WO2012052451A1 - Metabotropic glutamate receptor modulators - Google Patents

Metabotropic glutamate receptor modulators Download PDF

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WO2012052451A1
WO2012052451A1 PCT/EP2011/068205 EP2011068205W WO2012052451A1 WO 2012052451 A1 WO2012052451 A1 WO 2012052451A1 EP 2011068205 W EP2011068205 W EP 2011068205W WO 2012052451 A1 WO2012052451 A1 WO 2012052451A1
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dimethyl
ethynyl
mmol
dihydroquinolin
disease
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PCT/EP2011/068205
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French (fr)
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Markus Henrich
Ulrich Abel
Sibylle Muller
Holger Kubas
Udo Meyer
Mirko Hechenberger
Valerjans Kauss
Ronalds Zemribo
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Merz Pharma Gmbh & Co. Kgaa
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Publication of WO2012052451A1 publication Critical patent/WO2012052451A1/en

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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
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    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

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.
  • MGIuRI and mGluR5 belong to Group I which are positively coupled to phospholipase C and their activation leads to a mobilization of intracellular calcium ions.
  • MGIuR2 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.
  • 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.
  • drugs which possess activity at multiple targets may be useful in treating neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and their associated symptoms (Cavalli, et al., J. Med. Chem. , 2008, 51, 347-372 and Morphy, et al., J. Med. Chem., 2005, 48, 6523- 6543).
  • MAO-B monoamine oxidase B
  • MTDLs multi-target-directed ligands
  • MTDLs for Parkinson's disease have been based on MAO inhibition in combination with a second activity (Cavalli, et al., J. Med. Chem. , 2008, 51, 347-372).
  • mGluR modulators which also possess MAO-B inhibitory activity may be particularly useful in treating neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease and their associated symptoms.
  • mGluR modulators which do not possess MAO-B inhibitory activity may be particularly useful in treating dyskinesias e.g. L-dopa-induced dyskinesia.
  • GSH adducts indicate a certain likelihood of chemical reactivity which might lead to the formation of protein adducts in vivo, i.e. in the human body. Protein adducts are believed to be the cause, or at least associated with, severe types of toxicities, so-called idiosyncratic toxicities, that are a serious drawback for any compound. In most cases such toxicities lead to the discontinuation of further development. Compounds which do not exhibit formation of GSH adducts have a reduced risk of protein adduct formation and are therefore advantageous over compounds which form GSH adducts.
  • R 2 represents C 2- 6alkyl, cycloC 3- i 2 alkyl
  • R 3 represents hydrogen, cyano, nitro, halogen, Ci -6 alkyl, CF 3 , heteroaryl, 2,3-dihydro-1 H-indenyl, hydroxy, Ci -6 alkoxy, pyrrolidino, piperidino, or morpholino;
  • R 4 represents hydrogen, halogen, nitro,
  • International Publication No. WO 2007/023290 discloses tetrahydroquinolinones of general Formula I as metabotropic glutamate receptor modulators which may be useful in treating chronic neurolo ical disorders:
  • R 1 represents aryl or heteroaryl
  • R 2 and R 3 represent hydrogen or
  • Ci-6alkyl and R 4 and R 5 represent hydrogen or Ci-6alkyl.
  • WO 03/076416 and WO 03/076417 disclose oxo- azabicyclic compounds of general formula (l/e) as matrix metalloprotease-13 (MMP-13) inhibitors which are useful in treating inflammatory conditions such as rheumatoid arthritis and osteoarthritis and roliferative conditions such as cancer:
  • X-i, X 2 , and X 3 represent a nitrogen atom or -CR3 wherein R 3 represents hydrogen, Ci -6 alkyl, amino, Ci -6 alkylamino, di-Ci -6 alkylamino, hydroxyl, Ci -6 alkoxy, or halogen; d represents a grou selected from (i/a) and (i/b):
  • R 4 and R 5 represent hydrogen, Ci -6 alkyl, aryl, arylC-i -6 alkyl, cycloalkyl, cycloalkylCi -6 alkyl, heteroaryl, heteroarylC-i -6 alkyl, heterocycloalkyl, or heterocycloalkylCi -6 alkyl
  • R 6 represents hydrogen, trifluoromethyl, OR 7 , NR 7 R 8 , Ci- 6 alkyl, etc.
  • n represents 0 to 6
  • Zi represents -CR9R10
  • A represents aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ri represents hydrogen, C-i -6 alkyl, etc.
  • m represents 0 to 7
  • R 2 represents C-i -6 alkyl, halogen, -CN, N0 2 , etc.
  • R 1 represents optionally substituted phenyl, optionally substituted naphthyl, optionally substituted heteroaryl, etc.
  • R 2 represents hydrogen, Ci -6 alkyl, etc.
  • R 3 and R 4 represent hydrogen, Ci- 6 alkyl, optionally substituted phenylC-i-ealkyenyl etc.
  • R 5 represents hydrogen, Ci- 6 alkyl, NH 2 , OH, or halogen
  • n is 0 to 3
  • Q represents OC(O), CH(R 6 )C(O), C ⁇ C, CH 2 C ⁇ C, etc.
  • W 1 represents N-R 5 or CHR 5 when— is absent or N or CR 5 when— is a bond
  • W 2 W 3 , and W 4 represent N or CR 5
  • R 1 represents optionally substituted phenyl, optionally substituted naphthyl, optionally substituted heteroaryl, etc.
  • R 2 represents hydrogen, Ci -6 alkyl, etc.
  • Y 2 represents N
  • Y 4 represents O or N-R 5 , wherein R 5 represents hydrogen or Ci- 6 alkyl; one of U 5 , U 6 , and U 8 is C-R 4 or N and the other two are CH; and Q represents OC(O), CH(R 6 )C(O), C ⁇ C, CH 2 C ⁇ C, etc.
  • heterocyclic derivatives are potent mGluR5 modulators. Additionally, these heterocyclic derivatives may also exhibit MAO-B inhibitory activity. 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 and/or in the treatment of conditions in which MAO-B plays a role. 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.
  • heterocyclic derivatives may also avoid the formation of GSH-adducts and have therefore the advantage of a reduced protein adduct formation.
  • An additional object of the invention is the provision of processes for producing the heterocyclic derivatives.
  • Ri represents aryl, heteroaryl, cycloC3-i 2 alkyl, cycloCs- ⁇ alkenyl, or heterocyclyl;
  • R 2 represents hydrogen, fluorine, or Ci -6 alkyl;
  • R 3 represents hydrogen, fluorine, or Ci-6alkyl; or R 2 and R 3 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, C-i -6 alkylamino, di-(C-i -6 alkyl)amino, Ci -6 alkylcarbonylamino, and oxo;
  • W represents CH 2 , -CR 4 R 5 CH 2 - 0, S, -CR 6 R 7 0-, NR 8 , or -CR9R10NR11 -;
  • Y represents CR-
  • R 4 represents hydrogen, fluorine, or C h alky!
  • R 5 represents hydrogen, fluorine, or Ci -6 alkyl; or R 4 and R 5 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci -6 alkyl, Ci -6 alkoxy, amino, hydroxy, cyano, acyl, C-i -6 alkylamino, di-(C-i -6 alkyl)amino, Ci -6 alkylcarbonylamino, and oxo; R 6 represents hydrogen, fluorine, or C h alky!;
  • R 7 represents hydrogen, fluorine, or Ci -6 alkyl; or R 6 and R 7 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci -6 alkyl, Ci -6 alkoxy, amino, hydroxy, cyano, acyl, Ci- 6 alkylamino, di-(Ci- 6 alkyl)amino, Ci- 6 alkylcarbonylamino, and oxo;
  • R 8 represents hydrogen, Ci -6 alkyl, or acyl
  • R 9 represents hydrogen, fluorine, or Ci- 6 alkyl
  • R-io represents hydrogen, fluorine, or Ci -6 alkyl; or R 9 and R 0 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci -6 alkyl, Ci -6 alkoxy, amino, hydroxy, cyano, acyl, Ci- 6 alkylamino, di-(Ci- 6 alkyl)amino, Ci- 6 alkylcarbonylamino, and oxo;
  • R-I -I represents hydrogen, Ci -6 alkyl, or acyl
  • R-I2 represents hydrogen, fluorine, Ci- 6 alkyl, amino, Ci- 6 alkylamino, di-(Ci- 6 alkyl)amino, acylamino, or heterocyclyl;
  • R-I3 represents hydrogen, fluorine, or Ci -6 alkyl; or R 2 and R 3 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, C-i -6 alkyl, Ci -6 alkoxy, amino, hydroxy, cyano, acyl, Ci- 6 alkylamino, di-(Ci- 6 alkyl)amino, Ci- 6 alkylcarbonylamino, and oxo; and
  • R 4 represents hydrogen, Ci -6 alkyl, aryl, or heteroaryl; wherein the term "aryl” means phenyl or naphthyl, wherein the phenyl or naphthyl group is optionally substituted by one or more substituents, which may be the same or different, selected independently from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci -6 alkyl, hydroxyCi -6 alkyl, C 2-6 alkenyl, Ci -6 alkoxy, Ci- 6 alkoxyCi- 6 alkyl, amino, hydroxy, nitro, cyano, formyl, Ci- 6 alkylcarbonyl, Ci- 6 alkoxycarbonyl, Ci- 6 alkylcarbonyloxy, Ci- 6 alkylcarbonyloxyCi- 6 alkyl, Ci- 6 alkylamino, di-(Ci -6 alkyl)amino, cycloC 3- i 2 alkylamin
  • a further aspect of the invention relates to a compound of Formula I, wherein W represents CH 2 , -CR 4 R 5 CH 2 - O, -CReRyO- or NR 8 and Y represents CH 2 or NR 14 .
  • Such a compound of Formula I wherein R 4 , R 5 , R 6 , R 7 , and R 4 each independently represent hydrogen or Ci -6 alkyl.
  • Such a compound of Formula I wherein R 2 and R 3 represent hydrogen or Ci- 6 alkyl or R 2 and R 3 together with the carbon atom to which they are attached form a 3 to 6-membered ring optionally containing a heteroatom selected from sulfur, oxygen, and nitrogen, wherein the ring may be optionally substituted by one or more substituents selected from Ci- 6 alkyl, Ci- 6 alkoxy, and acyl.
  • Such a compound of Formula I wherein R 2 and R 3 represent hydrogen or Ci -6 alkyl or R 2 and R 3 together with the carbon atom to which they are attached form a 3 to 5-membered carbocyclic ring or R 2 and R 3 together with the carbon atom to which they are attached form a nitrogen-containing ring, wherein the nitrogen atom may be optionally substituted with a substituent selected from Ci -6 alkyl and acyl.
  • Such a compound of Formula I wherein Ri represents phenyl optionally substituted by one or more substituents selected from F, CI, Br, Ci -6 alkyl, cyano, Ci -6 alkylcarbonyl, Ci -6 alkoxycarbonyl, hydroxy, Ci -6 alkoxy, nitro, amino, Ci-6alkylcarbonylamino, and cyano; pyridinyl optionally substituted by one or more substituents selected from F, Ci-6alkyl, cyano, hydroxy, Ci-6alkoxy, amino, C-i -6 alkylamino, di-(Ci -6 alkyl)amino, cycloC 3- i 2 alkylamino, and piperidine; pyrimidinyl optionally substituted by one or more substituents selected from amino and Ci-6alkylamino; imidazopyridinyl; pyrrolopyridinyl; indazolyl; pyrazolopyridinyl; in
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IA
  • R-T represents aryl, heteroaryl, cycloC 3 -i 2 alkyl, cycloCs- ⁇ alkenyl, or heterocyclyl;
  • R 2 ' represents hydrogen, fluorine, or Ci -6 alkyl;
  • R 3 ' represents hydrogen or Ci- 6 alkyl; or R 2 and R 3 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci -6 alkyl, Ci -6 alkoxy, amino, hydroxy, cyano, acyl, Ci- 6 alkylamino, di-(Ci- 6 alkyl)amino, Ci- 6 alkylcarbonylamino, and oxo;
  • W represents CH 2 , -CR 4 R 5 CH 2 - 0, S, or NR 8 ;
  • Y' represents CH 2 or NRi 4 ;
  • R 4 represents hydrogen, fluorine, or Ci -6 alkyl
  • R 5 represents hydrogen or C h alky!; or R 4 and R 5 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, C h alky!, Ci- 6 alkoxy, amino, hydroxy, cyano, acyl, C-i -6 alkylamino, di-(C-i -6 alkyl)amino, Ci -6 alkylcarbonylamino, and oxo;
  • R 8 represents hydrogen, C h alky!, or acyl
  • R 4 represents hydrogen or Ci -6 alkyl; and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
  • Such a compound of Formula IA wherein W represents CH 2 , O, or NR 8 and Y' represents CH 2 or NRi 4 .
  • Such a compound of Formula IA wherein R 2 > and R 3 > represent hydrogen or Ci -6 alkyl or R 2 and R 3 together with the carbon atom to which they are attached form a 3 to 6-membered ring optionally containing a heteroatom selected from sulfur, oxygen, and nitrogen, wherein the ring may be optionally substituted by one or more substituents selected from Ci-6alkyl, Ci-6alkoxy, and acyl.
  • Such a compound of Formula IA wherein R 2' and Ry represent hydrogen or Ci-6alkyl or R 2' and Ry together with the carbon atom to which they are attached form a 5-membered ring or R 2' and Ry together with the carbon atom to which they are attached form a nitrogen-containing ring, wherein the nitrogen atom may be optionally substituted with a substituent selected from Ci -6 alkyl and acyl.
  • Such a compound of Formula IA wherein R represents aryl, heteroaryl, cycloC 3- i 2 alkyl or cycloC 5- i 2 alkenyl.
  • Such a compound of Formula IA wherein R represents phenyl optionally substituted by one or more substituents selected from F, CI, Br, Ci -6 alkyl, cyano, Ci -6 alkylcarbonyl, Ci -6 alkoxycarbonyl, hydroxy, Ci -6 alkoxy, nitro, amino, Ci-6alkylcarbonylamino, and cyano; pyridinyl optionally substituted by one or more substituents selected from F, Ci-6alkyl, cyano, hydroxy, Ci-6alkoxy, amino, C-i -6 alkylamino, di-Ci -6 alkylamino, cycloC 3- i 2 alkylamino, and piperidine; pyrimidinyl optionally substituted by one or more substituents selected from amino and Ci-6alkylamino; cyclohexenyl; or cyclopentyl.
  • R represents phenyl optionally substituted by one or more substituents selected from F, CI,
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IB
  • W" represents CH 2 , 0, or NR 8 ;
  • Y' represents CH 2 or NRi 4 ;
  • R-T represents aryl, heteroaryl, cycloC 3- i 2 alkyl, cycloC 5- i 2 alkenyl, or heterocyclyl;
  • R 2 ' represents hydrogen, fluorine, or C h alky!;
  • R 3 ' represents hydrogen or Ci -6 alkyl; or R 2 and R 3 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci -6 alkyl, Ci -6 alkoxy, amino, hydroxy, cyano, acyl, Ci- 6 alkylamino, di-(Ci- 6 alkyl)amino, Ci- 6 alkylcarbonylamino, and oxo;
  • R 8 represents hydrogen, Ci -6 alkyl, or acyl
  • Ri 4 represents hydrogen or C h alky!; and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
  • Ri 4 represents hydrogen or methyl.
  • R 2' and R 3 > represent hydrogen or Ci- 6 alkyl or R 2 and R 3 together with the carbon atom to which they are attached form a 3 to 6-membered ring optionally containing a heteroatom selected from sulfur, oxygen, and nitrogen, wherein the ring may be optionally substituted by one or more substituents selected from Ci -6 alkyl, Ci -6 alkoxy, and acyl.
  • Such a compound of Formula IB wherein R 2' and Ry represent hydrogen or Ci -6 alkyl or R-i and R 2 together with the carbon atom to which they are attached form a 5-membered ring or R 2 and R 3 together with the carbon atom to which they are attached form a nitrogen-containing ring, wherein the nitrogen atom may be optionally substituted with a substituent selected from Chalky! and acyl.
  • Such a compound of Formula IB wherein R represents aryl, heteroaryl, cycloC 3- i 2 alkyl or cycloCs- ⁇ alkenyl.
  • Such a compound of Formula IB wherein R represents phenyl optionally substituted by one or more substituents selected from F, CI, Br, Chalky!, cyano, Ci- 6 alkylcarbonyl, Ci- 6 alkoxycarbonyl, hydroxy, nitro, amino, Ci -6 alkylcarbonylamino, and cyano; pyridinyl optionally substituted by one or more substituents selected from F, Ci -6 alkyl, cyano, hydroxy, Ci -6 alkoxy, amino, Ci- 6 alkylamino, di-(Ci- 6 alkyl)amino, cycloC 3- i 2 alkylamino, and piperidine; pyrimidinyl optionally substituted by one or more substituents selected from amino and C-i -6 alkylamino; cyclohexenyl; or cyclopentyl.
  • R represents phenyl optionally substituted by one or more substituents selected from F, CI, Br, Chal
  • 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 use in therapy.
  • 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 and/or in the treatment or prevention of conditions in which MAO-B plays a role.
  • 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), synucleinopathies, alpha-synucle
  • 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.
  • DNP diabetic neuropathic pain
  • IBS irritable bowel syndrome
  • GSD gastroesophageal reflux
  • mGluR5 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.
  • Inhibition of MAO-B may be particularly useful for neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. Inhibition of MAO-B may also be useful for smoking cessation, depression and/or mood stabilization.
  • 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 neuro-protection.
  • 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.
  • This invention also relates to a method for treating or preventing a condition or disease in which MAO-B plays a role, including for the conditions or diseases selected from those described earlier in the description.
  • the invention relates to the a compound of Formula I as described herein for use in inhibiting MAO-B. This use may be in the treatment or prevention of a condition or disease as described herein.
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula I
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula I
  • R r Hal V in the presence of a suitable catalyst, such as PdCI 2 (PPh 3 ) 2 , to yield a compound of Formula I, which may be converted to a prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
  • a suitable catalyst such as PdCI 2 (PPh 3 ) 2
  • 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.
  • the prefix Cj. j indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive.
  • alkyl of one to three carbon atoms i.e.
  • Ci -6 alkyl represents straight or branched chain alkyl groups which may be optionally substituted by one or more (e.g., 1 , 2, 3, 4, or 5) substituents selected from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, Ci-6alkoxy, amino, hydroxy, Ci-6alkylamino, and di-(Ci-6alkyl)amino.
  • substituents selected from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, Ci-6alkoxy, amino, hydroxy, Ci-6alkylamino, and di-(Ci-6alkyl)amino.
  • alkyl groups include methyl, ethyl, n-propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, and -CF 3 ,
  • C 2 - 6 alkenyl represents straight or branched chain alkenyl groups.
  • Ci -6 alkoxy represents straight or branched chain -0-Ci -6 alkyl groups which may be optionally substituted by one or more (e.g., 1 , 2, 3, 4, or 5) substituents selected from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, amino, hydroxy, d- 6 alkylamino and di-(C-i-6alkyl)amino.
  • substituents selected from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, amino, hydroxy, d- 6 alkylamino and di-(C-i-6alkyl)amino.
  • alkoxy groups include methoxy, ethoxy, n-propoxy, /-propoxy, -OCF 3 and -OC2F5.
  • acyl represents Ci-6alkylcarbonyl, trifluoroacetyl, hydroxy- Ci -6 alkylcarbonyl, Ci -6 alkoxycarbonyl, /V-Ci -6 alkylaminocarbonyl, ⁇ /,/V-di- (Ci -6 alkyl)aminocarbonyl, C-i-ealkoxy-C-i-ealkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, cyclo-C 3- i 2 alkylcarbonyl, aryl-Ci -6 alkylcarbonyl, heteroaryl-Ci -6 alkylcarbonyl, arylamino- Ci-6alkylcarbonyl, heteroarylamino-Ci-6alkylcarbonyl, heterocyclylcarbonyl and heterocyclyl-Ci-6alkylcarbonyl.
  • 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- 6alkenyl, Ci -6 alkoxy, amino, hydroxy, cyano, Ci-6alkoxycarbonyl, Ci-6alkylamino, and di-(Ci-6alkyl)amino, Ci-6alkyl- carbonylamino, oxo, Ci-6alkoxyimino, Ci-6alkylaminocarbonyl, arylCi-6alkoxycarbony
  • cycloCs- ⁇ alkenyl represents monocyclic or bicyclic, or tricyclic alkenyl groups, including cyclopentenyl, cyclohexenyl, and bicyclo[2.2.1 ]heptenyl, 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, C2-6alkenyl, Ci-6alkoxy, amino, hydroxy, cyano, Ci-6alkoxycarbonyl, Ci-6alkylamino, and di-(Ci-6alkyl)amino, Ci-6alkyl- carbonylamino, oxo, Ci -6 alkoxyimino, Ci -6 alkylaminocarbonyl, arylCi -6 alkoxycarbonyl, and Ci
  • 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, trifluoromethoxy, Ci-6alkyl, hydroxyCi-6alkyl, C2-6alkenyl, Ci-6alkoxy, Ci-6alkoxyCi-6alkyl, amino, hydroxy, nitro, cyano, formyl, Ci-6alkylcarbonyl, Ci -6 alkoxycarbonyl, Ci -6 alkylcarbonyloxy, d-ealkylcarbonyloxyd-ealkyl, C-i -6 alkylamino, di-(Ci -6 alkyl)amino, cycloC 3- i 2 alkylamino, Ci -6 alkylcarbon
  • 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, trifluoromethoxy, Ci -6 alkyl, hydroxyCi -6 alkyl, C 2-6 alkenyl, Ci -6 alkoxy, amino, hydroxy, nitro, cyano, d.
  • substituents which may be the same or different, selected independently from halogen, fluoromethyl, difluoromethyl
  • heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, pyrazolyl, triazolyl, thiadiazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, purinyl, pyrazolyl, benzofuryl, benzothienyl, indolyl, indolizinyl, isoindolyl, indolinyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, isoquinoliny
  • 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci -6 alkyl, C 2-6 alkenyl, Ci -6 alkoxy, amino, hydroxy, nitro, cyano, d.
  • substituents which may be the same or different, selected independently from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci -6 alkyl, C 2-6 alken
  • 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.
  • 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, “h” for hour or hours, “min” for minute or minutes, and “r.t.” 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.
  • [00 01 ] 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.
  • Bromo-heterocyclic compounds 2 are prepared by condensation of enamines 8, derived from 1 ,3-cyclohexanediones or 1 ,3-cyclopentanediones 7, with bromomalonaldehyde as shown in Scheme 2.
  • Compounds thus obtained can be used for Sonogashira coupling as shown in Scheme 1 , or can be further modified, using Beckmann or Schmidt rearrangements to give 6- or 7-membered lactams 9.
  • the amide nitrogen in these compounds can be alkylated to give /V-alkyl derivatives 10.
  • Scheme 3 Synthesis of ring oxygen containing bromo-heterocyclic compounds
  • 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.
  • 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”.
  • 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.
  • 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.
  • 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 (such as
  • the drug components may be combined with nontoxic, pharmaceutically acceptable inert carriers (e.g., EtOH, 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.
  • 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.
  • 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.
  • 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.
  • Boc is defined as fe/f-butyloxycarbonyl, "BuLi” as n-butyl-Lithium, “DBU” as 1 ,8-diazabicyclo[5.4.0]undec-7-ene, "DCM” as dichloromethane, "DMAP” as /V,/V-dimethylpyridin-4-amine, “DMF” as ⁇ /,/V-dimethylformamide, "DMSO” as dimethylsulfoxide, "EtOAc” as ethyl acetate, “EtOH” as ethanol, “HCI” as hydrochloric acid, “MeOH” as methanol, “NaOH” as sodium hydroxide, "P(f-Bu) 3 " as tri-fe/f- butylphosphine, “SPhos” as 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl,
  • Aery lie acid (8.33 g, 1 15.6 mmol) is carefully added dropwise to a refluxing solution of 5-bromopyridin-2 -amine (10.00 g, 57.80 mmol) in toluene (25 mL). The mixture is stirred at reflux for 3 days, concentrated at reduced pressure and diluted with aqueous KOH (6.47 g, 1 15.6 mmol) solution (150 mL). The formed solid is filtered, and the filtrate is extracted with DCM (3x). The aqueous phase is acidified to pH 5. The formed solid is collected by filtration, washed with water and dried to provide 3-((5- bromopyridin-2-yl)amino)propanoic acid (12.75 g, 90%) as beige solid.
  • the obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to provide a product mixture of 6- ((trimethylsilyl)ethynyl)pyridin-2-amine and 6-ethynylpyridin-2-amine.
  • the obtained mixture is dissolved in THF (150 ml_), and 1 M solution of TBAF in THF (150 ml_) is added dropwise at -20 °C.
  • the mixture is stirred at 0 °C for 20 min, diluted with water and extracted with DCM.
  • the organic layer is dried over Na 2 SO 4 and concentrated at reduced pressure.
  • the obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to provide the title compound (1 1.90 g, 67%, for two steps) as grey solid.
  • 6-Ethynyl-2,2-dimethyl-2H-pyrano[2,3-b]pyridin-4(3H)-one [00168]To a solution of 6-bromo-2,2-dimethyl-2H-pyrano[2,3-b]pyridin-4(3H)-one (see Preparation 4; 506 mg, 1 .97 mmol) in anhydrous acetonitrile (10 mL) DIPEA (1 .04 mL, 5.93 mmol), Cul (23 mg, 0.12 mmol) and PdCI 2 [PPh 3 ] 2 (42 mg, 0.06 mmol) are added under argon atmosphere. The resulting mixture is stirred at r.t.
  • the obtained residue is purified by column chromatography (silica gel, EtOAc/hexane). Then a mixture of 1 N TBAF solution in THF (1 .40 mL) and THF (14 mL) is added dropwise to a solution of the obtained intermediate product in THF (70 mL) at -5 °C over a period of 45 min. The resulting mixture is stirred at 0 °C for 1 .5 h, poured into water and extracted with DCM. The combined organic phases are concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound (3.88 g, 90% for two steps) as brownish solid.
  • the crude product is purified by column chromatography (silica gel, EtOAc/hexane) and triturated with a small amount of acetonitrile. The precipitate is filtered off and dried to provide the title compound (78 mg, 17 %).
  • the crude intermediate is purified by column chromatography (silica gel, EtOAc/hexane) and washed with a EtOAc/hexane (10: 1 ) to give the pure intermediate fe/f-butyl (3-((7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)phenyl)carba- mate (363 mg, 56%), which is subsequently deprotected with TFA in DCM at r.t. The resulting reaction mixture is basified with an excess of solid sodium bicarbonate, filtered, and concentrated in high vacuum to provide the title compound (97%).
  • the crude intermediate is purified by column chromatography (DCM/EtOAc, 30: 1 ) and crystallized from EtOAc/hexane (1 :5) to give the pure intermediate fe/f-butyl (3-((7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)-4- fluorophenyl)carbamate (95 mg, 23%), which is subsequently deprotected with TFA (1 mL) in DCM (10 mL) at r.t. for 6 h. The resulting reaction mixture is basified by aqueous potassium carbonate and extracted with DCM. The crude product is purified by column chromatography (DCM/EtOAc, 10: 1 ) and triturated with EtOAc/hexane (1 : 10) to provide the title compound (54 mg, 76%).
  • this mixture (307 mg, 0.87 mmol) is reacted with 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one (199 mg, 1 .00 mmol), PdCI 2 [PPh 3 ] 2 (21 mg, 0.03 mmol), Cul (4 mg, 0.02 mmol) and TEA (3 mL) at 80 °C for 6 h. After addition of DMF (1 mL) the reaction mixture is stirred at 80 °C for 1 h, cooled down to r.t., diluted with EtOAc, washed with water and concentrated at reduced pressure.
  • the obtained residue is purified by column chromatography (silica gel, EtOAc/hexane, 1 :3) to give the intermediate compound 3-((7,7-dimethyl-5-oxo-5, 6,7,8- tetrahydroquinolin-3-yl)ethynyl)-5-methyl-phenyl tnfluoromethanesulfonate (339 mg), which is subsequently deprotected by 1 N TBAF solution (in THF, 0.80 mL, 0.80 mmol) in THF (3 mL) at 50 °C for 2 h.
  • the crude product is purified by column chromatography (silica gel, EtOAc/hexane) to provide the title compound (21 %, for two steps).
  • the crude intermediate is purified by column chromatography (silica gel, EtOAc/DCM, 1 :5; then EtOAc) to give the pure intermediate product fe/f-butyl (2-((7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)pyridin-4-yl)carbamate (206 mg, 53%), which is subsequently deprotected by TFA (1 .5 mL) in DCM (15 mL) at r.t. for 12 h.
  • the resulting reaction mixture is basified with aqueous potassium carbonate, purified by column chromatography (silica gel, DCM/MeOH, 25: 1 ), and triturated with hexane to provide the title compound (68 mg, 44%).
  • the crude product is purified by column chromatography (silica gel, DCM/acetone, 5:1 ; then DCM/MeOH, 25: 1 ) and triturated with diethyl ether to provide the title compound (120 mg, 41 %).
  • the obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to provide a mixture of /V-methyl-6-((trimethylsilyl)ethynyl)pyridin-2-amine and 6-ethynyl-/V- methylpyridin-2-amine.
  • the obtained mixture is dissolved in THF (30 mL), and 1 M solution of TBAF in THF (30 mL) is added dropwise at -20 °C. The mixture is stirred at 0 °C for 20 min, diluted with water and extracted with DCM. The organic layer is dried over Na 2 S0 4 and concentrated at reduced pressure.
  • the obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to give 6-ethynyl-/V-methylpyridin-2- amine (2.84 g, 72%, for two steps) as grey solid.
  • the organic phase is dried over magnesium sulfate and concentrated at reduced pressure.
  • the obtained residue is treated with hexane, and the formed precipitate is collected by filtration and washed with hexane.
  • the crude product is purified twice by column chromatography (silica gel, DCM/acetone) to provide the title compound (259 mg, 62%).
  • 6-(Phenylethynyl)-2,3-dihydro-1 ,8-naphthyridin-4(1 H)-one [00228]According to General Procedure 1 , 6-bromo-2,3-dihydro-1 ,8-naphthyridin-4(1 /-/)- one (200 mg, 0.88 mmol) is reacted with ethynylbenzene (450 mg, 4.40 mmol) in the presence of PdCI 2 [PPh 3 ] 2 (21 mg, 0.03 mmol), Cs 2 C0 3 (287 mg, 0.88 mmol), and P(f- Bu) 3 (14 mg, 0.07 mmol) in DMF (10 ml_) under argon atmosphere at 90 °C for 2 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane, 1 : 1 ) followed by preparative HPLC (C18, acetonitrile/
  • LiHMDS (1 M solution in THF, 0.44 mL, 0.44 mmol) is added dropwise to a solution of 6-(phenylethynyl)-2,3-dihydro-1 ,8-naphthyridin-4(1 /-/)-one (see Example 55; 73 mg, 0.29 mmol) in anhydrous THF (7 mL) under argon atmosphere at -75 °C. The resulting mixture is stirred at -75 °C for 30 min. Then a solution of methyl chloroformate (42 mg, 0.44 mmol) in anhydrous THF (0.5 mL) is added dropwise at -75 °C.
  • reaction mixture is stirred for 30 min at -70 °C, allowed to warm up to -10 °C, diluted with saturated aqueous ammonium chloride solution (5 mL), and extracted with EtOAc (x3). The combined organic phases are dried over Na 2 S0 4 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) followed by preparative HPLC (C18, acetonitrile/water) to provide the title compound (51 mg, 58%).
  • TEA 4 mL
  • P(f-Bu) 3 48 mg, 0.24 mmol
  • 6- bromo-2,3-dihydro-1 ,8-naphthyridin-4(1 /-/)-one see Preparation 5; 520 mg, 2.29 mmol
  • anhydrous DMF 4 mL
  • PdCl 2 [PPh 3 ] 2 48 mg, 0.07 mmol
  • the mixture is stirred for 10 min at r.t.
  • ⁇ /,/V-Di-Boc-protected 6-ethynylpyridin-2-amine (880 mg, 2.76 mmol) is added portionwise, and the reaction mixture is stirred at 85 °C for 1 .5 h, cooled down to r.t., diluted with cold water (50 mL), and extracted with DCM (x3). The combined organic layers are dried over Na 2 S0 4 and concentrated at reduced pressure.
  • the obtained residue is purified by column chromatography (silica gel, EtOAc/hexane, 1 : 1 ) to give ⁇ /,/V-di-Boc-protected methyl 6-((6-aminopyridin-2-yl)ethynyl)-4-oxo-3,4-dihydro- 1 ,8-naphthyridine-1 (2/-/)-carboxylate (190 mg, 85%) as yellowish oil.
  • Boc groups are cleaved with TFA (3 mL) in DCM (20 mL) at r.t. After 3 h the reaction mixture is neutralized with an aqueous solution of NaHCO 3 . The organic layer is separated, and the aqueous layer is extracted with DCM. The combined organic layers are dried over Na 2 SO 4 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/DCM, 1 : 1 ) to provide the title compound (69 mg, 59%).
  • TEA (2 mL) and P(f-Bu) 3 (20 mg, 0.10 mmol, 1 1 mol%) are added to a solution of 6-bromo-2,3-dihydro-1 ,8-naphthyridin-4(1 /-/)-one (200 mg, 0.88 mmol) in anhydrous DMF (2 mL).
  • the resulting mixture is stirred under argon atmosphere at r.t. for 5 min.
  • PdCl 2 [PPh 3 ] 2 (20 mg, 0.03 mmol) is added, and the mixture is stirred for 10 min at r.t.
  • LiHMDS (1 M solution in THF, 0.86 mL, 0.86 mmol) is added dropwise to a solution of 6-( r?-tolylethynyl)-2,3-dihydro-1 ,8-naphthyridin-4(1 /-/)-one (150 mg, 0.57 mmol) in anhydrous THF (13 mL) under argon atmosphere at -75 °C. The resulting mixture is stirred at -75 °C for 15 min. Then a solution of methyl chloroformate (81 mg, 0.86 mmol) in anhydrous THF (2 mL) is added dropwise at -75 °C.
  • reaction mixture is stirred for 30 min at -70 °C, allowed to warm up to 0 °C, diluted with a saturated aqueous ammonium chloride solution (7 mL), and extracted with EtOAc (x3). The combined organic phases are dried over Na 2 S0 4 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) and recrystallized from MeOH to provide the title compound (98 mg, 54%).
  • LiHMDS (1 M solution in THF, 2.90 mL, 2.90 mmol) is added dropwise to a solution of 3-((5-oxo-5,6,7,8-tetrahydro-1 ,8-naphthyridin-3-yl)ethynyl)benzonitrile (390 mg, 1 .43 mmol) in anhydrous THF (70 mL) under argon atmosphere at -75 °C. The resulting mixture is stirred at -75 °C for 30 min. Then a solution of methyl chloroformate (270 mg, 2.85 mmol) in anhydrous THF (0.5 mL) is added dropwise at -75 °C.
  • reaction mixture is stirred at -70 °C for 30 min, allowed to warm up to r.t. and stirred for 1 h at r.t., diluted with a saturated aqueous ammonium chloride solution (15 mL) and extracted with EtOAc (x3). The combined organic phases are dried over Na 2 S0 4 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) followed by preparative HPLC (C18, acetonitrile/water) to provide the title compound (24 mg, 5%).
  • Li HMDS (1 M solution in THF, 0.60 mL, 0.60 mmol) is added dropwise to a solution of 4-fluoro-3-((5-oxo-5,6,7,8-tetrahydro-1 ,8-naphthyridin-3- yl)ethynyl)benzonitrile (100 mg, 0.34 mmol) in anhydrous THF (18 mL) under argon atmosphere at -75 °C. The resulting mixture is stirred at -75 °C for 30 min. Then a solution of methyl chloroformate (57 mg, 0.60 mmol) in anhydrous THF (1 mL) is added dropwise at -75 °C.
  • the reaction mixture is stirred for 30 min at -70 °C, allowed to warm up to 10 °C, diluted with a saturated aqueous ammonium chloride solution (10 mL) and extracted with EtOAc (x3). The combined organic phases are dried over Na 2 S0 4 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc), washed with DCM/hexane (1 : 1 , 3 mL) and dried to provide the title compound (20 mg, 17%).
  • the crude product is purified by column chromatography (silica gel, EtOAc/EtOH) to provide 8,8-dimethyl-3-((3-nitropyridin-2-yl)ethynyl)-6,7,8,9-tetrahydro-5/-/-pyrido[3,2- c]azepin-5-one (213 mg, 67%) as yellow solid.
  • the crude product is purified by column chromatography (silica gel, DCM/EtOH) to provide the intermediate product fe/f-butyl 6-((6,8,8-trimethyl-5-oxo-6,7,8,9-tetrahydro-5/-/- pyrido[3,2-c]azepin-3-yl)ethynyl)-1 /-/-pyrrolo[2,3-b]pyridine-1 -carboxylate (72 mg, 27%), which is deprotected by means of TFA (72 ⁇ , 0.97 mmol) in dioxane (2 mL) at r.t. for 2 h. TFA (200 ⁇ ) is added and the resulted solution is stirred at r.t.
  • the crude product is purified by column chromatography (silica gel, EtOAc/DCM, 1 : 1 ) to provide the Boc-protected intermediate (1 17 mg, 45%) as yellowish oil, which is deprotected by means of TFA (200 ⁇ , 2.70 mmol) in DCM (5 mL) at r.t. over night.
  • the mixture is poured into an aqueous NaOH solution (1 N) and extracted with DCM.
  • the organic phase is washed with water and concentrated at reduced pressure.
  • the obtained residue is purified by column chromatography (silica gel, EtOAc/DCM) to provide the title compound (73 mg, 82%).
  • the crude product is purified by column chromatography (silica gel, EtOAc/hexane, 4: 1 ) and preparative TLC (silica gel, DCM/EtOH, 20:1 ) to provide the title compound (55 mg, 18%).
  • the crude product is purified by column chromatography (silica gel, EtOAc/hexane, 4: 1 ) and preparative TLC (silica gel, DCM/EtOH, 20: 1 ) to provide the title compound (60 mg, 19%).
  • 3-Bromo-7-methyl-7,8-dihydroquinolin-5(6/-/)-one is prepared in close analogy to the procedure descibed for the synthesis of 3-bromo-7,7-dimethyl-7,8- dihydroquinolin-5(6/-/)-one (Preparation 1 ) starting with 5-methylcyclohexane-1 ,3-dione.
  • 3-((6-Aminopyrimidin-4-yl)ethynyl)-7,7-dim [00292]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (199 mg, 1.00 mmol) is reacted with 6-bromopyrimidin-4-amine (174 mg, 1.00 mmol) in the presence of PdCI 2 (PPh 3 ) 2 (39 mg, 0.055 mmol), and Cul (10 mg, 0.05 mmol) in DMF (0.5 mL) at 80 °C for 40 min under microwave irradiation. The crude product is purified by preparative HPLC (C18, acetonitrile/water) to provide the title compound (48 mg, 9%) as TFA salt.
  • the crude product is purified by column chromatography (silica gel, EtOAc/hexane) to provide fe/f-butyl 5-((7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)-3/-/- imidazo[4,5-b]pyridine-3-carboxylate (85 mg, 24%), which is deprotected by means of TFA (1 mL) in DCM (2 mL) at r.t. for 1 h. After concentration at reduced pressure the obtained residue is purified by preparative HPLC (C18, acetonitrile/water+TFA) to provide the title compound (35 mg, 40%) as TFA salt.
  • 3-Bromo-7-methyl-7,8-dihydroquinolin-5(6/-/)-one is prepared in close analogy to the procedure descibed for the synthesis of 3-bromo-7,7-dimethyl-7,8- dihydroquinolin-5(6/-/)-one (Preparation 1 ) starting with 5-methylcyclohexane-1 ,3-dione.
  • the crude product is purified by column chromatography (silica gel, EtOAc/hexane, 1 :2) to provide 7, 7-dimethyl-3-((1 -tosyl-1 H-indazol-5-yl)ethynyl)-7,8-dihydroquinolin- 5(6H)-one (380 mg, 40%), which is deprotected using f-BuOK (1 12 mg, 1 .00 mmol) in t- BuOH (5 ml_) and THF (5 ml_) at reflux for 1 h. The mixture is cooled down to r.t., diluted with water and extracted with DCM. The organic layer is dried over Na 2 S0 4 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, DCM/EtOAc, 15: 1 ), triturated with diethyl ether and dried to provide the title compound (58 mg, 23%).
  • the crude product is purified by column chromatography (silica gel) to provide the intermediate product 7,7-dimethyl- 3-((3-nitropyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6/-/)-one (270 mg, 56%).
  • the obtained residue is purified by column chromatography (silica gel, DCM/hexane) to give 4-methyl-2-((trimethylsilyl)ethynyl)pyridine, which is dissolved in THF (15 mL).
  • the TMS group is removed by adding 1 N TBAF solution in THF (10 mL) dropwise at -30 °C.
  • the resulting mixture is stirred at 0 °C for 20 min, quenched with water (150 mL) at 0 °C and extracted with hexane (2x100 mL).
  • the combined organic phases are washed with water, dried over Na 2 S0 4 and concentrated at reduced pressure.
  • the obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) resulting in 2-ethynyl- 4-methylpyridine (1 .080 g, 79% for two steps) as brownish solid.
  • the crude product is purified by column chromatography (silica gel, DCM/EtOAc, 1 :1 ) and crystallized from EtOAc/diethyl ether to give the intermediate product ie/f-butyl 3-((7,7-dimethyl-5-oxo- 5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)-1 /-/-pyrrolo[3,2-b]pyridine-1 -carboxylate (615 mg, 66%) as yellowish solid.
  • the crude product is purified by column chromatography (silica gel) to give the intermediate product 7,7- dimethyl-3-((6-methyl-5-nitropyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6/-/)-one (80 mg, 16%) as yellow solid.

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Abstract

The invention relates to heterocyclic derivatives of formula (I) 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 mGluR5 modulators and are therefore useful for the control and prevention of acute and/or chronic neurological disorders wherein Y, W, R1, R2 and R3 are as defined in claim 1.

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. MGIuRI and mGluR5 belong to Group I which are positively coupled to phospholipase C and their activation leads to a mobilization of intracellular calcium ions. MGIuR2 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, cocaine addiction, cocaine 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, sleep disturbances, synucleinopathies, alpha-synucleinopathies, Lewy body dementia, neurodegeneration with Brain Iron Accumulation, Parkinson-plus syndrome, Pick's disease, progressive supranuclear palsy (PSP), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and neurodegenerative diseases.
[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] Furthermore, it has also been hypothesized that drugs which possess activity at multiple targets may be useful in treating neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and their associated symptoms (Cavalli, et al., J. Med. Chem. , 2008, 51, 347-372 and Morphy, et al., J. Med. Chem., 2005, 48, 6523- 6543).
[0015] Compounds which possess monoamine oxidase B (MAO-B) inhibitory activity have been disclosed to be useful in treating neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (Santana, et al., J. Med. Chem., 2008, 51, 6740-6751 ). It has been reported that preliminary data suggest that MAO inhibition may represent an interesting property to consider when designing multi-target-directed ligands (MTDLs) for Alzheimer's disease. Moreover, MTDLs for Parkinson's disease have been based on MAO inhibition in combination with a second activity (Cavalli, et al., J. Med. Chem. , 2008, 51, 347-372).
[0016] Thus, mGluR modulators which also possess MAO-B inhibitory activity may be particularly useful in treating neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease and their associated symptoms. mGluR modulators which do not possess MAO-B inhibitory activity may be particularly useful in treating dyskinesias e.g. L-dopa-induced dyskinesia.
[0017] The formation of GSH adducts indicates a certain likelihood of chemical reactivity which might lead to the formation of protein adducts in vivo, i.e. in the human body. Protein adducts are believed to be the cause, or at least associated with, severe types of toxicities, so-called idiosyncratic toxicities, that are a serious drawback for any compound. In most cases such toxicities lead to the discontinuation of further development. Compounds which do not exhibit formation of GSH adducts have a reduced risk of protein adduct formation and are therefore advantageous over compounds which form GSH adducts.
[0018] In the literature, several types of modulators of mGluR5 have already been described.
[0019] International Publication No. WO 2005/082856 discloses tetrahydroquinolinones of general Formula IA as metabotropic glutamate receptor antagonists which may be useful in treating chronic neurolo ical disorders:
Figure imgf000007_0001
IA
wherein R2 represents C2-6alkyl, cycloC3-i2alkyl,
Figure imgf000007_0002
C2-6alkenyl, C2-6alkynyl, aryl, biaryl, aryl-heteroaryl, heteroaryl-heteroaryl, heteroaryl- aryl, aryl-Ci-6alkyl, aryl-C2-6alkenyl, aryl-C2-6alkynyl, heteroaryl, heteroaryl-Ci-6alkyl, heteroaryl-C2-6alkenyl, heteroaryl-C2-6alkynyl, etc.; R3 represents hydrogen, cyano, nitro, halogen, Ci-6alkyl, CF3, heteroaryl, 2,3-dihydro-1 H-indenyl, hydroxy, Ci-6alkoxy, pyrrolidino, piperidino, or morpholino; R4 represents hydrogen, halogen, nitro,
Ci-6alkoxy, or hydroxy-C2-6alkoxy; and R5-R10 represent hydrogen, Chalky!, etc. [0020] International Publication No. WO 2007/023290 discloses tetrahydroquinolinones of general Formula I as metabotropic glutamate receptor modulators which may be useful in treating chronic neurolo ical disorders:
Figure imgf000008_0001
I
wherein R1 represents aryl or heteroaryl; R2 and R3 represent hydrogen or
Ci-6alkyl; and R4 and R5 represent hydrogen or Ci-6alkyl.
[0021 ] Furthermore, several types of heterocyclic compounds have been disclosed in the prior art.
[0022] International Publication Nos. WO 03/076416 and WO 03/076417 disclose oxo- azabicyclic compounds of general formula (l/e) as matrix metalloprotease-13 (MMP-13) inhibitors which are useful in treating inflammatory conditions such as rheumatoid arthritis and osteoarthritis and roliferative conditions such as cancer:
Figure imgf000008_0002
wherein X-i, X2, and X3 represent a nitrogen atom or -CR3 wherein R3 represents hydrogen, Ci-6alkyl, amino, Ci-6alkylamino, di-Ci-6alkylamino, hydroxyl, Ci-6alkoxy, or halogen; d represents a grou selected from (i/a) and (i/b):
Figure imgf000008_0003
(i/a) (i/b)
wherein the carbon atom with the number 2 is attached to the group N-R1 in the ring, R4 and R5 represent hydrogen, Ci-6alkyl, aryl, arylC-i-6alkyl, cycloalkyl, cycloalkylCi-6alkyl, heteroaryl, heteroarylC-i-6alkyl, heterocycloalkyl, or heterocycloalkylCi-6alkyl, and R6 represents hydrogen, trifluoromethyl, OR7, NR7R8, Ci-6alkyl, etc.; n represents 0 to 6; Zi represents -CR9R10; A represents aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; Ri represents hydrogen, C-i-6alkyl, etc.; m represents 0 to 7; and R2 represents C-i-6alkyl, halogen, -CN, N02, etc.
[0023] International Publication No. WO 2004/014866 discloses azaisoquinolinone derivatives of general formula (I) as matrix metalloprotease-13 (MMP-13) inhibitors which are useful in treating various conditions:
Figure imgf000009_0001
(I)
wherein R1 represents optionally substituted phenyl, optionally substituted naphthyl, optionally substituted heteroaryl, etc.; R2 represents hydrogen, Ci-6alkyl, etc.; R3 and R4 represent hydrogen, Ci-6alkyl, optionally substituted phenylC-i-ealkyenyl etc.; R5 represents hydrogen, Ci-6alkyl, NH2, OH, or halogen; n is 0 to 3; Q represents OC(O), CH(R6)C(O), C≡C, CH2C≡C, etc.; Y represents C=O, CH2, CH(R7), C(R7)2, O, S, S(O), or S(O)2; W1 represents N-R5 or CHR5 when— is absent or N or CR5 when— is a bond; and W2 W3, and W4 represent N or CR5
[0024] International Publication No. WO 2004/014880 discloses azaisoquinolinone derivatives of general formula (I) as matrix metalloprotease-13 (MMP-13) inhibitors which are useful in treating various conditions:
Figure imgf000009_0002
(I)
wherein R1 represents optionally substituted phenyl, optionally substituted naphthyl, optionally substituted heteroaryl, etc.; R2 represents hydrogen, Ci-6alkyl, etc.; Y2 represents N; Y3 represents CH2 or Y2 and Y3 combine to form C=C(R3); Y4 represents O or N-R5, wherein R5 represents hydrogen or Ci-6alkyl; one of U5, U6, and U8 is C-R4 or N and the other two are CH; and Q represents OC(O), CH(R6)C(O), C≡C, CH2C≡C, etc. THE PRESENT INVENTION
[0025] It now has been found that certain heterocyclic derivatives are potent mGluR5 modulators. Additionally, these heterocyclic derivatives may also exhibit MAO-B inhibitory activity. 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 and/or in the treatment of conditions in which MAO-B plays a role. 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.
[0026] Additionally, these heterocyclic derivatives may also avoid the formation of GSH-adducts and have therefore the advantage of a reduced protein adduct formation.
OBJECTS OF THE INVENTION
[0027] 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 CNS disorders involving MAO-B, and/or to provide symptomological effects, by employing a compound of the invention or a pharmaceutical composition containing the same.
[0028] An additional object of the invention is the provision of processes for producing the heterocyclic derivatives.
SUMMARY OF THE INVENTION
[0029] 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 imgf000011_0001
I wherein
Ri represents aryl, heteroaryl, cycloC3-i2alkyl, cycloCs-^alkenyl, or heterocyclyl; R2 represents hydrogen, fluorine, or Ci-6alkyl;
R3 represents hydrogen, fluorine, or Ci-6alkyl; or R2 and R3 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, C-i-6alkylamino, di-(C-i-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo;
W represents CH2, -CR4R5CH2- 0, S, -CR6R70-, NR8, or -CR9R10NR11 -;
Y represents CR-|2R-|3, or NR 4;
R4 represents hydrogen, fluorine, or Chalky!;
R5 represents hydrogen, fluorine, or Ci-6alkyl; or R4 and R5 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, C-i-6alkylamino, di-(C-i-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo; R6 represents hydrogen, fluorine, or Chalky!;
R7 represents hydrogen, fluorine, or Ci-6alkyl; or R6 and R7 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(Ci-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo;
R8 represents hydrogen, Ci-6alkyl, or acyl;
R9 represents hydrogen, fluorine, or Ci-6alkyl;
R-io represents hydrogen, fluorine, or Ci-6alkyl; or R9 and R 0 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(Ci-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo;
R-I -I represents hydrogen, Ci-6alkyl, or acyl;
R-I2 represents hydrogen, fluorine, Ci-6alkyl, amino, Ci-6alkylamino, di-(Ci-6alkyl)amino, acylamino, or heterocyclyl;
R-I3 represents hydrogen, fluorine, or Ci-6alkyl; or R 2 and R 3 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, C-i-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(Ci-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo; and
R 4 represents hydrogen, Ci-6alkyl, aryl, or heteroaryl; wherein the term "aryl" means phenyl or naphthyl, wherein the phenyl or naphthyl group is optionally substituted by one or more substituents, which may be the same or different, selected independently from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, hydroxyCi-6alkyl, C2-6alkenyl, Ci-6alkoxy, Ci-6alkoxyCi-6alkyl, 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, di-/V,/V-Ci-6alkylaminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, cycloCs-^alkyl, pyridinyl, and Ci-6alkylenedioxy; the term "heteroaryl" means 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 substituents, which may be the same or different, selected independently from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, hydroxyCi-6alkyl, C2-6alkenyl, Ci-6alkoxy, amino, hydroxy, nitro, cyano, Ci-6alkylcarbonyl, Ci-6alkoxycarbonyl, Ci-6alkoxycarbonyloxy, Ci-6alkylamino, and di-(Ci-6alkyl)amino, cycloC3-i2alkylamino, Ci-6alkylcarbonylamino, aminocarbonyl, /V-Ci-6alkylaminocarbonyl, di-/V,/V-Ci-6alkyl- aminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, cycloCs-^alkyl, Ci-6alkylenedioxy, aryl, and pyridinyl; and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof. [0030] A further aspect of the invention relates to a compound of Formula I, wherein W represents CH2, -CR4R5CH2- O, -CReRyO- or NR8 and Y represents CH2 or NR14.
[0031 ] Such a compound of Formula I, wherein R4, R5, R6, R7, and R 4 each independently represent hydrogen or Ci-6alkyl.
[0032] Such a compound of Formula I, wherein R4, R5, R6, R7, and Ri4 each independently represent hydrogen or methyl.
[0033] Such a compound of Formula I, wherein R8 represents hydrogen or acyl.
[0034] Such a compound of Formula I, wherein R8 represents hydrogen, Ci-6alkylcarbonyl, or Ci-6alkoxycarbonyl.
[0035] Such a compound of Formula I, wherein R8 represents hydrogen, acetyl, methoxycarbonyl, or ethoxycarbonyl.
[0036] Such a compound of Formula I, wherein R2 and R3 represent hydrogen or Ci-6alkyl or R2 and R3 together with the carbon atom to which they are attached form a 3 to 6-membered ring optionally containing a heteroatom selected from sulfur, oxygen, and nitrogen, wherein the ring may be optionally substituted by one or more substituents selected from Ci-6alkyl, Ci-6alkoxy, and acyl.
[0037] Such a compound of Formula I, wherein R2 and R3 represent hydrogen or Ci-6alkyl or R2 and R3 together with the carbon atom to which they are attached form a 3 to 5-membered carbocyclic ring or R2 and R3 together with the carbon atom to which they are attached form a nitrogen-containing ring, wherein the nitrogen atom may be optionally substituted with a substituent selected from Ci-6alkyl and acyl.
[0038] Such a compound of Formula I, wherein R2 and R3 represent hydrogen or methyl. [0039] Such a compound of Formula I, wherein R2 and R3 together with the carbon atom to which they are attached form a cyclopropane or cyclopentane ring.
[0040] Such a compound of Formula I, wherein R-i represents aryl, heteroaryl, cycloC3-i2alkyl, or cycloC5-i2alkenyl.
[0041 ] Such a compound of Formula I, wherein Ri represents phenyl optionally substituted by one or more substituents selected from F, CI, Br, Ci-6alkyl, cyano, Ci-6alkylcarbonyl, Ci-6alkoxycarbonyl, hydroxy, Ci-6alkoxy, nitro, amino, Ci-6alkylcarbonylamino, and cyano; pyridinyl optionally substituted by one or more substituents selected from F, Ci-6alkyl, cyano, hydroxy, Ci-6alkoxy, amino, C-i-6alkylamino, di-(Ci-6alkyl)amino, cycloC3-i2alkylamino, and piperidine; pyrimidinyl optionally substituted by one or more substituents selected from amino and Ci-6alkylamino; imidazopyridinyl; pyrrolopyridinyl; indazolyl; pyrazolopyridinyl; indolyl; benzotriazolyl; dihydropyridooxazinyl; tetrahydroimidazopyridinyl; cyclohexenyl; or cyclopentyl.
[0042] A further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IA
Figure imgf000015_0001
IA
wherein
R-T represents aryl, heteroaryl, cycloC3-i2alkyl, cycloCs-^alkenyl, or heterocyclyl; R2' represents hydrogen, fluorine, or Ci-6alkyl;
R3' represents hydrogen or Ci-6alkyl; or R2 and R3 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(Ci-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo;
W represents CH2, -CR4R5CH2- 0, S, or NR8;
Y' represents CH2 or NRi4;
R4 represents hydrogen, fluorine, or Ci-6alkyl;
R5 represents hydrogen or Chalky!; or R4 and R5 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Chalky!, Ci-6alkoxy, amino, hydroxy, cyano, acyl, C-i-6alkylamino, di-(C-i-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo;
R8 represents hydrogen, Chalky!, or acyl; and
R 4 represents hydrogen or Ci-6alkyl; and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
[0043] Such a compound of Formula IA, wherein W represents CH2, O, or NR8 and Y' represents CH2 or NRi4.
[0044] Such a compound of Formula IA, wherein R 4 represents hydrogen or Ci-6alkyl.
[0045] Such a compound of Formula IA, wherein Ri4 represents hydrogen or methyl.
[0046] Such a compound of Formula IA, wherein R2> and R3> represent hydrogen or Ci-6alkyl or R2 and R3 together with the carbon atom to which they are attached form a 3 to 6-membered ring optionally containing a heteroatom selected from sulfur, oxygen, and nitrogen, wherein the ring may be optionally substituted by one or more substituents selected from Ci-6alkyl, Ci-6alkoxy, and acyl.
[0047] Such a compound of Formula IA, wherein R2' and Ry represent hydrogen or Ci-6alkyl or R2' and Ry together with the carbon atom to which they are attached form a 5-membered ring or R2' and Ry together with the carbon atom to which they are attached form a nitrogen-containing ring, wherein the nitrogen atom may be optionally substituted with a substituent selected from Ci-6alkyl and acyl.
[0048] Such a compound of Formula IA, wherein R2' and Ry each represent methyl.
[0049] Such a compound of Formula IA, wherein R2> and Ry together with the carbon atom to which they are attached form a cyclopentane ring.
[0050] Such a compound of Formula IA, wherein R represents aryl, heteroaryl, cycloC3-i2alkyl or cycloC5-i2alkenyl.
[0051 ] Such a compound of Formula IA, wherein R represents phenyl optionally substituted by one or more substituents selected from F, CI, Br, Ci-6alkyl, cyano, Ci-6alkylcarbonyl, Ci-6alkoxycarbonyl, hydroxy, Ci-6alkoxy, nitro, amino, Ci-6alkylcarbonylamino, and cyano; pyridinyl optionally substituted by one or more substituents selected from F, Ci-6alkyl, cyano, hydroxy, Ci-6alkoxy, amino, C-i-6alkylamino, di-Ci-6alkylamino, cycloC3-i2alkylamino, and piperidine; pyrimidinyl optionally substituted by one or more substituents selected from amino and Ci-6alkylamino; cyclohexenyl; or cyclopentyl.
[0052] A further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IB
Figure imgf000018_0001
IB
wherein W" represents CH2, 0, or NR8; Y' represents CH2 or NRi4;
R-T represents aryl, heteroaryl, cycloC3-i2alkyl, cycloC5-i2alkenyl, or heterocyclyl; R2' represents hydrogen, fluorine, or Chalky!;
R3' represents hydrogen or Ci-6alkyl; or R2 and R3 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(Ci-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo;
R8 represents hydrogen, Ci-6alkyl, or acyl;
Ri4 represents hydrogen or Chalky!; and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
[0053] Such a compound of Formula IB, wherein W" represents CH2 or O.
[0054] Such a compound of Formula IB, wherein R 4 represents hydrogen or Ci-6alkyl.
[0055] Such a compound of Formula IB, wherein Ri4 represents hydrogen or methyl. [0056] Such a compound of Formula IB, wherein R2' and R3> represent hydrogen or Ci-6alkyl or R2 and R3 together with the carbon atom to which they are attached form a 3 to 6-membered ring optionally containing a heteroatom selected from sulfur, oxygen, and nitrogen, wherein the ring may be optionally substituted by one or more substituents selected from Ci-6alkyl, Ci-6alkoxy, and acyl.
[0057] Such a compound of Formula IB, wherein R2' and Ry represent hydrogen or Ci-6alkyl or R-i and R2 together with the carbon atom to which they are attached form a 5-membered ring or R2 and R3 together with the carbon atom to which they are attached form a nitrogen-containing ring, wherein the nitrogen atom may be optionally substituted with a substituent selected from Chalky! and acyl.
[0058] Such a compound of Formula IB, wherein R2> and R3> each represent methyl.
[0059] Such a compound of Formula IB, wherein R2> and R3> together with the carbon atom to which they are attached form a cyclopentane ring.
[0060] Such a compound of Formula IB, wherein R represents aryl, heteroaryl, cycloC3-i2alkyl or cycloCs-^alkenyl.
[0061 ] Such a compound of Formula IB, wherein R represents phenyl optionally substituted by one or more substituents selected from F, CI, Br, Chalky!, cyano, Ci-6alkylcarbonyl, Ci-6alkoxycarbonyl, hydroxy,
Figure imgf000019_0001
nitro, amino, Ci-6alkylcarbonylamino, and cyano; pyridinyl optionally substituted by one or more substituents selected from F, Ci-6alkyl, cyano, hydroxy, Ci-6alkoxy, amino, Ci-6alkylamino, di-(Ci-6alkyl)amino, cycloC3-i2alkylamino, and piperidine; pyrimidinyl optionally substituted by one or more substituents selected from amino and C-i-6alkylamino; cyclohexenyl; or cyclopentyl.
[0062] Specific compounds of Formula I within the present invention include, but are not limited to, the following compounds:
7,7-Dimethyl-3-(phenylethynyl)-7,8-dihydroquinolin-5(6/-/)-one,
3-((2-Fluorophenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one, 3-((3-Fluorophenyl)ethynyl)-77-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
3-((4-Fluorophenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
3-((2-Chlorophenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
3-((3-Chlorophenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
3-((3-Bromophenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
7,7-Dimethyl-3-(m-tolylethynyl)-7,8-dihydroquinolin-5(6/-/)-one,
3-((77-Dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)benzonitnle,
3-((3-Acetylphenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
Methyl 3-((7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)benzoate,
3-((3-Hydroxyphenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
3-((3-Methoxyphenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
7J-Dimethyl-3-((3-nitrophenyl)ethynyl)-7,8-dihydroquinolin-5(6/-/)-one,
3-((3-Aminophenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
N-(3-((77-Dimethyl-5-oxo-5,67,8-tetrahydroquinolin-3-yl)ethynyl)phenyl)acetamid
3-((77-Dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)-4-fluorobenzonitnle,
3-((5-Amino-2-fluorophenyl)ethynyl)-77-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
3-((3-Hydroxy-5-methylphenyl)ethynyl)-77-dimethyl-7,8-dihydroquinolin-5(6H)-on
7,7-Dimethyl-3-(pyndin-2-ylethynyl)-7,8-dihydroquinolin-5(6/-/)-one,
7J-Dimethyl-3-((6-methylpyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6H)-one,
2- ((77-Dimethyl-5-oxo-5,67,8-tetrahydroquinolin-3-yl)ethynyl)isonicotinonitn
3- ((6-Hydroxypyridin-2-yl)ethynyl)-77-dimethyl-7,8-dihydroquinolin-5(6/-/)-one, 3-((6-Methoxypyridin-2-yl)ethynyl)-77-dimethyl-7,8-dihydroquinolin-5(6H)-one, 3-((4-Aminopyridin-2-yl)ethynyl)-77-dimethyl-7,8-dihydroquinolin-5(6H)-one, 3-((6-Aminopyridin-2-yl)ethynyl)-77-dimethyl-7,8-dihydroquinolin-5(6H)-one, 7J-Dimethyl-3-((6-(methylamino)pyridin-2-yl)ethynyl)-7,8-dihydroquinolin-^
3-((6-(Cyclopropylamino)pyridin-2-yl)ethy^
one,
3-((6-(Dimethylamino)pyridin-2-yl)ethynyl)-77-dimethyl-7,8-dihydroquinoli
77-Dimethyl-3-((6-(piperidin-1 -yl)pyndin-2-yl)ethynyl)-7,8-dihydroquinolin-^
7,7-Dimethyl-3-(pyndin-3-ylethynyl)-7,8-dihydroquinolin-5(6/-/)-one,
3-((5-Fluoropyridin-3-yl)ethynyl)-77-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
5-((77-Dimethyl-5-oxo-5,67,8-tetrahydroquinolin-3-yl)ethynyl)nicotinonitri
7,7-Dimethyl-3-(pyndin-4-ylethynyl)-7,8-dihydroquinolin-5(6/-/)-one, 3- ((2-Fluoropyridin-4-yl)ethynyl)-77-dimethyl-7,8-dihydroquinolin-5(6H)-on 77-Dimethyl-3-((2-methylpyridin-4-yl)ethynyl)-7,8-dihydroquinolin-5(6H)-one,
4- ((77-Dimethyl-5-oxo-5,67,8-tetrahydroquinolin-3-yl)ethynyl)picolinonitrile,
3-((2-Methoxypyridin-4-yl)ethynyl)-77-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
3-((2-Aminopyridin-4-yl)ethynyl)-77-dimethyl-7,8-dihydroquinolin-5(6H)-one,
7J-Dimethyl-3-((2-(methylamino)pyridin-4-yl)ethynyl)-7,8-dihydroquinolin-5(^
3-((2-Aminopyrimidin-4-yl)ethynyl)-77-dim
7J-Dimethyl-3-((2-(methylamino)pyrimidin-4-yl)ethynyl)-7,8-dihydroquinoli
3-(Cyclohex-1 -en-1 -ylethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
3-(Cyclopentylethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
3'-(Phenylethynyl)-6',8'-dihydro-5'/-/-spiro[cyclopentane-1 ,7'-quinolin]-5'-one,
2,2-Dimethyl-6-(phenylethynyl)-2H-pyrano[2,3-b]pyndin-4(3/-/)-one,
6- ((6-Aminopyridin-2-yl)ethynyl)-2,2-dimethyl-2/-/-pyrano[2,3-b]pyridin-4(3/-/)-one, 2,2-Dimethyl-6-((6-(methylamino)pyridin-2-yl)ethynyl)-2H-pyrano[2,3-b]pyndi
one,
8,8-Dimethyl-3-(phenylethynyl)-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5-one, 6,8,8-Trimethyl-3-(phenylethynyl)-6,7,8,9-tetrahydro-5/-/-pyndo[3,2-c]azepin-5-one, 2,2-Dimethyl-7-(phenylethynyl)-3,4-dihydropyndo[3,2-f][1 ,4]oxazepin-5(2/-/)-one, 2,2,4-Trimethyl-7-(phenylethynyl)-3,4-dihydropyrido[3,2-f][1 ,4]oxazepin-5(2/-/)-one,
7- ((6-Aminopyridin-2-yl)ethynyl)-2,2-dimethyl-3,4-dihydropyrido[3,2-f][1 ,4]oxazepin- 5(2H)-one,
7-((6-Aminopyridin-2-yl)ethynyl)-2,2,4-trimethyl-3,4-dihydropyrido[3,2-f][1 ,4]oxazepin- 5(2H)-one,
6-(Phenylethynyl)-2,3-dihydro-1 ,8-naphthyridin-4(1 H)-one,
1 -Acetyl-6-(phenylethynyl)-2,3-dihydro-1 ,8-naphthyridin-4(1 H)-one,
2,2-Dimethyl-7-(m-tolylethynyl)-3,4-dihydropyndo[3,2-f][1 ,4]oxazepin-5(2/-/)-one,
3-((2,2-Dimethyl-5-oxo-2,3,4,5-tetrahydropyndo[3,2-f][1 ,4]oxazepin-7- yl)ethynyl)benzonitrile,
3-((2,2-Dimethyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1 ,4]oxazepin-7-yl)ethynyl)-4- fluorobenzonitrile,
3-((6-Aminopyridin-2-yl)ethynyl)-8,8-dimethyl-67,8,9-tetrahydro-5H-pyndo[3,2-c]azepin-
5- one,
Methyl 4-oxo-6-(phenylethynyl)-3,4-dihydro-1 ,8-naphthyridine-l (2/-/)-carboxylate, Methyl 6-((6-aminopyndin-2-yl)ethynyl)-4-oxo-3,4-dihydro-1 ,8-naphthyridine-1 (2H)- carboxylate,
Methyl 4-oxo-6-(m-tolylethynyl)-3,4-dihydro-1 ,8-naphthyridine-1 (2/-/)-carboxylate,
Ethyl 6-((6-aminopyridin-2-yl)ethynyl)-4-oxo-3,4-dihydro-1 ,8-naphthyridine-1 (2H)- carboxylate,
Methyl 6-((3-cyanophenyl)ethynyl)-4-oxo-3,4-dihydro-1 ,8-naphthyridine-1 (2H)- carboxylate,
Methyl 6-((5-cyano-2-fluorophenyl)ethynyl)-4-oxo-3,4-dihydro-1 ,8-naphthyridine-1 (2H)- carboxylate,
3-((3-Aminopyridin-2-yl)ethynyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5/-/-pyndo[3,2-c]azepin- 5-one,
3-((3-Amino-6-methylpyridin-2-yl)ethynyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2- c]azepin-5-one,
3-(lmidazo[1 ,2-a]pyndin-6-ylethynyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5/-/-pyndo[3,2- c]azepin-5-one,
3-((6-Aminopyridin-2-yl)ethynyl)-6,8,8-trimethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2- c]azepin-5-one,
3-((3-Aminopyridin-2-yl)ethynyl)-6,8,8-trimethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2- c]azepin-5-one,
3-((3-Amino-6-methylpyridin-2-yl)ethynyl)-6,8,8-trimethyl-6,7,8,9-tetrahydro-5/-/- pyrido[3,2-c]azepin-5-one,
3-(lmidazo[1 ,2-a]pyndin-6-ylethynyl)-6,8,8-tnmethyl-67,8,9-tetrahydro-5H-pyndo[3,2- c]azepin-5-one,
3-(lmidazo[1 ,2-a]pyndin-2-ylethynyl)-6,8,8-tnmethyl-67,8,9-tetrahydro-5H-pyndo[3,2- c]azepin-5-one,
3-(imidazo[1 ,2-a]pyndin-2-ylethynyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5/-/-pyndo[3,2- c]azepin-5-one,
3-((6,8,8-Tnmethyl-5-oxo-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-3- yl)ethynyl)benzonitrile,
3-((8,8-Dimethyl-5-oxo-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-3- yl)ethynyl)benzonitrile,
3-((8,8-Dimethyl-5-oxo-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-3-yl)ethynyl)-4- fluorobenzonitrile, 5- iil H-Pyrrolop.S-blpyridin^-y ethyny ^.e.e-trimethyl^J.e.S^etrahydro-SH- pyrido[3,2-c]azepin-5-one,
8,8-Dimethyl-3-( r?-tolylethynyl)-6,7,8,9-tetrahydro-5/-/-pyndo[3,2-c]azepin-5-one,
4-Fluoro-3-((6,8,8-trimethyl-5-oxo-6,7,8,9-tetrahydro-5/-/-pyndo[3,2-c]azepin-3- yl)ethynyl)benzonitrile,
3-((1 H-pyrrolo[2,3-b]pyridin-6-yl)^
c]azepin-5-one,
3-((1 /-/-lndazol-5-yl)ethynyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5/-/-pyndo[3,2-c]azepin-5- one,
3-((2-Fluorophenyl)ethynyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5- one,
3-((4-Fluorophenyl)ethynyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5- one,
2,2-Dimethyl-6-(m-tolylethynyl)-2/-/-pyrano[2,3-b]pyridin-4(3/-/)-one,
3-((2,2-Dimethyl-4-oxo-3,4-dihydro-2/-/-pyrano[2,3-b]pyndin-6-yl)ethynyl)benzonitrile, 3-((2,2-Dimethyl-4-oxo-3,4-dihydro-2/-/-pyrano[2,3-b]pyndin-6-yl)ethynyl)-4- fluorobenzonitrile,
6- (lmidazo[1 ,2-a]pyridin-6-ylethynyl)-2,2^
6-(lmidazo[1 ,2-a]pyridin-2-ylethynyl)-2,2^
6-((1 H-lndazol-5-yl)ethynyl)-2,2-dimethyl-2H-pyrano[2,3-b]pyndin-4(3/-/)-one,
6-((1 H-Pyrrolo[2,3-b]pyndin-6-yl)ethynyl)-2,2-dimethyl-2/-/-pyrano[2,3-b]pyridin-4(3/-/)- one,
3-(lmidazo[1 ,2-a]pyndin-5-ylethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
3-(lmidazo[1 ,2-a]pyndin-8-ylethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
7,7-Dimethyl-3-(pyrazolo[1 ,5-a]pyndin-7-ylethynyl)-7,8-dihydroquinolin-5(6/-/)-one,
3-((1 /-/-lndol-5-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
3-((1 H-Benzo[d][1 ,2,3]triazol-5-yl)ethynyl)-77-dimethyl-7,8-dihydroquinolin-5(6H)
3-((6-Aminopyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6/-/)-one,
3-((6-Aminopyridin-2-yl)ethynyl)-7-methyl-7,8-dihydroquinolin-5(6/-/)-one,
3-((6-Aminopyrimidin-4-yl)ethynyl)-77-dimethyl-7,8-dihydroquinolin-5(6H)-on
3-(lmidazo[1 ,2-a]pyndin-6-ylethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
3-((3-Amino-6-methylpyridin-2-yl)ethynyl)-77-dimethyl-7,8-dihydroquinolin-5
3-((3H-lmidazo[4,5-b]pyridin-5-yl)ethynyl)-77^ 3-(lmidazo[1 ,2-a]pyndin-2-ylethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one, 7,7-Dimethyl-3-(pyrazolo[1 ,5-a]pynmidin-5-ylethynyl)-7,8-dihydroquinolin-5(6/-/)-one, 7-Methyl-3-(phenylethynyl)-7,8-dihydroquinolin-5(6/-/)-one,
2- ((77-Dimethyl-5-oxo-5,67,8-tetrahydroquinolin-3-yl)ethynyl)nicotinonitrile,
3- ((1 H-Pyrrolo[2,3-b]pyridin-6-yl)e ^
3-((1 /-/-lndazol-5-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
3-((3-Aminopyridin-2-yl)ethynyl)-77-dimethyl-7,8-dihydroquinolin-5(6H)-one,
7J-Dimethyl-3-((4-methylpyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6H)-one,
2- ((77-Dimethyl-5-oxo-5,67,8-tetrahydroquinolin-3-yl)ethynyl)-6-methylnicotin
7-Methyl-3-((4-methylpyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6/-/)-one,
3- ((1 H-Pyrrolo[3,2-b]pyridin-3-yl)et^
3-((5-Amino-6-methylpyridin-2-yl)ethynyl)-77-dimethyl-7,8-dihydroquinolin-5
3'-((6-Aminopyridin-2-yl)ethynyl)-6',8'-dihydro-5'/-/-spiro[cyclopropane-1 ,7'-quinolin]-5'- one,
3-((3,4-Dihydro-2/-/-pyndo[3,2-b][1 ,4]oxazin-6-yl)ethynyl)-7,7-dimethyl-7,8- dihydroquinolin-5(6/-/)-one,
6-Methyl-2-((7-methyl-5-oxo-5,67,8-tetrahydroquinolin-3-yl)ethynyl)nicotinonitnle, 3-((3-Aminopyridin-2-yl)ethynyl)-7-methyl-7,8-dihydroquinolin-5(6/-/)-one,
7,7-Dimethyl-3-(pyrazolo[1 ,5-a]pyndin-2-ylethynyl)-7,8-dihydroquinolin-5(6/-/)-one, 3'-((6-(Methylamino)pyridin-2-yl)ethynyl)-6',8'-dihydro-5'/-/-spiro[cyclopropane-1 ,7'- quinolin]-5'-one,
3-((5-Amino-4-methylpyridin-2-yl)ethynyl)-77-dimethyl-7,8-dihydroquinolin-5
7,7-Dimethyl-3-((5,6,7,8-tetrahydroimidazo[1 ,2-a]pyndin-2-yl)ethynyl)-7,8- dihydroquinolin-5(6/-/)-one,
3-([1 ,2,4]Tnazolo[1 ,5-a]pyndin-2-ylethynyl)-77-dimethyl-7,8-dihydroquinolin-5(6^ 3-(Phenylethynyl)-7,8-dihydroquinolin-5(6/-/)-one,
3-((3-Fluorophenyl)ethynyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5- one,
3-((3-Fluorophenyl)ethynyl)-6,8,8-tnmethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5- one,
3-((2-Fluorophenyl)ethynyl)-6,8,8-tnmethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5- one, 3-((4-Fluorophenyl)ethynyl)-6,8,8-trimethyl-6,7,8,9-tetrahydro^
one,
6,8,8-Trimethyl-3-( r?-tolylethynyl)-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5-one,
3-((1 /-/-lndazol-5-yl)ethynyl)-6,8,8-trimethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5- one, and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
[0063] 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 use in therapy.
[0064] 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.
[0065] 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. [0066] 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 and/or in the treatment or prevention of conditions in which MAO-B plays a role. 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), synucleinopathies, alpha-synucleinopathies, Lewy body dementia, neurodegeneration with Brain Iron Accumulation, Parkinson- plus syndrome, Pick's disease, progressive supranuclear palsy (PSP), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and neurodegenerative diseases, 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. d) Inhibition of MAO-B may be particularly useful for neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. Inhibition of MAO-B may also be useful for smoking cessation, depression and/or mood stabilization.
[0067] 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.
[0068] 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.
[0069] 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.
[0070] 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.
[0071 ] 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.
[0072] 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.
[0073] 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 neuro-protection.
[0074] 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. [0075] 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).
[0076] 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.
[0077] 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.
[0078] This invention also relates to a method for treating or preventing a condition or disease in which MAO-B plays a role, including for the conditions or diseases selected from those described earlier in the description.
[0079] Furthermore, the invention relates to the a compound of Formula I as described herein for use in inhibiting MAO-B. This use may be in the treatment or prevention of a condition or disease as described herein.
[0080] The invention also relates to a process for the synthesis or preparation of a compound of Formula I
Figure imgf000029_0001
wherein a compound of Formula II
Figure imgf000030_0001
is treated with an arylacetylene of Formula III
^^Ri III, in the presence of a suitable catalyst, such as PdCl2(PPh3)2, to yield a
compound of Formula I, which may be converted to a prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
[0081 ] The invention also relates to a process for the synthesis or preparation of a compound of Formula I
Figure imgf000030_0002
wherein a compound of Formula II
Figure imgf000030_0003
is treated with trimethylacetylene to yield, after removal of the TMS group under appropriate conditions, a compound of Formula IV
Figure imgf000030_0004
which is reacted with a compound of Formula V
RrHal V, in the presence of a suitable catalyst, such as PdCI2(PPh3)2, to yield a compound of Formula I, which may be converted to a prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
DETAILED DESCRIPTION OF THE INVENTION
[0082] 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,
Figure imgf000031_0001
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).
[0083] As used herein, the following definitions are applicable unless otherwise described, the term "Ci-6alkyl" represents straight or branched chain alkyl groups which may be optionally substituted by one or more (e.g., 1 , 2, 3, 4, or 5) substituents selected from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, Ci-6alkoxy, amino, hydroxy, Ci-6alkylamino, and di-(Ci-6alkyl)amino. Examples of such alkyl groups include methyl, ethyl, n-propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, and -CF3,
[0084] The term "C2-6alkenyl" represents straight or branched chain alkenyl groups.
[0085] The term "Ci-6alkoxy" represents straight or branched chain -0-Ci-6alkyl groups which may be optionally substituted by one or more (e.g., 1 , 2, 3, 4, or 5) substituents selected from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, amino, hydroxy, d- 6alkylamino and di-(C-i-6alkyl)amino. Examples of such alkoxy groups include methoxy, ethoxy, n-propoxy, /-propoxy, -OCF3 and -OC2F5.
[0086] The term "acyl" represents Ci-6alkylcarbonyl, trifluoroacetyl, hydroxy- Ci-6alkylcarbonyl, Ci-6alkoxycarbonyl, /V-Ci-6alkylaminocarbonyl, Λ/,/V-di- (Ci-6alkyl)aminocarbonyl, C-i-ealkoxy-C-i-ealkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, cyclo-C3-i2alkylcarbonyl, aryl-Ci-6alkylcarbonyl, heteroaryl-Ci-6alkylcarbonyl, arylamino- Ci-6alkylcarbonyl, heteroarylamino-Ci-6alkylcarbonyl, heterocyclylcarbonyl and heterocyclyl-Ci-6alkylcarbonyl.
[0087] 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, Ci-6alkylamino, and di-(Ci-6alkyl)amino, Ci-6alkyl- carbonylamino, oxo, Ci-6alkoxyimino, Ci-6alkylaminocarbonyl, arylCi-6alkoxycarbonyl, and Ci-6alkylenedioxy.
[0088] The term "cycloCs-^alkenyl" represents monocyclic or bicyclic, or tricyclic alkenyl groups, including cyclopentenyl, cyclohexenyl, and bicyclo[2.2.1 ]heptenyl, 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, C2-6alkenyl, Ci-6alkoxy, amino, hydroxy, cyano, Ci-6alkoxycarbonyl, Ci-6alkylamino, and di-(Ci-6alkyl)amino, Ci-6alkyl- carbonylamino, oxo, Ci-6alkoxyimino, Ci-6alkylaminocarbonyl, arylCi-6alkoxycarbonyl, and Ci-6alkylenedioxy.
[0089] 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, trifluoromethoxy, Ci-6alkyl, hydroxyCi-6alkyl, C2-6alkenyl, Ci-6alkoxy, Ci-6alkoxyCi-6alkyl, amino, hydroxy, nitro, cyano, formyl, Ci-6alkylcarbonyl, Ci-6alkoxycarbonyl, Ci-6alkylcarbonyloxy, d-ealkylcarbonyloxyd-ealkyl, C-i-6alkylamino, di-(Ci-6alkyl)amino, cycloC3-i2alkylamino, Ci-6alkylcarbonylamino, phenylcarbonylamino, aminocarbonyl, /V-Ci-6alkylaminocarbonyl, di-/V,/V-Ci-6alkylaminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, cycloCs-^alkyl, pyridinyl, and Ci-6alkylenedioxy. [0090] 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, trifluoromethoxy, Ci-6alkyl, hydroxyCi-6alkyl, C2-6alkenyl, Ci-6alkoxy, amino, hydroxy, nitro, cyano, d. 6alkylcarbonyl, Ci-6alkoxycarbonyl, Ci-6alkoxycarbonyloxy, C-i-6alkylamino, and di-(Ci-6alkyl)amino, cycloC3--i2alkylamino, C-i-6alkylcarbonylamino, aminocarbonyl, /V-Ci-6alkylaminocarbonyl, di-/V,/V-Ci-6alkylaminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, cycloC3-i2alkyl, Ci-6alkylenedioxy, aryl, and pyridinyl. Representative heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, pyrazolyl, triazolyl, thiadiazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, purinyl, pyrazolyl, benzofuryl, benzothienyl, indolyl, indolizinyl, isoindolyl, indolinyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, isoquinolinyl, quinolizinyl, phthalazinyl, theridinyl.
[0091 ] 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, C2-6alkenyl, Ci-6alkoxy, amino, hydroxy, nitro, cyano, d. 6alkoxycarbonyl, Ci-6alkylamino, and di-(Ci-6alkyl)amino, Ci-6alkylcarbonylamino, oxo, C-i-6alkoxyimino, C-i-6alkylaminocarbonyl, 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.
[0092] The term "halogen" represents fluorine, chlorine, bromine and iodine.
[0093] 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, "h" for hour or hours, "min" for minute or minutes, and "r.t." for room temperature).
[0094] 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.
[0095] 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).
[0096] 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. [0097] 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.
[0098] 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).
[0099] 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.
[00100]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. [00 01 ] 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.
[00102]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 rocedure towards compounds of Formula I.
Figure imgf000036_0001
[00103] Sonogashira coupling of a bromo-heterocyclic compound 2 with an arylacetylene 3 in the presence of a suitable catalyst, such as Pd(PPh3)2Cl2, provides an arylethynyl substituted derivative of Formula I. Alternatively, a bromo-heterocyclic compound 2 may be reacted with tnmethylsilylacetylene (4) to give, after cleavage of the TMS group, ethynyl-substituted compound 5. Compound 5 is converted to an arylethynyl substituted derivative of Formula I via Sonogashira coupling with an aryl halide 6.
[00104] Methods for preparing bromo-heterocyclic compounds (2) are shown in Schemes 2-4.
Scheme 2 - Synthesis of bromo-heterocyclic compounds
Figure imgf000037_0001
[00105] Bromo-heterocyclic compounds 2 are prepared by condensation of enamines 8, derived from 1 ,3-cyclohexanediones or 1 ,3-cyclopentanediones 7, with bromomalonaldehyde as shown in Scheme 2. Compounds thus obtained can be used for Sonogashira coupling as shown in Scheme 1 , or can be further modified, using Beckmann or Schmidt rearrangements to give 6- or 7-membered lactams 9. The amide nitrogen in these compounds can be alkylated to give /V-alkyl derivatives 10. Scheme 3 - Synthesis of ring oxygen containing bromo-heterocyclic compounds
Figure imgf000038_0001
[00106]3,5-Dibromo-2-methoxypyridine 11 is ortho-lithiated and treated with an unsaturated aldehyde 12 to give an allylic alcohol 13. Allylic oxidation with Mn02 provides enone 14, which is cyclized in the presence of boron trichloride to compound 15. Similarly as shown in Scheme 2, this ketone can be ring-expanded to corresponding amides 16 using Beckmann or Schmidt reactions and finally N-alkylated to compounds 17. Compounds 15, 16 and 17 all can be used for Sonogashira couplings to provide compounds of Formula I.
Scheme 4 - Synthesis of 8-aza analogs of bromo-heterocyclic compounds
Figure imgf000038_0002
[00107]Aminopyridine 18 is reacted with acrylic acid (19) to give the corresponding carboxylic acid 20. Cyclization by means of triflic acid leads to the bromo-heterocyclic compound 21 , which can be used for Sonogashira coupling as shown in Scheme 1. Compounds thus obtained (22) can be further derivatized by alkylation or acylation (23).
[00108]lt 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.
[00109]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.
[001 10]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.
[001 1 1 ]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 C12 are substituted by C14, where one or more fluor atoms are substituted by F18 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
[001 12]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
[001 13]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.
[001 14]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.
[001 15]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
[001 16]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. [001 17]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.
[001 18]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.
[001 19]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.
[00120]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.
[00121 ]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.
[00122]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., EtOH, 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.
[00123]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.
[00124]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.
[00125]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.
[00126]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.
[00127]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.
[00128]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).
[00129]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.
[00130]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. [00131 ]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.
[00132]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.
[00133]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.
[00134]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.
[00135]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.
[00136]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.
[00137]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.
[00138]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.
[00139]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
[00140]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.
[00141 ]Hereinafter, "Boc" is defined as fe/f-butyloxycarbonyl, "BuLi" as n-butyl-Lithium, "DBU" as 1 ,8-diazabicyclo[5.4.0]undec-7-ene, "DCM" as dichloromethane, "DMAP" as /V,/V-dimethylpyridin-4-amine, "DMF" as Λ/,/V-dimethylformamide, "DMSO" as dimethylsulfoxide, "EtOAc" as ethyl acetate, "EtOH" as ethanol, "HCI" as hydrochloric acid, "MeOH" as methanol, "NaOH" as sodium hydroxide, "P(f-Bu)3" as tri-fe/f- butylphosphine, "SPhos" as 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, "TBAF" as tetra-n-butylammonium fluoride, "TBTU" as 0-(benzotriazol-1 -yl)-/V,/V,/V',/V'-tetra- methyluronium tetrafluoroborate, "TEA" as triethylamine, "Tf20" as trifluoromethanesulfonic acid anhydride, "TFA" as trifluoroacetic acid, and "THF" as tetrahydrofuran.
General Procedure 1 - Sonogashira coupling of bromo-heterocyclic compounds with substituted acetylenes
[00142]A mixture of bromo-heterocyclic compound, substituted acetylene, palladium catalyst, base, and additional reagents (see specific examples) in dry DMF or acetonitrile is stirred under argon atmosphere at elevated temperature. Product formation is monitored by TLC or HPLC. After completion of the reaction the resulting mixture is cooled to r.t., poured into water, and extracted with EtOAc or DCM. The organic phase is dried and concentrated. Purification by chromatography (flash column, preparative TLC or preparative HPLC) provides the title compound.
Preparation 1
3-Bromo-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one
[00143]A mixture of 5,5-dimethylcyclohexane-1 ,3-dione (1 1 .21 g, 80 mmol), ammonium acetate (12.33 g, 160 mmol), glacial acetic acid (1 mL), and benzene (150 mL) is stirred at reflux with a Dean-Stark trap for 1 h, cooled down to r.t., poured into saturated aqueous sodium bicarbonate solution, and extracted twice with EtOAc. The combined organic phases are washed with water, dried over sodium sulfate, concentrated at reduced pressure, and dried in vacuum to give 3-amino-5,5-dimethylcyclohex-2-enone (10.37 g, 93%) as yellow solid.
[00144]To a solution of 3-amino-5,5-dimethylcyclohex-2-enone (2.78 g, 20.00 mmol) in EtOH (50 mL) 46% aqueous solution of HBr (2.40 mL, 20.00 mmol) is added. The resulting solution is stirred at ambient temperature for 5 min and concentrated at reduced pressure. The obtained solid is dissolved in a mixture of acetonitrile/benzene, concentrated at reduced pressure, washed with dry acetonitrile and dried to yield 3- amino-5,5-dimethylcyclohex-2-enone hydrobromide (4.08 g, 93%) as white solid.
[00145]A mixture of 3-amino-5,5-dimethylcyclohex-2-enone hydrobromide (1 .98 g, 9.00 mmol), commercially available bromomalonaldehyde (1 .51 g, 10.00 mmol) and EtOH (30 ml_) is refluxed for 17 h, then cooled down to r.t., treated with excess of sodium bicarbonate, concentrated at reduced pressure, diluted with DCM, and filtered. The filtrate is concentrated at reduced pressure. Purification by column chromatography (silica gel, DCM/hexane, 1/20) gives 3-bromo-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)- one (1.04 g, 46%) as white solid.
Preparation 2
3,-Bromo-6 8,-dihydro-5Ή-spiro[cyclopentane-1,7,-quinolin]-5,-one
[00146]Cyclopentanone (3.73 g, 44.4 mmol) is added dropwise to a solution of (2-oxo- propyl)-phosphonic acid diethyl ester (10.27 g, 53 mmol) and potassium carbonate (12.25 g, 88.8 mmol) in 100 ml_ of water at r.t. The mixture is heated to reflux for 24 h, then cooled and extracted with hexane. The organic layer is separated, dried over anhydrous sodium sulfate and evaporated to dryness. Purification of the residue by flash column chromatography (hexane - EtOAc) provides 1 g (18%) of 1 - cyclopentylidene-propan-2-one.
[00147]A mixture of 1 -cyclopentylidene-propan-2-one (1 g, 9.4 mmol) and diethyl malonate (1 .75 g, 1 1 mmol) is added dropwise to a slution of sodium methoxide prepared by dissolving sodium (0.25 g, 1 1 mmol) in MeOH (3 ml_). The mixture is heated to reflux for 2 h, then a hot solution of barium hydroxide (1 1 .23 g, 73 mmol) in 100 ml_ of water is added and the mixture is refluxed for 24 h, then neutralized to pH 6 with diluted hydrochloric acid while still hot and filtered. The filtrate is cooled and acidified to pH 1 with diluted hydrochloric acid, refluxed for 15 min, filtered while hot and then cooled. The formed precipitate is filtered, washed with water and dried to give 0.87 g (56%) of spiro[4.5]decane-7,9-dione. [00148]Spiro[4.5]decane-7,9-dione is converted to 3'-bromo-6',8'-dihydro-5'/-/- spiro[cyclopentane-1 ,7'-quinolin]-5'-one by a two step procedure analogous to that described in Preparation 1 for conversion of 5,5-dimethylcyclohexane-1 ,3-dione to 3- bromo-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one.
Preparation 3
β'-ΒΓο ο-β',δ'-εΙΪΓΐγεΐΓθ-δΉ-βρϊΓθΙογοΙορΓορβηθ-Ι,Τ'- υϊηοΜηΙ-δ'-οηθ
[00149](1 -Ethoxycyclopropoxy)trimethylsilane (7.58 g, 43.5 mmol), 1 - (triphenylphosphoranylidene)propan-2-one (18 g, 56.5 mmol) and p-toluenesulfonic acid (0.75 g, 4.35 mmol), are dissolved in 1 ,2-dichlorobenzene (50 mL), and the mixture is heated to 100 °C for 4 h, then cooled to r.t. and directly purified by flash column chromatography on silica gel petroleum ether, DCM) to provide the intermediate 1 - cyclopropylidenepropan-2-one (2.67 g, 64%).
[00150]Sodium hydride (0.7 g, 80% suspension in toluene) is washed twice with benzene and suspended in THF (35 mL). Dimethylmalonate (1 .74 g, 13.2 mmol) is added followed by slow addition of 1 -cyclopropylidenepropan-2-one (1 .15 g, 12.0 mmol), and the mixture is heated to reflux for 4 h. A solution of KOH (1 .54 g, 27.5 mmol) in water (10 mL) is added, and the mixture is refluxed for additional 1 h. The mixture is cooled and treated with aqueous HCI to reach pH 1 , then extracted with EtOAc. The organic layer is dried over anhydrous Na2S04 and evaporated, and the residue is purified by flash column chromatography on silica gel to provide spiro[2.5]octane-5,7- dione (1 .3 g, 54%) as an oil.
[00151 ]A mixture of spiro[2.5]octane-5,7-dione (2.20 g, 15.92 mmol), ammonium acetate (2.45 g, 31 .78 mmol), and acetic acid (0.5 mL) in benzene (30 mL) is stirred at reflux for 5 h using a Dean-Stark trap, cooled down to r.t., poured into a saturated NaHC03.solution, and extracted twice with EtOAc. The organic phase is dried over anhydrous Na2SO4 and evaporated. The residue is dissolved in EtOH and treated with aqueous HBr solution, then evaporated to dryness again to give sufficiently pure 7- aminospiro[2.5]oct-6-en-5-one hydrobromide salt as yellow solid. [00152]A mixture of 2-bromomalonaldehyde (605 mg, 4.01 mmol) and 7- aminospiro[2.5]oct-6-en-5-one hydrobromide salt (500 mg, 3.64 mmol) in EtOH (8 mL) is heated to 50 °C for 18 h, then cooled down to r.t., poured into water and extracted with EtOAc. The organic phase is concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound (247 mg, 27%) as yellow solid.
Preparation 4
6-Bromo-2,2-dimethyl-2H-pyrano[2,3-b]pyridin-4(3H)-one
[00153]A solution of 3,5-dibromo-2-methoxypyridine (1 1 .4 g, 42.7 mmol) in dry diethyl ether is cooled to -65 °C and treated with BuLi (19 mL 2.5 M solution in hexane, 47.5 mmol) under argon atmosphere. The mixture is stirred at -70 °C for 0.5 h. A solution of 3-methylbut-2-enal (3.44 g, 40.9 mmol) in dry THF (10 mL) is added to the mixture, and stirring is continued for another 0.5 h at -70 °C. The reaction mixture is then warmed to r.t. and quenched with a saturated solution of sodium bicarbonate (100 mL). After extraction with DCM (3 x 100 mL) the combined organic layers are dried over Na2S04 and concentrated under reduced pressure to yield 1 -(5-bromo-2-methoxypyridin-3-yl)-3- methylbut-2-en-1 -ol (1 1 g, 95%).
[00154]MnO2 (18 g, 207 mmol) is added to a solution of 1 -(5-bromo-2-methoxypyridin- 3-yl)-3-methylbut-2-en-1 -ol (3 g, 1 1 mmol) in dry DCM (500 mL) in one portion. The mixture is stirred for 3 days and filtered. The filtrate is concentrated under reduced pressure, and the residue is purified by preparative TLC chromatography (S1O2, eluent - hexane-ethylacetate 4: 1 ) to yield 1 -(5-bromo-2-methoxypyridin-3-yl)-3-methylbut-2-en- 1 -one (2.4 g, 81 %).
[00155]To a solution of 1 -(5-bromo-2-methoxypyridin-3-yl)-3-methylbut-2-en-1 -one (1 .2 g, 4.4 mmol) in dry DCM (50 mL) a mixture of boron trichloride (2 g, 17.1 mmol) in dry DCM (50 mL) is added dropwise at -45 to -50 °C. After the addition the mixture is stirred for 0.5 h at -45 °C, allowed to warm to r.t., and stirred for another 0.5 h. The reaction mixture is quenched by a saturated aqueous sodium bicarbonate solution. The organic layer is separated, dried over magnesium sulfate, and concentrated in vacuum to obtain 6-bromo-2,2-dimethyl-2/-/-pyrano[2,3-b]pyridin-4(3/-/)-one (0.5 g, 44%).
Preparation 5
6-Bromo-2,3-dihydro-1 ,8-naphthyridin-4(1 H)-one
[00156] Aery lie acid (8.33 g, 1 15.6 mmol) is carefully added dropwise to a refluxing solution of 5-bromopyridin-2 -amine (10.00 g, 57.80 mmol) in toluene (25 mL). The mixture is stirred at reflux for 3 days, concentrated at reduced pressure and diluted with aqueous KOH (6.47 g, 1 15.6 mmol) solution (150 mL). The formed solid is filtered, and the filtrate is extracted with DCM (3x). The aqueous phase is acidified to pH 5. The formed solid is collected by filtration, washed with water and dried to provide 3-((5- bromopyridin-2-yl)amino)propanoic acid (12.75 g, 90%) as beige solid.
[00157]A mixture of the propanoic acid intermediate (5.50 g, 22.44 mmol) and CF3SO3H (50 mL) is stirred at 90 °C for 3 h, cooled down to r.t. and poured onto crushed ice (300 g). Then KOH is added to reach pH 12. The resulting mixture is extracted with DCM. The organic phase is concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane, 1 :5), recrystallized from EtOH and dried to provide the title compound (1 .019 g, 20%) as yellow solid.
Preparation 6
3-Bromo-8,8-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-5-one
[00158]3-Bromo-8,8-dimethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5-one is synthesized in two steps starting from 3-bromo-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)- one (accessible according to Preparation 1 ).
[00159]A mixture of 3-bromo-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one (10.16 g, 40.0 mmol), NH2OH*HCI (8.34 g, 120.0 mmol), and sodium acetate (16.32 g, 120.0 mmol) in MeOH (100 mL) and water (24 mL) is stirred at reflux for 6 h and cooled to r.t. MeOH is removed at reduced pressure. The obtained solid is collected by filtration, washed with water and hexane and dried at 50 °C to give the intermediate product 3-bromo-7,7- dimethyl-7,8-dihydroquinolin-5(6/-/)-one oxime (10.25 g, 95%) as a white solid.
[00160]A mixture of 3-bromo-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one oxime (10.21 g, 37.94 mmol), P205 (7.350 g, 51 .78 mmol) and POCI3 (32 mL) is stirred at 100 °C for 1.5 h. DMF (18.0 mL, 23.25 mmol) is added in one portion. The reaction mixture is stirred at 100 °C for 1.5 h, cooled to r.t, poured into iced water, basified with 50% aqueous NaOH solution, and extracted with EtOAc. The combined organic phases are washed with water and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to provide the title compound (5.41 g, 53%) as white solid.
Preparation 7
3-Bromo-6,8,8-trimethyl-6,7,8,9 etrahydro-5H-pyrido[3,2-c]azepin-5-one
[00161 ]Sodium hydride (60% suspension in oil, 640 mg, 15.95 mmol) is added portionwise to a solution of 3-bromo-8,8-dimethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2- c]azepin-5-one (3.90 g, 14.50 mmol) in THF (40 mL), and the reaction mixture is stirred at r.t. for 30 min. Methyl iodide (1 .08 mL, 17.40 mmol) is added, and the resulting mixture is stirred at r.t. for 60 h, poured into water and extracted with EtOAc. The combined organic phases are washed with water, concentrated at reduced pressure and dried to provide the title compound.
Preparation 8
7-Bromo-2,2-dimethyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one
[00162]A mixture of 6-bromo-2,2-dimethyl-2/-/-pyrano[2,3-b]pyridin-4(3/-/)-one (see Preparation 4; 256 mg, 1 .0 mmol), H2NOH hydrochloride (210 mg, 3.0 mmol), and sodium acetate (250 mg, 3.0 mmol) in acetonitrile (10 mL) and H20 (1 mL) is stirred at reflux for 6 h, cooled down to r.t. and concentrated at reduced pressure. The obtained residue is washed with water and hexane and purified by column chromatography (silica gel, EtOAc/hexane, 1 :4) to give the intermediate product 6-bromo-2,2-dimethyl-2/-/- pyrano[2,3-b]pyridin-4(3/-/)-one oxime (220 mg, 81 %) as white solid. [00163]POCI3 (1.3 ml_, 14.03 mmol) and P205 (290 mg, 2.1 1 mmol) are added to 6- bromo-2,2-dimethyl-2/-/-pyrano[2,3-b]pyridin-4(3/-/)-one oxime (423 mg, 1 .56 mmol), and the resulting mixture is stirred at 100 °C for 1.5 h. DMF (2 ml_) is added to the solution, and the mixture is stirred at 100 °C for 1 .5 h, cooled down to r.t., poured into iced water, neutralized with NaOH to reach pH 7-8, and extracted with EtOAc (3x30 ml_). The combined organic phases are dried over Na2S04 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane, 1 :5) to provide the title compound (120 mg, 28%) as light brown oil.
Preparation 9
6-Ethynylpyridin-2-amine
[00164]A mixture of 6-bromopyridin-2-amine (25.90 g, 150 mmol), ethynyltrimethylsilane (22.10 g, 225 mmol), PdCI2[PPh3]2 (3.50 g, 5 mmol), Cul (2.90 g, 15 mmol), TEA (70 ml_), and benzene (150 ml_) is stirred for 7 h at 50 °C under argon atmosphere, cooled down to r.t. and concentrated in vacuo. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to provide a product mixture of 6- ((trimethylsilyl)ethynyl)pyridin-2-amine and 6-ethynylpyridin-2-amine. The obtained mixture is dissolved in THF (150 ml_), and 1 M solution of TBAF in THF (150 ml_) is added dropwise at -20 °C. The mixture is stirred at 0 °C for 20 min, diluted with water and extracted with DCM. The organic layer is dried over Na2SO4 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to provide the title compound (1 1.90 g, 67%, for two steps) as grey solid.
Preparation 10
/V,/V-di-Boc-protected 6-ethynylpyridin-2-amine
[00165]Boc2O (26.50 g, 121 .4 mmol) is added portionwise to a solution of 6- bromopyridin-2 -amine (10.00 g. 57.8 mmol), TEA (18.0 ml_, 13.00 g, 128.5 mmol) and DMAP (0.40 g, 3.3 mmol) in DCM (500 ml_). The reaction mixture is stirred at r.t. for 17 h, washed with 10% aqueous K2CO3 solution (300 ml_) and the organic phase is concentrated at reduced pressure. The obtained residue is recrystallized from hexane to give Λ/,/V-di-Boc-protected 6-bromopyridin-2 -amine (20.50 g, 95%) as light beige solid, which is further converted to the title compound according to the procedure described for Preparation 9.
General Procedure 2 - Sonogashira coupling of ethynyl-heterocyclic compounds with aryl halides
[00166]A mixture of ethynyl-heterocyclic compound, aryl halide, Pd catalyst, base, and dry solvent is refluxed under argon atmosphere. Product formation is monitored by TLC or HPLC. After completion of the reaction the resulting mixture is cooled to r.t., poured into water, and extracted with EtOAc or DCM. The organic phase is dried and concentrated. Purification by chromatography (flash column, preparative TLC or preparative HPLC) provides the title compound.
Preparation 11
3-Ethynyl-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one
[00167]A mixture of 3-bromo-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one (2.00 g, 7.87 mmol), PdCI2[PPh3]2 (0.18 g, 0.25 mmol), Cul (0.05 g, 0.25 mmol), diisopropylamine (5 mL) and acetonitrile (10 mL) is stirred under argon for 5 min. Ethynyltrimethylsilane (1 .54 g, 15.75 mmol) is added, and the resulting mixture is refluxed for 4 h, cooled down to r.t., diluted with water and extracted with EtOAc. The organic layer is dried over Na2S04 and concentrated under reduced pressure. To a solution of the crude intermediate product in THF (20 mL) 1 M solution of TBAF in THF (8.5 mL) is added dropwise at -10 °C. The mixture is stirred at 0 °C for 1 h, diluted with water and extracted with DCM. The organic layer is dried over Na2S04 and concentrated at reduced pressure. The residue is purified by chromatography (silica gel, DCM) to give the title compound (1 .36 g, 87% for two steps) as beige solid.
Preparation 12
6-Ethynyl-2,2-dimethyl-2H-pyrano[2,3-b]pyridin-4(3H)-one [00168]To a solution of 6-bromo-2,2-dimethyl-2H-pyrano[2,3-b]pyridin-4(3H)-one (see Preparation 4; 506 mg, 1 .97 mmol) in anhydrous acetonitrile (10 mL) DIPEA (1 .04 mL, 5.93 mmol), Cul (23 mg, 0.12 mmol) and PdCI2[PPh3]2 (42 mg, 0.06 mmol) are added under argon atmosphere. The resulting mixture is stirred at r.t. for 10 min and ethynyltrimethylsilane (444 mg, 4.52 mmol) is added dropwise. The obtained mixture is stirred under argon atmosphere at 60 °C for 4 h, cooled down to r.t., filtered through Celite, concentrated at reduced pressure, diluted with DCM, reconcentrated at reduced pressure, diluted with anhydrous THF (1 1 mL), and cooled down to -10 °C. To the cooled solution 1 M TBAF solution in THF (2 mL) is added dropwise at -10 °C. The reaction mixture is stirred at -5 °C for 30 min, diluted with water (100 mL) and extracted with DCM (3x50 mL). The combined organic phases were washed with water, dried over Na2S04 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane, 1 :4) to provide the title compound (103 mg, 26% for two steps) as yellowish oil.
Preparation 13
3-Ethynyl-8,8-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-5-one
[00169]A mixture of 3-bromo-8,8-dimethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5- one (see Preparation 6; 5.410 g, 20.02 mmol), ethynyltrimethylsilane (5.70 mL, 40.33 mmol), PdCI2[PPh3]2 (420 mg, 0.60 mmol), Cul (1 10 mg, 0.58 mmol), and /-Pr2NH (8.50 mL, 60.60 mmol) in anhydrous acetonitrile (80 mL) is stirred under argon atmosphere at reflux for 6 h, cooled down to r.t., poured into water and extracted with EtOAc. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane). Then a mixture of 1 N TBAF solution in THF (1 .40 mL) and THF (14 mL) is added dropwise to a solution of the obtained intermediate product in THF (70 mL) at -5 °C over a period of 45 min. The resulting mixture is stirred at 0 °C for 1 .5 h, poured into water and extracted with DCM. The combined organic phases are concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound (3.88 g, 90% for two steps) as brownish solid.
Preparation 14
3-Ethynyl-6,8,8-trimethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-5-one [00170]The title compound is synthesized in close analogy to the procedure described in Preparation 13 starting with 3-bromo-6,8,8-trimethyl-6,7,8,9-tetrahydro-5/-/- pyrido[3,2-c]azepin-5-one.
Example 1
7,7-Dimethyl-3-(phenylethynyl)-7,8-dihydroquinolin-5(6H)-one
[00171 ]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (94 mg, 0.37 mmol) is reacted with ethynylbenzene (0.05 mL, 0.41 mmol), PdCI2(PPh3)2 (13 mg, 0.018 mmol), Cul (3.5 mg, 0.018 mmol), and TEA (0.20 mL, 1 .48 mmol) in DMF (3 mL) at 50 °C for 12 h. The crude product is purified by flash column chromatography (EtOAc/hexane) to provide the title compound (57 mg, 56%).
1H NMR (CDCI3), δΗ, 1 .12 (s, 6H), 2.57 (s, 2H), 3.06 (s, 2H), 7.35-7.39 (m, 3H), 7.52- 7.57 (m, 2H), 8.37 (d, 1 H), 8.82 (d, 1 H).
LC/MS (M+H)+ = 276
Example 2
3-((2-Fluorophenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one
[00172]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (254 mg, 1 .00 mmol) is reacted with 1 -ethynyl-2-fluorobenzene (170 μί, 1 .50 mmol), PdCI2(PPh3)2 (14 mg, 2 mol%), P(f-Bu)3 (10 μί, 4 mol%), DBU (15 μί, 10 mol%), and cesium carbonate (326 mg, 1 .00 mmol) in DMF (2 mL) at 95 °C for 2 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) to provide the title compound (66 mg, 22%).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 3.04 (s, 2H), 7.25-7.38 (m, 2H), 7.51 (dd, 1 H), 7.68 (t, 1 H), 8.22 (s, 1 H), 8.88 (s, 1 H).
LC/MS (M+H)+ = 294
Example 3
3-((3-Fluorophenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one [00173]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (254 mg, 1 .00 mmol) is reacted with 1 -ethynyl-3-fluorobenzene (173 μΙ_, 1 .50 mmol), PdCI2(PPh3)2 (14 mg, 2 mol%), P(f-Bu)3 (10 μΙ_, 4 mol%), DBU (15 μΙ_, 10 mol%), and cesium carbonate (326 mg, 1 .00 mmol) in DMF (2 mL) at 95 °C for 2 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) to provide the title compound (94 mg, 16%).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 3.04 (s, 2H), 7.29 (t, 1 H), 7.40-7.52 (m, 3H), 8.24 (s, 1 H), 8.88 (s, 1 H).
LC/MS (M+H)+ = 294
Example 4
3-((4-Fluorophenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one
[00174]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (254 mg, 1 .00 mmol) is reacted with 1 -ethynyl-4-fluorobenzene (149 μΙ_, 1 .30 mmol), PdCI2(PPh3)2 (14 mg, 2 mol%), P(f-Bu)3 (10 μΙ_, 4 mol%), DBU (15 μΙ_, 10 mol%), and cesium carbonate (326 mg, 1 .00 mmol) in DMF (2 mL) at 95 °C for 3.5 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) and triturated with hexane to provide the title compound (180 mg, 61 %).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 3.04 (s, 2H), 7.27 (t, 2H), 7.66 (dd, 2H), 8.23 (s, 1 H), 8.87 (s, 1 H).
LC/MS (M+H)+ = 294
Example 5
3-((2-Chlorophenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one
[00175]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (254 mg, 1 .00 mmol) is reacted with 1 -ethynyl-2-chlorobenzene (158 μί, 1 .50 mmol), PdCI2(PPh3)2 (14 mg, 2 mol%), P(f-Bu)3 (10 μί, 4 mol%), DBU (15 μί, 10 mol%), and cesium carbonate (326 mg, 1 .00 mmol) in DMF (2 mL) at 95 °C for 2 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) to provide the title compound (56 mg, 18%). 1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 3.04 (s, 2H), 7.41 (t, 1 H), 7.47 (t, 1 H), 7.60 (d, 1 H), 7.72 (d, 1 H), 8.22 (s, 1 H), 8.88 (s, 1 H).
LC/MS (M+H)+ = 310, 312
Example 6
3-((3-Chlorophenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one
[00176]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (254 mg, 1 .00 mmol) is reacted with 1 -ethynyl-3-chlorobenzene (178 mg, 1.30 mmol), PdCI2(PPh3)2 (14 mg, 2 mol%), P(f-Bu)3 (10 μΙ_, 4 mol%), DBU (15 μΙ_, 10 mol%), and cesium carbonate (326 mg, 1 .00 mmol) in DMF (2 mL) at 95 °C for 2 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) to provide the title compound (60 mg, 10%).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 3.04 (s, 2H), 7.40-7.54 (m, 2H), 7.56 (d, 1 H), 7.68 (s, 1 H), 8.25 (s, 1 H), 8.88 (s, 1 H).
LC/MS (M+H)+ = 310, 312
Example 7
3-((3-Bromophenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one
[00177]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (508 mg, 2.00 mmol) is reacted with 1 -ethynyl-3-bromobenzene (315 μί, 2.40 mmol), PdCI2(PPh3)2 (28 mg, 2 mol%), P(f-Bu)3 (19 μί, 4 mol%), DBU (30 μΙ_, 10 mol%), and cesium carbonate (652 mg, 2.00 mmol) in DMF (4 mL) at 95 °C for 3 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) and by preparative HPLC to provide the title compound (85 mg, 12%).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 3.04 (s, 2H), 7.40 (t, 1 H), 7.60 (d, 1 H), 7.64 (d, 1 H), 7.82 (s, 1 H), 8.25 (s, 1 H), 8.88 (s, 1 H).
LC/MS (M+H)+ = 354, 356
Example 8
7,7-Dimethyl-3-(An-tolylethynyl)-7,8-dihydroquinolin-5(6H)-one [00178]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (254 mg, 1.00 mmol) is reacted with 1 -ethynyl-3-methylbenzene (185 μΙ_, 1.50 mmol), PdCI2(PPh3)2 (14 mg, 2 mol%), P(f-Bu)3 (10 μΙ_, 4 mol%), DBU (15 μΙ_, 10 mol%), and cesium carbonate (326 mg, 1 .00 mmol) in DMF (2 mL) at 95 °C for 2.5 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) and washed with hexane to provide the title compound (153 mg, 53%).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.33 (s, 3H), 2.59 (s, 2H), 3.04 (s, 2H), 7.26 (d, 1 H), 7.33 (t, 1 H), 7.39 (d, 1 H), 7.43 (s, 1 H), 8.21 (s, 1 H), 8.86 (s, 1 H).
LC/MS (M+H)+ = 290
Example 9
3-((7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)benzonitrile
[00179]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (254 mg, 1.00 mmol) is reacted with 3-ethynylbenzonitrile (165 mg, 1 .30 mmol), PdCI2(PPh3)2 (14 mg, 2 mol%), P(f-Bu)3 (10 μΙ_, 4 mol%), DBU (15 μΙ_, 10 mol%), and cesium carbonate (326 mg, 1 .00 mmol) in DMF (2 mL) at 95 °C for 2.5 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) and washed with hexane to provide the title compound (128 mg, 21 %).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 3.04 (s, 2H), 7.65 (t, 1 H), 7.89 (d, 1 H), 7.92 (d, 1 H), 7.99 (s, 1 H), 8.27 (s, 1 H), 8.88 (s, 1 H).
LC/MS (M+H)+ = 301
Example 10
3-((3-Acetylphenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one
[00180]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (254 mg, 1 .00 mmol) is reacted with /V-(3-ethynylphenyl)acetamide (207 mg, 1.30 mmol), PdCI2(PPh3)2 (14 mg, 2 mol%), P(f-Bu)3 (10 μί, 4 mol%), DBU (15 μί, 10 mol%), and cesium carbonate (326 mg, 1 .00 mmol) in DMF (2 mL) at 95 °C for 3 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) to provide the title compound (85 mg, 26%). 1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 2.60 (s, 3H), 3.04 (s, 2H), 7.60 (t, 1 H), 7.84 (d, 2H), 7.99 (d, 1 H), 8.15, (s, 1 H), 8.27 (s, 1 H), 8.90 (s, 1 H).
LC/MS (M+H)+ = 318
Example 11
Methyl 3-((7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)benzoate
[00181 ]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (254 mg, 1 .00 mmol) is reacted with methyl 3-ethynylbenzoate (208 mg, 1 .30 mmol), PdCI2(PPh3)2 (14 mg, 2 mol%), P(f-Bu t)3 (10 μΙ_, 4 mol%), DBU (15 μΙ_, 10 mol%), and cesium carbonate (326 mg, 1 .00 mmol) in DMF (2 mL) at 95 °C for 3 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) and washed with hexane to provide the title compound (294 mg, 88%).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 3.04 (s, 2H), 3.88 (s, 3H), 7.60 (t, 1 H), 7.86 (d, 1 H), 8.00 (d, 1 H), 8.13 (s, 1 H), 8.27 (s, 1 H), 8.88 (s, 1 H).
LC/MS (M+H)+ = 334
Example 12
3-((3-Hydroxyphenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one
[00182]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (254 mg, 1.00 mmol) is reacted with 3-ethynylphenol (284 mg, 2.40 mmol), PdCI2(PPh3)2 (28 mg, 0.04 mmol), Cul (6 mg, 0.03 mmol), and TEA (1.50 mL) in dry DMF (1 .50 mL) at 95 °C for 4 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) and recrystallized from acetonitrile to provide the title compound (82 mg, 14%).
1H NMR (De-DMSO) δΗ: 1 .04 (s, 6H), 2.59 (s, 2H), 3.04 (s, 2H), 6.84 (d, 1 H), 6.95 (s, 1 H), 7.01 (d, 1 H), 7.22 (t, 1 H), 8.19 (s, 1 H), 8.85 (s, 1 H), 9.63 (s, 1 H).
LC/MS (M+H)+ = 292
Example 13
3-((3-Methoxyphenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one [00183]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (254 mg, 1 .00 mmol) is reacted with 1 -ethynyl-3-methoxybenzene (198 mg, 1.50 mmol), PdCI2(PPh3)2 (14 mg, 2 mol%), P(f-Bu)3 (8 mg, 0.02 mmol), DBU (15 mg, 0.10 mmol), and cesium carbonate (326 mg, 1 .00 mmol) in DMF (3 ml_) at 90 °C for 2 h. The crude product is purified by column chromatography (silica gel, DCM/hexane) to provide the title compound (47 mg, 15%).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 3.04 (s, 2H), 3.80 (s, 3H), 7.02 (d, 1 H), 7.16 (s, 1 H), 7.17 (d, 1 H), 7.35 (t, 1 H), 8.23 (s, 1 H), 8.89 (s, 1 H).
LC/MS (M+H)+ = 306, 347 ([M+MeCN+H]+)
Example 14
7,7-Dimethyl-3-((3-nitrophenyl)ethynyl)-7,8-dihydroquinolin-5(6H)-one
[00184]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (292 mg, 1 .15 mmol) is reacted with 1 -ethynyl-3-nitrobenzene (220 mg, 1 .50 mmol), PdCI2(PPh3)2 (16 mg, 2 mol%), P(f-Bu)3 (1 1 μΙ_, 4 mol%), DBU (17 μΙ_, 10 mol%), and cesium carbonate (375 mg, 1 .15 mmol) in acetonitrile (10 ml_) under microwave irradiation at 1 10 °C for 20 min and 130 °C for 10 min. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) and triturated with a small amount of acetonitrile. The precipitate is filtered off and dried to provide the title compound (78 mg, 17 %).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 3.04 (s, 2H), 7.74 (t, 1 H), 8.03 (d, 2H), 8.27 (d, 2H), 8.32 (s, 1 H), 8.42 (s, 1 H), 8.93 (s, 1 H).
LC/MS (M+H)+ = 321
Example 15
3-((3-Aminophenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one
[00185]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (419 mg, 1 .65 mmol) is reacted with fe/f-butyl (3-ethynylphenyl)carbamate (413 mg, 1 .90 mmol), PdCI2(PPh3)2 (23 mg, 2 mol%), P(f-Bu)3 (16 μΙ_, 4 mol%), DBU (25 μΙ_, 10 mol%), and cesium carbonate (538 mg, 1 .65 mmol) in DMF (4 ml_) at 95 °C for 4 h. The crude intermediate is purified by column chromatography (silica gel, EtOAc/hexane) and washed with a EtOAc/hexane (10: 1 ) to give the pure intermediate fe/f-butyl (3-((7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)phenyl)carba- mate (363 mg, 56%), which is subsequently deprotected with TFA in DCM at r.t. The resulting reaction mixture is basified with an excess of solid sodium bicarbonate, filtered, and concentrated in high vacuum to provide the title compound (97%).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 3.04 (s, 2H), 5.18 (br, 2H), 6.64 (d, 1 H), 6.72 (d, 1 H), 6.77 (s, 1 H), 7.06 (t, 1 H), 8.15 (s, 1 H), 8.82 (s, 1 H).
LC/MS (M+H)+ = 331
Example 16
yV-(3-((7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3- yl)ethynyl)phenyl)acetamide
[00186]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (254 mg, 1 .00 mmol) is reacted with 1 -(3-ethynylphenyl)ethanone (187 mg, 1 .30 mmol), PdCI2(PPh3)2 (14 mg, 2 mol%), P(f-Bu)3 (10 μΙ_, 4 mol%), DBU (15 μΙ_, 10 mol%), and cesium carbonate (326 mg, 1 .00 mmol) in DMF (2 mL) at 95 °C for 4 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) to provide the title compound (151 mg, 48%).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.07 (s, 3H), 2.59 (s, 2H), 3.04 (s, 2H), 7.26 (d, 1 H), 7.35 (t, 1 H), 7.54 (d, 1 H), 7.88 (s, 1 H), 8.21 (s, 1 H), 8.88 (s, 1 H), 9.97 (s, 1 H).
LC/MS (M+H)+ = 333
Example 17
3-((7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)-4-fluorobenzonitrile
[00187]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (559 mg, 2.20 mmol) is reacted with 3-ethynyl-4-fluorobenzonitrile (290 mg, 2.00 mmol), PdCI2(PPh3)2 (28 mg, 0.04 mmol), P(f-Bu)3 (20 μί, 0.08 mmol), DBU (30 μί, 0.02 mmol), and diisopropylamine (330 μί, 2.20 mmol) in DMF (4.00 mL) at 80 °C for 3 h. The crude product is purified by column chromatography (silica gel, EtOAc/DCM) and by preparative HPLC (acetonitrile/H2O) to provide the title compound (164 mg, 16%). 1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 3.04 (s, 2H), 7.60 (t, 1 H), 7.97-8.03 (m, 1 H), 8.26 (br, 2H), 8.90 (s, 1 H).
LC/MS (M+H)+ = 319
Example 18
3-((5-Amino-2-fluorophenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one
[00188]According to a modified General Procedure 1 , PdCI2(PPh3)2 (21 mg, 0.03 mmol) and Cul (6 mg, 0.03 mmol) are added to a solution of 3-bromo-7,7-dimethyl-7,8- dihydroquinolin-5(6/-/)-one (254 mg, 1 .00 mmol) in diisopropylamine (5 mL). The resulting mixture is stirred at r.t. for 5 min. Then fe/f-butyl (3-ethynyl-4- fluorophenyl)carbamate (306 mg, 1 .30 mmol) is added, and the reaction mixture is refluxed for 4 h. The crude intermediate is purified by column chromatography (DCM/EtOAc, 30: 1 ) and crystallized from EtOAc/hexane (1 :5) to give the pure intermediate fe/f-butyl (3-((7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)-4- fluorophenyl)carbamate (95 mg, 23%), which is subsequently deprotected with TFA (1 mL) in DCM (10 mL) at r.t. for 6 h. The resulting reaction mixture is basified by aqueous potassium carbonate and extracted with DCM. The crude product is purified by column chromatography (DCM/EtOAc, 10: 1 ) and triturated with EtOAc/hexane (1 : 10) to provide the title compound (54 mg, 76%).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.32 (s, 3H), 2.59 (s, 2H), 3.04 (s, 2H), 5.06 (s, 2H), 6.60-6.70 (m, 1 H), 6.70-6.80 (m, 1 H), 6.97 (t, 1 H), 8.17 (s, 1 H), 8.84 (s, 1 H).
LC/MS (M+H)+ = 309
Example 19
3-((3-Hydroxy-5-methylphenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)- one
[00189]5-Methylbenzene-1 ,3-diol (5.00 g, 40.28 mmol) is added gradually to a solution of Tf2O (6.80 mL, 40.26 mmol), 2,6-lutidine (5.14 mL, 44.13 mmol) and DMAP (0.09 g, 0.74 mmol) in anhydrous DCM (50 mL) at 0 °C. The resulting solution is stirred at r.t. for 4 h, poured into saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic phase is washed with brine and concentrated at reduced pressure. Purification by column chromatography (silica gel, EtOAc/hexane, 1 :20) gives a mixture of 3-hydroxy-5-methylphenyl tnfluoromethanesulfonate and 5-methyl-1 ,3-phenylene bis(trifluoromethanesulfonate) (6.67 g) with ratio 1 :2.7 as colorless oil.
[00190]According to General Procedure 2, this mixture (307 mg, 0.87 mmol) is reacted with 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one (199 mg, 1 .00 mmol), PdCI2[PPh3]2 (21 mg, 0.03 mmol), Cul (4 mg, 0.02 mmol) and TEA (3 mL) at 80 °C for 6 h. After addition of DMF (1 mL) the reaction mixture is stirred at 80 °C for 1 h, cooled down to r.t., diluted with EtOAc, washed with water and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane, 1 :3) to give the intermediate compound 3-((7,7-dimethyl-5-oxo-5, 6,7,8- tetrahydroquinolin-3-yl)ethynyl)-5-methyl-phenyl tnfluoromethanesulfonate (339 mg), which is subsequently deprotected by 1 N TBAF solution (in THF, 0.80 mL, 0.80 mmol) in THF (3 mL) at 50 °C for 2 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) to provide the title compound (21 %, for two steps).
1H NMR (De-DMSO) δΗ, 1 .02 (s, 6H), 2.21 (s, 3H), 2.58 (s, 2H), 3.02 (s, 2H), 6.65 (s, 1 H), 6.73 (s, 1 H), 6.84 (s, 1 H), 8.18 (s, 1 H), 8.83 (s, 1 H), 9.50 (s, 1 H).
LC/MS (M+H)+ = 306
Example 20
7,7-Dimethyl-3-(pyridin-2-ylethynyl)-7,8-dihydroquinolin-5(6H)-one
[00191 ]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (254 mg, 1.00 mmol) is reacted with 2-ethynylpyridine (151 μί, 1 .50 mmol), PdCI2(PPh3)2 (14 mg, 2 mol%), P(f-Bu)3 (10 μί, 4 mol%), DBU (15 μί, 10 mol%), and cesium carbonate (326 mg, 1 .00 mmol) in DMF (2 mL) at 95 °C for 4 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) and by preparative HPLC to provide the title compound (124 mg, 45%).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 3.04 (s, 2H), 7.43 (t, 1 H), 7.69 (d, 1 H), 7.86 (t, 1 H), 8.26 (s, 1 H), 8.62 (d, 1 H), 8.91 (s, 1 H).
LC/MS (M+H)+ = 277
Example 21 7,7-Dimethyl-3-((6-methylpyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6H)-on
[00192]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (254 mg, 1.00 mmol) is reacted with 2-ethynyl-6-methylpyridine (152 mg, 1 .30 mmol), PdCI2(PPh3)2 (21 mg, 0.03 mmol), P(f-Bu)3 (15 μΙ_, 0.06 mmol), Cul (4 mg, 0.02 mmol), and diisopropylamine (168 μΙ_, 1 .20 mmol) in DMF (2.00 mL) at 50-55 °C for 4 h. The crude product is purified by column chromatography (silica gel, EtOAc/DCM) to provide the title compound (58 mg, 20%).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.48 (s, 3H), 2.59 (s, 2H), 3.04 (s, 2H), 7.29 (d, 1 H), 7.49 (d, 1 H), 7.74 (t, 1 H), 8.25 (s, 1 H), 8.91 (s, 1 H).
LC/MS (M+H)+ = 291
Example 22
2- ((7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)isonicotinonitri
[00193]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (200 mg, 1 .00 mmol) is reacted with 2-ethynylisonicotinonitrile (153 mg, 1 .10 mmol), PdCI2(PPh3)2 (21 mg, 0.03 mmol), and TEA (1 mL) in acetonitrile (2 mL) at reflux for 1 h. The crude product is purified by column chromatography (DCM/acetone, 30: 1 ) to provide the title compound (40 mg, 13%).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 3.04 (s, 2H), 7.89 (d, 1 H), 8.21 (s, 1 H), 8.32 (s, 1 H), 8.86 (d, 1 H), 8.95 (s, 1 H).
LC/MS (M+H)+ = 302
Example 23
3- ((6-Hydroxypyridin-2-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one
[00194]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6H)-one (400 mg, 2.00 mmol) is reacted with 6-bromopyridin-2-ol (418 mg, 2.40 mmol), PdCI2[PPh3]2 (42 mg, 0.06 mmol), Cul (22 mg, 0.12 mmol), and TEA (420 μί, 3.00 mmol) in THF (3 mL) at 50 °C for 3 h. The crude product is purified by column chromatography (silica gel, EtOH/DCM), washed with EtOAc and dried to provide the title compound (46 mg, 8%). 1H NMR (De-DMSO) δΗ, 1 .05 (s, 6H), 2.61 (s, 2H), 3.06 (s, 2H), 6.48 (d, 1 H), 6.65 (d, 1 H), 7.49 (t, 1 H), 8.29 (s, 1 H), 8.89 (s, 1 H), 1 1 .9 (br, 1 H).
LC/MS (M+H)+ = 293
Example 24
3-((6-Methoxypyridin-2-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-on
[00195]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (200 mg, 1 .00 mmol) is reacted with 2-bromo-6-methoxypyridine (226 mg, 1.20 mmol), PdCI2[PPh3]2 (21 mg, 0.03 mmol), and TEA (209 μΙ_, 1 .50 mmol) in acetonitrile (3 mL) and DMF (1 mL) at reflux for 3 h. The crude product is purified by column chromatography (silica gel, EtOAc/DCM) to provide the title compound (68 mg, 22%).
1H NMR (De-DMSO) δΗ, 1 .05 (s, 6H), 2.61 (s, 2H), 3.06 (s, 2H), 3.89 (s, 3H), 6.90 (d, 1 H), 7.33 (d, 1 H), 7.77 (t, 1 H), 8.27 (s, 1 H), 8.93 (s, 1 H).
LC/MS (M+H)+ = 307
Example 25
3-((4-Aminopyridin-2-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one
[00196]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (200 mg, 1 .00 mmol) is reacted with fe/f-butyl (2-iodopyridin-4-yl)carbamate (383 mg, 1 .20 mmol), PdCI2[PPh3]2 (21 mg, 0.03 mmol), and TEA (1 mL) in acetonitrile (3 mL) at reflux for 1 .5 h. The crude intermediate is purified by column chromatography (silica gel, EtOAc/DCM, 1 :5; then EtOAc) to give the pure intermediate product fe/f-butyl (2-((7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)pyridin-4-yl)carbamate (206 mg, 53%), which is subsequently deprotected by TFA (1 .5 mL) in DCM (15 mL) at r.t. for 12 h. The resulting reaction mixture is basified with aqueous potassium carbonate, purified by column chromatography (silica gel, DCM/MeOH, 25: 1 ), and triturated with hexane to provide the title compound (68 mg, 44%).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 3.04 (s, 2H), 6.77 (s, 1 H), 6.49 (d, 1 H), 6.77 (s, 1 H), 7.99 (d, 1 H), 8.19 (s, 1 H), 8.87 (s, 1 H).
LC/MS (M+H)+ = 292 Example 26
3-((6-Aminopyridin-2-yl)ethynyl)-7,7-dimem^
[00197]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (643 mg, 2.53 mmol) is reacted with 6-ethynylpyridin-2-amine (250 mg, 2.1 1 mmol), PdCI2(PPh3)2 (35 mg, 0.05 mmol), P(f-Bu)3 (25 μΙ_, 0.10 mmol), and diisopropylamine (4.00 mL) at 80 °C for 3 h. The crude product is purified by column chromatography (silica gel, EtOAc/DCM) and recrystallized from acetonitrile to provide the title compound (1 15 mg, 19%).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 3.04 (s, 2H), 6.06 (s, 2H), 6.49 (d, 1 H), 6.80 (d, 1 H), 7.40 (t, 1 H), 8.18 (s, 1 H), 8.85 (s, 1 H).
LC/MS (M+H)+ = 292
Example 27
7,7-Dimethyl-3-((6-(methylamino)pyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6H)- one
[00198]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (216 mg, 0.85 mmol) is reacted with 6-ethynyl-/V-methylpyridin-2-amine (102 mg, 0.77 mmol), PdCI2(PPh3)2 (12 mg, 0.02 mmol), P(f-Bu)3 (9 μΙ_, 0.03 mmol), diisopropylamine (128 μΙ_, 0.85 mmol), and DBU (14 μΙ_, 0.01 mmol) in DMF (2 mL) at 80 °C for 3 h. The crude product is purified by column chromatography (silica gel, EtOAc/DCM) and recrystallized from acetonitrile to provide the title compound (56 mg, 10%).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 2.77 (d, 3H), 3.04 (s, 2H), 6.49 (d, 1 H), 6.60 (br d, 1 H), 6.81 (d, 1 H), 7.40 (t, 1 H), 8.21 (s, 1 H), 8.87 (s, 1 H).
LC/MS (M+H)+ = 306
Example 28
3-((6-(Cyclopropylamino)pyridin-2-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin- 5(6H)-one [00199]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (559 mg, 2.20 mmol) is reacted with /V-cyclopropyl-6-ethynylpyridin-2 -amine (293 mg, 1 .85 mmol), PdCI2(PPh3)2 (28 mg, 0.04 mmol), P(f-Bu)3 (20 μΙ_, 0.08 mmol) and TEA (4.00 mL) at 80 °C for 3 h. The crude product is purified by column chromatography (silica gel, EtOAc/DCM) to provide the title compound (81 mg, 13%). 1H NMR (De-DMSO) δΗ, 0.40-0.45 (m, 2H), 0.67-0.73 (m, 2H), 1 .04 (s, 6H), 2.51 -2.57 (m, 1 H), 2.59 (s, 2H), 3.04 (s, 2H), 6.65 (d, 1 H), 6.88 (d, 1 H), 6.90 (s, 1 H), 7.49 (t, 1 H), 8.20 (s, 1 H), 8.86 (s, 1 H).
LC/MS (M+H)+ = 332
Example 29
3-((6-(Dimethylamino)pyridin-2-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquin
one
[00200]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (419 mg, 1 .65 mmol) is reacted with 6-ethynyl-/V,/V-dimethylpyridin-2-amine (219 mg, 1 .50 mmol), PdCI2[PPh3]2 (21 mg, 0.03 mmol) and TEA (3.5 mL) at 70 °C for 6 h. The crude product is purified by column chromatography (silica gel, EtOAc/DCM) to provide the title compound (186 mg, 39%).
1H NMR (De-DMSO) δΗ, 1 .05 (s, 6H), 2.60 (s, 2H), 3.04 (s, 8H), 6.70 (d, 1 H), 6.89 (d, 1 H), 7.53 (t, 1 H), 8.23 (s, 1 H), 8.89 (s, 1 H).
LC/MS (M+H)+ = 320
Example 30
7,7-Dimethyl-3-((6-(piperidin-1 -yl)pyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6H)- one
[00201 ]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (254 mg, 1 .00 mmol) is reacted with 2-ethynyl-6-(piperidin-1 -yl)pyridine (224 mg, 1 .20 mmol), PdCI2(PPh3)2 (21 mg, 0.03 mmol), P(f-Bu)3 (15 μί, 0.06 mmol), and diisopropylamine (168 μί, 1 .20 mmol) in DMF (2.00 mL) at 90 °C for 2 h. The crude product is purified by column chromatography (silica gel, EtOAc/DCM) and preparative HPLC (acetonitrile/H2O) to provide the title compound (72 mg, 20%). 1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 1 .48-1 .57 (m, 4H), 1 .57-1 .66 (m, 2H), 2.59 (s, 2H), 3.04 (s, 2H), 3.47-3.57 (m, 4H), 6.85 (d, 1 H), 6.89 (d, 1 H), 7.52 (t, 1 H), 8.22 (s, 1 H), 8.89 S, 1 H).
LC/MS (M+H)+ = 360
Example 31
7,7-Dimethyl-3-(pyridin-3-ylethynyl)-7,8-dihydroquinolin-5(6H)-one
[00202]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (254 mg, 1 .00 mmol) is reacted with 3-ethynylpyridine (154 mg, 1 .50 mmol), PdCI2(PPh3)2 (14 mg, 2 mol%), P(f-Bu)3 (10 μΙ_, 4 mol%), DBU (15 μΙ_, 10 mol%), and cesium carbonate (326 mg, 1 .00 mmol) in DMF (2 mL) at 95 °C for 4 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) and by preparative HPLC to provide the title compound (1 17 mg, 21 %).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 3.04 (s, 2H), 7.47 (dd, 1 H), 8.01 (d, 1 H), 8.26 (s, 1 H), 8.60 (d, 1 H), 8.78 (s, 1 H), 8.89 (s, 1 H).
LC/MS (M+H)+ = 277
Example 32
3-((5-Fluoropyridin-3-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one
[00203]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (269 mg, 1 .35 mmol) is reacted with 3-bromo-5-fluoropyridine (285 mg, 1 .62 mmol), PdCI2(PPh3)2 (28 mg, 0.04 mmol), and TEA (4.00 mL) at 80 °C for 1.5 h. The crude product is purified by column chromatography (silica gel, EtOAc/DCM) to provide the title compound (53 mg, 14%).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.32 (s, 3H), 2.59 (s, 2H), 3.04 (s, 2H), 8.01 (d, 1 H), 8.29 (s, 1 H), 8.63 (d, 1 H), 8.67 (s, 1 H), 8.91 (s, 1 H).
LC/MS (M+H)+ = 295
Example 33
5-((7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)nicotinonitrile [00204]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (559 mg, 2.20 mmol) is reacted with 5-ethynylnicotinonitrile (256 mg, 2.00 mmol), PdCI2(PPh3)2 (28 mg, 0.04 mmol), P(f-Bu)3 (20 μΙ_, 0.08 mmol), DBU (30 μΙ_, 0.02 mmol), and diisopropylamine (330 μΙ_, 2.20 mmol) in DMF (4.00 mL) at 80 °C for 3 h. The crude product is purified by column chromatography (silica gel, EtOAc/DCM) and recrystallized from acetonitrile to provide the title compound (74 mg, 8%).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 3.04 (s, 2H), 8.30 (s, 1 H), 8.58 (s, 1 H), 8.91 (s, 1 H), 9.03 (s, 1 H), 9.05 (s, 1 H).
LC/MS (M+H)+ = 302
Example 34
7,7-Dimethyl-3-(pyridin-4-ylethynyl)-7,8-dihydroquinolin-5(6H)-one
[00205]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (381 mg, 1 .50 mmol) is reacted with 4-ethynylpyridine (309 mg, 3.00 mmol), PdCI2(PPh3)2 (63 mg, 3 mol%), Cul (17 mg, 3 mol%), and diisopropylamine (5 mL) at 80 °C for 3 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) and by preparative HPLC to provide the title compound (124 mg, 18 %). 1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 3.04 (s, 2H), 7.55 (d, 2H), 8.29 (s, 1 H), 8.64 (d, 2H), 8.92 (s, 1 H).
LC/MS (M+H)+ = 277
Example 35
3-((2-Fluoropyridin-4-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one
[00206]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (269 mg, 1 .35 mmol) is reacted with 4-bromo-2-fluoropyridine (285 mg, 1 .62 mmol), PdCI2(PPh3)2 (28 mg, 0.04 mmol), and TEA (4.00 mL) at 80 °C for 1.5 h. The crude product is purified by column chromatography (silica gel, EtOAc/DCM) to provide the title compound (227 mg, 57%).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 3.04 (s, 2H), 7.42 (s, 1 H), 7.53 (d, 1 H), 8.31 (br, 2H), 8.93 (s, 1 H).
LC/MS (M+H)+ = 295 Example 36
7,7-Dimethyl-3-((2-methylpyridin-4-yl)ethy
[00207]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (200 mg, 1.00 mmol) is reacted with diisopropylamine (0.28 mL, 2.00 mmol), Pd[(f-Bu)3P]2 (15 mg, 0.03 mmol), and Cul (6 mg, 0.03 mmol) in THF (5 mL). After 2 min 4-bromo-2-methylpyridine (190 mg, 1 .10 mmol) is added, and the reaction mixture is stirred at r.t. for 2 h. The crude product is purified by column chromatography (EtOAc/hexane, 1 :1 ) and triturated with hexane to provide the title compound (1 10 mg, 38%).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.49 (s, 3H), 2.59 (s, 2H), 3.04 (s, 2H), 7.34 (d, 1 H), 7.43 (s, 1 H), 8.27 (s, 1 H), 8.50 (d, 1 H), 8.90 (s, 1 H).
LC/MS (M+H)+ = 291
Example 37
4-((7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)picolinonitrile
[00208]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (200 mg, 1 .00 mmol) is reacted with 4-iodopicolinonitrile (253 mg, 1 .10 mmol), PdCI2(PPh3)2 (21 mg, 0.03 mmol), and TEA (1 mL) in acetonitrile (1 mL) at reflux for 1 h. The crude product is purified by column chromatography (EtOAc/hexane, 1 :2) and triturated with hexane to provide the title compound (220 mg, 73%).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 3.04 (s, 2H), 7.89 (d, 1 H), 8.25 (s, 1 H), 8.33 (s, 1 H), 8.80 (d, 1 H), 8.93 (s, 1 H).
LC/MS (M+H)+ = 302
Example 38
3-((2-Methoxypyridin-4-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one
[00209]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (200 mg, 1 .00 mmol) is reacted with 4-iodo-2-methoxypyridine (282 mg, 1 .20 mmol), PdCI2[PPh3]2 (21 mg, 0.03 mmol), and TEA (139 μί, 1 .00 mmol) in acetonitrile (3 ml_) at 70 °C for 3 h. The crude product is purified by column chromatography (silica gel, EtOAc/DCM) to provide the title compound (161 mg, 52%).
1H NMR (De-DMSO) δΗ, 1 .05 (s, 6H), 2.61 (s, 2H), 3.06 (s, 2H), 3.88 (s, 3H), 7.01 (s, 1 H), 7.14 (d, 1 H), 8.23 (d, 1 H), 8.29 (s, 1 H), 8.91 (s, 1 H).
LC/MS (M+H)+ = 307
Example 39
3-((2-Aminopyridin-4-yl)ethynyl)-7,7-dime
[00210]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (200 mg, 1.00 mmol) is reacted with 4-iodopyridin-2 -amine (242 mg, 1 .10 mmol), PdCI2(PPh3)2 (21 mg, 0.03 mmol), and TEA (1 ml_) in acetonitrile (2 ml_). The crude product is purified by column chromatography (DCM/MeOH, 50:1 ) and triturated with diethyl ether to provide the title compound (220 mg, 76%).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 3.04 (s, 2H), 6.02 (s, 2H), 6.59 (s, 1 H), 6.61 (d, 1 H), 7.95 (d, 1 H), 8.22 (s, 1 H), 8.87 (s, 1 H).
LC/MS (M+H)+ = 292
Example 40
7,7-Dimethyl-3-((2-(methylamino)pyridin-4-yl)ethynyl)-7,8-dihydroquinolin-5(6H)- one
[0021 1 ]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (200 mg, 1.00 mmol) is reacted with 4-iodo-/V-methylpyridin-2 -amine (280 mg, 1 .20 mmol), PdCI2(PPh3)2 (21 mg, 0.03 mmol), and TEA (3.00 ml_) at 80 °C for 1 .5 h. The crude product is purified by column chromatography (silica gel, EtOAc/DCM) and recrystallized from acetonitrile to provide the title compound (128 mg, 42%).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 2.78 (d, 3H), 3.04 (s, 2H), 6.48-6.68 (m, 3H), 8.02 (d, 1 H), 8.24 (s, 1 H), 8.89 (s, 1 H).
LC/MS (M+H)+ = 306
Example 41
3-((2-Aminopyrimidin-4-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one [00212]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (200 mg, 1 .00 mmol) is reacted with 4-iodopyrimidin-2-amine (154 mg, 1 .27 mmol), PdCI2[PPh3]2 (21 mg, 0.03 mmol), and TEA (2 mL) in acetonitrile (5 mL) at reflux for 1 h. The crude product is purified by column chromatography (silica gel, DCM/acetone, 5:1 ; then DCM/MeOH, 25: 1 ) and triturated with diethyl ether to provide the title compound (120 mg, 41 %).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 3.04 (s, 2H), 6.71 (s, 1 H), 6.79 (d, 1 H), 8.24 (s, 1 H), 8.30 (d, 1 H), 8.90 (s, 1 H).
LC/MS (M+H)+ = 293
Example 42
7,7-Dimethyl-3-((2-(methylamino)pyrimidin-4-yl)ethynyl)-7,8-dihydroquin
5(6H)-one
[00213]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6H)-one (200 mg, 1 .00 mmol) is reacted with 4-iodo-/V-methylpyrimidin-2 -amine (529 mg, 2.25 mmol), PdCI2[PPh3]2 (21 mg, 0.03 mmol), and TEA (2 mL) in acetonitrile (5 mL) at refluxing for 1 h. The crude product is purified by column chromatography (silica gel, DCM/acetone, 10: 1 ) and triturated with diethyl ether to provide the title compound (200 mg, 65%).
1H NMR (De-DMSO) δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 2.81 (d, 3H), 3.04 (s, 2H), 6.80 (d, 1 H), 7.19 (br, 1 H), 8.27 (s, 1 H), 8.34 (d, 1 H), 8.92 (s, 1 H).
LC/MS (M+H)+ = 307
Example 43
3-(Cyclohex-1 -en-1 -ylethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one
[00214]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (70 mg, 0.28 mmol) is reacted with 1 -ethynylcyclohexene (32 mg, 0.30 mmol), PdCI2(PPh3)2 (10 mg, 0.01 mmol), Cul (2.6 mg, 0.01 mmol), and TEA (0.15 mL, 1.10 mmol) in DMF (3 mL) at 50 °C for 18 h. The crude product is purified by flash column chromatography (EtOAc/hexane) to provide the title compound (70 mg, 89%). 1H NMR (CDCI3), δΗ, 1 .10 (s, 6H), 1 .62-1 .69 (m, 4H), 2.15-2.22 (m, 4H), 2.52 (s, 2H), 3.02 (s, 2H), 6.26 (m, 1 H), 8.24 (d, 1 H), 8.70 (d, 1 H).
LC/MS (M+H)+ = 280
Example 44
3-(Cyclopentylethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one
[00215]According to a modified General Procedure 1 , 3-bromo-7,7-dimethyl-7,8- dihydroquinolin-5(6/-/)-one (70 mg, 0.28 mmol) is reacted with cyclopentylethynyltrimethylsilane (0.05 mg, 0.30 mmol), PdCI2(PPh3)2 (10 mg, 0.01 mmol), Cul (2.6 mg, 0.01 mmol), TEA (0.15 mL, 1 .10 mmol), and TBAF (96 mg, 0.30 mmol) in DMF (3 mL) at 60 °C for 3 h. The crude product is purified by flash column chromatography (EtOAc/hexane) to provide the title compound (49 mg, 64%) as oil. 1H NMR (CDCI3), δΗ, 1 .09 (s, 6H), 1.57-2.03 (m, 8H), 2.53 (s, 2H), 2.83 (m, 1 H), 3.00 (s, 2H), 8.21 (d, 1 H), 8.66 (d, 1 H).
LC/MS (M+H)+ = 268
Example 45
S'-tPhenylethynylJ-e'^'-dihydro-S'H-spiroIcyclopentane-l^'-quinolinl-S'-one
[00216]According to General Procedure 1 , 3'-bromo-6',8'-dihydro-5'/-/- spiro[cyclopentane-1 ,7'-quinolin]-5'-one (30 mg, 0.1 1 mmol) is reacted with ethynylbenzene (14 μί, 0.13 mmol), PdCI2(PPh3)2 (4 mg, 0.005 mmol), Cul (1 mg, 0.005 mmol), and TEA (58 μί, 0.43 mmol) in DMF (1 mL) at 50 °C for 12 h. The crude product is purified by preparative TLC (EtOAc/hexane) to provide the title compound (26 mg, 80%) as oil.
1H NMR (CDCI3), δΗ, 1 .55-1 .75 (m, 8H), 2.68 (s, 2H), 3.14 (s, 2H), 7.26, 7.36-7.39 (m, 3H), 7.52-7.57 (m, 2H), 8.36 (d, 1 H), 8.80 (d, 1 H).
LC/MS (M+H)+ = 302
Example 46
2,2-Dimethyl-6-(phenylethynyl)-2H-pyrano[2,3-b]pyridin-4(3H)-one [00217]According to General Procedure 1 , 6-bromo-2,2-dimethyl-2/-/-pyrano[2,3- b]pyridin-4(3/-/)-one (0.2 g, 0.78 mmol) is reacted with ethynylbenzene (104 mg, 1 mmol), Pd(PPh3)2CI2 (30 mg), and Cul (40 mg, 0.2 mmol) in DMF (20 mL) at 75 °C for 24 h. The crude product is purified by preparative TLC (SiO2, eluent - hexane- ethylacetate 10: 1 ) to provide the title compound (34 mg, 15%).
1H NMR (CDCI3), δΗ, 1.50 (s, 6H), 2.60 (s, 2H), 7.40 (m, 3H), 7.60 (m, 2H), 8.40 (d, 1 H), 8.60 (d, 1 H).
LC/MS (M+H)+ = 278
Example 47
6-((6-Aminopyridin-2-yl)ethynyl)-2,2-dimethyl-2H^yrano[2,3-b]pyridin-4(3H)-one
[00218]P(f-Bu)3 (70 mg, 0.346 mmol) is added to a solution of 6-bromo-2,2-dimethyl- 2/-/-pyrano[2,3-b]pyridin-4(3/-/)-one (852 mg, 3.327 mmol) and TEA (5 mL) in anhydrous DMF (5 mL), and the mixture is stirred for 5 min at r.t. Then PdCI2[PPh3]2 (70 mg, 0.997 mmol) is added followed by portionwise addition of 6-ethynylpyridin-2-amine (395 mg, 3.343 mmol). The resulting mixture is stirred for 2.5 h at 80 °C, cooled down to r.t., diluted with water (30 mL), and extracted with EtOAc. The combined organic phases are dried over Na2S04, filtered and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc) and by prepHPLC (reverse phase, MeCN/H2O) to provide the title compound (195 mg, 20%).
1H NMR (CDCI3), δΗ, 1 .55 (s, 6H), 2.78 (s, 2H), 4.52 (br s, 2H), 6.48 (d, 1 H), 6.92 (d, 1 H), 7.42 (dd, 1 H), 8.36 (s, 1 H), 8.65 (s, 1 H).
LC/MS (M+H)+ = 294
Example 48
2,2-Dimethyl-6-((6-(methylamino)pyridin-2-yl)ethynyl)-2H-pyrano[2,3-b]pyridin- 4(3H)-one
[00219]A mixture of 2,6-dibromopyridine (100.0 g, 422 mmol) and methylamine (40% solution in water, 300 mL) is stirred at 60 °C for 16 h, cooled down to r.t., evaporated, diluted with water, and extracted with DCM. The organic layer is dried over Na2SO4, concentrated at reduced pressure and purified by column chromatography (EtOAc/hexane) to give 6-bromo-/V-methylpyridin-2 -amine (42.20 g, 53%) as beige solid.
[00220]A mixture of 6-bromo-/V-methylpyridin-2-amine (5.61 g, 30.0 mmol), ethynyltrimethylsilane (4.42 g, 45.0 mmol), PdCI2[PPh3]2 (702 mg, 1 .0 mmol), Cul (570 mg, 3.0 mmol), TEA (15 mL), and benzene (30 mL) is stirred for 7 h at 50 °C under argon atmosphere, cooled down to r.t. and concentrated in vacuum. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to provide a mixture of /V-methyl-6-((trimethylsilyl)ethynyl)pyridin-2-amine and 6-ethynyl-/V- methylpyridin-2-amine. The obtained mixture is dissolved in THF (30 mL), and 1 M solution of TBAF in THF (30 mL) is added dropwise at -20 °C. The mixture is stirred at 0 °C for 20 min, diluted with water and extracted with DCM. The organic layer is dried over Na2S04 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to give 6-ethynyl-/V-methylpyridin-2- amine (2.84 g, 72%, for two steps) as grey solid.
[00221 ]According to the procedure described for Example 47, 6-bromo-2,2-dimethyl- 2/-/-pyrano[2,3-b]pyridin-4(3/-/)-one (540 mg, 2.1 1 mmol) is reacted with 6-ethynyl-/V- methylpyridin-2-amine (279 mg, 2.1 1 mmol) in the presence of P(f-Bu)3 (44 mg, 0.217 mmol), Pd(PPh3)2CI2 (1 1 mg, 0.015 mmol), and TEA (3.2 mL) in anhydrous DMF (3 mL). The crude product is purified twice by column chromatography (1 . silica gel, MeOH/DCM; 2. silica gel, EtOAc/hexane) to provide the title compound (306 mg, 47%). 1H NMR (De-DMSO), δΗ, 1 .45 (s, 6H), 2.77 (d, 3H), 2.91 (s, 2H), 6.47 (d, 1 H), 6.59 (br d, 1 H), 6.77 (d, 1 H), 7.39 (dd, 1 H), 8.20 (s, 1 H), 8.65 (s, 1 H).
LC/MS (M+H)+ = 308, 349
Example 49
8,8-Dimethyl-3-(phenylethynyl)-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-5-one
[00222]3-Bromo-8,8-dimethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5-one (390 mg, 1.45 mmol) is reacted with ethynylbenzene (0.296 g, 2.9 mmol) in the presence of PdCI2[PPh3]2 (31 mg, 45 μΓηοΙ), Cul (15 mg, 79 μΓηοΙ), P(f-Bu)3 (35 μΐ, 144 μΓηοΙ), and TEA (4 mL) in acetonitrile (3 mL) at reflux for 4 h, cooled down to r.t., diluted with EtOAc (15 ml_), and washed with water (10 ml_). The organic phase is dried over magnesium sulfate and concentrated at reduced pressure. The obtained residue is treated with hexane, and the formed precipitate is collected by filtration and washed with hexane. The crude product is purified twice by column chromatography (silica gel, DCM/acetone) to provide the title compound (259 mg, 62%).
1H NMR (CDCIs), δΗ, 1 .09 (s, 6H), 2.80 (d, 2H), 2.86 (s, 2H), 6.33 (br s, 1 H), 7.37 (s, 3H), 7.54 (s, 2H), 8.14 (s, 1 H), 8.74 (s, 1 H).
LC/MS (M+H)+ = 291
Example 50
6,8,8-Trimethyl-3-(phenylethynyl)-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-5-one
[00223]To a stirred solution of 8,8-dimethyl-3-(phenylethynyl)-6,7,8,9-tetrahydro-5/-/- pyrido[3,2-c]azepin-5-one (208 mg, 0.72 mmol) in anhydrous THF (4 ml_) sodium hydride (60% suspension in mineral oil, 32 mg, 0.79 mmol) is added in two portions at r.t. The resulting mixture is stirred at r.t. for 30 min. Methyl iodide (54 μΙ_, 0.86 mmol) is added, and the mixture is stirred at r.t. for 3 h. The reaction mixture is purified by column chromatography (silica gel, DCM/acetone), and the crude product is triturated with cold hexane and dried to provide the title compound (128 mg, 58%).
1H NMR (CDCI3), δΗ, 1 .09 (s, 6H), 2.81 (s, 2H), 2.92 (s, 2H), 3.26 (s, 3H), 7.36 (d, 3H), 7.53 (d, 2H), 8.12 (s, 1 H), 8.69 (s, 1 H).
LC/MS (M+H)+ = 305
Example 51
2,2-Dimethyl-7-(phenylethynyl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one
[00224]According to General Procedure 1 , 7-bromo-2,2-dimethyl-3,4-dihydropyrido[3,2- f][1 ,4]oxazepin-5(2/-/)-one is reacted with ethynylbenzene, Pd(PPh3)2CI2, and Cul in
DMF. The crude product is purified by flash column chromatography to provide the title compound.
LC/MS (M+H)+ = 293
Example 52 2,2,4-Trimethyl-7-(phenylethynyl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one
[00225]2,2-Dimethyl-7-(phenylethynyl)-3l4-dihydropyrido[3l2-f][1 l4]oxazepin-5(2H)-one (Example 51 ) is treated with iodomethane in the presence of NaH in DMF. Purification of the crude product after aqueous workup provides the title compound.
LC/MS (M+H)+ = 307
Example 53
7-((6-Aminopyridin-2-yl)ethynyl)-2,2-dimethyl-3,4-dihydropyrido[3,2- f|[1 ,4]oxazepin-5(2H)-one
[00226]According to General Procedure 1 , 7-bromo-2,2-dimethyl-3,4-dihydropyrido[3,2- f][1 ,4]oxazepin-5(2/-/)-one (150 mg, 0.55 mmol) is reacted with 6-ethynylpyridin-2-amine (72 mg, 0.61 mmol) in the presence of PdCI2[PPh3]2 (19 mg, 0.027 mmol), P(f-Bu)3 (5 mg, 0.027 mmol), DBU (8 mg, 0.055 mmol), and TEA (2 mL) in acetonitrile (10 mL) at reflux for 6 h. The crude product is purified by column chromatography (silica gel, EtOH/EtOAc/hexane) to provide the title compound (30 mg, 18%).
1H NMR (De-DMSO), δΗ, 1 .38 (s, 6H), 3.16 (d, 2H), 6.04 (s, 2H), 6.50 (d, 1 H), 6.79 (d, 1 H), 7.41 (dd, 1 H), 8.14 (d, 1 H), 8.55 (d, 1 H), 8.60 (br s, 1 H).
LC/MS (M+H)+ = 309, 350
Example 54
7-((6-Aminopyridin-2-yl)ethynyl)-2,2,4-trimethyl-3,4-dihydropyrido[3,2- f|[1 ,4]oxazepin-5(2H)-one
[00227]7-((6-Aminopyridin-2-yl)ethynyl)-2,2-dimethyl-3,4-dihydropyrido[3,2- f][1 ,4]oxazepin-5(2/-/)-one (Example 53) is treated with iodomethane in the presence of
NaH in DMF. Purification of the crude product after aqueous workup provides the title compound.
LC/MS (M+H)+ = 323
Example 55
6-(Phenylethynyl)-2,3-dihydro-1 ,8-naphthyridin-4(1 H)-one [00228]According to General Procedure 1 , 6-bromo-2,3-dihydro-1 ,8-naphthyridin-4(1 /-/)- one (200 mg, 0.88 mmol) is reacted with ethynylbenzene (450 mg, 4.40 mmol) in the presence of PdCI2[PPh3]2 (21 mg, 0.03 mmol), Cs2C03 (287 mg, 0.88 mmol), and P(f- Bu)3 (14 mg, 0.07 mmol) in DMF (10 ml_) under argon atmosphere at 90 °C for 2 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane, 1 : 1 ) followed by preparative HPLC (C18, acetonitrile/water) to provide the title compound (87 mg, 40%).
1H NMR (CDCI3), δΗ, 2.70 (t, 2H), 3.62 (t, 2H), 5.44 (br s, 1 H), 7.25-7.33 (m, 3H), 7.45 (d, 2H), 8.17 (s, 1 H), 8.38 (s, 1 H).
LC/MS (M+H)+ = 247, 249, 290
Example 56
1 -Acetyl-6-(phenylethynyl)-2,3-dihydro-1 ,8-naphthyridin-4(1 H)-one
[00229]A mixture of 6-(phenylethynyl)-2,3-dihydro-1 ,8-naphthyridin-4(1 /-/)-one (Example 55) (146 mg, 0.59 mmol), DMAP (73 mg, 0.59 mmol), and acetyl chloride (46 mg, 0.59 mmol) is stirred in DMF (5 ml_) at 120 °C for 30 min, cooled down to r.t. and concentrated at reduced pressure. The crude product is purified by preparative HPLC (C18, acetonitrile/water) to provide the title compound (69 mg, 40%).
1H NMR (CDCI3), δΗ, 2.61 (s, 3H), 2.80 (t, 2H), 4.32 (t, 2H), 7.30-7.40 (m, 3H), 7.54 (d, 2H), 8.40 (s, 1 H), 8.64 (s, 1 H).
LC/MS (M+H)+ = 247, 291 , 332
Example 57
2,2-Dimethyl-7-(An-tolylethynyl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one
[00230]According to General Procedure 1 , 7-bromo-2,2-dimethyl-3,4-dihydropyrido[3,2- f][1 ,4]oxazepin-5(2/-/)-one (175 mg, 0.64 mmol) is reacted with 1 -ethynyl-3- methylbenzene (82 mg, 1 .10 mmol) in the presence of PdCI2[PPh3]2 (22 mg, 0.03 mmol), P(f-Bu)3 (7 mg, 0.03 mmol), DBU (10 mg, 0.06 mmol), and TEA (2 mL) in acetonitrile (10 mL) at reflux for 6 h. The crude product is purified by column chromatography (silica gel, hexane/EtOAc) to provide the title compound (55 mg, 28%). 1H NMR (CDCIs), δΗ, 1 .52 (s, 6H), 2.36 (s, 3H), 3.28 (d, 2H), 6.76 (s, 1 H), 7.13-7.41 (m, 4H), 8.38 (s, 1 H), 8.57 (s, 1 H).
LC/MS (M+H)+ = 307
Example 58
3-((2,2-Dimethyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7- yl)ethynyl)benzonitrile
[00231 ] According to General Procedure 1 , 7-bromo-2,2-dimethyl-3,4-dihydropyrido[3,2- f][1 ,4]oxazepin-5(2/-/)-one (150 mg, 0.55 mmol) is reacted with 3-ethynylbenzonitrile (77 mg, 0.60 mmol) in the presence of PdCI2[PPh3]2 (19 mg, 0.03 mmol), P(f-Bu)3 (6 mg, 0.03 mmol), DBU (9 mg, 0.06 mmol), and TEA (2 mL) in acetonitrile (10 mL) at reflux for 6 h. The crude product is purified by column chromatography (silica gel, hexane/EtOAc) to provide the title compound (60 mg, 34%).
1H NMR (CDCI3), δΗ, 1 .53 (s, 6H), 3.31 (d, 2H), 6.67 (s, 1 H), 7.48 (dd, 1 H), 7.63 (d, 1 H), 7.73 (d, 1 H), 7.80 (s, 1 H), 8.43 (s, 1 H), 8.59 (s, 1 H).
LC/MS (M+H)+ = 318, 359
Example 59 3-((2,2-Dimethyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7- yl)ethynyl)-4-fluorobenzonitrile
[00232] According to General Procedure 1 , 7-bromo-2,2-dimethyl-3,4-dihydropyrido[3,2- f][1 ,4]oxazepin-5(2/-/)-one (165 mg, 0.60 mmol) is reacted with 3-ethynyl-4- fluorobenzonitrile (95 mg, 0.66 mmol) in the presence of PdCl2[PPh3]2 (21 mg, 0.03 mmol), P(f-Bu)3 (6 mg, 0.03 mmol), DBU (9 mg, 0.06 mmol), and TEA (2 mL) in acetonitrile (10 mL) at reflux for 6 h. The crude product is purified by column chromatography (silica gel, hexane/EtOAc) to provide the title compound (30 mg, 15%). 1H NMR (CDCI3), δΗ, 1 .49 (s, 3H), 1 .53 (s, 3H), 3.31 (d, 2H), 6.37 (s, 1 H), 7.23 (d, 1 H), 7.63 (s, 1 H), 7.83 (d, 1 H), 8.46 (s, 1 H), 8.62 (s, 1 H).
LC/MS (M+H)+ = 336, 377 Example 60 3-((6-aminopyridin-2-yl)ethynyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5H- pyrido[3,2-c]azepin-5-one
[00233] According to General Procedure 2, 3-ethynyl-8,8-dimethyl-6,7,8,9-tetrahydro- 5H-pyrido[3,2-c]azepin-5-one (100 mg, 0.47 mmol) is reacted with 6-bromopyridin-2- amine (121 mg, 0.70 mmol) in the presence of PdCI2[PPh3]2 (15 mg, 0.02 mmol), P(f- Bu)3 (17 μΙ_, 0.07 mmol), and TEA (130 μΙ_, 0.94 mmol) in DMF (2 mL) at 90 °C for 1 h. Cs2C03 (228 mg, 0.70 mmol) is added, and the resulting mixture is stirred at 90 °C for 1.5 h. The crude product is purified by column chromatography (silica gel, DCM/EtOH) to provide the title compound (51 mg, 35%).
1H NMR (De-DMSO), δΗ, 0.98 (s, 6H), 2.64 (d, 2H), 2.69 (s, 2H), 6.09 (s, 2H), 6.50 (d, 1 H), 6.80 (d, 1 H), 7.41 (t, 1 H), 7.94 (d, 1 H), 8.45 (br s, 1 H), 8.71 (s, 1 H).
LC/MS (M+H)+ = 307, 348
Example 61
Methyl 4-oxo-6-(phenylethynyl)-3,4-dihydro-1 ,8-naphthyridine-1 (2H)-carboxylate
[00234] LiHMDS (1 M solution in THF, 0.44 mL, 0.44 mmol) is added dropwise to a solution of 6-(phenylethynyl)-2,3-dihydro-1 ,8-naphthyridin-4(1 /-/)-one (see Example 55; 73 mg, 0.29 mmol) in anhydrous THF (7 mL) under argon atmosphere at -75 °C. The resulting mixture is stirred at -75 °C for 30 min. Then a solution of methyl chloroformate (42 mg, 0.44 mmol) in anhydrous THF (0.5 mL) is added dropwise at -75 °C. The reaction mixture is stirred for 30 min at -70 °C, allowed to warm up to -10 °C, diluted with saturated aqueous ammonium chloride solution (5 mL), and extracted with EtOAc (x3). The combined organic phases are dried over Na2S04 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) followed by preparative HPLC (C18, acetonitrile/water) to provide the title compound (51 mg, 58%).
1H NMR (CDCIs), δΗ, 2.85 (t, 2H), 3.92 (s, 3H), 4.26 (t, 2H), 7.37 (t, 3H), 7.54 (t, 2H), 8.38 (d, 1 H), 8.72 (d, 1 H).
LC/MS (M+H)+ = 247, 307
Example 62 Methyl 6-((6-aminopyridin-2-yl)ethynyl)-4-oxo-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxylate
[00235] TEA (4 mL) and P(f-Bu)3 (48 mg, 0.24 mmol) are added to a solution of 6- bromo-2,3-dihydro-1 ,8-naphthyridin-4(1 /-/)-one (see Preparation 5; 520 mg, 2.29 mmol) in anhydrous DMF (4 mL). The resulting mixture is stirred under argon atmosphere at r.t. for 5 min. PdCl2[PPh3]2 (48 mg, 0.07 mmol) is added, and the mixture is stirred for 10 min at r.t. Λ/,/V-Di-Boc-protected 6-ethynylpyridin-2-amine (880 mg, 2.76 mmol) is added portionwise, and the reaction mixture is stirred at 85 °C for 1 .5 h, cooled down to r.t., diluted with cold water (50 mL), and extracted with DCM (x3). The combined organic layers are dried over Na2S04 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) and washed with 10% solution of EtOAc in hexane (1 mL) to give Λ/,/V-di-Boc-protected 6-((6- aminopyridin-2-yl)ethynyl)-2,3-dihydro-1 ,8-naphthyridin-4(1 /-/)-one (620 mg, 58%) as yellow solid.
[00236]To a solution of the Boc-protected intermediate (200 mg, 0.43 mmol) in anhydrous THF (30 mL) LiHMDS (1 M solution in THF, 0.65 mL, 0.65 mmol) is added dropwise under argon atmosphere at -65 °C. The resulting red solution is stirred at the same temperature for 5 min. Methyl chloroformate (61 mg, 0.65 mmol) is added dropwise. The reaction mixture is stirred for 15 min at -50 °C and quenched with saturated aqueous solution of NH4CI, warmed up to r.t., and extracted with EtOAc. The organic phase is dried over Na2SO4 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane, 1 : 1 ) to give Λ/,/V-di-Boc-protected methyl 6-((6-aminopyridin-2-yl)ethynyl)-4-oxo-3,4-dihydro- 1 ,8-naphthyridine-1 (2/-/)-carboxylate (190 mg, 85%) as yellowish oil.
[00237]The Boc groups are cleaved with TFA (3 mL) in DCM (20 mL) at r.t. After 3 h the reaction mixture is neutralized with an aqueous solution of NaHCO3. The organic layer is separated, and the aqueous layer is extracted with DCM. The combined organic layers are dried over Na2SO4 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/DCM, 1 : 1 ) to provide the title compound (69 mg, 59%). 1H NMR (CDCI3), δΗ, 2.85 (t, 2H), 3.80 (s, 3H), 4.18 (t, 2H), 6.06 (s, 2H), 6.50 (d, 1 H), 6.81 (d, 1 H), 7.42 (t, 1 H), 8.21 (d, 1 H), 8.73 (d, 1 H).
LC/MS (M+H)+ = 323, 645
Example 63
Methyl 4-oxo-6-(An-tolylethynyl)-3,4-dihydro-1 ,8-naphthyridine-1 (2H)-carboxylate
[00238] TEA (2 mL) and P(f-Bu)3 (20 mg, 0.10 mmol, 1 1 mol%) are added to a solution of 6-bromo-2,3-dihydro-1 ,8-naphthyridin-4(1 /-/)-one (200 mg, 0.88 mmol) in anhydrous DMF (2 mL). The resulting mixture is stirred under argon atmosphere at r.t. for 5 min. Then PdCl2[PPh3]2 (20 mg, 0.03 mmol) is added, and the mixture is stirred for 10 min at r.t. 1 -ethynyl-3-methylbenzene (205 mg, 1 .76 mmol) is added dropwise, and the reaction mixture is stirred at 80 °C for 1 .3 h, cooled down to r.t. and diluted with cold water (20 mL). The formed precipitate is collected by filtration, washed with water and dried. Purification by column chromatography (silica gel, EtOAc/hexane) provides the intermediate product 6-(m-tolylethynyl)-2,3-dihydro-1 ,8-naphthyridin-4(1 /-/)-one (180 mg, 78%).
[00239]LiHMDS (1 M solution in THF, 0.86 mL, 0.86 mmol) is added dropwise to a solution of 6-( r?-tolylethynyl)-2,3-dihydro-1 ,8-naphthyridin-4(1 /-/)-one (150 mg, 0.57 mmol) in anhydrous THF (13 mL) under argon atmosphere at -75 °C. The resulting mixture is stirred at -75 °C for 15 min. Then a solution of methyl chloroformate (81 mg, 0.86 mmol) in anhydrous THF (2 mL) is added dropwise at -75 °C. The reaction mixture is stirred for 30 min at -70 °C, allowed to warm up to 0 °C, diluted with a saturated aqueous ammonium chloride solution (7 mL), and extracted with EtOAc (x3). The combined organic phases are dried over Na2S04 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) and recrystallized from MeOH to provide the title compound (98 mg, 54%).
1H NMR (De-DMSO), δΗ, 2.34 (s, 3H), 2.85 (t, 2H), 3.80 (s, 3H), 4.18 (t, 2H), 7.24-7.46 (m, 4H), 8.23 (s, 1 H), 8.74 (s, 1 H).
LC/MS (M+H)+ = 321 , 261 Example 64
Ethyl 6-((6-aminopyridin-2-yl)ethynyl)-4-oxo-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxylate
[00240] The title compound is synthesized in close analogy to the procedure described for Example 62 starting with Λ/,/V-di-Boc-protected 6-((6-aminopyridin-2-yl)ethynyl)-2,3- dihydro-1 ,8-naphthyridin-4(1 /-/)-one (200 mg, 0.43 mmol), LiHMDS (1 M solution in THF, 0.65 mL, 0.65 mmol) and ethyl chloroformate (71 mg, 0.65 mmol) in anhydrous THF. After Boc deprotection the crude product is purified by column chromatography (silica gel, EtOAc) to provide the title compound (102 mg, 86%).
1H NMR (De-DMSO), δΗ, 1 .28 (t, 3H), 2.85 (t, 2H), 4.17 (t, 2H), 4.26 (q, 2H), 6.05 (s, 2H), 6.51 (d, 1 H), 6.81 (d, 1 H), 7.42 (dd, 1 H), 8.21 (s, 1 H), 8.73 (s, 1 H).
LC/MS (M+H)+ = 337
Example 65
Methyl 6-((3-cyanophenyl)ethynyl)-4-oxo-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxylate
[00241 ]According to General Procedure 1 , 6-bromo-2,3-dihydro-1 ,8-naphthyridin-4(1 /-/)- one (130 mg, 0.57 mmol) is reacted with 3-ethynylbenzonitrile (130 mg, 1 .02 mmol) in the presence of PdCI2[PPh3]2 (13 mg, 0.02 mmol), P(f-Bu)3 (13 mg, 0.06 mmol), DBU (9 mg, 0.06 mmol), and TEA (0.5 mL) in acetonitrile (3 mL) at 90 °C under microwave irradiation for 30 min. The residue is diluted with DCM (10 mL) and filtered through a pad of Celite, which is subsequently washed with DCM (TLC control). The first portion of the filtrate (10 mL) is discarded. The combined filtrate is concentrated and dried to provide the intermediate product 3-((5-oxo-5,6,7,8-tetrahydro-1 ,8-naphthyridin-3- yl)ethynyl)benzonitrile (131 mg, 84%).
[00242]LiHMDS (1 M solution in THF, 2.90 mL, 2.90 mmol) is added dropwise to a solution of 3-((5-oxo-5,6,7,8-tetrahydro-1 ,8-naphthyridin-3-yl)ethynyl)benzonitrile (390 mg, 1 .43 mmol) in anhydrous THF (70 mL) under argon atmosphere at -75 °C. The resulting mixture is stirred at -75 °C for 30 min. Then a solution of methyl chloroformate (270 mg, 2.85 mmol) in anhydrous THF (0.5 mL) is added dropwise at -75 °C. The reaction mixture is stirred at -70 °C for 30 min, allowed to warm up to r.t. and stirred for 1 h at r.t., diluted with a saturated aqueous ammonium chloride solution (15 mL) and extracted with EtOAc (x3). The combined organic phases are dried over Na2S04 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) followed by preparative HPLC (C18, acetonitrile/water) to provide the title compound (24 mg, 5%).
1H NMR (De-DMSO), δΗ, 2.84 (t, 2H), 3.93 (s, 3H), 4.27 (t, 2H), 7.49 (dd, 1 H), 7.64 (d, 1 H), 7.75 (d, 1 H), 7.82 (s, 1 H), 8.39 (d, 1 H), 8.72 (d, 1 H).
LC/MS (M+H)+ = 332, 279, 272
Example 66
Methyl 6-((5-cyano-2-fluorophenyl)ethynyl)-4-oxo-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxylate
[00243]According to General Procedure 1 , 6-bromo-2,3-dihydro-1 ,8-naphthyridin-4(1 /-/)- one (130 mg, 0.57 mmol) is reacted with 3-ethynyl-4-fluorobenzonitrile (150 mg, 1 .03 mmol) in the presence of PdCI2[PPh3]2 (13 mg, 0.02 mmol), P(f-Bu)3 (13 mg, 0.06 mmol), DBU (9 mg, 0.06 mmol), and TEA (0.5 mL) in acetonitrile (4 mL) at 90 °C under microwave irradiation for 30 min. The residue is diluted with DCM (10 mL) and filtered through a pad of Celite, which is subsequently washed with DCM (TLC control). The first portion of the filtrate (10 mL) is discarded. The combined filtrate is concentrated and dried to provide the intermediate product 4-fluoro-3-((5-oxo-5,6,7,8-tetrahydro-1 ,8- naphthyridin-3-yl)ethynyl)benzonitrile (150 mg, 90%).
[00244] Li HMDS (1 M solution in THF, 0.60 mL, 0.60 mmol) is added dropwise to a solution of 4-fluoro-3-((5-oxo-5,6,7,8-tetrahydro-1 ,8-naphthyridin-3- yl)ethynyl)benzonitrile (100 mg, 0.34 mmol) in anhydrous THF (18 mL) under argon atmosphere at -75 °C. The resulting mixture is stirred at -75 °C for 30 min. Then a solution of methyl chloroformate (57 mg, 0.60 mmol) in anhydrous THF (1 mL) is added dropwise at -75 °C. The reaction mixture is stirred for 30 min at -70 °C, allowed to warm up to 10 °C, diluted with a saturated aqueous ammonium chloride solution (10 mL) and extracted with EtOAc (x3). The combined organic phases are dried over Na2S04 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc), washed with DCM/hexane (1 : 1 , 3 mL) and dried to provide the title compound (20 mg, 17%).
1H NMR (De-DMSO), δΗ, 2.87 (t, 2H), 3.81 (s, 3H), 4.19 (t, 2H), 7.61 (dd, 1 H), 7.98-8.04 (m, 1 H), 8.27 (dd, 1 H), 8.30 (d, 1 H), 8.78 (d, 1 H).
LC/MS (M+H)+ = 350, 290
Example 67
3-((3-Aminopyridin-2-yl)ethynyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2- c]azepin-5-one
[00245]According to General Procedure 2, 3-ethynyl-8,8-dimethyl-6,7,8,9-tetrahydro- 5/-/-pyrido[3,2-c]azepin-5-one (200 mg, 0.94 mmol) is reacted with 2-bromo-3- nitropyridine (284 mg, 1 .40 mmol) in the presence of PdCI2[PPh3]2 (30 mg, 0.04 mmol),P(f-Bu)3 (34 μΙ_, 0.14 mmol), and TEA (6 mL) in DMF (1 mL) at 100 °C for 1 h. The crude product is purified by column chromatography (silica gel, EtOAc/EtOH) to provide 8,8-dimethyl-3-((3-nitropyridin-2-yl)ethynyl)-6,7,8,9-tetrahydro-5/-/-pyrido[3,2- c]azepin-5-one (213 mg, 67%) as yellow solid.
[00246]A mixture of 8,8-dimethyl-3-((3-nitropyridin-2-yl)ethynyl)-6,7,8,9-tetrahydro-5/-/- pyrido[3,2-c]azepin-5-one (201 mg, 0.60 mmol), SnCI2 *2H20 (675 mg, 2.99 mmol) and EtOH (8 mL) is stirred at reflux for 2 h, cooled down to r.t., poured into 1 N aqueous NaOH solution, and extracted with EtOAc. The combined organic phases are concentrated under reduced pressure. The obtained residue is purified by column chromatography (silica gel, DCM/EtOH) and washed with acetonitrile to provide the title compound (60 mg, 33%).
1H NMR (De-DMSO), δΗ, 0.98 (s, 6H), 2.64 (d, 2H), 2.70 (s, 2H), 5.72 (s, 2H), 7.1 1 (s, 2H), 7.81 (s, 1 H), 8.17 (s, 1 H), 8.43 (s, 1 H), 8.79 (s, 1 H).
LC/MS (M+H)+ = 307
Example 68
3-((3-Amino-6-methylpyridin-2-yl)ethynyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5H- pyrido[3,2-c]azepin-5-one [00247]According to General Procedure 2, 3-ethynyl-8,8-dimethyl-6,7,8,9-tetrahydro- 5/-/-pyrido[3,2-c]azepin-5-one (200 mg, 0.94 mmol) is reacted with 2-bromo-6- methylpyridin-3-amine (262 mg, 1 .40 mmol) in the presence of PdCl2[PPh3]2 (30 mg, 0.04 mmol), P(f-Bu)3 (34 μΙ_, 0.14 mmol), and TEA (260 μΙ_, 1 .90 mmol) in DMF (4 mL) at 100 °C for 1 h. The crude product is purified by column chromatography (silica gel, DCM/EtOH) to provide the title compound (60 mg, 20%).
1H NMR (De-DMSO), δΗ, 0.98 (s, 6H), 2.30 (s, 3H), 2.64 (d, 2H), 2.70 (s, 2H), 5.50 (s, 2H), 6.99 (dd, 2H), 8.16 (s, 1 H), 8.41 (s, 1 H), 8.78 (s, 1 H).
LC/MS (M+H)+ = 321 , 641
Example 69
3-(lmidazo[1,2-a]pyridin-6-ylethynyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5H- pyrido[3,2-c]azepin-5-one
[00248]According to General Procedure 2, 3-ethynyl-8,8-dimethyl-6,7,8,9-tetrahydro- 5/-/-pyrido[3,2-c]azepin-5-one (200 mg, 0.94 mmol) is reacted with 6-bromoimidazo[1 ,2- a]pyridine (276 mg, 1 .40 mmol) in the presence of PdCI2[PPh3]2 (29 mg, 0.04 mmol), Cul (10 mg, 0.05 mmol), and TEA (4 mL) in DMF (0.5 mL) at 100 °C for 1 .5 h. The crude product is purified by column chromatography (silica gel, DCM/EtOH) to provide the title compound (34 mg, 1 1 %).
1H NMR (De-DMSO), δΗ, 0.98 (s, 6H), 2.65 (d, 2H), 2.70 (s, 2H), 7.34 (d, 1 H), 7.62 (d, 1 H), 7.65 (s, 1 H), 7.97 (s, 1 H), 8.01 (s, 1 H), 8.44 (br s, 1 H), 8.74 (s, 1 H), 8.96 (s, 1 H). LC/MS (M+H)+ = 331
Example 70
3-((6-Aminopyridin-2-yl)ethynyl)-6,8,8-trimethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2- c]azepin-5-one
[00249]According to General Procedure 2, 3-ethynyl-6,8,8-trimethyl-6,7,8,9-tetrahydro- 5/-/-pyrido[3,2-c]azepin-5-one (137 mg, 0.60 mmol) is reacted with 6-bromopyridin-2- amine (156 mg, 0.90 mmol) in the presence of PdCI2[PPh3]2 (19 mg, 0.03 mmol), P(f- Bu)3 (22 μί, 0.09 mmol), TEA (125 μί, 0.90 mmol), and Cs2CO3 (293 mg, 0.90 mmol) in DMF (3 mL) at 100 °C for 1 .5 h. The crude product is purified by column chromatography (silica gel, DCM/EtOH) to provide the title compound (90 mg, 47%). 1H NMR (De-DMSO), δΗ, 1 .02 (s, 6H), 2.71 (s, 2H), 2.94 (s, 2H), 3.15 (s, 3H), 6.08 (s, 2H), 6.50 (d, 1 H), 6.80 (d, 1 H), 7.41 (t, 1 H), 7.95 (s, 1 H), 8.70 (s, 1 H).
LC/MS (M+H)+ = 321 , 362
Example 71
3-((3-Aminopyridin-2-yl)ethynyl)-6,8,8 rimethyl-6,7,8,9 etrahydro-5H-pyrido[3,2- c]azepin-5-one
[00250]According to General Procedure 2, 3-ethynyl-6,8,8-trimethyl-6,7,8,9-tetrahydro- 5/-/-pyrido[3,2-c]azepin-5-one (137 mg, 0.60 mmol) is reacted with 2-bromopyridin-3- amine (156 mg, 0.90 mmol) in the presence of PdCI2[PPh3]2 (19 mg, 0.03 mmol), P(f- Bu)3 (22 μΙ_, 0.09 mmol), TEA (125 μΙ_, 0.90 mmol), and Cs2C03 (293 mg, 0.90 mmol) in DMF (3 mL) at 100 °C for 1 .5 h. The crude product is purified by column chromatography (silica gel, DCM/EtOH) followed by preparative HPLC (C18, acetonitrile/water) to provide the title compound (38 mg, 20%).
1H NMR (De-DMSO), δΗ, 1 .01 (s, 6), 2.71 (s, 2H), 2.84 (s, 2H), 3.14 (s, 3H), 5.70 (br s, 2H), 7.05-7.15 (m, 2H), 7.78 (s, 1 H), 8.16 (s, 1 H), 8.77 (s, 1 H).
LC/MS (M+H)+ = 321 , 362
Example 72
3-((3-Amino-6-methylpyridin-2-yl)ethynyl)-6,8,8-trimethyl-6,7,8,9-tetrahydro-5H- pyrido[3,2-c]azepin-5-one
[00251 ]According to General Procedure 2, 3-ethynyl-6,8,8-trimethyl-6,7,8,9-tetrahydro- 5/-/-pyrido[3,2-c]azepin-5-one (137 mg, 0.60 mmol) is reacted with 2-bromo-6- methylpyridin-3-amine (168 mg, 0.90 mmol) in the presence of PdCI2[PPh3]2 (19 mg, 0.03 mmol), P(f-Bu)3 (22 μί, 0.09 mmol), DBU (14 μί, 0.09 mmol), and Cs2CO3 (293 mg, 0.90 mmol) in DMF (3 mL) at 100 °C for 1 .5 h. The crude product is purified by column chromatography (silica gel, DCM/EtOH), preparative HPLC (C18, acetonitrile/water) and recrystallization from DCM/hexane to provide the title compound (61 mg, 30%). 1H NMR (De-DMSO), δΗ, 1 .03 (s, 6), 2.28 (s, 3H), 2.72 (s, 2H), 2.90 (s, 2H), 3.16 (s, 3H), 5.46 (br s, 2H), 6.92 (d, 1 H), 7.03 (d, 1 H), 8.15 (s, 1 H), 8.75 (s, 1 H).
LC/MS (M+H)+ = 335, 669
Example 73
3-(lmidazo[1,2-a]pyridin-6-ylethynyl)-6,8,8 rimethyl-6,7,8,9-tetrahydro-5H- pyrido[3,2-c]azepin-5-one
[00252]According to General Procedure 2, 3-ethynyl-6,8,8-trimethyl-6,7,8,9-tetrahydro- 5/-/-pyrido[3,2-c]azepin-5-one (137 mg, 0.60 mmol) is reacted with 6-bromoimidazo[1 ,2- a]pyridine (177 mg, 0.90 mmol) in the presence of PdCl2[PPh3]2 (19 mg, 0.03 mmol), P(f-Bu)3 (22 μΙ_, 0.09 mmol), DBU (14 μΙ_, 0.09 mmol), and Cs2C03 (293 mg, 0.90 mmol) in DMF (3 ml_) at 100 °C for 1.5 h. The crude product is purified by column chromatography (silica gel, DCM/EtOH) followed by preparative HPLC (C18, acetonitrile/water) to provide the title compound (57 mg, 28%).
1H NMR (CDCIs), δΗ, 1 .10 (s, 6H), 2.83 (s, 2H), 2.93 (s, 2H), 3.27 (s, 3H), 7.25 (s, 1 H), 7.57-7.65 (m, 2H), 7.69 (s, 1 H), 8.1 1 (s, 1 H), 8.38 (s, 1 H), 8.70 (s, 1 H).
LC/MS (M+H)+ = 345
Example 74
3-(lmidazo[1,2-a]pyridin-2-ylethynyl)-6,8,8-trimethyl-6,7,8,9-tetrahydro-5H- pyrido[3,2-c]azepin-5-one
[00253]According to General Procedure 2, 3-ethynyl-6,8,8-trimethyl-6,7,8,9-tetrahydro- 5/-/-pyrido[3,2-c]azepin-5-one (137 mg, 0.60 mmol) is reacted with 2-bromoimidazo[1 ,2- a]pyridine (177 mg, 0.90 mmol) in the presence of PdCI2[PPh3]2 (19 mg, 0.03 mmol), P(f-Bu)3 (22 μΙ_, 0.09 mmol), DBU (14 μΙ_, 0.09 mmol), and Cs2C03 (293 mg, 0.90 mmol) in DMF (3 ml_) at 100 °C for 2 h. The crude product is purified by column chromatography (silica gel, DCM/EtOH) to provide the title compound (28 mg, 14%). 1H NMR (CDCIs), δΗ, 1 .10 (s, 6H), 2.82 (s, 2H), 2.93 (s, 2H), 3.27 (s, 3H), 6.83 (dd, 1 H), 7.22 (dd, 1 H), 7.60 (d, 1 H), 7.80 (s, 1 H), 8.08 (d, 1 H), 8.14 (s, 1 H), 8.75 (s, 1 H).
LC/MS (M+H)+ = 345 Example 75
3-(lmidazo[1,2-a]pyridin-2-ylethynyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5H- pyrido[3,2-c]azepin-5-one
[00254]According to General Procedure 2, 3-ethynyl-8,8-dimethyl-6,7,8,9-tetrahydro- 5/-/-pyrido[3,2-c]azepin-5-one (193 mg, 0.90 mmol) is reacted with 2-bromoimidazo[1 ,2- a]pyridine (177 mg, 0.90 mmol) in the presence of PdCl2[PPh3]2 (19 mg, 0.03 mmol), P(f-Bu)3 (22 μΙ_, 0.09 mmol), DBU (14 μΙ_, 0.09 mmol), and Cs2C03 (293 mg, 0.90 mmol) in DMF (3 mL) at 100 °C for 2 h. The crude product is purified by column chromatography (silica gel, DCM/EtOH) followed by preparative HPLC (C18, acetonitrile/water) to provide the title compound (52 mg, 17%).
1H NMR (De-DMSO), δΗ, 0.99 (s, 6H), 2.65 (d, 2H), 2.71 (s, 2H), 6.96 (dd, 1 H), 7.32 (dd, 1 H), 7.54 (d, 1 H), 7.98 (s, 1 H), 8.31 (s, 1 H), 8.43 (br s, 1 H), 8.52 (d, 1 H), 8.75 (s, 1 H). LC/MS (M+H)+ = 331
Example 76
3-((6,8,8-Trimethyl-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3- yl)ethynyl)benzonitrile
[00255]According to General Procedure 2, 3-ethynyl-6,8,8-trimethyl-6,7,8,9-tetrahydro- 5/-/-pyrido[3,2-c]azepin-5-one (228 mg, 1 .00 mmol) is reacted with 3-bromobenzonitrile (182 mg, 1 .00 mmol) in the presence of Pd(OAc)2 (7 mg, 0.03 mmol), Ph3P (16 mg, 0.06 mmol), and Cs2C03 (326 mg, 1 .00 mmol) in dioxane (6 mL) at reflux for 4 h. The crude product is purified by column chromatography (silica gel, DCM/EtOAc, 10: 1 ) to provide the title compound (129 mg, 39%).
1H NMR (De-DMSO), δΗ, 1 .02 (s, 6H), 2.72 (s, 2H), 2.94 (s, 2H), 3.16 (s, 3H), 7.66 (dd, 1 H), 7.91 (dd, 2H), 8.03 (s, 1 H), 8.08 (s, 1 H), 8.74 (s, 1 H).
LC/MS (M+H)+ = 330
Example 77
3-((8,8-Dimethyl-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3- yl)ethynyl)benzonitrile [00256]According to General Procedure 2, 3-ethynyl-8,8-dimethyl-6,7,8,9-tetrahydro- 5/-/-pyrido[3,2-c]azepin-5-one (214 mg, 1 .00 mmol) is reacted with 3-bromobenzonitrile (182 mg, 1 .00 mmol) in the presence of Pd(OAc)2 (7 mg, 0.03 mmol), Ph3P (16 mg, 0.06 mmol), and Cs2C03 (326 mg, 1 .00 mmol) in dioxane (6 mL) at reflux for 4 h. The crude product is purified by column chromatography (silica gel, DCM/EtOAc, 3: 1 ) to provide the title compound (52 mg, 17%).
1H NMR (De-DMSO), δΗ, 0.98 (s, 6H), 2.65 (d, 2H), 2.71 (s, 2H), 7.66 (dd, 1 H), 7.91 (dd, 2H), 8.03 (s, 1 H), 8.09 (s, 1 H), 8.43 (s, 1 H), 8.76 (s, 1 H).
LC/MS (M+H)+ = 316
Example 78
3-((8,8-Dimethyl-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl)ethynyl)-4- fluorobenzonitrile
[00257]According to General Procedure 2, 3-ethynyl-8,8-dimethyl-6,7,8,9-tetrahydro- 5/-/-pyrido[3,2-c]azepin-5-one (150 mg, 0.7 mmol) is reacted with 3-bromo-4- fluorobenzonitrile (140 mg, 0.7 mmol) in the presence of PdCI2[PPh3]2 (27 mg, 0.04 mmol), P(f-Bu)3 (1 1 mg, 0.06 mmol), and TEA (3 mL) at reflux for 4 h. The crude product is purified by preparative TLC (silica gel, DCM/EtOAc, 5:1 ) to provide the title compound (40 mg, 17%).
1H NMR (De-DMSO), δΗ, 1 .10 (s, 6H), 2.81 (d, 2H), 2.88 (s, 2H), 6.33 (s, 1 H), 7.24 (dd, 1 H), 7.62-7.69 (m, 1 H), 7.84 (dd, 1 H), 8.18 (s, 1 H), 8.77 (s, 1 H).
LC/MS (M+H)+ = 334, 375
Example 79
3-((1H-Pyrrolo[2,3-b]pyridin-6-yl)ethynyl)-6,8,8-trimethyl-6,7,8,9-tetrahydro-5H- pyrido[3,2-c]azepin-5-one
[00258] A mixture of 6-chloro-1 H-pyrrolo[2,3-b]pyridine (1 .018 g, 6.67 mmol), Boc2O (1 .60 g, 7.34 mmol), DMAP (0.04 g, 0.33 mmol), and TEA (0.93 mL, 6.67 mmol) in DCM (60 mL) is stirred at r.t. for 5 h and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane, 1 : 10) to give fe/f-butyl 6-chloro-1 /-/-pyrrolo[2,3-b]pyridine-1 -carboxylate (1 .652 g, 98%) as colorless oil.
[00259]According to General Procedure 2, 3-ethynyl-6,8,8-trimethyl-6,7,8,9-tetrahydro- 5/-/-pyrido[3,2-c]azepin-5-one (137 mg, 0.60 mmol) is reacted with fe/f-butyl 6-chloro- 1 /-/-pyrrolo[2,3-b]pyridine-1 -carboxylate (227 mg, 0.90 mmol) in the presence of PdCI2[PPh3]2 (19 mg, 0.03 mmol), P(f-Bu)3 (22 μΙ_, 0.09 mmol), DBU (14 μΙ_, 0.09 mmol), and Cs2C03 (293 mg, 0.90 mmol) in DMF (4 mL) at 140 °C for 1.5 h. The crude product is purified by column chromatography (silica gel, DCM/EtOH) to provide the intermediate product fe/f-butyl 6-((6,8,8-trimethyl-5-oxo-6,7,8,9-tetrahydro-5/-/- pyrido[3,2-c]azepin-3-yl)ethynyl)-1 /-/-pyrrolo[2,3-b]pyridine-1 -carboxylate (72 mg, 27%), which is deprotected by means of TFA (72 μί, 0.97 mmol) in dioxane (2 mL) at r.t. for 2 h. TFA (200 μί) is added and the resulted solution is stirred at r.t. for 16 h and poured into aqueous NaOH solution (1 N). The aqueous layer is extracted with EtOAc. The combined organic layers are concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) and crystallized from acetonitrile to provide the title compound (29 mg, 52%).
1H NMR (CDCIs), δΗ, 1 .1 1 (s, 6H), 2.83 (s, 2H), 2.94 (s, 2H), 3.28 (s, 3H), 6.55 (s, 1 H), 7.38 (d, 1 H), 7.41 (dd, 1 H), 7.94 (d, 1 H), 8.19 (s, 1 H), 8.79 (s, 1 H), 9.44 (s, 1 H).
LC/MS (M+H)+ = 345
Example 80
8,8-Dimethyl-3-(m olylethynyl)-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-5-one
[00260]According to General Procedure 1 , 3-bromo-8,8-dimethyl-6,7,8,9-tetrahydro-5/-/- pyrido[3,2-c]azepin-5-one (162 mg, 0.60 mmol) is reacted with 1 -ethynyl-3- methylbenzene (139 mg, 1 .20 mmol) in the presence of PdCI2[PPh3]2 (14 mg, 0.02 mmol), P(f-Bu)3 (15 μί, 0.06 mmol), and /'-Pr2NH (3 mL) in acetonitrile (1 mL) at reflux for 6 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) and preparative HPLC (C18, acetonitrile/water) to provide the title compound (76 mg, 42%).
1H NMR (De-DMSO), δΗ, 0.98 (s, 6H), 2.34 (s, 3H), 2.64 (d, 2H), 2.70 (s, 2H), 7.24-7.45 (m, 4H), 7.96 (s, 1 H), 8.42 (s, 1 H), 8.71 (s, 1 H). LC/MS (M+H)+ = 305
Example 81
4-Fluoro-3-((6,8,8-trimethyl-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3- yl)ethynyl)benzonitrile
[00261 ]According to General Procedure 2, 3-ethynyl-6,8,8-trimethyl-6,7,8,9-tetrahydro- 5/-/-pyrido[3,2-c]azepin-5-one (160 mg, 0.7 mmol) is reacted with 3-bromo-4- fluorobenzonitrile (140 mg, 0.7 mmol) in the presence of PdCI2[PPh3]2 (27 mg, 0.04 mmol), P(f-Bu)3 (1 1 mg, 0.06 mmol), and TEA (3 mL) at reflux for 4 h. The crude product is purified by preparative TLC (silica gel, DCM/EtOAc, 5:1 ) to provide the title compound (120 mg, 49%).
1H NMR (De-DMSO), δΗ, 1 .02 (s, 6H), 2.73 (s, 2H), 2.95 (s, 2H), 3.16 (s, 3H), 7.61 (dd, 1 H), 7.97-8.06 (m, 2H), 8.26 (d, 1 H), 8.76 (s, 1 H).
LC/MS (M+H)+ = 348, 389
Example 82
3-((1H-Pyrrolo[2,3-b]pyridin-6-yl)ethynyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5H- pyrido[3,2-c]azepin-5-one
[00262]6-Bromo-1 /-/-pyrrolo[2,3-b]pyridine is converted to the /V-Boc-protected derivative in close analogy to the procedure described for Example 103.
[00263]According to General Procedure 2, 3-ethynyl-6,8,8-trimethyl-6,7,8,9-tetrahydro- 5/-/-pyrido[3,2-c]azepin-5-one (129 mg, 0.60 mmol) is reacted with fe/f-butyl 6-bromo- 1 /-/-pyrrolo[2,3-b]pyridine-1 -carboxylate (267 mg, 0.90 mmol) in the presence of PdCI2[MeCN]2 (8 mg, 0.03 mmol), SPhos (37 mg, 0.09 mmol), and TEA (166 μί, 1 .20 mmol) in anhydrous acetonitrile (4 mL) at reflux for 3 h. The crude product is purified by column chromatography (silica gel, EtOAc/DCM, 1 : 1 ) to provide the Boc-protected intermediate (1 17 mg, 45%) as yellowish oil, which is deprotected by means of TFA (200 μί, 2.70 mmol) in DCM (5 mL) at r.t. over night. The mixture is poured into an aqueous NaOH solution (1 N) and extracted with DCM. The organic phase is washed with water and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/DCM) to provide the title compound (73 mg, 82%).
1H NMR (De-DMSO), δΗ, 0.99 (s, 6H), 2.65 (d, 2H), 2.71 (s, 2H), 6.52 (s, 1 H), 7.37 (d, 1 H), 7.60 (dd, 1 H), 7.98-8.05 (m, 2H), 8.45 (s, 1 H), 8.78 (s, 1 H), 1 1 .73 (s, 1 H).
LC/MS (M+H)+ = 331 , 372
Example 83
3-((1H-lndazol-5-yl)ethynyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2- c]azepin-5-one
[00264]According to General Procedure 2, 3-ethynyl-8,8-dimethyl-6,7,8,9-tetrahydro- 5H-pyrido[3,2-c]azepin-5-one (129 mg, 0.60 mmol) is reacted with 5-iodo-1 /-/-indazole (220 mg, 0.90 mmol) in the presence of PdCI2[PPh3]2 (19 mg, 0.03 mmol) and TEA (1 mL) in anhydrous DMF (2 mL) at 90 °C for 4 h. The crude product is dissolved in anhydrous DCM (10 mL), and TFA (230 μΐ, 3.10 mmol) is added at r.t. After 16 h the reaction mixture is poured into an aqueous NaOH solution (1 N) and extracted with DCM. The organic phase is washed with water and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane), and the obtained solid is washed with hot acetonitrile, collected by filtration and dried to provide the title compound (42 mg, 21 %).
1H NMR (De-DMSO), δΗ, 0.98 (s, 6H), 2.65 (d, 2H), 2.70 (s, 2H), 7.52 (d, 1 H), 7.60 (d, 1 H), 7.98 (s, 1 H), 8.06 (s, 1 H), 8.13 (s, 1 H), 8.41 (s, 1 H), 8.73 (s, 1 H), 13.21 (s, 1 H). LC/MS (M+H)+ = 331
Example 84
3-((2-Fluorophenyl)ethynyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2- c]azepin-5-one
[00265]According to General Procedure 1 , 3-bromo-8,8-dimethyl-6,7,8,9-tetrahydro-5/-/- pyrido[3,2-c]azepin-5-one (296 mg, 1.10 mmol) is reacted with 1 -ethynyl-2- fluorobenzene (249 μί, 2.20 mmol) in the presence of PdCI2[MeCN]2 (13 mg, 0.05 mmol), SPhos (45 mg, 0.1 1 mmol), Cul (6 mg, 0.03 mmol), and TEA (1 mL) in anhydrous acetonitrile (7 mL) at 60 °C for 2 h. The crude product is purified by column chromatography (silica gel, EtOAc/DCM) and recrystallized from DCM/hexane to provide the title compound (130 mg, 38%).
1H NMR (De-DMSO), δΗ, 0.91 (s, 6H), 2.65 (d, 2H), 2.71 (s, 2H), 7.26-7.40 (m, 2H), 7.52 (dd, 1 H), 7.68 (dd, 1 H), 7.99 (s, 1 H), 8.45 (s, 1 H), 8.74 (s, 1 H).
LC/MS (M+H)+ = 309
Example 85
3-((4-Fluorophenyl)ethynyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2- c]azepin-5-one
[00266]According to General Procedure 1 , 3-bromo-8,8-dimethyl-6,7,8,9-tetrahydro-5/-/- pyrido[3,2-c]azepin-5-one (296 mg, 1.10 mmol) is reacted with 1 -ethynyl-4- fluorobenzene (251 μί, 2.20 mmol) in the presence of PdCI2[MeCN]2 (13 mg, 0.05 mmol), SPhos (45 mg, 0.1 1 mmol), Cul (6 mg, 0.03 mmol), and TEA (1 mL) in anhydrous acetonitrile (7 mL) at 60 °C for 2 h. The crude product is purified by column chromatography (silica gel, EtOAc/DCM) and recrystallized from DCM/hexane to provide the title compound (76 mg, 51 %).
1H NMR (De-DMSO), δΗ, 0.98 (s, 6H), 2.64 (d, 2H), 2.69 (s, 2H), 7.29 (dd, 2H), 7.66 (dd, 2H), 7.98 (s, 1 H), 8.43 (s, 1 H), 8.73 (s, 1 H).
LC/MS (M+H)+ = 309
Example 86
2,2-Dimethyl-6-(An-tolylethynyl)-2H-pyrano[2,3-b]pyridin-4(3H)-one
[00267]According to General Procedure 1 , 6-bromo-2,2-dimethyl-2/-/-pyrano[2,3- b]pyridin-4(3/-/)-one (256 mg, 1 .00 mmol) is reacted with 1 -ethynyl-3-methylbenzene (127 mg, 1 .10 mmol) in the presence of PdCI2[PPh3]2 (35 mg, 0.05 mmol), P(f-Bu)3 (10 mg, 0.05 mmol), DBU (15 mg, 0.10 mmol), and TEA (2 mL) in acetonitrile (10 mL) at reflux for 6 h. The crude product is purified by column chromatography (silica gel, hexane/EtOAc, 4:1 ) to provide the title compound (105 mg, 36%).
1H NMR (De-DMSO), δΗ, 1 .46 (s, 6H), 2.33 (s, 3H), 2.91 (s, 2H), 7.22-7.43 (m, 4H), 8.20 (s, 1 H), 8.63 (s, 1 H). LC/MS (M+H)+ = 292
Example 87
3-((2,2-Dimethyl-4-oxo-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6- yl)ethynyl)benzonitrile
[00268]According to General Procedure 1 , 6-bromo-2,2-dimethyl-2/-/-pyrano[2,3- b]pyridin-4(3/-/)-one (256 mg, 1 .00 mmol) is reacted with 3-ethynylbenzonitrile (139 mg, 1.10 mmol) in the presence of PdCI2[PPh3]2 (35 mg, 0.05 mmol), P(f-Bu)3 (10 mg, 0.05 mmol), DBU (15 mg, 0.10 mmol), and TEA (2 mL) in acetonitrile (10 mL) at reflux for 6 h. The crude product is purified by column chromatography (silica gel, hexane/EtOAc) to provide the title compound (133 mg, 44%).
1H NMR (De-DMSO), δΗ, 1 .47 (s, 6H), 2.93 (s, 2H), 7.65 (dd, 1 H), 7.89 (dd, 2H), 8.06 (s, 1 H), 8.27 (s, 1 H), 8.67 (s, 1 H).
LC/MS (M+H)+ = 303, 344
Example 88
3-((2,2-Dimethyl-4-oxo-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl)ethynyl)-4- fluorobenzonitrile
[00269]According to General Procedure 1 , 6-bromo-2,2-dimethyl-2/-/-pyrano[2,3- b]pyridin-4(3/-/)-one (256 mg, 1 .00 mmol) is reacted with 3-ethynyl-4-fluorobenzonitrile (160 mg, 1 .10 mmol) in the presence of PdCI2[PPh3]2 (35 mg, 0.05 mmol), P(f-Bu)3 (10 mg, 0.05 mmol), DBU (15 mg, 0.10 mmol), and TEA (2 mL) in acetonitrile (10 mL) at reflux for 6 h. The crude product is purified by column chromatography (silica gel, hexane/EtOAc) to provide the title compound (47 mg, 15%).
1H NMR (De-DMSO), δΗ, 1 .47 (s, 6H), 2.93 (s, 2H), 7.59 (dd, 1 H), 7.98 (br s, 1 H), 8.21 - 8.28 (m, 2H), 8.68 (s, 1 H).
LC/MS (M+H)+ = 321 , 362
Example 89
6-(lmidazo[1,2-a]pyridin-6-ylethynyl)-2,2-dimethyl-2H-pyrano[2,3-b]pyridin-4(3H)- one [00270] A mixture of 6-bromoimidazo[1 ,2-a]pyridine (4.00 g, 20.30 mmol), ethynyltrimethylsilane (2.98 g, 30.30 mmol), PdCI2[PPh3]2 (460 mg, 0.66 mmol), Cul (380 mg, 2.02 mmol), and TEA (8.4 mL, 60.9 mmol) in benzene (25 mL) is stirred at 50 °C under argon atmosphere for 8 h, cooled down to r.t. and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to give 6-((trimethylsilyl)ethynyl)imidazo[1 ,2-a]pyridine (3.20 g, 74%) as yellow solid.
[00271 ]TBAF solution in THF (1 M, 1 .04 mL, 1 .04 mmol) is added dropwise to a solution of 6-((trimethylsilyl)ethynyl)imidazo[1 ,2-a]pyridine (3.20 g, 14.90 mmol) in THF (20 mL) at 0 °C. The resulting mixture is stirred at 0 °C for 1 h, diluted with water and extracted with DCM (3x30 mL). The combined organic phases were dried over Na2S04 and concentrated at reduced pressure. The obtained residue was purified by column chromatography (silica gel, EtOAc/hexane) to give 6-ethynylimidazo[1 ,2-a]pyridine (1 .37 g, 65%) as brown oil.
[00272]According to General Procedure 1 , 6-bromo-2,2-dimethyl-2/-/-pyrano[2,3- b]pyridin-4(3/-/)-one (256 mg, 1 .0 mmol) is reacted with 6-ethynylimidazo[1 ,2-a]pyridine (156 mg, 1 .1 mmol) in the presence of PdCI2[PPh3]2 (35 mg, 0.05 mmol), P(f-Bu)3 (10 mg, 0.05 mmol), DBU (15 mg, 0.1 mmol), and TEA (2 mL) in acetonitrile (10 mL) at reflux for 6 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) to provide the title compound (123 mg, 39%).
1H NMR (De-DMSO), δΗ, 1 .47 (s, 6H), 2.92 (s, 2H), 7.32 (d, 1 H), 7.60 (d, 1 H), 7.64 (s, 1 H), 7.96 (s, 1 H), 8.24 (s, 1 H), 8.66 (s, 1 H), 8.92 (s, 1 H).
LC/MS (M+H)+ = 318
Example 90
6-(lmidazo[1,2-a]pyridin-2-ylethynyl)-2,2-d^
one
[00273]A mixture of 2-iodoimidazo[1 ,2-a]pyridine (2.00 g, 8.20 mmol), ethynyltrimethylsilane (1 .21 g, 12.30 mmol), PdCI2[PPh3]2 (190 mg, 0.27 mmol), Cul (150 mg, 0.80 mmol), and TEA (3.4 mL, 24.0 mmol) in benzene (15 mL) is stirred at 50 °C under argon atmosphere for 12 h, cooled down to r.t. and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to give 2-((trimethylsilyl)ethynyl)imidazo[1 ,2-a]pyridine (1 .23 g, 70%) as light brown oil.
[00274]TBAF solution in THF (1 M, 0.20 mL, 0.20 mmol) is added dropwise to a solution of 2-((trimethylsilyl)ethynyl)imidazo[1 ,2-a]pyridine (636 mg, 2.90 mmol) in THF (10 mL) at 0 °C. The resulting mixture is stirred at 0 °C for 1 h, diluted with water and extracted with DCM (3x10 mL). The combined organic phases are dried over Na2S04 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to give 2-ethynylimidazo[1 ,2-a]pyridine (230 mg, 55%) as brown oil.
[00275]According to General Procedure 1 , 6-bromo-2,2-dimethyl-2/-/-pyrano[2,3- b]pyridin-4(3/-/)-one (256 mg, 1 .0 mmol) is reacted with 2-ethynylimidazo[1 ,2-a]pyridine (156 mg, 1 .1 mmol) in the presence of PdCI2[PPh3]2 (35 mg, 0.05 mmol), P(f-Bu)3 (10 mg, 0.05 mmol), DBU (15 mg, 0.1 mmol), and TEA (2 mL) in acetonitrile (10 mL) at reflux for 6 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) to provide the title compound (85 mg, 27%).
1H NMR (De-DMSO), δΗ, 1 .47 (s, 6H), 2.93 (s, 2H), 6.96 (t, 1 H), 7.29-7.34 (dd, 1 H), 7.54 (d, 1 H), 8.21 (s, 1 H), 8.28 (s, 1 H), 8.51 (d, 1 H), 8.67 (d, 1 H).
LC/MS (M+H)+ = 318
Example 91
6-((1H-lndazol-5-yl)ethynyl)-2,2-dimethyl-2H-pyrano[2,3-b]pyridin-4(3H)-one
[00276] 5-Bromo-1 H-indazole is converted to fe/f-butyl 5-ethynyl-1 /-/-indazole-1 - carboxylate in close analogy to the procedure described for Preparation 10.
[00277]According to General Procedure 1 , 6-bromo-2,2-dimethyl-2/-/-pyrano[2,3- b]pyridin-4(3/-/)-one (153 mg, 0.60 mmol) is reacted with fe/f-butyl 5-ethynyl-1 H- indazole-1 -carboxylate (160 mg, 0.66 mmol) in the presence of PdCI2[PPh3]2 (23 mg, 0.03 mmol), P(f-Bu)3 (7 mg, 0.03 mmol), DBU (10 mg, 0.06 mmol), and TEA (1 mL) in acetonitrile (10 mL) at reflux for 6 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane, 1 :4) to provide the Boc-protected intermediate (165 mg, 66%).
[00278]HCI saturated solution in dioxane (0.5 mL) is added dropwise to a solution of fe/f-butyl 5-((2,2-dimethyl-4-oxo-3,4-dihydro-2/-/-pyrano[2,3-b]pyridin-6-yl)ethynyl)-1 /-/- indazole-1 -carboxylate (165 mg, 0.40 mmol) in DCM (10 mL) at r.t. The mixture is stirred at r.t. for 2 h. The formed solid is collected by filtration, washed with hexane and diethyl ether and treated with an aqueous K2CO3 solution (pH 10-12). The mixture is extracted with DCM. The combined organic phases are dried over Na2S04 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, hexane/EtOAc) to provide the title compound (43 mg, 35%) 1H NMR (De-DMSO), δΗ, 1 .53 (s, 6H), 2.77 (s, 2H), 7.47 (s, 2H), 7.93 (s, 1 H), 8.04 (s, 1 H), 8.30 (s, 1 H), 8.60 (s, 1 H), 1 1 .33 (br s, 1 H).
LC/MS (M+H)+ = 318, 359
Example 92
6-((1H-Pyrrolo[2,3-b]pyridin-6-yl)ethynyl)-2,2-dimethyl-2H-pyrano[2,3-b]pyridin- 4(3H)-one
[00279]According to General Procedure 1 , 6-bromo-2,2-dimethyl-2/-/-pyrano[2,3- b]pyridin-4(3/-/)-one (125 mg, 0.49 mmol) is reacted with fe/f-butyl 6-ethynyl-1 H- pyrrolo[2,3-b]pyridine-1 -carboxylate (see Example 104, 130 mg, 0.53 mmol) in the presence of PdCI2[MeCN]2 (7 mg, 0.03 mmol), SPhos (8 mg, 0.02 mmol), and TEA (0.30 mL, 1 .47 mmol) in acetonitrile (10 mL) at reflux for 3 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) to provide the Boc- protected intermediate (138 mg, 69%).
[00280]TFA (75 mg, 0.66 mmol) is added dropwise to a solution of fe/f-butyl 6-((2,2- dimethyl-4-oxo-3,4-dihydro-2/-/-pyrano[2,3-b]pyridin-6-yl)ethynyl)-1 /-/-pyrrolo[2,3- b]pyridine-1 -carboxylate (138 mg, 0.33 mmol) in DCM (5 mL) at 0 °C. The resulting mixture is stirred at r.t. for 3 h, neutralized with an aqueous NaOH solution (1 N) and extracted with DCM. The combined organic phase is dried over Na2S04 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, hexane/EtOAc) to provide the title compound (35 mg, 35%). 1H NMR (CDCI3), δΗ, 1 .53 (s, 6H), 2.77 (s, 2H), 6.49 (s, 1 H), 7.32 (d, 1 H), 7.38 (s, 1 H), 7.89 (d, 1 H), 8.36 (s, 1 H), 8.66 (s, 1 H), 9.87 (s, 1 H).
LC/MS (M+H)+ = 318, 359
Example 93
3-(lmidazo[1,2-a]pyridin-5-ylethynyl)-7,7-dim
[00281 ]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (199 mg, 1 .00 mmol) is reacted with 5-bromoimidazo[1 ,2-a]pyridine (256 mg, 1 .30 mmol) in the presence of PdCI2[PPh3]2 (36 mg, 0.05 mmol), Cul (15 mg, 0.08 mmol), and dry TEA (5 mL) at 100 °C for 1 .5 h. The crude product is purified by column chromatography (silica gel, DCM/EtOH) and recrystallized from ACN to provide the title compound (153 mg, 49%).
1H NMR (De-DMSO), δΗ, 1 .06 (s, 6H), 2.63 (s, 2H), 3.08 (s, 2H), 7.31 (dd, 1 H), 7.37 (d, 1 H), 7.73 (d, 1 H), 7.74 (s, 1 H), 8.34 (s, 1 H), 8.50 (s, 1 H), 9.08 (s, 1 H).
LC/MS (M+H)+ = 316
Example 94
3-(lmidazo[1,2-a]pyridin-8-ylethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one
[00282]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (199 mg, 1 .00 mmol) is reacted with 8-bromoimidazo[1 ,2-a]pyridine (197 mg, 1 .00 mmol) in the presence of PdCI2[PPh3]2 (39 mg, 0.055 mmol), and TEA (1 .5 mL) in DMF (3 mL) at 100 °C for 3 h. The crude product is purified by column chromatography (silica gel, DCM/EtOH) followed by preparative TLC (silica gel, acetone) to provide the title compound (52 mg, 17%).
1H NMR (De-DMSO), δΗ, 1 .05 (s, 6H), 2.60 (s, 2H), 3.05 (s, 2H), 6.95 (dd, 1 H), 7.56 (d, 1 H), 7.62 (br, 1 H), 8.03 (br, 1 H), 8.25 (s, 1 H), 8.63 (d, 1 H), 8.90 (s, 1 H).
LC/MS (M+H)+ = 316 Example 95
7,7-Dimethyl-3-(pyrazolo[1,5-a]pyridin-7-ylethynyl)-7,8-dihydroquinolin-5(6H)-o
[00283]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (199 mg, 1.00 mmol) is reacted with 7-bromopyrazolo[1 ,5-a]pyridine (244 mg, 1 .00 mmol) in the presence of PdCI2[PPh3]2 (21 mg, 0.03 mmol), and TEA (0.5 ml_) in acetonitrile (3 ml_) at reflux for 1 h. The crude product is purified by column chromatography (silica gel, DCM/acetone, 10: 1 ) to provide the title compound (45 mg, 14%).
1H NMR (De-DMSO), δΗ, 1 .05 (s, 6H), 2.61 (s, 2H), 3.07 (s, 2H), 6.76 (br, 1 H), 7.25 (dd, 1 H), 7.36 (d, 1 H), 7,83 (d, 1 H), 8.10 (br, 1 H), 8.31 (s, 1 H), 8.96 (s, 1 H).
LC/MS (M+H)+ = 316
Example 96
3-((1H-lndol-5-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one
[00284]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (199 mg, 1 .00 mmol) is reacted with 5-bromo-1 /-/-indole (196 mg, 1 .00 mmol) in the presence of Pd(OAc)2 (9 mg, 0.04 mmol), PPh3 (21 mg, 0.08 mmol), and Cs2C03 (970 mg, 3.00 mmol) in dioxane (10 ml_) at reflux for 6 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane, 4: 1 ) and preparative TLC (silica gel, DCM/EtOH, 20:1 ) to provide the title compound (55 mg, 18%).
1H NMR (De-DMSO), δΗ, 1 .04 (s, 6H), 2.59 (s, 2H), 3.03 (s, 2H), 6.49 (s, 1 H), 7.29 (d, 1 H), 7.41 (s, 1 H), 7.44 (d, 1 H), 7.82 (s, 1 H), 8.18 (s, 1 H), 8.85 (s, 1 H), 1 1 .30 (br s, 1 H). LC/MS (M+H)+ = 315
Example 97
3-((1H-Benzo[d][1,2,3]triazol-5-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)- one
[00285]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6H)-one (199 mg, 1 .00 mmol) is reacted with 5-bromo-1 /-/-benzo[d][1 ,2,3]triazole (198 mg, 1 .00 mmol) in the presence of PdCI2[dppf] (32 mg, 0.04 mmol), and Cs2CO3 (970 mg, 3.00 mmol) in dioxane (10 mL) at reflux for 6 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane, 4: 1 ) and preparative TLC (silica gel, DCM/EtOH, 20: 1 ) to provide the title compound (60 mg, 19%).
1H NMR (CDCIs), δΗ, 1 .14 (s, 6H), 2.60 (s, 2H), 3.10 (s, 2H), 7.61 (d, 1 H), 7.91 (br d, 1 H), 8.12 (br s, 1 H), 8.42 (s, 1 H), 8.88 (s, 1 H), 13.30 (br, 1 H).
LC/MS (M+H)+ = 317
Example 98
3-((6-Aminopyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6H)-one
[00286] A mixture of cyclohexane-1 ,3-dione (30.0 g, 0.27 mol), ammonium acetate (44.49 g, 0.54 mol), and acetic acid (1 mL) in benzene (300 mL) is stirred at reflux for 7 h using a Dean-Stark trap, cooled down to r.t., concentrated at reduced pressure, and diluted with EtOH. The mixture is neutralized by means of NaHC03. The formed solid is collected by filtration, and the filtrate is concentrated in vacuo. The obtained residue is dissolved in dioxane, and the residual solids are filtered. A precipitate is formed, which is collected by filtration and dried at 50 °C to give 3-aminocyclohex-2-enone (intermediate I) (6.77 g, 23%) as yellow solid.
[00287]A mixture of 2-bromomalonaldehyde (7.51 g, 49.75 mmol) and thionyl chloride (3.65 mL, 49.75 mmol) in anhydrous DCM (35 mL) is stirred at reflux for 9 h, cooled down to r.t. and concentrated at reduced pressure to give 2-bromo-3- chloroacrylaldehyde (intermediate II) (6.55 g, 88%) as red oil, which is used in the next step without additional purification.
[00288] Intermediate I (3.90 g, 35.10 mmol) is added to a solution of LiCI (2.60 g, 61 .45 mmol) in DMF (60 mL) at 40 °C, and the resulting solution is stirred at 50 °C for 5 min. Intermediate II (6.550 g, 43.91 mmol) is added, and the reaction mixture is stirred at 90 °C for 1.5 h, cooled down to r.t., poured into water and extracted with EtOAc. The organic phase is concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to give a mixture of 3-bromo-7,8- dihydroquinolin-5(6/-/)-one and 3-chloro-7,8-dihydroquinolin-5(6/-/)-one (4.940 g) as yellowish oil (ratio approx. 1 : 1 according to LCMS). [00289]According to General Procedure 1 , the 1 : 1 mixture of halogenated 7,8- dihydroquinolin-5(6/-/)-ones (500 mg, approx. 2.45 mmol) is reacted with 6- ethynylpyridin-2-amine (292 mg, 2.45 mmol) in the presence of PdCI2[PPh3]2 (52 mg, 0.07 mmol), P(f-Bu)3 (0.061 mL, 0.25 mmol), and TEA (4 mL) in acetonitrile (4 mL) at 100 °C for 2 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) to provide the title compound (90 mg, 14%).
1H NMR (De-DMSO), δΗ, 2.05-2.15 (m, 2H), 2.67 (t, 2H), 3.09 (t, 2H), 6.1 1 (br s, 2H), 6.48 (d, 1 H), 6.80 (d, 1 H), 7.40 (dd, 1 H), 8.18 (s, 1 H), 8.83 (s, 1 H).
LC/MS (M+H)+ = 264
Example 99
3-((6-Aminopyridin-2-yl)ethynyl)-7-methyl-7,8-dihydroquinolin-5(6H)-one
[00290] 3-Bromo-7-methyl-7,8-dihydroquinolin-5(6/-/)-one is prepared in close analogy to the procedure descibed for the synthesis of 3-bromo-7,7-dimethyl-7,8- dihydroquinolin-5(6/-/)-one (Preparation 1 ) starting with 5-methylcyclohexane-1 ,3-dione.
[00291 ]According to General Procedure 1 , 3-bromo-7-methyl-7,8-dihydroquinolin-5(6/-/)- one (575 mg, 2.40 mmol) is reacted with 6-ethynylpyridin-2 -amine (280 mg, 2.40 mmol) in the presence of Pd(OAc)2 (21 mg, 0.01 mmol), PPh3 (50 mg, 0.19 mmol), and Cs2C03 (2.30 g, 7.20 mmol) in dioxane (10 mL) at reflux for 6 h. The crude product is purified twice by column chromatography (1 . silica gel, EtOAc/hexane, 1 :4; 2. silica gel, DCM/EtOH, 20: 1 ) to provide the title compound (171 mg, 26%).
1H NMR (De-DMSO), δΗ, 1 .09 (d, 3H), 2.28-2.42 (m, 1 H), 2.42-2.55 (m, 1 H), 2.63-2.73 (m, 1 H), 2.82-2.92 (m, 1 H), 3.08-3.18 (m, 1 H), 6.08 (br s, 2H), 6.49 (d, 1 H), 6.80 (d, 1 H), 7.40 (dd, 1 H), 8.17 (s, 1 H), 8.83 (s, 1 H).
LC/MS (M+H)+ = 278
Example 100
3-((6-Aminopyrimidin-4-yl)ethynyl)-7,7-dim [00292]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (199 mg, 1.00 mmol) is reacted with 6-bromopyrimidin-4-amine (174 mg, 1.00 mmol) in the presence of PdCI2(PPh3)2 (39 mg, 0.055 mmol), and Cul (10 mg, 0.05 mmol) in DMF (0.5 mL) at 80 °C for 40 min under microwave irradiation. The crude product is purified by preparative HPLC (C18, acetonitrile/water) to provide the title compound (48 mg, 9%) as TFA salt.
1H NMR (De-DMSO), δΗ, 1 .05 (s, 6H), 2.61 (s, 2H), 3.07 (s, 2H), 5.50 (br, 2H), 6.74 (s, 1 H), 7.65 (br s, 2H), 8.30 (s, 1 H), 8.47 (s, 1 H), 8.94 (s, 1 H).
LC/MS (M+H)+ = 293.
Example 101
3-(lmidazo[1,2-a]pyridin-6-ylethynyl)-7,7-dim
[00293]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (199 mg, 1 .00 mmol) is reacted with 6-bromoimidazo[1 ,2-a]pyridine (197 mg, 1 .00 mmol) in the presence of PdCI2[PPh3]2 (35 mg, 0.05 mmol), P(f-Bu)3 (20 mg, 0.10 mmol), and TEA (0.5 mL) in DMF (1 .5 mL) at 50 °C for 3 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane, 10: 1 ) to provide the title compound (28 mg, 9%).
1H NMR (CDCI3), δΗ, 1 .13 (s, 6H), 2.57 (s, 2H), 3.07 (s, 2H), 7.25 (d, 1 H), 7.59 (br, 1 H), 7.61 (d, 1 H), 7,68 (br s, 1 H), 8.36 (s, 1 H), 8.39 (s, 1 H), 8.39 (s, 1 H), 8.82 (s, 1 H).
LC/MS (M+H)+ = 316
Example 102
3-((3-Amino-6-methylpyridin-2-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)- one
[00294]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (199 mg, 1 .00 mmol) is reacted with 2-bromo-6-methylpyridin-3-amine (187 mg, 1.00 mmol) in the presence of PdCI2(PPh3)2 (39 mg, 0.055 mmol), and Cul (10 mg, 0.05 mmol) in DMF (0.5 mL) at 80 °C for 40 min under microwave irradiation. The crude product is purified by preparative HPLC (C18, acetonitrile/water) to provide the title compound (336 mg, 31 %) as TFA salt. 1H NMR (De-DMSO), δΗ, 1 .05 (s, 6H), 2.41 (s, 3H), 2.60 (s, 2H), 3.06 (s, 2H), 6.70 (br, 4H), 7.27 (d, 1 H), 7.38 (d, 1 H), 8.48 (s, 1 H), 8.97 (s, 1 H).
LC/MS (M+H)+ = 306
Example 103
3-((3H-lmidazo[4,5-b]pyridin-5-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin one
[00295] A mixture of 5-chloro-3/-/-imidazo[4,5-b]pyridine (1 .53 g, 10.0 mmol) and Boc20 (2.40 g, 1 1 .0 mmol) in THF (20 mL) is cooled to 0 °C, and a catalytic amount of DMAP is added. The reaction mixture is stirred at r.t. for 24 h, diluted with EtOAc, washed with saturated aqueous NaHC03 solution and brine, dried over Na2S04, and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to give ie/f-butyl 5-chloro-3H-imidazo[4,5-b]pyridine-3-carboxylate (2.40 g, 95%) as colorless oil.
[00296]The Boc-protected intermediate (1 .01 g, 4.0 mmol) is reacted with ethynyltrimethylsilane (0.6 mL, 6.0 mmol), PdCI2[PPh3]2 (140 mg, 0.2 mmol), Cul (38 mg, 0.2 mmol), and TEA (2 mL) in anhydrous acetonitrile (10 mL) under argon atmosphere, stirred at 70 °C for 48 h, cooled down to r.t., and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to give fe/f-butyl 5-((trimethylsilyl)ethynyl)-3/-/-imidazo[4,5-b]pyridine-3- carboxylate (380 mg, 30%) as brown oil.
[00297]A TBAF solution in THF (1 M, 3 mL, 3.0 mmol) is added dropwise to a solution of ie/f-butyl 5-((trimethylsilyl)ethynyl)-3/-/-imidazo[4,5-b]pyridine-3-carboxylate (650 mg, 2.1 mmol) in DCM (5 mL) at 0 °C. The reaction mixture is stirred at r.t. for 1 h, washed with water, dried over Na2SO4 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to give ie/f-butyl 5- ethynyl-3H-imidazo[4,5-b]pyridine-3-carboxylate (330 mg, 64%) as light brown powder.
[00298]According to General Procedure 1 , 3-bromo-7-methyl-7,8-dihydroquinolin-5(6/-/)- one (220 mg, 0.87 mmol) is reacted with ie/f-butyl 5-ethynyl-3/-/-imidazo[4,5-b]pyridine- 3-carboxylate (240 mg, 1 .00 mmol) in the presence of PdCI2[PPh3]2 (28 mg, 0.04 mmol), Cul (8 mg, 0.04 mmol), and TEA (1 mL) in anhydrous acetonitrile (3 mL) at reflux for 8 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) to provide fe/f-butyl 5-((7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)-3/-/- imidazo[4,5-b]pyridine-3-carboxylate (85 mg, 24%), which is deprotected by means of TFA (1 mL) in DCM (2 mL) at r.t. for 1 h. After concentration at reduced pressure the obtained residue is purified by preparative HPLC (C18, acetonitrile/water+TFA) to provide the title compound (35 mg, 40%) as TFA salt.
1H NMR (De-DMSO), δΗ, 1 .06 (s, 6H), 2.62 (s, 2H), 3.07 (s, 2H), 6.95 (br s, 2H), 7.63 (d, 1 H), 8.12 (d, 1 H), 8.29 (d, 1 H), 8.68 (s, 1 H), 8.95 (d, 1 H).
LC/MS (M+H)+ = 317
Example 104
3-(lmidazo[1,2-a]pyridin-2-ylethynyl)-7,7-dim
[00299]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (239 mg, 1 .20 mmol) is reacted with 2-bromoimidazo[1 ,2-a]pyridine (197 mg, 1 .00 mmol) in the presence of PdCI2(PPh3)2 (39 mg, 0.055 mmol), Cs2C03 (652 mg, 2.00 mmol), P(f-Bu)3 (19 mg, 0.08 mmol), and Cul (10 mg, 0.05 mmol) in DMF (3 mL) at 100 °C for 2 h. The crude product is purified by column chromatography (silica gel, DCM/EtOH) followed by preparative HPLC (C18, acetonitrile/water+formic acid) to provide the title compound (1 1 mg, 3%) as formate salt.
1H NMR (De-DMSO), δΗ, 1 .05 (s, 6H), 2.60 (s, 2H), 3.05 (s, 2H), 6.95 (dd, 1 H), 7.31 (dd, 1 H), 7.53 (d, 1 H), 8.17 (s, 1 H), 8.21 (s, 1 H), 8.31 (s, 1 H), 8.51 (d, 1 H), 8.89 (s, 1 H). LC/MS (M+H)+ = 316
Example 105
7,7-Dimethyl-3-(pyrazolo[1,5-a]pyrimidin-5-ylethynyl)-7,8-dihydroquinolin-5(6H)- one
[00300]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (100 mg, 0.39 mmol) is reacted with 5-ethynylpyrazolo[1 ,5-a]pyrimidine (WO2010/63487), (62 mg, 0.43 mmol) in the presence of PdCI2[PPh3]2 (14 mg, 0.020 mmol), Cul (4 mg, 0.020 mmol), and TEA (0.2 mL) in DMF (1.5 mL) at 70 °C for 16 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexanes) to provide the title compound (15 mg, 12%).
1H NMR (CDCIs), δΗ, 1 .13 (s, 6H), 2.58 (s, 2H), 3.08 (s, 2H), 6.75 (d, 1 H), 6.99 (d, 1 H), 8.18 (d, 1 H), 8.47 (d, 1 H), 8.68 (d, 1 H), 8.92 (d, 1 H).
LC/MS (M+H)+ = 317
Example 106
7-Methyl-3-(phenylethynyl)-7,8-dihydroquinolin-5(6H)-one
[00301 ] 3-Bromo-7-methyl-7,8-dihydroquinolin-5(6/-/)-one is prepared in close analogy to the procedure descibed for the synthesis of 3-bromo-7,7-dimethyl-7,8- dihydroquinolin-5(6/-/)-one (Preparation 1 ) starting with 5-methylcyclohexane-1 ,3-dione.
[00302]According to General Procedure 1 , 3-bromo-7-methyl-7,8-dihydroquinolin-5(6/-/)- one (200 mg, 0.83 mmol) is reacted with ethynylbenzene (82 mg, 0.80 mmol) in the presence of Pd(OAc)2 (7 mg, 0.03 mmol), PPh3 (17 mg, 0.06 mmol), and Cs2C03 (780 mg, 2.40 mmol) in dioxane (5 mL) at reflux for 6 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane, 1 :4) to provide the title compound (33 mg, 16%).
1H NMR (CDCI3), δΗ, 1 .20 (d, 3H), 2.34-2.49 (m, 2H), 2.73-2.92 (m, 2H), 3.25 (d, 1 H), 7.37 (s, 1 H), 7.55 (s, 2H), 8.37 (s, 1 H), 8.80 (s, 1 H).
LC/MS (M+H)+ = 262, 303
Example 107
2-((7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)nicotinonitrile
[00303]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (199 mg, 1.00 mmol) is reacted with 2-chloronicotinonitrile (208 mg, 1 .50 mmol) in the presence of PdCI2[PPh3]2 (58 mg, 0.08 mmol), P(f-Bu)3 (24 mg, 0.12 mmol), and TEA (1 .5 mL) in DMF (0.5 mL) under argon atmosphere in a closed vessel under microwave irradiation at 80 °C for 40 min. The crude product is purified by column chromatography (silica gel, DCM/EtOH, 20: 1 ) followed by preparative HPLC (C18, acetonitrile/water) to provide the title compound (93 mg, 21 %).
1H NMR (De-DMSO), δΗ, 1 .07 (s, 6H), 2.63 (s, 2H), 3.09 (s, 2H), 7.64-7.69 (dd, 1 H), 8.31 (s, 1 H), 8.42 (d, 1 H), 8.89 (d, 1 H), 8.97 (s, 1 H).
LC/MS (M+H)+ = 302, 343
Example 108
3-((1H-Pyrrolo[2,3-b]pyridin-6-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin one
[00304]6-Chloro-1 /-/-pyrrolo[2,3-b]pyridine is converted to the /V-Boc-protected derivative in close analogy to the procedure described for Example 103.
[00305]fe/f-Butyl 6-chloro-1 /-/-pyrrolo[2,3-b]pyridine-1 -carboxylate (1 .00 g, 4.0 mmol) is reacted with ethynyltrimethylsilane (0.6 mL, 6.0 mmol), PdCI2[MeCN]2 (50 mg, 0.2 mmol), SPhos (160 mg, 0.4 mmol), and TEA (2 mL) in anhydrous acetonitrile (10 mL) under argon atmosphere at 75 °C for 8 h, cooled down to r.t. and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to give fe/f-butyl 6-((trimethylsilyl)ethynyl)-1 /-/-pyrrolo[2,3-b]pyridine- 1 -carboxylate (430 mg, 35%) as brown oil. The TMS group is removed in close analogy to the procedure described for Example 103.
[00306]3-Bromo-7-methyl-7,8-dihydroquinolin-5(6/-/)-one (220 mg, 0.87 mmol) is reacted with fe/f-butyl 6-ethynyl-1 /-/-pyrrolo[2,3-b]pyridine-1 -carboxylate (210 mg, 0.87 mmol) in the presence of PdCI2[PPh3]2 (28 mg, 0.04 mmol), Cul (8 mg, 0.04 mmol), and TEA (1 mL) in anhydrous acetonitrile (5 mL) under argon atmosphere at 80 °C for 8 h and then cooled down to r.t. A concentrated aqueous HCI solution (1 mL) and MeOH (3 mL) are added. After stirring at r.t. for 30 min the reaction mixture is concentrated at reduced pressure. The obtained residue is purified by preparative HPLC (C18, acetonitrile/water) to give the title compound (45 mg, 16% for two steps).
1H NMR (De-DMSO), δΗ, 1 .06 (s, 6H), 2.61 (s, 2H), 3.06 (s, 2H), 6.52 (s, 1 H), 7.39 (d, 1 H), 7.61 (s, 1 H), 8.01 (d, 1 H), 8.26 (s, 1 H), 8.93 (s, 1 H), 1 1 .72 (s, 1 H).
LC/MS (M+H)+ = 318, 359 Example 109
3-((1H-lndazol-5-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one
[00307]To a solution of 5-bromo-1 /-/-indazole (720 mg, 3.65 mmol) in acetonitrile (15 ml_) tosyl chloride (768 mg, 4.00 mmol) and TEA (2 ml_) are added. The mixture is stirred at 50 °C for 8 h and diluted with water. The formed precipitate is collected by filtration, washed with water and hexane, and dried to give 5-bromo-1 -tosyl-1 /-/-indazole (1 .19 g, 93%) as beige solid.
[00308]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (398 mg, 2.00 mmol) is reacted with 5-bromo-1 -tosyl-1 /-/-indazole (702 mg, 2.00 mmol) in the presence of PdCI2(PPh3)2 (42 mg, 0.06 mmol), P(f-Bu)3 (20 mg, 0.10 mmol), TEA (1 ml_), and Cul (1 1 mg, 0.06 mmol) in acetonitrile (10 ml_) at 70-80 °C for 4 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane, 1 :2) to provide 7, 7-dimethyl-3-((1 -tosyl-1 H-indazol-5-yl)ethynyl)-7,8-dihydroquinolin- 5(6H)-one (380 mg, 40%), which is deprotected using f-BuOK (1 12 mg, 1 .00 mmol) in t- BuOH (5 ml_) and THF (5 ml_) at reflux for 1 h. The mixture is cooled down to r.t., diluted with water and extracted with DCM. The organic layer is dried over Na2S04 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, DCM/EtOAc, 15: 1 ), triturated with diethyl ether and dried to provide the title compound (58 mg, 23%).
1H NMR (De-DMSO), δΗ, 1 .07 (s, 6H), 2.60 (s, 2H), 3.05 (s, 2H), 7.56 (dd, 2H), 8.08 (s, 1 H), 8.13 (s, 1 H), 8.23 (s, 1 H), 8.89 (s, 1 H), 13.23 (s, 1 H).
LC/MS (M+H)+ = 316, 357
Example 110
3-((3-Aminopyridin-2-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one
[00309]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (199 mg, 1 .00 mmol) is reacted with 2-chloro-3-nitropyridine (158 mg, 1 .00 mmol) in the presence of PdCI2(PPh3)2 (42 mg, 0.06 mmol), P(f-Bu)3 (16 mg, 0.08 mmol), and TEA (1 .5 ml_) in DMF (3 ml_) at 100 °C for 3 h. The crude product is purified by column chromatography (silica gel) to provide the intermediate product 7,7-dimethyl- 3-((3-nitropyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6/-/)-one (270 mg, 56%).
[00310]7,7-Dimethyl-3-((3-nitropyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6/-/)-one (270 mg, 0.84 mmol) is dissolved in EtOAc (10 mL), and the solution is cooled to 0 °C. A solution of SnCI2 *2H2O (950 mg, 4.20 mmol) in concentrated aqueous HCI solution (1 mL) is added dropwise. The reaction mixture is stirred at r.t. for 3 h, poured onto ice, treated with 15% aqueous NaOH solution to reach pH 9-10, and extracted with EtOAc (3x25 mL). The combined organic phases are dried over Na2SO4 and concentrated at reduced pressure. The obtained residue is purified by preparative TLC (silica gel, DCM/EtOH, 40: 1 ) to provide the title compound (28 mg, 1 1 %).
1H NMR (CDCI3), δΗ, 1 .14 (s, 6H), 2.57 (s, 2H), 3.07 (s, 2H), 4.26 (br s, 2H), 7.02-7.12 (m, 3H), 8.06 (d, 1 H), 8.41 (s, 1 H), 8.89 (s, 1 H).
LC/MS (M+H)+ = 292
Example 111
7,7-Dimethyl-3-((4-methylpyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6H)-o
[0031 1 ]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (199 mg, 1 .00 mmol) is reacted with 2-bromo-4-methylpyridine (172 mg, 1 .00 mmol) in the presence of PdCI2(PPh3)2 (42 mg, 0.06 mmol), and TEA (1 .5 mL) in DMF (3 mL) at 100 °C for 3 h. The crude product is purified by column chromatography (silica gel) to provide the title compound (75 mg, 26%).
1H NMR (De-DMSO), δΗ, 1 .06 (s, 6H), 2.36 (s, 3H), 2.61 (s, 2H), 3.06 (s, 2H), 7.28 (d, 1 H), 7.57 (s, 1 H), 8.26 (d, 1 H), 8.48 (d, 1 H), 8.92 (d, 1 H).
LC/MS (M+H)+ = 291 , 332
Example 112
2-((7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)-6- methylnicotinonitrile
[00312]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (199 mg, 1.00 mmol) is reacted with 2-chloro-6-methylnicotinonitrile (152 mg, 1.00 mmol) in the presence of PdCI2(PPh3)2 (42 mg, 0.06 mmol), P(f-Bu)3 (16 mg, 0.08 mmol), and TEA (1 .5 mL) in DMF (3 mL) at 100 °C for 3 h. The crude product is purified by column chromatography (silica gel) to provide the title compound (65 mg, 21 %).
1H NMR (De-DMSO), δΗ, 1 .06 (s, 6H), 2.60 (s, 3H), 2.63 (s, 2H), 3.09 (s, 2H), 7.54 (d, 1 H), 8.28 (dd, 2H), 8.97 (s, 1 H).
LC/MS (M+H)+ = 316, 357
Example 113
7-Methyl-3-((4-methylpyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6H)-one
[00313]3-Bromo-7-methyl-7,8-dihydroquinolin-5(6/-/)-one is prepared in close analogy to the procedure descibed for the synthesis of 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (Preparation 1 ) starting with 5-methylcyclohexane-1 ,3-dione.
[00314]A mixture of 2-bromo-4-methylpyridine (1 .702 g, 10.00 mmol), ethynyltrimethylsilane (1 .473 g, 15.00 mmol), PdCI2[PPh3]2 (351 mg, 0.50 mmol), Cul (192 mg, 1.00 mmol), and TEA (10 mL) in benzene (20 mL) is stirred under argon atmosphere at 50 °C for 7 h, cooled down to r.t. and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, DCM/hexane) to give 4-methyl-2-((trimethylsilyl)ethynyl)pyridine, which is dissolved in THF (15 mL). The TMS group is removed by adding 1 N TBAF solution in THF (10 mL) dropwise at -30 °C. The resulting mixture is stirred at 0 °C for 20 min, quenched with water (150 mL) at 0 °C and extracted with hexane (2x100 mL). The combined organic phases are washed with water, dried over Na2S04 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) resulting in 2-ethynyl- 4-methylpyridine (1 .080 g, 79% for two steps) as brownish solid.
[00315]According to General Procedure 1 , 3-bromo-7-methyl-7,8-dihydroquinolin-5(6/-/)- one (200 mg, 0.83 mmol) is reacted with 2-ethynyl-4-methylpyridine (93 mg, 0.80 mmol) in the presence of Pd(OAc)2 (7 mg, 0.03 mmol), PPh3 (17 mg, 0.06 mmol), and Cs2C03 (780 mg, 2.40 mmol) in dioxane (5 mL) at reflux for 6 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane, 1 :4) to provide the title compound (24 mg, 5%). 1H NMR (CDCI3), δΗ, 1 .20 (d, 3H), 2.38-2.41 (m, 5H), 2.77-2.92 (m, 2H), 3.25 (d, 1 H), 7.1 1 (d, 1 H), 7.40 (s, 1 H), 8.42 (s, 1 H), 8.49 (d, 1 H), 8.89 (s, 1 H).
LC/MS (M+H)+ = 277, 318
Example 114
3-((1H-Pyrrolo[3,2-b]pyridin-3-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin one
[00316]To a mixture of 3-iodo-1 H-pyrrolo[3,2-b]pyridine (732 mg, 3.00 mmol), DMAP (37 mg, 0.30 mmol) and TEA (0.56 mL, 4.00 mmol) in THF (15 mL) Boc20 (785 mg, 3.60 mmol) is added. The reaction mixture is stirred at r.t. for 3 h and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, DCM/EtOAc, 10: 1 ) to give ie/f-butyl 3-iodo-1 /-/-pyrrolo[3,2-b]pyridine-1 -carboxylate (980 mg, 95%) as white solid.
[00317]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6H)-one (450 mg, 2.26 mmol) is reacted with ie/f-butyl 3-iodo-1 /-/-pyrrolo[3,2- b]pyridine-1 -carboxylate (772 mg, 2.24 mmol) in the presence of PdCl2(PPh3)2 (50 mg, 0.07 mmol), and TEA (1 mL) in acetonitrile (3 mL) at reflux for 3 h. The crude product is purified by column chromatography (silica gel, DCM/EtOAc, 1 :1 ) and crystallized from EtOAc/diethyl ether to give the intermediate product ie/f-butyl 3-((7,7-dimethyl-5-oxo- 5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)-1 /-/-pyrrolo[3,2-b]pyridine-1 -carboxylate (615 mg, 66%) as yellowish solid.
[00318]To a solution of the Boc-protected intermediate (390 mg, 0.94 mmol) in DCM (25 mL) TFA (5 mL) is added. The mixture is stirred at r.t. for 3 h and neutralized with aqueous solution of K2CO3. The organic layer is separated, and the aqueous layer is extracted with DCM (4x50 mL). The combined organic layers are dried over Na2SO4 and concentrated at reduced pressure. The obtained residue is crystallized from acetone, washed with water and diethyl ether and dried to provide the title compound (230 mg, 78%).
1H NMR (De-DMSO), δΗ, 1 .06 (s, 6H), 2.61 (s, 2H), 3.05 (s, 2H), 7.35 (dd, 1 H), 8.04 (d, 1 H), 8.21 (s, 2H), 8.51 (d, 1 H), 8.86 (s, 1 H), 12.1 1 (s, 1 H). LC/MS (M+H)+ = 316, 357
Example 115
3-((5-Amino-6-methylpyridin-2-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquino
one
[00319] A mixture of 6-methyl-5-nitropyridin-2-ol (500 mg, 3.24 mmol), POCI3 (0.5 mL) and PCI5 (200 mg) is stirred at 150 °C for 2 h, cooled to r.t, poured onto ice, and extracted with DCM (3x20 mL). The combined organic phases are washed with water to reach pH 7, dried over Na2S04 and concentrated at reduced pressure. The obtained residue is dried at reduced pressure to give 6-chloro-2-methyl-3-nitropyridine (430 mg, 78%) as light brown solid.
[00320]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (199 mg, 1 .00 mmol) is reacted with 6-chloro-2-methyl-3-nitropyridine (172 mg, 1.00 mmol) in the presence of PdCI2(PPh3)2 (42 mg, 0.06 mmol), P(f-Bu)3 (16 mg, 0.08 mmol), and TEA (1 .5 mL) in DMF (3 mL) at 100 °C for 3 h. The crude product is purified by column chromatography (silica gel) to give the intermediate product 7,7- dimethyl-3-((6-methyl-5-nitropyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6/-/)-one (80 mg, 16%) as yellow solid.
[00321 ]7,7-dimethyl-3-((6-methyl-5-nitropyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6/-/)- one (194 mg, 0.58 mmol) is dissolved in EtOAc (10 mL) and cooled down to 0 °C. A solution of SnCl2*2H2O (650 mg, 2.90 mmol) in concentrated aqueous HCI solution (1 mL) is added dropwise. The reaction mixture is stirred at r.t. for 3 h, poured onto ice, treated with 15% aqueous NaOH solution to reach pH 9-10, and extracted with EtOAc (3x25 mL). The combined organic phases are dried over Na2SO4 and concentrated at reduced pressure. The obtained residue is purified by preparative TLC (silica gel, DCM/EtOH, 40: 1 ) to provide the title compound (34 mg, 19%).
1H NMR (De-DMSO), δΗ, 1 .05 (s, 6H), 2.29 (s, 3H), 2.59 (s, 2H), 3.03 (s, 2H), 5.51 (br s, 2H), 6.92 (d, 1 H), 7.24 (d, 1 H), 8.15 (s, 1 H), 8.83 (s, 1 H).
LC/MS (M+H)+ = 306 Example 116
S'-tte-Aminopyridin^-ylJethynylJ-e'^'-dihydro-S'H-spiroIcyclopropane-l,?'- quinolin]-5'-one
[00322]According to General Procedure 1 , 3'-bromo-6',8'-dihydro-5'/-/- spiro[cyclopropane-1 ,7'-quinolin]-5'-one (340 mg, 1 .35 mmol) is reacted with 6- ethynylpyridin-2-amine (159 mg, 1 .35 mmol) in the presence of PdCl2[PPh3]2 (55 mg, 0.067 mmol), Cul (13 mg, 0.067 mmol) and TEA (0.6 mL) in DMF (2.5 mL) at 70 °C for 16 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexanes) to provide the title compound (15 mg, 4%).
1H NMR (CDCIs), δΗ, 0.54 (d, 4H), 2.56 (s, 2H), 3.03 (s, 2H), 4.62 (br s, 2 H), 6.51 (d, 1 H), 6.95 (d, 1 H), 7.44 (t, 1 H), 8.46 (d, 1 H), 8.85 (d, 1 H).
LC/MS (M+H)+ = 290
Example 117
3-((3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)ethynyl)-7,7-dimethyl-7,8- dihydroquinolin-5(6H)-one
[00323]The synthesis of 6-bromo-3,4-dihydro-2/-/-pyrido[3,2-b][1 ,4]oxazine is described in literature (e.g., WO 2007/141473).
[00324]A mixture of 6-bromo-3,4-dihydro-2/-/-pyrido[3,2-b][1 ,4]oxazine (107 mg, 0.50 mmol), PdCI2[PPh3]2 (35 mg, 0.05 mmol), and Cul (10 mg, 0.05 mmol) in anhydrous acetonitrile (5 mL) is degassed. Then 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)- one (100 mg, 0.50 mmol) is added followed by TEA (1 mL). The reaction mixture is stirred under argon atmosphere at 60 °C for 8 h, cooled down to r.t. and concentrated at reduced pressure. The obtained residue is purified by preparative HPLC (C18, acetonitrile/water) to provide the title compound (32 mg, 20%).
1H NMR (CDCI3), δΗ, 1 .12 (s, 6H), 2.56 (s, 2H), 3.05 (s, 2H), 3.58 (t, 2H), 4.26 (t, 2H), 5.07 (br s, 1 H), 6.89 (d, 1 H), 6.96 (d, 1 H), 8.38 (s, 1 H), 8.84 (s, 1 H).
LC/MS (M+H)+ = 334, 375 Example 118
6-Methyl-2-((7-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)nicotinonitrile
[00325]3-Bromo-7-methyl-7,8-dihydroquinolin-5(6/-/)-one is prepared in close analogy to the procedure descibed for the synthesis of 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (Preparation 1 ) starting with 5-methylcyclohexane-1 ,3-dione.
[00326]2-Ethynyl-6-methylnicotinonitrile is prepared in two steps starting from 2-chloro- 6-methylnicotinonitrile (1 .53 g, 10.0 mmol), which is reacted with ethynyltnmethylsilane (1 .473 g, 15.0 mmol), PdCI2[PPh3]2 (351 mg, 0.50 mmol), Cul (192 mg, 1 .00 mmol), P(t- Bu)3 (202 mg, 1 .00 mmol), and TEA (25 mL) in benzene (50 mL) under argon atmosphere at 50 °C for 7 h. The reaction mixture is cooled to r.t. and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, DCM/hexane), and the obtained intermediate product is dissolved in THF (15 mL). 1 N TBAF solution in THF (10 mL) is added dropwise at -30 °C. The resulting mixture is stirred at 0 °C for 20 min, quenched with water (150 mL) at 0 °C and extracted with hexane (2x100 mL). The combined organic phases are washed with water, dried over Na2S04 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to give 2-ethynyl-6- methylnicotinonitrile (980 mg, 69% for two steps) as brownish solid.
[00327]According to General Procedure 1 , 3-bromo-7-methyl-7,8-dihydroquinolin-5(6/-/)- one (200 mg, 0.83 mmol) is reacted with 2-ethynyl-6-methylnicotinonitrile (1 13 mg, 0.80 mmol) in the presence of PdCI2[dppf] (26 mg, 0.03 mmol), and Cs2C03 (780 mg, 2.40 mmol) in dioxane (10 mL) at reflux for 6 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) to provide the title compound (25 mg, 1 1 %). 1 H NMR (De-DMSO), δΗ, 1 .20 (d, 3H), 2.34-2.48 (m, 2H), 2.67 (s, 3H), 2.76-2.94 (m, 2H), 3.27 (d, 1 H), 7.25 (d, 1 H), 7.87 (d, 1 H), 8.50 (s, 1 H), 8.94 (s, 1 H).
LC/MS (M+H)+ = 302, 343
Example 119
3-((3-Aminopyridin-2-yl)ethynyl)-7-methyl-7,8-dihydroquinolin-5(6H)-one [00328]3-Bromo-7-methyl-7,8-dihydroquinolin-5(6/-/)-one is prepared in close analogy to the procedure descibed for the synthesis of 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (Preparation 1 ) starting with 5-methylcyclohexane-1 ,3-dione.
[00329]A mixture of 3-bromo-7-methyl-7,8-dihydroquinolin-5(6/-/)-one (500 mg, 2.08 mmol), PdCI2[PPh3]2 (45 mg, 0.06 mmol), Cul (125 mg, 0.07 mmol), DIPEA (2 mL), and ethynyltrimethylsilane (1 .1 mL, 8.00 mmol) in acetonitrile (20 mL) is stirred under argon atmosphere at 80 °C for 6 h, cooled to r.t. and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to give 7-methyl-3-((trimethylsilyl)ethynyl)-7,8-dihydroquinolin-5(6/-/)-one (270 mg, 53%), which is subsequently treated with 1 M solution of TBAF in THF (2 mL, 2 mmol) in THF (10 mL) at 0 °C. The reaction mixture is stirred at 0 °C for 2 h, diluted with water and extracted with DCM (3x10 mL). The combined organic phases are dried over Na2S04 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane, 1 :4) resulting in 3-ethynyl-7-methyl-7,8- dihydroquinolin-5(6/-/)-one (1 10 mg, 58%) as light brown solid.
[00330]According to General Procedure 2, 3-ethynyl-7-methyl-7,8-dihydroquinolin- 5(6/-/)-one (55 mg, 0.30 mmol) is reacted with 2-bromopyridin-3-amine (52 mg, 0.30 mmol) in the presence of Pd(OAc)2 (26 mg, 0.01 mmol), PPh3 (6 mg, 0.02 mmol), and Cs2CO3 (290 mg, 0.90 mmol) in dioxane (5 mL) at reflux for 6 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane, 1 :4) followed by preparative TLC (silica gel, DCM/EtOH) to provide the title compound (17 mg, 20%). 1H NMR (CDCIs), δΗ, 1 .20 (d, 3H), 2.34-2.49 (m, 2H), 2.74-2.92 (m, 2H), 3.25 (d, 1 H), 4.28 (br s, 2H), 7.01-7.1 1 (m, 2H), 8.05 (d, 1 H), 8.40 (s, 1 H), 8.87 (s, 1 H).
LC/MS (M+H)+ = 278
Example 120
7,7-Dimethyl-3-(pyrazolo[1,5-a]pyridin-2-ylet^
[00331 ]Pyrazolo[1 ,5-a]pyridine-2-carbaldehyde (J. Med. Chem., 2008, 51 (6), pp 1800- 1810), (673 mg, 4.6 mmol) is dissolved in 25 ml of MeOH, K2CO3 (1272 mg, 9.2 mmol) is added, and the solution is cooled to 0 °C. Dimethyl-1 -diazo-2-oxopropylphosphonate (Bestmann-Ohira reagent) (0.69 mL, 4.6 mmol) is added, and the reaction mixture is stirred at r.t. overnight. The reaction mixture is evaporated, treated with water, extracted with CHCI3, and the organic phase is dried over anhydrous Na2S04, filtered and evaporated. The residue is purified by flash column chromatography on silica to give 468 mg (71 %) of 2-ethynylpyrazolo[1 ,5-a]pyridine as a yellow oil.
[00332]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (368 mg, 1.45 mmol) is reacted with 2-ethynylpyrazolo[1 ,5-a]pyridine (206 mg, 1 .45 mmol) in the presence of PdCI2[PPh3]2 (50 mg, 0.072 mmol), Cul (14 mg, 0.072 mmol) and TEA (0.8 mL) in DMF (2 mL) at 50 °C for 16 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexanes) to provide the title compound (200 mg, 44%).
1H NMR (CDCI3), δΗ, 1 .12 (s, 6H), 2.56 (s, 2H), 3.05 (s, 2H), 6.73 (s, 1 H), 6.82 (t, 1 H), 7.15 (t, 1 H), 7.52 (d, 1 H), 8.42 (m, 2H), 8.88 (d, 1 H).
LC/MS (M+H)+ = 316
Example 121
3,-((6-(Methylamino)pyridin-2-yl)ethynyl)-6 8,-dihydro-5,H-spiro[cyclopropane-1,7,- quinolin]-5'-one
[00333]According to General Procedure 1 , 3'-bromo-6',8'-dihydro-5'/-/- spiro[cyclopropane-1 ,7'-quinolin]-5'-one (291 mg, 1 .15 mmol) is reacted with 6-ethynyl- /V-methylpyridin-2 -amine (168 mg, 1.27 mmol) in the presence of PdCl2[PPh3]2 (47 mg, 0.058 mmol), Cul (1 1 mg, 0.058 mmol) and TEA (0.6 mL) in DMF (2.5 mL) at 70 °C for 16 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexanes) to provide the title compound (15 mg, 4%).
1H NMR (CDCI3), δΗ, 0.54 (d, 4H), 2.56 (s, 2H), 2.94 (d, 3H), 3.03 (s, 2H), 4.74 (br s, 1 H), 6.41 (d, 1 H), 6.89 (d, 1 H), 7.46 (t, 1 H), 8.46 (d, 1 H), 8.84 (d, 1 H).
LC/MS (M+H)+ = 304
Example 122
3-((5-Amino-4-methylpyridin-2-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)- one [00334]A mixture of 4-methyl-5-nitropyridin-2-ol (500 mg, 3.24 mmol), POCI3 (0.5 mL) and PCI5 (200 mg) is stirred at 150 °C for 2 h, cooled down to r.t., poured onto ice and extracted with DCM (3x20 mL). The combined organic phases are washed with water to reach pH 7, dried over Na2S04 and concentrated at reduced pressure. The obtained residue is dried at reduced pressure to give crude 2-chloro-4-methyl-5-nitropyridine (480 mg, 86%).
[00335]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (199 mg, 1 .00 mmol) is reacted with 2-chloro-4-methyl-5-nitropyridine (172 mg, 1.00 mmol) in the presence of PdCI2(PPh3)2 (42 mg, 0.06 mmol), P(f-Bu)3 (16 mg, 0.08 mmol), and TEA (1 .5 mL) in DMF (3 mL) at 100 °C for 3 h. The crude product is purified by column chromatography (silica gel) to give the intermediate product 7,7- dimethyl-3-((4-methyl-5-nitropyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6/-/)-one (1 15 mg, 34%).
[00336]A mixture of 7,7-dimethyl-3-((4-methyl-5-nitropyridin-2-yl)ethynyl)-7,8- dihydroquinolin-5(6/-/)-one (1 14 mg, 0.34 mmol) and SnCI2 *2H20 (380 mg, 1 .70 mmol) in EtOH (10 mL) is stirred at reflux for 6 h, cooled to r.t., poured onto ice, treated with saturated aqueous NaHCOs solution to reach pH 7-8, and extracted with EtOAc (3x30 mL). The combined organic phases are dried over Na2S04 and concentrated at reduced pressure. The obtained residue is purified by washing with hexane and acetonitrile to provide the title compound (60 mg, 58%).
1H NMR (De-DMSO), δΗ, 1 .07 (s, 6H), 2.08 (s, 3H), 2.60 (s, 2H), 3.02 (s, 2H), 5.51 (s, 2H), 7.23 (s, 1 H), 7.90 (s, 1 H), 8.17 (s, 1 H), 8.80 (s, 1 H).
LC/MS (M+H)+ = 306
Example 123
7,7-Dimethyl-3-((5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)ethynyl)-7,8- dihydroquinolin-5(6H)-one
[00337]5,6,7,8-Tetrahydro[1 ,2-a]pyridine (Tetrahedron, 2007, 63 (7), pp 1644-1653), (1 .6 g, 13.26 mmol) is dissolved in DMF (4 mL) and /V-iodosuccinimide (6.56 g, 29.17 mmol) is added in one portion, and the mixture is heated to 40 °C for 2 days. An aqueous Na2S203 solution is added, the mixture is stirred at r.t. for 3 h, and the formed precipitate is filtered off, washed with ether and dried to give 3.49 g (70%) of 2,3-diiodo- 5,6,7,8-tetrahydroimidazo[1 ,2-a]pyridine.
[00338]A solution of isopropylmagnesium chloride (1 .84 mL of 2M solution in THF) is added dropwise to a cooled (-20 °C) solution of 2,3-diiodo-5,6,7,8- tetrahydroimidazo[1 ,2-a]pyridine (1 .37 g, 3.68 mmol) in THF (25 mL). The mixture is stirred at -20 °C for 2 h, then saturated ammonium chloride solution is added, and the mixture is warmed to r.t. The mixture is then diluted with water and extracted with DCM. The organic phase is dried over Na2S04, filtrated and evaporated to give 812 mg (89%) of 2-iodo-5,6,7,8-tetrahydroimidazo[1 ,2-a]pyridine.
[00339]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (34 mg, 0.17 mmol) is reacted with 2-iodo-5,6,7,8-tetrahydroimidazo[1 ,2- a]pyridine (55 mg, 0.22 mmol) in the presence of PdCI2[PPh3]2 (7 mg, 0.009 mmol), Cul (2 mg, 0.009 mmol) and TEA (0.6 mL) in DMF (2.5 mL) at 60 °C for 16 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexanes) to provide the title compound (6 mg, 1 1 %).
1H NMR (CDCIs), δΗ, 1 .1 1 (s, 6H), 1 .96 (m, 4H), 2.54 (s, 2H), 2.89 (t, 2H), 3.03 (s, 2H), 3.97 (t, 2H), 7.07 (s, 1 H), 8.31 (d, 1 H), 8.80 (d, 1 H).
LC/MS (M+H)+ = 320
Example 124
3-([1,2,4]Triazolo[1,5-a]pyridin-2-ylethynyl)-7,7-dimethyl-7,8-dihydroquinolin- 5(6H)-one
[00340]Ethyl [1 ,2,4]triazolo[1 ,5-a]pyridine-2-carboxylate {Tetrahedron, 1986, 42 (10), pp 2625-2634), (56 mg, 0.3 mmol) is dissolved in 7 mL of dry DCM, and the solution is cooled to 0 °C. DIBAL-H (1 .2 M solution in toluene, 2.2 mL, 2.7 mmol) is added dropwise. The reaction mixture is allowed to warm to r.t and then stirred overnight. A solution of sodium potassium tartrate and water are added, and the mixture is extracted with DCM. The organic phase is dried over Na2S04, filtrated and evaporated to give 85 mg (58%) of [1 ,2,4]triazolo[1 ,5-a]pyridin-2-ylmethanol as brown solid. [00341 ]Oxalylchloride (0.15 ml, 1 .7 mmol) is dissolved in 8 mL of DCM, the mixture is cooled to -78 °C and DMSO (0.24 mL, 3.4 mmol) is added, followed by dropwise addition of a solution of [1 ,2,4]triazolo[1 ,5-a]pyridin-2-ylmethanol (85 mg, 0.3 mmol) in DCM (5 mL). The reaction mixture is stired for 30 min at -78 °C, then TEA (0.96 mL, 6.8 mmol) is added, and the mixture is alowed to warm to r.t. The mixture is then treated with brine and extracted with DCM. The organic phase is dried over Na2S04, filtrated and evaporated to give 196 mg of crude [1 ,2,4]triazolo[1 ,5-a]pyridine-2-carbaldehyde which is used in the next step without further purification.
[00342][1 ,2,4]Triazolo[1 ,5-a]pyridine-2-carbaldehyde (149 mg, 1 mmol) is dissolved in 8 mL of MeOH, K2C03 (280 mg, 2 mmol) is added, and the solution is cooled to 0 °C. Dimethyl-1 -diazo-2-oxopropylphosphonate (Bestmann-Ohira reagent) (0.15 mL, 1 mmol) is added, and the reaction mixture is warmed to r.t. and stirred for 3 h, then evaporated to dryness. The residue is treated with water, extracted with CHCI3 and the organic phase is dried over Na2S04, filtered and evaporated. The residue is purified by flash column chromatography on silica to give 80 mg (54%) of 2-ethynyl- [1 ,2,4]triazolo[1 ,5-a]pyridine as yellowish solid.
[00343]According to General Procedure 1 , 3-bromo-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (53 mg, 0.21 mmol) is reacted with 2-ethynyl-[1 ,2,4]triazolo[1 ,5-a]pyridine (30 mg, 0.21 mmol) in the presence of PdCI2[PPh3]2 (7 mg, 0.01 mmol), Cul (2 mg, 0.01 mmol) and TEA (0.1 mL) in DMF (1 .5 mL) at 50 °C for 16 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexanes) to provide the title compound (17 mg, 26%).
1H NMR (CDCI3), δΗ, 1 .13 (s, 6H), 2.58 (s, 2H), 3.08 (s, 2H), 7.1 1 (t, 1 H), 7.59 (t, 1 H), 7.76 (d, 1 H), 8.48 (d, 1 H), 8.58 (d, 1 H), 8.94 (d, 1 H).
LC/MS (M+H)+ = 317
Example 125
3-(Phenylethynyl)-7,8-dihydroquinolin-5(6H)-one [00344]According to General Procedure 1 , 3-bromo-7,8-dihydroquinolin-5(6H)-one (see Example 94) (50 mg, 0.22 mmol) is reacted with ethynylbenzene (25 mg, 0.24 mmol) in the presence of PdCI2[PPh3]2 (8 mg, 0.01 mmol), Cul (2 mg, 0.01 mmol) and TEA (0.1 mL) in DMF (3 mL) at ambient temperature for 3 days. The crude product is purified by column chromatography (silica gel, EtOAc/hexanes) to provide the title compound (40 mg, 73%).
1H NMR (CDCIs), δΗ, 2.22 (m, 2H), 2.72 (t, 2H), 3.18 (t, 2H), 7.36-7.39 (m, 3H), 7.53- 7.57 (m, 2H), 8.39 (d, 1 H), 8.80 (d, 1 H).
LC/MS (M+H)+ = 248
Example 126
3-((3-Fluorophenyl)ethynyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2- c]azepin-5-one
[00345]According to General Procedure 1 , 3-bromo-8,8-dimethyl-6,7,8,9-tetrahydro-5/-/- pyrido[3,2-c]azepin-5-one (296 mg, 1.10 mmol) is reacted with 1 -ethynyl-3- fluorobenzene (254 μί, 2.20 mmol) in the presence of PdCI2[MeCN]2 (13 mg, 0.05 mmol), SPhos (45 mg, 0.1 1 mmol), Cul (6 mg, 0.03 mmol), and TEA (1 mL) in anhydrous acetonitrile (7 mL) at 60 °C for 2 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) and recrystallized from DCM/hexane to provide the title compound (83 mg, 24%).
1H NMR (De-DMSO), δΗ, 0.98 (s, 6H), 2.64 (d, 2H), 2.70 (s, 2H), 7.32 (dd, 1 H), 7.44- 7.55 (m, 3H), 8.02 (s, 1 H), 8.46 (s, 1 H), 8.76 (s, 1 H).
LC/MS (M+H)+ = 309
Example 127
3-((3-Fluorophenyl)ethynyl)-6,8,8-trimethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2- c]azepin-5-one
[00346]According to General Procedure 1 , 3-bromo-6,8,8-trimethyl-6,7,8,9-tetrahydro- 5/-/-pyrido[3,2-c]azepin-5-one (198 mg, 0.7 mmol) is reacted with 1 -ethynyl-3- fluorobenzene (168 mg, 1 .4 mmol) in the presence of PdCI2[MeCN]2 (15 mg, 0.06 mmol), SPhos (43 mg, 0.1 1 mmol), and TEA (1 .5 mL) in acetonitrile (5 mL) at reflux for 3 h. The crude product is purified by column chromatography (silica gel, DCM/EtOH, 50: 1 ) followed by preparative TLC (silica gel, hexane/EtOAc, 2:1 ) to provide the title compound (100 mg, 44%).
1H NMR (De-DMSO), δΗ, 1 .02 (s, 6H), 2.72 (s, 2H), 2.95 (s, 2H), 3.16 (s, 3H), 7.31 (dd, 1 H), 7.43-7.54 (m, 3H), 8.02 (s, 1 H), 8.74 (s, 1 H).
LC/MS (M+H)+ = 323
Example 128
3-((2-Fluorophenyl)ethynyl)-6,8,8-trimethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2- c]azepin-5-one
[00347]According to General Procedure 1 , 3-bromo-6,8,8-trimethyl-6,7,8,9-tetrahydro- 5/-/-pyrido[3,2-c]azepin-5-one (198 mg, 0.7 mmol) is reacted with 1 -ethynyl-2- fluorobenzene (168 mg, 1 .4 mmol) in the presence of PdCl2[MeCN]2 (15 mg, 0.06 mmol), SPhos (43 mg, 0.1 1 mmol), and TEA (1 .5 mL) in acetonithle (5 mL) at reflux for 3 h. The crude product is purified by column chromatography (silica gel, DCM/EtOH, 50: 1 ) followed by preparative TLC (silica gel, hexane/EtOAc, 2:1 ) to provide the title compound (42 mg, 19%).
1H NMR (De-DMSO), δΗ, 1 .02 (s, 6H), 2.72 (s, 2H), 2.95 (s, 2H), 3.16 (s, 3H), 7.27-7.42 (m, 2H), 7.49-7.58 (m, 1 H), 7.69 (dd, 1 H), 8.00 (s, 1 H), 8.75 (s, 1 H).
LC/MS (M+H)+ = 323
Example 129
3-((4-Fluorophenyl)ethynyl)-6,8,8-trimethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2- c]azepin-5-one
[00348]According to General Procedure 1 , 3-bromo-6,8,8-trimethyl-6,7,8,9-tetrahydro- 5/-/-pyrido[3,2-c]azepin-5-one (198 mg, 0.7 mmol) is reacted with 1 -ethynyl-4- fluorobenzene (168 mg, 1 .4 mmol) in the presence of PdCI2[MeCN]2 (15 mg, 0.06 mmol), SPhos (43 mg, 0.1 1 mmol), and TEA (1 .5 mL) in acetonithle (5 mL) at reflux for 3 h. The crude product is purified by column chromatography (silica gel, DCM/EtOH, 50: 1 ) followed by preparative TLC (silica gel, hexane/EtOAc, 2:1 ) to provide the title compound (46 mg, 20%). 1H NMR (De-DMSO), δΗ, 1 .01 (s, 6H), 2.72 (s, 2H), 2.94 (s, 2H), 3.16 (s, 3H), 7.30 (dd, 2H), 7.67 (dd, 2H), 8.01 (s, 1 H), 8.73 (s, 1 H).
LC/MS (M+H)+ = 323
Example 130
6,8,8-Trimethyl-3-(m olylethynyl)-6,7,8,9 etrahydro-5H-pyrido[3,2-c]azepin-5-one
[00349]According to General Procedure 1 , 3-bromo-6,8,8-trimethyl-6,7,8,9-tetrahydro- 5/-/-pyrido[3,2-c]azepin-5-one (170 mg, 0.6 mmol) is reacted with 1 -ethynyl-3- methylbenzene (139 mg, 1 .2 mmol) in the presence of PdCl2[MeCN]2 (8 mg, 0.05 mmol), SPhos (37 mg, 0.09 mmol), and TEA (1 .5 mL) in acetonitrile (5 mL) at reflux for 3 h. The crude product is purified by column chromatography (silica gel, DCM/EtOH, 50: 1 ) and by preparative TLC (silica gel, hexane/EtOAc, 3: 1 ) to provide the title compound (138 mg, 72%).
1H NMR (De-DMSO), δΗ, 1 .01 (s, 6H), 2.34 (s, 3H), 2.71 (s, 2H), 2.94 (s, 2H), 3.16 (s, 3H), 7.24-7.47 (m, 4H), 7.98 (s, 1 H), 8.71 (s, 1 H).
LC/MS (M+H)+ = 319
Example 131
3-((1H-lndazol-5-yl)ethynyl)-6,8,8-trimethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2- c]azepin-5-one
[00350]5-lodo-1 /-/-indazole is converted to the /V-Boc-protected derivative in close analogy to the procedure described for Example 103.
[00351 ]According to General Procedure 2, 3-ethynyl-6,8,8-trimethyl-6,7,8,9-tetrahydro- 5/-/-pyrido[3,2-c]azepin-5-one (160 mg, 0.70 mmol) is reacted with fe/f-butyl 5-iodo-1 /-/- indazole-1 -carboxylate (206 mg, 0.60 mmol) in the presence of PdCI2[PPh3]2 (14 mg, 0.02 mmol), and TEA (1 mL) in anhydrous acetonitrile (5 mL) at 50 °C for 1 h. The crude product is dissolved in anhydrous DCM (10 mL), and TFA (230 μί, 3.10 mmol) is added at r.t. After 16 h the reaction mixture is poured into an aqueous NaOH solution (1 N) and extracted with DCM. The organic phase is washed with water and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/DCM) to provide the title compound (108 mg, 52%).
1H NMR (De-DMSO), δΗ, 1.02 (s, 6H), 2.71 (s, 2H), 2.95 (s, 2H), 3.16 (s, 3H), 7.53 (d, 1H), 7.61 (d, 1H), 7.99 (s, 1H), 8.08 (s, 1H), 8.15 (s, 1H), 8.73 (s, 1H), 13.26 (s, 1H). LC/MS (M+H)+ = 345
Table 1
Figure imgf000125_0001
I
Figure imgf000125_0002
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
EXAMPLES OF REPRESENTATIVE PHARMACEUTICAL COMPOSITIONS
[00352]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 normal r.t. 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.
[00353]Other suitable pharmaceutical compositions will be immediately apparent to one skilled in the art.
FORMULATION EXAMPLES
[00354]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 1 Colloidal silicon dioxide 1
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 50
Corn starch 26
Dibasic calcium phosphate 50
Talcum 2
Colloidal silicon dioxide 2
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 2
Saccharose 250
Glucose 300
Sorbitol 150
Orange flavor 10
Colorant q.s.
Purified water add 1000 mL
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 Oleic acid EtOH
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
EtOH 57.5
Propyleneglycol 7.5
Dimethylsulfoxide 5.0 Hydroxyethylcellulose Purified water
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/EtOH 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: g
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: g
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 r.t. solution 1 is mixed with solution 2 by continuous stirring. The solution is sterilized by filtration of by autoclaving.
PHARMACOLOGY
[00355]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
PH]MPEP (2-methyl-6-(phenylethynyl)pyridine) binding to transmembrane allosteric modulatory sites of mGluR5 receptors in cortical membranes
Preparation of rat cortical membranes:
[00356]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 1000 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 8000 x g. Then the supernatant and the buffy coat are centrifuged at 48,000 x g for 20 minutes in the presence of 50 mM 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 mM Tris-HCI, pH 8.0, the membrane suspension is frozen rapidly at -80 °C.
[00357]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
[00358] Incubations 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 r.t. for 60 minutes (equilibrium is achieved under the conditions used). Non-specific binding is defined by the addition of unlabeled MPEP (10 μινι). 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
[00359]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
[00360]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
[00361 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 pm) 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.
[00362]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
[00363]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
[00364]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.
[00365]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
[00366]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.
[00367]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 or EC50) within a range of about 0.5 nM to about 100 μΜ. [00368]Results for representative compounds of the invention are shown in Tables A1 - A4.
Table A1 (Cytosolic Calcium studies with stably transfected cells)
Compound Chemical Name ICso [μΜ]
7,7-Dimethyl-3-(phenylethynyl)-7,8-
Example 1 dihydroquinolin-5(6/-/)-one 0.0684
3-((2-Fluorophenyl)ethynyl)-7,7-dimethyl-7,8-
Example 2 dihydroquinolin-5(6/-/)-one 0.108
3-((3-Fluorophenyl)ethynyl)-7,7-dimethyl-7,8-
Example 3 dihydroquinolin-5(6/-/)-one 0.0315
3-((4-Fluorophenyl)ethynyl)-7,7-dimethyl-7,8-
Example 4 dihydroquinolin-5(6/-/)-one 0.193
3-((2-Chlorophenyl)ethynyl)-7,7-dimethyl-7,8-
Example 5 dihydroquinolin-5(6/-/)-one 4.83
3-((3-Chlorophenyl)ethynyl)-7,7-dimethyl-7,8-
Example 6 dihydroquinolin-5(6/-/)-one 0.0188
3-((3-Bromophenyl)ethynyl)-7,7-dimethyl-7,8-
Example 7 dihydroquinolin-5(6/-/)-one 0.0372
7,7-Dimethyl-3-(m-tolylethynyl)-7,8-
Example 8 dihydroquinolin-5(6/-/)-one 0.0218
3-((7,7-Dimethyl-5-oxo-5,6,7,8-
Example 9 tetrahydroquinolin-3-yl)ethynyl)benzonitrile 0.0125
3-((3-Acetylphenyl)ethynyl)-7,7-dimethyl-7,8-
Example 10 dihydroquinolin-5(6/-/)-one 3.27
Methyl 3-((7,7-dimethyl-5-oxo-5,6,7,8-
Example 1 1 tetrahydroquinolin-3-yl)ethynyl)benzoate 3.41
3-((3-Hydroxyphenyl)ethynyl)-7,7-dimethyl-7,8-
Example 12 dihydroquinolin-5(6/-/)-one 0.168
3-((3-Methoxyphenyl)ethynyl)-7,7-dimethyl-7,8-
Example 13 dihydroquinolin-5(6/-/)-one 0.312
7,7-Dimethyl-3-((3-nitrophenyl)ethynyl)-7,8-
Example 14 dihydroquinolin-5(6/-/)-one 0.102
3-((3-Aminophenyl)ethynyl)-7,7-dimethyl-7,8-
Example 15 dihydroquinolin-5(6/-/)-one 0.0658 A/-(3-((7,7-Dimethyl-5-oxo-5,6,7,8- tetrahydroquinolin-3-
Example 16 yl)ethynyl)phenyl)acetamide 5.09
3-((7,7-Dimethyl-5-oxo-5,6,7,8- tetrahydroquinolin-3-yl)ethynyl)-4-
Example 17 fluorobenzonitrile 0.0249
3-((5-Amino-2-fluorophenyl)ethynyl)-7,7-
Example 18 dimethyl-7,8-dihydroquinolin-5(6/-/)-one 0.0833
7,7-Dimethyl-3-(pyridin-2-ylethynyl)-7,8-
Example 20 dihydroquinolin-5(6/-/)-one 0.00374
7,7-Dimethyl-3-((6-methylpyridin-2-yl)ethynyl)-
Example 21 7,8-dihydroquinolin-5(6/-/)-one 0.00784
2-((7,7-Dimethyl-5-oxo-5,6,7,8-
Example 22 tetrahydroquinolin-3-yl)ethynyl)isonicotinonitrile 0.144
3-((6-Hydroxypyridin-2-yl)ethynyl)-7,7-
Example 23 dimethyl-7,8-dihydroquinolin-5(6/-/)-one 6.38
3-((6-Methoxypyridin-2-yl)ethynyl)-7,7-
Example 24 dimethyl-7,8-dihydroquinolin-5(6/-/)-one 0.103
3-((4-Aminopyridin-2-yl)ethynyl)-7,7-dimethyl-
Example 25 7,8-dihydroquinolin-5(6/-/)-one 0.317
3-((6-Aminopyridin-2-yl)ethynyl)-7,7-dimethyl-
Example 26 7,8-dihydroquinolin-5(6/-/)-one 0.0182
7,7-Dimethyl-3-((6-(methylamino)pyridin-2-
Example 27 yl)ethynyl)-7,8-dihydroquinolin-5(6/-/)-one 0.0157
3-((6-(Cyclopropylamino)pyridin-2-yl)ethynyl)-
Example 28 7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one 0.148
3-((6-(Dimethylamino)pyridin-2-yl)ethynyl)-7,7-
Example 29 dimethyl-7,8-dihydroquinolin-5(6/-/)-one 7.40
7,7-Dimethyl-3-(pyridin-3-ylethynyl)-7,8-
Example 31 dihydroquinolin-5(6/-/)-one 2.47
3-((5-Fluoropyridin-3-yl)ethynyl)-7,7-dimethyl-
Example 32 7,8-dihydroquinolin-5(6/-/)-one 3.09
5-((7,7-Dimethyl-5-oxo-5,6,7,8-
Example 33 tetrahydroquinolin-3-yl)ethynyl)nicotinonitrile 0.552
7,7-Dimethyl-3-(pyridin-4-ylethynyl)-7,8-
Example 34 dihydroquinolin-5(6/-/)-one 0.194 3-((2-Fluoropyridin-4-yl)ethynyl)-7,7-dimethyl-
Example 35 7,8-dihydroquinolin-5(6/-/)-one 0.0665
7,7-Dimethyl-3-((2-methylpyridin-4-yl)ethynyl)-
Example 36 7,8-dihydroquinolin-5(6/-/)-one 0.00974
4-((7,7-Dimethyl-5-oxo-5,6,7,8-
Example 37 tetrahydroquinolin-3-yl)ethynyl)picolinonitrile 0.302
3-((2-Methoxypyridin-4-yl)ethynyl)-7,7-
Example 38 dimethyl-7,8-dihydroquinolin-5(6/-/)-one 0.899
3-((2-Aminopyridin-4-yl)ethynyl)-7,7-dimethyl-
Example 39 7,8-dihydroquinolin-5(6/-/)-one 0.182
7,7-Dimethyl-3-((2-(methylamino)pyridin-4-
Example 40 yl)ethynyl)-7,8-dihydroquinolin-5(6/-/)-one 1.29
3-((2-Aminopyrimidin-4-yl)ethynyl)-7,7-
Example 41 dimethyl-7,8-dihydroquinolin-5(6/-/)-one 0.0493
7,7-Dimethyl-3-((2-(methylamino)pyrimidin-4-
Example 42 yl)ethynyl)-7,8-dihydroquinolin-5(6/-/)-one 0.0656
3-(Cyclohex-1-en-1-ylethynyl)-7,7-dimethyl-
Example 43 7,8-dihydroquinolin-5(6/-/)-one 0.329
3-(Cyclopentylethynyl)-7,7-dimethyl-7,8-
Example 44 dihydroquinolin-5(6/-/)-one 0.616
3'-(Phenylethynyl)-6',8'-dihydro-5'H-
Example 45 spiro[cyclopentane-1 ,7'-quinolin]-5'-one 0.579
2,2-Dimethyl-6-(phenylethynyl)-2/-/-pyrano[2,3-
Example 46 b]pyridin-4(3/-/)-one 0.00808
6-((6-Aminopyridin-2-yl)ethynyl)-2,2-dimethyl-
Example 47 2/-/-pyrano[2,3-b]pyridin-4(3/-/)-one 0.0429
2,2-Dimethyl-6-((6-(methylamino)pyridin-2-
Example 48 yl)ethynyl)-2/-/-pyrano[2,3-b]pyridin-4(3/-/)-one 0.0327
8,8-Dimethyl-3-(phenylethynyl)-6,7,8,9-
Example 49 tetrahydro-5/-/-pyrido[3,2-c]azepin-5-one 0.0183
6,8,8-Trimethyl-3-(phenylethynyl)-6, 7,8,9-
Example 50 tetrahydro-5/-/-pyrido[3,2-c]azepin-5-one 0.0172
7-((6-Aminopyridin-2-yl)ethynyl)-2,2-dimethyl-
3,4-dihydropyrido[3,2-f][1 ,4]oxazepin-5(2/-/)-
Example 53 one 3.14
1 -Acetyl-6-(phenylethynyl)-2 , 3-dihydro- 1 , 8-
Example 56 naphthyridin-4(1 H)-one 0.628 2,2-Dimethyl-7-(m-tolylethynyl)-3,4-
Example 57 dihydropyrido[3,2-f][1 ,4]oxazepin-5(2/-/)-one 0.0734
3-((2,2-Dimethyl-5-oxo-2,3,4,5- tetrahydropyrido[3,2-f][1 ,4]oxazepin-7-
Example 58 yl)ethynyl)benzonitrile 1 .921
3-((2,2-Dimethyl-5-oxo-2,3,4,5- tetrahydropyrido[3,2-f][1 ,4]oxazepin-7-
Example 59 yl)ethynyl)-4-fluorobenzonitrile 3.76
3-((6-Aminopyridin-2-yl)ethynyl)-8,8-dimethyl-
6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5-
Example 60 one 0.336
Methyl 4-oxo-6-(phenylethynyl)-3,4-dihydro-
Example 61 1 ,8-naphthyridine-1 (2/-/)-carboxylate 0.095
Methyl 6-((6-aminopyridin-2-yl)ethynyl)-4-oxo-
3,4-dihydro-1 ,8-naphthyridine-1 (2H)-
Example 62 carboxylate 0.178
Methyl 4-oxo-6-(m-tolylethynyl)-3,4-dihydro-
Example 63 1 ,8-naphthyridine-1 (2/-/)-carboxylate 0.01 17
Ethyl 6-((6-aminopyridin-2-yl)ethynyl)-4-oxo-
3,4-dihydro-1 ,8-naphthyridine-1 (2H)-
Example 64 carboxylate 0.130
Methyl 6-((3-cyanophenyl)ethynyl)-4-oxo-3,4-
Example 65 dihydro-1 ,8-naphthyridine-1 (2/-/)-carboxylate 0.0591
Methyl 6-((5-cyano-2-fluorophenyl)ethynyl)-4- oxo-3,4-dihydro-1 ,8-naphthyridine-1 (2H)-
Example 66 carboxylate 0.1 12
3-((3-Aminopyridin-2-yl)ethynyl)-8,8-dimethyl-
6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5-
Example 67 one 0.672
3-((3-Amino-6-methylpyridin-2-yl)ethynyl)-8,8- dimethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-
Example 68 c]azepin-5-one 3.82
3-(lmidazo[1 ,2-a]pyridin-6-ylethynyl)-8,8- dimethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-
Example 69 c]azepin-5-one 0.180
3-((6-Aminopyridin-2-yl)ethynyl)-6,8,8- trimethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-
Example 70 c]azepin-5-one 0.171 3-((3-Aminopyridin-2-yl)ethynyl)-6,8,8- trimethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-
Example 71 c]azepin-5-one 0.412
3-((3-Amino-6-methylpyridin-2-yl)ethynyl)-
6,8,8- trimethyl-6, 7,8,9-tetrahydro-5/-/-
Example 72 pyrido[3,2-c]azepin-5-one 1.15
3-(lmidazo[1 ,2-a]pyridin-6-ylethynyl)-6,8,8- trimethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-
Example 73 c]azepin-5-one 0.157
3-(lmidazo[1 ,2-a]pyridin-2-ylethynyl)-6,8,8- trimethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-
Example 74 c]azepin-5-one 0.270
3-(lmidazo[1 ,2-a]pyridin-2-ylethynyl)-8,8- dimethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-
Example 75 c]azepin-5-one 0.656
3-((6,8,8-Trimethyl-5-oxo-6,7,8,9-tetrahydro-
5/-/-pyrido[3,2-c]azepin-3-
Example 76 yl)ethynyl)benzonitrile 0.0207
3-((8,8-Dimethyl-5-oxo-6,7,8,9-tetrahydro-5/-/-
Example 77 pyrido[3,2-c]azepin-3-yl)ethynyl)benzonitrile 0.0587
3-((8,8-Dimethyl-5-oxo-6,7,8,9-tetrahydro-5/-/- pyrido[3,2-c]azepin-3-yl)ethynyl)-4-
Example 78 fluorobenzonitrile 0.0662
3-((1 /-/-Pyrrolo[2,3-b]pyridin-6-yl)ethynyl)-6,8,8- trimethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-
Example 79 c]azepin-5-one 0.0587
8,8-Dimethyl-3-(m-tolylethynyl)-6, 7,8,9-
Example 80 tetrahydro-5/-/-pyrido[3,2-c]azepin-5-one 0.0275
4-Fluoro-3-((6,8,8-trimethyl-5-oxo-6,7,8,9- tetrahydro-5/-/-pyrido[3,2-c]azepin-3-
Example 81 yl)ethynyl)benzonitrile 0.0219
3-((1 /-/-Pyrrolo[2,3-b]pyridin-6-yl)ethynyl)-8,8- dimethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-
Example 82 c]azepin-5-one 0.133
3-((2-Fluorophenyl)ethynyl)-8,8-dimethyl-
6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5-
Example 84 one 0.103 3-((4-Fluorophenyl)ethynyl)-8,8-dimethyl-
6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5-
Example 85 one 0.114
2,2-Dimethyl-6-(m-tolylethynyl)-2/-/-pyrano[2,3-
Example 86 b]pyridin-4(3/-/)-one 0.00666
3-((2,2-Dimethyl-4-oxo-3,4-dihydro-2/-/-
Example 87 pyrano[2,3-b]pyridin-6-yl)ethynyl)benzonitrile 0.00333
3-((2,2-Dimethyl-4-oxo-3,4-dihydro-2/-/- pyrano[2 , 3- b] py rid i n-6-yl) ethynyl)-4-
Example 88 fluorobenzonitrile 0.00794
6-(lmidazo[1 ,2-a]pyridin-6-ylethynyl)-2,2-
Example 89 dimethyl-2/-/-pyrano[2,3-b]pyridin-4(3/-/)-one 0.0518
6-(lmidazo[1 ,2-a]pyridin-2-ylethynyl)-2,2-
Example 90 dimethyl-2/-/-pyrano[2,3-b]pyridin-4(3/-/)-one 0.0727
6-((1 H-lndazol-5-yl)ethynyl)-2,2-dimethyl-2H-
Example 91 pyrano[2,3-b]pyridin-4(3/-/)-one 0.0285
6-((1 H-Pyrrolo[2,3-b]pyridin-6-yl)ethynyl)-2,2-
Example 92 dimethyl-2/-/-pyrano[2,3-b]pyridin-4(3/-/)-one 0.0563
3-(lmidazo[1 ,2-a]pyridin-5-ylethynyl)-7,7-
Example 93 dimethyl-7,8-dihydroquinolin-5(6/-/)-one 9.84
3-(lmidazo[1 ,2-a]pyridin-8-ylethynyl)-7,7-
Example 94 dimethyl-7,8-dihydroquinolin-5(6/-/)-one 0.143
7,7-Dimethyl-3-(pyrazolo[1 ,5-a]pyridin-7-
Example 95 ylethynyl)-7,8-dihydroquinolin-5(6/-/)-one 0.384
3-((1 H-lndol-5-yl)ethynyl)-7,7-dimethyl-7,8-
Example 96 dihydroquinolin-5(6/-/)-one 0.471
3-((1 H-Benzo[d][1 ,2,3]triazol-5-yl)ethynyl)-7,7-
Example 97 dimethyl-7,8-dihydroquinolin-5(6/-/)-one 3.74
3-((6-Aminopyridin-2-yl)ethynyl)-7,8-
Example 98 dihydroquinolin-5(6/-/)-one 0.856
3-((6-Aminopyridin-2-yl)ethynyl)-7-methyl-7,8-
Example 99 dihydroquinolin-5(6/-/)-one 0.0346
3-((6-Aminopyrimidin-4-yl)ethynyl)-7,7-
Example 100 dimethyl-7,8-dihydroquinolin-5(6/-/)-one 0.698
3-(lmidazo[1 ,2-a]pyridin-6-ylethynyl)-7,7-
Example 101 dimethyl-7,8-dihydroquinolin-5(6/-/)-one 0.262 3-((3-Amino-6-methylpyridin-2-yl)ethynyl)-7,7-
Example 102 dimethyl-7,8-dihydroquinolin-5(6/-/)-one 0.0677
3-((3/-/-lmidazo[4,5-b]pyridin-5-yl)ethynyl)-7,7-
Example 103 dimethyl-7,8-dihydroquinolin-5(6/-/)-one 0.281
3-(lmidazo[1 ,2-a]pyridin-2-ylethynyl)-7,7-
Example 104 dimethyl-7,8-dihydroquinolin-5(6/-/)-one 0.0696
7,7-Dimethyl-3-(pyrazolo[1 ,5-a]pyrimidin-5-
Example 105 ylethynyl)-7,8-dihydroquinolin-5(6/-/)-one 0.0289
7-Methyl-3-(phenylethynyl)-7,8-
Example 106 dihydroquinolin-5(6/-/)-one 0.0278
2-((7,7-Dimethyl-5-oxo-5,6,7,8-
Example 107 tetrahydroquinolin-3-yl)ethynyl)nicotinonitrile 2.88
3-((1 H-Pyrrolo[2,3-b]pyridin-6-yl)ethynyl)-7,7-
Example 108 dimethyl-7,8-dihydroquinolin-5(6/-/)-one 0.0386
3-((1 H-lndazol-5-yl)ethynyl)-7,7-dimethyl-7,8-
Example 109 dihydroquinolin-5(6/-/)-one 0.236
3-((3-Aminopyridin-2-yl)ethynyl)-7,7-dimethyl-
Example 1 10 7,8-dihydroquinolin-5(6/-/)-one 0.0439
7.7- Dimethyl-3-((4-methylpyridin-2-yl)ethynyl)-
Example 1 11 7.8- dihydroquinolin-5(6/-/)-one 0.0620
2-((7,7-Dimethyl-5-oxo-5,6,7,8- tetrahydroquinolin-3-yl)ethynyl)-6-
Example 1 12 methylnicotinonitrile 0.236
7-Methyl-3-((4-methylpyridin-2-yl)ethynyl)-7,8-
Example 1 13 dihydroquinolin-5(6/-/)-one 0.160
3-((1 H-Pyrrolo[3,2-b]pyridin-3-yl)ethynyl)-7,7-
Example 1 14 dimethyl-7,8-dihydroquinolin-5(6/-/)-one 0.203
3-((5-Amino-6-methylpyridin-2-yl)ethynyl)-7,7-
Example 1 15 dimethyl-7,8-dihydroquinolin-5(6/-/)-one 0.0659
3'-((6-Aminopyridin-2-yl)ethynyl)-6',8'-dihydro-
Example 1 16 5'/-/-spiro[cyclopropane-1 ,7'-quinolin]-5'-one 0.0126
3-((3,4-Dihydro-2/-/-pyrido[3,2-b][1 ,4]oxazin-6- yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-
Example 1 17 5(6H)-one 1.04
6-Methyl-2-((7-methyl-5-oxo-5,6,7,8-
Example 1 18 tetrahydroquinolin-3-yl)ethynyl)nicotinonitrile 1.91 3-((3-Aminopyridin-2-yl)ethynyl)-7-methyl-7,8-
Example 1 19 dihydroquinolin-5(6/-/)-one 0.11 1
7,7-Dimethyl-3-(pyrazolo[1 ,5-a]pyridin-2-
Example 120 ylethynyl)-7,8-dihydroquinolin-5(6/-/)-one 0.121
3'-((6-(Methylamino)pyridin-2-yl)ethynyl)-6',8'- dihydro-5'/-/-spiro[cyclopropane-1 ,7'-quinolin]-
Example 121 5'-one 0.0135
3-((3-Fluorophenyl)ethynyl)-8,8-dimethyl-
6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5-
Example 126 one 0.0439
3-((3-Fluorophenyl)ethynyl)-6,8,8-trimethyl-
6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5-
Example 127 one 0.0206
3-((2-Fluorophenyl)ethynyl)-6,8,8-trimethyl-
6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5-
Example 128 one 0.0430
3-((4-Fluorophenyl)ethynyl)-6,8,8-trimethyl-
6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5-
Example 129 one 0.0710
6,8,8-Trimethyl-3-(m-tolylethynyl)-6,7,8,9-
Example 130 tetrahydro-5/-/-pyrido[3,2-c]azepin-5-one 0.0189
3-((1 H-lndazol-5-yl)ethynyl)-6,8,8-trimethyl-
6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5-
Example 131 one 0.100
Table A2 (Cytosolic Calcium studies with cultured rat astrocytes)
Compound Chemical Name ICso [μΜ]
7,7-Dimethyl-3-(phenylethynyl)-7,8-
Example 1 dihydroquinolin-5(6/-/)-one 0.00987
3-((2-Fluorophenyl)ethynyl)-7,7-dimethyl-7,8-
Example 2 dihydroquinolin-5(6/-/)-one 1.69
3-((3-Fluorophenyl)ethynyl)-7,7-dimethyl-7,8-
Example 3 dihydroquinolin-5(6/-/)-one 0.00795
3-((4-Fluorophenyl)ethynyl)-7,7-dimethyl-7,8-
Example 4 dihydroquinolin-5(6/-/)-one 0.0512
3-((3-Chlorophenyl)ethynyl)-7,7-dimethyl-7,8-
Example 6 dihydroquinolin-5(6/-/)-one 0.00285 3-((3-Bromophenyl)ethynyl)-7,7-dimethyl-7,8-
Example 7 dihydroquinolin-5(6/-/)-one 0.00483
7,7-Dimethyl-3-(m-tolylethynyl)-7,8-
Example 8 dihydroquinolin-5(6/-/)-one 0.00237
3-((7,7-Dimethyl-5-oxo-5,6,7,8-
Example 9 tetrahydroquinolin-3-yl)ethynyl)benzonitrile 0.00221
7,7-Dimethyl-3-((3-nitrophenyl)ethynyl)-7,8-
Example 14 dihydroquinolin-5(6/-/)-one 0.0191
3-((3-Aminophenyl)ethynyl)-7,7-dimethyl-7,8-
Example 15 dihydroquinolin-5(6/-/)-one 0.0328
3-((7,7-Dimethyl-5-oxo-5,6,7,8- tetrahydroquinolin-3-yl)ethynyl)-4-
Example 17 fluorobenzonitrile 0.00846
3-((5-Amino-2-fluorophenyl)ethynyl)-7,7-
Example 18 dimethyl-7,8-dihydroquinolin-5(6/-/)-one 0.106
7,7-Dimethyl-3-(pyridin-2-ylethynyl)-7,8-
Example 20 dihydroquinolin-5(6/-/)-one 0.00207
7.7- Dimethyl-3-((6-methylpyridin-2-yl)ethynyl)-
Example 21 7.8- dihydroquinolin-5(6/-/)-one 0.00567
2-((7,7-Dimethyl-5-oxo-5,6,7,8-
Example 22 tetrahydroquinolin-3-yl)ethynyl)isonicotinonitrile 0.0271
3-((6-Methoxypyridin-2-yl)ethynyl)-7,7-dimethyl-
Example 24 7,8-dihydroquinolin-5(6/-/)-one 0.0601
3-((6-Aminopyridin-2-yl)ethynyl)-7,7-dimethyl-
Example 26 7,8-dihydroquinolin-5(6/-/)-one 0.00788
7,7-Dimethyl-3-((6-(methylamino)pyridin-2-
Example 27 yl)ethynyl)-7,8-dihydroquinolin-5(6/-/)-one 0.0075
3-((6-(Cyclopropylamino)pyridin-2-yl)ethynyl)-
Example 28 7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one 0.0604
7,7-Dimethyl-3-(pyridin-3-ylethynyl)-7,8-
Example 31 dihydroquinolin-5(6/-/)-one 1.40
7,7-Dimethyl-3-(pyridin-4-ylethynyl)-7,8-
Example 34 dihydroquinolin-5(6/-/)-one 0.0452
3-((2-Fluoropyridin-4-yl)ethynyl)-7,7-dimethyl-
Example 35 7,8-dihydroquinolin-5(6/-/)-one 0.0204
3-((2-Aminopyrimidin-4-yl)ethynyl)-7,7-dimethyl-
Example 41 7,8-dihydroquinolin-5(6/-/)-one 0.0333 7,7-Dimethyl-3-((2-(methylamino)pyrimidin-4-
Example 42 yl)ethynyl)-7,8-dihydroquinolin-5(6H)-one 0.0446
2,2-Dimethyl-6-(phenylethynyl)-2H-pyrano[2,3-
Example 46 b]pyridin-4(3/-/)-one 0.00488
6-((6-Aminopyridin-2-yl)ethynyl)-2,2-dimethyl-
Example 47 2/-/-pyrano[2,3-b]pyridin-4(3/-/)-one 0.0163
2,2-Dimethyl-6-((6-(methylamino)pyridin-2-
Example 48 yl)ethynyl)-2/-/-pyrano[2,3-b]pyridin-4(3/-/)-one 0.0144
8,8-Dimethyl-3-(phenylethynyl)-6,7,8,9-
Example 49 tetrahydro-5/-/-pyrido[3,2-c]azepin-5-one 0.00757
6,8,8-Trimethyl-3-(phenylethynyl)-6, 7,8,9-
Example 50 tetrahydro-5/-/-pyrido[3,2-c]azepin-5-one 0.00724
Methyl 4-oxo-6-(phenylethynyl)-3,4-dihydro-1 ,8-
Example 61 naphthyridine-1 (2/-/)-carboxylate 0.0234
Methyl 4-oxo-6-(m-tolylethynyl)-3,4-dihydro-1 ,8-
Example 63 naphthyridine-1 (2/-/)-carboxylate 0.00452
3-(lmidazo[1 ,2-a]pyridin-6-ylethynyl)-8,8- dimethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-
Example 69 c]azepin-5-one 0.226
3-((6-Aminopyridin-2-yl)ethynyl)-6,8,8-trimethyl-
Example 70 6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5-one 0.132
3-((1 /-/-Pyrrolo[2,3-b]pyridin-6-yl)ethynyl)-6,8,8- trimethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-
Example 79 c]azepin-5-one 0.0197
8,8-Dimethyl-3-(m-tolylethynyl)-6, 7,8,9-
Example 80 tetrahydro-5/-/-pyrido[3,2-c]azepin-5-one 0.00715
4-Fluoro-3-((6,8,8-trimethyl-5-oxo-6,7,8,9- tetrahydro-5/-/-pyrido[3,2-c]azepin-3-
Example 81 yl)ethynyl)benzonitrile 0.0119
3-((1 /-/-Pyrrolo[2,3-b]pyridin-6-yl)ethynyl)-8,8- dimethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-
Example 82 c]azepin-5-one 0.0464
3-((2-Fluorophenyl)ethynyl)-8,8-dimethyl-
Example 84 6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5-one 0.0209
3-((4-Fluorophenyl)ethynyl)-8,8-dimethyl-
Example 85 6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5-one 0.0419 3-((2,2-Dimethyl-4-oxo-3,4-dihydro-2/-/-
Example 87 pyrano[2,3-b]pyridin-6-yl)ethynyl)benzonitrile 0.00190
3-((2,2-Dimethyl-4-oxo-3,4-dihydro-2/-/- pyrano[2 , 3- b] py rid i n-6-yl) ethynyl)-4-
Example 88 fluorobenzonitrile 0.00521
6-(lmidazo[1 ,2-a]pyridin-6-ylethynyl)-2,2-
Example 89 dimethyl-2/-/-pyrano[2,3-b]pyridin-4(3/-/)-one 0.0189
6-(lmidazo[1 ,2-a]pyridin-2-ylethynyl)-2,2-
Example 90 dimethyl-2/-/-pyrano[2,3-b]pyridin-4(3/-/)-one 0.0225
6-((1 H-Pyrrolo[2,3-b]pyridin-6-yl)ethynyl)-2,2-
Example 92 dimethyl-2/-/-pyrano[2,3-b]pyridin-4(3/-/)-one 0.0124
3-(lmidazo[1 ,2-a]pyridin-8-ylethynyl)-7,7-
Example 94 dimethyl-7,8-dihydroquinolin-5(6/-/)-one 0.0874
3-((6-Aminopyridin-2-yl)ethynyl)-7-methyl-7,8-
Example 99 dihydroquinolin-5(6/-/)-one 0.0192
3-((3-Amino-6-methylpyridin-2-yl)ethynyl)-7,7-
Example 102 dimethyl-7,8-dihydroquinolin-5(6/-/)-one 0.0563
3-(lmidazo[1 ,2-a]pyridin-2-ylethynyl)-7,7-
Example 104 dimethyl-7,8-dihydroquinolin-5(6/-/)-one 0.0247
7-Methyl-3-(phenylethynyl)-7,8-dihydroquinolin-
Example 106 5(6H)-one 0.00496
3-((3-Aminopyridin-2-yl)ethynyl)-7,7-dimethyl-
Example 110 7,8-dihydroquinolin-5(6/-/)-one 0.0357
7.7- Dimethyl-3-((4-methylpyridin-2-yl)ethynyl)-
Example 11 1 7.8- dihydroquinolin-5(6/-/)-one 0.0293
3-((5-Amino-6-methylpyridin-2-yl)ethynyl)-7,7-
Example 115 dimethyl-7,8-dihydroquinolin-5(6/-/)-one 0.0503
7,7-Dimethyl-3-(pyrazolo[1 ,5-a]pyridin-2-
Example 120 ylethynyl)-7,8-dihydroquinolin-5(6/-/)-one 0.0225
3'-((6-(Methylamino)pyridin-2-yl)ethynyl)-6',8'- dihydro-5'/-/-spiro[cyclopropane-1 ,7'-quinolin]-5'-
Example 121 one 0.00829 Table A3 (Cytosolic Calcium studies with stably transfected
Figure imgf000158_0001
Inhibition of Monoamine Oxidase MAO-B
[00369] The inhibition of the enzyme monoamine oxidase MAO-B is tested with an enzyme from recombinant source, namely of the human enzyme expressed in insect Hi5 cells. Following a pre-incubation of the test compounds with the enzyme for 15 minutes at 37 °C in the incubation buffer (100 mM potassium phosphate, pH 7.4), the enzymatic reaction with 50 uM kynuramine is carried out for 60 minutes. The reaction product 4-hydroxyquinoline is quantified by spectrofluorometry. The compound vehicle used for this assay is 1 % DMSO.
[00370] The compounds of the present invention have a potency (IC50) within a range of about 0.5 ηινι to about 100 μΜ.
[00371 ] Results for representative compounds of the invention are shown in Table A5 Table A5 (MAO-B assay)
Compound Chemical Name ICso [μΜ]
3-((2-Fluorophenyl)ethynyl)-7,7-dimethyl-7,8-
Example 2 dihydroquinolin-5(6/-/)-one 0.00726
3-((5-Amino-2-fluorophenyl)ethynyl)-7,7-dimethyl-
Example 18 7,8-dihydroquinolin-5(6/-/)-one 0.079
7,7-Dimethyl-3-(pyridin-2-ylethynyl)-7,8-
Example 20 dihydroquinolin-5(6/-/)-one 0.616
2-((7,7-Dimethyl-5-oxo-5,6,7,8-
Example 22 tetrahydroquinolin-3-yl)ethynyl)isonicotinonitrile 0.197
3-((6-Aminopyridin-2-yl)ethynyl)-7,7-dimethyl-7,8-
Example 26 dihydroquinolin-5(6/-/)-one 3.55
7,7-Dimethyl-3-((6-(methylamino)pyridin-2-
Example 27 yl)ethynyl)-7,8-dihydroquinolin-5(6/-/)-one 0.886
3-((6-(Cyclopropylamino)pyridin-2-yl)ethynyl)-7,7-
Example 28 dimethyl-7,8-dihydroquinolin-5(6/-/)-one 1.84
3-((2-Fluoropyridin-4-yl)ethynyl)-7,7-dimethyl-7,8-
Example 35 dihydroquinolin-5(6/-/)-one 0.017
6,8,8-Trimethyl-3-(phenylethynyl)-6, 7,8,9-
Example 50 tetrahydro-5/-/-pyrido[3,2-c]azepin-5-one 4.63
3-((6-Aminopyridin-2-yl)ethynyl)-6,8,8-trimethyl-
Example 70 6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5-one 100*
3-((8,8-Dimethyl-5-oxo-6,7,8,9-tetrahydro-5/-/- pyrido[3,2-c]azepin-3-yl)ethynyl)-4-
Example 78 fluorobenzonitrile 0.051
8,8-Dimethyl-3-(m-tolylethynyl)-6, 7,8,9-
Example 80 tetrahydro-5/-/-pyrido[3,2-c]azepin-5-one 2.40
4-Fluoro-3-((6,8,8-trimethyl-5-oxo-6,7,8,9- tetrahydro-5/-/-pyrido[3,2-c]azepin-3-
Example 81 yl)ethynyl)benzonitrile 0.0367
3-((1 /-/-Pyrrolo[2,3-b]pyridin-6-yl)ethynyl)-8,8- dimethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-
Example 82 c]azepin-5-one 40.0*
3-((2,2-Dimethyl-4-oxo-3,4-dihydro-2/-/-
Example 87 pyrano[2,3-b]pyridin-6-yl)ethynyl)benzonitrile 0.0345 3-((2,2-Dimethyl-4-oxo-3,4-dihydro-2/-/- pyrano[2 , 3- b] py rid i n-6-yl) ethynyl)-4-
Example 88 fluorobenzonitrile 6.27
6-(lmidazo[1 ,2-a]pyridin-6-ylethynyl)-2,2-
Example 89 dimethyl-2/-/-pyrano[2,3-b]pyridin-4(3/-/)-one 1.94
3-(lmidazo[1 ,2-a]pyridin-2-ylethynyl)-7,7-
Example 104 dimethyl-7,8-dihydroquinolin-5(6/-/)-one 15.6*
3-((5-Amino-6-methylpyridin-2-yl)ethynyl)-7,7-
Example 115 dimethyl-7,8-dihydroquinolin-5(6/-/)-one 6.97
*Estimated IC50
Glutathione (GSH) Trapping Assay
[00372] The glutathione (GSH) trapping assay may be used to identify potentially reactive structures or compounds. The formation of GSH adducts indicates a certain likelihood of chemical reactivity which might lead to the formation of protein adducts in vivo, i.e. in the human body. Protein adducts are believed to be the cause, or at least associated with, severe types of toxicities, so-called idiosyncratic toxicities, that are a serious drawback for any compound. In most cases such toxicities lead to the discontinuation of further development. Compounds which do not exhibit formation of GSH adducts have a reduced risk of protein adduct formation and are therefore advantageous over compounds which form GSH adducts.
[00373] In vitro assays are performed to identify reactive metabolites from incubations of test item with human liver microsomes fortified with nicotinamide adenine dinucleotide phosphate (reduced form) NADPH regenerating system and glutathione (GSH) as a reagent for trapping reactive metabolites/compounds. Additional incubations of test compounds are performed in presence of isolated components of the incubation system in order to distinguish between potential chemical reactions and biological metabolism, i.e. differentiation of the test item reactivity with GSH under the influence of NADPH regenerating system and pure buffer. [00374]A standardized test compound concentration of 10 μΜ and a standardized microsomal protein concentration of 0.5 mg/ml is used for the metabolic stability assays for the test compounds and for the positive control substrate, 7-ethyoxycoumarin.
[00375]GSH is dissolved as a stock solution in phosphate buffer (100 mM pH 7.4) to give a concentration of 20 mM. The incubation solutions (190 μΙ) consist of 90 μΙ of a microsomal suspension of 1 .1 mg/ml of protein in phosphate buffer 100 mM pH 7.4, 90 μΙ NADP-regenerating system (NADP: 1 mM, glucose-6-phosphate 5 mM, glucose- 6-phosphate dehydrogenase: 5 U/ml, MgCI2 5 mM) and 10 μΙ GSH stock solution. The reaction is initiated by the addition of 10 μΙ of test compound (200 μΜ in 40% acetonitrile) to the pre-incubated microsomes/buffer mix at 37 °C.
[00376]LC-MS analytical methods are used to identify GSH adducts, phase I metabolites and potential chemical turnover products in liver microsomes and assay components incubations.
[00377] Results for representative compounds of the invention are shown in Table A6
Table A6 (GSH Trapping assay)
All GSH-adduct
Parent-GSH signals/
Compound Chemical Name signals/
All signals
All signals (%)2
6,6-Dimethyl-2-
(phenylethynyl)-7,8- 21 23 dihydroquinolin-5(6/-/)-one3
7,7-Dimethyl-3-
Example 1 (phenylethynyl)-7,8- 0 0
dihydroquinolin-5(6/-/)-one
3-((2-
Fluorophenyl)ethynyl)-7,7-
Example 2 0 2
dimethyl-7,8- dihydroquinolin-5(6/-/)-one 3-((3-
Fluorophenyl)ethynyl)-7,7-
Example 3 0 4 dimethyl-7,8- dihydroquinolin-5(6/-/)-one
7,7-Dimethyl-3-(m-
Example 8 tolylethynyl)-7,8- 0 0 dihydroquinolin-5(6/-/)-one
3-((7,7-Dimethyl-5-oxo-
Example 9 5,6,7,8-tetrahydroquinolin- 0 0
3-yl)ethynyl)benzonitrile
3-((5-Amino-2- fluorophenyl)ethynyl)-7,7-
Example 18 0 0 dimethyl-7,8- dihydroquinolin-5(6/-/)-one
7,7-Dimethyl-3-(pyridin-2-
Example 20 ylethynyl)-7,8- < 1 < 1 dihydroquinolin-5(6/-/)-one
7,7-Dimethyl-3-((6- methylpyridin-2-
Example 21 < 1 < 1 yl)ethynyl)-7,8- dihydroquinolin-5(6/-/)-one
3-((6-Aminopyridin-2- yl)ethynyl)-7,7-dimethyl-
Example 26 < 1 < 1
7,8-dihydroquinolin-5(6/-/)- one
7,7-Dimethyl-3-((6- (methylamino)pyridin-2-
Example 27 < 1 < 1 yl)ethynyl)-7,8- dihydroquinolin-5(6/-/)-one
3-((6-
(Cyclopropylamino)pyridin-
Example 28 2-yl)ethynyl)-7,7-dimethyl- < 1 < 1
7,8-dihydroquinolin-5(6/-/)- one 7,7-Dimethyl-3-(pyridin-3-
Example 31 ylethynyl)-7,8- 0 0 dihydroquinolin-5(6/-/)-one
2,2-Dimethyl-6- (phenylethynyl)-2H-
Example 46 0 0 pyrano[2,3-b]pyridin- 4(3H)-one
8,8-Dimethyl-3- (phenylethynyl)-6,7,8,9-
Example 49 0 0 tetrahydro-5/-/-pyrido[3,2- c]azepin-5-one
6,8,8-Trimethyl-3- (phenylethynyl)-6,7,8,9-
Example 50 0 0 tetrahydro-5/-/-pyrido[3,2- c]azepin-5-one
Methyl 4-oxo-6- (phenylethynyl)-3,4-
Example 61 0 0 dihydro-1 ,8-naphthyridine- 1 (2/-/)-carboxylate
Methyl 4-oxo-6-(m- tolylethynyl)-3,4-dihydro-
Example 63 0 0
1 ,8-naphthyridine-1 {2H)- carboxylate
Methyl 6-((3- cyanophenyl)ethynyl)-4-
Example 65 oxo- 3 , 4-d i hy d ro- 1 , 8- 0 0 naphthyridine-1 (2H)- carboxylate
3-(lmidazo[1 ,2-a]pyridin-6- ylethynyl)-8,8-dimethyl-
Example 69 0 0
6,7,8,9-tetrahydro-5H- pyrido[3,2-c]azepin-5-one
3-((6-Aminopyridin-2- yl)ethynyl)-6,8,8-trimethyl-
Example 70 0 0
6,7,8,9-tetrahydro-5H- pyrido[3,2-c]azepin-5-one 3-((6,8,8-Trimethyl-5-oxo- 6,7,8,9-tetrahydro-5H-
Example 76 0 0 pyrido[3,2-c]azepin-3- yl)ethynyl)benzonitrile
3-((8,8-Dimethyl-5-oxo- 6,7,8,9-tetrahydro-5H-
Example 77 0 0 pyrido[3,2-c]azepin-3- yl)ethynyl)benzonitrile
3-((8,8-Dimethyl-5-oxo-
6,7,8,9-tetrahydro-5H-
Example 78 pyrido[3,2-c]azepin-3- 0 0 yl)ethynyl)-4- fluorobenzonitrile
3-((1 H-Pyrrolo[2,3- b] pyridin-6-yl)ethynyl)-
Example 79 6,8,8-trimethyl-6,7,8,9- 0 0 tetrahydro-5/-/-pyrido[3,2- c] azepin-5-one
8,8-Dimethyl-3-(m- tolylethynyl)-6,7,8,9-
Example 80 0 0 tetrahydro-5/-/-pyrido[3,2- c]azepin-5-one
4-Fluoro-3-((6,8,8- trimethyl-5-oxo-6, 7, 8, 9-
Example 81 tetrahydro-5/-/-pyrido[3,2- 0 0 c]azepin-3- yl)ethynyl)benzonitrile
3-((2,2-Dimethyl-4-oxo- 3,4-dihydro-2H-
Example 87 0 0 pyrano[2,3-b]pyridin-6- yl)ethynyl)benzonitrile
3-((2,2-Dimethyl-4-oxo-
3,4-dihydro-2H-
Example 88 pyrano[2,3-b]pyridin-6- 0 0 yl)ethynyl)-4- fluorobenzonitrile 6-(lmidazo[1 ,2-a]pyridin-6- ylethynyl)-2,2-dimethyl-2H-
Example 89 0 0
pyrano[2,3-b]pyridin- 4(3H)-one
3-(lmidazo[1 ,2-a]pyridin-2- ylethynyl)-7,7-dimethyl-
Example 104 0 0
7,8-dihydroquinolin-5(6/-/)- one
7-Methyl-3-
Example 106 (phenylethynyl)-7,8- 0 0
dihydroquinolin-5(6/-/)-one
3-((5-Amino-6- methylpyridin-2-
Example 115 yl)ethynyl)-7,7-dimethyl- 0 0
7,8-dihydroquinolin-5(6/-/)- one
7,7-Dimethyl-3- (pyrazolo[1 ,5-a]pyridin-2-
Example 120 0 0
ylethynyl)-7,8- dihydroquinolin-5(6/-/)-one
1 Ratio (%) of peak areas (mass spectrometry data) from signals with a mass per charge-ratio (m/z) corresponding to the mass (molecular weight) of the parent compound (i.e. respective example) plus the mass of GSH (307 g/mol) compared to all signals (peak areas) detected in the analytical sample.
2 Ratio (%) of peak areas (mass spectrometry data) from signals with a mass per charge-ratio (m/z) corresponding to the mass (molecular weight) of the parent compound (i.e. respective example) and additionally its metabolites plus the mass of GSH (307 g/mol) compared to all signals (peak areas) detected in the analytical sample.
3 WO 2007/023290
[00378] 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. [00379]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.
[00380]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.
[00381 ]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.
[00382]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.
[00383] 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.
[00384]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.
[00385] 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.
* * * * *
[00386]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.
[00387]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 imgf000168_0001
I
wherein
R-i represents aryl, heteroaryl, cycloC3-i2alkyl, cycloC5-i2alkenyl, or heterocyclyl; R2 represents hydrogen, fluorine, or Chalky!;
R3 represents hydrogen, fluorine, or Ci-6alkyl; or R2 and R3 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(Ci-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo;
W represents CH2, -CR4R5CH2- 0, S, -CR6R70-, NR8, or -CR9R10NR11 -;
Y represents CR-|2R-|3, or NRi4;
R4 represents hydrogen, fluorine, or Ci-6alkyl;
R5 represents hydrogen, fluorine, or Chalky!; or R4 and R5 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(Ci-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo;
R6 represents hydrogen, fluorine, or Ci-6alkyl;
R7 represents hydrogen, fluorine, or Chalky!; or R6 and R7 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Chalky!, Ci-6alkoxy, amino, hydroxy, cyano, acyl, C-i-6alkylamino, di-(C-i-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo;
R8 represents hydrogen, Chalky!, or acyl;
R9 represents hydrogen, fluorine, or Ci-6alkyl;
R-io represents hydrogen, fluorine, or Chalky!; or R9 and Rio 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Chalky!, Ci-6alkoxy, amino, hydroxy, cyano, acyl, C-i-6alkylamino, di-(C-i-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo;
Rii represents hydrogen, Chalky!, or acyl;
R-I2 represents hydrogen, fluorine, Ci-6alkyl, amino, Ci-6alkylamino, di-(C-i-6alkyl)amino, acylamino, or heterocyclyl;
R-I 3 represents hydrogen, fluorine, or Chalky!; or Ri2 and Ri3 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, C-i-6alkylamino, di-(C-i-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo; and
Ri4 represents hydrogen, Chalky!, aryl, or heteroaryl; wherein the term "aryl" means phenyl or naphthyl, wherein the phenyl or naphthyl group is optionally substituted by one or more substituents, which may be the same or different, selected independently from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Chalky!, hydroxyCi-6alkyl, C2-6alkenyl, Ci-6alkoxy, d-ealkoxyd-ealkyl, amino, hydroxy, nitro, cyano, formyl, Ci-6alkylcarbonyl, Ci-6alkoxycarbonyl, Ci-6alkylcarbonyloxy, d-ealkylcarbonyloxyd-ealkyl, C-i-6alkylamino, di-(Ci-6alkyl)amino, cycloCs-^alkylamino, Ci-6alkylcarbonylamino, phenylcarbonylamino, aminocarbonyl, N-Ci-6alkylaminocarbonyl, di-N,N-Ci-6alkylaminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, cycloC3-i2alkyl, pyridinyl, and Ci-6alkylenedioxy; the term "heteroaryl" means 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 substituents, which may be the same or different, selected independently from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, hydroxyCi-6alkyl, C2-6alkenyl, Ci-6alkoxy, amino, hydroxy, nitro, cyano, Ci-6alkylcarbonyl, Ci-6alkoxycarbonyl, Ci-6alkoxycarbonyloxy, Ci-6alkylamino, and di-(Ci-6alkyl)amino, cycloCs-^alkylamino, Ci-6alkylcarbonylamino, aminocarbonyl, N-C-i-6alkylaminocarbonyl, di-N,N-Ci-6alkyl- aminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, cycloC3-i2alkyl, Ci-6alkylenedioxy, aryl, and pyridinyl; and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
2. The compound as claimed in Claim 1 , wherein W represents CH2, -CR4R5CH2-, 0, -CR6R70-, or NR8 and Y represents CH2 or NR14.
3. The compound as claimed in Claim 2, wherein R4, R5, R6, R7, and Ri4 each independently represent hydrogen or Ci-6alkyl.
4. The compound as claimed in Claim 3, wherein R4, R5, R6, R7, and Ri4 each independently represent hydrogen or methyl.
5. The compound as claimed in Claim 2, wherein R8 represents hydrogen, Ci-6alkylcarbonyl, or Ci-6alkoxycarbonyl.
6. The compound as claimed in any of Claims 1 to 5, wherein R2 and R3 represent hydrogen or Ci-6alkyl or R2 and R3 together with the carbon atom to which they are attached form a 3 to 5-membered ring.
7. The compound as claimed in Claim 6, wherein R2 and R3 represent hydrogen or methyl or R2 and R3 together with the carbon atom to which they are attached form a cyclopropane or cyclopentane ring.
8. The compound as claimed in any of Claims 1 to 7, wherein R-i represents aryl, heteroaryl, cycloC3-i2alkyl or cycloC5-i2alkenyl.
9. The compound as claimed in Claim 8, wherein Ri represents phenyl optionally substituted by one or more substituents selected from F, CI, Br, Ci-6alkyl, cyano, Ci-6alkylcarbonyl, Ci-6alkoxycarbonyl, hydroxy, Ci-6alkoxy, nitro, amino, Ci-6alkylcarbonylamino, and cyano; pyridinyl optionally substituted by one or more substituents selected from F, Chalky!, cyano, hydroxy,
Figure imgf000171_0001
amino, C-i-6alkylamino, di-(C-i-6alkyl)amino, cycloC3-i2alkylamino, and piperidine; pyrimidinyl optionally substituted by one or more substituents selected from amino and Ci-6alkylamino; imidazopyridinyl; pyrrolopyridinyl; indazolyl; pyrazolopyridinyl; indolyl; benzotriazolyl; dihydropyridooxazinyl; tetrahydroimidazopyridinyl; cyclohexenyl; or cyclopentyl.
The compound as claimed in Claim 1 , which is selected from those of Formula IA
Figure imgf000172_0001
IA
wherein
R-T represents aryl, heteroaryl, cycloC3-i2alkyl, cycloC5-i2alkenyl, or heterocyclyl; R2' represents hydrogen, fluorine, or Chalky!;
R3' represents hydrogen or Ci-6alkyl; or R2 and R3 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Chalky!,
Figure imgf000172_0002
amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(Ci-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo;
W represents CH2, -CR4R5CH2- 0, S, or NR8;
Y' represents CH2 or NRi4;
R4 represents hydrogen, fluorine, or Ci-6alkyl;
R5 represents hydrogen or Chalky!; or R4 and R5 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, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(Ci-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo;
R8 represents hydrogen, Ci-6alkyl, or acyl;
Ri4 represents hydrogen or Ci-6alkyl; and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
1 1 . The compound as claimed in Claim 1 , which is selected from:
7,7-Dimethyl-3-(phenylethynyl)-7,8-dihydroquinolin-5(6H)-one,
3-((2-Fluorophenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
3-((3-Fluorophenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
3-((4-Fluorophenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
3-((2-Chlorophenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
3-((3-Chlorophenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
3-((3-Bromophenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
7,7-Dimethyl-3-(m-tolylethynyl)-7,8-dihydroquinolin-5(6H)-one,
3-((7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)benzonitrile,
3-((3-Acetylphenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
Methyl 3-((7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)benzoate, 3-((3-Hydroxyphenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
3-((3-Methoxyphenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
7,7-Dimethyl-3-((3-nitrophenyl)ethynyl)-7,8-dihydroquinolin-5(6/-/)-one,
3-((3-Aminophenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
/V-(3-((7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3- yl)ethynyl)phenyl)acetamide,
3-((7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)-4-fluorobenzonitrile, 3-((5-Amino-2-fluorophenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one, 3-((3-Hydroxy-5-methylphenyl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)- one, 77-Dimethyl-3-(pyndin-2-ylethynyl)-7,8-dihydroquinolin-5(6/-/)-one,
77-Dimethyl-3-((6-methylpyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6H)-one,
2- ((77-Dimethyl-5-oxo-5,67,8-tetrahydroquinolin-3-yl)ethynyl)isonicotinonitn
3- ((6-Hydroxypyridin-2-yl)ethynyl)-77-dimethyl-7,8-dihydroquinolin-5(6/-/)-one, 3-((6-Methoxypyridin-2-yl)ethynyl)-77-dimethyl-7,8-dihydroquinolin-5(6/-/)-one, 3-((4-Aminopyridin-2-yl)ethynyl)-77-dimethyl-7,8-dihydroquinolin-5(6/-/)-one, 3-((6-Aminopyridin-2-yl)ethynyl)-77-dimethyl-7,8-dihydroquinolin-5(6/-/)-one, 7,7-Dimethyl-3-((6-(methylamino)pyridin-2-yl)eth^^
one,
3-((6-(Cyclopropylamino)pyridin-2-yl)ethynyl)-77-dimethyl-7,8-dihydroquinolin- 5(6H)-one,
3-((6-(Dimethylamino)pyridin-2-yl)ethynyl)-77-dimethyl-7,8-dihydroquinolin one,
7,7-Dimethyl-3-((6-(piperidin-1 -yl)pyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6/-/)- one,
7,7-Dimethyl-3-(pyridin-3-ylethynyl)-7,8-dihydroquinolin-5(6/-/)-one,
3-((5-Fluoropyridin-3-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one, 5-((7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)nicotinonitrile, 7,7-Dimethyl-3-(pyridin-4-ylethynyl)-7,8-dihydroquinolin-5(6/-/)-one,
3- ((2-Fluoropyridin-4-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one, 7,7-Dimethyl-3-((2-methylpyridin-4-yl)ethynyl)-7,8-dihydroquinolin-5(6/-/)-one,
4- ((7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)picolinonitrile, 3-((2-Methoxypyridin-4-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one, 3-((2-Aminopyridin-4-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one, 7,7-Dimethyl-3-((2-(methylamino)pyridin-4-yl)ethynyl)-7,8-dihydroquinolin-5(6/-/)- one,
3-((2-Aminopyrimidin-4-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
7,7-Dimethyl-3-((2-(methylamino)pyrimidin-4-yl)ethynyl)-7,8-dihydroquinolin-5(6^ one,
3-(Cyclohex-1 -en-1 -ylethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one, 3-(Cyclopentylethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
3'-(Phenylethynyl)-6',8'-dihydro-5'/-/-spiro[cyclopentane-1 ,7'-quinolin]-5'-one, 2,2-Dimethyl-6-(phenylethynyl)-2H-pyrano[2,3-b]pyridin-4(3/-/)-one, 6- ((6-Aminopyridin-2-yl)ethynyl)-2,2-dimethyl-2H-pyrano[2,3-b]pyndin-4(3H)-one^ 2,2-Dimethyl-6-((6-(methylamino)pyridin-2-yl)ethynyl)-2H-pyrano[2,3-b]pyndin 4(3H)-one,
8,8-Dimethyl-3-(phenylethynyl)-6,7,8,9-tetrahydro-5/-/-pyndo[3,2-c]azepin-5-one, 6,8,8-Tnmethyl-3-(phenylethynyl)-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5-one, 2,2-Dimethyl-7-(phenylethynyl)-3,4-dihydropyndo[3,2-f][1 ,4]oxazepin-5(2/-/)-one, 2,2,4-Tnmethyl-7-(phenylethynyl)-3,4-dihydropyndo[3,2-f][1 ,4]oxazepin-5(2/-/)-one,
7- ((6-Aminopyndin-2-yl)ethynyl)-2,2-dimethyl-3,4-dihydropyndo[3,2-f][1 ,4]oxazepin- 5(2H)-one,
7-((6-Aminopyndin-2-yl)ethynyl)-2,2,4-tnmethyl-3,4-dihydropyndo[3,2- f][1 ,4]oxazepin-5(2/-/)-one,
6-(Phenylethynyl)-2,3-dihydro-1 ,8-naphthyridin-4(1 H)-one,
1 -Acetyl-6-(phenylethynyl)-2,3-dihydro-1 ,8-naphthyridin-4(1 H)-one,
2,2-Dimethyl-7-(m-tolylethynyl)-3,4-dihydropyndo[3,2-f][1 ,4]oxazepin-5(2/-/)-one,
3-((2,2-Dimethyl-5-oxo-2,3,4,5-tetrahydropyndo[3,2-f][1 ,4]oxazepin-7- yl)ethynyl)benzonitrile,
3-((2,2-Dimethyl-5-oxo-2,3,4,5-tetrahydropyndo[3,2-f][1 ,4]oxazepin-7-yl)ethynyl)-4- fluorobenzonitrile,
3-((6-Aminopyndin-2-yl)ethynyl)-8,8-dimethyl-67,8,9-tetrahydro-5H-pyndo[3,2- c]azepin-5-one,
Methyl 4-oxo-6-(phenylethynyl)-3,4-dihydro-1 ,8-naphthyridine-1 (2/-/)-carboxylate, Methyl 6-((6-aminopyridin-2-yl)ethynyl)-4-oxo-3,4-dihydro-1 ,8-naphthyridine-l (2H)- carboxylate,
Methyl 4-oxo-6-(m-tolylethynyl)-3,4-dihydro-1 ,8-naphthyridine-l (2/-/)-carboxylate, Ethyl 6-((6-aminopyridin-2-yl)ethynyl)-4-oxo-3,4-dihydro-1 ,8-naphthyridine-l (2H)- carboxylate,
Methyl 6-((3-cyanophenyl)ethynyl)-4-oxo-3,4-dihydro-1 ,8-naphthyridine-l (2H)- carboxylate,
Methyl 6-((5-cyano-2-fluorophenyl)ethynyl)-4-oxo-3,4-dihydro-1 ,8-naphthyridine- 1 (2/-/)-carboxylate,
3-((3-Aminopyridin-2-yl)ethynyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2- c]azepin-5-one, 3-((3-Amino-6-methylpyridin-2-yl)ethynyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5/-/- pyrido[3,2-c]azepin-5-one,
3-(lmidazo[1 ,2-a]pyndin-6-ylethynyl)-8,8-dimethyl-67,8,9-tetrahydro-5H-pyndo[3,2 c]azepin-5-one,
3-((6-Aminopyndin-2-yl)ethynyl)-6,8,8-tnmethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2- c]azepin-5-one,
3-((3-Aminopyndin-2-yl)ethynyl)-6,8,8-tnmethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2- c]azepin-5-one,
3-((3-Amino-6-methylpyridin-2-yl)ethynyl)-6,8,8-tnmethyl-6,7,8,9-tetrahydro-5/-/- pyrido[3,2-c]azepin-5-one,
3-(lmidazo[1 ,2-a]pyndin-6-ylethynyl)-6,8,8-tnmethyl-6,7,8,9-tetrahydro-5/-/- pyrido[3,2-c]azepin-5-one,
3-(lmidazo[1 ,2-a]pyndin-2-ylethynyl)-6,8,8-tnmethyl-6,7,8,9-tetrahydro-5/-/- pyrido[3,2-c]azepin-5-one,
3-(lmidazo[1 ,2-a]pyndin-2-ylethynyl)-8,8-dimethyl-67,8,9-tetrahydro-5H-pyndo[3,2- c]azepin-5-one,
3-((6,8,8-Trimethyl-5-oxo-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-3- yl)ethynyl)benzonitrile,
3-((8,8-Dimethyl-5-oxo-6,7,8,9-tetrahydro-5/-/-pyndo[3,2-c]azepin-3- yl)ethynyl)benzonitrile,
3-((8,8-Dimethyl-5-oxo-6,7,8,9-tetrahydro-5/-/-pyndo[3,2-c]azepin-3-yl)ethynyl)-4- fluorobenzonitrile,
3- ((1 H-Pyrrolo[2 b]pyridin-6-yl)ethy^
pyrido[3,2-c]azepin-5-one,
8,8-Dimethyl-3-( r?-tolylethynyl)-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5-one,
4- Fluoro-3-((6,8,8-tnmethyl-5-oxo-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-3- yl)ethynyl)benzonitrile,
3-((1 H-Pyrrolo[2,3-b]pyndin-6-yl)ethynyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5/-/- pyrido[3,2-c]azepin-5-one,
3-((1 /-/-lndazol-5-yl)ethynyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5/-/-pyndo[3,2- c]azepin-5-one,
3-((2-Fluorophenyl)ethynyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5/-/-pyndo[3,2- c]azepin-5-one, 3-((4-Fluorophenyl)ethynyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5/-/-pyndo[3,2- c]azepin-5-one,
2,2-Dimethyl-6-(m-tolylethynyl)-2/-/-pyrano[2,3-b]pyndin-4(3/-/)-one,
3-((2,2-Dimethyl-4-oxo-3,4-dihydro-2/-/-pyrano[2,3-b]pyridin-6- yl)ethynyl)benzonitrile,
3-((2,2-Dimethyl-4-oxo-3,4-dihydro-2/-/-pyrano[2,3-b]pyridin-6-yl)ethynyl)-4- fluorobenzonitrile,
6-(lmidazo[1 ,2-a]pyridin-6-ylethynyl)-2,2-dimethyl-2H-pyrano[2,3-b]pyndin-4(3H)- one,
6-(lmidazo[1 ,2-a]pyridin-2-ylethynyl)-2,2-dimethyl-2H-pyrano[2,3-b]pyndin-4(3/-/)- one,
6-((1 H-lndazol-5-yl)ethynyl)-2,2-dimethyl-2H-pyrano[2,3-b]pyndin-4(3/-/)-one,
6- ((1 H-Pyrrolo[2,3-b]pyridin-6-yl)ethynyl)-2,2-dimethyl-2H-pyrano[2,3-b]pyndin- 4(3H)-one,
3-(lmidazo[1 ,2-a]pyndin-5-ylethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
3-(lmidazo[1 ,2-a]pyndin-8-ylethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
7,7-Dimethyl-3-(pyrazolo[1 ,5-a]pyndin-7-ylethynyl)-7,8-dihydroquinolin-5(6/-/)-one,
3-((1 /-/-lndol-5-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
3-((1 H-Benzo[d][1 ,2,3]triazol-5-yl)ethynyl)-7,7^
one,
3-((6-Aminopyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6/-/)-one,
3-((6-Aminopyridin-2-yl)ethynyl)-7-methyl-7,8-dihydroquinolin-5(6/-/)-one,
3-((6-Am inopyrim idin-4-yl)ethynyl^
3-(lmidazo[1 ,2-a]pyridin-6-ylethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
3-((3-Amino-6-methylpyridin-2-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5 one,
3-((3H-lmidazo[4,5-b]pyridin-5-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)- one,
3-(lmidazo[1 ,2-a]pyridin-2-ylethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one, 7,7-Dimethyl-3-(pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl)-7,8-dihydroquinolin-5(6/-/)- one,
7- Methyl-3-(phenylethynyl)-7,8-dihydroquinolin-5(6/-/)-one,
2-((7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)nicotinonitrile, 3-((1 H-Pyrrolo[2,3-b]pyridin-6-yl)ethynyl)-77-dimethyl-7,8-dihydroquinolin one,
3-((1 /-/-lndazol-5-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
3-((3-Aminopyridin-2-yl)ethynyl)-77-dimethyl-7,8-dihydroquinolin-5(6/-/)-one,
77-Dimethyl-3-((4-methylpyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6H)-on
2- ((7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)-6- methylnicotinonitrile,
7-Methyl-3-((4-methylpyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6H)-one,
3- ((1 H-Pyrrolo[3,2-b]pyridin^-yl)ethynyl)-77-dimethyl-7,8 lihydroquinolin one,
3-((5-Amino-6-methylpyridin-2-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)- one,
3'-((6-Aminopyridin-2-yl)ethynyl)-6',8'-dihydro-5'/-/-spiro[cyclopropane-1 ,7'- quinolin]-5'-one,
3-((3,4-Dihydro-2/-/-pyrido[3,2-b][1 ,4]oxazin-6-yl)ethynyl)-7,7-dimethyl-7,8- dihydroquinolin-5(6/-/)-one,
6-Methyl-2-((7-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)nicotinonitrile, 3-((3-Aminopyridin-2-yl)ethynyl)-7-methyl-7,8-dihydroquinolin-5(6/-/)-one,
7,7-Dimethyl-3-(pyrazolo[1 ,5-a]pyridin-2-ylethynyl)-7,8-dihydroquinolin-5(6/-/)-one, 3'-((6-(Methylamino)pyridin-2-yl)ethynyl)-6',8'-dihydro-5'/-/-spiro[cyclopropane-1 ,7'- quinolin]-5'-one,
3-((5-Amino-4-methylpyridin-2-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)- one,
7,7-Dimethyl-3-((5,6,7,8-tetrahydroimidazo[1 ,2-a]pyridin-2-yl)ethynyl)-7,8- dihydroquinolin-5(6/-/)-one,
3-([1 ,2,4]Triazolo[1 ,5-a]pyridin-2-ylethynyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6/-/)- one,
3-(Phenylethynyl)-7,8-dihydroquinolin-5(6/-/)-one,
3-((3-Fluorophenyl)ethynyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2- c]azepin-5-one,
3-((3-Fluorophenyl)ethynyl)-6,8,8-trimethyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2- c]azepin-5-one, 3-((2-Fluorophenyl)ethynyl)-6,8,8-trimethyl-6,7,8,9-tetrahydro-5/-/-pyndo[3,2- c]azepin-5-one,
3-((4-Fluorophenyl)ethynyl)-6,8,8-trimethyl-6,7,8,9-tetrahydro-5/-/-pyndo[3,2- c]azepin-5-one,
6,8,8-Tnmethyl-3-(m-tolylethynyl)-67,8,9-tetrahydro-5/-/-pyrido[3,2-c]azepin-5-one,
3-((1 H-lndazol-5-yl)ethynyl)-6,8,8-tnmethyl-67,8,9-tetrahydro-5H-pyndo[3,2- c]azepin-5-one,
and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
12. A pharmaceutical composition comprising a compound as claimed in any preceding claim, together with one or more pharmaceutically acceptable excipients.
13. A compound as claimed in any of Claims 1 to 1 1 for use in the treatment and/or prevention of abnormal glutamate neurotransmission.
14. A compound as claimed any of Claims 1 to 1 1 , for 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), olivopontocerebellar atrophy, post-operative cognitive deficit (POCD), systemic lupus erythematosus, systemic clerosis, 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, cocaine addiction, cocaine 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, sleep disturbances, synucleinopathies, alpha- synucleinopathies, Lewy body dementia, neurodegeneration with Brain Iron Accumulation, Parkinson-plus syndrome, Pick's disease, progressive supranuclear palsy (PSP), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and neurodegenerative diseases.
Use of a compound as claimed in any of Claims 1 to 1 1 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 clerosis, 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, cocaine addiction, cocaine 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, sleep disturbances, synucleinopathies, alpha- synucleinopathies, Lewy body dementia, neurodegeneration with Brain Iron Accumulation, Parkinson-plus syndrome, Pick's disease, progressive supranuclear palsy (PSP), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and neurodegenerative diseases.
A pharmaceutical composition comprising a combination of at least one compound as claimed in any of Claims 1 to 1 1 and at least one NMDA receptor antagonist, together with one or more pharmaceutically acceptable excipients.
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 1 1 .
The method as claimed in Claim 17, 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 clerosis, 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, cocaine addiction, cocaine 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, sleep disturbances, synucleinopathies, alpha- synucleinopathies, Lewy body dementia, neurodegeneration with Brain Iron Accumulation, Parkinson-plus syndrome, Pick's disease, progressive supranuclear palsy (PSP), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and neurodegenerative diseases.
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