WO2010063487A1 - Pyrazolopyrimidines, a process for their preparation and their use as medicine - Google Patents

Pyrazolopyrimidines, a process for their preparation and their use as medicine Download PDF

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WO2010063487A1
WO2010063487A1 PCT/EP2009/008695 EP2009008695W WO2010063487A1 WO 2010063487 A1 WO2010063487 A1 WO 2010063487A1 EP 2009008695 W EP2009008695 W EP 2009008695W WO 2010063487 A1 WO2010063487 A1 WO 2010063487A1
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pyrazolo
pyrimidine
methyl
thiophen
ylethynyl
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PCT/EP2009/008695
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French (fr)
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Markus Henrich
Tanja Weil
Jens Nagel
Andreas Gravius
Sibylle MÜLLER
Valerjans Kauss
Ronalds Zemribo
Juris Fotins
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Merz Pharma Gmbh & Co. Kgaa
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Publication of WO2010063487A1 publication Critical patent/WO2010063487A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to pyrazolopyrimidine 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 mGluR ⁇ 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 Il and mGluR4, rnGluR ⁇ , mGluR7 and mGluR ⁇ 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 mGluR ⁇ 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 mGluR ⁇ modulators, such modulators may increase or inhibit the effects mediated through these metabotropic glutamate receptors.
  • Modulators which are negative mGluR ⁇ 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 mGluR ⁇ 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
  • MGIuR5 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.
  • MGIuR ⁇ 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
  • MGIuR ⁇ 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.
  • mGluR ⁇ negative or positive modulators include those indications wherein a particular condition does not necessarily exist but wherein a particular physiological parameter may be improved through administration of the instant compounds, for example cognitive enhancement, learning impairment and/or neuroprotection.
  • Positive modulators may be particularly useful in the treatment of positive and negative symptoms in schizophrenia and cognitive deficits in various forms of dementia and mild cognitive impairment.
  • mGluR modulators may have activity when administered in combination with other substances exhibiting neurological effects via different mechanisms.
  • Simultaneous administration of Group I mGluR modulators and NMDA receptor antagonists has also been shown to provide neuroprotection in animal models (Zieminska et al. Acta Neurobiol. Exp., 2006, 66, 301-309; Zieminska et al. Neurochemistry International, 2003, 43, 481-492; and Zieminska et al. Neurochemistry International, 2006, 48, 491-497).
  • Group I mGluR modulators and compounds such as L-DOPA, dopaminomimetics, and/or neuroleptics may be useful in treating various conditions including drug induced dyskinesias, neuroleptic-induced dyskinesias, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias.
  • EP 1849465 discloses compounds of general formula (Id) as GPR receptor function regulators which may be useful in treating immune disease, inflammatory disease, allergic disease, and cardiovascular disease:
  • a " is an optionally substituted isocyclic or heterocyclic ring and P is a bond or spacer and the other represents wherein R 3d represents hydrogen or an optionally substituted hydrocarbyl group, Qb is an optionally substituted spacer, and W is a carboxyl group or a group biologically equivalent to a carboxyl group; and wherein the rings F and G may be further substituted by substituents other than R 12 and R 13 .
  • A forms a benzene, pyridine, pyrimidine, thiophene, pyrrole, imidazole, pyrazole, thiazole, or oxazole ring
  • R y represents e.g., hydrogen, halogen, aryl, heteroaryl, cycloalkyl, heterocycyl, alkynyl, arylalkynyl, or heteroarylalkynyl, which groups may be further substituted
  • R 2 represents e.g., hydrogen, NR 5 2 (wherein R 5 represents hydrogen or alkyl), alkyl, cycloalkyl
  • Q represents e.g., hydrogen, halogen, NR 5 2 .
  • R 1 and R 2 represent e.g., hydrogen, halogen, C(O)NR 6 R 7 (wherein R 6 and R 7 represent e.g., Ci-C- ⁇ alkyl, C 3 -C- ⁇ ocycloalkyl or together form a ring); R 3 and R 5 represent e.g., hydrogen, optionally substituted C ⁇ -C- ⁇ alkynyl, optionally substituted aryl, optionally substituted hetaryl; and R 4 represents e.g., hydrogen, cyano, halogen, CrC 6 alkyl.
  • EP 1505068 discloses compounds of general formula (Ia) as NAD(P)H oxydase inhibitors for use in treating diseases due to inflammation, circulatory disorders, and enhanced proliferation activities:
  • R 1a , R2 a> R3, R4, and R 5 represent e.g., hydrogen, halogen, optionally substituted loweralkyl, optionally substituted loweralkenyl, optionally substituted loweralkynyl, optionally substituted amino.
  • G represents e.g., cyano, nitro, CO 2 R 4 (wherein R 4 represents e.g., hydrogen, optionally substituted alkyl); R 1 represents e.g., halogen, OR 5 , SR 5 (wherein R 5 represents e.g., optionally substituted alkynyl); R 2 represents halogen, OR 5 , or optionally substituted amino; and R 8 and R 10 represent hydrogen, halogen, or alkyl.
  • A represents aryl or heteroaryl
  • B represents N or CR 2 R 3
  • R 2 and R 3 represent e.g., hydrogen, alkyl, cycloalkyl
  • X 1 and X 2 represent C-i- ⁇ alkylene, C 2 - 6 alkenylene, O 2 - ⁇ alkynylene or a bond
  • Y represents e.g., CR 2 R 3 , O, S, a bond
  • R 1 represents e.g., alkyl, alkenyl, alkynyl, aryl, heterocyclyl
  • L represents a bond or a linker group.
  • Japanese Published Application No. 2002053466 discloses compounds of general formula (I) as apoptosis regulators which may be useful in treating apoptosis- related nerve disease:
  • R 1 represents e.g., hydrogen, optionally substituted loweralkyl.optionally substitued loweralkenyl
  • R 2 represents e.g., naphthyl, phenyl, cycloalkyl
  • R 3 represents hydrogen, phenyl, or loweralkyl
  • R 4 represents e.g., hydrogen, loweralkyl, loweralkoxycarbonyl
  • R 5 represents hydrogen or loweralkyl
  • R 6 represents hydrogen, loweralkyl optionally substituted by phenyl, or benzoyl
  • Q represents carbonyl or sulfonyl
  • A represents a bond, loweralkylene, or loweralkenylene.
  • CDK cyclin dependent kinase
  • R represents e.g., hydrogen, alkyl, alkenyl
  • R 2 represents e.g., hydrogen, halogen, cyano, alkyl, alkenyl, cycloalkyl
  • R 3 represents e.g., hydrogen, halogen, optionally substituted alkynyl
  • R 4 represents hydrogen, halogen, or alkyl.
  • R 1 represents hydrogen, halogen, or loweralkyl
  • A represents e.g., hydrogen, halogen, an aliphatic moiety
  • R 2 represents e.g., hydrogen, optionally substituted aryl, optionally substituted heteroaryl, an optionally substituted aliphatic residue
  • R 3 represents e.g., hydrogen, optionally substituted aryl, optionally substituted heteroaryl, an optionally substituted aliphatic residue, an optionally substituted aliphatic residue which is connected by a connecting group or atom.
  • pyrazolopyrimidine derivatives which differ in structure from the known pyrazolopyrimidines, are potent mGluR ⁇ modulators. Therefore, these substances may be therapeutically beneficial in the treatment of conditions which involve abnormal glutamate neurotransmission or in which modulation of mGluR ⁇ receptors results in therapeutic benefit. These substances may be administered in the form of a pharmaceutical composition, wherein they are present together with one or more pharmaceutically acceptable diluents, carriers, or excipients.
  • An additional object of the invention is the provision of processes for producing the pyrazolopyrimidine derivatives.
  • R 1 , R 2 , and R 3 which may be the same or different, each independently represent hydrogen, Ci -6 alkyl (e.g., methyl), trifluoromethyl, C- ⁇ -6 alkoxy (e.g., methoxy), cyano, halogen, or -NR 4 R 5 , wherein
  • R 4 and R 5 which may be the same or different, each independently represent hydrogen, d- ⁇ alkyl, or cycloC 3- i 2 alkyl, or R 4 and R 5 , together with the nitrogen atom to which they are attached, represent a 5- or 6- membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more groups selected from C h alky!
  • Cy represents aryl, heteroaryl, CyCIoC 3-12 a I kyl, cycloC 3- i 2 alkenyl, or heterocyclyl;
  • R 7 represents hydrogen, Ci -6 alkyl (e.g., methyl), C- ⁇ -6 alkoxy (e.g., methoxy), - C(O)NR 8 R 9 , carboxy, or aryl, wherein
  • R 8 and R 9 which may be the same or different, each independently represent hydrogen, C- ⁇ -6 alkyl, or cycloC 3-12 alkyl, or R 8 and R 9 , together with the nitrogen atom to which they are attached, represent a 5- or 6- membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more groups selected from d- ⁇ alkyl (e.g., methyl), halogen, trifluoromethyl, d- ⁇ alkoxy, and cyano;
  • d- ⁇ alkyl e.g., methyl
  • halogen trifluoromethyl
  • d- ⁇ alkoxy e.g., cyano
  • 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, 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, cyanomethyl, Ci -6 alkoxycarbonyl, d.
  • ⁇ alkylcarbonyloxy d- ⁇ alkylcarbonyloxyd- ⁇ alkyl, d- ⁇ alkylamino, di-(C-
  • arylene means a divalent aryl radical as defined above
  • 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, trifluoromethyl, trifluoromethoxy, Ci -6 alkyl, hydroxyd -6 alkyl, C 2- 6alkenyl, d- ⁇ alkoxy, amino, hydroxy, nitro, cyano, d- ⁇ alkoxycarbonyl, d- ⁇ alkoxycarbonyloxy, d- ⁇ alkylamino, and di-(Ci- 6 alkyl)amino, d- ⁇
  • heteroarylene means a divalent heteroaryl radical as defined above
  • Such a compound of Formula I wherein R 1 , R 2 , and R 3 , which may be the same or different, each independently represent hydrogen, Ci -6 alkyl, Ci -6 alkoxy, or -NR 4 R 5 , wherein R 4 and R 5 , which may be the same or different, each independently represent hydrogen or Ci -6 alkyl.
  • Such a compound of Formula I wherein R 1 , R 2 , and R 3 , which may be the same or different, each independently represent hydrogen, methyl, methoxy, amino, t- butylamino, or methoxybenzylamino.
  • Such a compound of Formula I wherein R 7 represents hydrogen, Ci -6 alkyl, Ci- ⁇ alkoxy, or -C(O)NR 8 R 9 , wherein R 8 and R 9 , which may be the same or different, each independently represent hydrogen or C h alky!, or R 8 and R 9 , together with the nitrogen atom to which they are attached, represent a 5- or 6-membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more C h alky! groups.
  • Such a compound of Formula I wherein R 7 represents hydrogen, methyl, methoxy, or -C(O)NR 8 R 9 , wherein R 8 and R 9 , which may be the same or different, each independently represent hydrogen, methyl, ethyl, n-propyl, or isopropyl or R 8 and R 9 together with the nitrogen atom to which they are attached, represent a pyrrolidine, piperazine or morpholine ring, wherein each of these rings may be optionally substituted by one or more C-i- ⁇ alkyl groups.
  • Such a compound of Formula I wherein Cy represents an aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally substituted by one or more substituents selected from halogen, trifluoromethyl, Ci. 6 alkyl, hydroxyd- ⁇ alkyl, d- ⁇ alkoxy, Ci. 6 alkoxyCi -6 alkyl, d- ⁇ alkylcarbonyloxyd- ⁇ alkyl, amino, cyano, formyl, d- ⁇ alkylcarbonylamino, phenylcarbonylamino, d- ⁇ alkoxycarbonyl, and pyridinyl.
  • substituents selected from halogen, trifluoromethyl, Ci. 6 alkyl, hydroxyd- ⁇ alkyl, d- ⁇ alkoxy, Ci. 6 alkoxyCi -6 alkyl, d- ⁇ alkylcarbonyloxyd- ⁇ alkyl, amino, cyano, formyl, d
  • Such a compound of Formula I wherein Cy represents phenyl, pyridinyl, thiophenyl, thiazolyl, benzofuryl, dihydrobenzofuryl, or imidazolyl, wherein each of these groups is optionally substituted by one or more substituents selected from halogen, trifluoromethyl, C h alky!, hydroxyd- ⁇ alkyl, d- ⁇ alkoxy, Ci- 6 alkoxyd-6alkyl, d- ⁇ alkylcarbonyloxyd- ⁇ alkyl, amino, cyano, formyl, d- ⁇ alkylcarbonylamino, phenylcarbonylamino, d- ⁇ alkoxycarbonyl, and pyridinyl.
  • Such a compound of Formula I wherein Cy represents a cycloCa- ⁇ alkyl, cycloC 3 -i 2 alkenyl, or heterocyclyl group, wherein the cycloCa- ⁇ alkyl, cycloCs- ⁇ alkenyl, or heterocyclyl group is optionally substituted by one or more substituents selected from d - 6 a Iky I, d- ⁇ alkoxycarbonyl, oxo, d- ⁇ alkoxyimino, d ealkylaminocarbonyl, and arylCi- ⁇ alkoxycarbonyl.
  • Such a compound of Formula I wherein Cy represents cyclopropyl, cyclohexyl, cyclohexenyl, tetrahydropyridinyl, dihydropyranyl, or dihydrothiopyranyl, wherein each of these groups is optionally substituted by one or more substituents selected from d -6 alkyl, d- ⁇ alkoxycarbonyl, oxo, d- ⁇ alkoxyimino, d- ⁇ alkylaminocarbonyl, and aryld- ⁇ alkoxycarbonyl.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula Ia
  • R 1 , R 2 , and R 3 which may be the same or different, each independently represent hydrogen, Ci -6 alkyl (e.g., methyl), trifluoro methyl, Ci -6 alkoxy (e.g., methoxy), cyano, halogen, or -NR 4 R 5 , wherein
  • R 4 and R 5 which may be the same or different, each independently represent hydrogen, C h alky!, or cycloC 3 . 12 alkyl, or R 4 and R 5 , together with the nitrogen atom to which they are attached, represent a 5- or 6- membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more groups selected from Ci ⁇ alkyl (e.g., methyl), halogen, trifluoromethyl, d- ⁇ alkoxy, and cyano;
  • Ci ⁇ alkyl e.g., methyl
  • halogen trifluoromethyl
  • d- ⁇ alkoxy cyano
  • Ar represents aryl or heteroaryl
  • R 7 represents hydrogen, Ci -6 alkyl (e.g., methyl), Ci -6 alkoxy (e.g., methoxy), - C(O)NR 8 R 9 , carboxy, or aryl, wherein
  • R 8 and R 9 which may be the same or different, each independently represent hydrogen, C h alky!, or cycloCa- ⁇ alkyl, or R 8 and R 9 , together with the nitrogen atom to which they are attached, represent a 5- or 6- membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more groups selected from d- ⁇ alkyl (e.g., methyl), halogen, trifluoromethyl, C-i- ⁇ alkoxy, and cyano;
  • d- ⁇ alkyl e.g., methyl
  • halogen trifluoromethyl
  • C-i- ⁇ alkoxy cyano
  • Such a compound of Formula Ia wherein Ar represents phenyl which is optionally substituted by one or more substituents selected from halogen, trifluoromethyl, Ci -6 alkyl, hydroxyCi -6 alkyl, Ci -6 alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci-ealkylcarbonyloxyCi- ⁇ alkyl, amino, cyano, formyl, Ci- ⁇ alkylcarbonylamino, and phenylcarbonylamino.
  • substituents selected from halogen, trifluoromethyl, Ci -6 alkyl, hydroxyCi -6 alkyl, Ci -6 alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci-ealkylcarbonyloxyCi- ⁇ alkyl, amino, cyano, formyl, Ci- ⁇ alkylcarbonylamino, and phenylcarbonylamino.
  • Such a compound of Formula Ia wherein Ar represents a heteroaryl group selected from pyridinyl, thiophenyl, thiazolyl, benzofuryl, dihydrobenzofuryl, and imidazolyl, wherein the heteroaryl group is optionally substituted by one or more substituents selected from halogen, Ci -6 alkyl, Ci -6 alkoxy, and C-i -6 alkoxycarbonyl.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula Ib
  • R 1 , R 2 , and R 3 which may be the same or different, each independently represent hydrogen, Ci- ⁇ alkyI (e.g., methyl), trifluoromethyl, C-i- ⁇ alkoxy (e.g., methoxy), cyano, halogen, or -NR 4 R 5 , wherein
  • R 4 and R 5 which may be the same or different, each independently represent hydrogen, d- ⁇ alkyl, or cycloC 3- i 2 alkyl, or R 4 and R 5 , together with the nitrogen atom to which they are attached, represent a 5- or 6- membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more groups selected from Ci -6 alkyl (e.g., methyl), halogen, trifluoromethyl, d- ⁇ alkoxy, and cyano;
  • L represents Ci -3 alkylene, arylene, heteroarylene, -X-Ci. 3 alkylene, or Ci- 3 alkylene-X-, wherein X represents oxygen or sulfur;
  • Ar represents aryl or heteroaryl
  • R 7 represents hydrogen, Ci -6 alkyl (e.g., methyl), Ci -6 alkoxy (e.g., methoxy), - C(O)NR 8 R 9 , carboxy, or aryl, wherein
  • R 8 and R 9 which may be the same or different, each independently represent hydrogen, C h alky!, or cycloCs- ⁇ alkyl, or R 8 and R 9 , together with the nitrogen atom to which they are attached, represent a 5- or 6- membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more groups selected from Ci ⁇ alkyl (e.g., methyl), halogen, trifluoromethyl, C-i- ⁇ alkoxy, and cyano;
  • Ci ⁇ alkyl e.g., methyl
  • halogen trifluoromethyl
  • C-i- ⁇ alkoxy cyano
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula Ic wherein
  • R 1 , R 2 , and R 3 which may be the same or different, each independently represent hydrogen, d- ⁇ alkyl (e.g., methyl), trifluoromethyl, d- ⁇ alkoxy (e.g., methoxy), cyano, halogen, or -NR 4 R 5 , wherein
  • R 4 and R 5 which may be the same or different, each independently represent hydrogen, C h alky!, or cycloC 3- i 2 alkyl, or R 4 and R 5 , together with the nitrogen atom to which they are attached, represent a 5- or 6- membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more groups selected from C h alky! (e.g., methyl), halogen, trifluoromethyl, C-i- ⁇ alkoxy, and cyano;
  • L represents Ci ⁇ alkylene, arylene, heteroarylene, -X-Ci- 3 alkylene, or Ci -3 alkylene-X-, wherein X represents oxygen or sulfur;
  • Ar represents aryl or heteroaryl
  • R 7 represents hydrogen, Ci -6 alkyl (e.g., methyl), d- ⁇ alkoxy (e.g., methoxy), - C(O)NR 8 R 9 , carboxy, or aryl, wherein
  • R 8 and R 9 which may be the same or different, each independently represent hydrogen, Ci -6 alkyl, or cycloC 3- i 2 alkyl, or R 8 and R 9 , together with the nitrogen atom to which they are attached, represent a 5- or 6- membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more groups selected from Ci -6 alkyl (e.g., methyl), halogen, trifluoromethyl, Ci -6 alkoxy, and cyano; and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
  • Such a compound of Formula Ic wherein L represents heteroarylene, or and Ar represents phenyl, optionally substituted by halogen, Ci -6 alkyl, Ci -6 alkoxy, and amino, or a heteroaryl group selected from pyridinyl, thiazolyl, pyrazolyl, and thiophenyl, wherein the heteroaryl group is optionally substituted with one or more substituents selected from halogen and Ci -6 alkyl.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula Id
  • R 1 , R 2 , and R 3 which may be the same or different, each independently represent hydrogen, Ci -6 alkyl (e.g., methyl), trifluoromethyl, Ci -6 alkoxy (e.g., methoxy), cyano, halogen, or -NR 4 R 5 , wherein
  • R 4 and R 5 which may be the same or different, each independently represent hydrogen, Ci- 6 alkyl, or cycloC 3- i 2 alkyl, or R 4 and R 5 , together with the nitrogen atom to which they are attached, represent a 5- or 6- membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more groups selected from C 1-6 alkyl (e.g., methyl), halogen, trifluoromethyl, d- ⁇ alkoxy, and cyano; , wherein L represents Ci ⁇ alkylene, arylene, heteroarylene, -X-Ci-3alkylene, or C ⁇ alkylene-X-, wherein X represents oxygen or sulfur, and
  • Ar represents aryl or heteroaryl
  • R 7 represents hydrogen, d- ⁇ alkyl (e.g., methyl), Ci -6 alkoxy (e.g., methoxy), - C(O)NR 8 R 9 , carboxy, or aryl, wherein
  • R 8 and R 9 which may be the same or different, each independently represent hydrogen, Ci -6 alkyl, or cycloC 3- i 2 alkyl, or R 8 and R 9 , together with the nitrogen atom to which they are attached, represent a 5- or 6- membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more groups selected from Ci- ⁇ alkyl (e.g., methyl), halogen, trifluoromethyl, C 1-6 alkoxy, and cyano;
  • 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, trifluoromethyl, trifluoromethoxy, d- ⁇ alkyl, hydroxyd- ⁇ alkyl, C 2 - 6 alkenyl, d- ⁇ alkoxy, Ci -6 alkoxyCi.
  • arylene means a divalent aryl radical as defined above;
  • 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, trifluoromethyl, trifluoromethoxy, Ci ⁇ alkyl, hydroxyC-i- ⁇ alkyl, C- 2 - 6 alkenyl, Ci- ⁇ alkoxy, amino, hydroxy, nitro, cyano, Ci- 6 alkoxycarbonyl, Ci- ⁇ alkoxycarbonyloxy, Ci- ⁇ alkylamino, and di
  • heteroarylene means a divalent heteroaryl radical as defined above
  • Such a compound of Formula Id wherein R 1 , R 2 , and R 3 , which may be the same or different, each independently represent hydrogen, C h alky!, d- ⁇ alkoxy, or -NR 4 R 5 , wherein R 4 and R 5 , which may be the same or different, each independently represent hydrogen or Ci -6 alkyl.
  • Such a compound of Formula Id wherein R 1 , R 2 , and R 3 , which may be the same or different, each independently represent hydrogen, methyl, methoxy, amino, or t-butylamino.
  • Such a compound of Formula Id wherein R 7 represents hydrogen, methyl, methoxy, or -C(O)NR 8 R 9 , wherein R 8 and R 9 , which may be the same or different, each independently represent hydrogen, methyl, ethyl, n-propyl, or isopropyl or R 8 and R 9 together with the nitrogen atom to which they are attached, represent a pyrrolidine, piperazine or morpholine ring, wherein each of these rings may be optionally substituted by one or more d- ⁇ alkyl groups.
  • Such a compound of Formula Id wherein Ar represents an aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally substituted by one or more substituents selected from halogen, trifluoromethyl, C h alky!, hydroxyCi- ⁇ alkyl, Ci- 6 alkoxy, Ci -6 alkoxyCi -6 alkyl, Ci- ⁇ alkylcarbonyloxyCi-ealkyl, amino, cyano, formyl, Ci- ⁇ alkylcarbonylamino, phenylcarbonylamino, and Ci- ⁇ alkoxycarbonyl.
  • substituents selected from halogen, trifluoromethyl, C h alky!, hydroxyCi- ⁇ alkyl, Ci- 6 alkoxy, Ci -6 alkoxyCi -6 alkyl, Ci- ⁇ alkylcarbonyloxyCi-ealkyl, amino, cyano, formyl, Ci- ⁇ alkylcarbonylamino,
  • Such a compound of Formula Id wherein Ar represents phenyl, pyridinyl, thiophenyl, thiazolyl, benzofuryl, dihydrobenzofuryl, or imidazolyl, wherein each of these groups is optionally substituted by one or more substituents selected from halogen, trifluoromethyl, C h alky!, hydroxyCi- ⁇ alkyl, Ci- ⁇ alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci- ⁇ alkylcarbonyloxyCi-ealkyl, amino, cyano, formyl, d- ⁇ alkylcarbonylamino, phenylcarbonylamino, and Ci -6 alkoxycarbonyl.
  • a further aspect of the invention relates to a compound of Formula I, wherein R 1 , R 2 , and R 3 represent hydrogen; R 6 represents , wne rein L represents -X-Ci -3 alkylene and X represents oxygen or sulfur; Ar represents aryl or heteroaryl; and R 7 represents hydrogen, or methyl.
  • Specific compounds of Formula I within the present invention include, but are not limited to, the following compounds: -Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-benzonitrile, 3-Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-phenylamine,
  • 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 mGluR ⁇ 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 mGluR ⁇ receptors results in therapeutic benefit.
  • the conditions which may be treated have already been described above.
  • Such conditions and indications include: a) For mGluR ⁇ modulators: chronic pain, neuropathic pain, diabetic neuropathic pain (DNP), cancer pain, pain related to rheumathic arthritis, inflammatory pain, L-dopa-induced dyskinesias, dopaminomimetic- induced dyskinesias, L-dopa-induced dyskinesias in Parkinson's disease therapy, dopaminomimetic-induced dyskinesias in Parkinson's disease therapy, tardive dyskinesias, Parkinson's disease, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), generalized anxiety disorder, substance-induced anxiety disorder, eating disorders, obesity, binge eating disorders, Huntington's chorea, epilepsy, Alzheimer's disease, positive and negative symptoms of schizophrenia, cognitive impairment, functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), migraine, irritable bowel syndrome (IBS), or for cognitive enhancement and/or neuroprotection.
  • Negative modulation of mGluR ⁇ 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
  • 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 mGluR ⁇ 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 and/or Neramexane.
  • 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.
  • 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 selected from Memantine and Neramexane (or a combination thereof) and pharmaceutically acceptable salts, polymorphs, hydrates and solvates thereof.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least two different active ingredients, selected from at least one compound of Formula I as defined above, and, additionally, at least one active ingredient selected from L-DOPA, other dopaminomimetics (such as antiparkinsonian dopaminomimetics, including bromocriptine, cabergolin, ropinirole, pramiperole, pergolide, rotigotine), and neuroleptics (such as classical neuroleptics, including haloperidol, perphenazin, chlorpromazine, metoclopramide).
  • dopaminomimetics such as antiparkinsonian dopaminomimetics, including bromocriptine, cabergolin, ropinirole, pramiperole, pergolide, rotigotine
  • neuroleptics such as classical neuroleptics, including haloperidol, perphenazin, chlorpromazine, metoclopramide.
  • the invention also relates to a method of providing neuroprotection in a living animal, including a human, comprising the step of administering to a living animal, including a human, a therapeutically effective amount of a composition as described above.
  • the invention relates to the use of a composition as described above for the manufacture of a medicament to provide neuroprotection in an animal, including a human.
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula Ia
  • R 1 , R 2 , R 3 , R 7 , and Ar are as defined above for Formula I, wherein a compound of Formula Il
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula Ia
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula Ia 1
  • R 8 , R 9 , and Ar are as defined above for Formula I, comprising reaction of 5- nitro-2H-pyrazole-3-carboxylic acid of Formula VII
  • a condensation agent e.g., O-Cbenzotriazol-i-ylJ-N.N.N'.N 1 - tetramethyluronium tetrafluoroborate (TBTU) or N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide (EDC)
  • TBTU tetramethyluronium tetrafluoroborate
  • EDC N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula Ic'
  • R 7 and Ar are as defined above for Formula I, wherein a 5-aminopyrazole of Formula XV
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula Ic"
  • R 7 and Ar are as defined above for Formula I, wherein a 5-aminopyrazole of Formula XV
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula Ic 1 "
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula Ic""
  • R 4 , R 7 , and Ar are as defined above for Formula I, wherein 5-bromo-thiophen-2- carboxylic acid of Formula XXX
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula Ib 1
  • R 1 , R 2 , R 3 , R 7 , and Ar are as defined above for Formula I, wherein a compound of Formula IV
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula Ib *
  • R 1 , R 2 , R 3 , R 7 , and Ar are as defined above for Formula I, wherein a compound of Formula IV
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula Ic
  • R 1 , R 2 , R 3 , R 7 , and Ar are as defined above for Formula I, wherein a compound of Formula IV
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula Ic
  • R 1 , R 2 , R 3 , R 7 , and Ar are as defined above for Formula I, wherein a compound of Formula IV
  • 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.
  • C-i ⁇ alkyl refers to alkyl of one to three carbon atoms (i.e.
  • C- ⁇ - 6 refers to a radical of one to six carbon atoms (i.e. 1 , 2, 3, 4, 5 or 6 carbon atoms).
  • 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, trifluoromethyl, C-i- ⁇ alkoxy, amino, hydroxy, Ci- ⁇ alkylamino, and di-(Ci- 6 alkyl)amino.
  • alkyl groups examples include methyl, ethyl, n-propyl, 2- propyl, n-butyl, tert-butyl, -CF 3 , -C 2 F 5 , -CBr 3 and -CCI 3 .
  • Ci -6 alkylene refers to a divalent "Ci. 6 alkyl” radical as defined above.
  • alkylene groups include methylene, ethylene, propylene, butylene, which groups may be straight or branched.
  • C 2 - 6 alkenyl represents straight or branched chain alkenyl groups.
  • Ci- ⁇ alkoxy represents straight or branched chain -O-Ci- ⁇ alkyl groups which may be optionally substituted by one or more (e.g., 1 , 2, 3, 4, or 5) substituents selected from halogen, trifluoromethyl, amino, hydroxy, Ci- ⁇ alkylamino and di-(Ci_ 6 alkyl)amino.
  • alkoxy groups include methoxy, ethoxy, n-propoxy, i- propoxy, -OCF 3 and -OC 2 F 5 .
  • 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, C h alky!, C 2-6 alkenyl, Ci- 6 alkoxy, amino, hydroxy, nitro, cyano, cyanomethyl, d- ⁇ alkoxycarbonyl, Ci- 6 alkylamino, and di-(Ci.
  • Ci- ⁇ alkylcarbonylamino Ci- ⁇ alkylcarbonylamino, oxo, d- ⁇ alkoxyimino, Ci- ⁇ alkylaminocarbonyl, arylCi- 6 alkoxycarbonyl, and Ci ⁇ alkylenedioxy.
  • cycloCs- ⁇ alkenyl 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, C h alky!, C 2-6 alkenyl, C-i- ⁇ alkoxy, amino, hydroxy, nitro, cyano, cyanomethyl, C-i- 6 alkoxycarbonyl, Ci -6 alkylamino, and di-(C-
  • Ci-ealkylcarbonylamino Ci-ealkylcarbonylamino, oxo, Ci -6 alkoxyimino, d-ealkylaminocarbonyl, arylCi- ⁇ alkoxycarbonyl, and Ci- ⁇ alkylenedioxy.
  • 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, trifluoromethyl, trifluoromethoxy, Ci -6 alkyl, hydroxyCi -6 alkyl, C 2-6 alkenyl, Ci -6 alkoxy, Ci- ⁇ alkoxyd. ⁇ alkyl, amino, hydroxy, nitro, cyano, formyl, cyanomethyl, Ci- ⁇ alkoxycarbonyl, C-i.
  • ⁇ alkylcarbonyloxy Ci- ⁇ alkylcarbonyloxyCi- ⁇ alkyl, Ci- ⁇ alkylamino, di-(Ci- 6 alkyl)amino, Ci- 6 alkylcarbonylamino, phenylcarbonylamino, aminocarbonyl, N-d-ealkylaminocarbonyl, di-N,N-Ci- 6 alkylaminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, cycloC 3 _i 2 alkyl, pyridinyl, and optionally d- ⁇ alkylenedioxy.
  • arylene represents a divalent aryl radical as defined above.
  • 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, trifluoromethyl, trifluoromethoxy, d- ⁇ alkyl, hydroxyC-i.
  • substituents which may be the same or different, selected independently from halogen, trifluoromethyl, trifluoromethoxy, d- ⁇ alkyl, hydroxyC-i.
  • ⁇ alkyl C ⁇ - ⁇ alkenyl, d- ⁇ alkoxy, amino, hydroxy, nitro, cyano, d- ⁇ alkoxycarbonyl, Ci- ⁇ alkoxycarbonyloxy, Ci- ⁇ alkylamino, and di-(Ci- 6 alkyl)amino, d- ⁇ alkylcarbonylamino, aminocarbonyl, N-d- ⁇ alkylaminocarbonyl, di-N.N-Ci- ⁇ alkylaminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, cycloCa- ⁇ alkyl, d- ⁇ alkylenedioxy, aryl, and pyridinyl.
  • 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
  • heteroarylene represents a divalent heteroaryl radical as defined above.
  • Representative heteroarylene groups include divalent pyridinyl and thiophenyl groups.
  • heterocyclyl represents a saturated or unsaturated non-aromatic 3 to 12 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, and a saturated or unsaturated non-aromatic bicyclic ring system having 3 to 12 members comprising one to six heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heterocyclic ring or ring system may be optionally substituted by one or more (e.g., 1 , 2, 3, 4, or 5) substituents, which may be the same or different, selected independently from halogen, trifluoromethyl, trifluoromethoxy, C h alky!, C 2 - 6 alkenyl, d- ⁇ alkoxy, amino, hydroxy, nitro, cyano, cyanomethyl, Ci- ⁇ alkoxycarbonyl, Ci- 6 alkylamino, and di-(Ci- 6 alkyl)amino, Ci-ealkylcarbonylamino, oxo, d- ⁇ al
  • halogen represents fluorine, chlorine, bromine and iodine.
  • the compounds of the present invention are usually named according to the IUPAC 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, and “rt” for room temperature).
  • Memantine also known as 1-amino-3,5-dimethyladamantane
  • 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.
  • Neramexane also known as 1-amino-1 ,3,3,5,5-pentamethylcyclohexane, is disclosed in detail in U.S. Patent Nos. 6,034,134 and 6,071,966, the subject matter of which patents is hereby incorporated by reference.
  • Memantine and neramexane are systemically-active noncompetitive NMDA receptor antagonists having moderate affinity for the receptor. They exhibit strong voltage dependent characteristics and fast blocking/unblocking kinetics (see e.g. G ⁇ rtelmeyer 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.
  • 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.
  • compositions 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.
  • Aryl halide (2) is treated with trimethylacetylene and PdCI2(PPh3)2 in a sovlent such as triethylamine to yield an aryl/heteroaryl-trimethylacetylene (3).
  • Compound 3 is reacted with a 5-chloro-pyrazolo[1 ,5-a]pyrimidine (1 ) to yield a pyrazolo[1 ,5-a]pyrimidine of Formula Ia.
  • 2-methyl-but-3-yn-2-ol is reacted with a 5-chloro-pyrazolo[1 ,5-a]pyrimidine (1) to yield a pyrazolo[1 ,5- a]pyrimidin-5-yl-but-3-yn-2-ol (5) which is treated with sodium hydride to yield a 5- ethynyl-pyrazolo[1 ,5-a]pyrimidine (6).
  • Compound 6 is then reacted with an aryl/heteroaryl halide (2) to yield a 5-aryl/heteroaryl-ethynyl-pyrazolo[1 ,5-a]pyrimidine of Formula Ia.
  • ⁇ -Nitro ⁇ H-pyrazole-S-carboxylic acid (7) is treated with thionyl chloride in methanol to yield 5-nitro-2H-pyrazole-3-carboxylic acid methyl ester which is then hydrogenated to yield 5-amino-2H-pyrazole-3-carboxylic acid methyl ester (8).
  • Compound 8 is treated with methyl propiolate (9) and heated to reflux for 24 hours to yield 5-oxo-4,5-dihydro-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid methyl ester (10).
  • Compound 10 is treated with phosphoryl bromide to yield 5-bromo-4,5-dihydro- pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid methyl ester (11) which is coupled with an aryl/heteroaryl-acetylene to yield a 5-aryl/heteroaryl-ethynyl-pyrazolo[1 ,5-a]pyrimidine- 2-carboxylic acid methyl ester (13).
  • 5-aminopyrazole (16) is treated with methyl propiolate (9) to yield a 4H- pyrazolo[1 ,5-a]pyrimidin-5-one (17).
  • Compound 17 is reacted with 3-aryl/heteroaryl- prop-2-yn-1 -ol (18), triphenyl phosphine, and diisopropyl azodicarboxylate (DIAD) to yield a 5-(3-aryl/heteroaryl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine of Formula Ic 1 .
  • 3-butyn-1-ol (19) is treated with n-butyllithium followed by chlorotrimethylsilane to yield 4-trimethylsilanyl-but-3-yn-1-ol (20).
  • Compound 20 is treated with n-butyllithium followed by p-toluenesulfonyl chloride to yield toluene-4- sulfonic acid 4-trimethylsilanyl-but-3-ynyl ester (21).
  • Compound 21 is treated with lithium bromide to yield 4-bromobut-1-ynyl)trimethylsilane (22) which is added to magnesium in the presence of iodine and dibromoethane in a solvent such as THF to yield the grignard reagent (23).
  • Intermediate 23 is added to a solution of ZnBr2 in a solvent such as THF to yield the 5-trimethylsilanyl-butyn-3-yl-zinc reagent (24).
  • ⁇ -Amino-I H-pyrazole ⁇ -carboxylic acid ethyl ester (29) is treated with methyl propiolate (9) to yield intermediate 30 which is treated with sodium hydride to yield 5-oxo-4,5-dihydro-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid ethyl ester (31).
  • Compound 31 is reacted with phosphorous oxychloride to yield 5-chloro-pyrazolo[1 ,5- a]pyrimidine-3-carboxylic acid ethyl ester (32).
  • Compound 32 is then coupled with an aryl/heteroaryl boronic acid (33) to yield a 5-aryl/heteroaryl-pyrazolo[1 ,5-a]pyrimidine (34). lodination of compound 34 yields an iodo intermediate (35). Compound 35 is then coupled with an aryl/heteroarylacetylene (12) to yield compound 36, which is subjected to hydrolysis followed by decarboxylation to yield a pyrazolo[1 ,5-a]pyrimidine of Formula Ic.
  • ⁇ -Bromo-thiophen ⁇ -carboxylic acid (38) is treated with carbonyldiimidazole followed by monomethyl monopotassium malonate (39) to yield 3- (5-bromo-thiophen-2-yl)-3-oxo-propionic acid methyl ester (40).
  • Compound 40 is then reacted with 5-aminopyrazole derivative 16 to yield a 5-(5-bromo-thiophen-2-yl)-4H- pyrazolo[1 ,5-a] pyrimidin-7-one (41).
  • Compound 45 (which is synthesized via reaction of 5-chloro-pyrazolo[1 ,5- a]pyrimidine (1) and Tl PS-acetylene followed by deprotection of the triple bond with sodium borofluoride) is alkylated with an aryl/heteroaryl-alkyl bromide (47) to yield a 5- (3-aryl/heteoraryl-prop-1-ynyl)-pyrazolo[1 ,5-a]pyrimidine of Formula Ib'.
  • compound 1 is coupled with a prop-2-ynyl-arene/heteroarene (48) to yield a 5-(3-aryl- prop-1-ynyl)-pyrazolo[1 ,5-a]pyrimidine of Formula Ib 1 .
  • compound 49 is reacted with lithium trimethylsilylacetylide to yield, after cleavage of the TMS group, 5-prop-2-ynyl-pyrazolo[1 ,5-a]pyrimidine (50).
  • Treatment of compound 50 with an arylZheteroaryl halide (2) yields a 5-(3- arylZheteroaryl-prop-2-ynyl)-pyrazolo[1 ,5-a]pyrimidine of Formula Ic
  • stereoisomeric forms (including optical isomers) of the compounds and the intermediates of this invention may be obtained by the application of art-known procedures.
  • Diastereomers may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g. liquid chromatography using chiral stationary phases.
  • Enantiomers (optically active isomers) may be separated from each other by selective crystallization of their diastereomeric salts with optically active acids.
  • enantiomers may be separated by chromatographic techniques using chiral stationary phases.
  • Stereoisomeric forms may also be derived from the corresponding pure stereoisomeric form of appropriate starting materials, provided that the reaction occur stereoselective ⁇ . Stereoisomeric forms of Formula I are included within the scope of this invention.
  • Compounds of Formula I which are marked by radioactive atoms may be obtained using art-known procedures. Typical compounds include those where one or more hydrogens are substituted by tritium, where one or more C 12 are substituted by C 14 , where one or more fluor atoms are substituted by F 18 or other isotopes. These may be used for the treatment of diseases (e.g. cancer) but also for diagnostic purposes. The radioactive atoms exchanged in the molecule are often isotopes of carbon, hydrogen, halogen, sulphur or phosphorus. Compounds of the Formula I which are marked by radioactive atoms are included within the scope of this invention.
  • salts of the compounds of Formula I are those wherein the counterion is pharmaceutically acceptable.
  • salts of acids and bases which are non-pharmaceutically acceptable, may also find use, for example, in the preparation and purification of pharmaceutically acceptable compounds. All salts whether pharmaceutically acceptable or not are included within the ambit of the present invention.
  • the pharmaceutically acceptable salts as mentioned above are meant to comprise the therapeutically active non-toxic salt forms, which the compounds of Formula I are able to form. The latter may conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, e.g.
  • hydrohalic acids such as hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids such as acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1 ,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfonic, 2-hydroxybenzoic, 4- amino-2-hydroxybenzoic and the like acids.
  • the salt form may be converted by treatment with alkali into the free base form.
  • the active ingredients of the compounds of the invention may be placed into the form of pharmaceutical compositions, c 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.
  • 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.
  • 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.
  • treat is used herein to mean to relieve or alleviate at least one symptom of a disease in a subject.
  • the term “treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.
  • compositions comprising a compound of the present invention and a second active ingredient (e.g., an NMDA receptor antagonist, L-DOPA, a dopaminomimetic, or a neuroleptic), in a formulation known in the art, or two separate pharmaceutical compositions (formulations), one comprising a compound of the present invention as formulated above and one comprising a second active ingredient (e.g., an NMDA receptor antagonist, L-DOPA, a dopaminomimetic, or a neuroleptic) in a formulation known in the art, to be administered conjointly.
  • a second active ingredient e.g., an NMDA receptor antagonist, L-DOPA, a dopaminomimetic, or a neuroleptic
  • the term “conjoint administration” is used to refer to administration of a compound of the present invention and a second active ingredient (e.g., an NMDA receptor antagonist, L-DOPA, a dopaminomimetic, or a neuroleptic) in one composition, or simultaneously in different compositions, or sequentially.
  • a second active ingredient e.g., an NMDA receptor antagonist, L-DOPA, a dopaminomimetic, or a neuroleptic
  • the sequential administration to be considered “conjoint”
  • the compound of the present invention and the NMDA receptor antagonist must be administered separated by a time interval that still permits the resultant beneficial effect in a mammal.
  • the compound of the present invention and the NMDA receptor antagonist must be administered on the same day (e.gf., 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 non-toxic, pharmaceutically acceptable inert carriers (e.g., ethanol, glycerol, water), suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid), and the like.
  • Stabilizing agents such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) may also be added to stabilize the dosage forms.
  • compositions of the invention containing as active compound a compound of Formula I may be also introduced in beads, microspheres or microcapsules, e.g., fabricated from polyglycolic acid/lactic acid (PGLA).
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups, emulsions or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Preparations for oral administration may be suitably formulated to give controlled or postponed release of the active compound.
  • Liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes may be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines, as is well known.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • Active drugs may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers include polyvinylpyrrolidone, 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.
  • 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.
  • 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.
  • 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 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 LD 50 /ED 50 .
  • Compositions that exhibit large therapeutic indices are preferred.
  • DMF N.N-dimethylformamide
  • HCF tetrahydrofurane
  • HCI hydrochloric acid
  • NaOH sodium hydroxide
  • MeOH methanol
  • DMSO dimethylsulfoxide
  • TBTU O-(benzotriazol-i-yl)- N.N.N'.N'-tetramethyluronium tetrafluoroborate
  • Trimethylsilylacetylene, aryl/heteroaryl iodide (or bromide) (1 equivalent), PdCl 2 (PPh 3 ) 2 (2 mol %) are placed in the flask containing freshly distilled Et 3 N. The resulting mixture is stirred for 5 min at room temperature, then copper (I) iodide (1 mol %) is added and the flask is flushed with argon and sealed. The reaction mixture is stirred for 10 h at room temperature, then precipitate is filtered off, filtrate is evaporated in vacuo and the residue is partitioned between Et 2 O and water. The organic phase is washed with water and brine, then dried over anhydrous Na 2 SO 4 .
  • Phosphoryl bromide (5 equivalents) is added to a suspension of 5-oxo-4,5- dihydro-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid methyl ester in dioxane.
  • the reaction mixture is refluxed for 4 h, then is cooled to room temperature and poured in ice water.
  • the aqueous solution is neutralized with potassium carbonate.
  • the formed precipitate is filtered off, washed with water and dried at 50 0 C to obtain 5-bromo- pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid methyl ester.
  • Methyl propiolate is added to a suspension of 5-methyl-2H-pyrazol-3- ylamine (1 equivalent) in 40 ml of anhydrous dioxane. The reaction mixture is refluxed for 10h. Then reaction mixture is allowed to cool to room temperature. Precipitated solids are filtered off, washed with EtOAc. After drying, the title compound is obtained as white solid.
  • Trifluoromethanesulfonic anhydride is added to solution of 2-methyl- pyrazolo[1 ,5-a]pyrimidin-5-ol (1 equivalent) in anhydrous DCM and DIPEA (1.3 equivalents) under an argon atmosphere at -78 0 C.
  • the reaction mixture is stirred at - 78°C for 5 minutes, then at room temperature for 30 min.
  • the reaction is evaporated under reduced pressure to afford an oil which is purified by was flash chromatography on silica (1 :3 ethyl acetate/hexanes as eluent) to give the title compound as a light- brown solid in high yield.
  • 5-(3-Aryl-prop-1-ynyl)-pyrazolo[1 ,5-a]pyrimidines are prepared by alkylation of 5-ethynyl-pyrazolo[1 ,5-a]pyrimidine (45a) with benzylbromides in the presence of base, such as n-BuLi, NaH or K 2 CO 3 .
  • 5-(3-aryl-prop-1-ynyl)- pyrazolo[1 ,5-a]pyrimidines are prepared by Sonigashira coupling of 5-chloro- pyrazolo[1 ,5-a]pyrimidine (1b) with prop-2-ynyl-arenes (48a) in the presence of Et 3 N, CuI and PdCI 2 [PPh 3 J 4 .
  • 5-(3-Aryl-prop-2-ynyl)-pyrazolo[1 ,5-a]pyrimidines are prepared by alkylation of arylacetylenes with 5-bromomethyl-pyrazolo[1 ,5-a]pyrimidine (49a) in the presence of base, such as n-BuLi, NaH or K 2 CO 3 .
  • 5-Bromomethyl-pyrazolo[1 ,5- a]pyrimidine (49a) is prepared from 5-chloro-pyrazolo[1 ,5-a]pyrimidine (1b) via a 3-step sequence consisting of Suzuki coupling with vinyltributylstannane to provide a vinyl derivative (46a), ozonolysis-reduction (0 3 /NaBhU) 1 and conversion of the intermediate alcohol to an alkyl bromide (CBr 4 /PPh 3 ).
  • 5-bromomethyl-pyrazolo[1 ,5- a]pyrimidine (49a) is reacted with lithium trimethylsilylacetylide to give, after cleavage of the TMS group, 5-prop-2-ynyl-pyrazolo[1 ,5-a]pyrimidine (50a).
  • Sonigashira coupling of the compound 50a with an arylhalide provides a 5-(3-aryl-prop-2-ynyl)-pyrazolo[1 ,5- a]pyrimidine (59).
  • 5-Ethynyl-pyrazolo[1 ,5-a]pyrimidine is prepared by coupling 5-chloro- pyrazolo[1 ,5-a]pyrimidine with trimethylsilylacetylene according to General Procedure 1 and subsequent cleavage of TMS group using K 2 CO 3 in methanol.
  • a mixture of 5- ethynyl-pyrazolo[1 ,5-a]pyrimidine (0.2 mmol), benzyl bromide (0.4 mmol) and K2CO3 (0.4 mmol) in acetone (1 ml.) is heated in a sealed vial at 100 0 C for 12h.

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Abstract

The invention relates to pyrazolopyrimidine derivatives as well as their pharmaceutically acceptable salts. The invention further relates to a process for the preparation of such compounds. The compounds of the invention are mGluR5 modulators and are therefore useful for the control and prevention of acute and/or chronic neurological disorders.

Description

PYRAZOLOPYRIMIDINES, A PROCESS FOR THEIR PREPARATION AND THEIR
USE AS MEDICINE
FIELD OF THE INVENTION
[0001] The present invention relates to pyrazolopyrimidine 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 mGluRδ 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 Il and mGluR4, rnGluRΘ, mGluR7 and mGluRδ 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 mGluRδ 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 mGluRδ modulators, such modulators may increase or inhibit the effects mediated through these metabotropic glutamate receptors.
[0005] Modulators which are negative mGluRδ 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 mGluRδ 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 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, 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 and sleep disturbances.
[0007] MGIuR5 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. MGIuRδ 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] MGIuRδ 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 mGluRδ 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.
[0011] Moreover, mGluR modulators may have activity when administered in combination with other substances exhibiting neurological effects via different mechanisms. [0012] Simultaneous administration of Group I mGluR modulators and NMDA receptor antagonists has also been shown to provide neuroprotection in animal models (Zieminska et al. Acta Neurobiol. Exp., 2006, 66, 301-309; Zieminska et al. Neurochemistry International, 2003, 43, 481-492; and Zieminska et al. Neurochemistry International, 2006, 48, 491-497).
[0013] Simultaneous administration of Group I mGluR modulators and compounds such as L-DOPA, dopaminomimetics, and/or neuroleptics may be useful in treating various conditions including drug induced dyskinesias, neuroleptic-induced dyskinesias, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias.
[0014] In the literature, several types of modulators of mGluRδ have already been described.
[0015] Furthermore, several types of pyrazolopyrimidine compounds have been disclosed in the prior art.
[0016] European Published Application No. EP 1849465 discloses compounds of general formula (Id) as GPR receptor function regulators which may be useful in treating immune disease, inflammatory disease, allergic disease, and cardiovascular disease:
Figure imgf000006_0001
wherein X3, Xb, Xc. and Xd represent N or CH; one of R 12 and i D R13 J represents
Figure imgf000006_0002
A" is an optionally substituted isocyclic or heterocyclic ring and P is a bond or spacer and the other represents
Figure imgf000007_0001
wherein R3d represents hydrogen or an optionally substituted hydrocarbyl group, Qb is an optionally substituted spacer, and W is a carboxyl group or a group biologically equivalent to a carboxyl group; and wherein the rings F and G may be further substituted by substituents other than R12 and R13.
[0017] International Publication No. WO 2004/080463 discloses compounds of general formula (V) as kinase inhibitors:
Figure imgf000007_0002
wherein A forms a benzene, pyridine, pyrimidine, thiophene, pyrrole, imidazole, pyrazole, thiazole, or oxazole ring; Ry represents e.g., hydrogen, halogen, aryl, heteroaryl, cycloalkyl, heterocycyl, alkynyl, arylalkynyl, or heteroarylalkynyl, which groups may be further substituted; R2 represents e.g., hydrogen, NR5 2 (wherein R5 represents hydrogen or alkyl), alkyl, cycloalkyl; and Q represents e.g., hydrogen, halogen, NR5 2.
[0018] International Publication No. WO 2004/089416 discloses compounds of general formula (I) as 11β-hydroxysteroid dehydrogenase type 1 inhibitors which may be used in combination with an anti-hypertensive agent for the treatment of insulin resistance, dyslipidemia, obesity, hypertension, and related diseases:
Figure imgf000007_0003
wherein R1 and R2 represent e.g., hydrogen, halogen, C(O)NR6R7 (wherein R6 and R7 represent e.g., Ci-C-βalkyl, C3-C-ιocycloalkyl or together form a ring); R3 and R5 represent e.g., hydrogen, optionally substituted C^-C-βalkynyl, optionally substituted aryl, optionally substituted hetaryl; and R4 represents e.g., hydrogen, cyano, halogen, CrC6alkyl.
[0019] European Published Application No. EP 1505068 discloses compounds of general formula (Ia) as NAD(P)H oxydase inhibitors for use in treating diseases due to inflammation, circulatory disorders, and enhanced proliferation activities:
Figure imgf000008_0001
wherein R1a, R2a> R3, R4, and R5 represent e.g., hydrogen, halogen, optionally substituted loweralkyl, optionally substituted loweralkenyl, optionally substituted loweralkynyl, optionally substituted amino.
[0020] US Published Application No. 2004/0043998 discloses compounds of general formula (I1) for the treatment of diabetes:
Figure imgf000008_0002
wherein G represents e.g., cyano, nitro, CO2R4 (wherein R4 represents e.g., hydrogen, optionally substituted alkyl); R1 represents e.g., halogen, OR5, SR5 (wherein R5 represents e.g., optionally substituted alkynyl); R2 represents halogen, OR5, or optionally substituted amino; and R8 and R10 represent hydrogen, halogen, or alkyl.
[0021] International Publication No. WO 2007/044407 discloses compounds of general formula (I) as protein kinase inhibitors which may be useful in the treatment of proliferative diseases such as cancer, inflammation and arthritis, and neurodegenerative diseases:
Figure imgf000009_0001
wherein R2 represents e.g., hydrogen, alkyl, cycloalkyl, -CONR8R9 (wherein R8 and R9 represent e.g., hydrogen, OR6 (wherein R6 represents e.g., hydrogen, alkyl, alkenyl)); R3 represents e.g., haloalkyl, optionally substituted alkenyl, optionally substituted alkynyl; R4 represents e.g., hydrogen, halogen, haloalkyl, alkyl; and Ra represents e.g., hydrogen, halogen, haloalkyl, alkyl.
[0022] International Publication No. WO 2004/092171 discloses compounds of general formula (I) as antagonists of the A2a subtype of adenosine receptors which are useful in treating various disorders, including neurodegenerative disorders:
Figure imgf000009_0002
wherein A represents aryl or heteroaryl; B represents N or CR2R3; R2 and R3 represent e.g., hydrogen, alkyl, cycloalkyl; X1 and X2 represent C-i-βalkylene, C2-6alkenylene, O2- βalkynylene or a bond; Y represents e.g., CR2R3, O, S, a bond; R1 represents e.g., alkyl, alkenyl, alkynyl, aryl, heterocyclyl; and L represents a bond or a linker group.
[0023] Japanese Published Application No. 2002053466 discloses compounds of general formula (I) as apoptosis regulators which may be useful in treating apoptosis- related nerve disease:
(I)
Figure imgf000009_0003
wherein R1 represents e.g., hydrogen, optionally substituted loweralkyl.optionally substitued loweralkenyl; R2 represents e.g., naphthyl, phenyl, cycloalkyl; R3 represents hydrogen, phenyl, or loweralkyl; R4 represents e.g., hydrogen, loweralkyl, loweralkoxycarbonyl; R5 represents hydrogen or loweralkyl; R6 represents hydrogen, loweralkyl optionally substituted by phenyl, or benzoyl; Q represents carbonyl or sulfonyl; and A represents a bond, loweralkylene, or loweralkenylene.
[0024] International Publication No. WO 2007/044449 discloses compounds of general Formula III as cyclin dependent kinase (CDK) inhibitors which may be useful in the treatment of proliferative diseases such as cancer, inflammation and arthritis, and neurodegenerative diseases:
Figure imgf000010_0001
wherein R represents e.g., hydrogen, alkyl, alkenyl; R2 represents e.g., hydrogen, halogen, cyano, alkyl, alkenyl, cycloalkyl; R3 represents e.g., hydrogen, halogen, optionally substituted alkynyl; and R4 represents hydrogen, halogen, or alkyl.
[0025] International Publication No. WO 2005/070431 discloses compounds of general formula (I) as kinase inhibitors which may be useful in the treatment of protein kinase dependent diseases, such as proliferative diseases:
Figure imgf000010_0002
wherein R1 represents hydrogen, halogen, or loweralkyl; A represents e.g., hydrogen, halogen, an aliphatic moiety; R2 represents e.g., hydrogen, optionally substituted aryl, optionally substituted heteroaryl, an optionally substituted aliphatic residue; R3 represents e.g., hydrogen, optionally substituted aryl, optionally substituted heteroaryl, an optionally substituted aliphatic residue, an optionally substituted aliphatic residue which is connected by a connecting group or atom.
THE PRESENT INVENTION
[0026] It now has been found that certain pyrazolopyrimidine derivatives which differ in structure from the known pyrazolopyrimidines, are potent mGluRδ modulators. Therefore, these substances may be therapeutically beneficial in the treatment of conditions which involve abnormal glutamate neurotransmission or in which modulation of mGluRδ receptors results in therapeutic benefit. These substances may be administered in the form of a pharmaceutical composition, wherein they are present together with one or more pharmaceutically acceptable diluents, carriers, or excipients.
OBJECTS OF THE INVENTION
[0027] It is an object of the present invention to provide novel pharmaceutical compounds which are mGluRδ modulators and pharmaceutical compositions thereof. It is a further object of the invention to provide a novel method of treating, eliminating, alleviating, palliating, modifying, or ameliorating undesirable CNS disorders which involve abnormal glutamate neurotransmission, and/or to provide symptomological effects, by employing a compound of the invention or a pharmaceutical composition containing the same.
[0028] An additional object of the invention is the provision of processes for producing the pyrazolopyrimidine 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 imgf000012_0001
wherein
R1, R2, and R3, which may be the same or different, each independently represent hydrogen, Ci-6alkyl (e.g., methyl), trifluoromethyl, C-ι-6alkoxy (e.g., methoxy), cyano, halogen, or -NR4R5, wherein
R4 and R5, which may be the same or different, each independently represent hydrogen, d-βalkyl, or cycloC3-i2alkyl, or R4 and R5, together with the nitrogen atom to which they are attached, represent a 5- or 6- membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more groups selected from Chalky! (e.g., methyl), halogen, trifluoromethyl, Ci-6alkoxy, and cyano;
Figure imgf000012_0002
wherein L represents Ci-3alkylene, arylene, heteroarylene, -X-Ci-3alkylene, or Ci-3alkylene-X-( wherein X represents oxygen or sulfur, and
Cy represents aryl, heteroaryl, CyCIoC3-12a I kyl, cycloC3-i2alkenyl, or heterocyclyl; and
R7 represents hydrogen, Ci-6alkyl (e.g., methyl), C-ι-6alkoxy (e.g., methoxy), - C(O)NR8R9, carboxy, or aryl, wherein
R8 and R9, which may be the same or different, each independently represent hydrogen, C-ι-6alkyl, or cycloC3-12alkyl, or R8 and R9, together with the nitrogen atom to which they are attached, represent a 5- or 6- membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more groups selected from d-βalkyl (e.g., methyl), halogen, trifluoromethyl, d-βalkoxy, and cyano;
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, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, hydroxyCi-6alkyl, C2-6alkenyl, Ci-6alkoxy, Ci-6alkoxyCi-6alkyl, amino, hydroxy, nitro, cyano, formyl, cyanomethyl, Ci-6alkoxycarbonyl, d. βalkylcarbonyloxy, d-βalkylcarbonyloxyd-βalkyl, d-βalkylamino, di-(C-|. 6alkyl)amino, d-βalkylcarbonylamino, phenylcarbonylamino, aminocarbonyl, N-Ci-βalkylaminocarbonyl, di-N,N-d-6alkylaminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, cycloCa-^alkyl, pyridinyl, and optionally d-βalkylenedioxy;
the term "arylene" means a divalent aryl radical as defined above;
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, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, hydroxyd-6alkyl, C2-6alkenyl, d-βalkoxy, amino, hydroxy, nitro, cyano, d- βalkoxycarbonyl, d-βalkoxycarbonyloxy, d-βalkylamino, and di-(Ci-6alkyl)amino, d-βalkylcarbonylamino, aminocarbonyl, N-d-βalkylaminocarbonyl, di-N, N-Ci- 6alkylaminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl,
Figure imgf000014_0001
d-βalkylenedioxy, aryl, and pyridinyl; and
the term "heteroarylene" means a divalent heteroaryl radical as defined above;
and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
[0030] Such a compound of Formula I, wherein R1, R2, and R3, which may be the same or different, each independently represent hydrogen, Ci-6alkyl, Ci-6alkoxy, or -NR4R5, wherein R4 and R5, which may be the same or different, each independently represent hydrogen or Ci-6alkyl.
[0031] Such a compound of Formula I, wherein R1, R2, and R3, which may be the same or different, each independently represent hydrogen, methyl, methoxy, amino, t- butylamino, or methoxybenzylamino.
[0032] Such a compound of Formula I, wherein R7 represents hydrogen, Ci-6alkyl, Ci- βalkoxy, or -C(O)NR8R9, wherein R8 and R9, which may be the same or different, each independently represent hydrogen or Chalky!, or R8 and R9, together with the nitrogen atom to which they are attached, represent a 5- or 6-membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more Chalky! groups.
[0033] Such a compound of Formula I, wherein R7 represents hydrogen, methyl, methoxy, or -C(O)NR8R9, wherein R8 and R9, which may be the same or different, each independently represent hydrogen, methyl, ethyl, n-propyl, or isopropyl or R8 and R9 together with the nitrogen atom to which they are attached, represent a pyrrolidine, piperazine or morpholine ring, wherein each of these rings may be optionally substituted by one or more C-i-βalkyl groups. [0034] Such a compound of Formula I, wherein Cy represents an aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally substituted by one or more substituents selected from halogen, trifluoromethyl, Ci.6alkyl, hydroxyd-εalkyl, d- βalkoxy, Ci.6alkoxyCi-6alkyl, d-θalkylcarbonyloxyd-βalkyl, amino, cyano, formyl, d- βalkylcarbonylamino, phenylcarbonylamino, d-εalkoxycarbonyl, and pyridinyl.
[0035] Such a compound of Formula I, wherein Cy represents phenyl, pyridinyl, thiophenyl, thiazolyl, benzofuryl, dihydrobenzofuryl, or imidazolyl, wherein each of these groups is optionally substituted by one or more substituents selected from halogen, trifluoromethyl, Chalky!, hydroxyd-βalkyl, d-βalkoxy, Ci-6alkoxyd-6alkyl, d-βalkylcarbonyloxyd-βalkyl, amino, cyano, formyl, d-βalkylcarbonylamino, phenylcarbonylamino, d-βalkoxycarbonyl, and pyridinyl.
[0036] Such a compound of Formula I, wherein Cy represents a cycloCa-^alkyl, cycloC3-i2alkenyl, or heterocyclyl group, wherein the cycloCa-^alkyl, cycloCs-^alkenyl, or heterocyclyl group is optionally substituted by one or more substituents selected from d -6a Iky I, d-βalkoxycarbonyl, oxo, d-βalkoxyimino, d ealkylaminocarbonyl, and arylCi-βalkoxycarbonyl.
[0037] Such a compound of Formula I, wherein Cy represents cyclopropyl, cyclohexyl, cyclohexenyl, tetrahydropyridinyl, dihydropyranyl, or dihydrothiopyranyl, wherein each of these groups is optionally substituted by one or more substituents selected from d-6alkyl, d-βalkoxycarbonyl, oxo, d-βalkoxyimino, d-βalkylaminocarbonyl, and aryld-βalkoxycarbonyl.
[0038] A further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula Ia
Figure imgf000015_0001
wherein
R1, R2, and R3, which may be the same or different, each independently represent hydrogen, Ci-6alkyl (e.g., methyl), trifluoro methyl, Ci-6alkoxy (e.g., methoxy), cyano, halogen, or -NR4R5, wherein
R4 and R5, which may be the same or different, each independently represent hydrogen, Chalky!, or cycloC3.12alkyl, or R4 and R5, together with the nitrogen atom to which they are attached, represent a 5- or 6- membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more groups selected from Ci^alkyl (e.g., methyl), halogen, trifluoromethyl, d-βalkoxy, and cyano;
Ar represents aryl or heteroaryl; and
R7 represents hydrogen, Ci-6alkyl (e.g., methyl), Ci-6alkoxy (e.g., methoxy), - C(O)NR8R9, carboxy, or aryl, wherein
R8 and R9, which may be the same or different, each independently represent hydrogen, Chalky!, or cycloCa-^alkyl, or R8 and R9, together with the nitrogen atom to which they are attached, represent a 5- or 6- membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more groups selected from d-βalkyl (e.g., methyl), halogen, trifluoromethyl, C-i-βalkoxy, and cyano;
and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
[0039] Such a compound of Formula Ia, wherein Ar represents phenyl which is optionally substituted by one or more substituents selected from halogen, trifluoromethyl, Ci-6alkyl, hydroxyCi-6alkyl, Ci-6alkoxy, Ci-βalkoxyCi-βalkyl, Ci-ealkylcarbonyloxyCi-βalkyl, amino, cyano, formyl, Ci-βalkylcarbonylamino, and phenylcarbonylamino.
[0040] Such a compound of Formula Ia, wherein Ar represents a heteroaryl group selected from pyridinyl, thiophenyl, thiazolyl, benzofuryl, dihydrobenzofuryl, and imidazolyl, wherein the heteroaryl group is optionally substituted by one or more substituents selected from halogen, Ci-6alkyl, Ci-6alkoxy, and C-i-6alkoxycarbonyl.
[0041] Such a compound of Formula Ia, wherein Ar represents pyridinyl.
[0042] A further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula Ib
Figure imgf000017_0001
wherein
R1, R2, and R3, which may be the same or different, each independently represent hydrogen, Ci-βalkyI (e.g., methyl), trifluoromethyl, C-i-βalkoxy (e.g., methoxy), cyano, halogen, or -NR4R5, wherein
R4 and R5, which may be the same or different, each independently represent hydrogen, d-βalkyl, or cycloC3-i2alkyl, or R4 and R5, together with the nitrogen atom to which they are attached, represent a 5- or 6- membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more groups selected from Ci-6alkyl (e.g., methyl), halogen, trifluoromethyl, d-βalkoxy, and cyano; L represents Ci-3alkylene, arylene, heteroarylene, -X-Ci.3alkylene, or Ci-3alkylene-X-, wherein X represents oxygen or sulfur;
Ar represents aryl or heteroaryl; and
R7 represents hydrogen, Ci-6alkyl (e.g., methyl), Ci-6alkoxy (e.g., methoxy), - C(O)NR8R9, carboxy, or aryl, wherein
R8 and R9, which may be the same or different, each independently represent hydrogen, Chalky!, or cycloCs-^alkyl, or R8 and R9, together with the nitrogen atom to which they are attached, represent a 5- or 6- membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more groups selected from Ci^alkyl (e.g., methyl), halogen, trifluoromethyl, C-i-βalkoxy, and cyano;
and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
[0043] Such a compound of Formula Ib1 wherein L represents C1-3alkylene, arylene, or heteroarylene, and Ar represents phenyl, which is optionally substituted by one or more substituents selected from halogen, Ci-6alkyl, Ci-6alkoxy, cyano and amino, or pyridinyl which is optionally substituted with one or more substituents selected from halogen, C1-6alkyl, and C-i-βalkoxy.
[0044] Such a compound of Formula Ib, wherein L represents CH2 or CH(Me), phenylene which is optionally substituted by one or more halogen atoms, or a divalent pyridinyl group.
[0045] A further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula Ic
Figure imgf000019_0001
wherein
R1, R2, and R3, which may be the same or different, each independently represent hydrogen, d-βalkyl (e.g., methyl), trifluoromethyl, d-βalkoxy (e.g., methoxy), cyano, halogen, or -NR4R5, wherein
R4 and R5, which may be the same or different, each independently represent hydrogen, Chalky!, or cycloC3-i2alkyl, or R4 and R5, together with the nitrogen atom to which they are attached, represent a 5- or 6- membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more groups selected from Chalky! (e.g., methyl), halogen, trifluoromethyl, C-i-βalkoxy, and cyano;
L represents Ci^alkylene, arylene, heteroarylene, -X-Ci-3alkylene, or Ci-3alkylene-X-, wherein X represents oxygen or sulfur;
Ar represents aryl or heteroaryl;
R7 represents hydrogen, Ci-6alkyl (e.g., methyl), d-βalkoxy (e.g., methoxy), - C(O)NR8R9, carboxy, or aryl, wherein
R8 and R9, which may be the same or different, each independently represent hydrogen, Ci-6alkyl, or cycloC3-i2alkyl, or R8 and R9, together with the nitrogen atom to which they are attached, represent a 5- or 6- membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more groups selected from Ci-6alkyl (e.g., methyl), halogen, trifluoromethyl, Ci-6alkoxy, and cyano; and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
[0046] Such a compound of Formula Ic, wherein L represents
Figure imgf000020_0001
heteroarylene, or
Figure imgf000020_0002
and Ar represents phenyl, optionally substituted by halogen, Ci-6alkyl, Ci-6alkoxy, and amino, or a heteroaryl group selected from pyridinyl, thiazolyl, pyrazolyl, and thiophenyl, wherein the heteroaryl group is optionally substituted with one or more substituents selected from halogen and Ci-6alkyl.
[0047] Such a compound of Formula Ic, wherein L represents CH2, CH2CH2, OCH2, or a divalent thiophenyl group.
[0048] A further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula Id
Figure imgf000020_0003
Id
wherein
R1, R2, and R3, which may be the same or different, each independently represent hydrogen, Ci-6alkyl (e.g., methyl), trifluoromethyl, Ci-6alkoxy (e.g., methoxy), cyano, halogen, or -NR4R5, wherein
R4 and R5, which may be the same or different, each independently represent hydrogen, Ci-6alkyl, or cycloC3-i2alkyl, or R4 and R5, together with the nitrogen atom to which they are attached, represent a 5- or 6- membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more groups selected from C1-6alkyl (e.g., methyl), halogen, trifluoromethyl, d-βalkoxy, and cyano;
Figure imgf000021_0001
, wherein L represents Ci^alkylene, arylene, heteroarylene, -X-Ci-3alkylene, or C^alkylene-X-, wherein X represents oxygen or sulfur, and
Ar represents aryl or heteroaryl; and
R7 represents hydrogen, d-βalkyl (e.g., methyl), Ci-6alkoxy (e.g., methoxy), - C(O)NR8R9, carboxy, or aryl, wherein
R8 and R9, which may be the same or different, each independently represent hydrogen, Ci-6alkyl, or cycloC3-i2alkyl, or R8 and R9, together with the nitrogen atom to which they are attached, represent a 5- or 6- membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more groups selected from Ci-βalkyl (e.g., methyl), halogen, trifluoromethyl, C1-6alkoxy, and cyano;
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, trifluoromethyl, trifluoromethoxy, d-βalkyl, hydroxyd-βalkyl, C2-6alkenyl, d-βalkoxy, Ci-6alkoxyCi.6alkyl, amino, hydroxy, nitro, cyano, formyl, cyanomethyl, d-βalkoxycarbonyl, d- 6alkylcarbonyloxy, d-βalkylcarbonyloxyd-βalkyl, Ci-βalkylamino, di-(d- 6alkyl)amino, d-βalkylcarbonylamino, phenylcarbonylamino, aminocarbonyl, N-d-βalkylaminocarbonyl, di-N.N-d-βalkylaminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, cycloC3-i2alkyl and optionally C1-6alkylenedioxy;
the term "arylene" means a divalent aryl radical as defined above; 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, trifluoromethyl, trifluoromethoxy, Ci^alkyl, hydroxyC-i-βalkyl, C-2-6alkenyl, Ci-βalkoxy, amino, hydroxy, nitro, cyano, Ci- 6alkoxycarbonyl, Ci-βalkoxycarbonyloxy, Ci-βalkylamino, and di-(Ci-6alkyl)amino, Ci-βalkylcarbonylamino, aminocarbonyl, N-Ci-βalkylaminocarbonyl, di-N, N-Ci- 6alkylaminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, cycloC-3.i2alkyl, d-βalkylenedioxy and aryl; and
the term "heteroarylene" means a divalent heteroaryl radical as defined above;
and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
[0049] Such a compound of Formula Id, wherein R1, R2, and R3, which may be the same or different, each independently represent hydrogen, Chalky!, d-βalkoxy, or -NR4R5, wherein R4 and R5, which may be the same or different, each independently represent hydrogen or Ci-6alkyl.
[0050] Such a compound of Formula Id, wherein R1, R2, and R3, which may be the same or different, each independently represent hydrogen, methyl, methoxy, amino, or t-butylamino.
[0051] Such a compound of Formula Id1 wherein R7 represents hydrogen, Chalky!, Ci- 6alkoxy, or -C(O)NR8R9, wherein R8 and R9, which may be the same or different, each independently represent hydrogen or Ci-6alkyl, or R8 and R9, together with the nitrogen atom to which they are attached, represent a 5- or 6-membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more Chalky! groups.
[0052] Such a compound of Formula Id, wherein R7 represents hydrogen, methyl, methoxy, or -C(O)NR8R9, wherein R8 and R9, which may be the same or different, each independently represent hydrogen, methyl, ethyl, n-propyl, or isopropyl or R8 and R9 together with the nitrogen atom to which they are attached, represent a pyrrolidine, piperazine or morpholine ring, wherein each of these rings may be optionally substituted by one or more d-βalkyl groups.
[0053] Such a compound of Formula Id, wherein Ar represents an aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally substituted by one or more substituents selected from halogen, trifluoromethyl, Chalky!, hydroxyCi-βalkyl, Ci- 6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-βalkylcarbonyloxyCi-ealkyl, amino, cyano, formyl, Ci- βalkylcarbonylamino, phenylcarbonylamino, and Ci-βalkoxycarbonyl.
[0054] Such a compound of Formula Id, wherein Ar represents phenyl, pyridinyl, thiophenyl, thiazolyl, benzofuryl, dihydrobenzofuryl, or imidazolyl, wherein each of these groups is optionally substituted by one or more substituents selected from halogen, trifluoromethyl, Chalky!, hydroxyCi-βalkyl, Ci-βalkoxy, Ci-βalkoxyCi-βalkyl, Ci-βalkylcarbonyloxyCi-ealkyl, amino, cyano, formyl, d-βalkylcarbonylamino, phenylcarbonylamino, and Ci-6alkoxycarbonyl.
[0055] A further aspect of the invention relates to a compound of Formula I, wherein R1, R2, and R3 represent hydrogen; R6 represents
Figure imgf000023_0001
, wnerein L represents -X-Ci-3alkylene and X represents oxygen or sulfur; Ar represents aryl or heteroaryl; and R7 represents hydrogen, or methyl.
[0056] Specific compounds of Formula I within the present invention include, but are not limited to, the following compounds: -Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-benzonitrile, 3-Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-phenylamine,
N-(3-Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-phenyl)-acetamide,
5-(3-Methoxy-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
3-Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-benzaldehyde,
5-(3-Bromo-5-fluoro-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(3-Fluoro-5-pyridin-3-yl-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(3-Fluoro-5-pyridin-4-yl-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(4-Fluoro-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-Phenylethynyl-pyrazolo[1 ,5-a]pyrimidine,
5-(4-Trifluoromethyl-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(4-Chloro-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-p-Tolylethynyl-pyrazolo[1 ,5-a]pyrimidine,
5-(2-Fluoro-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-m-Tolylethynyl-pyrazolo[1 ,5-a]pyrimidine,
5-o-Tolylethynyl-pyrazolo[1 ,5-a]pyrimidine,
5-(3-Fluoro-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
2-Phenyl-5-phenylethynyl-pyrazolo[1 ,5-a]pyrimidine,
5-(3-Trifluoromethyl-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(2-Trifluoromethyl-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(3-Chloro-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(2-Chloro-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-Pyridin-2-ylethynyl-pyrazolo[1 ,5-a]pyrimidine,
5-Pyridin-3-ylethynyl-pyrazolo[1 ,5-a]pyrimidine,
5-Thiophen-3-ylethynyl-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-phenylethynyl-pyrazolo[1 ,5-a]pyrimidine,
5-(6-Methyl-pyridin-2-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-Phenylethynyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid,
(5-Phenylethynyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1-yl-methanone,
(5-Phenylethynyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-pyrrolidin-1-yl-methanone,
5-(5-Fluoro-pyridin-2-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-Phenylethynyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid diethylamide,
Morpholin-4-yl-(5-phenylethynyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone,
5-Thiophen-2-ylethynyl-pyrazolo[1 ,5-a]pyrimidine, (2-Methyl-piperidin-1-yl)-(5-phenylethynyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone,
5-(2,4-Dimethyl-thiazol-5-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(2,3-Dihydro-benzofuran-5-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
(4-Methyl-piperazin-1-yl)-(5-phenylethynyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanoneI
5-Phenylethynyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid isopropyl-methyl-amide,
5-Benzofuran-2-ylethynyl-pyrazolo[1 ,5-a]pyrimidine,
(2-Methyl-pyrrolidin-1-yl)-(5-phenylethynyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone,
5-Pyridin-4-ylethynyl-pyrazolo[1 ,5-a]pyrimidine,
5-(3-Methyl-thiophen-2-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(1 -Methyl- 1 H-imidazol-2-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(1-Methyl-3H-imidazol-4-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-Phenylethynyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid dimethyl amide,
(5-Phenylethynyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperazin-1-yl-methanone,
5-(5-Methoxy-pyridin-3-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(2-Fluoro-pyridin-3-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
2-Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-isonicotinic acid ethyl ester,
(3-Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-phenyl)-methanol,
5-(3-Methoxymethyl-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
Acetic acid 3-pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-benzyl ester,
N-(3-Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-phenyl)-benzamide,
5-[3-Fluoro-5-(2-fluoro-pyridin-3-yl)-phenylethynyl]-pyrazolo[1 ,5-a]pyrimidine,
5-[3-Fluoro-5-(2-methoxy-pyridin-3-yl)-phenylethynyl]-pyrazolo[1 ,5-a]pyrimidine,
S-Pyrazoloti .S-alpyrimidin-δ-ylethynyl-tS.S'lbipyridinyl,
2-Fluoro-5I-pyrazolo[1 l5-a]pyrimidin-5-ylethynyl-[3,3I]bipyridinyl,
2-Methoxy-5l-pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-[3,3']bipyridinyl,
5-(3-Phenyl-prop-1 -ynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(3-Fluoro-phenyl)-prop-1-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(3-Methoxy-phenyl)-prop-1-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
3-(3-Pyrazolo[1 ,5-a]pyrimidin-5-yl-prop-2-ynyl)-benzonitrile,
3-(3-Pyrazolo[1 ,5-a]pyrimidin-5-yl-prop-2-ynyl)-phenylamine,
5-(3-Phenyl-but-1 -ynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(3-Phenyl-prop-2-ynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(3-Fluoro-phenyl)-prop-2-ynyl]-pyrazolo[1 ,5-a]pyrimidine, 5-[3-(3-Methoxy-phenyl)-prop-2-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
3-(3-Pyrazolo[1 ,5-a]pyrimidin-5-yl-prop-1 -ynyl)-phenylamine,
5-(4-Pyridin-2-yl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-[4-(6-Methyl-pyridin-2-yl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
5-[4-(6-Fluoromethyl-pyridin-2-yl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrinnidine,
5-[4-(2-Methyl-thiazol-4-yl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
5-[4-(2-Fluoromethyl-thiazol-4-yl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
5-[4-(1 -Methyl-1 H-pyrazol-3-yl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
5-(4-Phenyl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(4-Pyridin-3-yl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(4-o-Tolyl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(4-m-Tolyl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-[4-(2-Chloro-phenyl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
5-[4-(2-Fluoro-phenyl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
5-[4-(3-Chloro-phenyl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
5-[4-(3-Fluoro-phenyl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
5-(4-Thiophen-3-yl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(4-Thiophen-2-yl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-[4-(3-Methyl-thiophen-2-yl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-(4-pyridin-2-yl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-[4-(6-methyl-pyridin-2-yl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine, δ-^e-Fluoromethyl-pyridin^-yO-but-S-ynylJ^-methyl-pyrazoloti .δ-alpyrimidine,
2-Methyl-5-[4-(2-methyl-thiazol-4-yl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
5-[4-(2-Fluoromethyl-thiazol-4-yl)-but-3-ynyl]-2-methyl-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-[4-(1 -methyl-1 H-pyrazol-3-yl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-(4-phenyl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-(4-pyridin-3-yl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-(4-o-tolyl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-(4-m-tolyl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-[4-(2-Chloro-phenyl)-but-3-ynyl]-2-methyl-pyrazolo[1 ,5-a]pyrimidine,
5-[4-(2-Fluoro-phenyl)-but-3-ynyl]-2-methyl-pyrazolo[1 ,5-a]pyrimidine,
5-[4-(3-Chloro-phenyl)-but-3-ynyl]-2-methyl-pyrazolo[1 ,5-a]pyrimidine,
5-[4-(3-Fluoro-phenyl)-but-3-ynyl]-2-methyl-pyrazolo[1 ,5-a]pyrimidine, 2-Methyl-5-(4-thiophen-3-yl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-(4-thiophen-2-yl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-[4-(3-methyl-thiophen-2-yl)-but-3-ynyl]-pyrazolo[1 I5-a]pyrimidine,
5-(5-Pyridin-2-ylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidine,
5-[5-(6-Methyl-pyridin-2-ylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidine,
5-[5-(6-Fluoromethyl-pyridin-2-ylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidine,
5-[5-(2-Methyl-thiazol-4-ylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidine,
5-[5-(2-Fluoromethyl-thiazol-4-ylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidine,
5-[5-(1-Methyl-1 H-pyrazol-3-ylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidine,
5-(5-Phenylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidine,
5-(5-Pyridin-3-ylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidine,
5-(5-o-Tolylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidine,
5-(5-m-Tolylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidine,
5-[5-(2-Chloro-phenylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidine,
5-[5-(2-Fluoro-phenylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidine,
5-[5-(3-Chloro-phenylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidine,
5-[5-(3-Fluoro-phenylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidine,
5-(5-Thiophen-3-ylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidine,
5-(5-Thiophen-2-ylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidine,
5-[5-(3-Methyl-thiophen-2-ylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidine, tert-Butyl-[5-(5-pyridin-2-ylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidin-7-yl]-amine,
5-Pyrazolo[1.δ-ajpyrimidin-δ-ylethynyl-nicotinic acid methyl ester, tert-Butyl^S-IS-Ce-methyl-pyridin^-ylethynylHhiophen^-yπ-pyrazoloti .S-alpyrimidin-?- yl}-amine, tert-Butyl-{5-[5-(6-fluoromethyl-pyridin-2-ylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5- a]pyrimidin-7-yl}-amine, tert-Butyl-{5-[5-(2-methyl-thiazol-4-ylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidin-7- yl}-amine, tert-Butyl-{5-[5-(2-fluoromethyl-thiazol-4-ylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5- a]pyrimidin-7-yl}-amine, tert-Butyl-{5-[5-(1 -methyl-1 H-pyrazol-3-ylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5- a]pyrimidin-7-yl}-amine, tert-Butyl-[5-(5-phenylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidin-7-yl]-amine, tert-Butyl-[5-(5-pyridin-3-ylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidin-7-yl]-amine, tert-Butyl-fδ-Cδ-o-tolylethynyl-thiophen^-yO-pyrazoloti .S-alpyrimidin-T-ylJ-amine, tert-Butyl-[5-(5-m-tolylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidin-7-yl]-amine, tert-Butyl-{5-[5-(2-chloro-phenylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidin-7-yl}- amine, tert-Butyl-{5-[5-(2-fluoro-phenylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidin-7-yl}- amine, tert-Butyl-{5-[5-(3-chloro-phenylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidin-7-yl}- amine, tert-Butyl-{5-[5-(3-fluoro-phenylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidin-7-yl}- amine, tert-Butyl-[5-(5-thiophen-3-ylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidin-7-yl]-amine, tert-Butyl-[5-(5-thiophen-2-ylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidin-7-yl]-amine, tert-Butyl-{5-[5-(3-methyl-thiophen-2-ylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidin-
7-yl}-amine,
5-(3-Pyridin-2-yl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-(3-pyridin-2-yl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(6-Methyl-pyridin-2-yl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-[3-(6-methyl-pyridin-2-yl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(6-Fluoromethyl-pyridin-2-yl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(6-Fluoromethyl-pyridin-2-yl)-prop-2-ynyloxy]-2-methyl-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(2-Methyl-thiazol-4-yl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-[3-(2-methyl-thiazol-4-yl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(2-Fluoromethyl-thiazol-4-yl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(2-Fluoromethyl-thiazol-4-yl)-prop-2-ynyloxy]-2-methyl-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(1 -Methyl-1 H-pyrazol-3-yl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-[3-(1 -methyl-1 H-pyrazol-3-yl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
5-(3-Phenyl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-(3-phenyl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine,
5-(3-Pyridin-3-yl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-(3-pyridin-3-yl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine,
5-(3-o-Tolyl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-(3-o-tolyl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine, 5-(3-m-Tolyl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-(3-m-tolyl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(2-Chloro-phenyl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(2-Chloro-phenyl)-prop-2-ynyloxy]-2-methyl-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(2-Fluoro-phenyl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(2-Fluoro-phenyl)-prop-2-ynyloxy]-2-methyl-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(3-Chloro-phenyl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(3-Chloro-phenyl)-prop-2-ynyloxy]-2-methyl-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(3-Fluoro-phenyl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(3-Fluoro-phenyl)-prop-2-ynyloxy]-2-methyl-pyrazolo[1 ,5-a]pyrimidine,
5-(3-Thiophen-3-yl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-(3-thiophen-3-yl-prop-2-ynyloxy)-pyrazolo[1 l5-a]pyrimidine,
5-(3-Thiophen-2-yl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-(3-thiophen-2-yl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(3-Methyl-thiophen-2-yl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-[3-(3-methyl-thiophen-2-yl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
5-(5-Bromo-pyridin-3-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-Cyclohexylethynyl-pyrazolo[1 ,5-a]pyrimidine,
5-Cyclohex-1 -enylethynyl-pyrazolo[1 ,5-a]pyrimidine, δ-Pyrazoloπ .δ-aJpyrimidin-δ-ylethynyl-βΛibipyridinyl,
5-(2,6-Dimethyl-cyclohex-1-enylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
2-Phenyl-4-pyrazolo[1 ,5-a]pyrimidin-5-yl-but-3-yn-2-ol,
4-Pyrazolo[1.δ-aJpyrimidin-δ-ylethynyl-S.e-dihydro^H-pyridine-i-carboxylic acid tert- butyl ester,
5-(3,6-Dihydro-2H-pyran-4-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(3,6-Dihydro-2H-thiopyran-4-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(3-Methyl-3-phenyl-but-1 -ynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(2)6,6-Trimethyl-cyclohex-1-enylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-Cyclopropylethynyl-pyrazolo[1 ,5-a]pyrimidine,
3-Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-cyclohex-2-enone,
3-Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-cyclohex-2-enone O-methyl-oxime,
4-Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-3,6-dihydro-2H-pyridine-1-carboxylic acid isopropylamide, 4-Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester, and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
[0057] 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 mGluRδ receptor, including for the conditions or diseases selected from those described earlier in the description.
[0058] 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.
[0059] 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 mGluRδ receptors results in therapeutic benefit. The conditions which may be treated have already been described above. Such conditions and indications include: a) For mGluRδ modulators: chronic pain, neuropathic pain, diabetic neuropathic pain (DNP), cancer pain, pain related to rheumathic arthritis, inflammatory pain, L-dopa-induced dyskinesias, dopaminomimetic- induced dyskinesias, L-dopa-induced dyskinesias in Parkinson's disease therapy, dopaminomimetic-induced dyskinesias in Parkinson's disease therapy, tardive dyskinesias, Parkinson's disease, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), generalized anxiety disorder, substance-induced anxiety disorder, eating disorders, obesity, binge eating disorders, Huntington's chorea, epilepsy, Alzheimer's disease, positive and negative symptoms of schizophrenia, cognitive impairment, functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), migraine, irritable bowel syndrome (IBS), or for cognitive enhancement and/or neuroprotection.
b) Negative modulation of mGluRδ 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 mGluRδ may be particularly useful for: Alzheimer's disease, positive and/or negative symptoms of schizophrenia, cognitive impairment, or for cognitive enhancement and/or neuroprotection. [0060] 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.
[0061] 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.
[0062] 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 mGluRδ receptor, including for the conditions or diseases selected from those described earlier in the description.
[0063] 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.
[0064] 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.
[0065] 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 and/or Neramexane. [0066] 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.
[0067] 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 selected from Memantine and Neramexane (or a combination thereof) and pharmaceutically acceptable salts, polymorphs, hydrates and solvates thereof.
[0068] 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).
[0069] 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. [0070] 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.
[0071] The invention also relates to a process for the synthesis or preparation of a compound of Formula Ia
Figure imgf000034_0001
wherein R1, R2, R3, R7, and Ar are as defined above for Formula I, wherein a compound of Formula Il
Figure imgf000034_0003
is treated with trimethylacetylene and PdCI2(PPh3)2 in a solvent such as triethylamine to yield a compound of Formula III
Figure imgf000034_0004
which is reacted with a compound of Formula IV
Figure imgf000034_0002
to yield a compound of Formula Ia, which may be converted to a pharmaceutically acceptable salt, hydrate, solvate, or polymorph. [0072] The invention also relates to a process for the synthesis or preparation of a compound of Formula Ia
Figure imgf000035_0001
Ia wherein R1, R2, R3, R7, and Ar are as defined above for Formula I, wherein a compound of Formula IV
Figure imgf000035_0002
is reacted with 2-methyl-but-3-yn-2-ol to yield a compound of Formula V
Figure imgf000035_0003
which is treated with sodium hydride to yield a compound of Formula Vl
Figure imgf000035_0004
which is reacted with a compound of Formula Il
Figure imgf000036_0004
to yield a compound of Formula Ia, which may be converted to a pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
[0073] The invention also relates to a process for the synthesis or preparation of a compound of Formula Ia1
Figure imgf000036_0001
wherein R8, R9, and Ar are as defined above for Formula I, comprising reaction of 5- nitro-2H-pyrazole-3-carboxylic acid of Formula VII
Figure imgf000036_0002
with thionyl chloride to yield 5-nitro-2H-pyrazole-3-carboxylic acid methyl ester, which is hydrogenated to yield 5-amino-2H-pyrazole-3-carboxylic acid methyl ester of Formula VIII
Figure imgf000036_0003
which is treated with methyl propiolate to yield a compound of Formula IX
Figure imgf000037_0001
which is treated with phosphoryl bromide to yield a compound of Formula X
Figure imgf000037_0002
which is coupled with a compound of Formula Xl
Figure imgf000037_0005
to yield a compound of Formula XII
Figure imgf000037_0003
which is subjected to basic hydrolysis to yield a compound of Formula XIII
Figure imgf000037_0004
which is reacted with a secondary amine of Formula XIV
Figure imgf000038_0004
in the presence of a condensation agent (e.g., O-Cbenzotriazol-i-ylJ-N.N.N'.N1- tetramethyluronium tetrafluoroborate (TBTU) or N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide (EDC)) to yield a compound of Formula Ia1, which may be converted to a pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
[0074] The invention also relates to a process for the synthesis or preparation of a compound of Formula Ic'
Figure imgf000038_0001
wherein R7 and Ar are as defined above for Formula I, wherein a 5-aminopyrazole of Formula XV
Figure imgf000038_0002
is treated with methyl propiolate to yield a compound of Formula XVI
Figure imgf000038_0003
which is reacted with a compound of Formula XVII
Figure imgf000039_0004
in the presence of triphenyl phosphine and diisopropyl azodicarboxylate (DIAD) to yield a compound of Formula Ic1, which may be converted to a pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
[0075] The invention also relates to a process for the synthesis or preparation of a compound of Formula Ic"
Figure imgf000039_0001
wherein R7 and Ar are as defined above for Formula I, wherein a 5-aminopyrazole of Formula XV
Figure imgf000039_0002
is treated with methyl propiolate to yield a compound of Formula XVII
Figure imgf000039_0003
which is treated with trifluoromethanesulfonic anhydride to yield a compound of Formula XIX
Figure imgf000040_0001
which is treated with 5-trimethylsilanyl-butyn-3-yl-zinc reagent XX
Figure imgf000040_0004
to yield a compound of Formula XXI
Figure imgf000040_0002
which is reacted with a compound of Formula Il
Figure imgf000040_0005
to yield a compound of Formula Ic", which may be converted to a pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
[0076] The invention also relates to a process for the synthesis or preparation of a compound of Formula Ic1"
wherein Y represents arylene or heteroarylene and Ar is as defined above for Formula I, wherein δ-amino-I H-pyrazole-^carboxylic acid ethyl ester of Formula XXII
Figure imgf000041_0001
is treated with methyl propiolate followed by sodium hydride to yield a compound of Formula XXIII
Figure imgf000041_0002
which is treated with phosphorous oxychloride to yield a compound of Formula XXIV
Figure imgf000041_0003
which is coupled with a compound of Formula XXV
Figure imgf000041_0004
to yield a compound of Formula XXVI
Figure imgf000042_0001
which is subjected to an iodination reaction to yield a compound of Formula XXVII
Figure imgf000042_0002
which is coupled with a compound of Formula Xl
Figure imgf000042_0005
to yield a compound of Formula XXVIII
Figure imgf000042_0003
which is subjected to hydrolysis to yield a compound of Formula XXIX
Figure imgf000042_0004
which is decarboxylated to yield a compound of Formula Ic1", which may be converted to a pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
[0077] The invention also relates to a process for the synthesis or preparation of a compound of Formula Ic""
Figure imgf000043_0001
wherein R4, R7, and Ar are as defined above for Formula I, wherein 5-bromo-thiophen-2- carboxylic acid of Formula XXX
Figure imgf000043_0002
is treated with carbonyldiimidazole followed by monomethyl monopotassium malonate to yield 3-(5-bromo-thiophen-2-yl)-3-oxo-propionic acid methyl ester of Formula XXXI
Figure imgf000043_0003
which is reacted with a 5-aminopyrazole of Formula XV
Figure imgf000044_0001
to yield a compound of Formula XXXII
Figure imgf000044_0002
which is treated with phosphorous oxychloride to yield a compound of Formula XXXIII
Figure imgf000044_0003
which is treated with an amine of Formula XXXIV
Figure imgf000044_0005
to yield a compound of Formula XXXV
Figure imgf000044_0004
which is coupled with a compound of Formula Xl
Figure imgf000045_0004
to yield a compound of Formula Ic"", which may be converted to a pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
[0078] The invention also relates to a process for the synthesis or preparation of a compound of Formula Ib1
Figure imgf000045_0001
wherein R1, R2, R3, R7, and Ar are as defined above for Formula I, wherein a compound of Formula IV
Figure imgf000045_0002
is treated with triisopropylsilyl-acetylene followed by deprotection of the triple bond to yield a compound of Formula XXXVI
Figure imgf000045_0003
which is alkylated with a compound of Formula XXXVII
Figure imgf000046_0004
to yield a compound of Formula Ib', which may be converted to a pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
[0079] The invention also relates to a process for the synthesis or preparation of a compound of Formula Ib*
Figure imgf000046_0001
wherein R1, R2, R3, R7, and Ar are as defined above for Formula I, wherein a compound of Formula IV
Figure imgf000046_0002
is coupled with a compound of Formula XXXVIII
Figure imgf000046_0003
to yield a compound of Formula Ib', which may be converted to a pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
[0080] The invention also relates to a process for the synthesis or preparation of a compound of Formula Ic
Figure imgf000047_0001
wherein R1, R2, R3, R7, and Ar are as defined above for Formula I, wherein a compound of Formula IV
Figure imgf000047_0002
is treated with tributylvinylstannane to yield a compound of Formula XXXIX
Figure imgf000047_0003
which is subjected to ozonolysis-reduction conditions followed by treatment of with carbon tetrabromide and triphenylphospine to yield a compound of Formula XL
Figure imgf000047_0004
which is coupled with a compound of Formula Xl
Figure imgf000048_0004
to yield a compound of Formula Ic"1", which may be converted to a 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 Ic
Figure imgf000048_0001
wherein R1, R2, R3, R7, and Ar are as defined above for Formula I, wherein a compound of Formula IV
Figure imgf000048_0002
is treated with tributylvinylstannane to yield a compound of Formula XXXIX
Figure imgf000048_0003
which is subjected to ozonolysis-reduction conditions followed by treatment of with carbon tetrabromide and triphenylphospine to yield a compound of Formula XL
Figure imgf000049_0001
which is treated with lithium trimethylacetylide to yield, after cleavage of the trimethylsilyl group, a compound of Formula XLI
Figure imgf000049_0002
which is reacted with a compound of Formula Il
Figure imgf000049_0003
to yield a compound of Formula Ic , which may be converted to a 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, (C-i^alkyl refers to alkyl of one to three carbon atoms (i.e. 1 , 2 or 3 carbon atoms), inclusive, (i.e., methyl, ethyl, propyl, and isopropyl), straight and branched forms thereof, (C-ι-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, trifluoromethyl, C-i-βalkoxy, amino, hydroxy, Ci-βalkylamino, and di-(Ci-6alkyl)amino. Examples of such alkyl groups include methyl, ethyl, n-propyl, 2- propyl, n-butyl, tert-butyl, -CF3, -C2F5, -CBr3 and -CCI3.
[0084] The term "Ci-6alkylene" refers to a divalent "Ci.6alkyl" radical as defined above. Examples of such alkylene groups include methylene, ethylene, propylene, butylene, which groups may be straight or branched.
[0085] The term "C2-6alkenyl" represents straight or branched chain alkenyl groups.
[0086] The term "Ci-βalkoxy" represents straight or branched chain -O-Ci-βalkyl groups which may be optionally substituted by one or more (e.g., 1 , 2, 3, 4, or 5) substituents selected from halogen, trifluoromethyl, amino, hydroxy, Ci-βalkylamino and di-(Ci_ 6alkyl)amino. Examples of such alkoxy groups include methoxy, ethoxy, n-propoxy, i- propoxy, -OCF3 and -OC2F5.
[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, Chalky!, C2-6alkenyl, Ci-6alkoxy, amino, hydroxy, nitro, cyano, cyanomethyl, d-βalkoxycarbonyl, Ci-6alkylamino, and di-(Ci. 6alkyl)amino, Ci-βalkylcarbonylamino, oxo, d-βalkoxyimino, Ci-θalkylaminocarbonyl, arylCi-6alkoxycarbonyl, and Ci^alkylenedioxy.
[0088] The term "cycloCs-^alkenyl" 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, Chalky!, C2-6alkenyl, C-i-βalkoxy, amino, hydroxy, nitro, cyano, cyanomethyl, C-i-6alkoxycarbonyl, Ci-6alkylamino, and di-(C-|. 6alkyl)amino, Ci-ealkylcarbonylamino, oxo, Ci-6alkoxyimino, d-ealkylaminocarbonyl, arylCi-βalkoxycarbonyl, and Ci-βalkylenedioxy.
[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, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, hydroxyCi-6alkyl, C2-6alkenyl, Ci-6alkoxy, Ci-βalkoxyd. βalkyl, amino, hydroxy, nitro, cyano, formyl, cyanomethyl, Ci-βalkoxycarbonyl, C-i. βalkylcarbonyloxy, Ci-βalkylcarbonyloxyCi-βalkyl, Ci-βalkylamino, di-(Ci-6alkyl)amino, Ci- 6alkylcarbonylamino, phenylcarbonylamino, aminocarbonyl, N-d-ealkylaminocarbonyl, di-N,N-Ci-6alkylaminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, cycloC3_i2alkyl, pyridinyl, and optionally d-βalkylenedioxy.
[0090] The term "arylene" represents a divalent aryl radical as defined above.
[0091] 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, trifluoromethyl, trifluoromethoxy, d-βalkyl, hydroxyC-i. βalkyl, C^-βalkenyl, d-βalkoxy, amino, hydroxy, nitro, cyano, d-βalkoxycarbonyl, Ci- βalkoxycarbonyloxy, Ci-βalkylamino, and di-(Ci-6alkyl)amino, d-βalkylcarbonylamino, aminocarbonyl, N-d-βalkylaminocarbonyl, di-N.N-Ci-βalkylaminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, cycloCa-^alkyl, d-βalkylenedioxy, 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.
[0092] The term heteroarylene represents a divalent heteroaryl radical as defined above. Representative heteroarylene groups include divalent pyridinyl and thiophenyl groups.
[0093] The term heterocyclyl represents a saturated or unsaturated non-aromatic 3 to 12 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, and a saturated or unsaturated non-aromatic bicyclic ring system having 3 to 12 members comprising one to six heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heterocyclic ring or ring system may be optionally substituted by one or more (e.g., 1 , 2, 3, 4, or 5) substituents, which may be the same or different, selected independently from halogen, trifluoromethyl, trifluoromethoxy, Chalky!, C2- 6alkenyl, d-βalkoxy, amino, hydroxy, nitro, cyano, cyanomethyl, Ci-βalkoxycarbonyl, Ci- 6alkylamino, and di-(Ci-6alkyl)amino, Ci-ealkylcarbonylamino, oxo, d-βalkoxyimino, Ci- 6alkylaminocarbonyl, arylCi-6alkoxycarbonyl, and Ci^alkylenedioxy; 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.
[0094] The term "halogen" represents fluorine, chlorine, bromine and iodine.
[0095] The compounds of the present invention are usually named according to the IUPAC 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, and "rt" for room temperature).
[0096] 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. [0097] Neramexane, also known as 1-amino-1 ,3,3,5,5-pentamethylcyclohexane, is disclosed in detail in U.S. Patent Nos. 6,034,134 and 6,071,966, the subject matter of which patents is hereby incorporated by reference.
[0098] Memantine and neramexane are systemically-active noncompetitive NMDA receptor antagonists having moderate affinity for the receptor. They exhibit strong voltage dependent characteristics and fast blocking/unblocking kinetics (see e.g. Gόrtelmeyer 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).
[0099] 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.
[00100] 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.
[00101] 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.
[00102] 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.
[00103] 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.
[00104] The following Schemes 1-7 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 1-7 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.
Figure imgf000055_0001
Scheme 1 : General procedure towards 5-aryl/heteroaryl-ethynyl-pyrazolo[1 ,5- a]pyrimidines of Formula Ia.
[00105] Aryl halide (2) is treated with trimethylacetylene and PdCI2(PPh3)2 in a sovlent such as triethylamine to yield an aryl/heteroaryl-trimethylacetylene (3). Compound 3 is reacted with a 5-chloro-pyrazolo[1 ,5-a]pyrimidine (1 ) to yield a pyrazolo[1 ,5-a]pyrimidine of Formula Ia. Alternatively, 2-methyl-but-3-yn-2-ol is reacted with a 5-chloro-pyrazolo[1 ,5-a]pyrimidine (1) to yield a pyrazolo[1 ,5- a]pyrimidin-5-yl-but-3-yn-2-ol (5) which is treated with sodium hydride to yield a 5- ethynyl-pyrazolo[1 ,5-a]pyrimidine (6). Compound 6 is then reacted with an aryl/heteroaryl halide (2) to yield a 5-aryl/heteroaryl-ethynyl-pyrazolo[1 ,5-a]pyrimidine of Formula Ia.
Figure imgf000056_0001
Scheme 2: General procedure towards 5-aryl/heteroaryl-ethynyl-pyrazolo[1 ,5- a]pyrimidine-2-carboxylic acid amides of Formula Ia1
[00106] δ-Nitro^H-pyrazole-S-carboxylic acid (7) is treated with thionyl chloride in methanol to yield 5-nitro-2H-pyrazole-3-carboxylic acid methyl ester which is then hydrogenated to yield 5-amino-2H-pyrazole-3-carboxylic acid methyl ester (8). Compound 8 is treated with methyl propiolate (9) and heated to reflux for 24 hours to yield 5-oxo-4,5-dihydro-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid methyl ester (10). Compound 10 is treated with phosphoryl bromide to yield 5-bromo-4,5-dihydro- pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid methyl ester (11) which is coupled with an aryl/heteroaryl-acetylene to yield a 5-aryl/heteroaryl-ethynyl-pyrazolo[1 ,5-a]pyrimidine- 2-carboxylic acid methyl ester (13). Basic hydrolysis of compound 13 yields a 5- aryl/heteroaryl-ethynyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid (14) which is reacted with a secondary amine (15) in the presence of a condensation agent (e.g., O- (benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) or N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide (EDC)) to yield a 5-aryl/heteroaryl-ethynyl- pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid amide of Formula Ia'.
Figure imgf000057_0001
Scheme 3: General procedure towards 5-(3-aryl/heteroaryl-prop-2-ynyloxy)- pyrazolo[1 ,5-a]pyrimidines of Formula Ic1
[00107] 5-aminopyrazole (16) is treated with methyl propiolate (9) to yield a 4H- pyrazolo[1 ,5-a]pyrimidin-5-one (17). Compound 17 is reacted with 3-aryl/heteroaryl- prop-2-yn-1 -ol (18), triphenyl phosphine, and diisopropyl azodicarboxylate (DIAD) to yield a 5-(3-aryl/heteroaryl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine of Formula Ic1.
Figure imgf000057_0002
Scheme 4: General procedure towards pyrazolo[1 ,5-a]pyrimidines of Formula Ic"
[00108] 3-butyn-1-ol (19) is treated with n-butyllithium followed by chlorotrimethylsilane to yield 4-trimethylsilanyl-but-3-yn-1-ol (20). Compound 20 is treated with n-butyllithium followed by p-toluenesulfonyl chloride to yield toluene-4- sulfonic acid 4-trimethylsilanyl-but-3-ynyl ester (21). Compound 21 is treated with lithium bromide to yield 4-bromobut-1-ynyl)trimethylsilane (22) which is added to magnesium in the presence of iodine and dibromoethane in a solvent such as THF to yield the grignard reagent (23). Intermediate 23 is added to a solution of ZnBr2 in a solvent such as THF to yield the 5-trimethylsilanyl-butyn-3-yl-zinc reagent (24). Intermediate 24 is added to 2-methyl-pyrazolo[1 ,5-a]pyrimidin-5-yl trifluoro- methanesulfonic acid ester 27 (which is formed via reaction of an aminopyrazole (25) with methyl propiolate (9) to yield a 2-methyl-pyrazolo[1 ,5-a]pyrimidin-5-ol (26) which is then treated with trifluoromethanesulfonic anhydride) to yield a 5-(4-trimethylsilanyl-but- 3-ynyl)-pyrazolo[1 ,5-a]pyrimidine (28). Compound 28 is then reacted with an aryl/heteroaryl halide to yield a pyrazolo[1 ,5-a]pyrimidine derivative of Formula Ic".
Figure imgf000058_0001
Scheme 5: General procedure towards pyrazolo[1 ,5-a]pyrimidines of Formula Ic1"
[00109] δ-Amino-I H-pyrazole^-carboxylic acid ethyl ester (29) is treated with methyl propiolate (9) to yield intermediate 30 which is treated with sodium hydride to yield 5-oxo-4,5-dihydro-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid ethyl ester (31). Compound 31 is reacted with phosphorous oxychloride to yield 5-chloro-pyrazolo[1 ,5- a]pyrimidine-3-carboxylic acid ethyl ester (32). Compound 32 is then coupled with an aryl/heteroaryl boronic acid (33) to yield a 5-aryl/heteroaryl-pyrazolo[1 ,5-a]pyrimidine (34). lodination of compound 34 yields an iodo intermediate (35). Compound 35 is then coupled with an aryl/heteroarylacetylene (12) to yield compound 36, which is subjected to hydrolysis followed by decarboxylation to yield a pyrazolo[1 ,5-a]pyrimidine of Formula Ic.
Figure imgf000059_0001
Figure imgf000059_0002
Scheme 6: General procedure towards amino substituted pyrazolo[1 ,5-a]pyrimidines of Formula Ic11"
[00110] δ-Bromo-thiophen^-carboxylic acid (38) is treated with carbonyldiimidazole followed by monomethyl monopotassium malonate (39) to yield 3- (5-bromo-thiophen-2-yl)-3-oxo-propionic acid methyl ester (40). Compound 40 is then reacted with 5-aminopyrazole derivative 16 to yield a 5-(5-bromo-thiophen-2-yl)-4H- pyrazolo[1 ,5-a] pyrimidin-7-one (41). Treatment of compound 41 with phosphorous oxychloride yields a 5-(5-bromo-thiophen-2-yl)-7-chloro-pyrazolo[1 ,5-a]pyrimidine (42) which is treated with an amine (43) to yield amino substituted derivative 44. Compound 44 is coupled with an aryl/heteroarylacetylene to yield an amino substituted pyrazolo[1 ,5-a]pyrimidine of Formula Ic.
Figure imgf000060_0001
Scheme 7: General procedure towards 5-(3-aryl/heteroaryl-prop-1-ynyl)-pyrazolo[1 ,5- a]pyrimidines of Formula Ib1 and 5-(3-aryl/heteroaryl-prop-2-ynyl)-pyrazolo[1 ,5- a]pyrimidines of Formula Ic1""
[00111] Compound 45 (which is synthesized via reaction of 5-chloro-pyrazolo[1 ,5- a]pyrimidine (1) and Tl PS-acetylene followed by deprotection of the triple bond with sodium borofluoride) is alkylated with an aryl/heteroaryl-alkyl bromide (47) to yield a 5- (3-aryl/heteoraryl-prop-1-ynyl)-pyrazolo[1 ,5-a]pyrimidine of Formula Ib'. Alternatively, compound 1 is coupled with a prop-2-ynyl-arene/heteroarene (48) to yield a 5-(3-aryl- prop-1-ynyl)-pyrazolo[1 ,5-a]pyrimidine of Formula Ib1.
[00112] Treatment of 5-chloro-pyrazolo[1 ,5-a]pyrimidine (1) with vinyltributylstannane provides a vinyl derivative (46). Ozonolysis-reduction (O3ZNaBH4), and treatment of the alcohol intermediate with CBr4ZPPh3 yields 5- bromomethyl-pyrazolo[1 ,5-a]pyrimidine (49) which is treated with an arylZheteroaryl- acetylene (12) to yield a 5-(3-arylZheteroaryl-prop-2-ynyl)-pyrazolo[1 ,5-a]pyrimidine of Formula Ic'"". Alternatively, compound 49 is reacted with lithium trimethylsilylacetylide to yield, after cleavage of the TMS group, 5-prop-2-ynyl-pyrazolo[1 ,5-a]pyrimidine (50). Treatment of compound 50 with an arylZheteroaryl halide (2) yields a 5-(3- arylZheteroaryl-prop-2-ynyl)-pyrazolo[1 ,5-a]pyrimidine of Formula Ic
[00113] It will be appreciated that in the above transformations it may be necessary or desirable to protect any sensitive groups in the molecule of the compound in question in order to avoid undesirable side reactions.
[00114] 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.
[00115] Pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric form of appropriate starting materials, provided that the reaction occur stereoselective^. Stereoisomeric forms of Formula I are included within the scope of this invention. [00116] 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
[00117] 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
[00118] 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, c 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.
[00119] 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.
[00120] 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
[00121] 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.
[00122] 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.
[00123] 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.
[00124] 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.gf., each - once or twice daily), including within an hour of each other, and including simultaneously.
[00125] 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.
[00126] 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.
[00127] 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 non-toxic, pharmaceutically acceptable inert carriers (e.g., ethanol, glycerol, water), suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid), and the like. Stabilizing agents such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) may also be added to stabilize the dosage forms.
[00128] 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.
[00129] 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.
[00130] 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 polyvinylpyrrolidone, 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.
[00131] 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.
[00132] 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.
[00133] 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).
[00134] 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. [00135] 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.
[00136] 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.
EXPERIMENTAL PART
[00137] 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.
[00138] Hereinafter, "DMF" is defined as N.N-dimethylformamide, "THF" as tetrahydrofurane, "HCI" as hydrochloric acid, "NaOH" as sodium hydroxide, "MeOH" as methanol, "DMSO" as dimethylsulfoxide and "TBTU" as O-(benzotriazol-i-yl)- N.N.N'.N'-tetramethyluronium tetrafluoroborate. General Procedure 1 - Preparation of aryltrimethylsilylacetylenes
[00139] Trimethylsilylacetylene (0.48 ml, 3.39 mmol, 1 Eq), aryl iodide (or bromide or phenol trifluoromethanesulfonate) (3.39 mmol, 1 Eq), PdCI2(PPh3)2 (0.0476 g, 0.07 mmol, 2 mol %) are placed in the flask containing 10.00 ml_ of freshly distilled Et3N. The resulting mixture is stirred for 5 min at room temperature, then copper (I) iodide (0.0065 g, 0.03 mmol, 1 mol %) is added and the flask is flushed with argon and sealed. The reaction mixture is stirred for 10 h at room temperature, then precipitate is filtered off, filtrate is evaporated in vacuo and the residue is partitioned between Et2O and water. The organic phase is washed with water and brine, then dried over anhydrous Na2SO4. Evaporation of the solvent and filtration through silica pad gives the product as a colored oil. Purity of the final product is established by GC. Yield >95% for aryl iodides, 80-90% for aryl bromides.
General Procedure 1
Figure imgf000069_0001
4H-Pyrazolo[1 ,5-a]pyrimidin-5-one (17a)
[00140] In anhydrous dioxane compound (16a) and methyl ester of acetylene carboxylic acid (1 equivalent) are dissolved. The mixture is refluxed for 24 h (TLC control). After cooling the formed precipitate is filtered off and recrystallized from ethyl acetate to give the title compound in moderate yield. The filtrate is concentrated under reduced pressure and the residue is purified by column chromatography to give additional product.
1H NMR (DMSO-de, 400 MHz) δ (ppm) 5.78 (d, 1 H), 5.91 (d, 1 H), 7.71 (d, 1 H), 8.41 (m,
1 H), 11.95 (s, 1 H). m/z (APCI+) 136 (M+H+) 5-Chloro-pyrazolo[1 ,5-a]pyrimidine (1 a)
[00141] A mixture of compound 17a and phosphorus oxychloride (3 equivalents) in anhydrous acetonitrile is refluxed for 3 h. The mixture is cooled to room temperature, poured into ice water and neutralized with potassium carbonate. The product is extracted with dichloromethane twice, washed with water, dried over sodium sulfate and evaporated to give the title compound in excellent yield. m/z (APCI+) 154 (M+H+).
Aryl/heteroaryl-trimethylsilylacetylenes (3)
[00142] Trimethylsilylacetylene, aryl/heteroaryl iodide (or bromide) (1 equivalent), PdCl2(PPh3)2 (2 mol %) are placed in the flask containing freshly distilled Et3N. The resulting mixture is stirred for 5 min at room temperature, then copper (I) iodide (1 mol %) is added and the flask is flushed with argon and sealed. The reaction mixture is stirred for 10 h at room temperature, then precipitate is filtered off, filtrate is evaporated in vacuo and the residue is partitioned between Et2O and water. The organic phase is washed with water and brine, then dried over anhydrous Na2SO4. Evaporation of the solvent and filtration through silica pad gives the product as a colored oil. Purity of the final product is established by GC. Yield >95% for aryl/heteraryl iodides, 80-90% for aryl/heteroaryl bromides.
5-Aryl/heteroaryl-ethynyl-pyrazolo[1 ,5-a]pyrimidines (51 )
[00143] Under a strong stream of argon, aryltrimethylsilylacetylene, 5-chloro- pyrazolo[1 ,5-a]pyrimidine (1 equivalent), PdCI2(PPh3J2 (5 mol %) and copper (I) iodide (5 mol %) are placed in a vial containing DMF. The mixture is flushed thoroughly with argon and Et3N (4 equivalents) is added through the septum. The reaction mixture is warmed to 60 0C and TBAF (1.1 equivalent) in DMF is added dropwise. The mixture is stirred at 60 0C for 3h, the solvent is evaporated and the residue is purified by flash column chromatography to give the desired product. Yields 20-60%. General Procedure 2
Figure imgf000071_0001
5-Nitro-2H-pyrazole-3-carboxylic acid methyl ester (7a)
[00144] Thionyl chloride (2 equivalents) is added to a solution of 5-nitro-2H- pyrazole-3-carboxylic acid in methanol at 00C. The reaction mixture is refluxed for 8 h (TLC control), then cooled and evaporated in vacuo. The residue is diluted with hexane. The formed white precipitate is filtered, washed with hexane and dried to give 5-nitro-2H-pyrazole-3-carboxylic acid methyl ester as hydrochloride in high yield. m/z (APCI+) 170 (M-H").
5-Amino-2H-pyrazole-3-carboxylic acid methyl ester (8)
[00145] δ-Nitro^H-pyrazole-S-carboxylic acid methyl ester hydrochloride is hydrogenated in methanol over 10% Pd/C at 5 atm H2 at room temperature for 4 h. Then the reaction mixture is filtered, the filtrate is evaporated to give 5-amino-2H- pyrazole-3-carboxylic acid methyl ester as hydrochloride in high yield. m/z (APCI+) 142 (M+H+).
5-Oxo-4,5-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester (10)
[00146] Methyl propiolate (1.1 equivalent) is added to a suspension of 5-amino-2H- pyrazole-3-carboxylic acid methyl ester hydrochloride in dioxane. The reaction mixture is refluxed for 24 h (TLC control), then is cooled and evaporated in vacuo. The residue is purified by column chromatography on silica gel (eluent: chloroform/methanol - 20:1 ) to obtain 5-oxo-4,5-dihydro-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid methyl ester. m/z (APCI+) 194 (M+H+).
5-Bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester (11)
[00147] Phosphoryl bromide (5 equivalents) is added to a suspension of 5-oxo-4,5- dihydro-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid methyl ester in dioxane. The reaction mixture is refluxed for 4 h, then is cooled to room temperature and poured in ice water. The aqueous solution is neutralized with potassium carbonate. The formed precipitate is filtered off, washed with water and dried at 500C to obtain 5-bromo- pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid methyl ester.
1H NMR (DMSO-d6> 400 MHz), δ, ppm: 3.88 (3H, s), 7.16 (1 H, s), 7.39 (1 H1 d), 9.11
(1 H, d). m/z (APCI+) 256 (M+H+).
5-Aryl/heteroaryl-ethynyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester (13)
[00148] A mixture of 5-bromo-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid methyl ester, bis(triphenylphosphine)palladium(ll) dichloride (5 mol %), copper (I) iodide (10 mol %), aryl/heteroaryl-acetylene (2 equivalents) and triethylamine is refluxed under argon atmosphere for 4 h, then is cooled and evaporated in vacuo. The residue is purified by column chromatography on silica gel (eluent: hexane-ethyl acetate 1 :1 ) to obtain 5-aryl/heteroaryl-ethynyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid methyl ester in good yield. m/z (APCI+) 278 (M+H+).
5-Aryl/heteroaryl-ethynyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (14)
[00149] A mixture of 5-arylethynyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid methyl ester, sodium hydroxide (2 equivalents), water and methanol is stirred at 50°C for 2 h, then is evaporated in vacuo. After that water is added to the residue, the mixture is acidified with acetic acid to pH 6. The resulting precipitate is filtered off, washed with water and dried at 500C to obtain the 5-aryl/heteroaryl-ethynyl- pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid in excellent yields. S-Aryl/heteroaryl-ethynyl^.S-dihydro-pyrazoloII.S-alpyrimidine^-carboxylic acid amides (52)
[00150] A mixture of 5-aryl/heteroaryl-ethynyl-pyrazolo[1 ,5-a]pyrimidine-2- carboxylic acid (0.08 g, 0.3 mmol), secondary amine (1.4 equivalents), TBTU (1.6 equivalents) and Et3N (1.6 equivalents) in DMF is stirred at 50°C for 8h (TLC control). Then the reaction mixture was diluted with water, the resulting precipitate is filtered out and purified by TLC (eluent chloroform-ethyl acetate 5:1 ) to give the title compound in good yield.
General Procedure 3
Figure imgf000073_0001
2-Methyl-4-pyrazolo[1 ,5-a]pyrimidin-5-yl-but-3-yn-2-ol (5a)
[00151] Compound 1a, 2-methyl-but-3-yn-2-ol (1.5 equivalents), Pd CI2[PPh3]2 (5 mol %) and CuI (10 mol %) in diethyl amine is refluxed under argon for 2 h (TLC control), then cooled and evaporated to dryness. The residue is dissolved in dichloromethane; the target product is isolated by column chromatography (silica gel, ethyl acetate - hexane, 1 :2). The solvent is evaporated under reduced pressure; the residue is crystallized from diethyl ether to give the title compound in good yield.
1H NMR (DMSO-d6, 400 MHz) δ (ppm), 1.51 (s, 6H), 6.69 (s, 1 H), 6.98 (d, 1 H), 8.22 (s.
1 H)1 9.06 (d, 1 H). m/z (APCI+) 202 (M+H+). 5-Ethynyl-pyrazolo[1 ,5-a]pyrimidine (6a)
[00152] Compound 5a (1.7 g, 8.4 mmol) is dissolved in toluene, then 60% sodium hydride in mineral oil (1 equivalent) is added in small portions under stirring and the mixture is heated at 110 0C for 2 h (TLC control). The reaction mixture is cooled and poured into water. The organic phase is separated; the aqueous phase is extracted with ethyl acetate twice. The combined organic phases are dried over sodium sulfate and evaporated in vacuo. The resulting reaction crude was subjected to column chromatography (silica gel, ethyl acetate - hexane 1 :3) to obtain the title compound in good yield.
1H NMR (DMSO-de, 400 MHz) δ (ppm), 4361 (s, 1 H), 6.72 (s, 1 H), 7.08 (d, 1 H), 8.26 (S1 1 H), 9.11 (d, 1 H). m/z (APCI+) 144 (M+H+).
5-Aryl/heteroaryl-ethynyl-pyrazolo[1 ,5-a]pyrimidines (53)
[00153] Compound 6a (0.143 g, 1 mmol), bromoaryl/heteroaryl or iodoaryl/heteroaryl (1.5 equivalents), Pd CI2[PPh3J2 (5 mol %) and CuI (10 mol %) in triethylamine are refluxed under argon for 8 h (TLC control) then evaporated to dryness. The resulting reaction crude is dissolved in dichloromethane; the target product is isolated by column chromatography (silica gel, ethyl acetate - hexane, 1 :5). The solvent is evaporated under reduced pressure; the residue is crystallized from diethyl ether or ethyl acetate - hexane to give the title compound.
General Procedure 4
Figure imgf000074_0001
5-(3-Aryl/heteroaryl-prop-2-ynyloxy)-pyrazolo[1,5-a]pyrimidines (54)
[00154] A mixture of 4H-Pyrazolo[1 ,5-a]pyrimidin-5-one (0.203 g, 1.5 mmol), 3- aryl/heteroaryl-prop-2-yn-1-ol (1.5 equivalents), P(Ph)3 (2 equivalents) in anhydrous THF was stirred at room temperature for 15 min. Then 2 equivalents of diisopropyl azodicarboxylate (DIAD) was added dropwise and the mixture was stirred at room temperature for 2 h. Control by TLC (eluent: EA/hexane 1 :1 ). After evaporation of solvent the crude residue was purified by column chromatography (eluent: hexane/ethylacetate 1 :1) to give the final compounds.
General Procedure 5
Figure imgf000075_0001
4-Trimethylsilanyl-but-3-yn-1 -ol (20)
[00155] To a solution of 3-butyn-1-ol in THF at -78°C 2.5N n-BuLi in hexane (2 equivalents) is added. After 1 h at -78°C, the reaction mixture is treated with chlorotrimethylsilane (2 equivalents) and the resulting mixture is warmed to room temperature over 2h. The reaction mixture is quenched with water, extracted with Et2O, and concentrated. The concentrate is treated with HCI 3N, extracted with Et2O, washed with saturated aqueous NaHCO3 and NaCI, dried with Na2SO4, and concentrated. The crude product is used in the next step without further purification.
Toluene-4-sulfonic acid 4-trimethylsilanyl-but-3-ynyl ester (21)
[00156] Crude 4-Trimethylsilanyl-but-3-yn-1-ol is dissolved in THF1 the solution is cooled to -78°C before the addition of 2.5N n-BuLi in hexane. After 1 h at -78°C p- toluenesulfonyl chloride in THF solution is added. The reaction mixture is stirred over night at room temperature. The reaction mixture is treated with water, followed by extraction with ether, washing with saturated aqueous NaHCθ3, with NaCI, dried with Na2SU4 and concentrated. The crude product is used in the next step without further purification.
4-Bromobut-1-ynyl)trimethylsilane (22)
[00157] Crude toluene-4-sulfonic acid 4-trimethylsilanyl-but-3-ynyl ester is dissolved in dry acetone containing LiBr and the reaction mixture is stirred at room temperature for 5h. The reaction mixture is poured into water, extracted with ethylacetate, the organic layer is washed with brine, dried over Na2SO4, concentrated and distilled under reduced pressure (75-80°C/20Torr) to give 4-bromobut-1- ynyl)trimethylsilane as a colorless oil.
1H-NMR (400 MHz1 CDCI3); δ (ppm): 0.11 (s, 9H)1 2.58 (t, J=7.1 Hz1 2H)1 4.09 (t, J=7.1
Hz1 2H)
5-Trimethylsilanyl-butyn-3-yl-zinc (24)
[00158] To a flame-dried two-necked flask, Mg turnings were added. The flask is gently heated with a heating gun while stirring for 2 minutes. A solution of iodine in THF followed by Br(CH2)2Br is added. A solution of 4-bromobut-1-ynyl)trimethylsilane in THF is slowly added via a syringe over 1 h. Short heating is done with a heating gun, generating a slightly yellow clear solution which is stirred at r.t. for 2 h. The Grignard solution is then transferred via a cannula needle to a flask containing a solution of ZnBr2 in THF at -10 0C. The white creamy suspension is stirred at 0 0C for 1 h. The crude product is used in the next step without further purification.
2-Methyl-pyrazolo[1 ,5-a]pyrimidin-5-ol (26a)
[00159] Methyl propiolate is added to a suspension of 5-methyl-2H-pyrazol-3- ylamine (1 equivalent) in 40 ml of anhydrous dioxane. The reaction mixture is refluxed for 10h. Then reaction mixture is allowed to cool to room temperature. Precipitated solids are filtered off, washed with EtOAc. After drying, the title compound is obtained as white solid.
1H-NMR (400 MHz1 DMSO-d6); δ (ppm): 2.19 (s, 3H)1 5.63 (s, 1 H)1 5.79 (d, J=7.8 Hz,
1 H), 8.28 (d, J=7.8 Hz, 1 H), 11.81 (s, 1 H). m/z (APCI+) 150 (M+H+)
Trifluoro-methanesulfonic acid 2-methyl-pyrazolo[1,5-a]pyrimidin-5-yl ester (27a)
[00160] Trifluoromethanesulfonic anhydride is added to solution of 2-methyl- pyrazolo[1 ,5-a]pyrimidin-5-ol (1 equivalent) in anhydrous DCM and DIPEA (1.3 equivalents) under an argon atmosphere at -780C. The reaction mixture is stirred at - 78°C for 5 minutes, then at room temperature for 30 min. The reaction is evaporated under reduced pressure to afford an oil which is purified by was flash chromatography on silica (1 :3 ethyl acetate/hexanes as eluent) to give the title compound as a light- brown solid in high yield.
1H-NMR (400 MHz, CDCI3); δ (ppm): 2.52 (s, 3H), 6.38 (s, 1 H), 6.78 (d, J=7.1 Hz, 1 H),
8.45(d, J=7.1 Hz, 1 H). m/z (APCI+) 282 (M+H+), 323 (M+CH3CN+H+).
2-Methyl-5-(4-trimethylsilanyl-but-3-ynyl)-pyrazolo[1,5-a]pyrimidine (28a)
[00161] To a solution of trifluoro-methanesulfonic acid 2-methyl-pyrazolo[1 ,5- a]pyrimidin-5-yl ester in dry THF and PdCI2(dppf) (3,8 mol%) at -200C under an argon atmosphere, zinc reagent 5-trimethylsilanyl-butyn-3-yl-zinc is added; the reaction mixture is stirred at -200C for 30 minutes, then at r.t. for 5h; diluted with water, extracted with ethylacetate, the organic layer is washed with brine, dried over Na2SO4, and concentrated. The desired compound is obtained after chromatography on silica (1 :1ethyl acetate/hexanes as eluent).
1H-NMR (400 MHz, CDCI3); δ (ppm): 0.11 (s, 9H), 2.48 (s, 3H), 2.68 (t, J=4.3 Hz, 2H), 2.99 (t, J=4.3 Hz, 2H), 6.34 (s, 1 H), 6.63 (d, J=7.1 Hz, 1 H), 8.42 (d, J=7.1 Hz, 1 H). m/z (APCI+) 258 (M+H+)
Pyrazolo[1,5-a]pyrimidines (55)
[00162] To a solution of 2-methyl-5-(4-trimethylsilanyl-but-3-ynyl)-pyrazolo[1 ,5- a]pyrimidine in dry acetonitrile 1 M TBAF (2 equivalents) is added and then after 5 min DABCO (3 equivalents), Pd(OAc)2 (15 mol%) and aryl/heteroaryl-iodine (1.5 equivalents) are added. The reaction mixture is stirred at r.t. for 1h under argon, then evaporated to dryness and the residue is purified by column chromatography (silica gel, eluent: ethyl acetate/hexane-1 :1 ) to afford the target compound. General Procedure 6
Figure imgf000078_0001
5-Oxo-4,5-dihydro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (31)
[00163] A mixture of δ-amino-I H-pyrazole^-carboxylic acid ethyl ester, propynoic acid methyl ester (1.2 equivalents) and dioxane is refluxed for 24 h. The mixture is cooled to 2O0C and NaH (1.5 equivalents) is added. Reaction mixture is stirred at room temperature for 24 h (LCMS control). After evaporation of dioxane the residue is dissolved in water and AcOH is added till pH 5. The resulting white precipitate is filtered and washed with water, to give the title compound. m/z 207.74 (M+H+)
1H NMR (DMSO-de, 400 MHz ), δ (ppm): 1.4 (t, 3H); 4.35 (quart, 2H); 6.15 (d, 1 H); 8.0
(s, 1 H); 8.2 (d, 1 H). 5-Chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (32)
[00164] A mixture of 5-oxo-4,δ-dihydro-pyrazolo[1 ,δ-a]pyrimidine-3-carboxylic acid ethyl ester and phosphorus oxychloride (4.5 equivalents) in anhydrous acetonitrile is refluxed for 3 h. The mixture is cooled to 2O0C and evaporated under reduced pressure. Ice water is added, the resulting precipitate is filtered and washed with 5% sodium carbonate solution and water. The precipitate is dried at 2O0C, to afford the title compound. m/z 225.8 (M+H+)
1H NMR (DMSO-de, 400 MHz ), δ (ppm): 1.3 (t, 3H); 4.3 (quart, 2H); 7.35 (d, 1 H); 8.6 (s,
1 H); 9.25 (d, 1 H).
5-Thiophen-2-yl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (34a)
[00165] A mixture of δ-Chloro-pyrazolo[1 ,δ-a]pyrimidine-3-carboxylic acid ethyl ester, thiophen-2-boronic acid (1.3 equivalents), PdCI2[P(Ph)3J2 (10 mol%), 1 M Na2CO3 (1.5 equivalents) in acetonitrile is refluxed for 4 h. After cooling the solvent is evaporated under reduced pressure, the residue is diluted with DCM and washed with water. Organic phase is dried over sodium sulfate and evaporated under reduced pressure. The crude product is purified by column chromatography (eluent: DCM/ethanol δθ:1 ) to give the title compound. m/z 273.83 (M+H+)
1H NMR (DMSO-de, 400 MHz ), δ (ppm): 1.35 (t, 3H); 4.3 (quart, 2H); 7.25 (t, 1 H); 7.7δ
(d, 1 H); 7.88 (d, 1 H), 8.1 (s, 1 H); 8.δ2 (s, 1 H); 9.18 (d, 1 H).
5-(5-lodo-thiophen-2-yl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (35a)
[00166] To a solution of δ-Thiophen-2-yl-pyrazolo[1 ,δ-a]pyrimidine-3-carboxylic acid ethyl ester (1.9δ g, 7.14 mmol) in DCM, iodine (0.5 equivalents) is added, then 6M HNO3 is added dropwise. The mixture is refluxed for 5 h until the disappearance of peak of starting compound in LCMS-spectrum. The mixture is diluted with DCM and washed with 10% solution of Na2S2O3, then water. The organic phase is dried over Na2SO4 and evaporated under reduced pressure, to give the title compound as yellow- brown powder, m/z 399.7 (M+H+) 1H NMR (DMSO-de, 400 MHz ), δ (ppm): 1.35 (t, 3H); 4.35 (quart, 2H); 7.45 (d, 1 H); 7.7 (d, 1 H); 7.8 (d, 1 H), 8.5 (s, 1 H); 9.2 (d, 1 H).
S^Aryl/heteroaryl-ethynyl-thiophen^-yO-pyrazololi.S-alpyrimidine-S-carboxylic acid ethyl ester (36a)
[00167] A mixture of aryl/heteroaryl-acetylene (3 equivalents), 5-(5-iodo-thiophen- 2-yl)-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid ethyl ester, DABCO (3 equivalents), acetonitrile, Pd(OAc)2 (5 mol%) is stirred under argon at room temperature for 24 h until complete disapperance of peak of 5-(5-iodo-thiophen-2-yl)-pyrazolo[1 ,5- a]pyrimidine-3-carboxylic acid ethyl ester in LCMS-spectrum. The mixture is evaporated, diluted with DCM, washed with 5% citric acid and water. The organic phase is dried over Na2SO^ After evaporation the residue is purified by column chromatography (eluent: hexane/ethylacetate 1 :1 ) to give the title compound.
S-tS-Aryl/heteroaryl-ethynyl-thiophen^-ylJ-pyrazoloII.S-alpyrimidine-S-carboxylic acid (37a)
[00168] A mixture of 5-(aryl/heteroaryl-ethynyl-thiophen-2-yl)-pyrazolo[1 ,5- a]pyrimidine-3-carboxylic acid ethyl ester, sodium hydroxide (4 equivalents) and ethanol is refluxed for 1 h (LCMS control). The mixture is cooled to 2O0C and AcOH is added. After evaporation to dryness the residue is diluted with water. The resulting precipitate is filtered to give the title compound.
5-(5-Aryl/heteroaryl-ethynyl-thiophen-2-yl)-pyrazolo[1,5-a]pyrimidines (56)
[00169] 5-(5-Aryl/heteroaryl-ethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidine-3- carboxylic acid is heated under argon at 280-3000C for 20 min (LCMS control). Crude product is purified by column chromatography to give the title compound. General Procedure 7
Figure imgf000081_0001
3-(5-Bromo-thiophen-2-yl)-3-oxo-propionic acid methyl ester (39)
[00170] Carbonyldiimidazole (9.7 g, 59.9 mmol) is added portion-wise to a suspension of δ-bromo-thiophen^-carboxylic acid (10.3, 49.8 mmol) in 75 ml of acetonitrile, and the reaction mixture is stirred at 200C for 1 h. To the formed solution, a mixture of monomethyl monopotassium malonate (8.91 g, 55 mmol) and MgCI2 anhydrous (5.22 g, 55 mmol) is added; the mixture is stirred at 2O0C for 18 h. Acetonitrile is evaporated under reduced pressure and water (100 ml) is added, the resulting suspension is acidified with 10% HCI to pH 4.5; the mixture is extracted with DCM (2x200 ml). The organic phase is washed with concentrated NaHCO3 solution (2x80 ml), water (100 ml), dried over Na2SO4. After evaporation of solvent 12.14 g (92.3%) of the title compound is obtained. 1H NMR (CDCI3, 400 MHz), δ (ppm): 3.75 (s, 3H); 3.85 (s, 2H); 7.1 (d, 1 H); 7.5 (d, 1 H).
5-(5-Bromo-thiophen-2-yl)-4H-pyrazolo [1,5-a] pyrimidin-7-one (41)
[00171] A mixture of 5-aminopyrazole (3.2 g, 38.5 mmol), 3-(5-bromo-thiophen-2- yl)-3-oxo-propionic acid methyl ester (46 mol) and acetic acid (30 ml) is refluxed for 5 h. After cooling to 2O0C, the resulting precipitate is filtered and washed with Et2O (3x15 ml) to yield 3.2 g (28%) of the title compound as a white solid. m/z 297,8 (M+H+)
1H NMR (DMSO-d6, 400 MHz ), δ (ppm): 5.9 (s, 1 H); 6.2 (s, 1 H); 7.4 (s, 1 H); 7.65 (s,
1 H); 7.9 (s, 1 H); 12.5 (s, 1 H). 5-(5-Bromo-thiophen-2-yl)-7-chloro-pyrazolo [1,5-a] pyrimidine (42)
[00172] A mixture of 5-(5-Bromo-thiophen-2-yl)-4H-pyrazolo [1 ,5-a] pyrimidin-7- one (0.3 g, 1.01 mmol), phosphorus oxychloride ( 2.83 g, 18.6 mmol) and acetonitrile (5 ml) is refluxed for 4 h (control by LCMS). The resulting solution is evaporated under reduced pressure, and then ice water (10 ml) is added to the residue. The resulting precipitate is filtered and washed with 5% solution of sodium carbonate (10-15 ml), water (10 ml), then dried at 2O0C to give 0.29 g (91%) of the title compound. m/z 316.07 (M+H+)
1H NMR (DMSO-de, 400 MHz ), δ (ppm): 6.8 (s, 1 H); 7.3 (d, 1 H); 7.9 (d, 1 H); 7.98 (s,
1 H); 8.28 (s, 1 H).
[5-(5-Bromo-thiophen-2-yl)-pyrazolo [1,5-a] pyrimidin-7yl] tert-butylamine (44a)
[00173] A mixture of 5-(5-Bromo-thiophen-2-yl)-7-chloro-pyrazolo [1 ,5-a] pyrimidine (0.315 g, 1 mmol), acetonitrile (10 ml), tert-butylamine (0.44 g, 5.95 mmol), Et3N (0.2 g, 1.98 mmol) is refluxed in a sealed tube for 16 h. Control by LCMS. After evaporation of solvent, the residue is dissolved in DCM (50 ml), washed with water (2x15 ml), and dried over Na2SO-J. DCM is evaporated and the residue is triturated with hexane, the resulting precipitate is filtered to afford 0.28 g (80%) of the title compound. m/z 352.16 (M+H+)
1H NMR (DMSO-de, 400 MHz ), δ (ppm): 1.55 (s, 9H); 6.42 (s,1 H); 6.6(s,1 H); 6.8(s,1 H);
7.25 (s, 1 H); 7.85 (s, 1 H); 8.05 (s, 1 H).
tert-Butyl-[5-(5-aryl/heteroaryl-2-ylethynyl-thiophen-2-yl)-pyrazolo [1 ,5-a] pyrimidin-7-yl]-amines (57)
[00174] A mixture of [5-(5-Bromo-thiophen-2-yl)-pyrazolo [1 ,5-a] pyrimidin-7yl] tert- butylamine (0.15 g, 0.426 mmol), 2-aryl/heteroaryl-acetylene (2 equivalents), terakis (triphenylphosphine)palladium Pd[P(Ph)3]4 (5 mol%), CuI (5 mol%), pyrrolidine and dioxane is heated at 6O0C under argon for 12 h. (LCMS-control). After cooling, the solvent is evaporated under reduced pressure. The residue is diluted with DCM and washed with water. The organic phase is dried over Na2SO4. The solvent is evaporated and the residue is purified by column chromatography. Eluent: hexane/ethylacetate 2:1 to afford the title compounds in good to moderate yields. General Procedure 8
Figure imgf000083_0001
5-(3-Aryl-prop-1 -ynyl)-pyrazolo[1 ,5-a]pyrimidines (58)
[00175] 5-(3-Aryl-prop-1-ynyl)-pyrazolo[1 ,5-a]pyrimidines (58) are prepared by alkylation of 5-ethynyl-pyrazolo[1 ,5-a]pyrimidine (45a) with benzylbromides in the presence of base, such as n-BuLi, NaH or K2CO3. Alternatively, 5-(3-aryl-prop-1-ynyl)- pyrazolo[1 ,5-a]pyrimidines (58) are prepared by Sonigashira coupling of 5-chloro- pyrazolo[1 ,5-a]pyrimidine (1b) with prop-2-ynyl-arenes (48a) in the presence of Et3N, CuI and PdCI2[PPh3J4.
General Procedure 9
Figure imgf000083_0002
5-(3-Aryl-prop-2-ynyl)-pyrazolo[1 ,5-a]pyrimidines (59)
[00176] 5-(3-Aryl-prop-2-ynyl)-pyrazolo[1 ,5-a]pyrimidines (59) are prepared by alkylation of arylacetylenes with 5-bromomethyl-pyrazolo[1 ,5-a]pyrimidine (49a) in the presence of base, such as n-BuLi, NaH or K2CO3. 5-Bromomethyl-pyrazolo[1 ,5- a]pyrimidine (49a) is prepared from 5-chloro-pyrazolo[1 ,5-a]pyrimidine (1b) via a 3-step sequence consisting of Suzuki coupling with vinyltributylstannane to provide a vinyl derivative (46a), ozonolysis-reduction (03/NaBhU)1 and conversion of the intermediate alcohol to an alkyl bromide (CBr4/PPh3). Alternatively, 5-bromomethyl-pyrazolo[1 ,5- a]pyrimidine (49a) is reacted with lithium trimethylsilylacetylide to give, after cleavage of the TMS group, 5-prop-2-ynyl-pyrazolo[1 ,5-a]pyrimidine (50a). Sonigashira coupling of the compound 50a with an arylhalide provides a 5-(3-aryl-prop-2-ynyl)-pyrazolo[1 ,5- a]pyrimidine (59).
Example 1 3-Pyrazolo[1,5-a]pyrimidin-5-ylethynyl-benzonitrile
[00177] According to General Procedure 1 , 3-[(trimethylsilyl)ethynyl]benzonitrile is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield.
1H NMR (CDCI3, TMS) δ: 6.76, 6.98, 7.53, 7.72, 7.88, 8.19, 8.69.
LC/MS: (M+H)= 245
Example 2 3-Pyrazolo[1,5-a]pyrimidin-5-ylethynyl-phenylamine
[00178] According to General Procedure 1 , 3-[(trimethylsilyl)ethynyl]aniline is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield.
1H NMR (CDCI3, TMS) δ: 3.75, 6.74, 6.94, 7.03, 7.17, 8.14, 8.63
LC/MS: (M+H)= 235 Example 3 N-(3-Pyrazolo[1,5-a]pyrimidin-5-ylethynyl-phenyl)-acetamide
[00179] To a solution of 3-pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-phenylamine (example 2), (50 mg, 0,21 mmol) in pyridine (1 ml_) is added acetic anhydride (0.30 mmol) and the mixture is stirred at room temperature overnight. The mixture is diluted with water (5 ml_), and extracted with ethyl acetate. The organic layer is dried over anhydrous Na2SO4 and evaporated in vacuo. Purification of the residue by flash column chromatography provides the title compound as a colorless solid.
1H NMR (CDCI3, TMS) δ: 2.21 , 6.72, 6.97, 7.37, 7.52, 7.83, 8.15, 8.65
LC/MS: (M+H)= 277
Example 4 5-(3-Methoxy-phenylethynyl)-pyrazolo[1,5-a]pyrimidine
[00180] According to General Procedure 1 , 3-
[(methoxyphenyl)ethynyl]trimethylsilane is reacted with 5-chloro-pyrazolo[1 ,5- a]pyrimidine to provide the title compound in good yield.
1H NMR (CDCI3, TMS) δ: 3.83, 6.71 , 6.97, 7.22, 7.32, 8.16, 8.65
LC/MS: (M+H)= 250
Example 5 3-Pyrazolo[1,5-a]pyrimidin-5-ylethynyl-benzaldehyde
[00181] According to General Procedure 1 , 3-[(trimethylsilyl)ethynyl]benzaldehyde is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield.
1H NMR (CDCI3, TMS) δ: 6.75, 6.99, 7.59, 7.92, 8.16, 8.68, 10.04
LC/MS: (M+H)= 248
Example 6 5-(3-Bromo-5-fluoro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine [00182] According to General Procedure 1 , [(3-bromo-5- fluorophenyl)ethynyl]trimethylsilane is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield.
1H NMR (CDCI3, TMS) δ: 6.75, 6.96, 7.32, 7.58, 8.18, 8.67.
LC/MS: (M+H)= 317
Example 7 5-(3-Fluoro-5-pyridin-3-yl-phenylethynyl)-pyrazolo[1,5-a]pyrimidine
[00183] A solution of 5-(3-bromo-5-fluoro-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine (Example 6), (40 mg, 0.13 mmol), 3-pyridineboronic acid (0.15 mmol), Pd[PPh3J4 (0.01 mmol) and potassium carbonate (0.20 mmol) in 1 mL dioxane and 0.1 ml_ water is heated by microwaves at 2000C for 15 min. The mixture is diluted with water (5 ml_), and extracted with ethyl acetate. The organic layer is dried over anhydrous Na2SO4 and evaporated in vacuo. Purification of the residue by flash column chromatography provides the title compound as a colorless solid.
1H NMR (CDCI3, TMS) δ: 6.76, 6.99, 7.36, 7.42, 7.66, 7.88, 8.68, 8.85
LC/MS: (M+H)= 315
Example 8 5-(3-Fluoro-5-pyridin-4-yl-phenylethynyl)-pyrazolo[1,5-a]pyrimidine
[00184] A solution of 5-(3-bromo-5-fluoro-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine (Example 6), (40 mg, 0.13 mmol), 4-pyridineboronic acid (0.15 mmol), Pd[PPh3J4 (0.01 mmol) and potassium carbonate (0.20 mmol) in 1 mL dioxane and 0.1 mL water is heated by microwaves at 2000C for 15 min. The mixture is diluted with water (5 mL), and extracted with ethyl acetate. The organic layer is dried over anhydrous Na2SU4 and evaporated in vacuo. Purification of the residue by flash column chromatography provides the title compound as a colorless solid.
1H NMR (CDCI3, TMS) δ: 6.75, 6.99, 7.40, 7.49, 7.71 , 8.19, 8.70
LC/MS: (M+H)= 315 Example 9 5-(4-Fluoro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine
[00185] According to General Procedure 1 , [(4-fluorophenyl)ethynyl]trimethylsilane is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield.
1H NMR (DMSO-dβ, 400 MHz) δ: 6.76, 7.19, 7.34, 7.75), 8.27, 9.13
LC/MS: (M+H)= 238
Example 10 5-Phenylethynyl-pyrazolo[1,5-a]pyrimidine
[00186] According to General Procedure 1 , 1-phenyl-2-trimethylsilylacetylene is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield.
1H NMR (DMSO-d6, 400 MHz) δ: 6.75, 7.18, 7.30, 7.67, 8.27, 9.12
LC/MS: (M+H)= 220
Example 11 5-(4-Trifluoromethyl-phenylethynyl)-pyrazolo[1,5-a]pyrimidine
[00187] According to General Procedure 1 , [(4- trifluoromethylphenyl)ethynyl]trimethylsilane is reacted with 5-chloro-pyrazolo[1 ,5- a]pyrimidine to provide the title compound in good yield.
1H NMR (DMSO-de, 400 MHz) δ: 6.79, 7.23, 7.88, 8.31 , 9.17)
LC/MS: (M+H)= 288
Example 12 5-(4-Chloro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine
[00188] According to General Procedure 1 , [(4-chlorophenyl)ethynyl]trimethylsilane is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield. 1H NMR (DMSO-de, 400 MHz) δ: 6.77, 7.20, 7.55, 7.69, 8.27, 9.12 LC/MS: (M+H)= 254
Example 13 5-p-Tolylethynyl-pyrazolo[1 ,5-a]pyrimidine
[00189] According to General Procedure 1 , 4-[(trimethylsilyl)ethynyl]toluene is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield.
1H NMR (DMSO-de, 400 MHz) δ: 2.34, 6.74, 7.17, 7.31 , 7.56, 8.27, 9.12
LC/MS: (M+H)= 234
Example 14 5-(2-Fluoro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine
[00190] According to General Procedure 1 , [(2-fluorophenyl)ethynyl]trimethylsilane is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield.
1H NMR (DMSO-de, 400 MHz) δ: 6.78, 7.18 7.35, 7.58, 7.74, 8.28, 9.14
LC/MS: (M+H)= 238
Example 15 5-m-Tolylethynyl-pyrazolo[1,5-a]pyrimidine
[00191] According to General Procedure 1 , 3-[(trimethylsilyl)ethynyl]toluene is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield.
1H NMR (DMSO-de, 400 MHz) δ: 2.31 , 6.74, 7.15, 7.34, 7.46, 8.24, 9.11
LC/MS: (M+H)= 234
Example 16 5-o-Tolylethynyl-pyrazolo[1,5-a]pyrimidine [00192] According to General Procedure 1 , 2-[(trimethylsilyl)ethynyl]toluene is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield.
1H NMR (DMSO-de, 400 MHz) δ: 2.49, 6.77, 7.19, 7.30, 7.39, 7.62, 8.27, 9.12
LC/MS: (M+H)= 234
Example 17 5-(3-Fluoro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine
[00193] According to General Procedure 1 , [(3-fluorophenyl)ethynyl]trimethylsilane is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield.
1H NMR (DMSO-de, 400 MHz) δ: 6.76, 7.19, 7.36, 7.52, 8.26, 9.14
LC/MS: (M+H)= 238
Example 18 2-phenyl-5-phenylethynyl-pyrazolo[1,5-a]pyrimidine
[00194] According to General Procedure 1 , 1-phenyl-2-trimethylsilylacetylene is reacted with 5-chloro-2-phenyl-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield.
1H NMR (DMSO-de, 400 MHz) δ: 7.17, 7.23, 7.42-7.52, 7.66, 8.03, 9.12
LC/MS: (M+H)= 296
Example 19 5-(3-Trifluoromethyl-phenylethynyl)-pyrazolo[1,5-a]pyrimidine
[00195] According to General Procedure 1 , [(3- trifluoromethylphenyl)ethynyl]trimethylsilane is reacted with 5-chloro-pyrazolo[1 ,5- a]pyrimidine to provide the title compound in good yield.
1H NMR (DMSO-de, 400 MHz) δ: 6.79, 7.21 , 7.75, 7.87, 7.98, 8.09, 8.30, 9.17
LC/MS: (M+H)= 288 Example 20 5-(2-Trifluoromethyl-phenylethynyl)-pyrazolo[1,5-a]pyrimidine
[00196] According to General Procedure 1 , [(2- trifluoromethylphenyl)ethynyl]trimethylsilane is reacted with 5-chloro-pyrazolo[1 ,5- a]pyrimidine to provide the title compound in good yield.
1H NMR (DMSO-d6l 400 MHz) δ: 6.82, 7.15, 7.72, 7.80, 7.89, 7.95, 8.32, 9.16
LC/MS: (M+H)= 288
Example 21 5-(3-Chloro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine
[00197] According to General Procedure 1 , [(3-chlorophenyl)ethynyl]trimethylsilane is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield.
1H NMR (DMSO-d6) 400 MHz) δ: 6.78, 7.21 , 7.52, 7.58, 7.62, 7.77, 8.28, 9.15
LC/MS: (M+H)= 254
Example 22 5-(2-Chloro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine
[00198] According to General Procedure 1 , [(2-chlorophenyl)ethynyl]trimethylsilane is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield.
1H NMR (DMSO-de, 400 MHz) δ: 6.80, 7.20, 7.34, 7.46, 7.64, 7.80, 8.30, 9.15
LC/MS: (M+H)= 254
Example 23 5-Pyridin-2-ylethynyl-pyrazolo[1 ,5-a]pyrimidine
[00199] According to General Procedure 1 , 2-[(trimethylsilyl)ethynyl]pyridine is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield. 1H NMR (DMSO-Cl6, 400 MHz) δ: 6.81 , 7.24, 7.51 , 7.78, 7.92, 8.31 , 8.68, 9.17 LC/MS: (M+H)= 221
Example 24 5-Pyridin-3-ylethynyl-pyrazolo[1,5-a]pyrimidine
[00200] According to General Procedure 1 , 3-[(trimethylsilyl)ethynyl]pyridine is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield.
1H NMR (DMSO-de, 400 MHz) δ: 6.78, 7.23, 7.52, 8.08, 8.29, 8.68, 8.87, 9.16
LC/MS: (M+H)= 221
Example 25 5-Thiophen-3-ylethynyl-pyrazolo[1,5-a]pyrimidine
[00201] According to General Procedure 1 , 3-[(trimethylsilyl)ethynyl]thiophene is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield.
1H NMR (DMSO-d6l 400 MHz) δ: 6.74, 7.15, 7.37, 7.71 , 8.11 , 8.27, 9.11
LC/MS: (M+H)= 226
Example 26 2-Methyl-5-phenylethynyl-pyrazolo[1,5-a]pyrimidine
[00202] According to General Procedure 1 , 1-phenyl-2-trimethylsilylacetylene is reacted with 5-chloro-2-methyl-pyrazolo[1 ,5-a]pyrirnidine to provide the title compound in good yield.
1H NMR (DMSO-de, 400 MHz) δ: 2.42, 6.52, 7.09, 7.48, 7.17, 9.0
LC/MS: (M+H)= 234
Example 27 5-(6-Methyl-pyridin-2-ylethynyl)-pyrazolo[1,5-a]pyrimidine [00203] According to General Procedure 1 , 2-[(trimethylsilyl)ethynyl]-6- methylpyridine is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield.
1H NMR (DMSO-de, 400 MHz) δ: 6.79, 7.22, 7.37, 7.58, 7.78, 8.30
LC/MS: (M+H)= 235
Example 28
5-Phenylethynyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid
[00204] According to General Procedure 1 , i-phenyl-2-trimethylsilylacetylene is reacted with δ-bromo^.δ-dihydro-pyrazoloti .δ-ajpyrimidine^-carboxylic acid methyl ester and the ester is hydrolysed thereafter to provide the title compound in good yield.
1H NMR (DMSO-d6l 400 MHz), δ: 6.80-7.00, 7.15-7.30, 7.32-7.80, 9.10
LC/MS: (M+H)=264
Example 29 (5-Phenylethynyl-pyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl-methanone
[00205] According to General Procedure 2, 5-phenylethynyl-pyrazolo[1 ,5- a]pyrimidine-2-carboxylic acid is reacted with piperidine to provide the title compound in good yield.
1H NMR (DMSO-de, 400 MHz), δ: 1.46-1.73, 3.55-3.73, 6.92, 7.28, 7.46-7.58, 7.65-7.73,
9.15
LC/MS: (M+H)=331
Example 30 (5-Phenylethynyl-pyrazolo[1,5-a]pyrimidin-2-yl)-pyrrolidin-1-yl-methanone
[00206] According to General Procedure 2, 5-phenylethynyl-pyrazolo[1 ,5- a]pyrimidine-2-carboxylic acid is reacted with pyrrolidine to provide the title compound in good yield.
1H NMR (DMSO-de, 400 MHz), δ: 1.80-1.98, 4.46-4.63, 4,77-4.91 , 7.02, 7.29, 7.46-7.57,
7.68, 9.15 LC/MS: (M+H)=317
Example 31 5-(5-Fluoro-pyridin-2-ylethynyl)-pyrazolo[1,5-a]pyrimidine
[00207] According to General Procedure 1 , 2-[(trimethylsilyl)ethynyl]-5- fluoropyridine is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield.
1H NMR (DMSO-de, 400 MHz) δ: 6.79, 7.23, 7.87, 8.31 , 8.68, 9.18
LC/MS: (M+H)=239
Example 32
5-Phenylethynyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid diethylamide
[00208] According to General Procedure 2, 5-phenylethynyl-pyrazolo[1 ,5- a]pyrimidine-2-carboxylic acid is reacted with diethylamine to provide the title compound in good yield.
1H NMR (DMSO-de, 400 MHz), δ: 1.08-1.25, 3.40-3.60, 6.92, 7.27, 7.45-7.56, 7.68, 9.14
LC/MS: (M+H)=319
Example 33 Morpholin-4-yl-(5-phenylethynyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone
[00209] According to General Procedure 2, 5-phenylethynyl-pyrazolo[1 ,5- a]pyrimidine-2-carboxylic acid is reacted with morpholine to provide the title compound in good yield.
1H NMR (DMSO-d6, 400 MHz), δ: 4.50-4.90, 6.96, 7.28, 7.44-7.55, 7.67, 9.13
LC/MS: (M+H)=333
Example 34 5-Thiophen-2-ylethynyl-pyrazolo[1,5-a]pyrimidine [00210] According to General Procedure 1 , 2-[(trimethylsilyl)ethynyl]thiophene is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield.
1H NMR (DMSO-de, 400 MHz) δ: 6.74, 7.16-7.21 , 7.61 , 8.1 , 8.27, 9.12
LC/MS: (M+H)=226
Example 35
(2-Methyl-piperidin-1-yl)-(5-phenylethynyl-pyrazolo[1,5-a]pyrimidin-2-yl)- methanone
[00211] According to General Procedure 2, 5-phenylethynyl-pyrazolo[1 ,5- a]pyrimidine-2-carboxylic acid is reacted with 2-methyl piperidine to provide the title compound in good yield.
1H NMR (CDCI3, 400 MHz), δ: 1.30, 1.55-1.85, 2.80-3.30, 3.90-5.20, 6.90, 7.00, 7.35-
7.46, 7.59-7.66, 8.57
LC/MS: (M+H)=345
Example 36 5-(2,4-Dimethyl-thiazol-5-ylethynyl)-pyrazolo[1,5-a]pyrimidine
[00212] According to General Procedure 1 , 5-ethynyl-2,4-dimethyl-thiazole is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield.
1H NMR (DMSO-de, 400 MHz) δ: 2.66, 6.75, 7.19, 8.26, 9.11
LC/MS: (M+H)=255
Example 37 5-(2,3-Dihydro-benzofuran-5-ylethynyl)-pyrazolo[1,5-a]pyrimidine
[00213] According to General Procedure 1 , 2-bromo-benzofuran is reacted with 5- ethinyl-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield.
1H NMR (DMSO-de, 400 MHz) δ: 4.61 , 6.70, 6.85, 7.11 , 7.42, 7.52, 8.22, 9.08
LC/MS: (M+H)=262 Example 38
(4-Methyl-piperazin-1-yl)-(5-phenylethynyl-pyrazolo[1,5-a]pyrimidin-2-yl)- methanone
[00214] According to General Procedure 2, 5-phenylethynyl-pyrazolo[1 ,5- a]pyrimidine-2-carboxylic acid is reacted with 4-methyl piperazine to provide the title compound in good yield.
1H NMR (DMSO-d3, 400 MHz) δ: 2.21 , 2.22-2.46, 3.61-3.80, 6.94, 7.30, 7.47-7.56, 7.68,
9.16
LC/MS: (M+H)=346
Example 39
5-Phenylethynyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid isopropyl-methyl- amide
[00215] According to General Procedure 2, 5-phenylethynyl-pyrazolo[1 ,5- a]pyrimidine-2-carboxylic acid is reacted with isopropyl methyl amine to provide the title compound in good yield.
1H NMR (CDCI3, 400 MHz) δ: 1.22, 2.93-3.11 , 6.86-7.04, 7.30-7.47, 7.62, 8.58
LC/MS: (M+H)=319
Example 40 5-Benzofuran-2-ylethynyl-pyrazolo[1,5-a]pyrimidine
[00216] According to General Procedure 1 , 2-[(trimethylsilyl)ethynyl]benzofuran is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield.
1H NMR (DMSO-de, 400 MHz) δ: 6.78, 7.25, 7.34, 7.46, 7.59, 7.63, 7.73, 8.28, 9.16
LC/MS: (M+H)=260 Example 41
(2-Methyl-pyrrolidin-1-yl)-(5-phenylethynyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone
[00217] According to General Procedure 2, 5-phenylethynyl-pyrazolo[1 ,5- a]pyrimidine-2-carboxylic acid is reacted with 2-methyl pyrrolidine to provide the title compound in good yield.
1H NMR (CDCI3, 400 MHz) δ: 1.10-2.18, 3.52-4.05, 4.37-4.53, 6.98, 7.12, 7.30-7.50,
7.61 , 8.57
LC/MS: (M+H)=331
Example 42 5-Pyridin-4-ylethynyl-pyrazolo[1,5-a]pyrimidine
[00218] According to General Procedure 1 , 2-[(trimethylsilyl)ethynyl]pyridine is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield.
1H NMR (DMSO-de, 400 MHz) δ: 6.78, 7.21 , 7.60, 8.28, 8.67, 9.15
LC/MS: (M+H)=221
Example 43 5-(3-Methyl-thiophen-2-ylethynyl)-pyrazolo[1,5-a]pyrimidine
[00219] According to General Procedure 1 , 2-[(trimethylsilyl)ethynyl]-3-methyl- thiophene is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield.
1H NMR (DMSO-de, 400 MHz) δ: 2.47, 6.71 , 7.06, 7.15, 7.67, 8.21 , 9.09
LC/MS: (M+H)=240
Example 44
5-(1 -Methyl-1 H-imidazol-2-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine [00220] According to General Procedure 1 , 3-[(trimethylsilyl)ethynyl]-1-methyl- imidazole is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield.
1H NMR (DMSO-d6, 400 MHz) δ: 3.71 , 6.77, 7.08, 7.23, 7.79, 8.29, 9.14
LC/MS: (M+H)=224
Example 45 5-(1-Methyl-3H-imidazol-4-ylethynyl)-pyrazolo[1,5-a]pyrimidine
[00221] According to General Procedure 1 , 5-[(trimethylsilyl)ethynyl]-1-methyl- imidazole is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield.
1H NMR (DMSO-d6, 400 MHz) δ: 3.73, 6.72, 7.15, 7.51 , 7.86, 8.22, 9.10
LC/MS: (M+H)=224
Example 46
5-Phenylethynyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid dimethyl amide
[00222] According to General Procedure 2, 5-phenylethynyl-pyrazolo[1 ,5- a]pyrimidine-2-carboxylic acid is reacted with dimethylamine to provide the title compound in good yield.
1H NMR (CDCI3, 400 MHz) δ: 2.82-3.10, 3.72-3.93, 6.94-7.06, 7.35-7.47, 7.63, 8.58
LC/MS: (M+H)=291
Example 47 (5-Phenylethynyl-pyrazolo[1,5-a]pyrimidin-2-yl)-piperazin-1-yl-methanone
[00223] According to General Procedure 2, 5-phenylethynyl-pyrazolo[1 ,5- a]pyrimidine-2-carboxylic acid is reacted with piperazine to provide the title compound in good yield.
1H NMR (DMSO-de, 400 MHz) δ: 3.03, 6.91 , 7.27, 7.40-7.58, 7.67, 9.13
LC/MS: (M+H)=332 Example 48 5-(5-Methoxy-pyridin-3-ylethynyl)-pyrazolo[1,5-a]pyrimidine
[00224] According to General Procedure 1 , 5-methoxy-3-[(trimethylsilyl)ethynyl]- pyridine is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield. LC/MS: (M+H)=251
Example 49 5-(2-Fluoro-pyridin-3-ylethynyl)-pyrazolo[1,5-a]pyrimidine
[00225] According to General Procedure 1 , 3-[(trimethylsilyl)ethynyl]-2- fluoropyridine is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield. LC/MS: (M+H)=239
Example 50
2-Pyrazolo[1,5-a]pyrimidin-5-ylethynyl-isonicotinic acid ethyl ester
[00226] According to General Procedure 1 , 2-trimethylsilanylethynyl-isonicotinic acid ethyl ester is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield. LC/MS: (M+H)=293
Example 51 (3-Pyrazolo[1,5-a]pyrimidin-5-ylethynyl-phenyl)-methanol
[00227] According to General Procedure 1 , (3-trimethylsilanylethynyl-phenyl)- methanol is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield. LC/MS: (M+H)=250 Example 52 5-(3-Methoxymethyl-phenylethynyl)-pyrazolo[1,5-a]pyrimidine
[00228] According to General Procedure 1 , (3-methoxymethyl-phenylethynyl)- trimethylsilane is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield. LC/MS: (M+H)=264
Example 53
Acetic acid 3-pyrazolo[1,5-a]pyrimidin-5-ylethynyl-benzyl ester
[00229] According to General Procedure 1 , acetic acid 3-trimethylsilanylethynyl- benzyl ester is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield. LC/MS: (M+H)=292
Example 54 N-(3-Pyrazolo[1,5-a]pyrimidin-5-ylethynyl-phenyl)-benzamide
[00230] According to General Procedure 1 , N-(3-trimethylsilanylethynyl-phenyl)- benzamide is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield. LC/MS: (M+H)=339
Example 55 5-[3-Fluoro-5-(2-fluoro-pyridin-3-yl)-phenylethynyl]-pyrazolo[1,5-a]pyrimidine
[00231] According to General Procedure 1 , 2-fluoro-3-(3-fluoro-5- trimethylsilanylethynyl-phenyl)-pyridine is reacted with 5-chloro-pyrazolo[1 ,5- a]pyrimidine to provide the title compound in good yield. LC/MS: (M+H)=333 Example 56 5-[3-Fluoro-5-(2-methoxy-pyridin-3-yl)-phenylethynyl]-pyrazolo[1,5-a]pyrimidine
[00232] According to General Procedure 1 , 3-(3-fluoro-5-trimethylsilanylethynyl- phenyl)-2-methoxy-pyridine is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield. LC/MS: (M+H)=345
Example 57 5-Pyrazolo[1,5-a]pyrimidin-5-ylethynyl-[3,3']bipyridinyl
[00233] According to General Procedure 1 , 5-trimethylsilanylethynyl- [3,3']bipyridinyl is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield. LC/MS: (M+H)=298
Example 58 2-Fluoro-5'-pyrazolo[1,5-a]pyrlmidin-5-ylethynyl-[3,3I]bipyridinyl
[00234] According to General Procedure 1 , 2-fluoro-5'-trimethylsilanylethynyl- [3,3']bipyridinyl is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield. LC/MS: (M+H)=316
Example 59 2-Methoxy-5'-pyrazolo[1,5-a]pyrimidin-5-ylethynyl-[3,3']bipyridinyl
[00235] According to General Procedure 1 , 2-methoxy-5'-trimethylsilanylethynyl- [3,3']bipyridinyl is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield. LC/MS: (M+H)=328 Example 60
5-(3-Phenyl-prop-1 -ynyl)-pyrazolo[1 ,5-a]pyrimidine
[00236] 5-Ethynyl-pyrazolo[1 ,5-a]pyrimidine is prepared by coupling 5-chloro- pyrazolo[1 ,5-a]pyrimidine with trimethylsilylacetylene according to General Procedure 1 and subsequent cleavage of TMS group using K2CO3 in methanol. A mixture of 5- ethynyl-pyrazolo[1 ,5-a]pyrimidine (0.2 mmol), benzyl bromide (0.4 mmol) and K2CO3 (0.4 mmol) in acetone (1 ml.) is heated in a sealed vial at 1000C for 12h. The mixture is diluted with water (5 ml_), and extracted with ethyl acetate. The organic layer is dried over anhydrous Na2SO4 and evaporated in vacuo. Purification of the residue by flash column chromatography provides the title compound in moderate yield. LC/MS: (M+H)=234
Example 61 5-[3-(3-Fluoro-phenyl)-prop-1-ynyl]-pyrazolo[1,5-a]pyrimidine
[00237] In close analogy to procedure described in Example 60, 1-bromomethyl-3- fluorobenzene is reacted with 5-ethynyl-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in moderate yield. LC/MS: (M+H)=252
Example 62 5-[3-(3-Methoxy-phenyl)-prop-1-ynyl]-pyrazolo[1,5-a]pyrimidine
[00238] In close analogy to procedure described in Example 60, 1 -bromomethyl-3- methoxybenzene is reacted with 5-ethynyl-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in moderate yield. LC/MS: (M+H)=264
Example 63 3-(3-Pyrazolo[1,5-a]pyrimidin-5-yl-prop-2-ynyl)-benzonitrile
[00239] In close analogy to procedure described in Example 60, 1-bromomethyl-3- cyanobenzene is reacted with 5-ethynyl-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in moderate yield. LC/MS: (M+H)=259 Example 64 3-(3-Pyrazolo[1,5-a]pyrimidin-5-yl-prop-2-ynyl)-phenylamine
[00240] In close analogy to procedure described in Example 60, N-(3- bromomethyl-phenyl)-acetamide is reacted with 5-ethynyl-pyrazolo[1 ,5-a]pyrimidine to give N-[3-(3-pyrazolo[1 ,5-a]pyrimidin-5-yl-prop-2-ynyl)-phenyl]-acetamide, hydrolysis of which provides the title compound in moderate yield. LC/MS: (M+H)=249
Example 65 5-(3-Phenyl-but-1-ynyl)-pyrazolo[1,5-a]pyrimidine
[00241] In close analogy to procedure described in Example 60, (1-bromo-ethyl)- benzene is reacted with 5-ethynyl-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in moderate yield. LC/MS: (M+H)=248
Example 66 5-(3-Phenyl-prop-2-ynyl)-pyrazolo[1,5-a]pyrimidine
[00242] In close analogy to procedure described in Example 60, phenylacetylene is reacted with 5-bromomethyl-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in moderate yield. LC/MS: (M+H)=234
Example 67 5-[3-(3-Fluoro-phenyl)-prop-2-ynyl]-pyrazolo[1,5-a]pyrimidine
[00243] In close analogy to procedure described in Example 60, 3- fluorophenylacetylene is reacted with 5-bromomethyl-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in moderate yield. LC/MS: (M+H)=252
Example 68 5-[3-(3-Methoxy-phenyl)-prop-2-ynyl]-pyrazolo[1,5-a]pyrimidine [00244] In close analogy to procedure described in Example 60, 3- methoxyphenylacetylene is reacted with 5-bromomethyl-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in moderate yield. LC/MS: (M+H)=264
Example 69 3-(3-Pyrazolo[1,5-a]pyrimidin-5-yl-prop-1-ynyl)-phenylamine
[00245] In close analogy to procedure described in Example 60, N-(3-ethynyl- phenyl)-acetamide is reacted with 5-bromomethyl-pyrazolo[1 ,5-a]pyrimidine to give N- [3-(3-Pyrazolo[1 ,5-a]pyrimidin-5-yl-prop-1-ynyl)-phenyl]-acetamide, hydrolysis of which provides the title compound in moderate yield. LC/MS: (M+H)=249
Example 70 5-(4-Pyridin-2-yl-but-3-ynyl)-pyrazolo[1,5-a]pyrimidine
[00246] According to General Procedure 5, 5-(4-Trimethylsilanyl-but-3-ynyl)- pyrazolo[1 ,5-a]pyrimidine is reacted with 2-Bromo-pyridine to provide the title compound in good yield. LC/MS: (M+H)=249
Example 71 5-[4-(6-Methyl-pyridin-2-yl)-but-3-ynyl]-pyrazolo[1,5-a]pyrimidine
[00247] According to General Procedure 5, 5-(4-trimethylsilanyl-but-3-ynyl)- pyrazolo[1 ,5-a]pyrimidine is reacted with 2-bromo-6-methyl-pyridine to provide the title compound in good yield. LC/MS: (M+H)=263
Example 72 5-[4-(6-Fluoromethyl-pyridin-2-yl)-but-3-ynyl]-pyrazolo[1,5-a]pyrimidine [00248] According to General Procedure 5, 5-(4-trimethylsilanyl-but-3-ynyl)- pyrazolo[1 ,5-a]pyrimidine is reacted with 2-bromo-6-fluoromethyl-pyridine to provide the title compound in good yield. LC/MS: (M+H)=281
Example 73 5-[4-(2-Methyl-thiazol-4-yl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine
[00249] According to General Procedure 5, 5-(4-trimethylsilanyl-but-3-ynyl)- pyrazolo[1 ,5-a]pyrimidine is reacted with 4-bromo-2-methyl-4,5-dihydro-thiazole to provide the title compound in good yield. LC/MS: (M+H)=269
Example 74 5-[4-(2-Fluoromethyl-thiazol-4-yl)-but-3-ynyl]-pyrazolo[1,5-a]pyrimidine
[00250] According to General Procedure 5, 5-(4-trimethylsilanyl-but-3-ynyl)- pyrazolo[1 ,5-a]pyrimidine is reacted with 4-bromo-2-fluoromethyl-4,5-dihydro-thiazole to provide the title compound in good yield. LC/MS: (M+H)=287
Example 75 5-[4-(1-Methyl-1H-pyrazol-3-yl)-but-3-ynyl]-pyrazolo[1,5-a]pyrimidine
[00251] According to General Procedure 5, 5-(4-trimethylsilanyl-but-3-ynyl)- pyrazolo[1 ,5-a]pyrimidine is reacted with 3-bromo-1-methyl-1 H-pyrazole to provide the title compound in good yield. LC/MS: (M+H)=252 Example 76 5-(4-Phenyl-but-3-ynyl)-pyrazolo[1,5-a]pyrimidine
[00252] According to General Procedure 5, 5-(4-trimethylsilanyl-but-3-ynyl)- pyrazolo[1 ,5-a]pyrimidine is reacted with bromobenzene to provide the title compound in good yield. LC/MS: (M+H)=248
Example 77 5-(4-Pyridin-3-yl-but-3-ynyl)-pyrazolo[1,5-a]pyrimidine
[00253] According to General Procedure 5, 5-(4-trimethylsilanyl-but-3-ynyl)- pyrazolo[1 ,5-a]pyrimidine is reacted with 3-bromo-pyridine to provide the title compound in good yield. LC/MS: (M+H)=249
Example 78 5-(4-o-Tolyl-but-3-ynyl)-pyrazolo[1,5-a]pyrimidine
[00254] According to General Procedure 5, 5-(4-trimethylsilanyl-but-3-ynyl)- pyrazolo[1 ,5-a]pyrimidine is reacted with 1-bromo-2-methyl-benzene to provide the title compound in good yield. LC/MS: (M+H)=262
Example 79 5-(4-m-Tolyl-but-3-ynyl)-pyrazolo[1,5-a]pyrimidine
[00255] According to General Procedure 5, 5-(4-trimethylsilanyl-but-3-ynyl)- pyrazolo[1 ,5-a]pyrimidine is reacted with 1-bromo-3-methyl-benzene to provide the title compound in good yield. LC/MS: (M+H)=262 Example 80 5-[4-(2-Chloro-phenyl)-but-3-ynyl]-pyrazolo[1,5-a]pyrimidine
[00256] According to General Procedure 5, 5-(4-trimethylsilanyl-but-3-ynyl)- pyrazolo[1 ,5-a]pyrimidine is reacted with 1-bromo-2-chloro-benzene to provide the title compound in good yield. LC/MS: (M+H)=282
Example 81 5-[4-(2-Fluoro-phenyl)-but-3-ynyl]-pyrazolo[1,5-a]pyrimidine
[00257] According to General Procedure 5, 5-(4-trimethylsilanyl-but-3-ynyl)- pyrazolo[1 ,5-a]pyrimidine is reacted with 1-bromo-2-fluoro-benzene to provide the title compound in good yield. LC/MS: (M+H)=266
Example 82 5-[4-(3-Chloro-phenyl)-but-3-ynyl]-pyrazolo[1,5-a]pyrimidine
[00258] According to General Procedure 5, 5-(4-trimethylsilanyl-but-3-ynyl)- pyrazolo[1 ,5-a]pyrimidine is reacted with 1-bromo-3-chloro-benzene to provide the title compound in good yield. LC/MS: (M+H)=282
Example 83 5-[4-(3-Fluoro-phenyl)-but-3-ynyl]-pyrazolo[1,5-a]pyrimidine
[00259] According to General Procedure 5, 5-(4-trimethylsilanyl-but-3-ynyl)- pyrazolo[1 ,5-a]pyrimidine is reacted with 1-bromo-3-fluoro-benzene to provide the title compound in good yield. LC/MS: (M+H)=266 Example 84 5-(4-Thiophen-3-yl-but-3-ynyl)-pyrazolo[1,5-a]pyrimidine
[00260] According to General Procedure 5, 5-(4-trimethylsilanyl-but-3-ynyl)- pyrazoloti .δ-alpyrimidine is reacted with 3-bromo-thiophene to provide the title compound in good yield. LC/MS: (M+H)=254
Example 85 5-(4-Thiophen-2-yl-but-3-ynyl)-pyrazolo[1,5-a]pyrimidine
[00261] According to General Procedure 5, 5-(4-trimethylsilanyl-but-3-ynyl)- pyrazolo[1 ,5-a]pyrimidine is reacted with 2-bromo-thiophene to provide the title compound in good yield. LC/MS: (M+H)=254
Example 86 5-[4-(3-Methyl-thiophen-2-yl)-but-3-ynyl]-pyrazolo[1,5-a]pyrimidine
[00262] According to General Procedure 5, 5-(4-trimethylsilanyl-but-3-ynyl)- pyrazolo[1 ,5-a]pyrimidine is reacted with 2-bromo-3-methyl-thiophene to provide the title compound in good yield. LC/MS: (M+H)=268
Example 87 2-Methyl-5-(4-pyridin-2-yl-but-3-ynyl)-pyrazolo[1,5-a]pyrimidine
[00263] According to General Procedure 5, 2-methyl-5-(4-trimethylsilanyl-but-3- ynyl)-pyrazolo[1 ,5-a]pyrimidine is reacted with 2-bromo-pyridine to provide the title compound in good yield. LC/MS: (M+H)=263 Example 88 2-Methyl-5-[4-(6-methyl-pyridin-2-yl)-but-3-ynyl]-pyrazolo[1,5-a]pyrimidine
[00264] According to General Procedure 5, 2-methyl-5-(4-trimethylsilanyl-but-3- ynyl)-pyrazolo[1 ,5-a]pyrimidine is reacted with 2-bromo-6-methyl-pyridine to provide the title compound in good yield. LC/MS: (M+H)=277
Example 89 5-[4-(6-Fluoromethyl-pyridin-2-yl)-but-3-ynyl]-2-methyl-pyrazolo[1,5-a]pyrimidine
[00265] According to General Procedure 5, 2-methyl-5-(4-thmethylsilanyl-but-3- ynyl)-pyrazolo[1 ,5-a]pyrimidine is reacted with 2-bromo-6-fluoromethyl-pyridine to provide the title compound in good yield. LC/MS: (M+H)=295
Example 90 2-Methyl-5-[4-(2-methyl-thiazol-4-yl)-but-3-ynyl]-pyrazolo[1,5-a]pyrimidine
[00266] According to General Procedure 5, 2-methyl-5-(4-trimethylsilanyl-but-3- ynyl)-pyrazolo[1 ,5-a]pyrimidine is reacted with 4-bromo-2-methyl-4,5-dihydro-thiazole to provide the title compound in good yield. LC/MS: (M+H)=283
Example 91 5-[4-(2-Fluoromethyl-thiazol-4-yl)-but-3-ynyl]-2-methyl-pyrazolo[1,5-a]pyrimidine
[00267] According to General Procedure 5, 2-methyl-5-(4-trimethylsilanyl-but-3- ynyl)-pyrazolo[1 ,5-a]pyrimidine is reacted with 4-bromo-2-fluoromethyl-4,5-dihydro- thiazole to provide the title compound in good yield. LC/MS: (M+H)=301 Example 92
2-Methyl-5-[4-(1 -methyl-1 H-pyrazol-3-yl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine
[00268] According to General Procedure 5, 2-methyl-5-(4-trimethylsilanyl-but-3- ynyl)-pyrazolo[1 ,5-a]pyrimidine is reacted with 3-bromo-1 -methyl-1 H-pyrazole to provide the title compound in good yield. LC/MS: (M+H)=266
Example 93 2-Methyl-5-(4-phenyl-but-3-ynyl)-pyrazolo[1,5-a]pyrimidine
[00269] According to General Procedure 5, 2-methyl-5-(4-trimethylsilanyl-but-3- ynyl)-pyrazolo[1 ,5-a]pyrimidine is reacted with bromobenzene to provide the title compound in good yield.
1H-NMR (400 MHz1 CDCI3); δ: 2.49, 2.89, 3.08, 6.37, 6.69, 7.27, 7.32, 8.44
LC/MS: (M+H)=262
Example 94 2-Methyl-5-(4-pyridin-3-yl-but-3-ynyl)-pyrazolo[1,5-a]pyrimidine
[00270] According to General Procedure 5, 2-methyl-5-(4-trimethylsilanyl-but-3- ynyl)-pyrazolo[1 ,5-a]pyrimidine is reacted with 3-bromo-pyridine to provide the title compound in good yield.
1H-NMR (400 MHz, CDCI3); δ: 2.49, 2.92, 3.10, 6.37, 6.65, 7.17, 7.59, 8.45, 8.47, 8.57
LC/MS: (M+H)=263
Example 95 2-Methyl-5-(4-o-tolyl-but-3-ynyl)-pyrazolo[1,5-a]pyrimidine
[00271] According to General Procedure 5, 2-methyl-5-(4-trimethylsilanyl-but-3- ynyl)-pyrazolo[1 ,5-a]pyrimidine is reacted with 1-bromo-2-methyl-benzene to provide the title compound in good yield. LC/MS: (M+H)=276 Example 96 2-Methyl-5-(4-m-tolyl-but-3-ynyl)-pyrazolo[1,5-a]pyrimidine
[00272] According to General Procedure 5, 2-methyl-5-(4-trimethylsilanyl-but-3- ynyl)-pyrazolo[1 ,5-a]pyrimidine is reacted with 1 -bromo-3-methyl-benzene to provide the title compound in good yield. LC/MS: (M+H)=276
Example 97 5-[4-(2-Chloro-phenyl)-but-3-ynyl]-2-methyl-pyrazolo[1,5-a]pyrimidine
[00273] According to General Procedure 5, 2-methyl-5-(4-trimethylsilanyl-but-3- ynyl)-pyrazolo[1 ,5-a]pyrimidine is reacted with 1-bromo-2-chloro-benzene to provide the title compound in good yield.
1H-NMR (400 MHz1 CDCI3); δ: 2.48, 2.96, 3.12, 6.36, 6.73, 7.15, 7.35, 8.44
LC/MS: (M+H)=296
Example 98 5-[4-(2-Fluoro-phenyl)-but-3-ynyl]-2-methyl-pyrazolo[1,5-a]pyrimidine
[00274] According to General Procedure 5, 2-methyl-5-(4-trimethylsilanyl-but-3- ynyl)-pyrazolo[1 ,5-a]pyrimidine is reacted with 1-bromo-2-fluoro-benzene to provide the title compound in good yield. LC/MS: (M+H)=280
Example 99 5-[4-(3-Chloro-phenyl)-but-3-ynyl]-2-methyl-pyrazolo[1,5-a]pyrimidine
[00275] According to General Procedure 5, 2-methyl-5-(4-trimethylsilanyl-but-3- ynyl)-pyrazolo[1 ,5-a]pyrimidine is reacted with 1-bromo-3-chloro-benzene to provide the title compound in good yield.
1H-NMR (400 MHz, CDCI3); δ: 2.49, 2.89, 3.08, 6.37, 6.65, 7.16-7.23, 7.32, 8.45
LC/MS: (M+H)=296 Example 100 5-[4-(3-Fluoro-phenyl)-but-3-ynyl]-2-methyl-pyrazolo[1,5-a]pyrimidine
[00276] According to General Procedure 5, 2-methyl-5-(4-trimethylsilanyl-but-3- ynyl)-pyrazolo[1 ,5-a]pyrimidine is reacted with 1-bromo-3-fluoro-benzene to provide the title compound in good yield. LC/MS: (M+H)=280
Example 101 2-Methyl-5-(4-thiophen-3-yl-but-3-ynyl)-pyrazolo[1,5-a]pyrimidine
[00277] According to General Procedure 5, 2-methyl-5-(4-trimethylsilanyl-but-3- ynyl)-pyrazolo[1 ,5-a]pyrimidine is reacted with 3-bromo-thiophene to provide the title compound in good yield. LC/MS: (M+H)=268
Example 102 2-Methyl-5-(4-thiophen-2-yl-but-3-ynyl)-pyrazolo[1,5-a]pyrimidine
[00278] According to General Procedure 5, 2-methyl-5-(4-trimethylsilanyl-but-3- ynyl)-pyrazolo[1 ,5-a]pyrimidine is reacted with 2-bromo-thiophene to provide the title compound in good yield. LC/MS: (M+H)=268
Example 103 2-Methyl-5-[4-(3-methyl-thiophen-2-yl)-but-3-ynyl]-pyrazolo[1,5-a]pyrimidine
[00279] According to General Procedure 5, 2-methyl-5-(4-trimethylsilanyl-but-3- ynyl)-pyrazolo[1 ,5-a]pyrimidine is reacted with 2-bromo-3-methyl-thiophene to provide the title compound in good yield. LC/MS: (M+H)=282 Example 104 5-(5-Pyridin-2-ylethynyl-thiophen-2-yl)-pyrazolo[1,5-a]pyrimidine
[00280] According to General Procedure 6, 5-(5-pyridin-2-ylethynyl-thiophen-2-yl)- pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid is decarboxylated to provide the title compound in good yield. LC/MS: (M+H)=303
Example 105 5-[5-(6-Methyl-pyridin-2-ylethynyl)-thiophen-2-yl]-pyrazolo[1,5-a]pyrimidine
[00281] According to General Procedure 6, 5-[5-(6-methyl-pyridin-2-ylethynyl)- thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid is decarboxylated to provide the title compound in good yield. LC/MS: (M+H)=317
Example 106 5-[5-(6-Fluoromethyl-pyridin-2-ylethynyl)-thiophen-2-yl]-pyrazolo[1,5-a]pyrimidine
[00282] According to General Procedure 6, 5-[5-(6-fluoromethyl-pyridin-2- ylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid is decarboxylated to provide the title compound in good yield. LC/MS: (M+H)=335
Example 107 5-[5-(2-Methyl-thiazol-4-ylethynyl)-thiophen-2-yl]-pyrazolo[1,5-a]pyrimidine
[00283] According to General Procedure 6, 5-[5-(2-Methyl-thiazol-4-ylethynyl)- thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid is decarboxylated to provide the title compound in good yield. LC/MS: (M+H)=323 Example 108 5-[5-(2-Fluoromethyl-thiazol-4-ylethynyl)-thiophen-2-yl]-pyrazolo[1,5-a]pyrimidine
[00284] According to General Procedure 6, 5-[5-(2-fluoromethyl-thiazol-4- ylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid is decarboxylated to provide the title compound in good yield. LC/MS: (M+H)=341
Example 109 5-[5-(1-Methyl-1H-pyrazol-3-ylethynyI)-thiophen-2-yl]-pyrazolo[1,5-a]pyrimidine
[00285] According to General Procedure 6, 5-[5-(1-methyl-1 H-pyrazol-3-ylethynyl)- thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid is decarboxylated to provide the title compound in good yield. LC/MS: (M+H)=306
Example 110 5-(5-Phenylethynyl-thiophen-2-yl)-pyrazolo[1,5-a]pyrimidine
[00286] According to General Procedure 6, 5-(5-phenylethynyl-thiophen-2-yl)- pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid is decarboxylated to provide the title compound in good yield.
1H NMR (CDCI3, 400 MHz ), δ: 6.65, 7.11 , 7.29, 7.39, 7.51 , 7.59, 8.05, 8.61
LC/MS: (M+H)=302
Example 111 5-(5-Pyridin-3-ylethynyl-thiophen-2-yl)-pyrazolo[1,5-a]pyrimidine
[00287] According to General Procedure 6, 5-(5-pyridin-3-ylethynyl-thiophen-2-yl)- pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid is decarboxylated to provide the title compound in good yield.
1H NMR (CDCI3, 400 MHz ), δ: 6.69, 7.11 , 7.29, 7.31 , 7.68, 7.82, 8.11 , 8.51 , 8.65, 8.82
LC/MS: (M+H)=303 Example 112 5-(5-o-Tolylethynyl-thiophen-2-yl)-pyrazolo[1,5-a]pyrimidine
[00288] According to General Procedure 6, 5-(5-o-tolylethynyl-thiophen-2-yl)- pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid is decarboxylated to provide the title compound in good yield.
1H NMR (CDCI3, 400 MHz ), δ: 2.51 , 6.65, 7.09, 7.19, 7.25, 7.49, 7.59, 8.09, 8.61
LC/MS: (M+H)=316
Example 113 5-(5-m-Tolylethynyl-thiophen-2-yl)-pyrazolo[1,5-a]pyrimidine
[00289] According to General Procedure 6, 5-(5-m-tolylethynyl-thiophen-2-yl)- pyrazolo[1 ,5-a]pyrimidine -3-carboxylic acid is decarboxylated to provide the title compound in good yield.
1H NMR (DMSO-de, 400 MHz ), δ: 2.35, 6.65, 7.11 , 7.2, 7.25, 7.35, 7.6, 8.1 , 8.65
LC/MS: (M+H)=316
Example 114 5-[5-(2-Chloro-phenylethynyl)-thiophen-2-yl]-pyrazolo[1,5-a]pyrimidine
[00290] According to General Procedure 6, 5-[5-(2-chloro-phenylethynyl)-thiophen- 2-yl]-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid is decarboxylated to provide the title compound in good yield.
1H NMR (CDCI3, 400 MHz ), δ: 6.68, 7.11 , 7.25, 7.31 , 7.45, 7.51 , 7.62, 8.11 , 8.65
LC/MS: (M+H)=336
Example 115 5-[5-(2-Fluoro-phenylethynyl)-thiophen-2-yl]-pyrazolo[1,5-a]pyrimidine [00291] According to General Procedure 6, 5-[5-(2-fluoro-phenylethynyl)-thiophen- 2-yl]-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid is decarboxylated to provide the title compound in good yield.
1H NMR (CDCI3, 400 MHz ), δ: 6.65, 7.15, 7.31 , 7.39, 7.49, 7.59, 8.09, 8.61
LC/MS: (M+H)=320
Example 116 5-[5-(3-Chloro-phenylethynyl)-thiophen-2-yl]-pyrazolo[1,5-a]pyrimidine
[00292] According to General Procedure 6, 5-[5-(3-chloro-phenylethynyl)-thiophen- 2-yl]-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid is decarboxylated to provide the title compound in good yield.
1H NMR (CDCI3, 400 MHz ), δ: 6.68, 7.11 , 7.31 , 7.34, 7.45, 7.51 , 7.56, 8.11 , 8.51
LC/MS: (M+H)=336
Example 117 5-[5-(3-Fluoro-phenylethynyl)-thiophen-2-yl]-pyrazolo[1,5-a]pyrimidine
[00293] According to General Procedure 6, 5-[5-(3-fluoro-phenylethynyl)-thiophen- 2-yl]-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid is decarboxylated to provide the title compound in good yield.
1H NMR (CDCI3, 400 MHz ), δ: 6.69, 7.09, 7.15, 7.21 , 7.31 , 7.55, 8.11 , 8.61
LC/MS: (M+H)=320
Example 118 5-(5-Thiophen-3-ylethynyl-thiophen-2-yl)-pyrazolo[1,5-a]pyrimidine
[00294] According to General Procedure 6, 5-(5-thiophen-3-ylethynyl-thiophen-2- yl)-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid is decarboxylated to provide the title compound in good yield. LC/MS: (M+H)=308 Example 119 5-(5-Thiophen-2-ylethynyl-thiophen-2-yl)-pyrazolo[1,5-a]pyrimidine
[00295] According to General Procedure 6, 5-(5-thiophen-2-ylethynyl-thiophen-2- yl)-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid is decarboxylated to provide the title compound in good yield. LC/MS: (M+H)=308
Example 120 5-[5-(3-Methyl-thiophen-2-ylethynyl)-thiophen-2-yl]-pyrazolo[1,5-a]pyrimidine
[00296] According to General Procedure 6, 5-[5-(3-methyl-thiophen-2-ylethynyl)- thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid is decarboxylated to provide the title compound in good yield. LC/MS: (M+H)=322
Example 121 tert-Butyl-[5-(5-pyridin-2-ylethynyl-thiophen-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl]- amine
[00297] According to General Procedure 7, [5-(5-bromo-thiophen-2-yl)- pyrazolo[1 ,5-a]pyrimidin-7-yl]-tert-butyl-amine is reacted with 2-Ethynyl-pyridine to provide the title compound in good yield.
1H NMR (CDCI3, 400 MHz ), δ: 1.6, 6.43, 6.49, 6.53, 7.20, 7.37, 7.50, 7.65, 7.95, 8.65
LC/MS: (M+H)=374
Example 122
5-Pyrazolo[1,5-a]pyrimidin-5-ylethynyl-nicotinic acid methyl ester
[00298] According to General Procedure 1 , 5-trimethylsilanylethynyl-nicotinic acid methyl ester is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield. 1H NMR (CDCI3, TMS) δ: 3.99, 6.77, 6.99, 8.19, 8.52, 8.70, 9.00, 9.21. LC/MS: (M+H)= 279
Example 123 tert-Butyl-{5-[5-(6-methyl-pyridin-2-ylethynyl)-thiophen-2-yl]-pyrazolo[1,5- a]pyrimidin-7-yl}-amine
[00299] According to General Procedure 7, [5-(5-bromo-thiophen-2-yl)- pyrazolo[1 ,5-a]pyrimidin-7-yl]-tert-butyl-amine is reacted with 2-ethynyl-6-methyl- pyridine to provide the title compound in good yield. LC/MS: (M+H) = 388
Example 124 tert-Butyl-{5-[5-(6-fluoromethyl-pyridin-2-ylethynyl)-thiophen-2-yl]-pyrazolo[1,5- a]pyrimidin-7-yl}-amine
[00300] According to General Procedure 7, [5-(5-bromo-thiophen-2-yl)- pyrazolo[1 ,5-a]pyrimidin-7-yl]-tert-butyl-amine is reacted with 2-ethynyl-6-fluoromethyl- pyridine to provide the title compound in good yield. LC/MS: (M+H) = 406
Example 125 tert-Butyl-{5-[5-(2-methyl-thiazol-4-ylethynyl)-thiophen-2-yl]-pyrazolo[1,5- a]pyrimidin-7-yl}-amine
[00301] According to General Procedure 7, [5-(5-bromo-thiophen-2-yl)- pyrazolo[1 ,5-a]pyrimidin-7-yl]-tert-butyl-amine is reacted with 4-ethynyl-2-methyl- thiazole to provide the title compound in good yield. LC/MS: (M+H) = 394
Example 126 tert-Butyl-{5-[5-(2-fluoromethyl-thiazol-4-ylethynyl)-thiophen-2-yl]-pyrazolo[1,5- a] py ri m id i n-7-y l}-am i ne [00302] According to General Procedure 7, [5-(5-bromo-thiophen-2-yl)- pyrazolo[1 ,5-a]pyrimidin-7-yl]-tert-butyl-amine is reacted with 4-ethynyl-2-fluoromethyl- thiazole to provide the title compound in good yield. LC/MS: (M+H) = 412
Example 127 tert-Butyl-{5-[5-(1 -methy 1-1 H-py razol-3-y lethy nyl)-thiophen-2-y l]-py razolo[1 ,5- a]pyrimidin-7-yl}-amine
[00303] According to General Procedure 7, [5-(5-bromo-thiophen-2-yl)- pyrazolo[1 ,5-a]pyrimidin-7-yl]-tert-butyl-amine is reacted with 3-ethynyl-1-methyl-1 H- pyrazole to provide the title compound in good yield. LC/MS: (M+H) = 377
Example 128 tert-Butyl-[5-(5-phenylethynyl-thiophen-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl]-amine
[00304] According to General Procedure 7, [5-(5-bromo-thiophen-2-yl)- pyrazolo[1 ,5-a]pyrimidin-7-yl]-tert-butyl-amine is reacted with ethynyl-benzene to provide the title compound in good yield. LC/MS: (M+H) = 373
Example 129 tert-Butyl-[5-(5-pyridin-3-ylethynyl-thiophen-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl]- amine
[00305] According to General Procedure 7, [5-(5-bromo-thiophen-2-yl)- pyrazolo[1 ,5-a]pyrimidin-7-yl]-tert-butyl-amine is reacted with 3-ethynyl-pyridine to provide the title compound in good yield. LC/MS: (M+H) = 374
Example 130 tert-Butyl-[5-(5-o-tolylethynyl-thiophen-2-yl)-pyra2olo[1,5-a]pyrimidin-7-yl]-amine [00306] According to General Procedure 7, [5-(5-bromo-thiophen-2-yl)- pyrazolo[1 ,5-a]pyrimidin-7-yl]-tert-butyl-amine is reacted with 1-ethynyl-2-methyl- benzene to provide the title compound in good yield. LC/MS: (M+H) = 387
Example 131 tert-Butyl-[5-(5-m-tolylethynyl-thiophen-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl]-amine
[00307] According to General Procedure 7, [5-(5-bromo-thiophen-2-yl)- pyrazolo[1 ,5-a]pyrimidin-7-yl]-tert-butyl-amine is reacted with 1 -ethynyl-3-methyl- benzene to provide the title compound in good yield. LC/MS: (M+H) = 387
Example 132 tert-Butyl-{5-[5-(2-chloro-phenylethynyl)-thiophen-2-yl]-pyrazolo[1,5-a]pyrimidin-
7-yl}-amine
[00308] According to General Procedure 7, [5-(5-bromo-thiophen-2-yl)- pyrazolo[1 ,5-a]pyrimidin-7-yl]-tert-butyl-amine is reacted with 1 -chloro-2-ethynyl- benzene to provide the title compound in good yield. LC/MS: (M+H) = 407
Example 133 tert-Butyl-{5-[5-(2-fluoro-phenylethynyl)-thiophen-2-yl]-pyrazolo[1,5-a]pyrimidin-7- yl}-amine
[00309] According to General Procedure 7, [5-(5-bromo-thiophen-2-yl)- pyrazolo[1 ,5-a]pyrimidin-7-yl]-tert-butyl-amine is reacted with 1 -ethynyl-2-fluoro- benzene to provide the title compound in good yield. LC/MS: (M+H) = 391 Example 134 tert-Butyl^S-IS^S-chloro-phenylethynylHhiophen^-yπ-pyrazoloII.S-alpyrimidin-
7-yl}-amine
[00310] According to General Procedure 7, [5-(5-bromo-thiophen-2-yl)- pyrazolo[1 ,5-a]pyrimidin-7-yl]-tert-butyl-amine is reacted with 1 -chloro-3-ethynyl- benzene to provide the title compound in good yield. LC/MS: (M+H) = 407
Example 135 tert-Butyl-{5-[5-(3-fluoro-phenylethynyl)-thiophen-2-yl]-pyrazolo[1,5-a]pyrimidin-7- yl}-amine
[00311] According to General Procedure 7, [5-(5-bromo-thiophen-2-yl)- pyrazolo[1 ,5-a]pyrimidin-7-yl]-tert-butyl-amine is reacted with 1 -ethynyl-3-f luoro- benzene to provide the title compound in good yield. LC/MS: (M+H) = 391
Example 136 tert-Butyl-[5-(5-thiophen-3-ylethynyl-thiophen-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl]- amine
[00312] According to General Procedure 7, [5-(5-bromo-thiophen-2-yl)- pyrazolo[1 ,5-a]pyrimidin-7-yl]-tert-butyl-amine is reacted with 3-ethynyl-thiophene to provide the title compound in good yield. LC/MS: (M+H) = 379
Example 137 tert-Butyl-[5-(5-thiophen-2-ylethynyl-thiophen-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl]- amine [00313] According to General Procedure 7, [5-(5-bromo-thiophen-2-yl)- pyrazolo[1 ,5-a]pyrimidin-7-yl]-tert-butyl-amine is reacted with 2-ethynyl-thiophene to provide the title compound in good yield. LC/MS: (M+H) = 379
Example 138 tert-Butyl-{5-[5-(3-methyl-thiophen-2-ylethynyl)-thiophen-2-yl]-pyrazolo[1,5- a]pyrimidin-7-yl}-amine
[00314] According to General Procedure 7, [5-(5-Bromo-thiophen-2-yl)- pyrazoloII .S-aJpyrimidin^-ylHert-butyl-amine is reacted with 2-Ethynyl-3-methyl- thiophene to provide the title compound in good yield. LC/MS: (M+H) = 393
Example 139 5-(3-Pyridin-2-yl-prop-2-ynyloxy)-pyrazolo[1,5-a]pyrimidine
[00315] According to General Procedure 4, 4H-pyrazolo[1 ,5-a]pyrimidin-5-one is reacted with 3-pyridin-2-yl-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 251
Example 140 2-Methyl-5-(3-pyridin-2-yl-prop-2-ynyloxy)-pyrazolo[1,5-a]pyrimidine
[00316] According to General Procedure 4, 2-methyl-4H-pyrazolo[1 ,5-a]pyrimidin- 5-one is reacted with 3-pyridin-2-yl-prop-2-yn-1-ol provide the title compound in moderate yield. LC/MS: (M+H) = 265
Example 141 5-[3-(6-Methyl-pyridin-2-yl)-prop-2-ynyloxy]-pyrazolo[1,5-a]pyrimidine [00317] According to General Procedure 4, 4H-pyrazolo[1 ,5-a]pyrimidin-5-one is reacted with 3-(6-methyl-pyridin-2-yl)-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 265
Example 142 2-Methyl-5-[3-(6-methyl-pyridin-2-yl)-prop-2-ynyloxy]-pyrazolo[1,5-a]pyrimidine
[00318] According to General Procedure 4, 2-methyl-4H-pyrazolo[1 ,5-a]pyrimidin- 5-one is reacted with 3-(6-methyl-pyridin-2-yl)-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 279
Example 143 5-[3-(6-Fluoromethyl-pyridin-2-yl)-prop-2-ynyloxy]-pyrazolo[1,5-a]pyrimidine
[00319] According to General Procedure 4, 4H-pyrazolo[1 ,5-a]pyrimidin-5-one is reacted with 3-(6-fluoromethyl-pyridin-2-yl)-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 283
Example 144
5-[3-(6-Fluoromethyl-pyridin-2-yl)-prop-2-ynyloxy]-2-methyl-pyrazolo[1,5- a]pyrimidine
[00320] According to General Procedure 4, 2-methyl-4H-pyrazolo[1 ,5-a]pyrimidin- 5-one is reacted with 3-(6-fluoromethyl-pyridin-2-yl)-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 297
Example 145 5-[3-(2-Methyl-thiazol-4-yl)-prop-2-ynyloxy]-pyrazolo[1,5-a]pyrimidine [00321] According to General Procedure 4, 4H-pyrazolo[1 ,5-a]pyrimidin-5-one is reacted with 3-(2-methyl-thiazol-4-yl)-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 271
Example 146 2-Methyl-5-[3-(2-methyl-thiazol-4-yl)-prop-2-ynyloxy]-pyrazolo[1,5-a]pyrimidine
[00322] According to General Procedure 4, 2-methyl-4H-pyrazolo[1 ,5-a]pyrimidin- 5-one is reacted with 3-(2-methyl-thiazol-4-yl)-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 285
Example 147 5-[3-(2-Fluoromethyl-thiazol-4-yl)-prop-2-ynyloxy]-pyrazolo[1,5-a]pyrimidine
[00323] According to General Procedure 4, 4H-pyrazolo[1 ,5-a]pyrimidin-5-one is reacted with 3-(2-fluoromethyl-thiazol-4-yl)-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 289
Example 148
5-[3-(2-Fluoromethyl-thiazol-4-yl)-prop-2-ynyloxy]-2-methyl-pyrazolo[1,5- a]pyrimidine
[00324] According to General Procedure 4, 2-methyl-4H-pyrazolo[1 ,5-a]pyrimidin- 5-one is reacted with 3-(2-fluoromethyl-thiazol-4-yl)-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 303
Example 149 5-[3-(1-IVlethyl-1H-pyrazol-3-yl)-prop-2-ynyloxy]-pyrazolo[1,5-a]pyrimidine [00325] According to General Procedure 4, 4H-pyrazolo[1 ,5-a]pyrimidin-5-one is reacted with 3-(1-methyl-1H-pyrazol-3-yl)-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 254
Example 150
2-Methyl-5-[3-(1 -methyl-1 H-pyrazol-3-yl)-prop-2-ynyloxy]-pyrazolo[1 ,5- a]pyrimidine
[00326] According to General Procedure 4, 2-methyl-4H-pyrazolo[1 ,5-a]pyrimidin- 5-one is reacted with 3-( 1 -methyl-1 H-pyrazol-3-yl)-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 268
Example 151 5-(3-Phenyl-prop-2-ynyloxy)-pyrazolo[1,5-a]pyrimidine
[00327] According to General Procedure 4, 4H-pyrazolo[1 ,5-a]pyrimidin-5-one is reacted with 3-phenyl-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 250
Example 152 2-Methyl-5-(3-phenyl-prop-2-ynyloxy)-pyrazolo[1,5-a]pyrimidine
[00328] According to General Procedure 4, 2-methyl-4H-pyrazolo[1 ,5-a]pyrimidin- 5-one is reacted with 3-phenyl-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 264
Example 153 5-(3-Pyridin-3-yl-prop-2-ynyloxy)-pyrazolo[1,5-a]pyrimidine [00329] According to General Procedure 4, 4H-pyrazolo[1 ,5-a]pyrimidin-5-one is reacted with 3-pyridin-3-yl-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 251
Example 154 2-Methyl-5-(3-pyridin-3-yl-prop-2-ynyloxy)-pyrazolo[1,5-a]pyrimidine
[00330] According to General Procedure 4, 2-methyl-4H-pyrazolo[1 ,5-a]pyrimidin- 5-one is reacted with 3-pyridin-3-yl-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 265
Example 155 5-(3-o-Tolyl-prop-2-ynyloxy)-pyrazolo[1,5-a]pyrimidine
[00331] According to General Procedure 4, 4H-pyrazolo[1 ,5-a]pyrimidin-5-one is reacted with 3-o-tolyl-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 264
Example 156 2-Methyl-5-(3-o-tolyl-prop-2-ynyloxy)-pyrazolo[1,5-a]pyrimidine
[00332] According to General Procedure 4, 2-methyl-4H-pyrazolo[1 ,5-a]pyrimidin- 5-one is reacted with 3-o-tolyl-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 278
Example 157 5-(3-m-Tolyl-prop-2-ynyloxy)-pyrazolo[1,5-a]pyrimidine
[00333] According to General Procedure 4, 4H-pyrazolo[1 ,5-a]pyrimidin-5-one is reacted with 3-m-tolyl-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 264
Example 158 2-Methyl-5-(3-m-tolyl-prop-2-ynyloxy)-pyrazolo[1,5-a]pyrimidine
[00334] According to General Procedure 4, 2-methyl-4H-pyrazolo[1 ,5-a]pyrimidin- 5-one is reacted with 3-m-tolyl-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 278
Example 159 5-[3-(2-Chloro-phenyl)-prop-2-ynyloxy]-pyrazolo[1,5-a]pyrimidine
[00335] According to General Procedure 4, 4H-pyrazolo[1 ,5-a]pyrimidin-5-one is reacted with 3-(2-chloro-phenyl)-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 284
Example 160 5-[3-(2-Chloro-phenyl)-prop-2-ynyloxy]-2-methyl-pyrazolo[1,5-a]pyrimidine
[00336] According to General Procedure 4, 2-methyl-4H-pyrazolo[1 ,5-a]pyrimidin- 5-one is reacted with 3-(2-chloro-phenyl)-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 298
Example 161 5-[3-(2-Fluoro-phenyl)-prop-2-ynyloxy]-pyrazolo[1,5-a]pyrimidine
[00337] According to General Procedure 4, 4H-pyrazolo[1 ,5-a]pyrimidin-5-one is reacted with 3-(2-fluoro-phenyl)-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 268 Example 162 5-[3-(2-Fluoro-phenyl)-prop-2-ynyloxy]-2-methyl-pyrazolo[1,5-a]pyrimidine
[00338] According to General Procedure 4, 2-methyl-4H-pyrazolo[1 ,5-a]pyrimidin- 5-one is reacted with 3-(2-fluoro-phenyl)-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 282
Example 163 5-[3-(3-Chloro-phenyl)-prop-2-ynyloxy]-pyrazolo[1,5-a]pyrimidine
[00339] According to General Procedure 4, 4H-pyrazolo[1 ,5-a]pyrimidin-5-one is reacted with 3-(3-chloro-phenyl)-prop-2-yn-1-ol to provide the title compound in moderate yield.
1H NMR (CDCI3, 400 MHz ), δ: 5.21 , 6.31 , 6.39, 7.32, 7.62, 7.95, 8.42
LC/MS: (M+H) = 284
Example 164 5-[3-(3-Chloro-phenyl)-prop-2-ynyloxy]-2-methyl-pyrazolo[1,5-a]pyrimidine
[00340] According to General Procedure 4, 2-methyl-4H-pyrazolo[1 ,5-a]pyrimidin- 5-one is reacted with 3-(3-chloro-phenyl)-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 298
Example 165 5-[3-(3-Fluoro-phenyl)-prop-2-ynyloxy]-pyrazolo[1,5-a]pyrimidine
[00341] According to General Procedure 4, 4H-pyrazolo[1 ,5-a]pyrimidin-5-one is reacted with 3-(3-fluoro-phenyl)-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 268 Example 166 5-[3-(3-Fluoro-phenyl)-prop-2-ynyloxy]-2-methyl-pyrazolo[1,5-a]pyrimidine
[00342] According to General Procedure 4, 2-methyl-4H-pyrazolo[1 ,5-a]pyrimidin- 5-one is reacted with 3-(3-fluoro-phenyl)-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 282
Example 167 5-(3-Thiophen-3-yl-prop-2-ynyloxy)-pyrazolo[1,5-a]pyrimidine
[00343] According to General Procedure 4, 4H-pyrazolo[1 ,5-a]pyrimidin-5-one is reacted with 3-thiophen-3-yl-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 256
Example 168 2-Methyl-5-(3-thiophen-3-yl-prop-2-ynyloxy)-pyrazolo[1,5-a]pyrimidine
[00344] According to General Procedure 4, 2-methyl-4H-pyrazolo[1 ,5-a]pyrimidin- 5-one is reacted with 3-thiophen-3-yl-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 270
Example 169 5-(3-Thiophen-2-yl-prop-2-ynyloxy)-pyrazolo[1,5-a]pyrimidine
[00345] According to General Procedure 4, 4H-pyrazolo[1 ,5-a]pyrimidin-5-one is reacted with 3-thiophen-2-yl-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 256 Example 170 2-Methyl-5-(3-thiophen-2-yl-prop-2-ynyloxy)-pyrazolo[1,5-a]pyrimidine
[00346] According to General Procedure 4, 2-methyl-4H-pyrazolo[1 ,5-a]pyrimidin- 5-one is reacted with 3-thiophen-2-yl-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 270
Example 171 5-[3-(3-Methyl-thiophen-2-yl)-prop-2-ynyloxy]-pyrazolo[1,5-a]pyrimidine
[00347] According to General Procedure 4, 4H-pyrazolo[1 ,5-a]pyrimidin-5-one is reacted with 3-(3-methyl-thiophen-2-yl)-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 270
Example 172 2-Methyl-5-[3-(3-methyl-thiophen-2-yl)-prop-2-ynyloxy]-pyrazolo[1,5-a]pyrimidine
[00348] According to General Procedure 4, 2-methyl-4H-pyrazolo[1 ,5-a]pyrimidin- 5-one is reacted with 3-(3-methyl-thiophen-2-yl)-prop-2-yn-1-ol to provide the title compound in moderate yield. LC/MS: (M+H) = 284
Example 173 5-(5-Bromo-pyridin-3-ylethynyl)-pyrazolo[1,5-a]pyrimidine
[00349] According to General Procedure 1 , 3-[(trimethylsilyl)ethynyl]-5- bromopyridine is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield. LC/MS: (M+H)= 229, 301 Example 174 5-Cyclohexylethynyl-pyrazolo[1,5-a]pyrimidine
[00350] According to General Procedure 1 , cyclohexylethynyl-trimethyl-silane is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield. LC/MS: (M+H)= 226
Example 175 5-Cyclohex-1 -enylethynyl-pyrazolo[1 ,5-a]pyrimidine
[00351] According to General Procedure 1 , cyclohex-1-enylethynyl-trimethyl-silane is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield. LC/MS: (M+H)= 224
Example 176 5-Pyrazolo[1,5-a]pyrimidin-5-ylethynyl-[3,4']bipyridinyl
[00352] 5-(5-Bromo-pyridin-3-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine (Example 173) is reacted with 4-pyridineboronic acid in a Suzuki coupling reaction to provide the title compound in good yield LC/MS: (M+H)= 298
Example 177 5-(2,6-Dimethyl-cyclohex-1-enylethynyl)-pyrazolo[1,5-a]pyrimidine
[00353] According to General Procedure 1 , (2,6-dimethyl-cyclohex-1-enylethynyl)- trimethyl-silane is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield. LC/MS: (M+H)= 252 Example 178 2-Phenyl-4-pyrazolo[1,5-a]pyrimidin-5-yl-but-3-yn-2-ol
[00354] 5-Ethynyl-pyrazolo[1 ,5-a]pyrimidine is deprotonated with n-butyl lithium and the resulting lithium acetylide is reacted with acetophenone to provide, after the aqueous workup, the title compound in good yield. LC/MS: (M+H)= 264
Example 179
4-Pyrazolo[1,5-a]pyrimidin-5-ylethynyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester
[00355] According to General Procedure 1 , 4-trimethylsilanylethynyl-3,6-dihydro- 2H-pyridine-1-carboxylic acid tert-butyl ester is reacted with 5-chloro-pyrazolo[1 ,5- a]pyrimidine to provide the title compound in good yield. LC/MS: (M+H)= 325
Example 180 5-(3,6-Dihydro-2H-pyran-4-ylethynyl)-pyrazolo[1,5-a]pyrimidine
[00356] According to General Procedure 1 , (3,6-dihydro-2H-pyran-4-ylethynyl)- trimethyl-silane is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield. LC/MS: (M+H)= 226
Example 181 5-(3,6-Dihydro-2H-thiopyran-4-ylethynyl)-pyrazolo[1,5-a]pyrimidine
[00357] According to General Procedure 1 , (3,6-dihydro-2H-thiopyran-4-ylethynyl)- trimethyl-silane is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield. LC/MS: (M+H)= 242 Example 182 5-(3-Methyl-3-phenyl-but-1-ynyl)-pyrazolo[1,5-a]pyrimidine
[00358] According to General Procedure 1 , trimethyl-(3-methyl-3-phenyl-but-1- ynyl)-silane is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield. LC/MS: (M+H)= 262
Example 183 5-(2,6,6-Trimethyl-cyclohex-1-enylethynyl)-pyrazolo[1,5-a]pyrimidine
[00359] According to General Procedure 1 , trimethyl-(2,6,6-trimethyl-cyclohex-1- enylethynyl)-silane is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield. LC/MS: (M+H)= 266
Example 184 5-Cyclopropylethynyl-pyrazolo[1,5-a]pyrimidine
[00360] According to General Procedure 1 , cyclopropylethynyl-trimethyl-silane is reacted with 5-chloro-pyrazolo[1 ,5-a]pyrimidine to provide the title compound in good yield. LC/MS: (M+H)= 184
Example 185 3-Pyrazolo[1,5-a]pyrimidin-5-ylethynyl-cyclohex-2-enone
[00361] 5-Ethynyl-pyrazolo[1 ,5-a]pyrimidine is deprotonated with n-butyllithium and the resulting lithium acetylide is reacted with 3-ethoxy-cyclohex-2-enone to provide, after the aqueous workup, the title compound in good yield. LC/MS: (M+H)= 238 Example 186
3-Pyrazolo[1,5-a]pyrimidin-5-ylethynyl-cyclohex-2-enone O-methyl-oxime
[00362] 3-Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-cyclohex-2-enone (Example 190) is reacted with O-methyl-hydroxylamine hydrochloride to provide the title compound in good yield. LC/MS: (M+H)= 267
Example 187
4-Pyrazolo[1,5-a]pyrimidin-5-ylethynyl-3,6-dihydro-2H-pyridine-1 -carboxylic acid isopropylamide
[00363] 4-Pyrazolo[1.δ-alpyrimidin-δ-ylethynyl-S.β-dihydro^H-pyridine-i - carboxylic acid tert-butyl ester (Example 179) is treated with trifluoroacetic acid to give 5-(1 ,2,3,6-tetrahydro-pyridin-4-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine, which is reacted with isopropylisocyanate to provide the title compound in good yield. LC/MS: (M+H)= 310
Example 188
4-Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-3,6-dihydro-2H-pyridine-1 -carboxylic acid benzyl ester
[00364] 5-(1 ,2,3,6-Tetrahydro-pyridin-4-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine, prepared as in Example 192, is reacted with benzyl chloroformate to provide the title compound in good overall yield. LC/MS: (M+H)= 359 Table 1
Figure imgf000134_0001
Figure imgf000134_0002
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0002
Table 2
Figure imgf000138_0001
Figure imgf000138_0003
Figure imgf000139_0002
Table 3
Figure imgf000139_0001
Figure imgf000139_0003
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0002
Table 4
Figure imgf000147_0001
Figure imgf000147_0003
Figure imgf000148_0001
EXAMPLES OF REPRESENTATIVE PHARMACEUTICAL COMPOSITIONS
[00365] In 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 room temperature but which melts at or about body temperature.
(c) For parenteral (including intravenous and subcutaneous) sterile solutions, the active ingredient together with conventional ingredients in usual amounts are employed, such as for example sodium chloride and double-distilled water q.s., according to conventional procedure, such as filtration, aseptic filling into ampoules or IV-drip bottles, and autoclaving for sterility.
[00366] Other suitable pharmaceutical compositions will be immediately apparent to one skilled in the art.
FORMULATION EXAMPLES
[00367]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:
Figure imgf000149_0001
EXAMPLE 2
Tablet Formulation Another suitable formulation for a tablet containing 100 mg is as follows:
Figure imgf000150_0001
EXAMPLE 3
Capsule Formulation
A suitable formulation for a capsule containing 50 milligrams of active ingredient is as follows:
Figure imgf000151_0001
filled in a gelatin capsule.
EXAMPLE 4
Solution for injection A suitable formulation for an injectable solution is as follows:
Figure imgf000151_0002
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:
Figure imgf000152_0001
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:
Figure imgf000152_0002
Figure imgf000153_0001
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:
Figure imgf000153_0002
EXAMPLE 8
Aerosol formulation 18O g aerosol solution contain:
Figure imgf000154_0001
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:
Figure imgf000154_0002
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:
Figure imgf000155_0001
Polybutylcyanoacrylate nanoparticles are prepared by emulsion polymerization in a water/0.1 N HCI/ethanol mixture as polymerizsation medium. The nanoparticles in the suspension are finally lyophilized under vacuum.
EXAMPLE 11
Suspension formulation 1.0 g of the suspension contains the following:
Figure imgf000155_0002
Figure imgf000156_0002
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:
Figure imgf000156_0001
The active ingredient is dissolved in DMSO by stirring and heating (solution 1 ). The mannitol is dissolved in WFI (solution 2). After cooling down to room temperature solution 1 is mixed with solution 2 by continuous stirring. The solution is sterilized by filtration of by autoclaving.
PHARMACOLOGY
[00368] 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
[3H]MPEP (2-methyl-6-(phenylethynyl)pyridine) binding to transmembrane allosteric modulatory sites of mGluR5 receptors in cortical membranes
Preparation of rat cortical membranes:
[00369] 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 rriM 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 4CC. After resuspension in 5 volumes of 50 mM Tris-HCI, pH 8.0, the membrane suspension is frozen rapidly at -80°C.
[00370] 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 μg/ml) is determined according to the method of Lowry (Lowry O. H. et al. 1951. J. Biol. Chem. 193, 256-275).
[3H]MPEP Assay
[00371] Incubations are started by adding [3H]-MPEP (50.2 Ci/mmol, 5 ΠM, Tocris, GB) to vials with 125-250 μg protein (total volume 0.25 ml) and various concentrations of the agents. Alternatively, assays are performed with [3H]-MMPEP (2-(3- methoxyphenylethynyl)-6-rnethylpyridine hydrochloride) as radioligand. The incubations are continued at room temperature for 60 minutes (equilibrium is achieved under the conditions used). Non-specific binding is defined by the addition of unlabeled MPEP (10 μM). 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
[00372] 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 μg/ml) is within the linear portion of this dependence. Cold MPEP displaces hot ligand with an IC50 of 11.2 ± 0.64 ΠM. 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 Ka values (IC50 of cold MPEP equates to a Kj of 8.2 nM). Bmaχ is 0.56 pm / mg protein.
FUNCTIONAL ASSAY OF MGLUR5 RECEPTORS
Cytosolic Calcium studies with stably transfected cells
[00373] Chinese hamster ovary cells (CHO-K1 cells), stably transfected for inducible expression of a human metabotropic glutamate receptor mGluRδ, 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-β-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 ITIM 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
[00374] 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 μm) 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 mM glutamine and 50 μg/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.
[00375] 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 μg/ml heparan sulfate, and 1.5 μg/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.
lmmunocytochemistry
[00376] 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 mGluRδ receptors. Cytosolic Calcium studies with astrocytes
[00377] 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 μl of loading buffer consisting of Ca-sensitive dye reconstituted in sodium chloride (123 mM), potassium chloride (5.4 mM), magnesium chloride (0.8 mM), calcium chloride (1.8 mM), D-glucose (15 mM), and HEPES (20 mM), pH 7.3. Subsequently, plates are transferred to FLIPR to detect calcium increase with the addition of L-quisqualate (100 nM) 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.
[00378] For positive modulators, concentration-response curves for quisqualate are performed in the presence and absence of 10 μM 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
[00379] 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.
[0038O]AII responses (RFU-values) are determined as percentage of control (= maximum response). EC50 and IC50 are calculated according the logistic equation using GraFit 5.0 (Erithacus Software, GB) or Prism 4.0 (GraphPad Software, USA). The compounds of the present invention have a potency (IC50) within a range of about 0.5 nM to about 100 μM.
[00381] Results for representative compounds of the invention are shown in Tables A1 and A2.
Table A1 (Cytosolic Calcium studies with stably transfected cells)
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Table A2 (Astrocyte culture test)
Figure imgf000163_0002
Figure imgf000164_0001
[00382]ln 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.
[00383]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.
[00384]The instant compounds of Formula I represent a novel class of mGluRδ 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.
[00385]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.
[00386]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.
[00387]Neuroprotection as well as cognitive enhancement may also be achieved by administration of the instant compounds in combination with NMDA receptor antagonists like Memantine and Neramexane. [00388]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.
[00389] 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.
* * * * *
[00390]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.
[00391 ]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 imgf000167_0001
wherein
R1, R2, and R3, which may be the same or different, each independently represent hydrogen, Chalky!, trifluoromethyl, Ci-6alkoxy, cyano, halogen, or -NR4R5, wherein
R4 and R5, which may be the same or different, each independently represent hydrogen, Ci-6alkyl, or cycloC3-i2alkyl, or R4 and R5, together with the nitrogen atom to which they are attached, represent a 5- or 6- membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more groups selected from Chalky!, halogen, trifluoromethyl, Ci- 6alkoxy, and cyano;
Figure imgf000167_0002
wherein L represents Ci^alkylene, arylene, heteroarylene, -X-Ci^alkylene, or Ci-3alkylene-X-, wherein X represents oxygen or sulfur, and
Cy represents aryl, heteroaryl, cycloCa-^alkyl, cycloC3-i2alkenyl, or heterocyclyl; and R7 represents hydrogen, Ci-6alkyl, Ci-6alkoxy, -C(O)NR8R9, carboxy, or aryl, wherein
R8 and R9, which may be the same or different, each independently represent hydrogen, d-βalkyl, or cycloC3-12alkyl, or R8 and R9, together with the nitrogen atom to which they are attached, represent a 5- or 6- membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more groups selected from Ci-6alkyl, halogen, trifluoromethyl, Ci- βalkoxy, and cyano;
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, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, hydroxyCi-6alkyl, C2-6alkenyl, Ci-6alkoxy,
C-i-βalkoxyC-i-ealkyl, amino, hydroxy, nitro, cyano, formyl, cyanomethyl, Ci- βalkoxycarbonyl, Ci.6alkylcarbonyloxy, Ci-ealkylcarbonyloxyCi-βalkyl, Ci- 6alkylamino, di-(Ci-6alkyl)amino, Ci-βalkylcarbonylamino, phenylcarbonylamino, aminocarbonyl, N-Ci-βalkylaminocarbonyl, di-N.N-Ci-ealkylaminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, cycloC3-i2alkyl, pyridinyl, and optionally
Figure imgf000168_0001
the term "arylene" means a divalent aryl radical as defined above;
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, trifluoromethyl, trifluoromethoxy, d-βalkyl, hydroxyC-i-βalkyl, C2-6alkenyl, d-βalkoxy, amino, hydroxy, nitro, cyano, Ci- 6alkoxycarbonyl, d-βalkoxycarbonyloxy, Ci.6alkylamino, and di-(Ci-6alkyl)amino, d-βalkylcarbonylamino, aminocarbonyl, N-Ci-βalkylaminocarbonyl, di-N, N-Ci- βalkylaminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, cycloC3.i2alkyl, Ci-6alkylenedioxy, aryl, and pyridinyl; and
the term "heteroarylene" means a divalent heteroaryl radical as defined above;
and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
2. A compound as claimed in Claim 1 , wherein L represents Ci^alkylene, arylene, heteroarylene, or -X-Ci^alkylene.
3. A compound as claimed in Claim 2, wherein L represents CH2, CH2CH2, CH(Me), C(Me)2, C(OH)Me, OCH2, phenylene which is optionally substituted by one or more halogen atoms, a divalent pyridinyl group, or a divalent thiophenyl group.
4. A compound as claimed in any of Claims 1 to 3, wherein R1, R2, and R3, which may be the same or different, each independently represent hydrogen, Chalky!, Ci-βalkoxy, or -NR4R5, wherein R4 and R5, which may be the same or different, each independently represent hydrogen or Ci-6alkyl.
5. A compound as claimed in Claim 4, wherein R1, R2, and R3, which may be the same or different, each independently represent hydrogen, methyl, methoxy, amino, t-butylamino, or methoxybenzylamino.
6. A compound as claimed in any preceding claim, wherein R7 represents hydrogen, Ci-6alkyl, Ci-6alkoxy, or -C(O)NR8R9, wherein R8 and R9, which may be the same or different, each independently represent hydrogen or Ci-6alkyl, or R8 and R9, together with the nitrogen atom to which they are attached, represent a 5- or 6- membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more d-βalkyl groups.
7. A compound as claimed in Claim 6, wherein R7 represents hydrogen, methyl, methoxy, or -C(O)NR8R9, wherein R8 and R9, which may be the same or different, each independently represent hydrogen, methyl, ethyl, n-propyl, or isopropyl or R8 and R9 together with the nitrogen atom to which they are attached, represent a pyrrolidine, piperazine or morpholine ring, wherein each of these rings may be optionally substituted by one or more Ci-6alkyl groups.
8. A compound as claimed in any preceding claim, wherein Cy represents an aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally substituted by one or more substituents selected from halogen, trifluoromethyl, C-t^alkyl, hydroxyCi.6alkyl, C1-6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-ealkylcarbonyloxyCi-βalkyl, amino, cyano, formyl, Ci-6alkylcarbonylamino, phenylcarbonylamino, Ci- 6alkoxycarbonyl, and pyridinyl.
9. A compound as claimed in Claim 8, wherein Cy represents phenyl, pyridinyl, thiophenyl, thiazolyl, benzofuryl, dihydrobenzofuryl, or imidazolyl, wherein each of these groups is optionally substituted by one or more substituents selected from halogen, trifluoromethyl, Ci-6alkyl, hydroxyCi-βalkyl, Ci^alkoxy, Ci-βalkoxyCi-βalkyl, Ci-βalkylcarbonyloxyC-i-ealkyl, amino, cyano, formyl, d-βalkylcarbonylamino, phenylcarbonylamino, C-i-βalkoxycarbonyl, and pyridinyl.
10. A compound as claimed in any of Claims 1 to 7, wherein Cy represents a cycloC3-i2alkyl, cycloCa-^alkenyl, or heterocyclyl group, wherein the cycloC3. i2alkyl, cycloCa-^alkenyl, or heterocyclyl group is optionally substituted by one or more substituents selected from d-βalkyl, C-i-βalkoxycarbonyl, oxo, Ci-6alkoxyimino, Ci-ealkylaminocarbonyl, and arylC-i-βalkoxycarbonyl.
11. A compound as claimed in Claim 10, wherein Cy represents cyclopropyl, cyclohexyl, cyclohexenyl, tetrahydropyridinyl, dihydropyranyl, or dihydrothiopyranyl, wherein each of these groups is optionally substituted by one or more substituents selected from C-i-βalkyl, C-i-βalkoxycarbonyl, oxo, Ci-βalkoxyimino, Ci-βalkylaminocarbonyl, and arylC-i-βalkoxycarbonyl.
12. A compound as claimed in Claim 1 , wherein R1, R2, and R3 represent hydrogen; R6 represents = Ar or ~ L = Ar ■ wherein L represents
Figure imgf000171_0001
and X represents oxygen or sulfur; Ar represents aryl or heteroaryl; and R7 represents hydrogen, or methyl.
13. A compound as claimed in Claim 1 , which is selected from: 3-Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-benzonitrile, 3-Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-phenylamine, N-(3-Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-phenyl)-acetamide, 5-(3-Methoxy-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine, 3-Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-benzaldehyde, 5-(3-Bromo-5-fluoro-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine, 5-(3-Fluoro-5-pyridin-3-yl-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine, 5-(3-Fluoro-5-pyridin-4-yl-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine, 5-(4-Fluoro-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine, 5-Phenylethynyl-pyrazolo[1 ,5-a]pyrimidine, 5-(4-Trifluoromethyl-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine, 5-(4-Chloro-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine, 5-p-Tolylethynyl-pyrazolo[1 ,5-a]pyrimidine, 5-(2-Fluoro-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine, 5-m-Tolylethynyl-pyrazolo[1 ,5-a]pyrimidine, 5-o-Tolylethynyl-pyrazolo[1 ,5-a]pyrimidine, 5-(3-Fluoro-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine, 2-Phenyl-5-phenylethynyl-pyrazolo[1 ,5-a]pyrimidine, 5-(3-Trifluoromethyl-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine, 5-(2-Trifluoromethyl-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine, 5-(3-Chloro-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine, 5-(2-Chloro-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine, 5-Pyridin-2-ylethynyl-pyrazolo[1 ,5-a]pyrimidine, 5-Pyridin-3-ylethynyl-pyrazolo[1 ,5-a]pyrimidine,
5-Thiophen-3-ylethynyl-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-phenylethynyl-pyrazolo[1 ,5-a]pyrimidine,
S-Ce-Methyl-pyridin^-ylethynyO-pyrazoloti .δ-alpyrimidine,
5-Phenylethynyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid,
(5-Phenylethynyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperidin-1-yl-methanone,
(5-Phenylethynyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-pyrrolidin-1-yl-methanone,
5-(5-Fluoro-pyridin-2-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-Phenylethynyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid diethylamide,
Morpholin-4-yl-(5-phenylethynyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-methanone,
5-Thiophen-2-ylethynyl-pyrazolo[1 ,5-a]pyrimidine,
(2-Methyl-piperidin-1-yl)-(5-phenylethynyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone,
5-(2,4-Dimethyl-thiazol-5-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(2,3-Dihydro-benzofuran-5-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
(4-Methyl-piperazin-1-yl)-(5-phenylethynyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone,
5-Phenylethynyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid isopropyl-methyl- amide,
5-Benzofuran-2-ylethynyl-pyrazolo[1 ,5-a]pyrimidine,
(2-Methyl-pyrrolidin-1-yl)-(5-phenylethynyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)- methanone,
5-Pyridin-4-ylethynyl-pyrazolo[1 ,5-a]pyrimidine,
5-(3-Methyl-thiophen-2-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(1 -Methyl- 1 H-imidazol-2-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(1-Methyl-3H-imidazol-4-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-Phenylethynyl-pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid dimethyl amide,
(5-Phenylethynyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-piperazin-1-yl-methanone,
5-(5-Methoxy-pyridin-3-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(2-Fluoro-pyridin-3-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
2-Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-isonicotinic acid ethyl ester,
(3-Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-phenyl)-methanol,
5-(3-Methoxymethyl-phenylethynyl)-pyrazolo[1 ,5-a]pyrimidine, Acetic acid 3-pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-benzyl ester,
N-(3-Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-phenyl)-benzamide,
5-[3-Fluoro-5-(2-fluoro-pyridin-3-yl)-phenylethynyl]-pyrazolo[1 J5-a]pyrimidine,
5-[3-Fluoro-5-(2-methoxy-pyridin-3-yl)-phenylethynyl]-pyrazolo[1 ,5-a]pyrimidine, δ-Pyrazoloti .δ-alpyrimidin-δ-ylethynyl-^.S'lbipyridinyl,
2-Fluoro-5l-pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-[3,3']bipyridinyl)
2-Methoxy-5'-pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-[3,3']bipyridinyl,
5-(3-Phenyl-prop-1 -ynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(3-Fluoro-phenyl)-prop-1-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(3-Methoxy-phenyl)-prop-1-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
3-(3-Pyrazolo[1 ,5-a]pyrimidin-5-yl-prop-2-ynyl)-benzonitrile,
3-(3-Pyrazolo[1 ,5-a]pyrimidin-5-yl-prop-2-ynyl)-phenylamine,
5-(3-Phenyl-but-1 -ynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(3-Phenyl-prop-2-ynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(3-Fluoro-phenyl)-prop-2-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(3-Methoxy-phenyl)-prop-2-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
3-(3-Pyrazolo[1 ,5-a]pyrimidin-5-yl-prop-1 -ynyl)-phenylamine,
5-(4-Pyridin-2-yl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-[4-(6-Methyl-pyridin-2-yl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
5-[4-(6-Fluoromethyl-pyridin-2-yl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
5-[4-(2-Methyl-thiazol-4-yl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
5-[4-(2-Fluoromethyl-thiazol-4-yl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
5-[4-(1 -Methyl-1 H-pyrazol-3-yl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
5-(4-Phenyl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(4-Pyridin-3-yl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(4-o-Tolyl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(4-m-Tolyl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-[4-(2-Chloro-phenyl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
5-[4-(2-Fluoro-phenyl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
5-[4-(3-Chloro-phenyl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
5-[4-(3-Fluoro-phenyl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine,
5-(4-Thiophen-3-yl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(4-Thiophen-2-yl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine, -[4-(3-Methyl-thiophen-2-yl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine, -Methyl-5-(4-pyridin-2-yl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine, -Methyl-5-[4-(6-methyl-pyridin-2-yl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine,-[4-(6-Fluoromethyl-pyridin-2-yl)-but-3-ynyl]-2-methyl-pyrazolo[1 ,5-a]pyrimidine,-Methyl-5-[4-(2-methyl-thiazol-4-yl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine,-[4-(2-Fluoromethyl-thiazol-4-yl)-but-3-ynyl]-2-methyl-pyrazolo[1 ,5-a]pyrimidine,-Methyl-5-[4-(1-methyl-1 H-pyrazol-3-yl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine>-Methyl-5-(4-phenyl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine, -Methyl-5-(4-pyridin-3-yl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine, -Methyl-5-(4-o-tolyl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine, -Methyl-5-(4-m-tolyl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine, -[4-(2-Chloro-phenyl)-but-3-ynyl]-2-methyl-pyrazolo[1 ,5-a]pyrimidine, -[4-(2-Fluoro-phenyl)-but-3-ynyl]-2-methyl-pyrazolo[1 ,5-a]pyrimidine, -[4-(3-Chloro-phenyl)-but-3-ynyl]-2-methyl-pyrazolo[1 ,5-a]pyrimidine, -[4-(3-Fluoro-phenyl)-but-3-ynyl]-2-methyl-pyrazolo[1 ,5-a]pyrimidine, -Methyl-5-(4-thiophen-3-yl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine, -Methyl-5-(4-thiophen-2-yl-but-3-ynyl)-pyrazolo[1 ,5-a]pyrimidine, -Methyl-5-[4-(3-methyl-thiophen-2-yl)-but-3-ynyl]-pyrazolo[1 ,5-a]pyrimidine,-(5-Pyridin-2-ylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidine, -[5-(6-Methyl-pyridin-2-ylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidine,-[5-(6-Fluoromethyl-pyridin-2-ylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidine,-[5-(2-Methyl-thiazol-4-ylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidine,-[5-(2-Fluoromethyl-thiazol-4-ylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidine,-[5-(1 -Methyl-1 H-pyrazol-3-ylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidine,-(5-Phenylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidine, -(5-Pyridin-3-ylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidine, -(5-o-Tolylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidine, -(5-m-Tolylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidine, -[5-(2-Chloro-phenylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidine, -[5-(2-Fluoro-phenylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidine, -[5-(3-Chloro-phenylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidine, -[5-(3-Fluoro-phenylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidine, -(5-Thiophen-3-ylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidine, 5-(5-Thiophen-2-ylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidine,
S-Iδ^S-Methyl-thiophen^-ylethynyO-thiophen^-ylJ-pyrazolofi .δ-alpyrimidine, tert-Butyl-[5-(5-pyridin-2-ylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidin-7-yl]- amine,
5-Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-nicotinic acid methyl ester, tert-Butyl-{5-[5-(6-methyl-pyridin-2-ylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5- a]pyrimidin-7-yl}-amine, tert-Butyl-{5-[5-(6-fluoromethyl-pyridin-2-ylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5- a]pyrimidin-7-yl}-amine, tert-Butyl-{5-[5-(2-methyl-thiazol-4-ylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5- a]pyrimidin-7-yl}-amine, tert-Butyl-{5-[5-(2-fluoromethyl-thiazol-4-ylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5- a]pyrimidin-7-yl}-amine, tert-Butyl-{5-[5-(1-methyl-1 H-pyrazol-3-ylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5- a]pyrimidin-7-yl}-amine, tert-Butyl-[5-(5-phenylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidin-7-yl]-amine, tert-Butyl-[5-(5-pyridin-3-ylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidin-7-yl]- amine, tert-Butyl-[5-(5-o-tolylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidin-7-yl]-amine, tert-Butyl-[5-(5-m-tolylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidin-7-yl]-amine, tert-Butyl-{5-[5-(2-chloro-phenylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidin-7- yl}-amine, tert-Butyl-{5-[5-(2-fluoro-phenylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidin-7- yl}-amine, tert-Butyl-{5-[5-(3-chloro-phenylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidin-7- yl}-amine, tert-Butyl-{5-[5-(3-fluoro-phenylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5-a]pyrimidin-7- yl}-amine, tert-Butyl-[5-(5-thiophen-3-ylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidin-7-yl]- amine, tert-Butyl-[5-(5-thiophen-2-ylethynyl-thiophen-2-yl)-pyrazolo[1 ,5-a]pyrimidin-7-yl]- amine, tert-Butyl-{5-[5-(3-methyl-thiophen-2-ylethynyl)-thiophen-2-yl]-pyrazolo[1 ,5- a]pyrimidin-7-yl}-amine,
5-(3-Pyridin-2-yl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-(3-pyridin-2-yl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(6-Methyl-pyridin-2-yl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-[3-(6-methyl-pyridin-2-yl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(6-Fluoromethyl-pyridin-2-yl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(6-Fluoromethyl-pyridin-2-yl)-prop-2-ynyloxy]-2-methyl-pyrazolo[1 ,5- a]pyrimidine,
5-[3-(2-Methyl-thiazol-4-yl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-[3-(2-methyl-thiazol-4-yl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(2-Fluoromethyl-thiazol-4-yl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(2-Fluoromethyl-thiazol-4-yl)-prop-2-ynyloxy]-2-methyl-pyrazolo[1 ,5- a]pyrimidine,
5-[3-(1 -Methyl-1 H-pyrazol-3-yl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-[3-(1 -methyl-1 H-pyrazol-3-yl)-prop-2-ynyloxy]-pyrazolo[1 ,5- a]pyrimidine,
5-(3-Phenyl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-(3-phenyl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine,
5-(3-Pyridin-3-yl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-(3-pyridin-3-yl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine,
5-(3-o-Tolyl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-(3-o-tolyl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine,
5-(3-m-Tolyl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-(3-m-tolyl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(2-Chloro-phenyl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(2-Chloro-phenyl)-prop-2-ynyloxy]-2-methyl-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(2-Fluoro-phenyl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(2-Fluoro-phenyl)-prop-2-ynyloxy]-2-methyl-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(3-Chloro-phenyl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(3-Chloro-phenyl)-prop-2-ynyloxy]-2-methyl-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(3-Fluoro-phenyl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(3-Fluoro-phenyl)-prop-2-ynyloxy]-2-methyl-pyrazolo[1 ,5-a]pyrimidine, 5-(3-Thiophen-3-yl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrirnidine,
2-Methyl-5-(3-thiophen-3-yl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine,
5-(3-Thiophen-2-yl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-(3-thiophen-2-yl-prop-2-ynyloxy)-pyrazolo[1 ,5-a]pyrimidine,
5-[3-(3-Methyl-thiophen-2-yl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
2-Methyl-5-[3-(3-methyl-thiophen-2-yl)-prop-2-ynyloxy]-pyrazolo[1 ,5-a]pyrimidine,
5-(5-Bromo-pyridin-3-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-Cyclohexylethynyl-pyrazolo[1 ,5-a]pyrimidine,
5-Cyclohex-1 -enylethynyl-pyrazolo[1 ,5-a]pyrimidine,
5-Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-[3,4']bipyridinyl, δ^.e-Dimethyl-cyclohex-i-enylethynyO-pyrazoloti .δ-aJpyrimidine,
2-Phenyl-4-pyrazolo[1 l5-a]pyrimidin-5-yl-but-3-yn-2-ol,
4-Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-3,6-dihydro-2H-pyridine-1 -carboxylic acid tert-butyl ester,
5-(3,6-Dihydro-2H-pyran-4-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(3,6-Dihydro-2H-thiopyran-4-ylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(3-Methyl-3-phenyl-but-1 -ynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-(2>6,6-Trimethyl-cyclohex-1-enylethynyl)-pyrazolo[1 ,5-a]pyrimidine,
5-Cyclopropylethynyl-pyrazolo[1 ,5-aJpyrimidine,
3-Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-cyclohex-2-enone,
3-Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-cyclohex-2-enone O-methyl-oxime,
4-Pyrazolo[1 ,5-a]pyrimidin-5-ylethynyl-3,6-dihydro-2H-pyridine-1 -carboxylic acid isopropylamide,
4-Pyrazolo[1.δ-aJpyrimidin-δ-ylethynyl-S.β-dihydro^H-pyridine-i -carboxylic acid benzyl ester, and
optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
14. A pharmaceutical composition comprising a compound as claimed in any preceding claim, together with one or more pharmaceutically acceptable excipients.
15. A compound as claimed in any of Claims 1 to 13 for the prevention and/or treatment of a condition or disease associated with abnormal glutamate neurotransmission or for modulating mGluR5 receptors to achieve therapeutic benefit.
16. A compound as claimed in Claim 15, wherein the condition associated with abnormal glutamate transmission, or wherein modulation of mGluRδ 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 and sleep disturbances.
17. Use of a compound as claimed in any of Claims 1 to 13 for the manufacture of a medicament for treating or preventing a condition or disease associated with abnormal glutamate neurotransmission, or for modulating mGluRδ receptors to achieve therapeutic benefit.
18. Use as claimed in Claim 17, wherein the condition associated with abnormal glutamate transmission, or wherein modulation of mGluRδ receptors results in therapeutic benefit is selected from: Alzheimer's disease, Creutzfeld-Jakob's syndrome/disease, bovine spongiform encephalopathy (BSE)1 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 and sleep disturbances.
19. A method for treating or preventing a condition or disease associated with abnormal glutamate neurotransmission, or a method for modulating mGluRδ 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 13.
20. The method as claimed in Claim 19, wherein the condition associated with abnormal glutamate transmission, or wherein modulation of mGluRδ 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), 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 and sleep disturbances, such method comprising the step of administering to a living animal, including a human, a therapeutically effective amount of a compound as claimed in any of Claims 1 to 13.
21. A pharmaceutical composition comprising a combination of at least one compound as claimed in any of Claims 1 to 13 and at least one NMDA receptor antagonist, together with one or more pharmaceutically acceptable excipients.
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US8637526B2 (en) * 2008-10-31 2014-01-28 Genentech, Inc. Pyrazolopyrimidine JAK inhibitor compounds and methods
US8999998B2 (en) 2009-07-02 2015-04-07 Genentech, Inc. Pyrazolopyrimidine JAK inhibitor compounds and methods
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JP2017504648A (en) * 2014-01-31 2017-02-09 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ (Hetero) arylimidazoles / pyrazoles for the treatment of neurological disorders
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US10316044B2 (en) 2015-07-02 2019-06-11 Tp Therapeutics, Inc. Chiral diaryl macrocycles as modulators of protein kinases
US11529359B2 (en) 2016-01-27 2022-12-20 Universitat Zurich Use of GABAA receptor modulators for treatment of itch
US10307426B2 (en) 2017-05-22 2019-06-04 Genentech, Inc. Therapeutic compounds and compositions, and methods of use thereof
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