,
/V-(2,4-Dimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine,
/V-(2-Fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine,
/V-(3,5-Dimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine,
/V-(3-Methoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine,
/V-(4-Fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine,
/V-(4-Methoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine,
/V-Phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine,
fe/f-Butyl 2-((2,4-difluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)- carboxylate,
fe/f-Butyl 2-((2,4-dimethoxyphenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5/-/)-carboxylate,
ie/f-Butyl 2-((2,5-dimethoxyphenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5/-/)-carboxylate,
ie/f-Butyl 2-((2-methoxyphenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)- carboxylate,
ie/f-Butyl 2-((3,5-dimethoxyphenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5/-/)-carboxylate,
fe/f-Butyl 2-((3-methoxyphenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)- carboxylate,
ie/f-Butyl 2-((4-fluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)- carboxylate,
fe/f-Butyl 2-((4-methoxyphenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)- carboxylate,
1 -(4-(5,6,7,8-Tetrahydropyrido[4,3-d]pyrimidin-2-ylamino)phenyl)ethanone, or
/V-(4-Phenoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine. [0019] A further aspect of the invention relates to a compound of Formula I, wherein R8 represents Chalky! which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, d- 6alkylamino, and di-(C-i-6alkyl)amino, cycloC3-6alkyl, heterocyclyl, aryl, heteroaryl, d- 6alkylcarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, d- 6alkylamino, and di-(C-i-6alkyl)amino, cycloC3-6alkylcarbonyl, arylcarbonyl,
heteroarylcarbonyl, Ci-6alkoxycarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, C-i-6alkylamino, and di-(Ci-6alkyl)amino, aminocarbonyl, N- C-i-6alkylaminocarbonyl, wherein the alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy,
Ci-6alkoxy, amino, hydroxy, C-i-6alkylamino, and di-(C-i-6alkyl)amino, Λ/,/V-di- (Ci-6alkyl)aminocarbonyl, wherein the alkyl moieties may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, C-i-6alkylamino, and di-(C-i-6alkyl)amino, Ci-6alkylsulfonyl, wherein the alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, d- 6alkylamino, and di-(d-6alkyl)amino, cycloC3-6alkylsulfonyl, aminosulfonyl, /V-d.
6alkylaminosulfonyl, wherein the alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, d-6alkoxy, amino, hydroxy, d-6alkylamino, and di-(d-6alkyl)amino, or Λ/,/V-di- (Ci-6alkyl)aminosulfonyl, wherein the alkyl moieties may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy,
Ci-6alkoxy, amino, hydroxy, d-6alkylamino, and di-(d-6alkyl)amino.
[0020] A further aspect of the invention relates to a compound of Formula I, wherein R1 and R2 together with the carbon atom to which they are attached form a carbonyl group, and X represents NR8, wherein R8 represents H.
[0021 ] A further aspect of the invention relates to a compound of Formula I, wherein R1 and R2 represent H, and X represents CR6(C=0)R7, wherein R6 represents H and R7 represents d-6alkyl or heterocyclyl. [0022] Such a compound of Formual I, wherein R6 represents H and R7 represents heterocyclyl.
[0023] Such a compound of Formula I, wherein R7 represents piperidino.
[0024] A further aspect of the invention relates to a compound of Formula I, wherein R1 and R2 represent H, and X represents NR8, wherein R8 represents Ci-6alkylcarbonyl, cycloC3-6alkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, Ci-6alkoxycarbonyl, /V-C-i- 6alkylaminocarbonyl, /V./V-di^Ci-ealky aminocarbonyl, Λ/,/V-di-
(Ci-6alkyl)aminothiocarbonyl, /V-d-ealkyl-ZV-cycloCs-ealkylaminocarbonyl, /V-Ci-6alkyl-/V- cycloC3-6alkyl-Ci-6alkylaminocarbonyl, Ci-6alkylsulfonyl, cycloC3-6alkylsulfonyl, Λ/,/V-di- (Ci-6alkyl)aminosulfonyl, or heteroaryl.
[0025] Such a compound of Formula I, wherein R8 represents C-i-6alkylcarbonyl, cycloC3-6alkylcarbonyl, arylcarbonyl, Ci-6alkoxycarbonyl, A/-Ci-6alkylaminocarbonyl, N,N- di-(Ci-6alkyl)aminocarbonyl, Ci-6alkylsulfonyl, cycloC3-6alkylsulfonyl, Λ/,/V-di- (Ci-6alkyl)aminosulfonyl, or heteroaryl.
[0026] Such a compound of Formula I, wherein R8 represents optionally substituted pyridyl, tetrazolyl, pyrimidyl, furyl, thiazolyl, or imidazolyl.
[0027] Such a compound of Formula I, wherein represents optionally substituted pyridyl or tetrazolyl.
[0028] A further aspect of the invention relates to a compound of Formula I, wherein R5 represents phenyl optionally substituted by one or more substituents selected from halogen, Ci-6alkyl, and cyano.
[0029] A further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IA
Figure imgf000014_0001
wherein R3-R5 and R8-R10 are as defined above for Formula I, and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
[0030] Such a compound of Formula IA, wherein R5 represents a monocyclic moiety selected from aryl and heteroaryl.
[0031 ] Such a compound of Formula IA, wherein R3, R4, R8, R9, and R10 each represent H and R5 represents a monocyclic moiety selected from aryl and heteroaryl.
[0032] Such a compound of Formula IA, wherein R3, R4, R8, R9, and R10 each represent H and R5 represents phenyl optionally substituted by one or more halogen atoms.
[0033] A further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IB
Figure imgf000014_0002
wherein R1-R4, R9-R12 are as defined above for Formula I, and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
[0034] Such a compound of Formula IB, wherein R5 represents a monocyclic moiety selected from aryl and heteroaryl. [0035] Such a compound of Formula IB, wherein R3, R4, R9, and R10 each represent H, R11 and R12 represent Chalky! (e.g., methyl or ethyl) or R11 and R12 together with the nitrogen atom to which they are attached combine to form a 3-7 membered saturated ring, and R5 represents a monocyclic moiety selected from aryl and heteroaryl.
[0036] Such a compound of Formula IB, wherein R3, R4, R9, and R10 each represent H, R11 and R12 together with the nitrogen atom to which they are attached combine to form piperidino, and R5 represents phenyl optionally substituted by one or more halogen atoms.
[0037] A further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IC
Figure imgf000015_0001
wherein R1-R5 and R8-R10 are as defined above for Formula I, and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
[0038] Such a compound of Formula IC, wherein R5 represents a monocyclic moiety selected from aryl and heteroaryl.
[0039] Such a compound of Formula IC, wherein R1-R4, R9, and R10 each represent H; R5 represents a monocyclic moiety selected from aryl and heteroaryl; and R8 represents Ci-6alkylcarbonyl, cycloC3-6alkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, d. 6alkoxycarbonyl, /V-Ci-6alkylaminocarbonyl, /V,/V-di-(Ci-6alkyl)aminocarbonyl, Λ/,/V-di- (Ci-6alkyl)aminothiocarbonyl, /V-d-ealkyl-ZV-cycloCs-ealkylaminocarbonyl, /V-Ci-6alkyl-/V- cycloC3-6alkyl-Ci-6alkylaminocarbonyl, Ci-6alkylsulfonyl, cycloC3-6alkylsulfonyl, Λ/,/V-di- (Ci-6alkyl)aminosulfonyl, or heteroaryl.
[0040] Such a compound of Formula IC, wherein R8 represents Ci-6alkylcarbonyl, cycloC3-6alkylcarbonyl, arylcarbonyl, Ci-6alkoxycarbonyl, /V-Ci-6alkylaminocarbonyl, N,N- di-(Ci-6alkyl)aminocarbonyl, Ci-6alkylsulfonyl, cycloC3-6alkylsulfonyl, Λ/,/V-di- (Ci-6alkyl)aminosulfonyl, or heteroaryl.
[0041 ] Such a compound of Formula IC, wherein R1-R4, R9, and R10 each represent H; R5 represents phenyl optionally substituted by one or more substituents selected from halogen, Chalky!, and cyano; and R8 represents Ci-6alkylcarbonyl, cycloC3-6alkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, Ci-6alkoxycarbonyl, N-C<\. 6alkylaminocarbonyl, /V,/V-di-(Ci-6alkyl)aminocarbonyl, Λ/,/V-di-
(Ci-6alkyl)aminothiocarbonyl, /V-Ci-6alkyl-/V-cycloC3-6alkylaminocarbonyl, /V-Ci-6alkyl-/V- cycloCs-ealkyl-Ci-ealkylaminocarbonyl, Ci-6alkylsulfonyl, cycloC3-6alkylsulfonyl, Λ/,/V-di- (Ci-6alkyl)aminosulfonyl, or heteroaryl.
[0042] Such a compound of Formula IC, wherein R8 represents Ci-6alkylcarbonyl, cycloC3-6alkylcarbonyl, arylcarbonyl, Ci-6alkoxycarbonyl, /V-Ci-6alkylaminocarbonyl, N,N- di-(Ci-6alkyl)aminocarbonyl, Ci-6alkylsulfonyl, cycloC3-6alkylsulfonyl, Λ/,/V-di- (Ci-6alkyl)aminosulfonyl, or heteroaryl.
[0043] Such a compound of Formula IC, wherein R1-R4, R9, and R10 each represent H; R5 represents phenyl optionally substituted by one or more substituents selected from halogen, Ci-6alkyl, and cyano; and R8 represents optionally substituted pyridyl, tetrazolyl, pyrimidyl, furyl, thiazolyl, or imidazolyl.
[0044] Such a compound of Formula IC, wherein R8 represents optionally substituted pyridyl or tetrazolyl.
[0045] A further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula ID
Figure imgf000016_0001
wherein R1-R5 and R9 and R10 are as defined above for Formula I and
R13 represents Ci-6alkyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, Ci-6alkylamino, and di-(Ci-6alkyl)amino, cycloC3-6alkyl, heterocyclyl, aryl, heteroaryl, Ci-6alkoxy which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, d- 6alkylamino, and di-(C-i-6alkyl)amino, aminocarbonyl, /V-C-i-6alkylamino, wherein the alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, C-i-6alkylamino, and di-(Ci-6alkyl)amino, /V,/V-di-(Ci-6alkyl)amino, wherein the alkyl moieties may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, Ci-6alkoxycarbonyl, cyano, amino, hydroxy, C-i-6alkylamino, and di-(Ci-6alkyl)amino, / -d-ealkyl-Z -cycloCs-ealkylamino, or /V-C-i. ealkyl-Z -cycloCs-ealkyl-Ci-ealkylamino, and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
[0046] Such a compound of Formula ID, wherein R13 represents Ci-6alkyl, cycloC3- 6alkyl, heterocyclyl, aryl, Ci-6alkoxy, /V-C-i-6alkylamino, /V,/V-di-(Ci-6alkyl)amino, N-C-\. 6alkyl-/V-cycloC3-6alkylamino, or / -Ci-ealkyl-Z -cycloCs-ealkyl-d-ealkylamino.
[0047] Such a compound of Formula ID, wherein R5 represents a monocyclic moiety selected from aryl and heteroaryl.
[0048] Such a compound of Formula ID, wherein R1-R4, R9, and R10 each represent H and R5 represents a monocyclic moiety selected from aryl and heteroaryl.
[0049] Such a compound of Formula ID, wherein R3, R4, R8, R9, and R10 each represent H and R5 represents phenyl optionally substituted by one or more substituents selected from halogen, Ci-6alkyl, and cyano.
[0050] Specific compounds of Formula I within the present invention include, but are not limited to, the following compounds:
2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6/-/)-one, (rac)-(2-((3-Chlorophenyl)amino)-5,67,8-tetrahydroquinazolin-6-yl)(piperidin-1 - yl)methanone,
1 -(2-((3-Fluorophenyl)amino)-7,8-dihydropyndo[4,3-d]pynmidin-6(5/-/)-yl)-2- methylpropan-1 -one,
1 - (2-((3-Chlorophenyl)amino)-7,8-dihydropyndo[4,3-d]pynmidin-6(5/-/)-yl)-2- methylpropan-1 -one,
2- Methyl-1 -(2-(m-tolylamino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5/-/)-yl)propan-1 - one,
(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5/-/)- yl)(cyclopropyl)methanone,
1 -(2-((4-Fluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5/-/)-yl)-2,2- dimethylpropan-1 -one,
1 -(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5/-/)-yl)-2,2- dimethylpropan-1 -one,
3- ((6-Pivaloyl-5,6,7,8-tetrahydropyrido[4,3-d]pynmidin-2-yl)amino)benzonitnle, (rac)-1 -(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5/-/)-yl)-2- methylbutan-1 -one,
(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5/-/)- yl)(cyclobutyl)methanone,
1 -(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5/-/)-yl)-2- ethylbutan-1 -one,
(2-((3-Fluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5/-/)- yl)(phenyl)methanone,
(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5/-/)- yl)(phenyl)methanone,
Methyl 2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidine-6(5/-/)- carboxylate,
Ethyl 2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidine-6(5/-/)- carboxylate,
Isopropyl 2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidine-6(5/-/)- carboxylate,
ie f-Butyl 2-((3-fluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidine-6(5/-/)- carboxylate, fe/f-Butyl 2-((3-chlorophenyl)amino)-7,8-dihydropyndo[4,3-d]pynmidine-6(5/-/)- carboxylate,
fe/f-Butyl 2-( r?-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)-carboxylate, fe/f-Butyl 2-((3-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)- carboxylate,
2-((3-Chlorophenyl)amino)-/V-ethyl-7,8-dihydropyrido[4,3-d]pynmidine-6(5/-/)- carboxamide,
2-((3-Chlorophenyl)amino)-/V,/V-dimethyl-7,8-dihydropyrido[4,3-d]pynmidine-6( carboxamide,
/V-(3-Chlorophenyl)-6-(isopropylsulfonyl)-5,67,8-tetrahydropyndo[4,3-d]pynmidin- 2-amine,
/V-(3-Chlorophenyl)-6-(cyclopropylsulfonyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2-amine,
2-((3-Chlorophenyl)amino)-/V,/V-dimethyl-7,8-dihydropyrido[4,3-d]pynmidine-6( sulfonamide,
/V-(3-Chlorophenyl)-6-(pyndin-2-yl)-5,67,8-tetrahydropyndo[4,3-d]pynmidin-2- amine,
6-(1 -(ie/f-Butyl)-1 /-/-tetrazol-5-yl)-/V-(3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2-amine,
/V-(3-Chlorophenyl)-6-(1 -isopropyl-1 /-/-tetrazol-5-yl)-5,6,7,8-tetrahydropyndo[4,3- d]pyrimidin-2-amine,
2-((3-Cyanophenyl)amino)-/V,/V-dimethyl-7,8^
carboxamide,
2-((3-Chlorophenyl)amino)-/V,/V-diethyl-7,8-dihydropyrido[4,3-d]pyrimidine-^ carboxamide,
2-((3-Cyanophenyl)amino)-/V,/V-diethyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)^ carboxamide,
(rac)-3-((6-(2-Methylbutanoyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2- yl)amino)benzonitrile,
(rac)-2-((3-Chlorophenyl)amino)-/V,/V-dim
carboxamide,
(rac)-2-((3-Chlorophenyl)amino)-/V,/V-diethyl-5,6,7,8-tetrahydroquinazolin carboxamide, 2-((3-Chlorophenyl)amino)-/V,/V-dimethyl-7,8-dihydropyrido[4,3-d]pynmi carbothioamide,
(rac)-1 -(2-((3-Chlorophenyl)amino)-5,6,7,8-tetrahydroquinazolin-6-yl)-2- methylpropan-1 -one,
2-(2-((3-Chlorophenyl)amino)-7,8-dihydropyndo[4,3-d]pynmidin-6(5/-/)- yl)nicotinonitrile,
(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5H)-yl)(pyrrolidin-
1 - yl)methanone,
2- ((3-Cyanophenyl)amino)-/V,/V-diisopropyl-7,8-dihydropyndo[4,3-d]pyrimidine- 6(5/-/)-carboxam ide,
3- ((6-(2-Methoxy-2-methylpropanoyl)-5,6,7,8-tetrahydropyrido[4,3-d]pynmidin-2- yl)amino)benzonitrile,
3-((6-(Morpholine-4-carbonyl)-5,6,7,8-tetrahydropyndo[4,3-d]pynmidin-2- yl)amino)benzonitrile,
/V-(3-Chlorophenyl)-6-(pynmidin-2-yl)-5,67,8-tetrahydropyrido[4,3-d]pynmidin-2- amine,
(2-((3-Chlorophenyl)amino)-7,8-dihydropyndo[4,3-d]pynmidin-6(5/-/)-yl)(furan-2- yl)methanone,
(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5/-/)-yl)(thiazol-2- yl)methanone,
(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5/-/)-yl)(thiazol-5- yl)methanone,
2- ((5-Chloropyndin-3-yl)amino)-/V,/V-dimethyl-7,8-dihydropyrido[4,3-d]pynmidi 6(5/-/)-carboxam ide,
/V-(3-Chlorophenyl)-6-(1 -methyl-1 /-/-tetrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2-amine,
/V-(3-Chlorophenyl)-6-(1 -methyl-1 H-imidazol-2-yl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2-amine,
3- ((6-(2-Ethylbutanoyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2- yl)amino)benzonitrile,
/V-Butyl-2-((3-cyanophenyl)amino)-/V-methyl-7,8-dihydropyrido[4,3-d]pynmidin 6(5/-/)-carboxam ide, 2-((3-Cyanophenyl)amino)-/V-cyclopropyl-/V-methyl-7,8-dihydropyrido[4,3- d]pyrim idine-6(5/-/)-carboxam ide,
2-((3-Chlorophenyl)amino)-/V-ethyl-/V-propyl-7,8-dihydropyrido[4,3-d]pynmidine- 6(5/-/)-carboxam ide,
/V,/V-Dimethyl-2-((6-methylpyridin-2-yl)am
6(5/-/)-carboxam ide,
(rac)-3-((6-(2-Ethylpyrrolidine-1 -carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-
2- yl)amino)benzonitrile,
/V-(Cyanomethyl)-2-((3-cyanophenyl)amino)-/V-methyl-7,8-dihydropyrido[4,3- d]pyrim idine-6(5/-/)-carboxam ide,
3- ((6-(1 -Methylcyclopropanecarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pynmidin-2- yl)amino)benzonitrile,
3-((6-(2-Methylcyclopropanecarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pynmidin-2- yl)amino)benzonitrile,
2,2-Dimethyl-1 -(2-((6-methylpyridin-2-yl)amino)-7,8-dihydropyndo[4,3-d]pynmidi 6(5/-/)-yl)propan-1 -one,
3-((6-(2-Hydroxy-2-methylpropanoyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2- yl)amino)benzonitrile,
/V,/V-Diethyl-2-(m-tolylamino)-7,8-dihydropyrido[4,3-d]pynmidine-6(5/-/)- carboxamide,
2-((3-Cyanophenyl)amino)-/V-isopropyl-/V-methyl-7,8-dihydropyrido[4,3- d]pyrim idine-6(5/-/)-carboxam ide,
2-((3-Cyanophenyl)amino)-/V-ethyl-/V-methyl-7,8-dihydropyrido[4,3-d]pynmidin 6(5/-/)-carboxam ide,
2-((3-Chlorophenyl)amino)-/V-(cyclopropylmethyl)-/V-methyl-7,8-dihydropyrido[4,3- d]pyrim idine-6(5/-/)-carboxam ide,
/V,/V-Dimethyl-2-(m-tolylamino)-7,8-dihydropyrido[4,3-d]pynmidine-6(5/-/)- carboxamide,
2-((3-Chlorophenyl)amino)-/V-cyclopropyl-/V-ethyl-7,8-dihydropyndo[4,3- d]pyrim idine-6(5/-/)-carboxam ide,
Pyrrolidin-1 -yl(2-(m-tolylamino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5/-/)- yl)methanone, (2-((3-Chlorophenyl)amino)-7,8-dihydropyndo[4,3-d]pynmidin-6(5/-/)-yl)(1 - methylcyclopropyl)methanone,
(1 -Methylcyclopropyl)(2-(m-tolylamino)-7,8-dihydropyndo[4,3-d]pynmidin-6(5/-/)- yl)methanone,
/V-Ethyl-/V-propyl-2-(m-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)- carboxamide,
(rac)-3-((6-(3-Methylpyrrolidine-1 -carbonyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2-yl)amino)benzonitnle,
(rac)-3-((6-(2-Methylpyrrolidine-1 -carbonyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2-yl)amino)benzonitnle,
3-((6-(3,3-Dimethylazetidine-1 -carbonyl)-5,67,8-tetrahydropyndo[4,3-d]pynmidin- 2-yl)amino)benzonitrile,
2-((3-Cyanophenyl)amino)-/V-ethyl-/V-propyl-7,8-dihydropyrido[4,3-d]pynmidine- 6(5/-/)-carboxam ide,
(rac)-1 -(2-((3-Chlorophenyl)amino)-5-methyl-7,8-dihydropyndo[4,3-d]pynmidin- 6(5/-/)-yl)-2,2-dimethylpropan-1 -one,
(rac)-1 -(2-((3-Chlorophenyl)amino)-7-methyl-7,8-dihydropyndo[4,3-d]pynmidin- 6(5/-/)-yl)-2,2-dimethylpropan-1 -one,
2-((3-Cyanophenyl)amino)-/V,/V-bis(2,2,2-tnfluoroethyl)-7,8-dihydropyndo[4,^ d]pyrim idine-6(5/-/)-carboxam ide,
Azetidin-1 -yl(2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5/-/)- yl)methanone,
Methyl 2-(2-((3-chlorophenyl)amino)-/V-methyl-5,6,7,8-tetrahydropyndo[4,3- d]pyrim idine-6-carboxam ido)acetate,
/V-(2-Cyanoethyl)-2-((3-cyanophenyl)amino)-/V-methyl-7,8-dihydropyrido[4,3- d]pyrim idine-6(5/-/)-carboxam ide,
2-((3-Cyanophenyl)amino)-/V-(2-methoxyethyl)-/V-methyl-7,8-dihydropyrido[4,3- d]pyrim idine-6(5/-/)-carboxam ide,
2-(2-(p-Tolylamino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5H)-yl)nicotinonitn
2-((3-Cyanophenyl)amino)-/V-methyl-/V-propyl-7,8-dihydropyrido[4,3-d]pynmidin 6(5/-/)-carboxam ide,
6-(2-((3-Cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5/-/)- yl)picolinonitrile, 2-(2-((3-Cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5H)- yl)isonicotinonitrile,
2-(2-((3-Cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5/-/)-yl)-6- methylnicotinonitrile,
Azetidin-1 -yl(2-(m-tolylamino)-7,8-dihydropyndo[4,3-d]pynmidin-6(5/-/)- yl)methanone,
/V-Ethyl-/V-methyl-2-(m-tolylamino)-7,8-dihydro^
carboxamide,
/V-Methyl-/V-propyl-2-(m-tolylamino)-7,8-dihydropyrido[4,3-d]pynmidine-6(5H)- carboxamide,
2-((3-Chlorophenyl)amino)-/V-methyl-/V-propyl-7,8-dihydropyrido[4,3-d]pynm
6(5/-/)-carboxam ide,
2- ((3-Chlorophenyl)amino)-/V-ethyl-/V-methyl-7,8-dihydropyrido[4,3-d]pyn
6(5/-/)-carboxam ide,
3- ((6-(1 -lsopropyl-1 H-imidazol-2-yl)-5,6,7,8-tetrahydropyndo[4,3-d]pyrimidin-2- yl)amino)benzonitrile,
3-((6-(3-Methyloxetane-3-carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2- yl)amino)benzonitrile,
(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5/-/)-yl)(3- methyloxetan-3-yl)methanone,
(3-Methyloxetan-3-yl)(2-(m-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5/-/)- yl)methanone, and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
[0051 ] Moreover, the invention relates to a compound of Formula I as defined above or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for the treatment and/or prevention of a condition or disease associated with abnormal glutamate neurotransmission, including a condition or disease which is affected or facilitated by modulation of the mGluR5 receptor, including for the conditions or diseases selected from those described earlier in the description. [0052] In a further aspect, the invention relates to a compound of Formula I as defined above or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for the treatment and/or prevention of a CNS disorder. Moreover, the invention relates to a compound of Formula I as defined above or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for the treatment and/or prevention of abnormal glutamate neurotransmission. The invention additionally relates to a compound of Formula I as defined above or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for modulation of the mGluR5 receptor. The invention furthermore relates to such a compound for treatment, prevention and or modulation of a condition or disease selected from those described earlier in the description. The invention still further relates to such a compound for treatment, prevention and or modulation of a a physiological parameter, such as cognitive disorder, whether or not a specific identifiable condition exists.
[0053] A further aspect of the invention relates to a compound of Formula I as defined above or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for the treatment and/or prevention of a condition associated with abnormal glutamate neurotransmission or in which modulation of mGluR5 receptors results in therapeutic benefit. The conditions which may be treated have already been described above. Such conditions and indications include: a) For mGluR5 modulators: chronic pain, neuropathic pain, diabetic neuropathic pain (DNP), cancer pain, pain related to rheumathic arthritis, inflammatory pain, L-dopa-induced dyskinesias, dopaminomimetic- induced dyskinesias, L-dopa-induced dyskinesias in Parkinson's disease therapy, dopaminomimetic-induced dyskinesias in Parkinson's disease therapy, tardive dyskinesias, Parkinson's disease, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), generalized anxiety disorder, substance-induced anxiety disorder, eating disorders, obesity, binge eating disorders, Huntington's chorea, epilepsy, Alzheimer's disease, positive and negative symptoms of schizophrenia, cognitive impairment, functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), migraine, irritable bowel syndrome (IBS), or for cognitive enhancement and/or neuroprotection. b) Negative modulation of mGluR5 may be particularly useful for: chronic pain, neuropathic pain, diabetic neuropathic pain (DNP), cancer pain, pain related to rheumathic arthritis, inflammatory pain, L-dopa-induced dyskinesias, dopaminomimetic-induced dyskinesias, L-dopa-induced dyskinesias in Parkinson's disease therapy, dopaminomimetic-induced dyskinesias in Parkinson's disease therapy, tardive dyskinesias, Parkinson's disease, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), generalized anxiety disorder, substance-induced anxiety disorder, eating disorders, obesity, binge eating disorders, migraine, irritable bowel syndrome (IBS), functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), Huntington's chorea and/or epilepsy. c) Positive modulation of mGluR5 may be particularly useful for: Alzheimer's disease, positive and/or negative symptoms of schizophrenia, cognitive impairment, or for cognitive enhancement and/or neuroprotection.
[0054] A further aspect of the invention relates to a compound of Formula I as defined above or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for the treatment of binge eating disorders.
[0055] Further, the invention relates to the use of a compound of Formula I as defined above or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for the preparation of a medicament for treating or preventing a condition or disease associated with abnormal glutamate neurotransmission. Such a use includes the use of such a compound for the preparation of a medicament for the prevention and/or treatment of a condition or disease in an animal including a human being which condition or disease is affected or facilitated by modulation of the mGluR5 receptor. [0056] Moreover, the invention relates to a method for treating or preventing a condition associated or disease associated with abnormal glutamate neurotransmission, including a condition or disease which is affected or facilitated by modulation of the mGluR5 receptor, including for the conditions or diseases selected from those described earlier in the description.
[0057] Further, the invention relates to a pharmaceutical composition comprising as active ingredient at least one compound of Formula I as defined above or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, together with one or more pharmaceutically acceptable excipients.
[0058] Moreover, the mGluR modulators as described above are expected to have a high activity when administered in combination with other substances exhibiting neurological effects via different mechanisms.
[0059] In a yet further aspect, the invention thus relates to a compound of Formula I as defined above or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for Neuroprotection and/or for cognitive enhancement in combination with at least one NMDA receptor antagonist such as Memantine.
[0060] A further aspect of the invention relates to a pharmaceutical composition comprising at least two different active ingredients, selected from least one compound of Formula I as defined above, and, additionally, at least one NMDA-antagonist, together with one or more pharmaceutically acceptable excipients. These compositions may be used for the treatment of CNS-related diseases, cognitive enhancement and for neuro-protection. The invention thus additionally provides a composition comprising at least two different active ingredients, selected from least one compound of Formula I as defined above, and, additionally, at least one NMDA-antagonist for the treatment of any of the conditions indicated herein, including CNS-related diseases, cognitive enhancement and for neuroprotection.
[0061 ] This invention also relates to a pharmaceutical composition comprising a combination of a compound of Formula I as described above and an NMDA receptor antagonist, including compositions wherein the NMDA receptor antagonist is e.g. Memantine and pharmaceutically acceptable salts, polymorphs, hydrates and solvates thereof.
[0062] The invention also relates to a pharmaceutical composition comprising at least two different active ingredients, selected from at least one compound of Formula I as defined above, and, additionally, at least one active ingredient selected from L-DOPA, other dopaminomimetics (such as antiparkinsonian dopaminomimetics, including bromocriptine, cabergolin, ropinirole, pramiperole, pergolide, rotigotine), and neuroleptics (such as classical neuroleptics, including haloperidol, perphenazin, chlorpromazine, metoclopramide).
[0063] The invention also relates to a method of providing neuroprotection in a living animal, including a human, comprising the step of administering to a living animal, including a human, a therapeutically effective amount of a composition as described above.
[0064] Furthermore, the invention relates to the use of a composition as described above for the manufacture of a medicament to provide neuroprotection in an animal, including a human.
[0065] The invention also relates to a process for the synthesis or preparation of a compound of Formula ΙΑ'
Figure imgf000027_0001
or an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R5 is as defined above for Formula I, wherein β-alanine ester of Formula II
Figure imgf000027_0002
HCI is treated with methylmalonylchloride of Formula III
o o to yield a diester of Formula IV
o o o
^Ο^^^Ν^^Ο^ I ,
H
which is subjected to cyclization conditions to yield a lactam of Formula V
Figure imgf000028_0001
which is subjected to decarboxylation conditions to yield a compound of Formula VI
Figure imgf000028_0002
which is treated with dimethylformamide dimethyl acetal at elevated temperature to yield a compound of Formula VII
Figure imgf000028_0003
which is reacted with a guanidine of Formula VIII
Figure imgf000028_0004
to yield a compound of Formula ΙΑ', which may be converted, if desired, to an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
[0066] The invention also relates to a process for the synthesis or preparation of a compound of Formula IB'
o
R12 N H.«s IB' or an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R5, R11 , and R12 are as defined above for Formula I, wherein methyl 4-oxocyclohexanecarboxylate of Formula IX
Figure imgf000029_0001
is treated with dimethylformamide dimethyl acetal at elevated temperature to yield a compound of Formula X
Figure imgf000029_0002
which is reacted with a guanidine of Formula VIII
NH
H2N- 'K VIM,
H
to yield a compound of Formula XI
Figure imgf000029_0003
which is hydrolyzed, for example, with LiOH, to form a carboxylic acid of Formula XII
Figure imgf000029_0004
which is coupled with an amine of Formula XIII
1
'NH XIII,
R12
in the presence of a coupling agent (such as EDC), to yield a compound of Formula IB', which may be converted, if desired, to an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
[0067] The invention also relates to a process for the synthesis or preparation of a compound of Formula IB'
Figure imgf000029_0005
or an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R5, R11 , and R12 are as defined above for Formula I, wherein a compound of Formula XI
Figure imgf000030_0001
prepared as described above, is treated with an amine of Formula XIII
R11
NH XIII,
R12
to yield a compound of Formula IB', which may be converted, if desired, to an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
[0068] The invention also relates to a process for the synthesis or preparation of a compound of Formula IC
Figure imgf000030_0002
or an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R5 and R8 are as defined above for Formula I, wherein a compound of Formula XIV
Figure imgf000030_0003
is treated with dimethylformamide dimethyl acetal at elevated temperature to yield a compound of Formula XV
Figure imgf000030_0004
which is reacted with a guanidine of Formula VIII
NH
sl N VIII,
H
to yield a compound of Formula XVI
Figure imgf000030_0005
which is deprotected (e.g., via treatment with trifluoroacetic acid) to yield a compound of Formula XVII
Figure imgf000031_0001
which is treated with an appropriate reagent (e.g., an acyl chloride, a chloroformate, a sulfonyl chloride, a carbamoyl chloride, an alkyl halide, an isocyanate, an
isothiocyanate, or an arylating agent) to yield a compound of Formula IC, which may be converted, if desired, to an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
[0069] The invention also relates to a process for the synthesis or preparation of a compound of Formula IC
Figure imgf000031_0002
or an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R5 and R8 are as defined above for Formula I, wherein a compound of Formula XIV
is deprotected (e.g., via treatment w "ithX trifluXoroace -tic acid) to yield a compound of Formula XVIII
XVIII,
Figure imgf000031_0003
which is reacted with an appropriate acylating or alkylating agent to yield a compound of Formula XIX
Figure imgf000031_0004
which is treated with dimethylformamide dimethyl acetal at elevated temperature to yield a compound of Formula XX
Figure imgf000031_0005
"· which is reacted with a guanidine of Formula VIII
Figure imgf000032_0001
to yield a compound of Formula IC, which may be converted, if desired, to an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
[0070] The invention also relates to a process for the synthesis or preparation of a compound of Formula ID'
Figure imgf000032_0002
or an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R5 represents aryl or heteroaryl and R13 is as defined above for Formula ID, wherein a com ound of Formula XIV
Figure imgf000032_0003
is treated with dimethylformamide dimethyl acetal at elevated temperature to yield a compound of Formula XV
Figure imgf000032_0004
which is reacted with methyl carbarn imidothioate of Formula XXI
NH
¾S^NH2 I- to yield a compound of Formula XXII
Figure imgf000032_0005
which is deprotected (e.g., via treatment with trifluoroacetic acid) and then treated with an acylating agent of Formula XXIII
o
R13^CI XXIII, to yield a compound of Formula XXIV
Figure imgf000033_0001
which is treated with an oxidizing reagent (e.g., mCPBA) to yield a compound of
Formula XXV
Figure imgf000033_0002
which is treated with a compound of Formula XXVI
R5'NH2 XXVI,
to yield a compound of Formula ID', which may be converted, if desired, to an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
DETAILED DESCRIPTION OF THE INVENTION
[0071 ] For the purpose of the present invention, in the compounds of Formula I the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Cj.j indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive. Thus, for example, (d^alkyl refers to alkyl of one to three carbon atoms (i.e. 1 , 2 or 3 carbon atoms), inclusive, (i.e., methyl, ethyl, propyl, and isopropyl), straight and branched forms thereof, (Ci-6) for instance refers to a radical of one to six carbon atoms (i.e. 1 , 2, 3, 4, 5 or 6 carbon atoms).
[0072] As used herein, the following definitions are applicable unless otherwise described, the term "Ci-6alkyl" represents straight or branched chain alkyl groups. Examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert -butyl.
[0073] The term "C2-6alkenyl" represents straight or branched chain alkenyl groups. [0074] The term "Ci-6alkoxy" represents straight or branched chain -0-Ci-6alkyl groups. Examples of such alkoxy groups include methoxy, ethoxy, n-propoxy, and isopropoxy, sec-butoxy, fe/f-butoxy.
[0075] The term "acyl" represents Ci-6alkylcarbonyl, trifluoroacetyl, hydroxy- Ci-6alkylcarbonyl, Ci-6alkoxycarbonyl, /V-Ci-6alkylaminocarbonyl, Λ/,/V-di- (C-i-6alkyl)aminocarbonyl, Ci-6alkoxy-Ci-6alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, cyclo-C3-i2alkylcarbonyl, aryl-Ci-6alkylcarbonyl, heteroaryl-Ci-6alkylcarbonyl, arylamino- Ci-6alkylcarbonyl, heteroarylamino-Ci-6alkylcarbonyl, heterocyclylcarbonyl and heterocyclyl-Ci-6alkylcarbonyl.
[0076] The term "cycloC3-i2alkyl" represents monocyclic or bicyclic, or tricyclic alkyl groups, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1 ]heptyl and adamantanyl, which may be optionally substituted by one or more (e.g., 1 , 2, 3, 4, or 5) substituents, which may be the same or different, selected independently from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, C2-6alkenyl, Ci-6alkoxy, amino, hydroxy, cyano, Ci-6alkoxycarbonyl, C-i-6alkylamino, and di-(C-i-6alkyl)amino, Ci-6alkyl- carbonylamino, oxo, C-i-6alkoxyimino, /V-Ci-6alkylaminocarbonyl, Λ/,/V-di- (C-i-6alkyl)aminocarbonyl, arylCi-6alkoxycarbonyl, and Ci-6alkylenedioxy.
[0077] The term "cycloC3-6alkyl" represents monocyclic alkyl groups, including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, which may be optionally substituted by one or more (e.g., 1 , 2, 3, 4, or 5) substituents, which may be the same or different, selected independently from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, C2- 6alkenyl, Ci-6alkoxy, amino, hydroxy, cyano, Ci-6alkoxycarbonyl, Ci-6alkylamino, and di- (C-i-6alkyl)amino, Ci-6alkylcarbonylamino, oxo, C-i-6alkoxyimino, /V-d. 6alkylaminocarbonyl, /V,/V-di-(Ci-6alkyl)aminocarbonyl, arylCi-6alkoxycarbonyl, and Ci_ 6alkylenedioxy.
[0078] The term "aryl" represents phenyl or naphthyl, wherein the phenyl or naphthyl group is optionally substituted by one or more (e.g., 1 , 2, 3, 4, or 5) substituents, which may be the same or different, selected independently from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, d. 6alkyl, hydroxyCi-6alkyl, C2-6alkenyl, Ci-6alkoxy, C-i-ealkoxyd-ealkyl, amino, hydroxy, nitro, cyano, formyl, Ci-6alkylcarbonyl, Ci-6alkoxycarbonyl, Ci-6alkylcarbonyloxy, Ci-6alkylcarbonyloxyCi-6alkyl, Ci-6alkylamino, di-(Ci-6alkyl)amino, cycloC3-i2alkylamino, Ci-6alkylcarbonylamino, phenylcarbonylamino, aminocarbonyl,
/V-Ci-6alkylaminocarbonyl, /V,/V-di-(Ci-6alkyl)aminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, cycloC3--i2alkyl, pyridyl, and Ci-6alkylenedioxy.
[0079] The term "heteroaryl" represents an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic group comprising a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl group may be optionally substituted by one or more (e.g., 1 , 2, 3, 4, or 5) substituents, which may be the same or different, selected independently from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, Ci-6alkyl, hydroxyCi-6alkyl, C2-6alkenyl, Ci-6alkoxy, amino, hydroxy, nitro, cyano, Ci-6alkylcarbonyl, Ci-6alkoxycarbonyl, Ci-6alkoxycarbonyloxy, d. 6alkylamino, and di-(Ci-6alkyl)amino, cycloC3-i2alkylamino, C-i-6alkylcarbonylamino, aminocarbonyl, /V-Ci-6alkylaminocarbonyl, /V,/V-di-Ci-6alkylaminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, cycloC3-i2alkyl, Ci-6alkylenedioxy, aryl, and pyridyl. Representative heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, pyrazolyl, triazolyl, thiadiazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, purinyl, benzofuryl, benzothienyl, indolyl, indolizinyl, isoindolyl, indolinyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, isoquinolinyl, quinolizinyl, phthalazinyl, and pteridinyl.
[0080] The term "heterocyclyl" represents a saturated or unsaturated non-aromatic 3 to 12 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, and a saturated or unsaturated non-aromatic bicyclic ring system having 3 to 12 members comprising one to six heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heterocyclic ring or ring system may be optionally substituted by one or more (e.g., 1 , 2, 3, 4, or 5) substituents, which may be the same or different, selected independently from halogen, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, Chalky!, C2-6alkenyl,
Figure imgf000036_0001
amino, hydroxy, nitro, cyano, Ci-6alkoxycarbonyl, Ci-6alkylamino, and di-(Ci-6alkyl)amino, Ci-6alkylcarbonylamino, oxo, Ci-6alkoxyimino, /V-Ci-6alkylaminocarbonyl, /V,/V-di-(Ci-6alkyl)aminocarbonyl, arylCi-6alkoxycarbonyl, and Ci-6alkylenedioxy; examples of such heterocyclyl groups include piperidinyl, morpholinyl, thiomorpholinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, or piperazinyl, wherein the heterocyclic ring or ring system is linked to the group to which it is attached optionally via nitrogen or a carbon atom.
[0081 ] The term "halogen" represents fluorine, chlorine, bromine and iodine.
[0082] The compounds of the present invention are usually named according to the lUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g. "Ph" for phenyl, "Me" for methyl, "Et" for ethyl, "min" for minute or minutes, "h" for hour or hours, and "rt" for room temperature).
[0083] Memantine, also known as 1 -amino-3,5-dimethyladamantane, is disclosed, U.S. Patent Nos. 4, 122, 193; 4,273,774; and 5,061 ,703, the subject matter of which patents is hereby incorporated by reference.
[0084] Memantine is a system ically-active noncompetitive NMDA receptor antagonists having moderate affinity for the receptor. It exhibits strong voltage dependent characteristics and fast blocking/unblocking kinetics (see e.g. Gortelmeyer et al., Arzneim-Forsch/Drug Res., 1992, 42:904-913; Winblad et al., Int. J. Geriat. Psychiatry, 1999, 14: 135-146; Rogawski, Amino Acids, 2000, 19: 133-49; Danysz et al., Curr. Pharm. Des., 2002, 8:835-43; Jirgensons et. al. Eur. J. Med. Chem., 2000, 35: 555- 565).
[0085] The term "analog" or "derivative" is used herein in the conventional pharmaceutical sense, to refer to a molecule that structurally resembles a reference molecule, but has been modified in a targeted and controlled manner to replace one or more specific substituents of the reference molecule with an alternate substituent, thereby generating a molecule which is structurally similar to the reference molecule. Synthesis and screening of analogs (e.g., using structural and/or biochemical analysis), to identify slightly modified versions of a known compound which may have improved or biased traits (such as higher potency and/or selectivity at a specific targeted receptor type, greater ability to penetrate blood-brain barriers, fewer side effects, etc.) is a drug design approach that is well known in pharmaceutical chemistry.
[0086] In addition, using methods known to those skilled in the art, analogs and derivatives of the compounds of the invention may be created which have improved therapeutic efficacy, i.e., higher potency and/or selectivity at a specific targeted receptor type, either greater or lower ability to penetrate mammalian blood-brain barriers (e.g., either higher or lower blood-brain barrier permeation rate), fewer side effects, etc.
[0087] The term "prodrug" is used herein in the conventional pharmaceutical sense, to refer to a molecule which undergoes a transformation in vivo (e.g., an enzymatic or chemical transformation) to release an active parent drug. Prodrugs of the compounds of Formula I of the present invention may be prepared by chemically modifying a functional group present in the compound of Formula I such that the chemically modified compound may undergo a transformation in vivo (e.g., enzymatic hydrolysis) to provide the compound of Formula I. Examples of functional groups present in the compounds of Formula I which may be modified to produce prodrugs include carboxy, hydroxy, amino, and thio groups. Prodrugs of the compounds of Formula I of the present invention may be prepared according to conventional techniques which have been described in the art (see, for example, Stella V., et al., Prodrugs: Challenges and Rewards, AAPS Press/Springer, New York, 2007).
[0088] The phrase "pharmaceutically acceptable", as used in connection with compositions of the invention, refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g., human). The term "pharmaceutically acceptable" may also mean approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans. [0089] Compounds of the present invention may be in the form of pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" refers to those salts which possess the biological effectiveness and properties of the parent compound and which are not biologically or otherwise undesirable. The nature of the salt is not critical, provided that it is non-toxic and does not substantially interfere with the desired pharmacological activity.
[0090] It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically active, polymorphic, tautomeric, or stereoisomeric form, or mixture thereof, of a compound of the invention, which possesses the useful properties described herein.
[0091 ] The following Schemes 1 -4 describe the preparation of compounds of Formula I of the present invention. All of the starting materials may be prepared by procedures described in these schemes, by procedures well known to one of ordinary skill in organic chemistry, or may be obtained commercially. All of the final compounds of the present invention may be prepared by procedures described in these charts or by procedures analogous thereto, which would be well known to one of ordinary skill in organic chemistry. All of the variables used in Schemes 1 -4 are as defined below or as in the claims. Compounds containing one or more chiral centers may be prepared as racemates or mixtures of various stereoisomers and then separated. However, they also may be prepared by a special enantioselective synthesis. For several of the chiral compounds, the enantiomers differ in pharmacological activity. Scheme 1 - General procedure towards compounds of Formula ΙΑ'.
Figure imgf000039_0001
ΙΑ'
[0092] β-Alanine ester 1 is acylated with methylmalonylchloride (2). The resulting diester 3 is cyclized to lactam 4, which is subsequently decarboxylated to piperidine-2,4-dione (5). Treatment of intermediate 5 with dimethylformamide dimethyl acetal (DMF-DMA) at elevated temperature results in the formation of dimethylaminomethylene derivative 6, which is reacted with an appropriate guanidine 7 to provide a compound of Formula ΙΑ'.
Scheme 2 - General procedure towards compounds of Formula IB'.
Figure imgf000039_0002
[0093] Treatment of methyl 4-oxocyclohexanecarboxylate 8 with dimethylformamide dimethyl acetal (DMF-DMA) at elevated temperature results in the formation of dimethylaminomethylene derivative 9, which is reacted with a substituted guanidine 7 to give tetrahydroquinazoline-6-carboxylic acid methyl ester 10. The ester group is hydrolized to carboxylic acid using LiOH, and the carboxylic acid 11 may be used to prepare compounds of Formula 1 B' under standard conditions (e.g., amine 12, EDC). Alternatively, ester 10 may be directly converted to a compound of Formula 1 B'(for example, via reaction with an excess of of amine 12 employing a catalyst such as KCN).
Scheme 3 - General procedure towards compounds of Formula IC
Figure imgf000040_0001
18 19
[0094] Treatment of Boc-protected piperidone 13 with dimethylformamide dimethyl acetal (DMF-DMA) at elevated temperature results in formation of dimethylaminomethylene derivative 14, which is reacted with a substituted guanidine 7 to give intermediate 15. The Boc group is cleaved with trifluoroacetic acid (TFA) to provide an amine 16, which is acylated using acyl chlorides, chloroformates, sulfonyl or carbamoyl chlorides, or alkylated with alkyl halides to provide compounds of Formula IC Amine 16 may also be reacted with isocyanates or isothiocyanates to give ureas or thioureas, or it can be arylated to give the corresponding /V-aryl derivatives.
[0095] Alternatively, deprotected piperidone 17 may be directly reacted with an appropriate acylating or alkylating reagent to obtain ketone 18, which is subsequently converted to dimethylaminomethylene derivative 19 by means of DMF-DMA. The final compound IC is formed analogously to the above described method using substituted guanidine 7 in the presence of triethylamine or another suitable base.
Scheme 4 - Alternative synthesis route towards dihydropyrido[4,3-d]pyrimidines.
Figure imgf000041_0001
13 14 21
1. TFA/DCM, rt
2. Et3N, DCM
O
22 jl
Figure imgf000041_0002
R5' = aryl or eteroaryl
[0096] BOC-protected intermediate 14 is reacted with methyl carbarn imidothioate (20) under acidic conditions at elevated temperature to form intermediate 21 , which is deprotected and converted to the corresponding acylated compound 23. After oxidation to methylsulfonyl derivative 24 by means of an oxidizing reagent like mCPBA the mesylate group is substituted by an arylamine 25 to provide compounds of formula ID'.
[0097] It will be appreciated that in the above transformations it may be necessary or desirable to protect any sensitive groups in the molecule of the compound in question in order to avoid undesirable side reactions.
[0098] Pure stereoisomeric forms (including optical isomers) of the compounds and the intermediates of this invention may be obtained by the application of art-known procedures. Diastereomers may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g. liquid chromatography using chiral stationary phases. Enantiomers (optically active isomers) may be separated from each other by selective crystallization of their diastereomeric salts with optically active acids. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases.
[0099] Pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric form of appropriate starting materials, provided that the reaction occur stereoselectively. Stereoisomeric forms of Formula I are included within the scope of this invention.
[00100]Compounds of Formula I which are marked by radioactive atoms may be obtained using art-known procedures. Typical compounds include those where one or more hydrogens are substituted by tritium, where one or more 12C are substituted by 14C, where one or more fluor atoms are substituted by 18F or other isotopes. These may be used for the treatment of diseases (e.g. cancer) but also for diagnostic purposes. The radioactive atoms exchanged in the molecule are often isotopes of carbon, hydrogen, halogen, sulphur or phosphorus. Compounds of the Formula I which are marked by radioactive atoms are included within the scope of this invention.
ADDITION SALTS
[00101 ]For therapeutic use, salts of the compounds of Formula I are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases, which are non-pharmaceutically acceptable, may also find use, for example, in the preparation and purification of pharmaceutically acceptable compounds. All salts whether pharmaceutically acceptable or not are included within the ambit of the present invention. The pharmaceutically acceptable salts as mentioned above are meant to comprise the therapeutically active non-toxic salt forms, which the compounds of Formula I are able to form. The latter may conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, e.g. hydrohalic acids such as hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids such as acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1 ,2,3- propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4- methylbenzenesulfonic, cyclohexanesulfonic, 2-hydroxybenzoic, 4-amino-2- hydroxybenzoic and the like acids. Conversely, the salt form may be converted by treatment with alkali into the free base form.
PHARMACEUTICAL COMPOSITIONS
[00102]The active ingredients of the compounds of the invention, together with one or more excipients such as adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions, unit dosages or dosage forms. The pharmaceutical compositions may be employed as solid dosage forms, such as powders, granules, pellets, coated or uncoated tablets or filled capsules, or liquid dosage forms, such as solutions, suspensions, emulsions, or capsules filled with the same, or semi solid dosage forms, such as gels, creams and ointments. The active ingredient(s) dissolution and release profiles of the pharmaceutical dosage forms may be varied from seconds to months.
[00103]The pharmaceutical compositions are designed for the use in animals and humans and may be applied via all application routes. Preferred application routes will be the oral route, the dermal route, the pulmonary route, the nasal route, the rectal route, the parenteral route. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional or new ingredients in conventional or special proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containing one (1 ) to one hundred (100) milligrams of active ingredient or, more broadly, zero point five (0.5) to five hundred (500) milligrams per tablet, are accordingly suitable representative unit dosage forms.
[00104]The term "carrier" applied to pharmaceutical compositions of the invention refers to a diluent, excipient, or vehicle with which an active compound is administered. Such pharmaceutical carriers may be sterile liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. A.R. Gennaro, 20th Edition, describes suitable pharmaceutical carriers in "Remington: The Science and Practice of Pharmacy". METHOD OF TREATING
[00105]Due to their high degree of activity and their low toxicity, together presenting a most favorable therapeutic index, the active principles of the invention may be administered to a subject, e.g., a living animal (including a human) body, in need thereof, for the treatment, alleviation, or amelioration, palliation, or elimination of an indication or condition which is susceptible thereto, or representatively of an indication or condition set forth elsewhere in this application, preferably concurrently, simultaneously, or together with one or more pharmaceutically-acceptable excipients, carriers, or diluents, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parental (including intravenous and subcutaneous) or in some cases even topical route, in an effective amount. Suitable dosage ranges are 1 -1000 milligrams daily, optionally 10-500 milligrams daily, and optionally 50-500 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
[00106]The term "treat" is used herein to mean to relieve or alleviate at least one symptom of a disease in a subject. Within the meaning of the present invention, the term "treat" also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.
[00107]The term "combination" is used herein to define a single pharmaceutical composition (formulation) comprising a compound of the present invention and a second active ingredient (e.g., an NMDA receptor antagonist, L-DOPA, a dopaminomimetic, or a neuroleptic), in a formulation known in the art, or two separate pharmaceutical compositions (formulations), one comprising a compound of the present invention as formulated above and one comprising a second active ingredient (e.g., an NMDA receptor antagonist, L-DOPA, a dopaminomimetic, or a neuroleptic) in a formulation known in the art, to be administered conjointly. [00108]Within the meaning of the present invention, the term "conjoint administration" is used to refer to administration of a compound of the present invention and a second active ingredient (e.g., an NMDA receptor antagonist, L-DOPA, a dopaminomimetic, or a neuroleptic) in one composition, or simultaneously in different compositions, or sequentially. For the sequential administration to be considered "conjoint", however, the compound of the present invention and the NMDA receptor antagonist must be administered separated by a time interval that still permits the resultant beneficial effect in a mammal. For example, the compound of the present invention and the NMDA receptor antagonist must be administered on the same day (e.g., each - once or twice daily), including within an hour of each other, and including simultaneously.
[00109]The term "therapeutically effective" applied to dose or amount refers to that quantity of a compound or pharmaceutical composition that is sufficient to result in a desired activity upon administration to a living animal body in need thereof.
[001 10]Compounds of the present invention may be administered orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. It is usually desirable to use the oral route. The active agents may be administered orally in the form of a capsule, a tablet, or the like (see Remington: The Science and Practice of Pharmacy, 20th Edition). The orally administered pharmaceutical compositions may be administered in the form of a time-controlled release vehicle, including diffusion- controlled systems, osmotic devices, dissolution-controlled matrices, and erodible/degradable matrices.
[001 1 1 ]For oral administration in the form of a tablet or capsule, the active drug component of Formula I may be combined with non-toxic, pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, and the like); disintegrants (e.g., potato starch or sodium starch glycolate); and/or wetting agents (e.g., sodium lauryl sulphate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth or alginates), buffer salts, carboxymethylcellulose, polyethyleneglycol, waxes, and the like. For oral administration in liquid form, the drug components may be combined with nontoxic, pharmaceutically acceptable inert carriers (e.g., ethanol, glycerol, water), suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid), and the like. Stabilizing agents such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) may also be added to stabilize the dosage forms.
[001 12]Tablets may be coated by methods well known in the art. Compositions of the invention containing as active compound a compound of Formula I may be also introduced in beads, microspheres or microcapsules, e.g., fabricated from polyglycolic acid/lactic acid (PGLA). Liquid preparations for oral administration may take the form of, for example, solutions, syrups, emulsions or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Preparations for oral administration may be suitably formulated to give controlled or postponed release of the active compound.
[001 13]Compounds of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes may be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines, as is well known.
[001 14]Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. Active drugs may also be coupled with soluble polymers as targetable drug carriers. Such polymers include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxy- propyl methacrylamide-phenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, active drug may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
[001 15]For administration by inhalation, the therapeutics according to the present invention containing as active compound a compound of Formula I may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. , dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
[001 16]Formulations comprising compounds of the present invention may be delivered parenterally, i.e., by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c), intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.), or intradermal (i.d.) administration, by direct injection, via, for example, bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as excipients, suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory 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.
[001 17]Compounds of the present invention may also be formulated for rectal administration, e.g., as suppositories or retention enemas (e.g., containing conventional suppository bases such as cocoa butter or other glycerides).
[001 18]Compositions containing a compound of Formula I may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient and/or may contain different dosage levels to facilitate dosage titration. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. Compositions of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
[001 19]As disclosed herein, the dose of the components in the compositions of the present invention is determined to ensure that the dose administered continuously or intermittently will not exceed an amount determined after consideration of the results in test animals and the individual conditions of a patient. A specific dose naturally varies depending on the dosage procedure, the conditions of a patient or a subject animal such as age, body weight, sex, sensitivity, feed, dosage period, drugs used in combination, seriousness of the disease. The appropriate dose and dosage times under certain conditions may be determined by the test based on the above-described indices but may be refined and ultimately decided according to the judgment of the practitioner and each patient's circumstances (age, general condition, severity of symptoms, sex, etc.) according to standard clinical techniques.
[00120]Toxicity and therapeutic efficacy of the compositions of the invention may be determined by standard pharmaceutical procedures in experimental animals, e.g., by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index and it may be expressed as the ratio LD50/ED50. Compositions that exhibit large therapeutic indices are preferred.
[00121 ]From the Examples described herein below, it is apparent that the present invention provides novel and valuable applications and uses of the compounds of the present invention, which compounds comprise the active principle according to the present invention, as well as novel pharmaceutical compositions thereof and methods of preparation thereof and of treating therewith.
[00122]The high order of activity of the active agent of the present invention and compositions thereof, as evidenced by the tests reported, is indicative of utility based on its valuable activity in human beings as well as in lower animals. Clinical evaluation in human beings has not been completed. It will be clearly understood that the distribution and marketing of any compound or composition falling within the scope of the present invention for use in human beings will of course have to be predicated upon prior approval by governmental agencies which are responsible for and authorized to pass judgment on such questions.
[00123]The instant compounds of Formula I represent a novel class of mGluR5 modulators. In view of their potency, they will be useful therapeutics in a wide range of disorders, in particular CNS disorders, which involve excessive glutamate induced excitation.
[00124]These compounds accordingly find application in the treatment of the disorders of a living animal body, especially a human, as listed earlier in the description.
[00125]These compounds also find application in the treatment of indications in a living animal body, especially a human, wherein a particular condition does not necessarily exist but wherein a particular physiological parameter may be improved through administration of the instant compounds, including cognitive enhancement.
[00126]Neuroprotection as well as cognitive enhancement may also be achieved by administration of the instant compounds in combination with a NMDA receptor antagonist like Memantine.
[00127]The method-of-treating a living animal body with a compound of the invention, for the inhibition of progression or alleviation of the selected ailment therein, is as previously stated by any normally-accepted pharmaceutical route, employing the selected dosage which is effective in the alleviation of the particular ailment desired to be alleviated. Use of the compounds of the present invention in the manufacture of a medicament for the treatment of a living animal for inhibition of progression or alleviation of selected ailments or conditions, particularly ailments or conditions susceptible to treatment with a Group I mGluR modulator is carried out in the usual manner comprising the step of admixing an effective amount of a compound of the invention with a pharmaceutically-acceptable diluent, excipient, or carrier, and the method-of- treating, pharmaceutical compositions, and use of a compound of the present invention in the manufacture of a medicament.
[00128]Representative pharmaceutical compositions prepared by admixing the active ingredient with a suitable pharmaceutically-acceptable excipient, diluent, or carrier, include tablets, capsules, solutions for injection, liquid oral formulations, aerosol formulations, TDS formulations, and nanoparticle formulations, thus to produce medicaments for oral, injectable, or dermal use, also in accord with the foregoing.
EXPERIMENTAL PART
[00129]The compounds and their preparation of the present invention will be better understood in connection with the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention.
[00130]Hereinafter, "ACN" is defined as acetonitrile, "Boc" as fe/f-butyloxycarbonyl, "DCM" as dichloromethane, "DEE" as diethyl ether, "DMAP" as 4- dimethylaminopyridine (/V,/V-dimethylpyridin-4-amine), "DIPEA" as N,N- diisopropylethylamine (/V-ethyl-/V-isopropylpropan-2-amine), "DMF" as N,N- dimethylformamide, "DMF-DMA" as Λ/,/V-dimethylformamide dimethyl acetal, "EDC" as 1 -ethyl-3-(3-dimethylaminopropyl) carbodiimide (/V1-((ethylimino)methylene)-/V3,/V3- dimethylpropane-1 ,3-diamine), "EtOAc" as ethyl acetate, "EtOH" as ethanol, "HOBt" as hydroxybenzotriazole (1 /-/-benzo[d][1 ,2,3]triazol-4-ol), "mCPBA" as m- chloroperoxybenzoic acid, "MeOH" as methanol, "TBTU" as O-(benzotriazol-l -yl)- Λ/,Λ/,Λ/',Λ/'-tetramethyluronium tetrafluoroborate, "TEA" as triethylamine, and "THF" as tetrahydrofuran.
General Procedure 1 - Preparation of substituted guanidines
[00131 ] To a stirred solution of an appropriate amine in EtOH at 20 °C an aqueous HNO3 solution (67%, d=1 .4) and subsequently cyanamide are added. The resulting solution is stirred at reflux for 4-8 h. Then the mixture is cooled to 15 °C and DEE is added to induce crystallization of the product. The formed suspension is stirred at 20 °C for 15 min or overnight. The precipitate is filtered off, washed with a mixture of DEE and EtOH (3: 1 ), and air-dried to provide the title compound.
Preparation 1
Ethyl 2-((3-chlorophenyl)amino)-5,6,7,8-tetrahydroquinazoline-6-carboxylate
[00132] To a suspension of ethyl 4-oxocyclohexanecarboxylate (2.00 g, 1 1 .75 mmol) in abs. benzene (7 ml_) DMF-DMA (2.10 g, 17.63 mmol) is added, and the resulting mixture is heated at 100 °C for 2 days. The reaction mixture is cooled, diluted with water and extracted with EtOAc. The organic phase is dried over anhydrous Na2S04 and evaporated to give 1 .5 g (57%) of ethyl 3-((dimethylamino)methylene)-4- oxocyclohexanecarboxylate as brown oil. This intermediate is dissolved in abs. EtOH (7 ml_), and 1 -(3-chlorophenyl)guanidine (1 .13 g, 6.66 mmol) is added. The mixture is heated in a closed vial to 100 °C for 24 h. After cooling the reaction mixture is evaporated and the residue is purified by flash column chromatography to give 1 .03 g (47%) of the title compound as a yellow solid.
General Procedure 2a - Acylation of ^-substituted 5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2-amines
[00133] /V-substituted 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (1 eq) is dissolved in dry DCM and powdered K2CO3 (5 eq.) is added, followed by an acylating agent (acyl chloride, chloroformate, carbamoyl or sulfonyl chloride), (1 .05 eq.). The mixture is stirred at room temperature overnight, filtered, and evaporated. The residue is purified by flash column chromatography or preparative HPLC to provide /V-acylated products.
General Procedure 2b - Alternative acylation procedure
[00134]Substituted 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine is reacted with the corresponding acylating agent (1 .2 eq) in the presence of TBTU (1.3 eq) and TEA (2.7 eq) in acetonitrile for 22 h at room temperature. The reaction mixture is then diluted with water and extracted with DCM. The combined organic phases are dried over Na2SO4 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, DCM/EtOH or DCM/EtOAc) to give the final product.
Preparation 2
W-(3-Chlorophenyl)-5,6,7,8 etrahydropyrido[4,3-d]pyrimidin-2-amine
[00135]fe/f-Butyl 4-oxopiperidine-1 -carboxylate (2.0 g, 10.04 mmol) is dissolved in DMF (2.5 ml_) and DMF-DMA (1 .67 g, 14.05 mmol) is added. The mixture is heated at 100 °C for 60 h, then cooled and evaporated to dryness to give fe/f-butyl 3- ((dimethylamino)methylene)-4-oxopiperidine-1 -carboxylate. This intermediate (1 .0 g, 3.93 mmol) is dissolved in abs. EtOH (20 ml_), and 3-chlorophenylguanidine (0.444 g, 2.62 mmol) is added. The mixture is heated at 100 °C for 16 h, then cooled and evaporated to dryness. Purification of the residue by flash column chromatography provides fe/f-butyl 2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)- carboxylate (0.54 g, 57%) as a yellow solid. This intermediate (0.085 g, 0.23 mmol) is dissolved in DCM (5 ml_), TFA (1 ml_) is added and the mixture is stirred at room temperature for 6 h. The mixture is evaporated and partitioned between DCM and saturated aqueous NaHC03 solution. The organic phase is separated, dried over anhydrous Na2S04 and evaporated to give the title compound (60 mg, 98%) as a brown solid.
[00136]/V-(3-Fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, Λ/-(3- methylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, and 3-((5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile are all prepared in close analogy to the procedure described above.
General Procedure 3 - Formation of diarylamines via 2-(methylsulfonyl)-5,6,7,8- tetrahydroquinazoline derivatives
[00137]To a solution of the optionally substituted aniline or aminopyridine (3 eq) in dry toluene is added a solution of LiHMDS in THF (1 M, 3 eq.), and the mixture is stirred at room temperature for 15 min under nitrogen atmosphere. Then, a suspension of an appropriate 2-(methylsulfonyl)-5,6,7,8-tetrahydroquinazoline derivative (1 eq.) in THF is added, and the mixture is heated at 90 °C for 1 h. After cooling down to room temperature the mixture is quenched with a few drops of H20 and concentrated in vacuo. Purification is performed by means of flash column chromatography or by preparative HPLC to obtain the final compound.
Preparation 3
2,2-Dimethyl-1 -(2-(methylsulfonyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)- yl)propan-1-one
[00138]To a solution of crude fe/f-butyl 3-((dimethylamino)methylene)-4-oxopiperidine- 1 -carboxylate (see Preparation 2) (10.70 g, 42.1 mmol) and methyl carbamimidothioate hemisulfate (14.05 g, 50.5 mmol, 1 .2 eq.) in DMSO (200 ml_) is added 4M HCI solution in dioxane (1 .1 ml_, 4.2 mmol, 0.1 eq.). The mixture is heated at 130 °C overnight. After cooling down to room temperature EtOAc (330 ml_) and DEE (660 ml_) are added, and the organic layer is washed with water (1 L), brine (3 x, each 1 L), dried over Na2S04, and concentrated in vacuo. Purification by flash column chromatography (silica, gradient 100% heptane to 40% EtOAc/heptane) affords 4.6 g (35%, purity 90%) of the
intermediate product fe/f-butyl 2-(methylthio)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)- carboxylate.
[00139]To a solution of fe/f-butyl 2-(methylthio)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5/-/)-carboxylate (2.35 g, 8.4 mmol) in DCM (50 ml_) is added trifluoroacetic acid (25.7 ml_, 334 mmol, 40 eq.), and the mixture is stirred at room temperature for 45 min. The mixture is concentrated in vacuo and co-evaporated with DCM (2 x) to afford 2- (methylthio)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine as TFA salt as an orange oil, which is used in the next step without further purification.
[00140]To a solution of 2-(methylthio)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (TFA- salt, 1 .51 g, 8.4 mmol) in DCM (50 ml_) are added TEA (5.8 ml_, 41 .8 mmol, 5 eq.) and pivaloyl chloride (1 .2 ml_, 10.0 mmol, 1 .2 eq.), and the mixture is stirred overnight at room temperature. The solution is diluted with additional DCM (100 ml_), and the organic layer is washed with saturated aqueous NaHC03 solution (150 ml_), brine (150 ml_), dried over Na2S04 and concentrated in vacuo. Purification by flash column chromatography (adsorbed onto hydromatrix, silica gel, gradient 7% to 60% EtOAc/heptane) affords 1 .64 g (74% over 2 steps, purity 80%) of 2,2-dimethyl-1 -(2- (methylthio)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5/-/)-yl)propan-1 -one as a yellow oil, which solidifies upon standing.
[00141 ]To a solution of 2,2-dimethyl-1 -(2-(methylthio)-7,8-dihydropyrido[4,3-d]pyrimidin- 6(5/-/)-yl)propan-1 -one (1 .64 g, 6.2 mmol) in DCM (100 mL) is added 3- chlorobenzoperoxoic acid (3.13 g, 13.6 mmol, 2.2 eq.). After stirring at room
temperature for 45 min the mixture is diluted with additional DCM (100 mL), and the organic layer is washed with half saturated aqueous K2C03 (2x, each 200 mL). The combined aqueous layers are extracted with additional DCM (200 mL), then washed with brine (200 mL), dried over Na2S04 and concentrated in vacuo to provide the title compound (1.60 g, 87%) as a yellow oil, which solidifies upon standing.
[00142]/V,/V-dimethyl-2-(methylsulfonyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)- carboxamide is prepared in close analogy to the procedure described above using dimethylcarbamoyl chloride instead of pivaloyl chloride (third step).
Example 1
2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one
[00143] A mixture of 1 ,3-((dimethylamino)methylene)piperidine-2,4-dione (3.79 g, 33.5 mmol) and DMF-DMA (8.00 g, 67.0 mmol) in ACN (35 mL) is stirred at room temperature overnight and concentrated in vacuum. The mixture is triturated with DEE, filtered, washed with DEE, and dried in vacuum to give 3- ((dimethylamino)methylene)piperidine-2,4-dione (3.84 g, 68%) as a brown solid.
[00144] The obtained intermediate (0.168 g, 1 .00 mmol) is refluxed together with 1 -(3- chlorophenyl)guanidine nitrate (233 mg, 1.00 mmol) and TEA (0.3 mL) in EtOH (6 mL) for 4 h and cooled down to room temperature The formed precipitate is collected by filtration, washed with MeOH, water, DEE and dried to provide the title compound (220 mg, 80%) as a beige solid. 1H NMR (CDCI3), δΗ, 2.93 (t, 2H), 3.40-3.50 (m, 2H), 7.03, (d, 1 H), 7.32 (t, 1 H), 7.72 (d, 1 H), 7.74 (br s, 1 H), 7.97 (s, 1 H), 8.76 (s, 1 H), 10.15 (br s, 1 H).
LC/MS (M+H)+ = 275, 277
Example 2
(2-((3-Chlorophenyl)amino)-5,6,7,8-tetrahydroquinazolin-6-yl)(piperidin-1 - yl)methanone
[00145]Ethyl 2-((3-chlorophenyl)amino)-5,6,7,8-tetrahydroquinazoline-6-carboxylate (100 mg, 0.30 mmol) and DMAP (4 mg, 0.03 mmol) are dissolved in piperidine (3.0 mL), and the mixture is heated in a closed vial to 100 °C for 3 days. After cooling the reaction mixture is evaporated and the residue is purified by flash column chromatography to give 8 mg (7%) of the title compound as a colorless solid.
1H NMR (CDCI3), δΗ, 1 .50-1 .75 (m, 6H), 1 .85-2.12 (m, 2H), 2.61 -3.05 (m, 5H), 3.49 (m, 2H), 3.61 (m, 2H), 6.95 (d, 1 H), 7.1 1 -7.39 (m, 3H), 7.85 (s, 1 H), 8.16 (s, 1 H).
LC/MS (M+H)+ = 371
Example 3
1-(2-((3-Fluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2- methylpropan-1 -one
[00146]According to General Procedure 2a, /V-(3-fluorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine (75 mg, 0.21 mmol) is reacted with isobutyroyi chloride to provide the title compound (15 mg, 23%) as a yellow solid.
1H NMR (CDCI3), δΗ, 1 .15-1 .17 (overlapping d, 6H), 2.86-2.92 (m, 3H), 3.79 and 3.90
(each m, 2H), 4.58 and 4.65 (each s, 2H), 6.69 (t, 1 H), 7.15 (d, 1 H), 7.20-7.25 (m, 1 H),
7.68-7.73 (m, 2H), 8.20 (s, 1 H).
LC/MS (M+H)+ = 315
Example 4
1-(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2- methylpropan-1 -one [00147]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine (50 mg, 0.19 mmol) is reacted with isobutyroyl chloride to provide the title compound (15 mg, 24%) as a yellow solid.
1H NMR (CDCIs), δΗ, 1 .16-1 .19 (overlapping d, 6H), 2.85-2.95 (m, 3H), 3.82-3.91 (m,
2H), 4.60 and 4.66 (each s, 2H), 6.98 (d, 1 H), 7.22 (t, 1 H), 7.42 (d, 1 H), 7.86 (s, 1 H),
7.98 (s, 1 H), 8.21 (s, 1 H).
LC/MS (M+H)+ = 331
Example 5
2-Methyl-1 -(2-(m4olylamino)-7,8-dihydropyri^
one
[00148]According to General Procedure 2a, /V-(m-tolyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2-amine (51 mg, 0.15 mmol) is reacted with isobutyryl chloride to provide the title compound (10 mg, 22%) as a yellow solid.
1H NMR (CDCI3), δΗ, 1 .15-1 .17 (overlapping d, 6H), 2.33 (s, 3H), 2.83-2.89 (m, 3H), 3.79 and 3.89 (each m, 2H), 4.56 and 4.63 (each s, 2H), 6.84 (d, 1 H), 7.19 (t, 1 H), 7.29 (s, 1 H), 7.37 (s, 2H), 7.43 (d, 1 H), 8.17 (s, 1 H).
LC/MS (M+H)+ = 31 1
Example 6
(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)- yl)(cyclopropyl)methanone
[00149]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine (70 mg, 0.27 mmol) is reacted with
cyclopropanecarbonyl chloride to provide the title compound (30 mg, 34%) as a yellow solid.
1H NMR (CDCI3), δΗ, 0.76 (m, 2H), 0.98 (m, 2H), 1 .76 (m, 1 H), 2.81 and 9.92 (each m, 2H), 3.86 and 3.92 (each m, 2H), 4.61 and 4.72 (each s, 2H), 6.93 (d, 1 H), 7.06 (s, 1 H), 7.16 (t, 1 H), 7.31 (d, 1 H), 7.78 (s, 1 H), 8.16 (s, 1 H). LC/MS (M+H)+ = 329
Example 7
1-(2-((4-Fluorophenyl)amino)-7,8-dihydro^
dimethylpropan-1 -one
[00150]According to General Procedure 2a, /V-(4-fluorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine (50 mg, 0.20 mmol) is reacted with pivaloyi chloride to provide the title compound (20 mg, 30%) as a white solid.
1H NMR (CDCI3), δΗ, 1 .31 (s, 9H), 2.86 (t, 2H), 3.91 (t, 2H), 4.65 (s, 2H), 7.01 (t, 2H),
7.23 (s, 1 H), 7.51 -7.58 (m, 2H), 8.16 (s, 1 H).
LC/MS (M+H)+ = 329
Example 8
1- (2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2,2- dimethylpropan-1 -one
[00151 ]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine (50 mg, 0.19 mmol) is reacted with pivaloyi chloride to provide the title compound (27 mg, 41 %) as a white solid.
1H NMR (CDCI3), δΗ, 1 .32 (s, 9H), 2.89 (t, 2H), 3.92 (t, 2H), 4.66 (s, 2H), 6.98 (d, 2H),
7.21 (t, 1 H), 7.36-7.40 (m, 2H), 7.84 (m, 1 H), 8.20 (s, 1 H).
LC/MS (M+H)+ = 345
Example 9
3-((6-Pivaloyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile
[00152]According to General Procedure 2a, 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-
2- yl)amino)benzonitrile (97 mg, 0.40 mmol) is reacted with pivaloyi chloride to provide the title compound (30 mg, 21 %) as a white solid.
1H NMR (CDCI3), δΗ, 1 .33 (s, 6H), 2.91 (t, 2H), 3.96 (t, 2H), 4.69 (s, 2H), 7.30-7.42 (m, 2H), 7.64 (d, 1 H), 8.23 (s, 1 H), 8.24 (s, 1 H),
LC/MS (M+H)+ = 336 Example 10
1-(2-((3-Chlorophenyl)amino)-7,8-dihyd^
methylbutan-1 -one
[00153]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine (70 mg, 0.27 mmol) is reacted with 2- methylbutanoyl chloride to provide the title compound (40 mg, 43%) as a white solid. 1H NMR (CDCIs), δΗ, 0.90 (m, 3H), 1.16 (m, 3H), 1 .46 (m, 1 H), 1 .75 (m, 1 H), 2.71 (m, 1 H), 2.90 (m, 2H), 3.79-3.95 (m, 2H), 4.60 and 4.67 (each s, 2H), 6.98 (d, 1 H), 7.22 (t, 1 H), 7.25 (s, 1 H), 7.38 (d, 2H), 7.84 (s, 1 H), 8.23 (s, 1 H).
LC/MS (M+H)+ = 345
Example 11
(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)- yl)(cyclobutyl)methanone
[00154]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine (70 mg, 0.27 mmol) is reacted with
cyclobutanecarbonyl chloride to provide the title compound (60 mg, 65%) as a yellow solid.
1H NMR (CDCI3), δΗ, 1 .85-2.44 (m, 6H), 2.84 (t, 2H), 3.34 (m, 1 H), 3.64 and 3.89 (each t, 2H), 4.41 and 4.64 (each s, 2H), 6.97 (d, 1 H), 7.21 (t, 1 H), 7.26-7.37 (m, 2H), 7.83 (s, 1 H), 8.16 and 8.21 (each s, 1 H).
LC/MS (M+H)+ = 343
Example 12
1-(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2- ethylbutan-1 -one
[00155]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine (70 mg, 0.27 mmol) is reacted with 2- ethylbutanoyl chloride to provide the title compound (45 mg, 47%) as a white solid. 1H NMR (CDCI3), δΗ, 0.84 (m, 6H), 1.51 (m, 2H), 1 .68 (m, 2H), 2.57 (m, 1 H), 2.84 and 2.88 (each t, 2H), 3.83 and 3.93 (each t, 2H), 4.62 and 4.69 (each s, 2H), 6.96 (d, 1 H), 7.20 (t, 1 H), 7.28 (s, 1 H), 7.36 (d, 1 H), 7.82 (s, 1 H), 8.18 and 8.21 (each s, 1 H).
LC/MS (M+H)+ = 359
Example 13
(2-((3-Fluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)- yl)(phenyl)methanone
[00156]According to General Procedure 2a, /V-(3-fluorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine (75 mg, 0.21 mmol) is reacted with benzoyl chloride to provide the title compound (9 mg, 12%) as a yellow solid.
1H NMR (CDCI3), δΗ, 2.95-3.00 (m, 2H), 3.78-3.99 (m, 2H), 4.67 and 4.72 (each s, 2H),
6.72 (m, 1 H), 7.25 (m, 1 H), 7.46-7.56 (m, 5H), 7.76 (d, 1 H), 8.1 1 -8.24 (m, 2H), 8.44 and
8.58 (each s, 1 H).
LC/MS (M+H)+ = 349
Example 14
(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)- yl)(phenyl)methanone
[00157]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine (50 mg, 0.19 mmol) is reacted with benzoyl chloride to provide the title compound (60 mg, 86%) as a yellow solid.
1H NMR (CDCI3), δΗ, 2.90 (m, 2H), 3.75 (m, 2H), 4.73 (m, 2H), 6.97 (d, 1 H), 7.20 (t, 1 H),
7.35-7.47 (m, 7H), 7.82 (s, 1 H), 8.22 (s, 1 H).
LC/MS (M+H)+ = 365
Example 15
Methyl 2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)- carboxylate [00158]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine (70 mg, 0.27 mmol) is reacted with methyl chloroformate to provide the title compound (30 mg, 35%) as a yellow solid.
1H NMR (CDCI3), δΗ, 2.86 (t, 2H), 3.76 (s, 3H), 3.78 (t, 2H), 4.55 (s, 2H), 6.98 (d, 1 H),
7.15 (s, 1 H), 7.22 (t, 1 H), 7.38 (d, 1 H), 7.83 (m, 1 H), 8.19 (s, 1 H).
LC/MS (M+H)+ = 319
Example 16
Ethyl 2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)- carboxylate
[00159]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine (70 mg, 0.27 mmol) is reacted with ethyl chloroformate to provide the title compound (25 mg, 28%) as a yellow solid.
1H NMR (CDCI3), δΗ, 1 .30 (t, 3H), 2.86 (t, 2H), 3.77 (s, 3H), 4.20 (q, 2H), 4.55 (s, 2H),
6.98 (d, 1 H), 7.18-7.22 (m, 2H), 7.38 (d, 1 H), 7.82 (m, 1 H), 8.19 (s, 1 H).
LC/MS (M+H)+ = 333
Example 17
Isopropyl 2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)- carboxylate
[00160]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine (70 mg, 0.27 mmol) is reacted with isopropyl chloroformate to provide the title compound (30 mg, 32%) as a yellow solid.
1H NMR (CDCI3), δΗ, 1 .28 (d, 6H), 2.86 (t, 2H), 3.76 (s, 3H), 3.76 (t, 2H), 4.53 (s, 2H), 4.98 (m, 1 H), 6.98 (d, 1 H), 7.17-7.22 (m, 2H), 7.38 (d, 1 H), 7.84 (m, 1 H), 8.20 (s, 1 H). LC/MS (M+H)+ = 347
Example 18
ferf-Butyl 2-((3-fluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)- carboxylate [00161 ]fe/f-Butyl 3-((dimethylamino)methylene)-4-oxopiperidine-1 -carboxylate (1 .0 g, 3.93 mmol) is dissolved in abs. EtOH (20 ml_), and 1 -(3-fluorophenyl)guanidine (0.401 mg, 2.62 mmol) is added. The mixture is heated at 100 °C for 20 h, then cooled and evaporated to dryness. Purification of the residue by flash column chromatography provides the title compound (0.50 g, 56%) as a yellow solid.
1H NMR (CDCI3), δΗ, 1 .49 (s, 6H), 2.85 (t, 2H), 3.72 (t, 2H), 4.95 (s, 2H), 6.72 (t, 1 H), 7.1 1 -7.23 (m, 2H), 7.73 (m, 1 H), 8.18 (s, 1 H).
LC/MS (M+H)+ = 345
Example 19
ferf-Butyl 2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)- carboxylate
[00162]fe/f-Butyl 3-((dimethylamino)methylene)-4-oxopiperidine-1 -carboxylate (1 .0 g, 3.93 mmol) is dissolved in abs. EtOH (20 ml_), and 1 -(3-chlorophenyl)guanidine
(0.444g, 2.62 mmol) is added. The mixture is heated at 100 °C for 16 h, then cooled and evaporated to dryness. Purification of the residue by flash column chromatography provides the title compound (0.54 g, 57%) as a yellow solid.
1H NMR (CDCI3), δΗ, 1 .50 (s, 6H), 2.85 (t, 2H), 3.73 (t, 2H), 4.50 (s, 2H), 6.97 (d, 1 H), 7.15 (s, 1 H), 7.22 (t, 1 H), 7.38 (d, 1 H), 7.84 (m, 1 H), 8.19 (s, 1 H).
LC/MS (M+H)+ = 361
Example 20
ferf-Butyl 2-(An-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate
[00163]fe/f-Butyl 3-((dimethylamino)methylene)-4-oxopiperidine-1 -carboxylate (0.51 g, 2.01 mmol) is dissolved in abs. EtOH (20 ml_), and 1 -(m-tolyl)guanidine (0.20 g, 1 .34 mmol) is added. The mixture is heated at 100 °C for 16 h, then cooled and evaporated to dryness. Purification of the residue by flash column chromatography provides the title compound (0.25 g, 55%) as a yellow solid.
1H NMR (CDCI3), δΗ, 1 .49 (s, 6H), 2.35 (s, 3H), 2.83 (t, 2H), 3.72 (t, 2H), 4.48 (s, 2H), 6.84 (d, 1 H), 7.10 (s, 1 H), 7.21 (t, 1 H), 7.38 (s, 1 H), 7.45 (d, 1 H), 8.16 (s, 1 H). LC/MS (M+H)+ = 341
Example 21
ferf-Butyl 2-((3-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)- carboxylate
[00164]fe/f-Butyl 3-((dimethylamino)methylene)-4-oxopiperidine-1 -carboxylate (1 .1 g, 4.33 mmol) is dissolved in abs. EtOH (20 mL), and 1 -(3-cyanophenyl)guanidine (0.46 g, 2.90 mmol) is added. The mixture is heated at 100 °C for 16 h, then cooled and evaporated to dryness. Purification of the residue by flash column chromatography provides the title compound (0.62 g, 60%) as a yellow solid.
1H NMR (CDCI3), δΗ, 1 .49 (s, 9H), 2.85 (t, 2H), 3.73 (t, 2H), 4.51 (s, 2H), 7.24 - 7.41 (m, 3H), 7.62 - 7.66 (m, 1 H), 8.20 (s, 1 H), 8.24 (s, 1 H)
LC/MS (M+H)+ = 352
Example 22
2-((3-Chlorophenyl)amino)-yV-ethyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)- carboxamide
[00165]/V-(3-Chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (70 mg, 0.27 mmol) is dissolved in DCM (0.5 mL), and 1 -isocyanatopropane (20 mg, 0.28 mmol) is added. The mixture is stirred overnight at room temperature and then evaporated. The residue is recrystaiiized from EtOH to provide the title compound (50 mg, 56%) as a yellow solid.
1H NMR (CDCI3), δΗ, 1 .19 (t, 3H), 2.89 (t, 2H), 3.32 (q, 2H), 3.69 (t, 2H), 4.76 (s, 2H), 6.98 (d, 1 H), 7.13 (s, 1 H), 7.22 (t, 1 H), 7.40 (d, 1 H), 7.85 (m, 1 H), 8.21 (s, 1 H).
LC/MS (M+H)+ = 332
Example 23
2-((3-Chlorophenyl)amino)-yV,yV-dimethyl-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-carboxamide [00166]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine (70 mg, 0.27 mmol) is reacted with
dimethylcarbamic chloride to provide the title compound (50 mg, 56%) as a yellow solid. 1H NMR (CDCI3), δΗ, 2.83 (s, 6H), 2.86 (t, 2H), 3.46 (t, 2H), 4.23 (s, 2H), 6.90 (d, 1 H), 7.10 (s, 1 H), 7.15 (t, 1 H), 7.31 (d, 1 H), 7.77 (m, 1 H), 8.12 (s, 1 H).
LC/MS (M+H)+ = 332
Example 24
W-(3-Chlorophenyl)-6-(isopropylsulfonyl)-5,6,7,8 etrahydropyrido[4,3-d]pyrimidin- 2-amine
[00167]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine (70 mg, 0.27 mmol) is reacted with
isopropylsulfonyl chloride to provide the title compound (45 mg, 46%) as a yellow solid. 1H NMR (CDCI3), δΗ, 1 .36 (d, 6H), 2.93 (t, 2H), 3.24 (m, 1 H), 3.68 (t, 2H), 4.44 (s, 2H), 6.97 (d, 1 H), 7.14 (s, 1 H), 7.21 (t, 1 H), 7.37 (d, 1 H), 7.82 (m, 1 H), 8.16 (s, 1 H).
LC/MS (M+H)+ = 367
Example 25
yV-(3-Chlorophenyl)-6-(cyclopropylsulfonyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2-amine
[00168]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine (70 mg, 0.27 mmol) is reacted with
cyclopropylsulfonyl chloride to provide the title compound (30 mg, 31 %) as a yellow solid.
1H NMR (CDCI3), δΗ, 1 .01 (m, 2H), 1.24 (m, 2H), 2.31 (m, 1 H), 2.99 (t, 2H), 3.68 (t, 2H), 4.44 (s, 2H), 7.00 (d, 1 H), 7.15 (s, 1 H), 7.23 (t, 1 H), 7.37 (d, 1 H), 7.84 (m, 1 H), 8.20 (s, 1 H).
LC/MS (M+H)+ = 365
Example 26 2-((3-Chlorophenyl)amino)-W,W-dimethyl-7,8-dihydropyrido[4,3-d]pyrimid 6(5H)-sulfonamide
[00169]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine (70 mg, 0.27 mmol) is reacted with
dimethylsulfamoyi chloride to provide the title compound (50 mg, 51 %) as a yellow solid. 1H NMR (CDCIs), δΗ, 2.79 (s, 6H), 2.89 (t, 2H), 3.53 (t, 2H), 4.27 (s, 2H), 6.92 (d, 1 H), 7.05 (s, 1 H), 7.16 (t, 1 H), 7.31 (d, 1 H), 7.77 (s, 1 H), 8.12 (s, 1 H).
LC/MS (M+H)+ = 368
Example 27
W-(3-Chlorophenyl)-6-(pyridin-2-yl)-5,6,7,8 etrahydropyrido[4,3-d]pyrimidin-2- amine
[00170]/V-(3-Chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (77 mg, 0.30 mmol), DIPEA (1 14 mg, 0.89 mmol), and 2-bromopyridine (93 mg, 0.59 mmol) are dissolved in dioxane (0.5 mL), and the mixture is heated in a closed vial at 150 °C for 14 h. After cooling the mixture is evaporated, and the residue is purified by preparative HPLC to give 10 mg (10%) of the title compound as a yellow solid.
1H NMR (CDCI3), δΗ, 2.99 (t, 2H), 3.93 (t, 2H), 4.63 (s, 2H), 6.61 -6.75 (m, 2H), 6.98 (dd, 1 H), 7.19 (d, 1 H), 7.39-7.57 (m, 2H), 7.72 (s, 1 H), 7.87 (t, 1 H), 8.82-8.27 (m, 2H).
LC/MS (M+H)+ = 338
Example 28
6-(1 -(ieri-Butyl)-1H-tetrazol-5-yl)-yV-(3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2-amine
[00171 ]/V-(3-Chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (100 mg, 0.38 mmol) is dissolved in 1 mL dry THF, and fe/f-butylisothiocyanate (44 mg, 0.38 mmol) is added. The mixture is stirred at room temperature for 40 h and then
evaporated to dryness to provide an intermediate thiourea (120 mg, 84%) as a yellow solid, which is dissolved in DMF (10 mL). NaN3 (62 mg, 0.96 mmol), mercuric chloride (95 mg, 0.35 mmol) and TEA (96 mg, 0.96 mmol) are added, and the mixture is stirred at room temperature for 12 h and then partitioned between DCM and saturated aqueous NaHC03 solution. The organic phase is separated, dried over anhydrous Na2S04 and evaporated. The residue is purified by flash column chromatography to provide the title compound (45 mg, 37%) as a yellow solid.
1H NMR (CDCI3), δΗ, 1 .74 (s, 9H), 3.07 (t, 2H), 3.44 (t, 2H), 4.21 (s, 2H), 7.00 (dd, 1 H), 7.15 (s, 1 H), 7.25 (t, 1 H), 7.38 (dd, 1 H), 7.87 (s, 1 H), 8.18 (s, 1 H).
LC/MS (M+H)+ = 385
Example 29
W-(3-Chlorophenyl)-6-(1 -isopropyl-1H-tetrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2 -amine
[00172]/V-(3-Chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (100 mg, 0.38 mmol) is dissolved in 1 mL dry DCM, and isopropylisothiocyanate (39 mg, 0.38 mmol) is added. The mixture is stirred at room temperature for 40 h and then
evaporated to dryness to provide an intermediate thiourea (130 mg, 93%) as a yellow solid, which is dissolved in DMF (5 mL). NaN3 (70 mg, 1 .08 mmol), HgCI2 (107 mg, 0.40 mmol) and TEA (109 mg, 1 .08 mmol) are added, and the mixture is stirred at room temperature for 12 h and then partitioned between DCM and saturated aqueous
NaHC03 solution. The organic phase is separated, dried over anhydrous Na2S04 and evaporated. The residue is purified by flash column chromatography to provide the title compound (60 mg, 45%) as a yellow solid.
1H NMR (CDCI3), δΗ, 1 .62 (d, 6H), 3.07 (t, 2H), 3.57 (t, 2H), 4.38 (s, 2H), 4.53 (m, 1 H), 7.00 (dd, 1 H), 7.22 (t, 1 H), 7.29 (s, 1 H), 7.37-7.40 (m, 2H), 7.86 (s, 1 H), 8.24 (s, 1 H). LC/MS (M+H)+ = 371
Example 30
2-((3-Cyanophenyl)amino)-yV,yV-dimethyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)- carboxamide
[00173]According to General Procedure 2a, /V-(3-cyanophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine (67 mg, 0.27 mmol) is reacted with dimethylcarbamoyl chloride to provide the title compound (71 mg, 82%) as a yellow solid.
1H NMR (CDCI3), δΗ, 2.90 (s, 6H), 2.95 (t, 2H), 3.54 (t, 2H), 4.32 (s, 2H), 7.19 (s, 1 H), 7.28 (d, 1 H), 7.38 (t, 1 H), 7.64 (d, 1 H), 8.21 (s, 1 H), 8.26 (s, 1 H).
LC/MS (M+H)+ = 323
Example 31
2-((3-Chlorophenyl)amino)-W,W-diethyl-7,8-dihydropyrido[4,3-d]pyrimidi carboxamide
[00174]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine (50 mg, 0.19 mmol) is reacted with
diethylcarbamoyl chloride to provide the title compound (60 mg, 87%) as a yellow solid. 1H NMR (CDCI3), δΗ, 1 .15 (t, 6H), 2.92 (t, 2H), 3.26 (q, 4H), 3.50 (t, 2H), 4.27 (s, 2H), 6.97 (d, 1 H), 7.21 (t, 1 H), 7.23 (s, 1 H), 7.37 (d, 1 H), 7.84 (m, 1 H), 8.18 (s, 1 H).
LC/MS (M+H)+ = 360
Example 32
2- ((3-Cyanophenyl)amino)-yV,yV-diethyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)- carboxamide
[00175]According to General Procedure 2a, /V-(3-cyanophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine (50 mg, 0.20 mmol) is reacted with diethyl carbamoylchloride chloride to provide the title compound (60 mg, 87%) as a yellow solid.
1H NMR (CDCI3), δΗ, 1 .16 (t, 6H), 2.94 (t, 2H), 3.27 (q, 4H), 3.52 (t, 2H), 4.28 (s, 2H), 7.28 (d, 1 H), 7.32-7.42 (m, 3H), 7.65 (d, 2H), 8.20 (s, 1 H), 8.26 (s, 1 H).
LC/MS (M+H)+ = 351
Example 33
3- ((6-(2-Methylbutanoyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2- yl)amino)benzonitrile [00176]According to General Procedure 2a, /V-(3-cyanophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine (79 mg, 0.31 mmol) is reacted with 2- methylbutyryl chloride to provide the title compound (50 mg, 48%) as a yellow solid. 1H NMR (CDCIs), δΗ, 0.91 and 1 .19 (each m, 6H), 1 .50 and 1 .75 (each m, 2H), 2.47 and 2.71 (each q, 1 H), 2.91 (m, 2H), 3.84 and 3.93 (each t, 2H), 4.63 and 4.69 (each s, 2H), 7.28 (d, 1 H), 7.39 (t, 1 H), 7.52 (s, 1 H), 7.65 (d, 1 H), 8.26 (s, 2H),
LC/MS (M+H)+ = 351
Example 34
2-((3-Chlorophenyl)amino)-W,W-dimethyl-5,6,7,8-tetrahydroquinazoline-6- carboxamide
[00177]A solution of 2-((3-chlorophenyl)amino)-5,6,7,8-tetrahydroquinazoline-6- carboxylic acid (100 mg, 0.33 mmol), HOBt (66 mg, 0.43 mmol), EDC (82 mg, 0.43 mmol), DIPEA (140 mg, 1 .09 mmol), and dimethylamine hydrochloride (35 mg, 0.43 mmol) in dry DMF (1 mL) is stirred at room temperature for 24 h. The mixture is diluted with water and extracted with EtOAc. The organic phase is dried over anhydrous sodium sulfate and evaporated to dryness. The residue is purified by flash column chromatography to provide the title compound (64 mg, 59%) as a yellow solid.
1H NMR (CDCI3), δΗ, 1 .94-2.12 (m, 2H), 2.17-3.01 (m, 4H), 3.12 (s, 6H), 3.72 (m, 1 H), 7.19 (s, 1 H), 6.96 (d, 1 H), 7.1 1 (s, 1 H), 7.20 (t, 1 H), 7.37 (d, 1 H), 7.85 (s, 1 H), 8.16 (s, 1 H).
LC/MS (M+H)+ = 331 Example 35
2-((3-Chlorophenyl)amino)-yV,yV-diethyl-5,6,7,8-tetrahydroquinazoline-6- carboxamide
[00178]A solution of 2-((3-chlorophenyl)amino)-5,6,7,8-tetrahydroquinazoline-6- carboxylic acid (80 mg, 0.26 mmol), HOBt (52 mg, 0.34 mmol), EDC (66 mg, 0.34 mmol), DIPEA (75 mg, 0.58 mmol), and diethylamine (25 mg, 0.34 mmol) in dry DMF (1 mL) is stirred at room temperature for 24 h. The mixture is diluted with water and extracted with EtOAc. The organic phase is dried over anhydrous sodium sulfate and evaporated to dryness. The residue is purified by flash column chromatography to provide the title compound (50 mg, 53%) as a yellow solid.
1H NMR (CDCI3), δΗ, 1 .07-1 .29 (m, 6H), 1 .97-2.12 (m, 2H), 2.65-3.07 (m, 5H), 3.27-3.51 (m, 4H), 6.95 (d, 1 H), 7.13 (s, 1 H), 7.20 (t, 1 H), 7.37, 7.85 (s, 1 H), 8.16 (s, 1 H).
LC/MS (M+H)+ = 359
Example 36
2-((3-Chlorophenyl)amino)-W,W-dimethyl-7,8-dihydropyrido[4,3-d]pyrimid
6(5H)-carbothioamide
[00179]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine is reacted with dimethylcarbamothioic chloride to provide the title compound (37%) as a beige solid.
1H NMR (CDCI3), δΗ, 3.05 (t, 2H), 3.21 (s, 6H), 3.72 (t, 2H), 4.52 (s, 2H), 6.98 (d, 1 H), 7.19-7.22 (m, 2H), 7.37 (d, 1 H), 7.84 (s, 1 H), 8.20 (s, 1 H).
LC/MS (M+H)+ = 347, 349
Example 37
(rac)-1 -(2-((3-Chlorophenyl)amino)-5,6,7,8-tetrahydroquinazolin-6-yl)-2- methylpropan-1 -one
[00180]/V, O-Dimethylhydroxylamine hydrochloride (0.13 g, 1 .28 mmol) is added to a solution of 2-((3-chlorophenyl)amino)-5,6,7,8-tetrahydroquinazoline-6-carboxylic acid 0.30 g, 0.98 mmol), HOBt hydrate (0.20 g, 1 .28 mmol), EDC (0.25 g, 1 .28 mmol) and DIPEA (0.56 mL ,3.26 mmol) in dry DMF (3 mL), and the resulting mixture is stirred at room temperature for 24 h. The reaction mixture is diluted with water, extracted with EtOAc, dried over anhydrous Na2SO4 and evaporated. The residue is purified by flash column chromatography to give 154 mg (45%) of 2-((3-chlorophenyl)amino)-/V- (methoxymethyl)-5,6,7,8-tetrahydroquinazoline-6-carboxamide as a yellow powder.
[00181 ]To a solution of 2-((3-chlorophenyl)amino)-/V-(methoxymethyl)-5, 6,7,8- tetrahydroquinazoline-6-carboxamide (0.08 g, 0.23 mmol) in THF (2 mL) is added dropwise a solution of isopropylmagnesium chloride (1 .0 mmol), and the resulting mixture is stirred at room temperature for 12 h. The reaction mixture is quenched with saturated NH4CI solution, extracted with EtOAc, and the organic phase is dried over anhydrous Na2S04 and evaporated. Purification of the residue by flash column chromatography provides the title compound (4 mg, 5%) as a colorless solid.
1H NMR (CDCIs), δΗ, 1 .15 (d, 6H), 1.72-1.93 (m, 1 H), 2.07-2.24 (m, 1 H), 2.67-3.05 (m,
6H), 6.96 (d, 1 H), 7.21 (t, 1 H), 7.37 (d, 1 H), 7.85 (s, 1 H), 8.17 (s, 1 H).
LC/MS (M+H)+ = 329, 331
Example 38
2-(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)- yl)nicotinonitrile
[00182]ln close analogy to the procedure described in Example 27, /V-(3-chlorophenyl)- 5,6,7, 8-tetrahydropyrido[4,3-d]pyrimidin-2-amine is reacted with 2-bromonicotinonitrile to provide the title compound (39%) as a beige solid.
1H NMR (CDCI3), δΗ, 3.04 (t, 2H), 3.99 (t, 2H), 4.68 (s, 2H), 6.74 (dd, 1 H), 6.91 (dd, 1 H), 7.10 (s, 1 H), 7.15 (t, 1 H), 7.32 (dd, 1 H), 7.74-7.78 (m, 2H), 8.20 (s, 1 H), 8.31 (dd, 1 H). LC/MS (M+H)+ = 363, 365
Example 39
(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyrrolidin-
1 - yl)methanone
[00183]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine is reacted with pyrrolidine-1 -carbonyl chloride to provide the title compound (22%) as a solid.
1H NMR (CDCI3), δΗ, 1 .83-1 .90 (m, 4H), 2.92 (t, 2H), 3.93-3.46 (m, 4H), 3.57 (t, 2H), 4.35 (s, 2H), 6.97 (d, 1 H), 7.08-7.28 (m, 2H), 7.38 (d, 1 H), 7.85 (s, 1 H), 8.19 (s, 1 H). LC/MS (M+H)+ = 357, 359
Example 40
2- ((3-Cyanophenyl)amino)-yV,yV-diisopropyl-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-carboxamide [00184]According to General Procedure 2a, 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-
2- yl)amino)benzonitrile is reacted with diisopropylcarbamic chloride to provide the title compound (37%) as a colorless solid.
1H NMR (CDCI3), δΗ, 1 .30 (d, 12H), 2.92 (t, 2H), 3.41 (t, 2H), 3.69 (m, 2H), 4.17 (s, 2H), 7.28-7.41 (m, 3H), 7.63 (d, 1 H), 8.17 (s, 1 H), 8.26 (s, 1 H).
LC/MS (M+H)+ = 379
Example 41
3- ((6-(2-Methoxy-2-methylpropanoyl)-5,6,7,8 etrahydropyrido[4,3-d]pyrimidin-2- yl)amino)benzonitrile
[00185]According to General Procedure 2b, 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-
2- yl)amino)benzonitrile is reacted with 2-methoxy-2-methylpropanoic acid to provide the title compound (42 mg, 8%) as a yellowish solid.
1H NMR (CDCI3), δΗ, 1 .48 (s, 6H), 2.93 (t, 2H), 3.23 (s, 3H), 3.86-4.39 (br d, 2H), 4.60- 5.15 (br d, 2H), 7.16 (s, 1 H), 7.28 (d, 1 H), 7.39 (dd, 1 H), 7.65-7.70 (m, 1 H), 8.22 (s, 1 H), 8.25 (s, 1 H).
LC/MS (M+H)+ = 352, 248 Example 42
3- ((6-(Morpholine-4-carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2- yl)amino)benzonitrile
[00186]According to General Procedure 2a, 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin- 2-yl)amino)benzonitrile is reacted with morpholine-4-carbonyl chloride to provide the title compound (4%) as a colorless solid.
1H NMR (CDCI3), δΗ, 2.96 (t, 2H), 3.19-3.34 (m, 4H), 3.55 (t, 2H), 3.72 (m, 4H), 4.36 (s, 2H), 7.19-7.43 (m, 3H), 7.63 (d, 1 H), 8.22-8.26 (m, 2H).
LC/MS (M+H)+ = 365 Example 43
W-(3-Chlorophenyl)-6-(pyrimidin-2-yl)-5,6,7,8 etrahydropyrido[4,3-d]pyrimid amine
[00187]ln close analogy to the procedure described in Example 27, /V-(3-chlorophenyl)- 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine is reacted with 2-bromopyrimidine to provide the title compound (62%) as a solid.
1H NMR (CDCI3), δΗ, 2.96 (t, 2H), 4.17 (t, 2H), 4.86 (s, 2H), 6.57 (t, 1 H), 6.97 (dd, 1 H), 7.07 (s, 1 H), 7.23 9t, 1 H), 7.40 (dd, 1 H), 7.85 (t, 1 H), 8.28 (s, 1 H), 8.37 (d, 2H).
LC/MS (M+H)+ = 338, 340
Example 44
(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(furan-2- yl)methanone
[00188]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine is reacted with furan-2-carbonyl chloride to provide the title compound (43%) as a solid.
1H NMR (CDCI3), δΗ, 2.99 (t, 2H), 4.07 (t, 2H), 4.83 (s, 2H), 6.52 (dd, 1 H), 6.98 (d, 1 H), 7.10 (d, 1 H), 7.22 (t, 1 H), 7.39 (dd, 1 H), 7.54 (s, 1 H), 7.84 (dd, 1 H), 8.23 (s, 1 H).
LC/MS (M+H)+ = 354, 356
Example 45
(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(thiazol-2- yl)methanone
[00189]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine is reacted with thiazole-2-carbonyl chloride to provide the title compound (41 %) as a solid.
1H NMR (CDCI3), δΗ, 3.02 (t, 2H), 4.10 (t, 2H), 4.84 (s, 2H), 6.98 (d, 1 H), 7.18-7.23 (m, 2H), 7.39 (d, 1 H), 7.58 (d, 1 H), 7.85 (s, 1 H), 7.94 (d, 1 H), 8.26 (s, 1 H).
LC/MS (M+H)+ = 371 , 373 Example 46
(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido
yl)methanone
[00190]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine is reacted with thiazole-5-carbonyl chloride to provide the title compound (55%) as a solid.
1H NMR (CDCI3), δΗ, 3.00 (t, 2H), 4.01 (t, 2H), 4.80 (s, 2H), 6.99 (d, 1 H), 7.21 -7.23 (m, 2H), 7.40 (d, 1 H), 7.83 (s, 1 H), 8.16 (s, 1 H), 8.23 (s, 1 H), 8.93 (s, 1 H).
LC/MS (M+H)+ = 371 , 373
Example 47
2-((5-Chloropyridin-3-yl)amino)-yV,yV-dimethyl-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-carboxamide
[00191 ]According to General Procedure 3, /V,/V-dimethyl-2-(methylsulfonyl)-7,8- dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxamide is reacted with 3-amino-5- chloropyridine to provide the title compound (96 mg, 81 %) as a brown oil after trituration with toluene/MeOH.
1H NMR (CDCI3), δΗ, 2.93 (s, 6H), 3.09 (t, 2H), 3.58 (t, 2H), 4.36 (s, 2H), 8.30 (s, 1 H), 8.33-8.36 (m, 1 H), 9.02 (d, 1 H), 10.39 (br s, 1 H).
LC/MS (M+H)+ = 333, 335
Example 48
yV-(3-Chlorophenyl)-6-(1 -methyl-1H-tetrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2 -amine
[00192]ln close analogy to the procedure given in Example 28, /V-(3-chlorophenyl)- 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine is reacted with methylisothiocyanate to provide the intermediate thiourea, which is treated with sodium azide and mercuric chloride to give the title compound (43%) as a solid.
1H NMR (DMSO-de), δΗ, 2.96 (t, 2H), 3.66 (t, 2H), 3.95 (s, 3H), 4.51 (s, 2H), 6.93 (d, 1 H), 7.26 (t, 1 H), 7.62 (d, 1 H), 7.97 (s, 1 H), 8.38 (s, 1 H), 9.81 (s, 1 H). LC/MS (M+H)+ = 342, 344
Example 49
W-(3-Chlorophenyl)-6-(1 -methyl-1H-imidazol-2-yl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2 -amine
[00193]ln close analogy to the procedure given in Example 28, /V-(3-chlorophenyl)- 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine is reacted with methylisothiocyanate to provide the intermediate 2-((3-chlorophenyl)amino)-/V-methyl-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carbothioamide. This intermediate (0.38 mmol, 128 mg) is dissolved in 2.5 ml_ of dry DMF, and a solution of Mel (0.96 mmol, 136 mg) in 0.8 ml_ of dry DMF is added dropwise. The mixture is stirred overnight at room temperature, then the solvent is evaporated to give crude methyl 2-((3-chlorophenyl)amino)-/V-methyl-7,8- dihydropyrido[4,3-d]pyrimidine-6(5/-/)-carbimidothioate which is used in the next step without further purification.
[00194]Methyl 2-((3-chlorophenyl)amino)-/V-methyl-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5/-/)-carbimidothioate (0.30 mmol, 104 mg) is dissolved in 2 ml_ of pyridine, and 2,2- dimethoxyethylamine (0.33 mmol, 34 mg) is added. The mixture is heated to 100 °C for 3 h and then stirred overnight at ambient temperature. The solvent is evaporated, 2 ml_ of 2N aq. HCI is added, and the solution is refluxed for 2 h. The reaction mixture is then basified with K2CO3 and extracted with DCM. The organic phase is dried over Na2S04, and the solvent is removed under reduced pressure. The residue is purified by flash column chromatography to provide the title compound (55 mg, 54%) as a yellow solid. 1H NMR (CDCI3), δΗ, 3.00 (t, 2H), 3.37 (t, 2H), 3.53 (s, 3H), 4.21 (s, 2H), 6.71 (d, 1 H), 6.81 (d, 1 H), 6.96 (d, 1 H), 7.20 (t, 1 H), 7.36-7.40 (m, 2H), 7.85 (s, 1 H), 8.17 (s, 1 H). LC/MS (M+H)+ = 340, 342
Example 50
3-((6-(2-Ethylbutanoyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2- yl)amino)benzonitrile [00195]According to General Procedure 2a, 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin- 2-yl)amino)benzonitrile is reacted with 2-ethylbutanoyl chloride to provide the title compound (43%) as a colorless solid.
1H NMR (CDCIs), δΗ, 0.77-1 .00 (m, 6H), 1 .46-1 .78 (m, 4H), 2.60 (m, 1 H), 2.84-2.95 (m, 2H), 3.84-3.99 (m, 2H), 4.66 and 4.73 (both s, 2H), 7.29 (s, 1 H), 7.38 (t, 1 H), 7.66 (d, 1 H), 7.79 (s, 1 H), 8.24 (s, 1 H), 8.25 (s, 1 H).
LC/MS (M+H)+ = 350
Example 51
W-Butyl-2-((3-cyanophenyl)amino)-W-methyl-7,8-dihydropyrido[4,3-d]pyrimid 6(5H)-carboxamide
[00196]According to General Procedure 2a, 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin- 2-yl)amino)benzonitrile is reacted with butyl(methyl)carbamic chloride to provide the title compound (14%) as a colorless solid.
1H NMR (CDCI3), δΗ, 0.92 (t, 3H), 1 .30 (m, 2H), 1 .54 (m, 2H), 2.89 (s, 3H), 2.94 (t, 2H), 3.22 (t, 2H), 3.51 (t, 2H), 4.29 (s, 2H), 7.29 (s, 1 H), 7.38 (t, 1 H), 7.66 (d, 1 H), 8.21 (s, 1 H), 8.25 (s, 1 H).
LC/MS (M+H)+ = 365
Example 52
2-((3-Cyanophenyl)amino)-yV-cyclopropyl-yV-methyl-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carboxamide
[00197]According to General Procedure 2a, 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin- 2-yl)amino)benzonitrile is reacted with cyclopropyl(methyl)carbamic chloride to provide the title compound (12%) as a colorless solid.
1H NMR (CDCI3), δΗ, 0.64 (m, 2H), 0.76 (m, 2H), 2.70 (m, 1 H), 2.89 (s, 3H), 2.94 (t, 2H) 3.64 (t, 2H), 4.42 (s, 2H), 7.29-7.42 (m, 3H), 7.64 (d, 1 H), 8.21 (s, 1 H), 8.26 (s, 1 H). LC/MS (M+H)+ = 349 Example 53
2-((3-Chlorophenyl)amino)-W-ethyl-W-propyl-7,8-dihydropyrido[4,3-d]pyrimidi 6(5H)-carboxamide
[00198]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine is reacted with propyl(ethyl)carbamic chloride to provide the title compound (22%) as a solid.
1H NMR (CDCI3), δΗ, 0.89 (t, 3H), 1 .14 (t, 3H), 1.57 (m, 2H), 2.92 (t, 2H), 3.12-3.32 (m, 4H), 3.50 (t, 2H), 4.26 (s, 2H), 6.97 (d, 1 H), 7.05-7.22 (m, 2H), 7.38 (d, 1 H), 7.85 (s, 1 H), 8.19 (s, 1 H).
LC/MS (M+H)+ = 373, 375
Example 54
W,W-Dimethyl-2-((6-methylpyridin-2-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimi 6(5H)-carboxamide
[00199]According to General Procedure 3, /V,/V-dimethyl-2-(methylsulfonyl)-7,8- dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxamide is reacted with 6-methylpyridin-2- amine to provide the title compound (35 mg, 21 %) as a light yellow solid.
1H NMR (CDCI3), δΗ, 2.46 (s, 3H), 2.90 (s, 6H), 2.95 (t, 2H), 3.54 (t, 2H), 4.32 (s, 2H),
6.78 (d, 1 H), 7.75 (t, 1 H), 7.75 (br s, 1 H), 8.19 (d, 1 H), 8.22 (s, 1 H).
LC/MS (M+H)+ = 313
Example 55
(rac)-3-((6-(2-Ethylpyrrolidine-1 -carbonyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2-yl)amino)benzonitrile
[00200]According to General Procedure 2a, 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin- 2-yl)amino)benzonitrile is reacted with 2-ethylpyrrolidine-1 -carbonyl chloride to provide the title compound (45%) as a colorless solid.
1H NMR (CDCI3), δΗ, 0.85 (t, 3H), 1 .25-1 .85 (m, 5H), 2.10 (m, 1 H), 2.74-3.1 1 (m, 2H), 3.38-3.43 (m, 3H), 3.76-3.85 (m, 2H), 4.35 (s, 2H), 7.29-7.42 (m, 3H), 7.64 (d, 1 H), 8.21 (s, 1 H), 8.26 (s, 1 H). LC/MS (M+H)+ = 377
Example 56
W-(Cyanomethyl)-2-((3-cyanophenyl)amino)-W-methyl-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carboxamide
[00201 ]According to General Procedure 2a, 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-
2- yl)amino)benzonitrile is reacted with (cyanomethyl)(methyl)carbamic chloride to provide the title compound (6%) as a colorless solid.
1H NMR (CDCIs), δΗ, 2.96 (t, 2H), 3.06 (s, 3H), 3.63 (t, 2H), 4.07 (s, 2H), 4.41 (s, 2H), 7.23-7.35 (m, 2H), 7.40 (t, 1 H), 7.62 (d, 1 H), 8.22 (s, 1 H), 8.25 (s, 1 H).
LC/MS (M+H)+ = 348
Example 57
3- ((6-(1 -Methylcyclopropanecarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2- yl)amino)benzonitrile
[00202]According to General Procedure 2b, 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-
2- yl)amino)benzonitrile is reacted with 1 -methylcyclopropanecarboxylic acid to provide the title compound (162 mg, 32%) as a beige solid.
1H NMR (CDCI3), δΗ, 0.63-0.68 (m, 2H), 0.97-1 .02 (m, 2H), 1 .37 (s, 3H), 2.93 (t, 2H), 3.98 (t, 2H), 4.70 (s, 2H), 7.19 (s, 1 H), 7.29 (d, 1 H), 7.39 (dd, 1 H), 7.64-7.69 (m, 1 H), 8.23 (s, 1 H), 8.25 (s, 1 H).
LC/MS (M+H)+ = 334, 248
Example 58
3- ((6-(2-Methylcyclopropanecarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2- yl)amino)benzonitrile
[00203]According to General Procedure 2b, 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin- 2-yl)amino)benzonitrile is reacted with 2-methylcyclopropanecarboxylic acid to provide the title compound (57 mg, 1 1 %) as a white solid (mixture of cis and trans isomers, approx. 1 :3). 1H NMR (CDCI3), δΗ, 0.63-1 .85 (m, 4H), 1 .17 (d, 3H), 2.94 (s, 2H) 3.85-4.24 (m, 2H), 4.61 -4.87 (m, 2H), 7.18 (s, 1 H), 7.29 (d, 1 H), 7.39 (dd, 1 H), 7.66 (d, 1 H), 8.23 (s, 1 H), 8.25 (s, 1 H).
LC/MS (M+H)+ = 334, 248 Example 59
2,2-Dimethyl-1 -(2-((6-methylpyridin-2-yl)amino)-7,8-dihydropyrido[4,3-d^
6(5H)-yl)propan-1 -one
[00204]According to General Procedure 3, 2,2-dimethyl-1 -(2-(methylsulfonyl)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-yl)propan-1 -one is reacted with 6-methylpyridin-2- amine to provide the title compound (15 mg, 9%).
1H NMR (CDCI3), δΗ, 1 .33 (s, 9H), 2.46 (s, 3H), 2.92 (t, 2H), 3.94 (t, 2H), 4.68 (s, 2H), 6.79 (d, 1 H), 7.58 (t, 1 H), 7.73 (br s, 1 H), 8.18 (d, 1 H), 8.24 (s, 1 H).
LC/MS (M+H)+ = 326
Example 60
3-((6-(2-Hydroxy-2-methylpropanoyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2- yl)amino)benzonitrile
[00205]According to General Procedure 2b, 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin- 2-yl)amino)benzonitrile is reacted with 2-hydroxy-2-methylpropanoic acid to provide the title compound (32 mg, 3%) as a beige solid.
1H NMR (CDCI3), δΗ, 1 .55 (s, 6H), 2.94 (t, 2H), 3.61 (s, 1 H), 4.02 (t, 2H), 4.78 (s, 2H), 7.19 (s, 1 H), 7.29 (d, 1 H), 7.39 (dd, 1 H), 7.64-7.69 (m, 1 H), 8.21 (s, 1 H), 8.24 (s, 1 H). LC/MS (M+H)+ = 338
Example 61
yV,yV-Diethyl-2-(An-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)- carboxamide [00206]According to General Procedure 2a, /V-(m-tolyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2 -amine is reacted with diethylcarbamic chloride to provide the title compound (66%) as a colorless solid.
1H NMR (CDCI3), δΗ, 1 .15 (t, 6H), 2.34 (s, 3H), 2.89 (t, 2H), 3.25 (q, 4H), 3.48 (t, 2H), 4.25 (s, 2H), 6.83 (d, 1 H), 7.16-7.25 (m, 2H), 7.38 (s, 1 H), 7.44 (d, 1 H), 8.15 (s, 1 H). LC/MS (M+H)+ = 340
Example 62
2-((3-Cyanophenyl)amino)-W-isopropyl-W-methyl-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carboxamide
[00207]According to General Procedure 2a, 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin- 2-yl)amino)benzonitrile is reacted with isopropyl(methyl)carbamic chloride to provide the title compound (50%) as a colorless solid.
1H NMR (CDCI3), δΗ, 1 .17 (d, 6H), 2.77 (s, 3H), 2.95 (t, 2H), 3.51 (t, 2H), 4.12 (m, 1 H), 4.28 (s, 2H), 7.18 (s, 1 H), 7.28 (d, 1 H), 7.38 (t, 1 H), 7.63 (d, 1 H), 8.21 (s, 1 H), 8.26 (s, 1 H).
LC/MS (M+H)+ = 351 Example 63
2-((3-Cyanophenyl)amino)-yV-ethyl-yV-methyl-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-carboxamide
[00208]According to General Procedure 2a, 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin- 2-yl)amino)benzonitrile is reacted with ethyl(methyl)carbamic chloride to provide the title compound (28%) as a colorless solid.
1H NMR (CDCI3), δΗ, 1 .18 (t, 3H), 2.94 (s, 3H), 2.97 (t, 2H), 3.27 (q, 2H), 3.52 (t, 2H), 4.30 (s, 2H), 7.20 (s, 1 H), 7.32 (d, 1 H), 7.40 (t, 1 H), 7.63 (d, 1 H), 8.21 (s, 1 H), 8.26 (s, 1 H).
LC/MS (M+H)+ = 337 Example 64
2-((3-Chlorophenyl)amino)-W-(cyclopropylmethyl)-W-methyl-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carboxamide
[00209]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine is reacted with cyclopropylmethyl(methyl)carbamic chloride to provide the title compound (8%) as a solid.
1H NMR (CDCI3), δΗ, 0.21 (m, 2H), 0.54 (m, 2H), 0.97 (m, 1 H), 2.94 (t, 2H), 2.97 (s, 3H), 3.1 1 (d, 2H), 3.53 (t, 2H), 4.29 (s, 2H), 6.98 (d, 1 H), 7.05 (s, 1 H), 7.22 (t, 1 H), 7.38 (d, 1 H), 7.84 (s, 1 H), 8.19 (s, 1 H).
LC/MS (M+H)+ = 371 , 373
Example 65
W,W-Dimethyl-2-(m olylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)- carboxamide
[00210]According to General Procedure 2a, /V-(m-tolyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2 -amine is reacted with dimethylcarbamic chloride to provide the title compound (54%) as a colorless solid.
1H NMR (CDCI3), δΗ, 2.34 (s, 3H), 2.89 (s, 6H), 2.90 (t, 3H), 3.52 (t, 2H), 4.29 (s, 2H), 6.83 (d, 1 H), 7.1 1 (s, 1 H), 7.20 (t, 1 H), 7.38 (s, 1 H), 7.44 (d, 1 H), 8.16 (s, 1 H).
LC/MS (M+H)+ = 312
Example 66
2-((3-Chlorophenyl)amino)-yV-cyclopropyl-yV-ethyl-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carboxamide
[0021 1 ]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine is reacted with cyclopropyl(ethyl)carbamic chloride to provide the title compound (7%) as a solid. 1H NMR (CDCI3), δΗ, 0.64 (m, 2H), 0.77 (m, 2H), 1 .19 (t, 3H), 2.93 (m, 1 H), 3.15 (t, 2H) 3.34 (t, 2H), 3.64 (t, 2H), 4.42 (s, 2H), 6.98 (d, 1 H), 7.08 (s, 1 H), 7.22 (t, 1 H), 7.38 (d, 1 H), 7.85 (s, 1 H), 8.23 (s, 1 H).
LC/MS (M+H)+ = 371 , 373
Example 67
Pyrrolidin-1 -yl(2-(m4olylamino)-7,8-dih^
yl)methanone
[00212]According to General Procedure 2a, /V-(m-tolyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2-amine is reacted with pyrrolidine-1 -carbonyl chloride to provide the title compound (53%) as a colorless solid.
1H NMR (CDCI3), δΗ, 1 .85 (m, 4H), 2.34 (s, 3H), 2.89 (t, 2H), 3.43 (m, 4H), 3.56 (t, 2H), 4.33 (s, 2H), 6.83 (d, 1 H), 7.16-7.24 (m, 2H), 7.37 (s, 1 H), 7.44 (d, 1 H), 8.15 (s, 1 H). LC/MS (M+H)+ = 338
Example 68
(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(1 - methylcyclopropyl)methanone
[00213]According to General Procedure 2b, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine is reacted with 1 - methylcyclopropanecarboxylic acid to provide the title compound (243 mg, 16%) as a beige solid.
1H NMR (CDCI3), δΗ, 0.64 (t, 2H), 0.99 (t, 2H), 1.37 (s, 3H), 2.91 (t, 2H), 3.96 (t, 2H), 4.68 (s, 2H), 6.99 (d, 1 H), 7.08 (s, 1 H), 7.22 (dd, 1 H), 7.39 (d, 1 H), 7.84 (s, 1 H), 8.23 (s, 1 H).
LC/MS (M+H)+ = 345, 343, 259, 257 Example 69
(1 -Methylcyclopropyl)(2-(An-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)- yl)methanone [00214]According to General Procedure 2b, /V-(m-tolyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2-amine is reacted with 1 -methylcyclopropanecarboxylic acid to provide the title compound (72 mg, 15%) as a beige solid.
1H NMR (CDCI3), δΗ, 0.64 (t, 2H), 0.99 (t, 2H), 1.36 (s, 3H), 2.36 (s, 3H), 2.89 (t, 2H), 3.95 (t, 2H), 4.66 (s, 2H), 6.86 (d, 1 H), 7.02 (s, 1 H), 7.21 (dd, 1 H), 7.39 (s, 1 H), 7.45 (d, 1 H), 8.20 (s, 1 H).
LC/MS (M+H)+ = 323, 237
Example 70
W-Ethyl-W-propyl-2-(m olylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H^ carboxamide
[00215]According to General Procedure 2a, /V-(m-tolyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2 -amine is reacted with propyl(ethyl)carbamic chloride to provide the title compound (51 %) as a colorless solid.
1H NMR (CDCI3), δΗ, 0.88 (t, 3H), 1 .14 (t, 3H), 1.57 (m, 2H), 2.35 (s, 3H), 2.91 (t, 2H), 3.12-3.32 (m, 4H), 3.50 (t, 2H), 4.25 (s, 2H), 6.84 (d, 1 H), 7.00 (s, 1 H), 7.21 (t, 1 H), 7.38 (s, 1 H), 7.45 (d, 1 H), 8.16 (s, 1 H).
LC/MS (M+H)+ = 354
Example 71
(rac)-3-((6-(3-Methylpyrrolidine-1 -carbonyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2-yl)amino)benzonitrile
[00216]According to General Procedure 2a, 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin- 2-yl)amino)benzonitrile is reacted with 3-methylpyrrolidine-1 -carbonyl chloride to provide the title compound (10%) as a colorless solid.
1H NMR (CDCI3), δΗ, 1 .07 (d, 3H), 1.20 (m, 1 H), 1 .95-2.03 (m, 1 H), 2.17-2.30 (m, 1 H), 2.88-3.07 (m, 3H), 3.38-3.75 (m, 5H), 4.35 (s, 2H), 7.28 (d, 1 H), 7.33 (t, 1 H), 7.42 (s, 1 H), 7.65 (d, 1 H), 8.20 (s, 1 H), 8.26 (s, 1 H).
LC/MS (M+H)+ = 363 Example 72
(rac)-3-((6-(2-Methylpyrrolidine-1 -carbonyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2-yl)amino)benzonitrile
[00217]According to General Procedure 2a, 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-
2- yl)amino)benzonitrile is reacted with 2-methylpyrrolidine-1 -carbonyl chloride to provide the title compound (18%) as a colorless solid.
1H NMR (CDCI3), δΗ, 1 .20 (d, 3H), 1.42 (m, 1 H), 1 .62-1 .95 (m, 2H), 2.1 1 (m, 1 H), 2.71 - 3.13 (m, 2H), 3.30-3.51 (m, 3H), 3.83 (m, 1 H), 4.05 (m, 1 H), 4.35 (s, 2H), 7.24-7.47 (m, 3H), 7.64 (d, 1 H), 8.20 (s, 1 H), 8.25 (s, 1 H).
LC/MS (M+H)+ = 363
Example 73
3- ((6-(3,3-Dimethylazetidine-1 -carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin- 2-yl)amino)benzonitrile
[00218]According to General Procedure 2a, 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin- 2-yl)amino)benzonitrile is reacted with 3,3-dimethylazetidine-1 -carbonyl chloride to provide the title compound (10%) as a colorless solid.
1H NMR (CDCI3), δΗ, 1 .28 (s, 6H), 2.87 (t, 2H), 3.61 (t, 2H), 3.74 (s, 4H), 4.42 (s, 2H), 7.29-7.42 (m, 3H), 7.64 (d, 1 H), 8.20 (s, 1 H), 8.25 (s, 1 H).
LC/MS (M+H)+ = 363
Example 74
2-((3-Cyanophenyl)amino)-yV-ethyl-yV-propyl-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-carboxamide
[00219]According to General Procedure 2a, 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin- 2-yl)amino)benzonitrile is reacted with propyl(ethyl)carbamic chloride to provide the title compound (44%) as a colorless solid. 1H NMR (CDCI3), δΗ, 0.89 (t, 3H), 1 .15 (t, 3H), 1.57 (m, 2H), 2.93 (t, 2H), 3.13-3.32 (m, 4H), 3.51 (t, 2H), 4.28 (s, 2H), 7.22-7.42 (m, 3H), 7.63 (d, 1 H), 8.20 (s, 1 H), 8.26 (s, 1 H).
LC/MS (M+H)+ = 365 Example 75
(rac)-1 -(2-((3-Chlorophenyl)amino)-5-m
6(5H)-yl)-2,2-dimethylpropan-1 -one
[00220]A mixture of fe/f-butyl 2-methyl-4-oxopiperidine-1 -carboxylate (1 .965 g, 9.21 mmol) and DMF-DMA (4.93 mL, 4.391 g, 36.85 mmol) is stirred at 120 °C for 8 h, cooled down to room temperature and concentrated at reduced pressure. The residue is diluted with water (10 mL) and extracted with EtOAc (40 mL). The organic phase is washed with brine, dried over Na2S04, concentrated at reduced pressure and dried resulting in a mixture of fe/f-butyl 3-((dimethylamino)methylene)-2-methyl-4- oxopiperidine-1 -carboxylate and its regioisomer fe/f-butyl 5-
((dimethylamino)methylene)-2-methyl-4-oxopiperidine-1 -carboxylate (2.404 g, 97%) as oil used on the next stage without separation and further purification.
[00221 ]The obtained mixture (1 .320 g, 4.91 mmol) is reacted with 1 -(3- chlorophenyl)guanidine nitrate (953 mg, 4.10 mmol) in the presence of NaHC03 (1.032 g, 12.29 mmol) in DMF (3 mL) at 120 °C for 3 h, cooled down to room temperature and diluted with water (10 mL). The water layer is decanted, and the resulting oil is dissolved in DCM. The obtained solution is dried over Na2S04 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane, 1 :5) and washed with DEE/hexane mixture (1 : 1 ) to give an impure mixture of fe/f-butyl 2-((3-chlorophenyl)amino)-5-methyl-7,8-dihydropyrido[4,3- d]pyrimidine-6(5/-/)-carboxylate and fe/f-butyl 2-((3-chlorophenyl)amino)-7-methyl-7,8- dihydropyrido[4,3-d]pyrimidine-6(5/-/)-carboxylate (in total 369 mg). Another batch (263 mg) is obtained after purification of the mother liquor by evaporation of the solvents and subsequent column chromatography (silica gel, EtOAc/hexane, 1 :5). Both batches were combined and purified by preparative HPLC (C18, acetonitrile/water) to provide an inseparable mixture of fe/f-butyl 2-((3-chlorophenyl)amino)-5-methyl-7,8- dihydropyrido[4,3-d]pyrimidine-6(5/-/)-carboxylate and fe/f-butyl 2-((3- chlorophenyl)amino)-7-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)-carboxylate (595 mg, 39%, ratio 1 .3: 1 according to NMR and HPLC) as a white solid.
[00222]The obtained mixture (553 mg, 1 .48 mmol) and dioxane (2 mL) is stirred in a solution of HCI in dioxane (18%, 3.0 mL, 14.75 mmol) at reflux for 1 h, cooled down to room temperature and diluted with DEE (20 mL). The formed solid is collected by filtration, washed with acetone/DEE (1 :1 ) and air-dried to obtain a mixture of Λ/-(3- chlorophenyl)-5-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and Λ/-(3- chlorophenyl)-7-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (496 mg, 97%) as a white solid.
[00223] Pivaloyl chloride (0.21 mL, 204 mg, 1 .69 mmol) is added dropwise to a solution of the obtained mixture (489 mg, 1 .41 mmol) and TEA (0.79 mL, 569 mg, 5.63 mmol) in DCM (10 mL) at room temperature. The reaction mixture is stirred at room temperature for 30 min, diluted with DCM (40 mL), washed with water, dried over Na2S04, and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane, 1 :2) resulting in a mixture of the title compound with its regioisomer 1 -(2-((3-chlorophenyl)amino)-7-methyl-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-yl)-2,2-dimethylpropan-1 -one (see Example 76).
[00224]Separation of the isomers is performed by column chromatography (silica gel, EtOAc/hexane). Combined samples of each isomer are triturated with DEE/hexane (1 : 1 ), washed with hexane and air-dried to provide the title compound (207 mg, 35%) as a white solid.
1H NMR (CDCIs), δΗ, 1 .33 (s, 9H), 1 .45 (d, 3H), 2.74-2.82 (m, 1 H), 2.90-3.01 (m, 1 H), 3.38 (t, 1 H), 4.38-4.50 (m, 1 H), 5.53-5.63 (m, 1 H), 6.99 (d, 1 H), 7.08 (d, 1 H), 7.23 (dd, 1 H), 7.39 (d, 1 H), 7.84 (s, 1 H), 8.23 (s, 1 H).
LC/MS (M+H)+ = 359, 361
Example 76
(rac)-1 -(2-((3-Chlorophenyl)amino)-7-methyl-7,8-dihydropyrido[4,3-d]pyrimidin- 6(5H)-yl)-2,2-dimethylpropan-1 -one [00225]After purification of the product mixture obtained during the synthesis of
Example 75 the title compound (78 mg, 13%) is separated as a white solid.
1H NMR (CDCI3), δΗ, 1 .24 (d, 3H), 1.34 (s, 9H), 2.63-2.68 (two s, 1 H), 3.10-3.15 (two d,
1 H), 4.1 1 -4.15 (two s, 1 H), 4.98 (m, 1 H), 5.16-5.20 (two s, 1 H), 6.99 (d, 1 H), 7.09 (s,
1 H), 7.22 (dd, 1 H), 7.39 (d, 1 H), 7.85 (s, 1 H), 8.23 (s, 1 H).
LC/MS (M+H)+ = 359, 361
Example 77
2-((3-Cyanophenyl)amino)-W,W-bis(2,2,2 rifluoroethyl)-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carboxamide
[00226]According to General Procedure 2a, 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin- 2-yl)amino)benzonitrile is reacted with bis(2,2,2-trifluoroethyl)carbamic chloride to provide the title compound (6%) as a colorless solid.
1H NMR (CDCI3), δΗ, 2.97 (t, 2H), 3.64 (t, 2H), 3.98 (q, 4H), 4.41 (s, 2H), 7.21 (s, 1 H), 7.29 (d, 1 H), 7.40 (t, 1 H), 7.64 (d, 1 H), 8.24 (s, 2H).
LC/MS (M+H)+ = 505
Example 78
Azetidin-1 -yl(2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)- yl)methanone
[00227]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine is reacted with azetidine-1 -carbonyl chloride to provide the title compound (54%) as a solid.
1H NMR (CDCI3), δΗ, 2.28 (m, 2H), 2.87 (t, 2H), 3.61 (t, 2H), 4.06 (t, 2H), 4.40 (s, 2H), 6.98 (d, 1 H), 7.00 (s, 1 H), 7.18 (t, 1 H), 7.39 (d, 1 H), 7.84 (s, 1 H), 8.19 (s, 1 H).
LC/MS (M+H)+ = 343, 345
Example 79
Methyl 2-(2-((3-chlorophenyl)amino)-yV-methyl-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidine-6-carboxamido)acetate [00228]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine is reacted with methyl 2- ((chlorocarbonyl)(methyl)amino)acetate to provide the title compound (10%) as a solid. 1H NMR (CDCI3), δΗ, 2.94 (t, 2H), 3.03 (s, 3H), 3.57 (t, 2H), 3.75 (s, 3H), 3.97 (s, 2H), 4.33 (s, 2H), 6.97 (d, 1 H), 7.17-7.21 (m, 2H), 7.38 (d, 1 H), 7.83 (s, 1 H), 8.18 (s, 1 H). LC/MS (M+H)+ = 389, 391
Example 80
W-(2-Cyanoethyl)-2-((3-cyanophenyl)amino)-W-methyl-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carboxamide
[00229]According to General Procedure 2a, 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin- 2-yl)amino)benzonitrile is reacted with (2-cyanoethyl)(methyl)carbamic chloride to provide the title compound (28%) as a colorless solid.
1H NMR (CDCI3), δΗ, 2.67 (m, 3H), 2.97-3.06 (m, 4H), 3.43-3.60 (m, 4H), 4.34 (s, 2H), 7.21 -7.30 (m, 2H), 7.39 (t, 1 H), 7.64 (d, 1 H), 8.22 (s, 2H).
LC/MS (M+H)+ = 362
Example 81
2-((3-Cyanophenyl)amino)-yV-(2-methoxyethyl)-yV-methyl-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carboxamide
[00230]According to General Procedure 2a, 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin- 2-yl)amino)benzonitrile is reacted with (2-methoxyethyl)(methyl)carbamic chloride to provide the title compound (53%) as a colorless solid.
1H NMR (CDCI3), δΗ, 2.94 (t, 2H), 2.98 (s, 3H), 3.35 (s, 3H), 3.43 (t, 2H), 3.51 -3.57 (m, 4H), 4.32 (s, 2H), 7.23 (d, 1 H), 7.29 (s, 1 H), 7.38 (t, 1 H), 7.63 (d, 1 H), 8.20 (s, 1 H), 8.25 (s, 1 H).
LC/MS (M+H)+ = 367 Example 82
2-(2-(p-Tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)nicotinonitrile [00231 ]ln close analogy to the procedure described in Example 27, /V-(p-tolyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine is reacted with 2-bromonicotinonitrile to provide the title compound (24%) as a colorless solid.
1H NMR (CDCI3), δΗ, 2.36 (s, 3H), 3.09 (t, 2H), 4.05 (t, 2H), 4.73 (s, 2H), 6.77-6.87 (m, 2H), 7.17-7.28 (m, 2H), 7.41 -7.48 (m, 2H), 7.82 (dd, 1 H), 8.24 (s, 1 H), 8.37 (m, 1 H). LC/MS (M+H)+ = 343
Example 83
2-((3-Cyanophenyl)amino)-W-methyl-W-propyl-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-carboxamide
[00232]According to General Procedure 2a, 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin- 2-yl)amino)benzonitrile is reacted with propyl(methyl)carbamic chloride to provide the title compound (79%) as a colorless solid.
1H NMR (CDCI3), δΗ, 0.89 (t, 3H), 1 .60 (m, 2H), 2.89 (s, 3H), 2.94 (t, 2H), 3.19 (t, 2H), 3.52 (t, 2H), 4.29 (s, 2H), 7.25-7.29 (m, 2H), 7.38 (t, 1 H), 7.64 (d, 1 H), 8.21 (s, 1 H), 8.25 (s, 1 H).
LC/MS (M+H)+ = 351 Example 84
6-(2-((3-Cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)- yl)picolinonitrile
[00233]ln close analogy to the procedure described in Example 27, 3-((5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile is reacted with 6- bromopicolinonitrile to provide the title compound (13%) as a colorless solid.
1H NMR (CDCI3), δΗ, 3.00 (t, 2H), 3.96 (t, 2H), 4.69 (s, 2H), 6.92 (d, 1 H), 7.04 (d, 1 H),
7.30 (s, 1 H), 7.40 (t, 1 H), 7.56-7.68 (m, 3H), 8.28 (s, 1 H), 8.31 (m, 1 H).
LC/MS (M+H)+ = 354 Example 85
2-(2-((3-Cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)- yl)isonicotinonitrile
[00234]ln close analogy to the procedure described in Example 27, 3-((5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile is reacted with 2- bromoisonicotinonitrile to provide the title compound (7%) as a colorless solid.
1H NMR (CDCI3), δΗ, 3.02 (t, 2H), 3.97 (t, 2H), 4.68 (s, 2H), 6.82 (d, 1 H), 6.90 (s, 1 H), 7.23 (s, 1 H), 7.29 (d, 1 H), 7.40 (t, 1 H), 7.65 (d, 1 H), 8.26 (s, 1 H), 8.32 (m, 2H).
LC/MS (M+H)+ = 354
Example 86
2-(2-((3-Cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-6- methylnicotinonitrile
[00235]ln close analogy to the procedure described in Example 27, 3-((5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile is reacted with 2-bromo-6- methylnicotinonitrile to provide the title compound (43%) as a colorless solid.
1H NMR (CDCI3), δΗ, 2.46 (s, 3H), 3.09 (t, 2H), 4.03 (t, 2H), 4.74 (s, 2H), 6.65 (d, 1 H), 7.26 (d, 1 H), 7.35 (t, 1 H), 7.40 (s, 1 H), 7.67 (m, 2H), 8.21 (s, 1 H), 8.27 (s, 1 H).
LC/MS (M+H)+ = 368
Example 87
Azetidin-1 -yl(2-(An-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)- yl)methanone
[00236]According to General Procedure 2a, /V-(m-tolyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2-amine is reacted with azetidine-1 -carbonyl chloride to provide the title compound (30%) as a colorless solid.
1H NMR (CDCI3), δΗ, 2.27 (m, 2H), 2.35 (s, 3H), 2.85 (t, 2H), 3.60 (t, 2H), 4.06 (t, 4H), 4.39 (s, 2H), 6.84 (d, 1 H), 6.99 (s, 1 H), 7.21 (t, 1 H), 7.37 (s, 1 H), 7.44 (d, 1 H), 8.16 (s, 1 H).
LC/MS (M+H)+ = 324 Example 88
W-Ethyl-W-methyl-2-(m olylamino)-7,8-dihydropyrido[4,3-d]pyrimidin
carboxamide
[00237]According to General Procedure 2a, /V-(m-tolyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2 -amine is reacted with ethyl(methyl)carbamic chloride to provide the title compound (25%) as a colorless solid.
1H NMR (CDCI3), δΗ, 1 .17 (t, 3H), 2.35 (s, 3H), 2.87 (s, 3H), 2.91 (t, 2H), 3.26 (q, 2H), 3.51 (t, 2H), 4.27 (s, 2H), 6.84 (d, 1 H), 7.00 (s, 1 H), 7.21 (t, 1 H), 7.38 (s, 1 H), 7.45 (d, 1 H), 8.16 (s, 1 H).
LC/MS (M+H)+ = 326
Example 89
W-Methyl-W-propyl-2-(m olylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)- carboxamide
[00238]According to General Procedure 2a, /V-(m-tolyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2 -amine is reacted with propyl(methyl)carbamic chloride to provide the title compound (26%) as a colorless solid.
1H NMR (CDCI3), δΗ, 0.89 (t, 3H), 1 .59 (m, 2H), 2.35 (s, 3H), 2.88 (s, 3H), 2.91 (t, 2H), 3.18 (t, 2H), 3.50 (t, 2H), 4.26 (s, 2H), 6.84 (d, 1 H), 7.16 (s, 1 H), 7.20 (t, 1 H), 7.38 (s, 1 H), 7.45 (d, 1 H), 8.16 (s, 1 H).
LC/MS (M+H)+ = 340
Example 90
2-((3-Chlorophenyl)amino)-yV-methyl-yV-propyl-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-carboxamide
[00239]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine is reacted with propyl(methyl)carbamic chloride to provide the title compound (62%) as a solid. 1H NMR (CDCI3), δΗ, 1 .16 (t, 3H), 1 .60 (m, 2H), 2.89 (s, 3H), 2.93 (t, 2H), 3.26 (t, 2H) 3.51 (t, 2H), 4.27 (s, 2H), 6.96 (d, 1 H), 7.1 1 (s, 1 H), 7.22 (t, 1 H), 7.37 (d, 1 H), 7.85 (s, 1 H), 8.19 (s, 1 H).
LC/MS (M+H)+ = 359, 361
Example 91
2- ((3-Chlorophenyl)amino)-W-ethyl-W-methyl-7,8-dihydropyrido[4,3-d]pyrimi 6(5H)-carboxamide
[00240]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine is reacted with ethyl(methyl)carbamic chloride to provide the title compound (52%) as a solid.
1H NMR (CDCI3), δΗ, 1 .16 (t, 3H), 2.86 (s, 3H), 2.91 (t, 2H), 3.24 (q, 2H) 3.52 (t, 2H), 4.28 (s, 2H), 6.96 (d, 1 H), 7.1 1 (s, 1 H), 7.21 (t, 1 H), 7.37 (d, 1 H), 7.84 (s, 1 H), 8.18 (s, 1 H).
LC/MS (M+H)+ = 345, 347 Example 92
3- ((6-(1 -lsopropyl-1H-imidazol-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2- yl)amino)benzonitrile
[00241 ]ln close analogy to the procedure given in Example 49, 3-((5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile is reacted with isopropyhsothiocyanate and further converted to the title compound in 19% overall yield. 1H NMR (CDCI3), δΗ, 1 .40 (d, 6H), 3.02 (t, 2H), 3.36 (t, 2H), 4.20 (s, 2H), 4.48 (m, 1 H), 6.79 (s, 1 H), 6.87 (s, 1 H), 7.27-7.40 (m, 3H), 7.64 (d, 1 H), 8.18 (s, 1 H), 8.26 (s, 1 H). LC/MS (M+H)+ = 360
Example 93
3-((6-(3-Methyloxetane-3-carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2- yl)amino)benzonitrile [00242]According to General Procedure 2a, 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin- 2-yl)amino)benzonitrile is reacted with 3-methyloxetane-3-carbonyl chloride to provide the title compound (16%) as a colorless solid.
1H NMR (CDCI3), δΗ, 1 .65 and 1 .73 (both s, 3H), 2.92 (t, 2H), 3.35 (t, 1 H), 3.93 and 4.1 1 (both m, 1 H), 4.42 (d, 2H), 4.68 (s, 1 H), 5.03 (d, 2H), 7.21 -7.44 (m, 3H), 7.62 (d, 1 H), 8.18 (s, 1 H), 8.26 (s, 1 H).
LC/MS (M+H)+ = 350
Example 94
(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(3- methyloxetan-3-yl)methanone
[00243]According to General Procedure 2a, /V-(3-chlorophenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2 -amine is reacted with 3-methyloxetane-3-carbonyl chloride to provide the title compound (19%) as a solid.
1H NMR (CDCI3), δΗ, 1 .56 and 1 .65 (both s, 3H), 2.90 (t, 2H), 3.34 (t, 1 H), 4.09 and 4.41 (both m, 1 H), 4.67 (d, 2H), 4.67 (s, 1 H), 5.03 (d, 2H), 7.00 (d, 1 H), 7.09 (s, 1 H), 7.21 (t, 1 H), 7.37 (d, 1 H), 7.85 (s, 1 H), 8.26 (s, 1 H).
LC/MS (M+H)+ = 358, 360
Example 95
(3-Methyloxetan-3-yl)(2-(An-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)- yl)methanone
[00244]According to General Procedure 2a, /V-( 7?-tolyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2 -amine is reacted with 3-methyloxetane-3-carbonyl chloride to provide the title compound (59%) as a colorless solid.
1H NMR (CDCI3), δΗ, 1 .63 and 1 .71 (both s, 3H), 2.34 (s, 3H), 2.83 (t, 2H), 3.29 (t, 1 H), 3.89 and 4.05 (both m, 1 H), 4.39 (d, 2H), 4.63 (s, 1 H), 5.01 (d, 2H) 6.85 (d, 1 H), 7.20 (t, 1 H), 7.36 (s, 2H), 7.44 (d, 1 H), 8.20 (s, 1 H).
LC/MS (M+H)+ = 339 Table 1
Figure imgf000092_0001
Figure imgf000092_0002
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
EXAMPLES OF REPRESENTATIVE PHARMACEUTICAL COMPOSITIONS
[00245]ln combination with commonly used solvents, excipients, auxiliary agents and carriers, the instant compounds may be processed into tablets, coated tablets, capsules, drip solutions, suppositories, injection and infusion preparations, and the like and may be therapeutically applied by the oral, rectal, parenteral, and additional routes. Representative pharmaceutical compositions according to the present invention follow:
(a) Tablets suitable for oral administration which contain the active ingredient, may be prepared by conventional tabletting techniques.
(b) For suppositories, any usual suppository base may be employed for incorporation thereinto by usual procedure of the active ingredient, such as a polyethyleneglycol which is a solid at room temperature but which melts at or about body temperature.
(c) For parenteral (including intravenous and subcutaneous) sterile solutions, the active ingredient together with conventional ingredients in usual amounts are employed, such as for example sodium chloride and double-distilled water q.s., according to conventional procedure, such as filtration, aseptic filling into ampoules or IV-drip bottles, and autoclaving for sterility.
[00246]Other suitable pharmaceutical compositions will be immediately apparent to one skilled in the art.
FORMULATION EXAMPLES
[00247]The following examples are again given by way of illustration only and are not to be construed as limiting.
EXAMPLE 1
Tablet Formulation
A suitable formulation for a tablet containing 10 milligrams of active ingredient is as follows: mg
Active Ingredient 10
Lactose 61
Microcrystalline Cellulose 25
Talcum 2
Magnesium stearate
Colloidal silicon dioxide EXAMPLE 2
Tablet Formulation
Another suitable formulation for a tablet containing 100 mg is as follows:
mg
Active Ingredient 100
Polyvinylpyrrolidone, crosslinked 10
Potato starch 20
Polyvinylpyrrolidone 19
Magnesium stearate 1
Microcrystalline Cellulose 50 Film coated and colored. The film coating material consists of:
Hypromellose 10
Microcryst. Cellulose 5
Talcum 5
Polyethylene glycol 2
Color pigments 5
EXAMPLE 3
Capsule Formulation A suitable formulation for a capsule containing 50 milligrams of active ingredient is as follows:
mg
Active Ingredient Corn starch
Dibasic calcium phosphate Talcum
Colloidal silicon dioxide
filled in a gelatin capsule.
EXAMPLE 4
Solution for injection
A suitable formulation for an injectable solution is as follows:
Active Ingredient mg 10
Sodium chloride mg q.s.
Water for Injection mL add 1 .0
EXAMPLE 5
Liquid oral formulation
A suitable formulation for 1 liter of a an oral solution containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows: mg
Active Ingredient
Saccharose 250
Glucose 300
Sorbitol 150
Orange flavor 10
Colorant
Purified water
EXAMPLE 6
Liquid oral formulation
Another suitable formulation for 1 liter of a liquid mixture containing 20 milligrams of active ingredient in one milliliter of the mixture is as follows:
G
Active Ingredient 20.00
Tragacanth 7.00
Glycerol 50.00
Saccharose 400.00
Methylparaben 0.50 Propylparaben 0.05 Black currant-flavor 10.00 Soluble Red color 0.02 Purified water add 1000 mL
EXAMPLE 7
Liquid oral formulation
Another suitable formulation for 1 liter of a liquid mixture containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows:
G
Active Ingredient 2 Saccharose 400
Bitter orange peel tincture 20 Sweet orange peel tincture 15 Purified water add 1000 mL
EXAMPLE 8
Aerosol formulation
180 g aerosol solution contain:
G
Active Ingredient 10 Oleic acid Ethanol Purified Water Tetrafluoroethane
15 ml of the solution are filled into aluminum aerosol cans, capped with a dosing valve, purged with 3.0 bar.
EXAMPLE 9
TDS formulation
100 g solution contain
G
Active Ingredient 10.0
Ethanol 57.5
Propyleneglycol 7.5
Dimethylsulfoxide 5.0
Hydroxyethylcellulose 0.4
Purified water 19.6
1.8 ml of the solution are placed on a fleece covered by an adhesive backing foil. The system is closed by a protective liner which will be removed before use. EXAMPLE 10
Nanoparticle formulation
10 g of polybutylcyanoacrylate nanoparticles contain:
G
Active Ingredient 1 .00
Poloxamer 0.10
Butylcyanoacrylate 8.75
Mannitol 0.10
Sodium chloride 0.05
Polybutylcyanoacrylate nanoparticles are prepared by emulsion polymerization in a water/0.1 N HCI/ethanol mixture as polymerizsation medium. The nanoparticles in the suspension are finally lyophilized under vacuum.
EXAMPLE 11
Suspension formulation
1.0 g of the suspension contains the following:
9
Active Ingredient 0.10
Hypromellose 0.01
Purified water Ad 1 .0 g
Hypromellose is dispersed in water homogeneously with a high speed mixer/blender. After about one hour of hydration time of the hypromellose, the active ingredient is blended homogeneously into the hypromellose solution. The viscosity of the suspension may be adjusted by the amount of hypromellose, resulting in a very stable suspension with a very slow tendency of particle sedimentation and particle agglomeration.
EXAMPLE 12
Solution for Injection
1.0 ml of solution contain:
9
Active Ingredient 0.05
Mannitol q.s.
DMSO 0.10
Water for injection Ad 1 .0 ml
The active ingredient is dissolved in DMSO by stirring and heating (solution 1 ). The mannitol is dissolved in WFI (solution 2). After cooling down to room temperature solution 1 is mixed with solution 2 by continuous stirring. The solution is sterilized by filtration of by autoclaving.
PHARMACOLOGY
[00248]The active principles of the present invention, and pharmaceutical compositions containing them and method of treating therewith, are characterized by unique and advantageous properties. The compounds and pharmaceutical compositions thereof exhibit, in standard accepted reliable test procedures, the following valuable properties and characteristics.
METHODS
BINDING ASSAYS FOR THE CHARACTERIZATION OF mGluR5 ANTAGONIST PROPERTIES
ΡΗ]ΜΡΕΡ (2-methyl-6-(phenylethynyl)pyridine) binding to transmembrane allosteric modulatory sites of mGluR5 receptors in cortical membranes Preparation of rat cortical membranes:
[00249]Male Sprague-Dawley rats (200-250 g) are decapitated and their brains are removed rapidly. The cortex is dissected and homogenized in 20 volumes of ice-cold 0.32 M sucrose using a glass-Teflon homogenizer. The homogenate is centrifuged at 1 ,000 x g for 10 minutes. The pellet is discarded and the supernatant centrifuged at 20,000 x g for 20 minutes. The resulting pellet is re-suspended in 20 volumes of distilled water and centrifuged for 20 minutes at 8,000 x g. Then the supernatant and the buffy coat are centrifuged at 48,000 x g for 20 minutes in the presence of 50 m M Tris-HCI, pH 8.0. The pellet is then re-suspended and centrifuged two to three more times at 48,000 x g for 20 minutes in the presence of 50 mM Tris-HCI, pH 8.0. All centrifugation steps are carried out at 4 °C. After resuspension in 5 volumes of 50 m M Tris-HCI, pH 8.0, the membrane suspension is frozen rapidly at -80 °C.
[00250]On the day of assay the membrane suspensions are thawed and washed four times by resuspension in 50 mM Tris-HCI, pH 8.0, and centrifugation at 48,000 x g for 20 minutes and finally re-suspended in 50 mM Tris-HCI, pH 7.4. The amount of protein in the final membrane preparation (500-700 pg/ml) is determined according to the method of Lowry (Lowry O. H. et al. 1951 . J. Biol. Chem. 193, 256-275).
[Ή]ΜΡΕΡ Assay
[00251 ]lncubations are started by adding [3H]-MPEP (50.2 Ci/mmol, 5 nM, Tocris, GB) to vials with 125-250 g protein (total volume 0.25 ml) and various concentrations of the agents. Alternatively, assays are performed with [3H]-MMPEP (2-(3- methoxyphenylethynyl)-6-methylpyridine hydrochloride) as radioligand. The incubations are continued at room temperature for 60 minutes (equilibrium is achieved under the conditions used). Non-specific binding is defined by the addition of unlabeled MPEP (10 μΜ). Incubations are terminated using a Millipore filter system. The samples are rinsed twice with 4 ml of ice-cold assay buffer over glass fibre filters (Schleicher & Schuell, Germany) under a constant vacuum. Following separation and rinse, the filters are placed into scintillation liquid (5 ml Ultima Gold, Perkin Elmer, Germany) and radioactivity retained on the filters is determined with a conventional liquid scintillation counter (Canberra Packard, Germany). Characterization
[00252]Specific binding is extremely high i.e. normally > 85% and essentially independent of buffer (Tris or HEPES both 50 rriM) and pH (6.8-8.9). There is a clear saturable protein dependence and the chosen protein concentration used for subsequent assays (500-700 pg/ml) is within the linear portion of this dependence. Cold MPEP displaces hot ligand with an IC5o of 1 1 .2 ± 0.64 nM. The Kd of [3H]-MPEP of 13.6 nM is determined by Scatchard analysis and used according to the Cheng Prussoff relationship to calculate the affinity of displacers as Kd values (IC50 of cold MPEP equates to a Kj of 8.2 nM). Bmax is 0.56 pm / mg protein.
FUNCTIONAL ASSAY OF mGluR5 RECEPTORS
Cytosolic Calcium studies with stably transfected cells
[00253]Chinese hamster ovary cells (CHO-K1 cells), stably transfected for inducible expression of a human metabotropic glutamate receptor mGluR5, are seeded into black clear bottom 96 well plates at a density of 35.000 cells per well. The standard growth medium used (Dulbecco's modified Eagle Medium, DMEM plus L-proline) contains the appropriate inducer isopropyl-p-D-thiogalactopyranosid (IPTG) to achieve optimal receptor expression. One day after seeding the growth medium is exchanged for reconstituted Ca-Kit (Molecular Devices, USA) and incubated for one hour. Ca-Kit is reconstituted in an assay buffer containing 20 rriM HEPES pH 7.4, glutamic-pyruvate transaminase, pyridoxal phosphate and sodium pyruvate in Hank's balanced salt solution (HBBS). Agonistic compounds to the receptor elicit increases in cytosolic calcium which can be measured as increases in fluorescence signals by use of a fluorescence imaging plate reader (Molecular Devices). To analyze their potency to modulate the Ca-response test compounds, dissolved in a final DMSO concentration of 0.5%, are added on-line 5 minutes before the agonist to the receptor (L-quisqualic acid at a concentration giving ~80% of the maximal signal).
Astrocyte culture
[00254]Primary astrocyte cultures are prepared from cortices of newborn rats as described by Booher and Sensenbrenner (1972, Neurobiology 2(3):97-105). Briefly, Sprague-Dawley rat pups (2 - 4 d old) are decapitated and neocortices are dissected, disintegrated with a nylon filter (pore size 80 m) and carefully triturated. The cell suspension is plated on poly-D-lysine pre-coated flasks (Costar, Netherlands) and cultivated in Dulbecco's Modified Eagle's Medium (DMEM, Invitrogen, Germany) supplemented with 10% foetal calf serum (FCS, Sigma, Germany), 4 rri M glutamine and 50 pg/ml gentamycin (both Biochrom, Germany) at 37 °C in a humidified atmosphere of 5% CO2 95% air for 7 days with exchanging the medium at day 2 and 6.
[00255]After 7 days in vitro (DIV), cells are shaken overnight at 250 rpm to remove oligodendrocytes and microglia. The next day, astrocytes are rinsed twice with CMF- PBS (calcium- and magnesium-free phosphate buffered saline, Biochrom, Germany), trypsinized and subplated on poly-D-lysine pre-coated 96-well plates (Greiner, Germany) at a density of 40,000 cells/well. 24 h after establishing the secondary culture the astrocytes are rinsed with PBS++ (phosphate buffered saline, Biochrom, Germany) and fed with astrocyte-defined medium (ADM) consisting of DMEM containing 1x G5- supplement (Invitrogen, Germany), 0.5 pg/ml heparan sulfate, and 1 .5 pg/ml fibronectin (both Sigma, Germany) (Miller et al., (1993) Brain Res. 618(1 ): 175-8). 3 days later the medium is exchanged and the cells incubated for another 2-3 days, so that at the time of experiments astrocytes are 14-15 DIV.
Immunocytochemistry
[00256]lmmunostaining is performed to confirm the presence of astrocytic markers such as the glial fibrillary acidic protein (GFAP) as well as to monitor the expression of mGluR5 receptors.
Cytosolic Calcium studies with astrocytes
[00257]The increase of cytosolic calcium after stimulation with the mGluR5 agonist L- quisqualate is measured using a fluorometric imaging plate reader (FLIPR) and the Ca- Kit (both Molecular Devices). Prior to addition of agonist or antagonist the medium is aspirated and cells are loaded for 2 h at RT with 150 μΙ of loading buffer consisting of Ca-sensitive dye reconstituted in sodium chloride (123 rri M), potassium chloride (5.4 rriM), magnesium chloride (0.8 rri M), calcium chloride (1.8 rri M), D-glucose (15 rri M), and HEPES (20 m M), pH 7.3. Subsequently, plates are transferred to FLIPR to detect calcium increase with the addition of L-quisqualate (100 ηινι) measured as relative fluorescence units (RFU). If antagonists are tested, these compounds are pre-incubated for 10 minutes at RT before addition of the respective agonist.
[00258]For positive modulators, concentration-response curves for quisqualate are performed in the presence and absence of 10 μΜ modulator to determine the extent of potentiation / agonist potency increase. Thereafter, concentration-response curves for the positive modulator are performed in the presence of a fixed concentration of quisqualate showing the biggest window for potentiation (normally 10-30 nM).
Data analysis
[00259]The fluorescence signal increase after addition of agonist reflects the increase of cytosolic calcium. Inconsistencies in the amount of cells per well are normalised by using the spatial uniformity correction of the FLIPR operating software Screenworks. The mean of replicated temporal data (n=3-5) is calculated and used for graphical representation. For the evaluation of the pharmacology, the calcium changes in response to different concentrations of agonist or antagonist are determined using a maximum minus minimum (MaxMin) calculation.
[00260]AII responses (RFU-values) are determined as percentage of control (= maximum response). EC50 and IC50 are calculated according the logistic equation using GraFit 5.0 (Erithacus Software, GB) or Prism 4.0 (GraphPad Software, USA). The compounds of the present invention have a potency (IC50) within a range of about 0.5 nM to about 100 μΜ.
[00261 ]Results for representative compounds of the invention are shown in Table A1 . Table A1
Human Rat (rpA) mGluR5 mGluR5
Compound Chemical Name IC50 [μΜ] IC50 [μΜ]
2-((3-Chlorophenyl)amino)-7,8-
Example 1 dihydropyrido[4,3-d]pyrimidin-5(6/-/)-one 4.9 (est.) n.d.
(rac)-(2-((3-Chlorophenyl)amino)-5, 6,7,8- tetrahydroquinazolin-6-yl)(piperidin-1-
Example 2 yl)methanone 1.47 n.d.
1-(2-((3-Fluorophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-yl)-2-
Example 3 methylpropan-1-one 2.71 n.d.
1-(2-((3-Chlorophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-yl)-2-
Example 4 methylpropan-1-one 0.186 n.d.
2-Methyl-1-(2-(m-tolylamino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-
Example 5 yl)propan-1-one 0.803 n.d.
(2-((3-Chlorophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-
Example 6 yl)(cyclopropyl)methanone 2.19 n.d.
1-(2-((4-Fluorophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-yl)-2,2-
Example 7 dimethylpropan-1-one 9.07 n.d.
1-(2-((3-Chlorophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-yl)-2,2-
Example 8 dimethylpropan-1-one 0.119 0.0295
3-((6-Pivaloyl-5,6,7,8-tetrahydropyrido[4,3-
Example 9 d]pyrimidin-2-yl)amino)benzonitrile 0.0736 0.0524
(rac)-1-(2-((3-Chlorophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-
Example 10 methylbutan-1-one 0.170 n.d.
(2-((3-Chlorophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-
Example 1 1 yl)(cyclobutyl)methanone 1.41 n.d.
1-(2-((3-Chlorophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-yl)-2-
Example 12 ethylbutan-1-one 0.455 n.d.
(2-((3-Fluorophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-
Example 13 yl)(phenyl)methanone 7.5 (est.) n.d. (2-((3-Chlorophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-
Example 14 yl)(phenyl)methanone 3.72 n.d.
Methyl 2-((3-chlorophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidine-6(5/-/)-
Example 15 carboxylate 0.917 n.d.
Ethyl 2-((3-chlorophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidine-6(5/-/)-
Example 16 carboxylate 0.792 n.d.
Isopropyl 2-((3-chlorophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidine-6(5/-/)-
Example 17 carboxylate 0.839 n.d.
te/f-Butyl 2-((3-fluorophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidine-6(5/-/)-
Example 18 carboxylate 4.60 n.d.
te/f-Butyl 2-((3-chlorophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidine-6(5/-/)-
Example 19 carboxylate 2.06 n.d.
terf- Butyl 2-(m-tolylamino)-7,8- dihydropyrido[4,3-d]pyrimidine-6(5/-/)-
Example 20 carboxylate 1.23 n.d.
fe/f-Butyl 2-((3-cyanophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidine-6(5/-/)-
Example 21 carboxylate 0.946 1.37
2-((3-Chlorophenyl)amino)-/V-ethyl-7,8- dihydropyrido[4,3-d]pyrimidine-6(5/-/)-
Example 22 carboxamide 3.92 n.d.
2-((3-Chlorophenyl)amino)-/V,/\/-dimethyl- 7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)-
Example 23 carboxamide 0.0496 0.0320
A/-(3-Chlorophenyl)-6-(isopropylsulfonyl)-
5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-
Example 24 amine 1.59 n.d.
A/-(3-Chlorophenyl)-6-(cyclopropylsulfonyl)-
5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-
Example 25 amine 8.4 (est.) n.d.
2-((3-Chlorophenyl)amino)-/V,/\/-dimethyl- 7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)-
Example 26 sulfonamide 1.95 n.d.
A/-(3-Chlorophenyl)-6-(pyridin-2-yl)-5, 6,7,8-
Example 27 tetrahydropyrido[4,3-d]pyrimidin-2-amine 1.98 n.d.
6-(1-(te f-Butyl)-1 H-tetrazol-5-yl)-A/-(3- chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-
Example 28 d]pyrimidin-2-amine 3.35 n.d. A/-(3-Chlorophenyl)-6-( 1 -isopropyl- 1 H- tetrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-
Example 29 d]pyrimidin-2-amine 0.638 n.d.
2-((3-Cyanophenyl)amino)-A/,A/-dimethyl- 7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-
Example 30 carboxamide 0.105 0.1 18
2-((3-Chlorophenyl)amino)-/V,/V-diethyl-7,8- dihydropyrido[4,3-d]pyrimidine-6(5/-/)-
Example 31 carboxamide 0.0544 0.275
2-((3-Cyanophenyl)amino)-A/,A/-diethyl-7,8- dihydropyrido[4,3-d]pyrimidine-6(5/-/)-
Example 32 carboxamide 0.0580 0.0433
(rac)-3-((6-(2-Methylbutanoyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2-
Example 33 yl)amino)benzonitrile 0.606 n.d.
(rac)-2-((3-Chlorophenyl)amino)-/\/,/\/- dimethyl-5,6,7,8-tetrahydroquinazoline-6-
Example 34 carboxamide 0.196 n.d.
2-((3-Chlorophenyl)amino)-A/,A/-diethyl-
5,6,7,8-tetrahydroquinazoline-6-
Example 35 carboxamide 0.277 n.d.
2-((3-Chlorophenyl)amino)-/V,/\/-dimethyl- 7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)-
Example 36 carbothioamide 0.0808 n.d.
(rac)-1-(2-((3-Chlorophenyl)amino)-5,6,7,8- tetrahydroquinazolin-6-yl)-2-methylpropan-
Example 37 1-one 0.168 n.d.
2-(2-((3-Chlorophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-
Example 38 yl)nicotinonitrile 0.234 n.d.
(2-((3-Chlorophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-
Example 39 yl)(pyrrolidin-1-yl)methanone 0.141 0.142
2-((3-Cyanophenyl)amino)-/V,/\/-diisopropyl-
7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)-
Example 40 carboxamide 8.83 n.d.
3-((6-(2-Methoxy-2-methylpropanoyl)-
5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-
Example 41 yl)amino)benzonitrile 0.376 n.d.
3-((6-(Morpholine-4-carbonyl)-5, 6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2-
Example 42 yl)amino)benzonitrile 1.36 n.d.
A/-(3-Chlorophenyl)-6-(pyrimidin-2-yl)-
5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-
Example 43 amine 0.915 n.d. (2-((3-Chlorophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-
Example 44 yl)(furan-2-yl)methanone 0.663 n.d.
(2-((3-Chlorophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-
Example 45 yl)(thiazol-2-yl)methanone 4.62 n.d.
(2-((3-Chlorophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-
Example 46 yl)(thiazol-5-yl)methanone 4.35 n.d.
2-((5-Chloropyridin-3-yl)amino)-/V,/\/- dimethyl-7,8-dihydropyrido[4,3-d]pyrimidine-
Example 47 6(5/-/)-carboxamide 6.01 n.d.
A/-(3-Chlorophenyl)-6-(1-methyl-1 H-tetrazol-
5-yl)-5,6,7,8-tetrahydropyrido[4,3-
Example 48 d]pyrimidin-2-amine 4.62 n.d.
A/-(3-Chlorophenyl)-6-(1-methyl-1 H- imidazol-2-yl)-5,6,7,8-tetrahydropyrido[4,3-
Example 49 d]pyrimidin-2-amine 0.313 n.d.
3-((6-(2-Ethylbutanoyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2-
Example 50 yl)amino)benzonitrile 0.914 n.d.
A/-Butyl-2-((3-cyanophenyl)amino)-/\/- methyl-7,8-dihydropyrido[4,3-d]pyrimidine-
Example 51 6(5/-/)-carboxamide 0.835 n.d.
2-((3-Cyanophenyl)amino)-/V-cyclopropyl-/\/- methyl-7,8-dihydropyrido[4,3-d]pyrimidine-
Example 52 6(5/-/)-carboxamide 0.207 n.d.
2-((3-Chlorophenyl)amino)-/V-ethyl-/\/- propyl-7,8-dihydropyrido[4,3-d]pyrimidine-
Example 53 6(5/-0-carboxamide 0.266 n.d.
A/,/\/-Dimethyl-2-((6-methylpyridin-2- yl)amino)-7,8-dihydropyrido[4,3-
Example 54 d]pyrimidine-6(5 i -carboxamide 0.608 n.d.
(rac)-3-((6-(2-Ethylpyrrolidine-1-carbonyl)- 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-
Example 55 yl)amino)benzonitrile 0.858 n.d.
A/-(Cyanomethyl)-2-((3- cyanophenyl)amino)-/V-methyl-7,8- dihydropyrido[4,3-d]pyrimidine-6(5/-/)-
Example 56 carboxamide 0.227 n.d.
3-((6-(1-Methylcyclopropanecarbonyl)-
5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-
Example 57 yl)amino)benzonitrile 0.231 n.d.
3-((6-(2-Methylcyclopropanecarbonyl)-
5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-
Example 58 yl)amino)benzonitrile 0.875 n.d. 2,2-Dimethyl-1-(2-((6-methylpyridin-2- yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-
Example 59 6(5H)-yl) propan- 1 -one 0.229 n.d.
3-((6-(2-Hydroxy-2-methylpropanoyl)-
5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-
Example 60 yl)amino)benzonitrile 3.89 n.d.
A/,A/-Diethyl-2-(m-tolylamino)-7,8- dihydropyrido[4,3-d]pyrimidine-6(5/-/)-
Example 61 carboxamide 0.0443 0.0288
2-((3-Cyanophenyl)amino)-/V-isopropyl-/\/- methyl-7,8-dihydropyrido[4,3-d]pyrimidine-
Example 62 6(5/-/)-carboxamide 0.113 0.060
2-((3-Cyanophenyl)amino)-/V-ethyl-/\/- methyl-7,8-dihydropyrido[4,3-d]pyrimidine-
Example 63 6(5/-/)-carboxamide 0.0694 0.0410
2-((3-Chlorophenyl)amino)-/V- (cyclopropylmethyl)-/V-methyl-7,8- dihydropyrido[4,3-d]pyrimidine-6(5/-/)-
Example 64 carboxamide 0.157 n.d.
A/,A/-Dimethyl-2-(m-tolylamino)-7,8- dihydropyrido[4,3-d]pyrimidine-6(5/-/)-
Example 65 carboxamide 0.0645 0.0473
2-((3-Chlorophenyl)amino)-/V-cyclopropyl-/\/- ethyl-7,8-dihydropyrido[4,3-d]pyrimidine-
Example 66 6(5/-/)-carboxamide 0.155 n.d.
Pyrrolidin-1-yl(2-(m-tolylamino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-
Example 67 yl)methanone 0.364 n.d.
(2-((3-Chlorophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-yl)(1-
Example 68 methylcyclopropyl)methanone 0.149 n.d.
(1-Methylcyclopropyl)(2-(m-tolylamino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-
Example 69 yl)methanone 0.242 n.d.
A/-Ethyl-A/-propyl-2-(m-tolylamino)-7,8- dihydropyrido[4,3-d]pyrimidine-6(5/-/)-
Example 70 carboxamide 0.0542 0.0283
(rac)-3-((6-(3-Methylpyrrolidine-1-carbonyl)-
5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-
Example 71 yl)amino)benzonitrile 0.493 n.d.
(rac)-3-((6-(2-Methylpyrrolidine-1-carbonyl)-
5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-
Example 72 yl)amino)benzonitrile 0.341 n.d.
3-((6-(3,3-Dimethylazetidine-1-carbonyl)-
5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-
Example 73 yl)amino)benzonitrile 0.608 n.d. 2-((3-Cyanophenyl)amino)-/V-ethyl-/\/- propyl-7,8-dihydropyrido[4,3-d]pyrimidine-
Example 74 6(5/-/)-carboxamide 0.0536 0.0349
(rac)-1-(2-((3-Chlorophenyl)amino)-5- methyl-7,8-dihydropyrido[4,3-d]pyrimidin-
Example 75 6(5/-/)-yl)-2,2-dimethylpropan-1-one 0.572 n.d.
(rac)-1-(2-((3-Chlorophenyl)amino)-7- methyl-7,8-dihydropyrido[4,3-d]pyrimidin-
Example 76 6(5/-/)-yl)-2,2-dimethylpropan-1-one 0.595 n.d.
2-((3-Cyanophenyl)amino)-/V,/\/-bis(2,2,2- trifluoroethyl)-7,8-dihydropyrido[4,3-
Example 77 d]pyrimidine-6(5/-/)-carboxamide 0.124 n.d.
Azetidin-1-yl(2-((3-chlorophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-
Example 78 yl)methanone 0.135 0.122
Methyl 2-(2-((3-chlorophenyl)amino)-/V- methyl-5,6,7,8-tetrahydropyrido[4,3-
Example 79 d]pyrimidine-6-carboxamido)acetate 0.350 n.d.
A/-(2-Cyanoethyl)-2-((3- cyanophenyl)amino)-/V-methyl-7,8- dihydropyrido[4,3-d]pyrimidine-6(5/-/)-
Example 80 carboxamide 1.52 n.d.
2-((3-Cyanophenyl)amino)-/V-(2- methoxyethyl)-/V-methyl-7,8- dihydropyrido[4,3-d]pyrimidine-6(5/-/)-
Example 81 carboxamide 0.700 n.d.
2-(2-(p-Tolylamino)-7,8-dihydropyrido[4,3-
Example 82 d]pyrimidin-6(5/-/)-yl)nicotinonitrile 0.130 n.d.
2-((3-Cyanophenyl)amino)-/V-methyl-/\/- propyl-7,8-dihydropyrido[4,3-d]pyrimidine-
Example 83 6(5/-/)-carboxamide 0.0930 0.0520
6-(2-((3-Cyanophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-
Example 84 yl)picolinonitrile 4.39 n.d.
2-(2-((3-Cyanophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-
Example 85 yl)isonicotinonitrile 4.22 n.d.
2-(2-((3-Cyanophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-yl)-6-
Example 86 methylnicotinonitrile 3.17 n.d.
Azetidin-1-yl(2-(m-tolylamino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-
Example 87 yl)methanone 0.555 n.d.
A/-Ethyl-/\/-methyl-2-(m-tolylamino)-7,8- dihydropyrido[4,3-d]pyrimidine-6(5/-/)-
Example 88 carboxamide 0.0434 0.0364 A/-Methyl-A/-propyl-2-(m-tolylamino)-7,8- dihydropyrido[4,3-d]pyrimidine-6(5/-/)-
Example 89 carboxamide 0.0625 n.d.
2-((3-Chlorophenyl)amino)-/V-methyl-/\/- propyl-7,8-dihydropyrido[4,3-d]pyrimidine-
Example 90 6(5/-/)-carboxamide 0.0930 n.d.
2-((3-Chlorophenyl)amino)-/V-ethyl-/\/- methyl-7,8-dihydropyrido[4,3-d]pyrimidine-
Example 91 6(5/-/)-carboxamide 0.0533 n.d.
3-((6-(1-lsopropyl-1/-/-imidazol-2-yl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2-
Example 92 yl)amino)benzonitrile 1.03 n.d.
3-((6-(3-Methyloxetane-3-carbonyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2-
Example 93 yl)amino)benzonitrile 4.0 (est.) n.d.
(2-((3-Chlorophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-yl)(3-
Example 94 methyloxetan-3-yl)methanone 1.10 n.d.
(3-Methyloxetan-3-yl)(2-(m-tolylamino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5/-/)-
Example 95 yl)methanone 1.33 n.d.
Human mGluR5 values were obtained with CHO-cells stably expressing human mGluR5: IC50 values below 500 nM were determined in at least independent triplicates. Estimated values (est.) rely on one single point experiment performed in quadruplicate. rpA data were generated with rat primary astrocytes.
[00262] In conclusion, from the foregoing, it is apparent that the present invention provides novel and valuable applications and uses of the compounds of the present invention, which compounds comprise the active principle according to the present invention, as well as novel pharmaceutical compositions thereof and methods of preparation thereof and of treating therewith.
[00263]The high order of activity of the active agent of the present invention and compositions thereof, as evidenced by the tests reported, is indicative of utility based on its valuable activity in human beings as well as in lower animals. Clinical evaluation in human beings has not been completed. It will be clearly understood that the distribution and marketing of any compound or composition falling within the scope of the present invention for use in human beings will of course have to be predicated upon prior approval by governmental agencies which are responsible for and authorized to pass judgment on such questions. [00264]The instant compounds of Formula I represent a novel class of mGluR5 modulators. In view of their potency, they will be useful therapeutics in a wide range of disorders, in particular CNS disorders, which involve excessive glutamate induced excitation.
[00265]These compounds accordingly find application in the treatment of the disorders of a living animal body, especially a human, as listed earlier in the description.
[00266]These compounds also find application in the treatment of indications in a living animal body, especially a human, wherein a particular condition does not necessarily exist but wherein a particular physiological parameter may be improved through administration of the instant compounds, including cognitive enhancement.
[00267] Neuroprotection as well as cognitive enhancement may also be achieved by administration of the instant compounds in combination with a NMDA receptor antagonist like Memantine.
[00268]The method-of-treating a living animal body with a compound of the invention, for the inhibition of progression or alleviation of the selected ailment therein, is as previously stated by any normally-accepted pharmaceutical route, employing the selected dosage which is effective in the alleviation of the particular ailment desired to be alleviated. Use of the compounds of the present invention in the manufacture of a medicament for the treatment of a living animal for inhibition of progression or alleviation of selected ailments or conditions, particularly ailments or conditions susceptible to treatment with a Group I mGluR modulator is carried out in the usual manner comprising the step of admixing an effective amount of a compound of the invention with a pharmaceutically-acceptable diluent, excipient, or carrier, and the method-of-treating, pharmaceutical compositions, and use of a compound of the present invention in the manufacture of a medicament.
[00269] Representative pharmaceutical compositions prepared by admixing the active ingredient with a suitable pharmaceutically-acceptable excipient, diluent, or carrier, include tablets, capsules, solutions for injection, liquid oral formulations, aerosol formulations, TDS formulations, and nanoparticle formulations, thus to produce medicaments for oral, injectable, or dermal use, also in accord with the foregoing.
* * * * *
[00270]The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description.
[00271 ]AII patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference.

Claims

1. A compound selected from those of Formula I
Figure imgf000121_0001
wherein
X represents CR6(C=0)R7 or NR8; R1 represents H, Ci-6alkyl, or F; R2 represents H, Ci-6alkyl, or F; or R1 and R2 together with the carbon atom to which they are attached form a carbonyl group; or R1 and R2 together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, C-i-6alkylamino, di-(C-i-6alkyl)amino, d. 6alkylcarbonylamino, and oxo;
R3 represents H, Chalky!, or F;
R4 represents H, Ci-6alkyl, or F; or R3 and R4 together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(Ci-6alkyl)amino, d- 6alkylcarbonylamino, and oxo;
R5 represents a monocyclic moiety selected from aryl, heteroaryl, cycloC3-6alkyl, and heterocyclyl;
R6 represents H, Ci-6alkyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, C-i-6alkylamino, and di-(Ci-6alkyl)amino, or F;
R7 represents Ci-6alkyl, which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, C-i-6alkylamino, and di-(C-i-6alkyl)amino, cycloC3-6alkyl, heterocyclyl, or NR11 R12; or R6 and R7 together with the carbon atoms to which they are attached form a 3- 7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, C-i-6alkylamino, di-(C-i-6alkyl)amino, d- 6alkylcarbonylamino, and oxo;
R8 represents Ci-6alkyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, C-i-6alkylamino, and di-(C-i-6alkyl)amino, cycloC3-6alkyl, heterocyclyl, aryl, heteroaryl, Ci-6alkylcarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, C-i-6alkoxy, amino, hydroxy, C-i-6alkylamino, and di- (Ci-6alkyl)amino, cycloC3-6alkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, heteroarylcarbonyl, Ci-6alkoxycarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, Ci-6alkylamino, and di-(C-i-6alkyl)amino, aminocarbonyl, /V-Ci-6alkylaminocarbonyl, wherein the alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, C-i-6alkylamino, and di-(Ci-6alkyl)amino, /V,/V-di-(Ci-6alkyl)aminocarbonyl, wherein the alkyl moieties may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, Ci-6alkoxycarbonyl, cyano, amino, hydroxy, Ci-6alkylamino, and di-(Ci-6alkyl)amino, /V-Ci-6alkyl-/V- cycloC3-6alkylaminocarbonyl, /V-C-i-ealkyl-ZV-cycloCs-ealkyl-C-i- 6alkylaminocarbonyl,aminothiocarbonyl, /V-Ci-6alkylaminothiocarbonyl, wherein the alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, Ci-6alkylamino, and di-(Ci-6alkyl)amino, /V,/V-di-(Ci- 6alkyl)aminothiocarbonyl, wherein the alkyl moieties may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, C-i-6alkylamino, and di- (C-i-6alkyl)amino, Ci-6alkylsulfonyl, wherein the alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, Ci-6alkylamino, and di- (Ci-6alkyl)amino, cycloC3-6alkylsulfonyl, aminosulfonyl, /V-Ci-6alkylaminosulfonyl, wherein the alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, Ci-6alkylamino, and di-(Ci-6alkyl)amino, or /V,/V-di-(Ci. 6alkyl)aminosulfonyl, wherein the alkyl moieties may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, Ci-6alkylamino, and di-(Ci-6alkyl)amino;
R9 represents H, Ci-6alkyl, or F; R10 represents H, Ci-6alkyl, or F; or R9 and R10 together with the carbon atom to which they are attached form a 3- 7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, C-i-6alkylamino, di-(C-i-6alkyl)amino, d. 6alkylcarbonylamino, and oxo;
R11 represents H, Chalky!, or cycloC3-6alkyl;
R12 represents H, Ci-6alkyl, or cycloC3-6alkyl; or R11 and R12 together with the nitrogen atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, C-i-6alkylamino, di-(C-i-6alkyl)amino, d. 6alkylcarbonylamino, and oxo; and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof; it being understood that: if R1 and R2 together with the carbon atom to which they are attached form a carbonyl group, then R8 may also represent H;
R5 may not represent optionally substituted thiazolyl; if R8 represents unsubstituted Ci-6alkyl, then R5 does not represent optionally substituted phenyl; and the compound of formula (I) may not represent:
/V-(2,4-Difluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine,
/V-(2,4-Dimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine,
/V-(2-Fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine,
/V-(3,5-Dimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine,
/V-(3-Methoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine,
/V-(4-Fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine,
/V-(4-Methoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine,
/V-Phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine,
fe/f-Butyl 2-((2,4-difluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)- carboxylate,
fe/f-Butyl 2-((2,4-dimethoxyphenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5/-/)-carboxylate,
ie/f-Butyl 2-((2,5-dimethoxyphenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5/-/)-carboxylate,
ie/f-Butyl 2-((2-methoxyphenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)- carboxylate,
ie/f-Butyl 2-((3,5-dimethoxyphenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5/-/)-carboxylate,
fe/f-Butyl 2-((3-methoxyphenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)- carboxylate,
ie/f-Butyl 2-((4-fluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)- carboxylate,
fe/f-Butyl 2-((4-methoxyphenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)- carboxylate,
1 -(4-(5,6,7,8-Tetrahydropyrido[4,3-d]pyrimidin-2-ylamino)phenyl)ethanone, or /V-(4-Phenoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine.
2. The compound as claimed in Claim 1 , wherein R1 and R2 together with the carbon atom to which they are attached form a carbonyl group, and X represents NR8, wherein R8 represents H.
3. The compound as claimed in Claim 1 , wherein R1 and R2 represent H, and X represents CR6(C=0)R7, wherein R6 represents H and R7 represents Chalky!, heterocyclyl or NR11 R12, wherein R11 and R12 represent Ci-6alkyl.
4. The compound as claimed in Claim 1 , wherein R1 and R2 represent H, and X represents NR8, wherein R8 represents Ci-6alkylcarbonyl, cycloC3-6alkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, Ci-6alkoxycarbonyl, /V-Ci-6alkylaminocarbonyl, /V,/V-di-(Ci-6alkyl)aminocarbonyl, /V,/V-di-(Ci-6alkyl)aminothiocarbonyl, /V-Ci-6alkyl- /V-cycloC3-6alkylaminocarbonyl, /V-C-i-ealkyl-ZV-cycloCs-ealkyl-C-i- 6alkylaminocarbonyl, Ci-6alkylsulfonyl, cycloC3-6alkylsulfonyl, Λ/,/V-di- (Ci-6alkyl)aminosulfonyl, or heteroaryl.
5. The compound as claimed in Claim 4, wherein R8 represents optionally substituted pyridyl, tetrazolyl, pyrimidyl, furyl, thiazolyl, or imidazolyl.
6. The compound as claimed in any of Claims 1 to 5, wherein R5 represents phenyl optionally substituted by one or more substituents selected from halogen, Ci-6alkyl, and cyano.
7. The compound as claimed in Claim 1 , which is selected from:
2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6/-/)-one,
(rac)-(2-((3-Chlorophenyl)amino)-5,6,7,8-tetrahydroquinazolin-6-yl)(piperidin-1 - yl)methanone,
1 -(2-((3-Fluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5/-/)-yl)-2- methylpropan-1 -one,
1 - (2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5/-/)-yl)-2- methylpropan-1 -one,
2- Methyl-1 -(2-( r?-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5/-/)-yl)propan-1 - one, (2-((3-Chlorophenyl)amino)-7,8-dihydropyndo[4,3-d]pynmidin-6(5/-/)- yl)(cyclopropyl)methanone,
1 -(2-((4-Fluorophenyl)amino)-7,8-dihydropyndo[4,3-d]pynmidin-6(5/-/)-yl)-2,2- dimethylpropan-1 -one,
1 -(2-((3-Chlorophenyl)amino)-7,8-dihydropyndo[4,3-d]pynmidin-6(5/-/)-yl)-2,2- dimethylpropan-1 -one,
3-((6-Pivaloyl-5,6,7,8-tetrahydropyrido[4,3-d]pynmidin-2-yl)amino)benzonitnle,
(rac)-1 -(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5/-/)-yl)-2- methylbutan-1 -one,
(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5/-/)- yl)(cyclobutyl)methanone,
1 - (2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5/-/)-yl)-2- ethylbutan-1 -one,
(2-((3-Fluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5/-/)- yl)(phenyl)methanone,
(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5/-/)- yl)(phenyl)methanone,
Methyl 2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidine-6(5/-/)- carboxylate,
Ethyl 2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidine-6(5/-/)- carboxylate,
Isopropyl 2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)- carboxylate,
ie f-Butyl 2-((3-fluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)- carboxylate,
ierf-Butyl 2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)- carboxylate,
ierf-Butyl 2-( r?-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)-carboxylate, fe f-Butyl 2-((3-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)- carboxylate,
2- ((3-Chlorophenyl)amino)-/V-ethyl-7,8-dihydropyndo[4,3-d]pynmidine-6(5/-/)- carboxamide, 2-((3-Chlorophenyl)amino)-/V,/V-dimethyl-7,8-dihydropyrido[4,3-d]pynmi carboxamide,
/V-(3-Chlorophenyl)-6-(isopropylsulfonyl)-5,67,8-tetrahydropyndo[4,3-d]pynmidin- 2-amine,
/V-(3-Chlorophenyl)-6-(cyclopropylsulfonyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2-amine,
2-((3-Chlorophenyl)amino)-/V,/V-dimethyl-7,8-dihydropyrido[4,3-d]pynmidine-6( sulfonamide,
/V-(3-Chlorophenyl)-6-(pyndin-2-yl)-5,67,8-tetrahydropyndo[4,3-d]pynmidin-2- amine,
6-(1 -(ie/f-Butyl)-1 /-/-tetrazol-5-yl)-/V-(3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2-amine,
/V-(3-Chlorophenyl)-6-(1 -isopropyl-1 /-/-tetrazol-5-yl)-5,6,7,8-tetrahydropyndo[4,3- d]pyrimidin-2-amine,
2-((3-Cyanophenyl)amino)-/V,/V-dimethyl-7,8-dihydropyrido[4,3-d]pynmidine-6(^ carboxamide,
2-((3-Chlorophenyl)amino)-/V,/V-diethyl-7,8-dihydropyrido[4,3-d]pyrimidine-^ carboxamide,
2-((3-Cyanophenyl)amino)-/V,/V-diethyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)^ carboxamide,
(rac)-3-((6-(2-Methylbutanoyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2- yl)amino)benzonitrile,
(rac)-2-((3-Chlorophenyl)amino)-/V,/V-dimethyl-5,6,7,8-tetrahydroquinazoline^^ carboxamide,
(rac)-2-((3-Chlorophenyl)amino)-/V,/V-diethyl-5,6,7,8-tetrahydroquinazolin carboxamide,
2-((3-Chlorophenyl)amino)-/V,/V-dimethyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H^ carbothioamide,
(rac)-1 -(2-((3-Chlorophenyl)amino)-5,6,7,8-tetrahydroquinazolin-6-yl)-2- methylpropan-1 -one,
2-(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5/-/)- yl)nicotinonitrile, (2-((3-Chlorophenyl)amino)-7,8-dihydropyrido
1 - yl)methanone,
2- ((3-Cyanophenyl)amino)-/V,/V-diisopropyl-7,8-dihydropyndo[4,3-d]pyrimidine- 6(5/-/)-carboxam ide,
3- ((6-(2-Methoxy-2-methylpropanoyl)-5,6,7,8-tetrahydropyrido[4,3-d]pynmidin-2- yl)amino)benzonitrile,
3-((6-(Morpholine-4-carbonyl)-5,6,7,8-tetrahydropyndo[4,3-d]pynmidin-2- yl)amino)benzonitrile,
/V-(3-Chlorophenyl)-6-(pynmidin-2-yl)-5,67,8-tetrahydropyndo[4,3-d]pynmidin-2- amine,
(2-((3-Chlorophenyl)amino)-7,8-dihydropyndo[4,3-d]pynmidin-6(5/-/)-yl)(furan-2- yl)methanone,
(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5/-/)-yl)(thiazol-2- yl)methanone,
(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5/-/)-yl)(thiazol-5- yl)methanone,
2- ((5-Chloropyndin-3-yl)amino)-/V,/V-dimethyl-7,8-dihydropyrido[4,3-d]pynmidi 6(5/-/)-carboxam ide,
/V-(3-Chlorophenyl)-6-(1 -methyl-1 /-/-tetrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2-amine,
/V-(3-Chlorophenyl)-6-(1 -methyl-1 H-imidazol-2-yl)-5,6,7,8-tetrahydropyndo[4,3- d]pyrimidin-2-amine,
3- ((6-(2-Ethylbutanoyl)-5,6,7,8-tetrahydropyndo[4,3-d]pynmidin-2- yl)amino)benzonitrile,
/V-Butyl-2-((3-cyanophenyl)amino)-/V-methyl-7,8-dihydropyrido[4,3-d]pynmidine 6(5/-/)-carboxam ide,
2-((3-Cyanophenyl)amino)-/V-cyclopropyl-N-methyl-7,8-dihydropyrido[4,3- d]pyrim idine-6(5/-/)-carboxam ide,
2-((3-Chlorophenyl)amino)-/V-ethyl-/V-propyl-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5/-/)-carboxam ide,
/V,/V-Dimethyl-2-((6-methylpyridin-2-yl)ami
6(5/-/)-carboxam ide, (rac)-3-((6-(2-Ethylpyrrolidine-1 -carbonyl)-5,67,8-tetrahydropyrido[4,3-d]pynmi
2- yl)amino)benzonitrile,
/V-(Cyanomethyl)-2-((3-cyanophenyl)amino)-/V-methyl-7,8-dihydropyrido[4,3- d]pyrim idine-6(5/-/)-carboxam ide,
3- ((6-(1 -Methylcyclopropanecarbonyl)-5,6,7,8-tetrahydropyndo[4,3-d]pynmidin-2- yl)amino)benzonitrile,
3-((6-(2-Methylcyclopropanecarbonyl)-5,6,7,8-tetrahydropyndo[4,3-d]pynmidin-2- yl)amino)benzonitrile,
2,2-Dimethyl-1 -(2-((6-methylpyndin-2-yl)amino)-7,8-dihydropyrido[4,3-d]pynmidi 6(5/-/)-yl)propan-1 -one,
3-((6-(2-Hydroxy-2-methylpropanoyl)-5,6,7,8-tetrahydropyrido[4,3-d]pynmidin-2- yl)amino)benzonitrile,
/V,/V-Diethyl-2-(m-tolylamino)-7,8-dihydropyrido[4,3-d]pynmidine-6(5/-/)- carboxamide,
2-((3-Cyanophenyl)amino)-/V-isopropyl-/V-methyl-7,8-dihydropyrido[4,3- d]pyrim idine-6(5/-/)-carboxam ide,
2-((3-Cyanophenyl)amino)-/V-ethyl-/V-methyl-7,8-dihydropyrido[4,3-d]pynmidin 6(5/-/)-carboxam ide,
2-((3-Chlorophenyl)amino)-/V-(cyclopropylmethyl)-/V-methyl-7,8-dihydropyrido[4,3- d]pyrim idine-6(5/-/)-carboxam ide,
/V,/V-Dimethyl-2-(m-tolylamino)-7,8-dihydropyrido[4,3-d]pynmidine-6(5/-/)- carboxamide,
2-((3-Chlorophenyl)amino)-/V-cyclopropyl-/V-ethyl-7,8-dihydropyndo[4,3- d]pyrim idine-6(5/-/)-carboxam ide,
Pyrrolidin-1 -yl(2-(m-tolylamino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5/-/)- yl)methanone,
(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5/-/)-yl)(1 - methylcyclopropyl)methanone,
(1 -Methylcyclopropyl)(2-(m-tolylamino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5/-/)- yl)methanone,
/V-Ethyl-/V-propyl-2-(m-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5/-/)- carboxamide, (rac)-3-((6-(3-Methylpyrrolidine-1 -carbonyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2-yl)amino)benzonitnle,
(rac)-3-((6-(2-Methylpyrrolidine-1 -carbonyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2-yl)amino)benzonitnle,
3-((6-(3,3-Dimethylazetidine-1 -carbonyl)-5,67,8-tetrahydropyndo[4,3-d]pynmidin- 2-yl)amino)benzonitrile,
2-((3-Cyanophenyl)amino)-/V-ethyl-/V-propyl-7,8-dihydropyrido[4,3-d]pynmidine- 6(5/-/)-carboxam ide,
(rac)-1 -(2-((3-Chlorophenyl)amino)-5-methyl-7,8-dihydropyndo[4,3-d]pynmidin- 6(5H)-yl)-2,2-dimethylpropan-1 -one,
(rac)-1 -(2-((3-Chlorophenyl)amino)-7-methyl-7,8-dihydropyndo[4,3-d]pynmidin- 6(5/-/)-yl)-2,2-dimethylpropan-1 -one,
2-((3-Cyanophenyl)amino)-/V,/V-bis(2,2,2-tnfluoroethyl)-7,8-dihydropyndo[4,^ d]pyrim idine-6(5/-/)-carboxam ide,
Azetidin-1 -yl(2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5/-/)- yl)methanone,
Methyl 2-(2-((3-chlorophenyl)amino)-/V-methyl-5,6,7,8-tetrahydropyndo[4,3- d]pyrim idine-6-carboxam ido)acetate,
/V-(2-Cyanoethyl)-2-((3-cyanophenyl)amino)-/V-methyl-7,8-dihydropyrido[4,3- d]pyrim idine-6(5/-/)-carboxam ide,
2-((3-Cyanophenyl)amino)-/V-(2-methoxyethyl)-/V-methyl-7,8-dihydropyrido[4,3- d]pyrim idine-6(5/-/)-carboxam ide,
2-(2-(p-Tolylamino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5H)-yl)nicotinonitn
2-((3-Cyanophenyl)amino)-/V-methyl-/V-prop
6(5/-/)-carboxam ide,
6-(2-((3-Cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5/-/)- yl)picolinonitrile,
2-(2-((3-Cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5/-/)- yl)isonicotinonitrile,
2-(2-((3-Cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5/-/)-yl)-6- methylnicotinonitrile,
Azetidin-1 -yl(2-(m-tolylamino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5/-/)- yl)methanone, /V-Ethyl-/V-methyl-2-(m-tolylamino)-7,8-dihydropyrido[4,3-d]pynmi
carboxamide,
/V-Methyl-/V-propyl-2-(m-tolylamino)-7,8-dihydropyrido[4,3-d]pynmidine-6(5H)- carboxamide,
2-((3-Chlorophenyl)amino)-/V-methyl-/V-propyl-7,8-dihydropyrido[4,3-d]pynm
6(5/-/)-carboxam ide,
2- ((3-Chlorophenyl)amino)-/V-ethyl-/V-methyl-7,8-dihydropyrido[4,3-d]pyn
6(5/-/)-carboxam ide,
3- ((6-(1 -lsopropyl-1 H-imidazol-2-yl)-5,6,7,8-tetrahydropyndo[4,3-d]pyrimidin-2- yl)amino)benzonitrile,
3-((6-(3-Methyloxetane-3-carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2- yl)amino)benzonitrile,
(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pynmidin-6(5/-/)-yl)(3- methyloxetan-3-yl)methanone,
(3-Methyloxetan-3-yl)(2-(m-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5/-/)- yl)methanone, and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
8. A pharmaceutical composition comprising a compound as claimed in any preceding claim, together with one or more pharmaceutically acceptable excipients.
9. A compound as claimed in any of Claims 1 to 7 for use in the treatment and/or prevention of abnormal glutamate neurotransmission.
10. A compound as claimed any of Claims 1 to 7, for use in the prevention and/or treatment of a condition or disease selected from Alzheimer's disease, Creutzfeld- Jakob's syndrome/disease, bovine spongiform encephalopathy (BSE), prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tauopathy, Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivoponto-cerebellar atrophy, post-operative cognitive deficit (POCD), systemic lupus erythematosus, systemic sclerosis, Sjogren's syndrome, Neuronal Ceroid Lipofuscinosis, neurodegenerative cerebellar ataxias, Parkinson's disease, Parkinson's dementia, mild cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, macular degeneration, head or brain or spinal cord injuries, head or brain or spinal cord trauma, trauma, hypoglycaemia, hypoxia, perinatal hypoxia, ischaemia, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, myoclonic epilepsy, inner ear insult, inner ear insult in tinnitus, tinnitus, sound- or drug-induced inner ear insult, sound- or drug-induced tinnitus, L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy, dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced dyskinesias, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, tic disorder, torticollis spasmodicus, blepharospasm, focal and generalized dystonia, nystagmus, hereditary cerebellar ataxias, corticobasal degeneration, tremor, essential tremor, abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, ***e addiction, ***e abuse, amphetamine addiction, amphetamine abuse, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), restless leg syndrome (RLS), hyperactivity in children, autism, dementia, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, Korsakoff syndrome, vascular dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, AIDS dementia complex, AIDS-related dementia, major depressive disorder, major depression, depression, depression resulting from Borna virus infection, major depression resulting from Borna virus infection, bipolar manic-depressive disorder, drug tolerance, drug tolerance to opioids, movement disorders, fragile-X syndrome, irritable bowel syndrome (IBS), migraine, multiple sclerosis (MS), muscle spasms, pain, chronic pain, acute pain, inflammatory pain, neuropathic pain, diabetic neuropathic pain (DNP), pain related to rheumatic arthritis, allodynia, hyperalgesia, nociceptive pain, cancer pain, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, spasticity, Tourette's syndrome, urinary incontinence, vomiting, pruritic conditions, pruritis, sleep disorders, micturition disorders, neuromuscular disorder in the lower urinary tract, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, regurgitation, respiratory tract infection, bulimia nervosa, chronic laryngitis, asthma, reflux-related asthma, lung disease, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, agoraphobia, generalized anxiety disorder, obsessive- compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, or delirium; inhibition of tumour cell growth, migration, invasion, adhesion and toxicity in the peripheral tissues, peripheral nervous system and CNS; neoplasia, hyperplasia, dysplasia, cancer, carcinoma, sarcoma, oral cancer, squamous cell carcinoma (SCC), oral squamous cell carcinoma (SCC), lung cancer, lung adenocarcinoma, breast cancer, prostate cancer, gastric cancer, liver cancer, colon cancer, colorectal carcinoma, rhabdomyosarcoma, brain tumour, tumour of a nerve tissue, glioma, malignant glioma, astroglioma, neuroglioma, neuroblastoma, glioblastoma, medulloblastoma, cancer of skin cells, melanoma, malignant melanoma, epithelial neoplasm, lymphoma, myeloma, Hodgkin's disease, Burkitt's lymphoma, leukemia, thymoma, tumours, diabetes, hyperammonemia and liver failure and sleep disturbances. Use of a compound as claimed in any of Claims 1 to 7 for the manufacture of a medicament for treating or preventing a condition or disease selected from Alzheimer's disease, Creutzfeld-Jakob's syndrome/disease, bovine spongiform encephalopathy (BSE), prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tauopathy, Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivoponto-cerebellar atrophy, post-operative cognitive deficit (POCD), systemic lupus erythematosus, systemic sclerosis, Sjogren's syndrome, Neuronal Ceroid Lipofuscinosis, neurodegenerative cerebellar ataxias, Parkinson's disease, Parkinson's dementia, mild cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, macular degeneration, head or brain or spinal cord injuries, head or brain or spinal cord trauma, trauma, hypoglycaemia, hypoxia, perinatal hypoxia, ischaemia, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, myoclonic epilepsy, inner ear insult, inner ear insult in tinnitus, tinnitus, sound- or drug-induced inner ear insult, sound- or drug-induced tinnitus, L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy, dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced dyskinesias, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, tic disorder, torticollis spasmodicus, blepharospasm, focal and generalized dystonia, nystagmus, hereditary cerebellar ataxias, corticobasal degeneration, tremor, essential tremor, abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, ***e addiction, ***e abuse, amphetamine addiction, amphetamine abuse, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), restless leg syndrome (RLS), hyperactivity in children, autism, dementia, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, Korsakoff syndrome, vascular dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, AIDS dementia complex, AIDS-related dementia, major depressive disorder, major depression, depression, depression resulting from Borna virus infection, major depression resulting from Borna virus infection, bipolar manic-depressive disorder, drug tolerance, drug tolerance to opioids, movement disorders, fragile-X syndrome, irritable bowel syndrome (IBS), migraine, multiple sclerosis (MS), muscle spasms, pain, chronic pain, acute pain, inflammatory pain, neuropathic pain, diabetic neuropathic pain (DNP), pain related to rheumatic arthritis, allodynia, hyperalgesia, nociceptive pain, cancer pain, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, spasticity, Tourette's syndrome, urinary incontinence, vomiting, pruritic conditions, pruritis, sleep disorders, micturition disorders, neuromuscular disorder in the lower urinary tract, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, regurgitation, respiratory tract infection, bulimia nervosa, chronic laryngitis, asthma, reflux-related asthma, lung disease, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, agoraphobia, generalized anxiety disorder, obsessive- compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, or delirium; inhibition of tumour cell growth, migration, invasion, adhesion and toxicity in the peripheral tissues, peripheral nervous system and CNS; neoplasia, hyperplasia, dysplasia, cancer, carcinoma, sarcoma, oral cancer, squamous cell carcinoma (SCC), oral squamous cell carcinoma (SCC), lung cancer, lung adenocarcinoma, breast cancer, prostate cancer, gastric cancer, liver cancer, colon cancer, colorectal carcinoma, rhabdomyosarcoma, brain tumour, tumour of a nerve tissue, glioma, malignant glioma, astroglioma, neuroglioma, neuroblastoma, glioblastoma, medulloblastoma, cancer of skin cells, melanoma, malignant melanoma, epithelial neoplasm, lymphoma, myeloma, Hodgkin's disease, Burkitt's lymphoma, leukemia, thymoma, tumours, diabetes, hyperammonemia and liver failure and sleep disturbances.
A method for treating or preventing a condition or disease associated with abnormal glutamate neurotransmission, or a method for modulating mGluR5 receptors to achieve therapeutic benefit, such method comprising the step of administering to a living animal, including a human, a therapeutically effective amount of a compound of as claimed in any of Claims 1 to 7. The method as claimed in Claim 12, wherein the condition associated with abnormal glutamate transmission, or wherein modulation of mGluR5 receptors results in therapeutic benefit is selected from: Alzheimer's disease, Creutzfeld- Jakob's syndrome/disease, bovine spongiform encephalopathy (BSE), prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tauopathy, Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, post-operative cognitive deficit (POCD), systemic lupus erythematosus, systemic sclerosis, Sjogren's syndrome, Neuronal Ceroid Lipofuscinosis, neurodegenerative cerebellar ataxias, Parkinson's disease, Parkinson's dementia, mild cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, macular degeneration, head or brain or spinal cord injuries, head or brain or spinal cord trauma, trauma, hypoglycaemia, hypoxia, perinatal hypoxia, ischaemia, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, myoclonic epilepsy, inner ear insult, inner ear insult in tinnitus, tinnitus, sound- or drug-induced inner ear insult, sound- or drug-induced tinnitus, L-dopa- induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy, dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced dyskinesias, haloperidol-induced dyskinesias,
dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, tic disorder, torticollis
spasmodicus, blepharospasm, focal and generalized dystonia, nystagmus, hereditary cerebellar ataxias, corticobasal degeneration, tremor, essential tremor, abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, ***e addiction, ***e abuse, amphetamine addiction, amphetamine abuse, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), restless leg syndrome (RLS), hyperactivity in children, autism, dementia, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, Korsakoff syndrome, vascular dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, AIDS dementia complex, AIDS-related dementia, major depressive disorder, major depression, depression, depression resulting from Borna virus infection, major depression resulting from Borna virus infection, bipolar manic-depressive disorder, drug tolerance, drug tolerance to opioids, movement disorders, fragile-X syndrome, irritable bowel syndrome (IBS), migraine, multiple sclerosis (MS), muscle spasms, pain, chronic pain, acute pain, inflammatory pain, neuropathic pain, diabetic neuropathic pain (DNP), pain related to rheumatic arthritis, allodynia, hyperalgesia, nociceptive pain, cancer pain, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, spasticity, Tourette's syndrome, urinary incontinence, vomiting, pruritic conditions, pruritis, sleep disorders, micturition disorders, neuromuscular disorder in the lower urinary tract, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, regurgitation, respiratory tract infection, bulimia nervosa, chronic laryngitis, asthma, reflux- related asthma, lung disease, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, or delirium; inhibition of tumour cell growth, migration, invasion, adhesion and toxicity in the peripheral tissues, peripheral nervous system and CNS; neoplasia, hyperplasia, dysplasia, cancer, carcinoma, sarcoma, oral cancer, squamous cell carcinoma (SCC), oral squamous cell carcinoma (SCC), lung cancer, lung adenocarcinoma, breast cancer, prostate cancer, gastric cancer, liver cancer, colon cancer, colorectal carcinoma, rhabdomyosarcoma, brain tumour, tumour of a nerve tissue, glioma, malignant glioma, astroglioma, neuroglioma, neuroblastoma, glioblastoma,
medulloblastoma, cancer of skin cells, melanoma, malignant melanoma, epithelial neoplasm, lymphoma, myeloma, Hodgkin's disease, Burkitt's lymphoma, leukemia, thymoma, tumours, diabetes, hyperammonemia and liver failure and sleep disturbances.
A pharmaceutical composition comprising a combination of at least one compound as claimed in any of Claims 1 to 7 and at least one NMDA receptor antagonist, together with one or more pharmaceutically acceptable excipients.
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