WO2016046404A1 - Substituted pyrazoloquinazolinones and pyrroloquinazolinones as allosteric modulators of group iimetabotropic glutamate receptors - Google Patents

Substituted pyrazoloquinazolinones and pyrroloquinazolinones as allosteric modulators of group iimetabotropic glutamate receptors Download PDF

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WO2016046404A1
WO2016046404A1 PCT/EP2015/072178 EP2015072178W WO2016046404A1 WO 2016046404 A1 WO2016046404 A1 WO 2016046404A1 EP 2015072178 W EP2015072178 W EP 2015072178W WO 2016046404 A1 WO2016046404 A1 WO 2016046404A1
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alkyl
pyridin
methyl
pyrazolo
quinazolin
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PCT/EP2015/072178
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French (fr)
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Stephan Schann
Stanislas Mayer
Baptiste Manteau
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Domain Therapeutics
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Priority to CN201580064277.3A priority Critical patent/CN107223126A/en
Priority to EP15778627.8A priority patent/EP3197897A1/en
Priority to JP2017516453A priority patent/JP2017534588A/en
Priority to CA2962121A priority patent/CA2962121A1/en
Priority to AU2015323708A priority patent/AU2015323708B2/en
Priority to US15/514,431 priority patent/US10221179B2/en
Publication of WO2016046404A1 publication Critical patent/WO2016046404A1/en
Priority to IL251230A priority patent/IL251230A0/en
Priority to US16/251,646 priority patent/US20190152979A1/en

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Definitions

  • the present invention provides pyrazoloquinazolinone and pyrroloquinazolinone derivatives of the general formula (I) and pharmaceutical compositions containing them. Moreover, the compounds of formula (I) and the compositions containing them are provided for use in the treatment and/or prophylaxis of conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling in mammals.
  • pyrazoloquinazolinone and pyrroloquinazolinone derivatives of the general formula (I) can act as modulators of nervous system receptors sensitive to glutamate, in particular as modulators of metabotropic glutamate receptors (mGluRs), which makes them particularly suitable for the treatment and/or prophylaxis of acute and chronic neurological and/or psychiatric disorders.
  • Glutamatergic pathways have been shown to be clearly involved in the physiopathology of a number of neuronal damages and injuries.
  • Many nervous system disorders including epilepsy and chronic or acute degenerative processes, such as for example Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis (Mattson MP., Neuromolecular Med., 3(2), 65-94, 2003), but also AIDS-induced dementia, multiple sclerosis, spinal muscular atrophy, retinopathy, stroke, ischemia, hypoxia, hypoglycaemia and various traumatic brain injuries, involve neuronal cell death caused by imbalanced levels of glutamate.
  • compounds modulating glutamate level or signalling may be of great therapeutic value for diseases and/or disorders not directly mediated by glutamate levels and/or glutamate receptor malfunctioning, but which could be affected by alteration of glutamate levels or signalling.
  • L-glutamate is the main excitatory neurotransmitter and is referred to as an excitatory amino-acid (EAA), and gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter.
  • EAA excitatory amino-acid
  • GABA gamma-aminobutyric acid
  • Glutamate is ubiquitously distributed in the nervous system in high concentrations, especially in the brain and spinal cord of mammals, where it is working at a variety of excitatory synapses being thereby involved in virtually all physiological functions such as motor control, vision, central control of heart, processes of learning and memory.
  • excitotoxicity This combination of neuroexcitatory activities and neurotoxic properties is called excitotoxicity.
  • Glutamate operates through two classes of receptors (Brauner-Osborne H et al., J. Med. Chem. 43(14), 2609-45, 2000).
  • the first class of glutamate receptors is directly coupled to the opening of cation channels in the cellular membrane of the neurons. Therefore they are called ionotropic glutamate receptors (IGluRs).
  • IGluRs ionotropic glutamate receptors
  • the IGluRs are divided in three subtypes, which are named according to the depolarizing action of their selective agonists: N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AM PA), and kainic acid (KA).
  • NMDA N-methyl-D-aspartate
  • AM PA a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid
  • KA kainic acid
  • the second class of glutamate receptor consists of G-protein coupled receptors (GPCRs) called metabotropic glutamate receptors (mGluRs). These mGluRs are localized both pre- and post-synaptically. They are coupled to multiple second messenger systems and their role is to regulate the activity of the ionic channels or enzymes producing second messengers via G- proteins binding the GTP (Nicoletti F et al.; Neuropharmacol., 60(7-8), 1017-41 , 201 1 ).
  • GPCRs G-protein coupled receptors
  • mGluRs metabotropic glutamate receptors
  • mGluRs modulate the efficacy of the synapses by regulating either the post-synaptic channels and their receptors, or the pre-synaptic release or recapture of glutamate. Therefore, mGluRs play an important role in a variety of physiological processes such as long-term potentiation and long- term depression of synaptic transmission, regulation of baroreceptive reflexes, spatial learning, motor learning, and postural and kinetic integration. To date, eight mGluRs have been cloned and classified in three groups according to their sequence homologies, pharmacological properties and signal transduction mechanisms.
  • Group I is constituted of mGluRI and mGluR5, group II of mGluR2 and mGluR3 and group III of mGluR4, mGluR6, mGluR7 and mGluR8 (Schoepp DD et al., Neuropharmacology, 38(10), 1431 -76, 1999).
  • mGluR modulators can be classified into two families depending on their site of interaction with the receptor (see Brauner-Osborne H et al., J. Med. Chem. 43(14), 2609-45, 2000 for review).
  • the first family consists in orthosteric modulators (or competitive modulators) able to interact with the glutamate binding-site of the mGluRs, which is localized in the large extra-cellular N- terminal part of the receptor (about 560 amino acids). Therefore, they are glutamate analogs and constitute a highly polar family of ligand.
  • orthosteric modulators are S-DHPG or LY-367385 for group I mGluRs, LY-354740 or LY-379268 for group II mGluRs and ACPT-I or L-AP4 for group III mGluRs.
  • the second family of mGluR modulators consists in allosteric modulators that interact with a different site from the extracellular active site of the receptor (see Bridges TM et al., ACS Chem Biol, 3(9), 530-41 , 2008 for review). Their action results in a modulation of the effects induced by the endogenous ligand glutamate.
  • allosteric modulators are Ro-674853, MPEP or JNJ16259685 for group I mGluRs and CBiPES, BINA, LY487379 or R04491533 for group II mGluRs and PHCCC, VU0155041 or VU0359516 for group III mGluRs.
  • mGluR allosteric modulators stabilize a receptor conformation and equilibrium shift that increases or decreases the affinity and/or efficacy of an orthosteric agonist of the receptor, without activating the receptor on its own (Bridges TM et al., ACS Chem Biol, 3(9), 530-41 , 2008).
  • Such modulators are respectively termed positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs).
  • Group II mGluR activation or potentiation has been shown to be associated with positive effects in animal models of anxiety (Swanson CJ.; Nat Rev Drug Discov, 4, 131-44, 2005), schizophrenia (Conn PJ et al.; Trends in Pharmacol Sci, 30, 25-31 , 2009), drug-addiction (Adewale AS et al.; J Pharmacol Exp Ther, 318, 922-31 , 2006) or chronic pain (Jones CK et al.; Neuropharmacology, 49 (Suppl 1 ), 206-18, 2005).
  • Antagonists and NAMs of group II mGluRs have been shown to exert antidepressant-like and cognitive enhancing properties (Chaki S et al.; Neuropharmacology, 46, 457-67, 2004 - Higgins GA et al.; Neuropharmacology, 46, 907-17, 2004 - Yoshimizu T and Shaki S.; Biochem Biophys Res Commun, 315, 493-6, 2004 - Knoflach F et al.; 5 th International Meeting on Metabotropic Glutamate Receptors, Taormina Italy, 2005 - Yoshimizu T et al.; Psychopharmacology (Berl), 183, 587-93, 2006 - Campo B et al.; Annual Meeting of the Society for Neuroscience, Chicago IL, 2009, 343.8 - Kalinichev M et al.; Annual Meeting of the Society for Neuroscience, San Diego CA, 2010, 406.9 - Kalinichev M et al.; Annual Meeting of the Society for Neuroscience
  • group II mGluR PAMs Numerous examples of group II mGluR PAMs have already been described in research articles and patent literature (see Trabanco AA, et al.; Curr Med Chem, 18(1 ), 47-68, 201 1 for review). However, less information is available regarding group II mGluR NAMs.
  • Benzodiazepinone derivatives (Woltering TJ, et al.; Bioorg Med Chem Lett, 17, 681 1 -5, 2007 - Woltering TJ, et al.; Bioorg Med Chem Lett, 18, 1091-5, 2008; Woltering TJ, et al., Bioorg Med Chem Lett, 18, 2725-9, 2008; Woltering TJ, et al., Bioorg Med Chem Lett, 20, 6969-74, 2010; and WO 2013/033246), pyrazolopyrimidine derivatives (WO 2005/040171 , WO 2005/123738, WO 2006/084634, WO 2006/099072 and WO2007/039439), pyridine / pyrimidine derivatives (WO 2007/1 10337 and WO 2007/1 19689), pyrazoloquinazolinone and pyrroloquinazolinone derivatives (WO 2013/174822; EP-A-2666775), heteroaryl-
  • group II mGluR NAMs Little information is available with regard to the selectivity of group II mGluR NAMs for either mGluR2 or mGluR3.
  • Some of the group II mGluR NAMs mentioned in the previous paragraph like R04491533, R04988546, RO5488608 or certain pyrazoloquinazolinone derivatives, have been described as non-selective group II NAMs blocking both mGluR2 and mGluR3 with similar potency and efficacy (Woltering TJ, et al., Bioorg Med Chem Lett, 20, 6969-74, 2010; Lundstrom L, et al., British Journal of Pharmacology, 164, 521-37, 201 1 ; Wenthur CJ, et al., Bioorg Med Chem Lett, 24, 2693-98, 2014).
  • mGluR3 NAM LY2389575 was previously reported as amplifying neurotoxicity induced by ⁇ amyloid (Caraci F, et al., Molecular Pharmacology, 79(3), 618-26, 201 1 ). It would therefore be advantageous to develop group II mGluR NAMs that are selective for mGluR2 over mGluR3 for the treatment of CNS disorders, and more particularly for the treatment of neurodegenerative disorders like Alzheimer's disease.
  • compounds of formula (I) constitute potent NAMs of the mGluR2 subtype, showing an advantageous selectivity for mGluR2 over mGluR3.
  • compounds of formula (I) constitute potent NAMs of the mGluR2 subtype, showing an advantageous selectivity for mGluR2 over mGluR3.
  • the compounds of the present invention are thus highly advantageous in terms of their mGluR2/3 selectivity.
  • structurally related compounds disclosed in WO 2013/174822 and EP-A-2666775 such as the compounds A and B shown below, have a similar potency on mGluR2 (IC 50 ⁇ 100 nM) but lack selectivity for mGluR2 over mGluR3 (ratio [ICso hmGluR3] / [IC 50 hmGluR2] ⁇ 1 ).
  • the two reference drugs R04491533 and decoglurant (RG1578), which are known group II mGluR NAMs, also display a ratio [IC 50 hmGluR3] / [IC 50 hmGluR2] ⁇ 1 when tested under the same conditions, and thus likewise lack selectivity for mGluR2 over mGluR3.
  • Pyrazoloquinazolinone structures have further been described as poly(ADP-ribose)polymerase (PARP) inhibitors in Orvieto F, et al., Bioorg Med Chem Lett, 2009, 19(15):4196-4200 and also in the patent applications WO 2007/144669, WO 2007/149907 and WO 2008/090379.
  • These pyrazoloquinazolinones mimick the nicotinamide moiety of NAD + , the cofactor of PARP, and therefore invariably comprise an unsubstituted lactam nitrogen, i.e. a hydrogen in position 4 of the pyrazoloquinazolinone scaffold, as an essential feature.
  • the compounds of the present invention are substituted at position 4 of the pyrazoloquinazolinone ring and thus form a different class of therapeutic agents.
  • Pyrazoloquinazolinone structures were also described as anti-secretory, anti-inflammatory, anti-allergic and anti-parasitic agents in patent documents US 4,105,764 and US 4, 105,766 or as photographic material in patent applications such as EP0374781 , JP4003154, JP4003155, JP4009050, JP4039656, JP4037741 or JP4037748.
  • the invention hence solves the problem of providing improved means and methods for the medical intervention in diseases, disorders and conditions associated with altered glutamatergic signalling and/or functions as well as conditions which can be affected by alteration of glutamate level or signalling in mammals, in particular for the treatment and/or prophylaxis of acute and chronic neurological and/or psychiatric disorders.
  • the present invention relates to a compound of the general formula (I):
  • A represents N or -CH.
  • R 1 , R 2 and R 4 are each independently selected from R 7 , halogen, -CN, -OR 7 , -NR 7 R 8 , -COOR 7 , -SO 3 H, -B(OH) 2 , -CONR 7 R 8 , -COR 7 , -SR 7 ,
  • R 3 is selected from hydrogen, halogen, -CN, -OR 7 , -NR 7 R 8 , -COOR 7 , -S0 3 H, - B(OH) 2 , -CONR 7 R 8 , -COR 7 , -SR 7 , -SOR 7 , -S0 2 R 7 , -S0 2 NR 7 R 8 , -NR 7 COR 8 , - NR 7 S0 2 R 8 , -OCOR 7 , -NR 7 C(0)NR 8 R 9 , -NR 7 C(S)NR 8 R 9 , -NR 7 COOR 8 , C1-C4 alkyl, C 2 -C 4 alkenyl, cycloalkyi or heterocycloalkyi, wherein said C1-C4 alkyl and said C 2 -C 4 alkenyl are each optionally substituted with one or more groups independently selected from halogen, - CF 3 , -CN, -OH
  • R 5 is heteroaryl which is optionally substituted with one or more groups independently selected from R 7 , halogen, -CN, -NR 7 R 8 , -CONR 7 R 8 , -COR 7 , -OR 7 , -SR 7 , -SOR 7 , -S0 2 R 7 , - S0 2 NR 7 R 8 , -NR 7 COR 8 , -NR 7 S0 2 R 8 , -OCOR 7 , or -COOR 7 .
  • R 6 is selected from C1-C4 alkyl, cycloalkyi, or heterocycloalkyi, wherein said C1-C4 alkyl is optionally substituted with one or more groups independently selected from cycloalkyi, halogen, -CF 3 , -CN, -OH or -0(CrC 4 alkyl), and further wherein, if R 6 is cycloalkyi or heterocycloalkyi, then said cycloalkyi and said heterocycloalkyi are each optionally substituted with one or more groups independently selected from C1-C4 alkyl, cycloalkyi, halogen, - CF 3 , -CN, -OH or -0(Ci-C 4 alkyl).
  • Each R 7 , R 8 and R 9 is independently selected from hydrogen, C1-C4 alkyl, C 2 -C 4 alkenyl, cycloalkyi, cycloalkenyl, heterocycloalkyi, heterocycloalkenyl, aryl or heteroaryl, wherein said C1-C4 alkyl and said C 2 -C 4 alkenyl are each optionally substituted with one or more groups independently selected from halogen, -CF 3 , -CN, cycloalkyi, cycloalkenyl, heterocycloalkyi, heterocycloalkenyl, aryl, heteroaryl, -OH, -0(C C 4 alkyl), -N H 2 , -NH(Ci-C 4 alkyl) or -N(Ci-C 4 alkyl)(Ci-C 4 alkyl), and further wherein, if R 7 , R 8 or R 9 is cycloalkyi, cycloalkenyl,
  • the present invention further provides novel compounds.
  • the invention in particlar, in a second aspect, relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof as described and defined in the first aspect of the invention, with the proviso that the following compounds are excluded:
  • the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof as described and defined in the first aspect of the invention, wherein the groups/variables A, R 1 , R 2 and R 4 to R 9 have the same meanings as defined in the first aspect of the invention, and wherein the group R 3 is selected from hydrogen, -F, -CI, -I, -CN, -OR 7 , -NR 7 R 8 , -COOR 7 , -S0 3 H, -B(OH) 2 , -CONR 7 R 8 , - COR 7 , -SR 7 , -SOR 7 , -S0 2 R 7 , -S0 2 NR 7 R 8 , -NR 7 COR
  • the present invention provides a pharmaceutical composition containing a compound of formula (I) as defined in the first, second or third aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and optionally a pharmaceutically acceptable excipient.
  • the invention further relates to the compounds of formula (I) as well as their pharmaceutically acceptable salts, solvates and prodrugs as defined in the first, second or third aspect for use in the treatment and/or prophylaxis of conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling.
  • the invention likewise relates to a pharmaceutical composition containing a compound of formula (I) as defined in the first, second or third aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and optionally a pharmaceutically acceptable excipient, for use in the treatment and/or prophylaxis of conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling.
  • a pharmaceutical composition containing a compound of formula (I) as defined in the first, second or third aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and optionally a pharmaceutically acceptable excipient, for use in the treatment and/or prophylaxis of conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling.
  • the present invention also relates to the use of a compound of formula (I) as defined in the first, second or third aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the preparation of a medicament for the treatment and/or prophylaxis of conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling.
  • the invention further provides a method of treating and/or preventing conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling in a mammal.
  • the invention relates to a method of treating and/or preventing a disease or disorder, in particular a condition associated with altered glutamatergic signalling and/or functions, and/or a condition which can be affected by alteration of glutamate level or signalling, the method comprising the administration of a compound of formula (I) as defined in the first, second or third aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising any of the aforementioned entities and optionally a pharmaceutically acceptable excipient, to a subject (preferably a mammal, more preferably a human) in need of such treatment or prevention.
  • a subject preferably a mammal, more preferably a human
  • the compounds of formula (I) as defined in the first, second or third aspect of the invention can be used as modulators of mGluRs of the nervous system, preferably as allosteric modulators of the mGluRs, more preferably as negative allosteric modulators (NAMs) of group II mGluRs, even more preferably as NAMs of mGluR2, and yet even more preferably as NAMs of mGluR2 that are selective for mGluR2 over mGluR3. It is preferred that such NAMs that are selective for mGluR2 over mGluR3 have a ratio of [IC 50 mGluR3] / [IC 50 mGluR2] > 3, more preferably > 5, and even more preferably > 10. The ratio [IC 5 o mGluR3] / [IC 5 o mGluR2] can be determined as described in Example 127.
  • the invention relates to the compounds of formula (I) as defined in the first, second or third aspect, their pharmaceutically acceptable salts, solvates and prodrugs, as well as pharmaceutical compositions comprising any of the aforementioned entities and optionally a pharmaceutically acceptable excipient, for use in the treatment and/or prophylaxis of conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling.
  • the conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling, to be treated and/or prevented with the compounds or the pharmaceutical compositions according to the invention include in particular: epilepsy, including newborn, infantile, childhood and adult syndromes, partial (localization-related) and generalized epilepsies, with partial and generalized, convulsive and non-convulsive seizures, with and without impairment of consciousness, and status epilepticus; Dementias and related diseases, including dementias of the Alzheimer's type (DAT), Alzheimer's disease, Pick's disease, vascular dementias, Lewy- body disease, dementias due to metabolic, toxic and deficiency diseases (including alcoholism, hypothyroidism, and vitamin B12 deficiency), AIDS-dementia complex, Creutzfeld- Jacob disease and atypical subacute spongiform encephalopathy; Parkinsonism and movement disorders, including Parkinson's disease, multiple system atrophy, progressive supra
  • the present invention relates to a compound of formula (I), as described and defined in the first, second or third aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition containing any of the aforementioned entities and optionally a pharmaceutically acceptable excipient, for use in the treatment and/or prophylaxis of any of the above-mentioned diseases, disorders or conditions.
  • the invention also encompasses methods for the treatment and/or prophylaxis of any of the above-mentioned diseases, disorders or conditions, comprising administering an effective amount of a compound of formula (I), as defined in the first, second or third aspect, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition containing any of the aforementioned entities and optionally a pharmaceutically acceptable excipient, to a subject in need thereof (preferably a mammal, more preferably a human).
  • a subject in need thereof preferably a mammal, more preferably a human.
  • the conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling, to be treated and/or prevented by the compounds or the pharmaceutical compositions according to the invention include: Dementias and related diseases, including dementias of the Alzheimer's type (DAT), Alzheimer's disease, Pick's disease, vascular dementias, Lewy-body disease, dementias due to metabolic, toxic and deficiency diseases (including alcoholism, hypothyroidism, and vitamin B12 deficiency), AIDS-dementia complex, Creutzfeld-Jacob disease and atypical subacute spongiform encephalopathy; Parkinsonism and movement disorders, including Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, hepatolenticular degeneration, chorea (including Huntington's disease and hemiballismus), athetosis, dystonias (including spasmodic tortic
  • the compounds and the pharmaceutical compositions according to the invention are envisaged to be used particularly in the treatment or prevention/prophylaxis of the following conditions/diseases/disorders: Dementias and related diseases, including dementias of the Alzheimer's type (DAT), Alzheimer's disease, Pick's disease, vascular dementias, Lewy-body disease, dementias due to metabolic, toxic and deficiency diseases (including alcoholism, hypothyroidism, and vitamin B12 deficiency), AIDS-dementia complex, Creutzfeld-Jacob disease and atypical subacute spongiform encephalopathy; Mood disorders, including depressive disorders and bipolar disorders; Endocrine and metabolic diseases including diabetes, disorders of the endocrine glands and hypoglycaemia; or cancers, including gliomas, colorectal cancer, melanoma, prostate cancer.
  • DAT Alzheimer's type
  • Alzheimer's disease Alzheimer's disease
  • Pick's disease vascular dementias
  • the present invention relates to the compounds of formula (I), as defined in the first, second or third aspect, their pharmaceutically acceptable salts, solvates and prodrugs, as well as pharmaceutical compositions comprising any of the aforementioned entities and optionally a pharmaceutically acceptable excipient, for use in the treatment or prevention/prophylaxis of any of the above-mentioned conditions/diseases/disorders.
  • the invention relates to a compound of formula (I) as defined in the first, second or third aspect, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising any of the aforementioned entities and optionally a pharmaceutically acceptable excipient, for use in the treatment or prevention/prophylaxis of Alzheimer's disease.
  • the present invention thus provides a compound of formula (I) as defined in the first, second or third aspect, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising any of the aforementioned entities and optionally a pharmaceutically acceptable excipient, for use in the treatment or prophylaxis of a neurodegenerative disorder (particularly Alzheimer's disease).
  • the present invention furthermore provides a method for identifying an agent that binds to metabotropic glutamate receptor 2 (mGluR2), or in other words for determining the capability of one or more test agent(s) to bind to mGluR2, comprising the following steps: (a) contacting mGluR2 with a compound of the present invention (i.e., a compound of formula (I) as defined in the first, second or third aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof) which is labeled, preferably radio-labeled or fluorescence-labeled, under conditions that permit binding of the compound to mGluR2, thereby generating a bound, labeled compound; (b) detecting a signal that corresponds to the amount of the bound, labeled compound in the absence of test agent; (c) contacting the bound, labeled compound with a test agent; (d) detecting a signal that corresponds to the amount of the bound labeled compound in the presence of test agent; and
  • a substantially unchanged signal detected in step (d) in comparison with the signal detected in step (b) indicates that the test agent does not bind to the receptor, or binds to the receptor less strongly than the compound according to the invention.
  • a decreased or increased signal detected in step (d) in comparison with the signal detected in step (b) indicates that the test agent binds to the receptor.
  • agents that bind to mGluR2 can be identified among the test agents employed in this method. It will further be understood that it is preferred to remove unbound labeled compounds, e.g. in a washing step, before carrying out steps (b) and (d).
  • the method may be carried out in any suitable in vitro environment, e.g., in an aqueous solution which may be provided, e.g., in a flask, a test tube, a Petri dish, or a microtiter plate.
  • an aqueous solution which may be provided, e.g., in a flask, a test tube, a Petri dish, or a microtiter plate.
  • the mGluR2 that is used in the above method may be a human form (Flor PJ, et al. Eur J Neurosci. 1995. 7(4):622-629), e.g., a protein of the accession number NP_000830.2, or a protein having at least 80% (preferably at least 90%, more preferably at least 95%, even more preferably at least 99%) amino acid identity to said protein of the accession number NP_000830.2, or a non-human form, including e.g. a mouse form or a homolog thereof found in a different species (e.g.
  • a mutein of any of the aforementioned entities wherein the mutein retains the mGluR2 activity Said mutein can preferably be obtained by substitution, insertion, addition and/or deletion of one or more (such as, e.g., 1 to 20, including 1 to 10 or 1 to 3) amino acid residues of said aforementioned entities.
  • the mGluR2 to be used in the above method may also be a functional fragment of any of the aforementioned entities (including said muteins), i.e.
  • a fragment which retains the mGluR2 activity of the respective aforementioned entity or, in other words, a fragment having essentially the same biological activity (i.e., at least about 60% activity, preferably at least about 70% activity, more preferably at least about 80% activity, even more preferably at least about 90% activity) as the respective aforementioned entity.
  • a skilled person is readily in a position to determine whether mGluR2 activity is retained using techniques known in the art, e.g., knock-out and rescue experiments.
  • the mGluR2 to be used in the above method may also be a compound comprising any one or more of the aforementioned entities (including, without limitation, a protein of the accession number NP_000830.2, a protein having at least 80% amino acid identity to said protein of the accession number NP_000830.2, or a functional fragment thereof), wherein the mGluR2 activity is retained.
  • the mGluR2 to be used in the above method is human mGluR2.
  • A represents N or -CH.
  • A is N.
  • R 1 , R 2 and R 4 are each independently selected from R 7 , halogen, -CN, -OR 7 , -NR 7 R 8 , -COOR 7 , -SO 3 H, -B(OH) 2 , -CONR 7 R 8 , -COR 7 , -SR 7 ,
  • R 1 , R 2 and R 4 are each independently selected from R 7 , halogen, -CN, -OR 7 , -NR 7 R 8 , -COOR 7 , -S0 3 H, -B(OH) 2 , -CONR 7 R 8 , -COR 7 , -SR 7 , - SOR 7 , -S0 2 R 7 , -S0 2 NR 7 R 8 , -NR 7 COR 8 ,
  • R 1 , R 2 and R 4 are each independently selected from R 7 , halogen, -CN, -OR 7 , -NR 7 R 8 , -CONR 7 R 8 , - COR 7 , or -NR 7 COR 8 .
  • R 1 , R 2 and R 4 are each independently selected from hydrogen, halogen (e.g., -F, -CI or -Br), C1-C4 haloalkyl (e.g., -CF 3 ), C1-C4 haloalkoxy (e.g., -OCF 3 ), -CN, C1-C4 alkyl, C 2 -C 4 alkenyl, cycloalkyi, heterocycloalkyl, aryl, heteroaryl, -OH, -0(d-C 4 alkyl), -0-(d-C 4 alkylene)-OH, -0-(C C 4 alkylene)-0(Ci-C 4 alkyl), -O-cycloalkyl, -0-(Ci-C 4 alkylene)-cycloalkyl, -O-heterocycloalkyl, -0-(Ci-C 4 alkylene)-heterocycloalkyl, -0-
  • R 1 , R 2 and R 4 are each independently selected from hydrogen, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, C1-C4 alkyl, C 2 -C 4 alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -0(C C 4 alkyl), -0-(d-C 4 alkylene)-OH, -0-(C C 4 alkylene)-0(Ci-C 4 alkyl), -O-cycloalkyl, -0-(Ci-C 4 alkylene)-cycloalkyl, -O-heterocycloalkyl, -0-(Ci-C 4 alkylene)-heterocycloalkyl, -O-aryl, -0-(Ci-C 4 alkylene)-aryl, -O-heteroaryl, -0-(Ci-C 4 alky
  • R 1 , R 2 and R 4 are each independently selected from hydrogen, halogen, d-d haloalkyl, d-d haloalkoxy, -CN, d-d alkyl, d-d alkenyl, cycloalkyl, heterocycloalkyl, -OH, -0(d-C 4 alkyl), -0-(d-d alkylene)-OH, -0-(d-d alkylene)-0(d-d alkyl), -O-cycloalkyl, -0-(d-d alkylene)-cycloalkyl, -O-heterocycloalkyl, -0-(Crd alkylene)-heterocycloalkyl, -NH 2 , -NH(Ci- d alkyl), -N(d-d alkyl)(d-d alkyl), -NH-cycloalkyl, -N(d-d alkyl)-N(d-
  • R 1 , R 2 and R 4 are each independently selected from hydrogen, halogen, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, Ci-C 4 alkyl, -OH, -0(C C 4 alkyl), -NH(C C 4 alkyl), or -N(C C 4 alkyl)(C C 4 alkyl). Yet even more preferably, R 1 , R 2 and R 4 are each independently selected from hydrogen, halogen (e.g., -F or -CI), -CF 3 , methyl, -OCH 3 , or -NH(CH 3 ).
  • halogen e.g., -F or -CI
  • R 1 and R 4 are each hydrogen and R 2 is selected from hydrogen, halogen (e.g., -F, -CI or -Br), d-C 4 haloalkyl (e.g., -CF 3 ), C C 4 haloalkoxy (e.g., -OCF 3 ), -CN, Ci-C 4 alkyl, C 2 -C 4 alkenyl, cycloalkyi, heterocycloalkyl, aryl, heteroaryl, -OH, -0(Ci-C 4 alkyl), -0-(C C 4 alkylene)-OH, -0-(C C 4 alkylene)-0(C C 4 alkyl), -O-cycloalkyl, -0-(C C 4 alkylene)-cycloalkyl, -O-heterocycloalkyl, -0-(Ci-C 4 alkylene)-heterocycloalkyl, -O-aryl
  • R 1 and R 4 are each hydrogen and R 2 is selected from hydrogen, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, C1-C4 alkyl, C 2 -C 4 alkenyl, cycloalkyi, heterocycloalkyi, -OH, -0(Ci-C 4 alkyl), -0-(C C 4 alkylene)-OH, -0-(d-C 4 alkylene)-0(C C 4 alkyl), -O-cycloalkyl, -0-(d-C 4 alkylene)-cycloalkyl, -O-heterocycloalkyl, -0-(Ci-C 4 alkylene)-heterocycloalkyl, -NH 2 , -NH(Ci- C 4 alkyl), -N(C C 4 alkyl)(C C 4 alkyl), -NH-cycloalkyl, -N
  • R 1 and R 4 are each hydrogen and R 2 is selected from hydrogen, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkyl, -OH, -0(C C 4 alkyl), -NH(C C 4 alkyl), or -N(C C 4 alkyl)(C C 4 alkyl).
  • R 1 and R 4 are each hydrogen and R 2 is selected from hydrogen, -F, -CI, -CF 3 , methyl, -OCH 3 , or -NH(CH 3 ).
  • R 1 and R 4 are each hydrogen and R 2 is hydrogen or -F.
  • R 1 , R 2 and R 4 are each hydrogen.
  • R 3 is selected from hydrogen, halogen, -CN, -OR 7 , -NR 7 R 8 , -COOR 7 , -S0 3 H, - B(OH) 2 , -CONR 7 R 8 , -COR 7 , -SR 7 , -SOR 7 , -S0 2 R 7 , -S0 2 NR 7 R 8 , -NR 7 COR 8 , - NR 7 S0 2 R 8 , -OCOR 7 , -NR 7 C(0)NR 8 R 9 , -NR 7 C(S)NR 8 R 9 , -NR 7 COOR 8 , C C 4 alkyl, C 2 -C 4 alkenyl, cycloalkyi or heterocycloalkyi, wherein said C1-C4 alkyl and said C 2 -C 4 alkenyl are each optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from halogen, -CF
  • R 3 is selected from hydrogen, halogen, -CN, -OR 7 , NR 7 R 8 , -COOR 7 , -CONR 7 R 8 , -COR 7 , -NR 7 COR 8 , C C 4 alkyl, C 2 -C 4 alkenyl, cycloalkyi or heterocycloalkyi, wherein said C1-C4 alkyl and said C 2 -C 4 alkenyl are each optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from halogen, -CF 3 , -CN, -OH, -0(C C 4 alkyl), -NH 2 , -NH(C C 4 alkyl) or -N(C C 4 alkyl)(Ci-C 4 alkyl), and further wherein said cycloalkyl and said heterocycloalkyl are each optionally substituted with one or more groups (e.g., one, two or three
  • R 3 is selected from hydrogen, halogen (e.g., -F, -CI or -Br), C C 4 haloalkyl (e.g., -CF 3 ), Ci-C 4 haloalkoxy (e.g., -OCF 3 ), -CN, C C 4 alkyl, C 2 -C 4 alkenyl, cycloalkyl, heterocycloalkyl, -OH, -0(C C 4 alkyl), -O-cycloalkyl, -0-(C C 4 alkylene)-cycloalkyl, -O-heterocycloalkyl, -0-(Ci-C 4 alkylene)-heterocycloalkyl, -NH 2 , -NH(Ci- C 4 alkyl), -N(C C 4 alkyl)(C C 4 alkyl), -NH-cycloalkyl, -N(C C 4 alkyl)-cycloalkyl,
  • R 3 is selected from hydrogen, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, C1-C4 alkyl, cycloalkyl, heterocycloalkyi, -OH, -0(Ci-C 4 alkyl), -O-cycloalkyl, -O-heterocycloalkyl, -NH 2 , -NH(C C 4 alkyl), -N(C C 4 alkyl)(Ci-C 4 alkyl), -NH-cycloalkyl, -N(Ci-C 4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(Ci-C 4 alkyl)-heterocycloalkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-heterocycloalkyl, -CO-NH 2 , -CO-
  • R 3 is selected from hydrogen, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, C1-C4 alkyl, cycloalkyl, heterocycloalkyi, -OH, -0(d-C 4 alkyl), -O-cycloalkyl, -O-heterocycloalkyl, -NH 2 , -NH(C C 4 alkyl), -N(C C 4 alkyl)(Ci-C 4 alkyl), -NH-cycloalkyl, -N(Ci-C 4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(Ci-C 4 alkyl)-heterocycloalkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-heterocycloalkyl, -CO-NH 2 , -CO-NH
  • R 3 is selected from hydrogen, halogen (e.g., -F or -CI), Ci-C 4 haloalkyl (e.g., -CF 3 ), -CN, heterocycloalkyi (e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl), -0(Ci-C 4 alkyl), -NH(C C 4 alkyl), or -CO-N(C C 4 alkyl)(Ci-C 4 alkyl), wherein said heterocycloalkyi is optionally substituted with one or more groups (e.g., one or two groups) independently selected from: C C 4 alkyl; halogen; -CF 3 ; -CN; -OH; -0(C C 4 alkyl); C C 4 alkyl substituted with one or more -OH groups (e.g., -(CH 2 ) 1 -4 -
  • R 3 is selected from hydrogen, -F, -CI, -CF 3 , -CN, 3-hydroxyazetidin-1-yl, 4-hydroxypiperidin-1 -yl, morpholin-4-yl, -OCH 3 , -NHCH 3 , -CO-N(CH 3 ) 2 , or -CO-N(CH 2 CH 3 )2. Most preferably, R 3 is hydrogen.
  • R 5 is heteroaryl which is optionally substituted with one or more groups (e.g., one, two or three groups; preferably one or two groups; more preferably one group) independently selected from R 7 , halogen, -CN, -NR 7 R 8 , -CONR 7 R 8 , -COR 7 , -OR 7 , -SR 7 , -SOR 7 , S0 2 R 7 , -S0 2 NR 7 R 8 , -NR 7 COR 8 , -NR 7 S0 2 R 8 , -OCOR 7 , or -COOR 7 .
  • groups e.g., one, two or three groups; preferably one or two groups; more preferably one group
  • Said heteroaryl is preferably a heteroaryl having 5 to 14 ring members and comprising one or more (preferably one, two, three or four) ring heteroatoms independently selected from O, S or N; more preferably, said heteroaryl is a heteroaryl having 5 or 6 ring members and comprising one or more (preferably one, two or three) ring heteroatoms independently selected from O, S or N (wherein the 5- to 14-membered heteroaryl and the 5- or 6-membered heteroaryl are optionally substituted, as defined for said heteroaryl).
  • said heteroaryl is pyridinyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, furanyl, thienyl, pyridazinyl, pyrimidinyl or pyrazinyl (wherein these specific groups are optionally substituted, as defined for said heteroaryl).
  • said heteroaryl is pyridinyl or pyrazolyl, yet even more preferably pyridinyl (such as, e.g., pyridin-4-yl, pyridin-3-yl or pyridin- 2-yl), and most preferably pyridin-4-yl (wherein the aforementioned specific heteroaryl groups are optionally substituted, as defined for said heteroaryl).
  • Said heteroaryl (including any of the above-mentioned specific heteroaryl groups) is preferably unsubstituted or substituted with one, two or three groups, more preferably it is substituted with one or two groups, and even more preferably it is substituted with one group. If said heteroaryl is pyridin-4-yl substituted with one group, it is preferred that this one substituent group is attached to the pyridin-4-yl group in position 2. If said heteroaryl is pyridin-4-yl substituted with two groups, it is preferred that these two substituent groups are attached to the pyridin-4-yl group in positions 2 and 6, respectively.
  • the optional substituent groups with which the heteroaryl as R 5 are independently selected from R 7 , halogen, -CN, -NR 7 R 8 , -CONR 7 R 8 , -COR 7 , -OR 7 , -SR 7 , -SOR 7 , -S0 2 R 7 , - S0 2 NR 7 R 8 , -NR 7 COR 8 , -NR 7 S0 2 R 8 , -OCOR 7 , or -COOR 7 .
  • these optional substituent groups are independently selected from R 7 , halogen, -CN, -NR 7 R 8 , -CONR 7 R 8 , -COR 7 , -OR 7 , or -NR 7 COR 8 , more preferably from R 7 , halogen, -CN, -NR 7 R 8 , -COR 7 , or -OR 7 .
  • these optional substituent groups are independently selected from C1-C4 alkyl, C 2 -C 4 alkenyl, halogen (e.g., -F, -CI or -Br), C1-C4 haloalkyl (e.g., -CF 3 , -CHF 2 , or -CF 2 -CH 3 ), C C 4 haloalkoxy (e.g., -O-CH2-CF3, -O-CH2-CHF2, -O-CH2-CF2-CH3, -O-CH2-CF2-CF3, -0-CH(CF 3 ) 2 , or -OCF 3 ), -CN, cycloalkyi, heterocycloalkyl, aryl (e.g., phenyl), heteroaryl, -OH, -0(Ci-C 4 alkyl), -O-cycloalkyl, -0-(Ci-C 4 alkylene)-cycloalkyl, -O
  • the optional substituent groups with which the heteroaryl as R 5 may be substituted are independently selected from C1-C4 alkyl, C 2 -C 4 alkenyl, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, cycloalkyi, heterocycloalkyl, -0(Ci-C 4 alkyl), -O-cycloalkyl, or -O-heterocycloalkyl.
  • these optional substituent groups are independently selected from methyl, vinyl, propenyl (e.g., propen-2-yl), -F, -CI, -CF 3 , -0-CH 2 -CF 3 , -CN, cyclopropyl, or pyrrolidinyl (e.g., pyrrolidin-1 -yl).
  • R 5 is heteroaryl having 5 or 6 ring members and comprising one or more (preferably one, two or three) ring heteroatoms independently selected from O, S or N, wherein said heteroaryl having 5 or 6 ring members is optionally substituted with one or more groups (preferably one or two groups; more preferably one group) independently selected from C1-C4 alkyl, C 2 -C 4 alkenyl, halogen (e.g., -F, -CI or -Br), C1-C4 haloalkyl (e.g., -CF 3 , -CHF 2 , or -CF 2 -CH 3 ), C C 4 haloalkoxy (e.g., -O-CH2-CF3, -O-CH2-CHF2, -O-CH2-CF2-CH3, -O-CH2-CF2-CF3, -0-CH(CF 3 ) 2 ), or -OCF 3 ), -CN, cycloalkyl, hetero
  • R 5 is heteroaryl having 5 or 6 ring members and comprising one or more (preferably one, two or three) ring heteroatoms independently selected from O, S or N (e.g., pyridinyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, furanyl, thienyl, pyridazinyl, pyrimidinyl or pyrazinyl), wherein said heteroaryl having 5 or 6 ring members is optionally substituted with one or more substituent groups (preferably one or two substituent groups; more preferably one substituent group) independently selected from C1-C4 alkyl, C 2 -C 4 alkenyl, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, cycloalkyl, heterocycloalkyl, -0(Ci-C 4 alkyl), -
  • R 5 is pyridinyl (particularly pyridin-4-yl) which is optionally substituted with one or more groups (preferably one or two groups; more preferably one group) independently selected from C1-C4 alkyl, C 2 -C 4 alkenyl, halogen (e.g., -F, -CI or -Br), C1-C4 haloalkyl (e.g., -CF 3 , -CHF 2 , or -CF 2 -CH 3 ), C C 4 haloalkoxy (e.g., -0-CH 2 -CF 3 , -0-CH 2 -CHF 2 , -0-CH 2 -CF 2 -CH 3 , -0-CH 2 -CF 2 -CF 3 , or -0-CH(CF 3 ) 2 ), -CN, cycloalkyi, heterocycloalkyi, aryl, heteroaryl, -OH, -0(Ci-C 4
  • R 5 is pyridinyl (particularly pyridin-4-yl) which is optionally substituted with one or more substituent groups (preferably one or two substituent groups; more preferably one substituent group) independently selected from C1-C4 alkyl, C 2 -C 4 alkenyl, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, cycloalkyi, heterocycloalkyi, -0(Ci-C 4 alkyi), -O-cycloalkyl, or -O-heterocycloalkyl, wherein it is furthermore preferred that said substituent group(s) is/are selected independently from methyl, vinyl, propenyl (e.g., propen-2-yl), -F, -CI, -CF 3 , -0-CH 2 -CF 3 , -CN, cyclopropyl, or pyrrolidinyl (e.g.,
  • R 5 is pyridin-4-yl which is substituted with one substituent group at position 2 of said pyridin-4-yl or with two substituent groups at position 2 and 6 of said pyridin- 4-yl, wherein said one or two substituent group(s) is/are selected independently from C1-C4 alkyi, C 2 -C 4 alkenyl, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, cycloalkyl, heterocycloalkyl, -0(Ci-C 4 alkyi), -O-cycloalkyl, or -O-heterocycloalkyl, and wherein it is furthermore preferred that said one or two substituent group(s) is/are selected independently from methyl, vinyl, propenyl (e.g., propen-2-yl), -F, -CI, -CF 3 , -0-CH 2 -CF 3 , -
  • R 5 is pyridin-4-yl which is substituted with one substituent group at position 2 of said pyridin-4-yl, wherein said substituent group is selected from C1-C4 alkyi, C 2 -C 4 alkenyl, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, cycloalkyl, heterocycloalkyl, -0(Ci-C 4 alkyi), -O-cycloalkyl, or -O-heterocycloalkyl, preferably said substituent group is selected from methyl, vinyl, propenyl (e.g., propen-2-yl), -F, -CI, -CF 3 , -0-CH 2 -CF 3 , -CN, cyclopropyl, or pyrrolidinyl (e.g., pyrrolidin-1 -yl), more preferably said substituent group is -CF 3 or
  • R 6 is selected from C1-C4 alkyi, cycloalkyl (e.g., cyclopropyl), or heterocycloalkyl, wherein said C1-C4 alkyi is optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from cycloalkyl (e.g., cyclopropyl), halogen, -CF 3 , -CN, -OH or -0(C C 4 alkyi), and further wherein, if R 6 is cycloalkyl or heterocycloalkyl, then said cycloalkyl and said heterocycloalkyl are each optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from C1-C4 alkyi, cycloalkyl, halogen, -CF 3 , -CN, -OH or -0(C C 4 alkyi).
  • groups e.g., one, two or three groups
  • R 6 is C1-C4 alkyi which is optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from cycloalkyl, halogen, -CF 3 , -CN, -OH or -0(C C 4 alkyi). More preferably, R 6 is C1-C4 alkyi which is optionally substituted with one or more fluoro atoms (such as, e.g., -(Ci-C 3 alkylene)-CF 3 or -(CrC 3 alkylene)-CHF 2 ).
  • groups e.g., one, two or three groups
  • R 6 is C1-C4 alkyi which is optionally substituted with one or more fluoro atoms (such as, e.g., -(Ci-C 3 alkylene)-CF 3 or -(CrC 3 alkylene)-CHF 2 ).
  • R 6 is C1-C4 alkyi, and yet even more preferably R 6 is methyl (e.g., deuterium- enriched methyl, -CD 3 ; or -C( 1 H) 3 ) or ethyl. Most preferably, R 6 is methyl.
  • Each R 7 , R 8 and R 9 is independently selected from hydrogen, C1-C4 alkyi, C 2 -C 4 alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, wherein said C1-C4 alkyl and said C 2 -C 4 alkenyl are each optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from halogen, -CF 3 , -CN, cycloalkyi, cycloalkenyl, heterocycloalkyi, heterocycloalkenyl, aryl, heteroaryl, -OH, -0(Ci-C 4 alkyl), - NH 2 , -NH(Ci-C 4 alkyl) or -N(C C 4 alkyl)(C C 4 alkyl), and further wherein, if R 7 , R 8 or R 9 is cycloal
  • the group R 3 is selected from hydrogen, -F, -CI, -I, -CN, -OR 7 , -NR 7 R 8 , -COOR 7 , -SO 3 H, -B(OH) 2 , -CONR 7 R 8 , - COR 7 , -SR 7 , -SOR 7 , -S0 2 R 7 , -S0 2 NR 7 R 8 , -NR 7 COR 8 , -NR 7 S0 2 R 8 , -OCOR 7 , - NR 7 C(0)NR 8 R 9 , -NR 7 C(S)NR 8 R 9 , -NR 7 COOR 8 , C C 4 alkyl, C 2 -C 4 alkenyl, cycloalkyi or heterocycloalkyi, wherein said C1-C4 alkyl and said C 2 -C 4 alkenyl are each optionally substituted with one or more groups independently selected from
  • R 3 is preferably selected from hydrogen, -F, -CI, -I, -CN, -OR 7 , - NR 7 R 8 , -COOR 7 , -CONR 7 R 8 , -COR 7 , -NR 7 COR 8 , C C 4 alkyl, C 2 -C 4 alkenyl, cycloalkyi or heterocycloalkyi, wherein said C1-C4 alkyl and said C 2 -C 4 alkenyl are each optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from halogen, -CF 3 , -CN, -OH, -0(C C 4 alkyl), -NH 2 , -NH(C C 4 alkyl) or -N(C C 4 alkyl)(Ci-C 4 alkyl), and further wherein said cycloalkyi and said heterocycloalkyi are each optionally substituted with one or
  • R 3 is selected from hydrogen, -F, -CI, -I, C1-C4 haloalkyl (e.g., -CF 3 ), C1-C4 haloalkoxy (e.g., -OCF 3 ), -CN, C1-C4 alkyl, C 2 -C 4 alkenyl, cycloalkyl, heterocycloalkyi, -OH, -0(d-C 4 alkyl), -O-cycloalkyl, -0-(CrC 4 alkylene)-cycloalkyl, -O-heterocycloalkyl, -0-(Ci-C 4 alkylene)-heterocycloalkyl, -N H 2 , -NH(C C 4 alkyl), -N(C C 4 alkyl)(Ci-C 4 alkyl), -NH-cycloalkyl, -N(Ci-C 4 alkyl)-cycloalkyl,
  • R 3 is selected from hydrogen, -F, -CI, -I, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, C1-C4 alkyl, cycloalkyl, heterocycloalkyi, -OH, -0(Ci-C 4 alkyl), -O-cycloalkyl, -O-heterocycloalkyl, -NH 2 , -NH(C C 4 alkyl), -N(C C 4 alkyl)(Ci-C 4 alkyl), -NH-cycloalkyl, -N(Ci-C 4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(Ci-C 4 alkyl)-heterocycloalkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-heterocycloalkyl, -CO-
  • R 3 is selected from hydrogen, -F, -CI, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, C1-C4 alkyl, cycloalkyl, heterocycloalkyi, -OH, -0(Ci-C 4 alkyi), -O-cycloalkyl, -O-heterocycloalkyl, -NH 2 , -NH(C C 4 alkyi), -N(C C 4 alkyl)(Ci-C 4 alkyi), -NH-cycloalkyl, -N(C C 4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(C C 4 alkyl)-heterocycloalkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-heterocycloalkyl, -CO-NH 2 , -CO-
  • R 3 is selected from hydrogen, -F, -CI, Ci-C 4 haloalkyl (e.g., -CF 3 ), -CN, heterocycloalkyi (e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl), -0(Ci-C 4 alkyi), -NH(d-C 4 alkyi), or -CO-N(Ci-C 4 alkyl)(Ci-C 4 alkyi), wherein said heterocycloalkyi is optionally substituted with one or more groups (e.g., one or two groups) independently selected from: C1-C4 alkyi; halogen; -CF 3 ; -CN; -OH; -0(Ci-C 4 alkyi); C1-C4 alkyi substituted with one or more -OH groups (e.g., -(CH 2 )i-4-OH);
  • R 3 is selected from hydrogen, -F, -CI, -CF 3 , -CN, 3-hydroxyazetidin-1-yl, 4-hydroxypiperidin-1-yl, morpholin-4-yl, -OCH 3 , -NHCH 3 , -CO-N(CH 3 ) 2 , or -CO-N(CH 2 CH 3 ) 2 .
  • R 3 is hydrogen. It is particularly preferred that the compound of formula (I) according to the first, second or third aspect of the invention is selected from:
  • Compounds of the general formula (I) may exist in the form of different isomers, in particular stereoisomers (including geometric isomers (or cis-trans isomers), enantiomers and diastereomers) or tautomers. All such isomers of the compounds according to the invention are contemplated as being part of the present invention, either in admixture or in pure or substantially pure form. As for stereoisomers, the invention embraces mixtures (such as racemic forms) and the isolated optical isomers of the compounds according to the invention. The racemic forms can be resolved by physical methods, such as, e.g., fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography.
  • the scope of the invention also embraces compounds of the general formula (I), in which one or more atoms are replaced by a specific isotope of the corresponding atom.
  • the invention encompasses compounds of formula (I), in which one or more hydrogen atoms (or, e.g., all hydrogen atoms) are replaced by deuterium atoms (i.e., 2 H; also referred to as "D").
  • the invention also embraces compounds of formula (I) which are enriched in deuterium.
  • Naturally occurring hydrogen is an isotopic mixture comprising about 99.98 mol-% hydrogen-1 ( 1 H) and about 0.0156 mol-% deuterium ( 2 H or D).
  • the content of deuterium in one or more hydrogen positions in the compounds of formula (I) can be increased using deuteration techniques known in the art.
  • a compound of formula (I) or a reactant or precursor to be used in the synthesis of the compound of formula (I) can be subjected to an H/D exchange reaction using, e.g., heavy water (D 2 0).
  • deuteration techniques are described in: Atzrodt J et al., Bioorg Med Chem, 20(18), 5658-5667, 2012; William JS et al., Journal of Labelled Compounds and Radiopharmaceuticals, 53(1 1 -12), 635-644, 2010; Modvig A et al., J Org Chem, 79, 5861 -5868, 2014.
  • the content of deuterium can be determined, e.g., using mass spectrometry or NMR spectroscopy.
  • it is preferred that the compound of formula (I) is not enriched in deuterium. Accordingly, the presence of naturally occurring hydrogen atoms or 1 H hydrogen atoms in the compounds of formula (I) is preferred.
  • the present invention also embraces compounds of formula (I), in which one or more atoms are replaced by a positron-emitting isotope of the corresponding atom, such as, e.g., 18 F, 11 C, 13 N, 15 0, 76 Br, 77 Br, 120 l and/or 124 l.
  • a positron-emitting isotope of the corresponding atom such as, e.g., 18 F, 11 C, 13 N, 15 0, 76 Br, 77 Br, 120 l and/or 124 l.
  • Such compounds can be used as tracers or imaging probes in positron emission tomography (PET).
  • the invention thus includes (i) compounds of formula (I), in which one or more fluorine atoms (or, e.g., all fluorine atoms) are replaced by 18 F atoms, (ii) compounds of formula (I), in which one or more carbon atoms (or, e.g., all carbon atoms) are replaced by 11 C atoms, (iii) compounds of formula (I), in which one or more nitrogen atoms (or, e.g., all nitrogen atoms) are replaced by 13 N atoms, (iv) compounds of formula (I), in which one or more oxygen atoms (or, e.g., all oxygen atoms) are replaced by 15 0 atoms, (v) compounds of formula (I), in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by 76 Br atoms, (vi) compounds of formula (I), in which one or more bromine atoms (or, e.g.,
  • the scope of the invention embraces all pharmaceutically acceptable salt forms of the compounds of the general formula (I) which may be formed, e.g., by protonation of an atom carrying an electron lone pair which is susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of a carboxylic acid group with a physiologically acceptable cation as they are well known in the art.
  • Exemplary base addition salts comprise, for example, alkali metal salts such as sodium or potassium salts; alkaline-earth metal salts such as calcium or magnesium salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, diethanol amine salts or ethylenediamine salts; aralkyl amine salts such as ⁇ , ⁇ -dibenzylethylenediamine salts, benetamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltribu
  • Exemplary acid addition salts comprise, for example, mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts, nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts or perchlorate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, undecanoate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, nicotinate, benzoate, salicylate or ascorbate salts; sulfonate salts such as methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate
  • the scope of the invention embraces solid forms of the compounds of the general formula (I) in any solvated form, including e.g. solvates with water, for example hydrates, or with organic solvents such as, e.g., methanol, ethanol or acetonitrile, i.e. as a methanolate, ethanolate or acetonitrilate, respectively; or in the form of any polymorph.
  • solvates with water, for example hydrates, or with organic solvents such as, e.g., methanol, ethanol or acetonitrile, i.e. as a methanolate, ethanolate or acetonitrilate, respectively; or in the form of any polymorph.
  • prodrugs of compounds of the general formula (I) are derivatives which have chemically or metabolically cleavable groups and become, by solvolysis or under physiological conditions, the compounds of formula (I) which are pharmaceutically active in vivo.
  • Prodrugs of compounds of formula (I) may be formed in a conventional manner with a functional group of the compounds such as with an amino, hydroxy or carboxy group.
  • the prodrug derivative form often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgaard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985).
  • Prodrugs include acid derivatives well known to the person skilled in the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine.
  • esters prepared by reaction of the parent acidic compound with a suitable alcohol
  • amides prepared by reaction of the parent acid compound with a suitable amine.
  • An especially preferred ester derivative as a prodrug is methylester, ethylester, n-propylester, isopropylester, n-butylester, isobutylester, tert-butylester, morpholinoethylester or ⁇ , ⁇ -diethylglycolamidoester.
  • a compound of formula (I) has a hydroxy group
  • an acyloxy derivative prepared by reacting the hydroxyl group with a suitable acylhalide or a suitable acid anhydride is exemplified as a prodrug.
  • an amide derivative prepared by reacting the amino group with a suitable acid halide or a suitable mixed anhydride is exemplified as a prodrug.
  • the compounds of general formula (I) or pharmaceutically acceptable salts, solvates or prodrugs thereof may be administered as compounds per se or may be formulated as medicaments.
  • pharmaceutical compositions comprising as an active ingredient one or more compounds of the general formula (I), or pharmaceutically acceptable salts, solvates or prodrugs thereof.
  • the pharmaceutical compositions may optionally comprise one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, or antioxidants.
  • the pharmaceutical compositions may also comprise one or more solubility enhancers, such as, e.g., poly(ethylene glycol), including poly(ethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da, ethylene glycol, propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 80, macrogol-15-hydroxystearate, phospholipids, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, cyclodextrins, hydroxyethyl-3-cyclodextrin, hydroxypropyl-3-cyclodextrin, hydroxyethyl- ⁇ - cyclodextrin, hydroxypropyl-Y-cyclodextrin, dihydroxypropyl-3-cyclodextrin, glucosyl-a- cyclodextrin, glucosyl
  • the pharmaceutical compositions can be formulated by techniques known to the person skilled in the art, such as the techniques published in Remington's Pharmaceutical Sciences, 20 th Edition.
  • the pharmaceutical compositions can be formulated as dosage forms for oral, parenteral, such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, rectal, nasal, topical, aerosol or vaginal administration.
  • Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewing tablets and effervescent tablets.
  • Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions and powders and granules for reconstitution. Emulsions are a preferred dosage form for parenteral administration.
  • Dosage forms for rectal and vaginal administration include suppositories and ovula.
  • Dosage forms for nasal administration can be administered via inhalation and insufflation, for example by a metered inhaler.
  • Dosage forms for topical administration include creams, gels, ointments, salves, patches and transdermal delivery systems.
  • the compounds of the general formula (I) or pharmaceutically acceptable salts, solvates or prodrugs thereof, or the above described pharmaceutical compositions may be administered to a subject by any convenient route of administration, whether systemically/peripherally or at the site of desired action, including but not limited to one or more of: oral (e.g. as a tablet, capsule, or as an ingestible solution), topical (e.g., transdermal, intranasal, ocular, buccal, and sublingual), parenteral (e. g., using injection techniques or infusion techniques, and including, for example, by injection, e.g.
  • oral e.g. as a tablet, capsule, or as an ingestible solution
  • topical e.g., transdermal, intranasal, ocular, buccal, and sublingual
  • parenteral e. g., using injection techniques or infusion techniques, and including, for example, by injection, e.g.
  • implant of a depot for example, subcutaneously or intramuscularly
  • pulmonary e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g. through mouth or nose
  • examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecal ⁇ , intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously administering the compounds pharmaceutical compositions, and/or by using infusion techniques.
  • parenteral administration the compounds are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • the aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
  • the preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • Said compounds or pharmaceutical compositions can also be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.
  • the tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
  • excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine
  • disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glyco
  • Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols.
  • the agent may be combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • Said compounds or pharmaceutical compositions may also be administered by sustained release systems. Suitable examples of sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules.
  • Sustained-release matrices include, e.g., polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman, U. et al., Biopolymers 22:547-556 (1983)), poly(2-hydroxyethyl methacrylate) (R. Langer et al., J. Biomed. Mater. Res. 15:167- 277 (1981 ), and R. Langer, Chem. Tech. 12:98-105 (1982)), ethylene vinyl acetate (R.
  • Liposomes containing a compound of the present invention can be prepared by methods known in the art, such as, e.g., the methods described in any one of: DE3218121 ; Epstein et al., Proc. Natl. Acad. Sci. (USA) 82:3688-3692 (1985); Hwang et al., Proc. Natl. Acad. Sci.
  • said compounds or pharmaceutical compositions can be administered in the form of a suppository or pessary, or may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder.
  • the compounds of the present invention may also be dermally or transdermal ⁇ administered, for example, by the use of a skin patch.
  • Said compounds or pharmaceutical compositions may also be administered by the pulmonary route, rectal routes, or the ocular route.
  • they can be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride.
  • a preservative such as a benzylalkonium chloride.
  • they may be formulated in an ointment such as petrolatum.
  • said compounds or pharmaceutical compositions can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water.
  • they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, 2-octyldodecanol, benzyl alcohol and water.
  • a physician will determine the actual dosage which will be most suitable for an individual subject.
  • the specific dose level and frequency of dosage for any particular individual subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual subject undergoing therapy.
  • a proposed, yet non-limiting dose of the compounds of the general formula (I) for administration to a human may be 0.05 to 2000 mg, preferably 0.1 mg to 1000 mg, of the active ingredient per unit dose.
  • the unit dose may be administered, for example, 1 to 4 times per day.
  • the unit dose may also be administered 1 to 7 times per week, e.g., with not more than one administration per day.
  • the dose will depend on the route of administration. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient/subject as well as the severity of the condition to be treated. The precise dose and route of administration will ultimately be at the discretion of the attendant physician or veterinarian.
  • the subject or patient may be an animal (e.g., a non-human animal), a vertebrate animal, a mammal (e.g., a non-human mammal), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), a murine (e.g., a mouse), a canine (e.g., a dog), a feline (e.g., a cat), an equine (e.g., a horse), a primate, a simian (e.g., a monkey or ape), a monkey (e.g., a marmoset, a baboon), an ape (e.g., a gorilla, chimpanzee, orang-utan, gibbon), or a human.
  • an animal e.g., a non-human animal
  • a vertebrate animal e.g.,
  • animals are to be treated which are economically, agronomically or scientifically important.
  • Scientifically important organisms include, but are not limited to, mice, rats, and rabbits.
  • Lower organisms such as, e.g., fruit flies like Drosophila melagonaster and nematodes like Caenorhabditis elegans may also be used in scientific approaches.
  • Non-limiting examples of agronomically important animals are sheep, cattle and pigs, while, for example, cats and dogs may be considered as economically important animals.
  • the subject/patient is a mammal.
  • the subject/patient is a human or a non-human mammal (such as, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orang-utan, a gibbon, a sheep, cattle, or a pig).
  • a human or a non-human mammal such as, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orang-utan, a gibbon, a sheep, cattle, or a pig.
  • Treatment of a condition, disorder or disease as used herein is well known in the art.
  • Treatment of a condition, disorder or disease implies that a disorder or disease is suspected or has been diagnosed in a patient/subject.
  • a patient/subject suspected of suffering from a disorder or disease typically shows specific clinical and/or pathological symptoms which a skilled person can easily attribute to a specific pathological condition (i.e. diagnose a disorder or disease).
  • the treatment of a condition, disorder or disease may, for example, lead to a halt in the progression of the condition, disorder or disease (e.g. no deterioration of symptoms) or a delay in the progression of the disorder or disease (in case the halt in progression is of a transient nature only).
  • Treatment may also lead to a partial response (e.g. amelioration of symptoms) or complete response (e.g. disappearance of symptoms) of the subject/patient suffering from the condition, disorder or disease.
  • Amelioration of a condition, disorder or disease may, for example, lead to a halt in the progression of the disorder or disease or a delay in the progresssion of the disorder or disease.
  • Such a partial or complete response may be followed by a relapse.
  • a subject/patient may experience a broad range of responses to a treatment (e.g. the exemplary responses as described herein above).
  • Treatment of a condition, disorder or disease may, inter alia, comprise curative treatment (preferably leading to a complete response and eventually to healing of the disorder or disease) and palliative treatment (including symptomatic relief).
  • a patient/subject suspected of being prone to suffer from a condition, disorder or disease as defined herein may, in particular, benefit from a prophylaxis of the disorder or disease.
  • Said subject/patient may have a susceptibility or predisposition for a condition, disorder or disease, including but not limited to hereditary predisposition.
  • Such a predisposition can be determined by standard assays, using, for example, genetic markers or phenotypic indicators.
  • a condition, disorder or disease to be prevented in accordance with the present invention has not been diagnosed or cannot be diagnosed in said patient/subject (for example, said patient/subject does not show any clinical or pathological symptoms).
  • the term “prophylaxis” comprises the use of compounds of the present invention before any clinical and/or pathological symptoms are diagnosed or determined or can be diagnosed or determined by the attending physician.
  • the terms “prophylaxis” and “prevention” are used herein interchangeably.
  • the test agent may, for example, be selected from nucleic acids, DNA, RNA, PNA, oligonucleotides, aptamers (Gold, Ann. Rev. Biochem.
  • RNAzymes see e.g., EP-B1 0 291 533, EP-A1 0 321 201 , EP- B1 0 360 257), antisense DNA, antisense oligonucleotides, antisense RNA, siRNA, RNAi, shRNA, amino acids, peptides, polypeptides, proteins, glycoproteins, lipoproteins, nucleoproteins, antibodies (Harlow and Lane “Antibodies, A Laboratory Manual", CSH Press, Cold Spring Harbor, 1988), monocloncal antibodies, polyclonal antibodies, immunoglobulins, affibodies (Hansson, Immunotechnology 4 (1999), 237-252; Henning, Hum Gene Ther.
  • anticalins EP-B-1 1 017 814
  • hormones peptide and protein hormones, non-peptide hormones, steroids, interleukins, interferons, cytokines, neurotransmitters, toxins, enzymes, polysaccharides, carbohydrates, lipids, lipopolysaccharides, vitamins, crown ethers, cyclodextrins, cryptands, calixarenes, aldehydes, thiols, amines, drugs, drugs of abuse, therapeutic agents, medicaments, pharmaceuticals, substrates, fragments, portions, components or products of microorganisms, metabolites of or antibodies to any of the above substances and the like.
  • the present invention specifically relates to each and every combination of features and embodiments described herein, including any combination of general and/or preferred features/embodiments.
  • the invention specifically relates to each combination of meanings (including general and/or preferred meanings) for the various groups and variables comprised in the general formula (I).
  • alkyl represents a straight or branched chain saturated acyclic hydrocarbon residue (i.e., a group consisting of carbon atoms and hydrogen atoms) which does not comprise any carbon-to-carbon double bonds or carbon-to-carbon triple bonds.
  • acyclic hydrocarbon residue i.e., a group consisting of carbon atoms and hydrogen atoms
  • methyl, ethyl, propyl and butyl are mentioned.
  • alkenyl represents a straight or branched chain unsaturated acyclic hydrocarbon residue comprising one or more than one (such as two or three) carbon-to-carbon double bond(s) which does not comprise any carbon-to-carbon triple bonds.
  • alkylene represents a straight or branched chain alkanediyl group which does not comprise any carbon-to-carbon double bonds or carbon-to-carbon triple bonds.
  • aryl represents an aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic).
  • Aryl may, for example, refer to phenyl or naphthyl. Unless defined otherwise, an “aryl” preferably has 6 to 10 ring members, and most preferably refers to phenyl.
  • heteroaryl represents an aromatic ring group, including monocyclic aromatic rings as well as fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic), wherein said aromatic ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S, or N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized.
  • aromatic ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S, or N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized.
  • Heteroaryl may, for example, refer to thienyl (thiophenyl), benzo[b]thienyl, naphtho[2,3- b]thienyl, thianthrenyl, furyl (furanyl), isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, pyrrolyl (including, without limitation, 2H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (pyridinyl; including, without limitation, 2-pyridyl, 3-pyridyl, and 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl (including, without limitation, 3H-indolyl), indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, nap
  • a "heteroaryl” preferably refers to a 5 to 14 membered monocyclic ring or fused ring system comprising one or more (e.g., one, two, three or four) ring heteroatoms independently selected from O, S or N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized; and more preferably refers to a 5 or 6 membered monocyclic ring comprising one or more (e.g., one, two or three) ring heteroatoms independently selected from O, S or N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized.
  • cycloalkyl represents a saturated hydrocarbon ring, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings, such as ring systems composed of two or three fused rings).
  • Cycloalkyl may, for example, refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • a “cycloalkyl” preferably has 3 to 1 1 ring members, and more preferably has 3 to 7 ring members.
  • heterocycloalkyl represents a saturated ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings, such as ring systems composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S, or N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized.
  • Heterocycloalkyl may, for example, refer to oxetanyl, tetrahydrofuranyl, piperidinyl, piperazinyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, morpholinyl, pyrazolidinyl, tetrahydrothienyl, octahydroquinolinyl, octahydroisoquinolinyl, oxazolidinyl, isoxazolidinyl, azepanyl, diazepanyl, oxazepanyl or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl.
  • heterocycloalkyl preferably refers to a 3 to 1 1 membered saturated ring group, which is a monocyclic ring or a fused ring system, containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from O, S, or N.
  • cycloalkenyl represents an unsaturated alicyclic (non-aromatic) hydrocarbon ring, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings, such as ring systems composed of two or three fused rings), wherein said hydrocarbon ring comprises at least one carbon-to-carbon double bond and does not comprise any carbon-to-carbon triple bond.
  • Non-limiting examples of cycloalkenyl groups are cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cyclohexadienyl.
  • a "cycloalkenyl” preferably has 3 to 1 1 ring members, and more preferably has 3 to 7 ring members.
  • heterocycloalkenyl represents an unsaturated alicyclic (non-aromatic) ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings, such as ring systems composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S, or N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and further wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms.
  • Heterocycloalkenyl may, for example, refer to 1 ,2,3,6-tetrahydropyridinyl. Unless defined otherwise, a “heterocycloalkenyl” preferably refers to a 3 to 1 1 membered unsaturated alicyclic ring group, which is a monocyclic ring or a fused ring system, containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from O, S, or N, wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms.
  • halogen represents fluoro, chloro, bromo, or iodo.
  • haloalkyl represents an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms. It will be understood that the maximum number of halogen atoms is limited by the number of available attachment sites and, thus, depends on the number of carbon atoms comprised in the alkyl moiety of the haloalkyl group.
  • Haloalkyl may, for example, refer to -CF 3 , -CHF 2 , or -CF 2 -CH 3 .
  • haloalkoxy represents an -O-alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms. It will be understood that the maximum number of halogen atoms is limited by the number of available attachment sites and, thus, depends on the number of carbon atoms comprised in the -O-alkyl moiety of the haloalkoxy group.
  • Haloalkoxy may, for example, refer to -OCF3, -O-CH2-CF3, -O-CH2-CHF2, -O-CH2-CF2-CH3, -O-CH2-CF2-CF3, or -0-CH(CF 3 ) 2 .
  • the terms “optional”, “optionally” and “may” denote that the indicated feature may be present but can also be absent. Whenever the term “optional”, “optionally” or “may” is used, the present invention specifically relates to both possibilities, i.e., that the corresponding feature is present or, alternatively, that the corresponding feature is absent.
  • the expression “X is optionally substituted with Y” (or “X may be substituted with Y”) means that X is either substituted with Y or is unsubstituted.
  • a component of a composition is indicated to be “optional"
  • the invention specifically relates to both possibilities, i.e., that the corresponding component is present (contained in the composition) or that the corresponding component is absent from the composition.
  • Various groups are referred to as being “optionally substituted” in the context of this description. Generally, these groups may carry one or more than one, such as e.g. one, two, three or four substituents. It will be understood that the maximum number of substituents is limited by the number of attachment sites available on the substituted moiety. Unless defined otherwise in the specific context, these groups carry preferably not more than two substituents and may, in particular, carry only one substituent. Moreover, unless specifically defined otherwise, it is preferred that the optional substituents are absent.
  • the compounds of the invention can be prepared in accordance with or in analogy to the synthetic routes described in detail in the examples section.
  • the compounds of formula (I) can be synthesized in accordance with the methods described in the following schemes (the substituent groups and variables shown in schemes 1 and 2 have the same meanings as the corresponding groups and variables in general formula (I)).
  • Intermediates E can be obtained in one step in the presence of the hydrazines D and the ⁇ -ketonitriles B under acidic conditions (Vasquez TE et al., Mol Divers, 7(2-4), 161-4, 2003).
  • a way to generate hydrazines D is to convert the amino group of C into a diazonium salt in the presence of sodium nitrite under aqueous acidic conditions and to reduce it, e.g., with tin chloride (II).
  • ⁇ -ketonitriles B can be generated from an activated acid A such as an acid chloride or an ester in the presence of the acetonitrile anion formed, e.g., from acetonitrile and butyl lithium (see scheme 1 ).
  • Example G can be obtained from the pyrazolo[1 ,5-a]quinazolin-5-ones E in the presence of a base such as NaH, fBuOK or K 2 C0 3 and the electrophiles F where X 1 is a halide or a pseudo halide (see scheme 2).
  • Example G can be further modified by methods well known in the art. For instance, on an example G containing a halide or a pseudo halide a cross coupling reaction involving a metallic species such as boronic derivatives, tin derivatives or zinc derivatives (and a catalytic amount of a transition metal like palladium or nickel) can be used to introduce groups such as an aryl, a heteroaryl, an alkene or an alkyne. Also, on an example G containing a halide or a pseudo halide a nucleophile like an alcohol or an amine can be introduced. In some cases the nucleophilic displacement can be facilitated by a catalytic amount of a transition metal such palladium (David S. Surry and Stephen L.
  • a cross coupling reaction involving a metallic species such as boronic derivatives, tin derivatives or zinc derivatives (and a catalytic amount of a transition metal like palladium or nickel)
  • groups such as an aryl,
  • an alkyl chain can be introduced with an electrophile such as a halo alkyl in the presence of a base such as NaH, tBuOK or K 2 C0 3 .
  • a nucleophile such as an amine can furnish an amide via activating agents (Christian A. G. N. Montalbetti and Virginie Falque, Tetrahedron, 61 , (2005) 10827-10852).
  • the compounds of formula (I) having a pyrroloquinazolinone scaffold can be obtained in 2 steps, as shown in scheme 3 below.
  • the dicyanide H is prepared according to procedures well known in the art. This compound reacts with 2-amino benzoic acid derivatives C to give the cyanide derivatives J. Then, the cyanide moiety can be removed under acidic conditions or other conditions such as basic hydrolysis followed by thermal decarboxylation.
  • example L can be obtained from the pyrroloquinazolinone K in the presence of a base such as NaH, fBuOK or K 2 C0 3 and the electrophiles F where X 1 is a halide or a pseudo halide.
  • a base such as NaH, fBuOK or K 2 C0 3
  • electrophiles F where X 1 is a halide or a pseudo halide.
  • example L can be further modified by methods well known in the art.
  • the present invention particularly relates to the following items:
  • A is N or -CH
  • R 1 , R 2 and R 4 are each independently selected from R 7 , halogen, - CN, -OR 7 , -NR 7 R 8 , -COOR 7 , -S0 3 H, -B(OH) 2 , -CONR 7 R 8 , - COR 7 , -SR 7 , -SOR 7 , -S0 2 R 7 , -S0 2 NR 7 R 8 , -NR 7 COR 8 , NR 7 S0 2 R 8 , -OCOR 7 , -NR 7 C(0)NR 8 R 9 , -NR 7 C(S)NR 8 R 9 , -NR 7 COOR 8 , aryl, or heteroaryl, wherein said aryl and said heteroaryl are each substituted with one or more groups independently selected from R 7 , halogen, -CN, - OR 7 , -NR 7 R 8 , -COOR 7 , -S0 3 H, -B(OH) 2
  • R 3 is selected from hydrogen, halogen, -CN, -OR 7 , NR 7 R 8 , -COOR 7 , -SO 3 H, -B(OH) 2 , -CONR 7 R 8 , -COR 7 , -SR 7 , - SOR 7 , -S0 2 R 7 , -S0 2 NR 7 R 8 , -NR 7 COR 8 , -NR 7 S0 2 R 8 , -OCOR 7 , -NR 7 C(0)NR 8 R 9 , - NR 7 C(S)NR 8 R 9 , -NR 7 COOR 8 , C C 4 alkyl, C 2 -C 4 alkenyl, cycloalkyi or heterocycloalkyi, wherein said C1-C4 alkyl and said C 2 -C 4 alkenyl are each optionally substituted with one or more groups independently selected from halogen, -CF 3 , -CN, -OH, -0(
  • R 5 is heteroaryl which is optionally substituted with one or more groups independently selected from R 7 , halogen, -CN, -NR 7 R 8 , -CONR 7 R 8 , -COR 7 , -OR 7 , -SR 7 , -SOR 7 , -S0 2 R 7 , - S0 2 NR 7 R 8 , -NR 7 COR 8 , -NR 7 S0 2 R 8 , -OCOR 7 , or -COOR 7 ;
  • R 6 is selected from C1-C4 alkyl, cycloalkyi, or heterocycloalkyi, wherein said C1-C4 alkyl is optionally substituted with one or more groups independently selected from cycloalkyi, halogen, -CF 3 , -CN, -OH or -0(Ci-C 4 alkyl), and further wherein, if R 6 is cycloalkyi or heterocycloalkyi, then said cycloalkyi and said heterocycloalkyi are each optionally substituted with one or more groups independently selected from C1-C4 alkyl, cycloalkyi, halogen, -CF 3 , -CN, -OH or -0(C C 4 alkyl); and each R 7 , R 8 and R 9 is independently selected from hydrogen, C1-C4 alkyl, C 2 -C 4 alkenyl, cycloalkyi, cycloalkenyl, heterocycloalkyi, heterocycloalken
  • A is N or -CH
  • R 1 , R 2 and R 4 are each independently selected from R 7 , halogen, - CN, -OR 7 , -NR 7 R 8 , -COOR 7 , -SO 3 H, -B(OH) 2 , -CONR 7 R 8 , - COR 7 , -SR 7 , -SOR 7 , -SO2R 7 , -S0 2 NR 7 R 8 , -NR 7 COR 8 , NR 7 S0 2 R 8 , -OCOR 7 , -NR 7 C(0)NR 8 R 9 , -NR 7 C(S)NR 8 R 9 , -NR 7 COOR 8 , aryl, or heteroaryl, wherein said aryl and said heteroaryl are each substituted with one or more groups independently selected from R 7 , halogen, -CN, - OR 7 , -NR 7 R 8 , -COOR 7 , -SO 3 H, -B(OH) 2 ,
  • R 3 is selected from hydrogen, halogen, -CN, -OR 7 , NR 7 R 8 , -COOR 7 , -SO 3 H, -B(OH) 2 , -CONR 7 R 8 , -COR 7 , -SR 7 , - SOR 7 , -S0 2 R 7 , -S0 2 NR 7 R 8 , -NR 7 COR 8 , -NR 7 S0 2 R 8 , -OCOR 7 , -NR 7 C(0)NR 8 R 9 , - NR 7 C(S)NR 8 R 9 , -NR 7 COOR 8 , C C 4 alkyl, C 2 -C 4 alkenyl, cycloalkyi or heterocycloalkyi, wherein said CrC 4 alkyl and said C 2 -C 4 alkenyl are each optionally substituted with one or more groups independently selected from halogen, -CF 3 , -CN, -OH, -0(C C
  • R 5 is heteroaryl which is optionally substituted with one or more groups independently selected from R 7 , halogen, -CN, -NR 7 R 8 , -CONR 7 R 8 , -COR 7 , -OR 7 , -SR 7 , -SOR 7 , -S0 2 R 7 , - S0 2 NR 7 R 8 , -NR 7 COR 8 , -NR 7 S0 2 R 8 , -OCOR 7 , or -COOR 7 ;
  • R 6 is selected from C1-C4 alkyl, cycloalkyi, or heterocycloalkyi, wherein said C1-C4 alkyl is optionally substituted with one or more groups independently selected from cycloalkyi, halogen, -CF 3 , -CN, -OH or -0(Ci-C 4 alkyl), and further wherein, if R 6 is cycloalkyi or heterocycloalkyi, then said cycloalkyi and said heterocycloalkyi are each optionally substituted with one or more groups independently selected from C1-C4 alkyl, cycloalkyi, halogen, -CF 3 , -CN, -OH or -0(C C 4 alkyl); and each R 7 , R 8 and R 9 is independently selected from hydrogen, C1-C4 alkyl, C 2 -C 4 alkenyl, cycloalkyi, cycloalkenyl, heterocycloalkyi, heterocycloalken
  • A is N or -CH;
  • R 1 , R 2 and R 4 are each independently selected from R 7 , halogen, -
  • R 3 is selected from hydrogen, -F, -CI, -I, -CN, -OR 7 , -NR 7 R 8 , -COOR 7 , - S0 3 H, -B(OH) 2 , -CONR 7 R 8 , COR 7 , -SR 7 , -SOR 7 , -S0 2 R 7 , -S0 2 NR 7 R 8 , -NR 7 COR 8 , -NR 7 S0 2 R 8 , -OCOR 7 , - NR 7 C(0)NR 8 R 9 , -NR 7 C(S)NR 8 R 9 , -NR 7 COOR 8 , C1-C4 alkyl, C 2 -C 4 alkenyl, cycloalkyi or heterocycloalkyi, wherein said C1-C4 alkyl and said C 2 -C 4 alkenyl are each optionally substituted with one or more groups independently selected from halogen, -CF 3 , -
  • R 5 is heteroaryl which is optionally substituted with one or more groups independently selected from R 7 , halogen, -CN, -NR 7 R 8 , -CONR 7 R 8 , -COR 7 , -OR 7 , -SR 7 , -SOR 7 , -S0 2 R 7 , - S0 2 NR 7 R 8 , -NR 7 COR 8 , -NR 7 S0 2 R 8 , -OCOR 7 , or -COOR 7 ;
  • R 6 is selected from C1-C4 alkyl, cycloalkyi, or heterocycloalkyi, wherein said C1-C4 alkyl is optionally substituted with one or more groups independently selected from cycloalkyi, halogen, -CF 3 , -CN, -OH or -0(Ci-C 4 alkyl), and further wherein, if R 6 is cycloalkyi or heterocycloalkyi, then said cycloalkyi and said heterocycloalkyi are each optionally substituted with one or more groups independently selected from C1-C4 alkyl, cycloalkyi, halogen, -CF 3 , -CN, -OH or -0(C C 4 alkyl); and each R 7 , R 8 and R 9 is independently selected from hydrogen, C1-C4 alkyl, C 2 -C 4 alkenyl, cycloalkyi, cycloalkenyl, heterocycloalkyi, heterocycloalken
  • R 3 is selected from hydrogen, halogen, C1-C4 haloalkyl, Ci-C 4 haloalkoxy, -CN, Ci-C 4 alkyl, cycloalkyl, heterocycloalkyl, -OH, -0(Ci-C 4 alkyl), -O-cycloalkyl, -O-heterocycloalkyl, -NH 2 , -NH(C C 4 alkyl), -N(C C 4 alkyl)(C C 4 alkyl), -NH-cycloalkyl, -N(C C 4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(C C 4 alkyl)-heterocycloalkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-NH 2 , -CO-NH(Ci-C
  • R 3 is selected from hydrogen, halogen, Ci-C 4 haloalkyl, -CN, heterocycloalkyl, -0(Ci-C 4 alkyl), -NH(C C 4 alkyl), or -CO-N(C C 4 alkyl)(C C 4 alkyl), wherein said heterocycloalkyl is optionally substituted with one or more groups independently selected from: C C 4 alkyl; halogen; -CF 3 ; -CN; -OH; -0(C C 4 alkyl); C C 4 alkyl substituted with one or more -OH groups; -NH 2 ; -NH(Ci-C 4 alkyl); or -N(Ci-C 4 alkyl)(Ci- C 4 alkyl).
  • R 3 is selected from hydrogen, -F, -CI, -I, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, -CN, C C 4 alkyl, cycloalkyl, heterocycloalkyl, -OH, -0(Ci- C 4 alkyl), -O-cycloalkyl, -O-heterocycloalkyl, -NH 2 , -NH(C C 4 alkyl), -N(C C 4 alkyl)(C C 4 alkyl), -NH-cycloalkyl, -N(C C 4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(C C 4 alkyl)-heterocycloalkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-NH 2 , -CO-NH(C C 4 alkyl),
  • R 3 is selected from hydrogen, -F, -CI, C1-C4 haloalkyl, -CN, heterocycloalkyl, -0(d-C 4 alkyl), -NH(C C 4 alkyl), or -CO-N(Ci-C 4 alkyl)(Ci-C 4 alkyl), wherein said heterocycloalkyl is optionally substituted with one or more groups independently selected from: C1-C4 alkyl; halogen; -CF 3 ; -CN; -OH; -0(Ci- C 4 alkyl); C1-C4 alkyl substituted with one or more -OH groups; -NH 2 ; -NH(Ci-C 4 alkyl); or -N(Ci-C 4 alkyl)(C C 4 alkyl).
  • R 1 , R 2 and R 4 are each independently selected from hydrogen, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, C1-C4 alkyl, C 2 -C 4 alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -0(Ci-C 4 alkyl), -0-(Ci-C 4 alkylene)-OH, -0-(d-C 4 alkylene)-0(C C 4 alkyl), -O-cycloalkyl, -0-(d-C 4 alkylene)-cycloalkyl, -O-heterocycloalkyl, -0-(Ci-C 4 alkylene)-heterocycloalkyl, -O-aryl, -0-(Ci-C 4 alkyl
  • R 1 , R 2 and R 4 are each independently selected from hydrogen, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, Ci-C 4 alkyl, -OH, -0(Ci-C 4 alkyl), -NH(C C 4 alkyl), or -N(C C 4 alkyl)(C C 4 alkyl).
  • R 5 is heteroaryl having 5 or 6 ring members and comprising one or more ring heteroatoms independently selected from O, S or N, wherein said heteroaryl having 5 or 6 ring members is optionally substituted with one or more groups independently selected from C1-C4 alkyl, C 2 -C 4 alkenyl, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, - OH, -0(Ci-C 4 alkyl), -O-cycloalkyl, -0-(d-C 4 alkylene)-cycloalkyl, -O-heterocycloalkyl, -0-(Ci-C 4 alkylene)-heterocycloalkyl, -NH 2 , -NH(C
  • R 5 is pyridinyl which is optionally substituted with one or more groups independently selected from C1-C4 alkyl, C 2 -C 4 alkenyl, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -0(d-C 4 alkyl), -O-cycloalkyl, -0-(d-C 4 alkylene)-cycloalkyl, -O-heterocycloalkyl, -0-(Ci-C 4 alkylene)-heterocycloalkyl, -NH 2 , -NH(C C 4 alkyl), -N(C C 4 alkyl)(Ci-C 4 alkyl), -NH-cycloal
  • R 5 is pyridin-4-yl which is substituted with one substituent group at position 2 of said pyridin-4-yl or with two substituent groups at position 2 and 6 of said pyridin-4-yl, wherein said one or two substituent group(s) is/are selected independently from C1-C4 alkyl, C 2 -C 4 alkenyl, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, cycloalkyl, heterocycloalkyl, -0(Ci-C 4 alkyl), -O-cycloalkyl, or -O-heterocycloalkyl.
  • R 5 is pyridin-4-yl which is substituted with one substituent group at position 2 of said pyridin-4-yl, wherein said substituent group is selected from C1-C4 alkyl, C 2 -C 4 alkenyl, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, cycloalkyl, heterocycloalkyl, -0(Ci-C 4 alkyl), -O-cycloalkyl, or -O-heterocycloalkyl.
  • R 5 is 2-trifluoromethyl-pyridin-4-yl.
  • R 6 is CrC 4 alkyl which is optionally substituted with one or more groups independently selected from cycloalkyl, halogen, -CF 3 , -CN, -OH or -0(Ci-C 4 alkyl).
  • R 6 is methyl.
  • A is N.
  • a pharmaceutical composition comprising a compound as defined in any one of items 1 to 18 or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable excipient.
  • a method of treating and/or preventing a condition associated with altered glutamatergic signalling and/or functions, and/or a condition which can be affected by alteration of glutamate level or signalling comprising the administration of a compound as defined in any one of items 1 to 18 or a pharmaceutically acceptable salt, solvate or prodrug thereof or the pharmaceutical composition of item 19 to a subject in need of such treatment or prevention.
  • the compound for use according to item 20 or 23 or the pharmaceutical composition for use according to item 20 or 23 or the use of item 21 or 23 or the method of item 22 or 23, wherein the condition to be treated or prevented is selected from: dementias; parkinsonism and movement disorders; acute or chronic pain; anxiety disorders; schizophrenia; mood disorders; endocrine or metabolic diseases; or cancers.
  • dementias are selected from: dementias of the Alzheimer's type (DAT); Alzheimer's disease; Pick's disease; vascular dementias; Lewy-body disease; dementias due to metabolic, toxic and deficiency diseases, including alcoholism, hypothyroidism, and vitamin B12 deficiency; AIDS-dementia complex; Creutzfeld-Jacob disease; or atypical subacute spongiform encephalopathy.
  • DAT Alzheimer's type
  • Pick's disease vascular dementias
  • Lewy-body disease dementias due to metabolic, toxic and deficiency diseases, including alcoholism, hypothyroidism, and vitamin B12 deficiency
  • AIDS-dementia complex including Creutzfeld-Jacob disease
  • Creutzfeld-Jacob disease or atypical subacute spongiform encephalopathy.
  • parkinsonism and movement disorders are selected from: Parkinson's disease; multiple system atrophy; progressive supranuclear palsy; corticobasal degeneration; hepatolenticular degeneration; chorea, including Huntington's disease and hemiballismus; athetosis; dystonias, including spasmodic torticollis, occupational movement disorder, and Gilles de la Tourette syndrome; tardive or drug induced dyskinesias; tremor; or myoclonus.
  • a method of treating and/or preventing Alzheimer's disease comprising the administration of a compound as defined in any one of items 1 to 18 or a pharmaceutically acceptable salt, solvate or prodrug thereof or the pharmaceutical composition of item 19 to a subject in need of such treatment or prevention.
  • a method for identifying an agent that binds to metabotropic glutamate receptor 2 comprising the following steps:
  • step (e) comparing the signal detected in step (d) to the signal detected in step (b) to determine whether the test agent binds to mGluR2.
  • the HPLC system was a Waters platform with a 2767 sample manager, a 2525 pump, a photodiode array detector (190-400 nM).
  • the column used was a XSelect Ci 8 3.5 ⁇ (4.6 x 50 mm) in analytical mode and a XSelect d 8 5 ⁇ (30 x 100 mm) in preparative mode.
  • the mobile phase in both cases consisted in an appropriate gradient of A and B.
  • A was water with 0.05 % of TFA and B was MeOH with 0.05 % of TFA.
  • Flow rate was 1 mL per min in analytical mode and 25 ml. min in preparative mode. All LCMS were performed at room temperature.
  • HPLC is coupled with a Waters micromass platform. All mass spectra were full-scan experiments (mass range 100-800 amu). Mass spectra were obtained using electro spray ionization.
  • the UPLC system was a Waters Aquity platform with a photodiode array detector (190-400 nM).
  • the column used was a Acuity CSH d 8 1.7 ⁇ (2.1 x 30 mm)
  • the mobile phase consisted in a gradient of A and B.
  • A was water with 0.025 % of TFA and B was Acetonitrile with 0.025 % of TFA.
  • Flow rate was 0.8 ml. per min. All analysis were performed at 55°C.
  • Acetic acid (10.0 equiv.) was added and hydrazine D, HCI salt (1 .0 equiv.) was introduced.
  • the reaction mixture was warmed for 18 hours at 100°C. After cooling, the reaction mixture was concentrated and the residue was coevaporated twice with toluene before hydrolysis with saturated aqueous NaHC0 3 solution. The precipitate was collected, washed with water and dried under reduced pressure at 60°C with P 2 0 5 for 18 hours.
  • the reaction mixture was stirred at - 78°C for 1 hour, then was allowed to warm to room temperature and hydrolysed with saturated aqueous NH 4 CI solution and extracted with DCM. The organic layer was washed with brine, dried over MgS0 4 or Na 2 S0 4 and concentrated. The ketonitrile B was used in the next step without further purification and was supposed quantitative.
  • HCI salt was added (1.0 equiv.).
  • the reaction mixture was heated for 2 Hours at 120°C. After cooling, the reaction mixture was concentrated and the residue was coevaporated twice with toluene before hydrolysis with saturated aqueous NaHC0 3 solution. The precipitate was collected, washed with water and dried under reduced pressure at 60°C with P 2 0 5 for 18 hours.
  • Compound 1 was obtained according to general procedure l(i), starting from 2-Chloro- isonicotinic acid methyl ester in presence of 2-hydrazino-benzoic acid as a beige solid in 91 % yield.
  • Example 1 was obtained according to general procedure ll(i), starting from
  • Example 1 was obtained as a beige
  • Negeshi coupling cross-coupling reaction of a halide and an organozinc derivative.
  • the HCI salt was prepared.
  • Example 2 was obtained according to general procedure III starting from
  • example 2 as a beige solid in 58% yield.
  • Example 3 2-(2-Ethyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one, HCI salt.
  • Example 3 was obtained according to general procedure III starting from
  • Example 4 2-(2-propyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one, HCI salt.
  • Example 4 was obtained according to general procedure III starting from example 1 in presence of propylzinc bromide (in THF 0.5M - 3.0 equiv.). Purification by flash- chromatography (MeOH in DCM, 0 to 10%) and salt formation
  • Example 5 2-( 2-Cyclopropyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1, 5-a]quinazolin-5-one, HCI salt.
  • Example 5 was obtained according to general procedure III starting from
  • Example 6 2-(2-cyclobutyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one, HCI salt.
  • Example 6 was obtained according to general procedure III starting
  • example 6 as a white solid in 8% yield.
  • Example 7 2-(2-cyclopentyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one, HCI salt.
  • Example 7 was obtained according to general procedure III starting
  • example 7 as a white solid in 9% yield.
  • Example 8 2-(2-cyclohexyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one, HCI salt.
  • Example 8 was obtained according to general procedure III starting
  • example 8 as a white solid in 25% yield.
  • Example 9 4-Methyl-2-(2-vinyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one.
  • Example 9 was obtained as a brown solid in 63% yield.
  • Example 10 2-(2-lsopropenyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one.
  • Example 10 was obtained according to general procedure V starting
  • example 10 as a beige solid in 68% yield.
  • Example 1 2-(2-lsopropyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one, HCI salt.
  • Example 12 4-(4-Methyl-5-oxo-4, 5-dihydro-pyrazolo[1,5-a]quinazolin-2-yl)-pyridine-2- carbonitrile.
  • Example 12 was obtained according to general procedure VI starting
  • example 12 as a white solid in 94% yield.
  • Compound 2 2-(2-Fluoro-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one.
  • Example 13 2-(2-Fluoro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one.
  • Example 13 was obtained according to general procedure ll(i), starting
  • Example 13 was obtained as a
  • Example 15 2-(2-ethoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one.
  • Example 16 2-(2-lsopropoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one.
  • Example 16 was obtained according to general procedure Vll(i) starting
  • example 16 from example 13 in presence of isopropanol. Purification by flash- chromatography (MeOH in DCM, 0 to 5%) afforded example 16 as a
  • Example 17 2-(2-Cyclobutoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one.
  • Example 17 was obtained according to general procedure Vll(i) starting from example 13 in presence of cyclobutanol. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 17 as a white solid in 24% yield.
  • Example 18 4-Methyl-2-[2-(oxetan-3-yloxy)-pyndin-4-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one.
  • Example 18 was obtained according to general procedure Vll(i)
  • example 18 as a white solid in 20% yield.
  • Example 19 2-(2-Cyclopropylmethoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5- one.
  • Example 20 2-[2-( 2-Methoxy-ethoxy)-pyridin-4-yl]-4-methyl-4H-pyrazolo[1, 5-a]quinazolin-5- one.
  • Example 20 was obtained according to general procedure Vll(i) starting from example 13 in presence of 2-methoxyethanol. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 20 as a white solid in 40% yield.
  • Example 21 4-Methyl-2-[2-(2, 2, 2-trifluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1 , 5-a]quinazolin-5- one.
  • Example 22 4-Methyl-2-[2-(2, 2-difluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1 , 5-a]quinazolin-5- one.
  • Example 24 4-Methyl-2-[2-(2, 2, 3, 3, 3-pentafluoro-propoxy)-pyridin-4-yl]-4H-pyrazolo[1 ,5- a]quinazolin-5-one.
  • Example 24 was obtained according to general procedure Vll(ii)
  • example 24 as a white solid in 55% yield.
  • Example 25 4-Methyl-2-[2-(2, 2, 2-trifluoro-1-trifluoromethyl-ethoxy)-pyridin-4-yl]-4H- pyrazolo[1,5-a]quinazolin-5-one
  • Example 25 was obtained as a white solid in 19% yield.
  • Compound 3 2-(2-Trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one.
  • Compound 3 was obtained according to general procedure l(iii), starting from 2-trifluoromethyl- isonicotinic acid ethyl ester in presence of 2-hydrazino-benzoic acid as a beige solid in 86% yield.
  • Example 26 4-Methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H- pyrazolo[1, 5-a]quinazolin-5-one.
  • Example 26 was obtained according to general procedure ll(i), starting
  • Example 27 was obtained according to general procedure ll(ii),
  • Example 28 4 ⁇ thyl-2-(2-trifluoromethyl ⁇ yridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one.
  • Example 28 was obtained according to general procedure ll(ii), starting
  • example 28 as a white solid in 18% yield.
  • Example 29 4-(2,2-Difluoro-ethyl)-2-(2-tn luoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one.
  • Example 29 was obtained according to general procedure ll(ii), starting
  • Example 30 4-(2-Methoxy-ethyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5- a]quinazolin-5-one.
  • Example 30 was obtained according to general procedure ll(ii), starting
  • Compound 4 was obtained according to general procedure VIII using bis ⁇ [(difluoromethyl)sulfonyl]oxy ⁇ zinc (DFMS). The reaction mixture was stirred for 4 hours at room temperature. Compound 4 was isolated as a yellow oil in a quantitative yield. To facilitate the extraction step, EDTA (8% w/w) was added to the NaHC0 3 solution.
  • DFMS bis ⁇ [(difluoromethyl)sulfonyl]oxy ⁇ zinc
  • Example 31 was obtained according to general procedure ll(ii), starting
  • Compound 6 was obtained according to general procedure VIII using sodium 1 ,1 - difluoromethanesulfinate. The reaction mixture was stirred for 20 hours at room temperature. Compound 6 was isolated as a yellow oil in quantitative yield. To ensure a full conversion, sodium 1 , 1 -difluoromethanesulfinate (2.0 equiv.) and tertbutyl hydroperoxide (3.0 equiv.) were added a second time after 18 hours.
  • Example 32 2-[2-(1 , 1 -Difluoro-ethyl)-pyridin-4-yl]-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5- one.
  • Example 32 was obtained according to general procedure ll(i), starting
  • Example 33 2-[2-( 1 , 1 -Difluoro-e thy I) -pyridin-4-yl]-4-methyl( D 3 ) -4H-pyrazolo[1 , 5-a ]quinazolin-5- one.
  • Example 33 was obtained according to general procedure ll(i), starting
  • Compound 8 was obtained according to general procedure IX, starting from 2-amino-5-methyl- benzoic acid, as a beige solid in 90% yield.
  • Example 34 7-Methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one.
  • Example 34 was obtained according to general procedure ll(i), starting
  • Compound 1 1 was obtained according to general procedure l(iii), starting from 2- trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 10 as a brown solid in 31 % yield.
  • Example 35 7-Chloro-2-( 2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1, 5-a]quinazolin-5-one.
  • Example 35 was obtained according to general procedure ll(i), starting
  • Compound 13 was obtained according to general procedure l(iii), starting from 2- trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 12 as a brown solid in 37% yield.
  • Example 36 was obtained according to general procedure ll(i),
  • Example 36 was
  • Compound 15 was obtained according to general procedure l(iii), starting from 2- trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 14 as a brown solid in 40% yield.
  • Compound 16 5-fluoro-2-hydrazino-5-trifluoromethyl-benzoic acid, HCI.
  • Compound 16 was obtained according to general procedure IX, starting from 2-amino-5- fluoromethylbenzoic acid, as a beige solid in 46% yield.
  • Compound 17 7-fluoro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one.
  • Compound 17 was obtained according to general procedure l(iv), starting from 2- trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 16 as a brown solid in 54% yield.
  • Example 38 was obtained according to general procedure ll(iii),
  • Example 38 was
  • Compound 19 7-Bromo-2-( 2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1, 5-a]quinazolin-5-one.
  • Compound 19 was obtained according to general procedure l(i), starting from 2-trifluoromethyl- isonicotinic acid ethyl ester in presence of hydrazine 8 as a brown solid in 24% yield.
  • Example 39 7-Bromo-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one.
  • Example 39 was obtained according to general procedure ll(i),
  • Example 39 was
  • Example 40 4-Methyl-7-methylamino-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5- a]quinazolin-5-one.
  • Example 40 was obtained according to general procedure X(i) starting
  • Example 41 4-Methyl-7-methyl(D3)amino-2-(2 rifluoromethyl-pyridin-4-yl)-4H-pyrazolol1 ,5- a]quinazolin-5-one.
  • Example 41 was obtained according to general procedure X(i) starting
  • example 41 as a beige solid in 30% yield.
  • Example 42 N-[4-Methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5- a]quinazolin-7-yl]-acetamide.
  • Example 43 7-Amino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin- 5-one.
  • a suspension of amide 42 (23.2 mg, 1.0 equiv.) in
  • example 43 as a brown solid in 71 % yield.
  • Example 44 7-Dimethylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazob a]quinazolin-5-one.
  • Example 44 was obtained according to general procedure X(i)
  • Example 45 7-Ethylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one.
  • Example 45 was obtained according to general procedure X(i) starting
  • example 45 0 to 50% afforded example 45 as a beige solid in 26% yield.
  • Example 46 7-Cyclobutylamino-4-methyl-2-(2-tn luoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one.
  • Example 46 was obtained according to general procedure X(i)
  • Example 47 4-Methyl-7-morpholin-4-yl-2-(2-tn luoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one.
  • Example 47 was obtained according to general procedure X(ii)
  • Example 48 7-Hydroxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one.

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Abstract

The present invention provides pyrazoloquinazolinone and pyrroloquinazolinone derivatives of the general formula (I) and pharmaceutical compositions containing them. Moreover, the compounds of formula (I) and the compositions containing them are provided for use in the treatment and/or prophylaxis of conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling in mammals. These pyrazoloquinazolinone and pyrroloquinazolinone derivatives of the general formula (I) can act as modulators of nervous system receptors sensitive to glutamate, in particular as modulators of metabotropic glutamate receptors (mGlu Rs), which makes them particularly suitable for the treatment and/or prophylaxis of acute and chronic neurological and/or psychiatric disorders.

Description

SUBSTITUTED PYRAZOLOQUINAZOLINONES AND PYRROLOQUINAZOLINONES AS ALLOSTERIC MODULATORS OF GROUP II METABOTROPIC GLUTAMATE RECEPTORS
The present invention provides pyrazoloquinazolinone and pyrroloquinazolinone derivatives of the general formula (I) and pharmaceutical compositions containing them. Moreover, the compounds of formula (I) and the compositions containing them are provided for use in the treatment and/or prophylaxis of conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling in mammals. These pyrazoloquinazolinone and pyrroloquinazolinone derivatives of the general formula (I) can act as modulators of nervous system receptors sensitive to glutamate, in particular as modulators of metabotropic glutamate receptors (mGluRs), which makes them particularly suitable for the treatment and/or prophylaxis of acute and chronic neurological and/or psychiatric disorders. Glutamatergic pathways have been shown to be clearly involved in the physiopathology of a number of neuronal damages and injuries. Many nervous system disorders including epilepsy and chronic or acute degenerative processes, such as for example Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis (Mattson MP., Neuromolecular Med., 3(2), 65-94, 2003), but also AIDS-induced dementia, multiple sclerosis, spinal muscular atrophy, retinopathy, stroke, ischemia, hypoxia, hypoglycaemia and various traumatic brain injuries, involve neuronal cell death caused by imbalanced levels of glutamate. It has also been shown that drug-induced neurotoxicity, for example neurotoxic effects of methamphetamine (METH) on striatal dopaminergic neurons, could actually be mediated by over-stimulation of the glutamate receptors (Stephens SE and Yamamoto BK, Synapse 17(3), 203-9, 1994). Antidepressant and anxiolytic-like effects of compounds acting on glutamate have also been observed in mice, suggesting that glutamatergic transmission is implicated in the pathophysiology of affective disorders such as major depression, schizophrenia and anxiety (Palucha A et al., Pharmacol. Ther. 1 15(1 ), 1 16-47, 2007; Cryan JF et al., Eur. J. Neurosc. 17(1 1 ), 2409-17, 2003; Conn PJ et al., Trends Pharmacol. Sci. 30(1 ), 25-31 , 2009). Consequently, any compound able to modulate glutamatergic signalling or function would constitute a promising therapeutic compound for many disorders of the nervous system.
Moreover, compounds modulating glutamate level or signalling may be of great therapeutic value for diseases and/or disorders not directly mediated by glutamate levels and/or glutamate receptor malfunctioning, but which could be affected by alteration of glutamate levels or signalling.
In the central nervous system (CNS), L-glutamate (Glu) is the main excitatory neurotransmitter and is referred to as an excitatory amino-acid (EAA), and gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter. The balance between excitation and inhibition is of utmost importance to CNS functions, and dysfunctions of either of the two can be related to various neurodegenerative or neurological disorders.
Glutamate is ubiquitously distributed in the nervous system in high concentrations, especially in the brain and spinal cord of mammals, where it is working at a variety of excitatory synapses being thereby involved in virtually all physiological functions such as motor control, vision, central control of heart, processes of learning and memory. However, a large number of studies have established that cellular communication involving glutamate can also lead to a mechanism of cell destruction. This combination of neuroexcitatory activities and neurotoxic properties is called excitotoxicity.
Glutamate operates through two classes of receptors (Brauner-Osborne H et al., J. Med. Chem. 43(14), 2609-45, 2000). The first class of glutamate receptors is directly coupled to the opening of cation channels in the cellular membrane of the neurons. Therefore they are called ionotropic glutamate receptors (IGluRs). The IGluRs are divided in three subtypes, which are named according to the depolarizing action of their selective agonists: N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AM PA), and kainic acid (KA). The second class of glutamate receptor consists of G-protein coupled receptors (GPCRs) called metabotropic glutamate receptors (mGluRs). These mGluRs are localized both pre- and post-synaptically. They are coupled to multiple second messenger systems and their role is to regulate the activity of the ionic channels or enzymes producing second messengers via G- proteins binding the GTP (Nicoletti F et al.; Neuropharmacol., 60(7-8), 1017-41 , 201 1 ). Although they are generally not directly involved in rapid synaptic transmission, the mGluRs modulate the efficacy of the synapses by regulating either the post-synaptic channels and their receptors, or the pre-synaptic release or recapture of glutamate. Therefore, mGluRs play an important role in a variety of physiological processes such as long-term potentiation and long- term depression of synaptic transmission, regulation of baroreceptive reflexes, spatial learning, motor learning, and postural and kinetic integration. To date, eight mGluRs have been cloned and classified in three groups according to their sequence homologies, pharmacological properties and signal transduction mechanisms. Group I is constituted of mGluRI and mGluR5, group II of mGluR2 and mGluR3 and group III of mGluR4, mGluR6, mGluR7 and mGluR8 (Schoepp DD et al., Neuropharmacology, 38(10), 1431 -76, 1999). mGluR modulators can be classified into two families depending on their site of interaction with the receptor (see Brauner-Osborne H et al., J. Med. Chem. 43(14), 2609-45, 2000 for review). The first family consists in orthosteric modulators (or competitive modulators) able to interact with the glutamate binding-site of the mGluRs, which is localized in the large extra-cellular N- terminal part of the receptor (about 560 amino acids). Therefore, they are glutamate analogs and constitute a highly polar family of ligand. Examples of orthosteric modulators are S-DHPG or LY-367385 for group I mGluRs, LY-354740 or LY-379268 for group II mGluRs and ACPT-I or L-AP4 for group III mGluRs. The second family of mGluR modulators consists in allosteric modulators that interact with a different site from the extracellular active site of the receptor (see Bridges TM et al., ACS Chem Biol, 3(9), 530-41 , 2008 for review). Their action results in a modulation of the effects induced by the endogenous ligand glutamate. Examples of such allosteric modulators are Ro-674853, MPEP or JNJ16259685 for group I mGluRs and CBiPES, BINA, LY487379 or R04491533 for group II mGluRs and PHCCC, VU0155041 or VU0359516 for group III mGluRs.
By interacting with allosteric binding sites, mGluR allosteric modulators stabilize a receptor conformation and equilibrium shift that increases or decreases the affinity and/or efficacy of an orthosteric agonist of the receptor, without activating the receptor on its own (Bridges TM et al., ACS Chem Biol, 3(9), 530-41 , 2008). Such modulators are respectively termed positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs). Group II mGluR activation or potentiation has been shown to be associated with positive effects in animal models of anxiety (Swanson CJ.; Nat Rev Drug Discov, 4, 131-44, 2005), schizophrenia (Conn PJ et al.; Trends in Pharmacol Sci, 30, 25-31 , 2009), drug-addiction (Adewale AS et al.; J Pharmacol Exp Ther, 318, 922-31 , 2006) or chronic pain (Jones CK et al.; Neuropharmacology, 49 (Suppl 1 ), 206-18, 2005).
Antagonists and NAMs of group II mGluRs have been shown to exert antidepressant-like and cognitive enhancing properties (Chaki S et al.; Neuropharmacology, 46, 457-67, 2004 - Higgins GA et al.; Neuropharmacology, 46, 907-17, 2004 - Yoshimizu T and Shaki S.; Biochem Biophys Res Commun, 315, 493-6, 2004 - Knoflach F et al.; 5th International Meeting on Metabotropic Glutamate Receptors, Taormina Italy, 2005 - Yoshimizu T et al.; Psychopharmacology (Berl), 183, 587-93, 2006 - Campo B et al.; Annual Meeting of the Society for Neuroscience, Chicago IL, 2009, 343.8 - Kalinichev M et al.; Annual Meeting of the Society for Neuroscience, San Diego CA, 2010, 406.9 - Kalinichev M et al.; Annual Meeting of the Society for Neuroscience, San Diego CA, 2010, 886.14 - Lambeng N et al.; Annual Meeting of the Society for Neuroscience, San Diego CA, 2010, 651.15 - Lambeng N et al.; 3rd RSC/SCI Symposium on GPCRs in Medicinal Chemistry, Oss The Netherlands, 2010 - Woltering TJ, et al.; Bioorg Med Chem Lett, 20, 6969-74, 2010), cytotoxic properties against colorectal cancer cell lines and human glioblastoma stem cells (Mosillo P et al.; Annual Meeting of the Society for Neuroscience, San Diego CA, 2010, 642.28 - Bonelli M et al.; Annual Meeting of the Society for Neuroscience, San Diego CA, 2010, 642.29 - Ciceroni C, et al.; Cell Death and Differentiation, 20(3), 396-407, 2013), sleep/wake disorders (Feinberg I, et al.; J Pharmacol Exp Ther, 312(2), 826-33, 2005 - Ahnaou A, et al.; Behav Brain Res, 270, 56- 67, 2014 - WO2012068041 - WO2012068067) and autism spectrum disorders such as Fragile X syndrome and Rett syndrome (WO2014064028).
Numerous examples of group II mGluR PAMs have already been described in research articles and patent literature (see Trabanco AA, et al.; Curr Med Chem, 18(1 ), 47-68, 201 1 for review). However, less information is available regarding group II mGluR NAMs. Benzodiazepinone derivatives (Woltering TJ, et al.; Bioorg Med Chem Lett, 17, 681 1 -5, 2007 - Woltering TJ, et al.; Bioorg Med Chem Lett, 18, 1091-5, 2008; Woltering TJ, et al., Bioorg Med Chem Lett, 18, 2725-9, 2008; Woltering TJ, et al., Bioorg Med Chem Lett, 20, 6969-74, 2010; and WO 2013/033246), pyrazolopyrimidine derivatives (WO 2005/040171 , WO 2005/123738, WO 2006/084634, WO 2006/099072 and WO2007/039439), pyridine / pyrimidine derivatives (WO 2007/1 10337 and WO 2007/1 19689), pyrazoloquinazolinone and pyrroloquinazolinone derivatives (WO 2013/174822; EP-A-2666775), heteroaryl-pyrazole derivatives (WO 2012/020820, WO 2012/015024, WO 2012/099200 and WO 2013/1 1 1796) and quinoline derivatives (WO 2013/066736) have been disclosed as group II mGluR NAMs.
Little information is available with regard to the selectivity of group II mGluR NAMs for either mGluR2 or mGluR3. Some of the group II mGluR NAMs mentioned in the previous paragraph, like R04491533, R04988546, RO5488608 or certain pyrazoloquinazolinone derivatives, have been described as non-selective group II NAMs blocking both mGluR2 and mGluR3 with similar potency and efficacy (Woltering TJ, et al., Bioorg Med Chem Lett, 20, 6969-74, 2010; Lundstrom L, et al., British Journal of Pharmacology, 164, 521-37, 201 1 ; Wenthur CJ, et al., Bioorg Med Chem Lett, 24, 2693-98, 2014). The specific mGluR3 NAM LY2389575 was previously reported as amplifying neurotoxicity induced by Αβ amyloid (Caraci F, et al., Molecular Pharmacology, 79(3), 618-26, 201 1 ). It would therefore be advantageous to develop group II mGluR NAMs that are selective for mGluR2 over mGluR3 for the treatment of CNS disorders, and more particularly for the treatment of neurodegenerative disorders like Alzheimer's disease.
In the context of the present invention, it has surprisingly been found that compounds of formula (I) constitute potent NAMs of the mGluR2 subtype, showing an advantageous selectivity for mGluR2 over mGluR3. This can be illustrated with reference to the compounds of examples 1 and 9 according to the invention, which show IC50 < 100 nM for human mGluR2 and IC50 > 1 μΜ for human mGluR3, resulting in a ratio [IC50 hmGluR3] / [IC50 hmGluR2] > 10, i.e., a more than ten-fold greater negative allosteric modulator activity on mGluR2 than on mGluR3.
Figure imgf000006_0001
Example 1 Example 9
mGluR2 ICso < 100 nM mGluR2 ICso < 100 nM ratio [ICso hmGluR3] / [IC50 hmGluR2] > 10 ratio [ICso hmGluR3] / [IC50 hmGluR2] > 10
The compounds of the present invention are thus highly advantageous in terms of their mGluR2/3 selectivity. In comparison thereto, structurally related compounds disclosed in WO 2013/174822 and EP-A-2666775, such as the compounds A and B shown below, have a similar potency on mGluR2 (IC50 < 100 nM) but lack selectivity for mGluR2 over mGluR3 (ratio [ICso hmGluR3] / [IC50 hmGluR2] < 1 ).
Figure imgf000006_0002
Compound A Compound B
(Example 2 of WO 2013/174822) (Example 1 of WO 2013/174822)
mGluR2 ICso < 100 nM mGluR2 ICso < 100 nM ratio [ICso hmGluR3] / [IC50 hmGluR2] < 1 ratio [ICso hmGluR3] / [IC50 hmGluR2] < 1
Moreover, the two reference drugs R04491533 and decoglurant (RG1578), which are known group II mGluR NAMs, also display a ratio [IC50 hmGluR3] / [IC50 hmGluR2] <1 when tested under the same conditions, and thus likewise lack selectivity for mGluR2 over mGluR3.
Figure imgf000007_0001
Pyrazoloquinazolinone structures have further been described as poly(ADP-ribose)polymerase (PARP) inhibitors in Orvieto F, et al., Bioorg Med Chem Lett, 2009, 19(15):4196-4200 and also in the patent applications WO 2007/144669, WO 2007/149907 and WO 2008/090379. These pyrazoloquinazolinones mimick the nicotinamide moiety of NAD+, the cofactor of PARP, and therefore invariably comprise an unsubstituted lactam nitrogen, i.e. a hydrogen in position 4 of the pyrazoloquinazolinone scaffold, as an essential feature. In contrast thereto, the compounds of the present invention are substituted at position 4 of the pyrazoloquinazolinone ring and thus form a different class of therapeutic agents.
Pyrazoloquinazolinone compounds and their microwave-assisted preparations were described in Vasquez TE et al., Mol Divers, 7(2-4), 161-4, 2003. However, all the compounds disclosed in this publication differ structurally from those of the present invention, e.g., due to a hydrogen atom on position 4 of the pyrazoloquinazolinone scaffold and due to the lack of an aromatic ring group in position 8 of the pyrazoloquinazolinone scaffold.
Pyrazoloquinazolinone structures were also described as anti-secretory, anti-inflammatory, anti-allergic and anti-parasitic agents in patent documents US 4,105,764 and US 4, 105,766 or as photographic material in patent applications such as EP0374781 , JP4003154, JP4003155, JP4009050, JP4039656, JP4037741 or JP4037748.
Pyrroloquinazolinone compounds and their preparations were described in Volovenko YM et al., Chemistry of Heterocyclic Compounds, 38(3), 324-30, 2002. The pyrroloquinazolin-2,5- diones disclosed in this publication differ structurally from the compounds of the present invention, e.g., since they have a carbonyl on position 2, a thiazole substituent in position 3, and an unsubstituted lactam nitrogen in position 4. The present invention thus provides compounds which are potent mGluR2 negative allosteric modulators, showing selectivity for mGluR2 over mGluR3, which renders them particularly suitable as medicaments. The invention hence solves the problem of providing improved means and methods for the medical intervention in diseases, disorders and conditions associated with altered glutamatergic signalling and/or functions as well as conditions which can be affected by alteration of glutamate level or signalling in mammals, in particular for the treatment and/or prophylaxis of acute and chronic neurological and/or psychiatric disorders.
Accordingly, in a first aspect the present invention relates to a compound of the general formula (I):
Figure imgf000008_0001
(I) or a pharmaceutically acceptable salt, solvate or prodrug thereof for use as a medicament.
In formula (I), A represents N or -CH.
R1, R2 and R4 are each independently selected from R7, halogen, -CN, -OR7, -NR7R8, -COOR7, -SO3H, -B(OH)2, -CONR7R8, -COR7, -SR7,
SOR7, -SO2R7, -S02NR7R8, -NR7COR8, -NR7S02R8, -OCOR7,
NR7C(0)NR8R9, -NR7C(S)NR8R9, -NR7COOR8, aryl, or heteroaryl, wherein said aryl and said heteroaryl are each substituted with one or more groups independently selected from R7, halogen, -CN, -OR7, -NR7R8, -COOR7, -SO3H, -B(OH)2, -CONR7R8, -COR7, -SR7, - SOR7, -SO2R7, -S02NR7R8, -NR7COR8, -NR7S02R8, -OCOR7, -NR7C(0)NR8R9, - NR7C(S)NR8R9, or -NR7COOR8. R3 is selected from hydrogen, halogen, -CN, -OR7, -NR7R8, -COOR7, -S03H, - B(OH)2, -CONR7R8, -COR7, -SR7, -SOR7, -S02R7, -S02NR7R8, -NR7COR8, - NR7S02R8, -OCOR7, -NR7C(0)NR8R9, -NR7C(S)NR8R9, -NR7COOR8, C1-C4 alkyl, C2-C4 alkenyl, cycloalkyi or heterocycloalkyi, wherein said C1-C4 alkyl and said C2-C4 alkenyl are each optionally substituted with one or more groups independently selected from halogen, - CF3, -CN, -OH, -0(Ci-C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(C C4 alkyl)(C C4 alkyl), and further wherein said cycloalkyi and said heterocycloalkyi are each optionally substituted with one or more groups independently selected from: C1-C4 alkyl; halogen; -CF3; -CN; -OH; -0(Ci- C4 alkyl); C1-C4 alkyl substituted with one or more -OH groups; -NH2; -NH(d-C4 alkyl); or -N(Ci-C4 alkyl)(C C4 alkyl).
R5 is heteroaryl which is optionally substituted with one or more groups independently selected from R7, halogen, -CN, -NR7R8, -CONR7R8, -COR7, -OR7, -SR7, -SOR7, -S02R7, - S02NR7R8, -NR7COR8, -NR7S02R8, -OCOR7, or -COOR7.
R6 is selected from C1-C4 alkyl, cycloalkyi, or heterocycloalkyi, wherein said C1-C4 alkyl is optionally substituted with one or more groups independently selected from cycloalkyi, halogen, -CF3, -CN, -OH or -0(CrC4 alkyl), and further wherein, if R6 is cycloalkyi or heterocycloalkyi, then said cycloalkyi and said heterocycloalkyi are each optionally substituted with one or more groups independently selected from C1-C4 alkyl, cycloalkyi, halogen, - CF3, -CN, -OH or -0(Ci-C4 alkyl).
Each R7, R8 and R9 is independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, cycloalkyi, cycloalkenyl, heterocycloalkyi, heterocycloalkenyl, aryl or heteroaryl, wherein said C1-C4 alkyl and said C2-C4 alkenyl are each optionally substituted with one or more groups independently selected from halogen, -CF3, -CN, cycloalkyi, cycloalkenyl, heterocycloalkyi, heterocycloalkenyl, aryl, heteroaryl, -OH, -0(C C4 alkyl), -N H2, -NH(Ci-C4 alkyl) or -N(Ci-C4 alkyl)(Ci-C4 alkyl), and further wherein, if R7, R8 or R9 is cycloalkyi, cycloalkenyl, heterocycloalkyi, heterocycloalkenyl, aryl or heteroaryl, then said cycloalkyi, said cycloalkenyl, said heterocycloalkyi, said heterocycloalkenyl, said aryl and said heteroaryl are each optionally substituted with one or more groups independently selected from: C1-C4 alkyl; halogen; - CF3; -CN; -OH; -0(C C4 alkyl); C C4 alkyl substituted with one or more -OH groups; -NH2; -NH(C C4 alkyl); or -N(C C4 alkyl)(C C4 alkyl). The present invention further provides novel compounds. In particlar, in a second aspect, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof as described and defined in the first aspect of the invention, with the proviso that the following compounds are excluded:
8-bromo-2-furan-2-yl-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
8-bromo-2-(2,6-dimethyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
8-bromo-4-methyl-2-(1 -methyl-1 H-pyrazol-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
8-bromo-4-methyl-2-(1 -ethyl-1 H-pyrazol-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
8-bromo-2-(2-methyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
8-bromo-4-methyl-2-pyridin-3-yl-4H-pyrazolo[1 ,5-a]quinazolin-5-one; and
8-bromo-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one. In a third aspect, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof as described and defined in the first aspect of the invention, wherein the groups/variables A, R1, R2 and R4 to R9 have the same meanings as defined in the first aspect of the invention, and wherein the group R3 is selected from hydrogen, -F, -CI, -I, -CN, -OR7, -NR7R8, -COOR7, -S03H, -B(OH)2, -CONR7R8, - COR7, -SR7, -SOR7, -S02R7, -S02NR7R8, -NR7COR8, -NR7S02R8, -OCOR7, - NR7C(0)NR8R9, -NR7C(S)NR8R9, -NR7COOR8, C C4 alkyl, C2-C4 alkenyl, cycloalkyl or heterocycloalkyl, wherein said C C4 alkyl and said C2-C4 alkenyl are each optionally substituted with one or more groups independently selected from halogen, -CF3, -CN, - OH, -0(Ci-C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(C C4 alkyl)(C C4 alkyl), and further wherein said cycloalkyl and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from: Ci-C4 alkyl; halogen; -CF3; -CN; -OH; -0(Ci-C4 alkyl); d- C4 alkyl substituted with one or more -OH groups; -NH2; -NH(Ci-C4 alkyl); or -N(Ci-C4 alkyl)(Ci-C4 alkyl). Moreover, the present invention provides a pharmaceutical composition containing a compound of formula (I) as defined in the first, second or third aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and optionally a pharmaceutically acceptable excipient. The invention further relates to the compounds of formula (I) as well as their pharmaceutically acceptable salts, solvates and prodrugs as defined in the first, second or third aspect for use in the treatment and/or prophylaxis of conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling. The invention likewise relates to a pharmaceutical composition containing a compound of formula (I) as defined in the first, second or third aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and optionally a pharmaceutically acceptable excipient, for use in the treatment and/or prophylaxis of conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling.
The present invention also relates to the use of a compound of formula (I) as defined in the first, second or third aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the preparation of a medicament for the treatment and/or prophylaxis of conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling.
The invention further provides a method of treating and/or preventing conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling in a mammal. Accordingly, the invention relates to a method of treating and/or preventing a disease or disorder, in particular a condition associated with altered glutamatergic signalling and/or functions, and/or a condition which can be affected by alteration of glutamate level or signalling, the method comprising the administration of a compound of formula (I) as defined in the first, second or third aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising any of the aforementioned entities and optionally a pharmaceutically acceptable excipient, to a subject (preferably a mammal, more preferably a human) in need of such treatment or prevention.
The compounds of formula (I) as defined in the first, second or third aspect of the invention can be used as modulators of mGluRs of the nervous system, preferably as allosteric modulators of the mGluRs, more preferably as negative allosteric modulators (NAMs) of group II mGluRs, even more preferably as NAMs of mGluR2, and yet even more preferably as NAMs of mGluR2 that are selective for mGluR2 over mGluR3. It is preferred that such NAMs that are selective for mGluR2 over mGluR3 have a ratio of [IC50 mGluR3] / [IC50 mGluR2] > 3, more preferably > 5, and even more preferably > 10. The ratio [IC5o mGluR3] / [IC5o mGluR2] can be determined as described in Example 127.
As noted above, the invention relates to the compounds of formula (I) as defined in the first, second or third aspect, their pharmaceutically acceptable salts, solvates and prodrugs, as well as pharmaceutical compositions comprising any of the aforementioned entities and optionally a pharmaceutically acceptable excipient, for use in the treatment and/or prophylaxis of conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling. The conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling, to be treated and/or prevented with the compounds or the pharmaceutical compositions according to the invention, include in particular: epilepsy, including newborn, infantile, childhood and adult syndromes, partial (localization-related) and generalized epilepsies, with partial and generalized, convulsive and non-convulsive seizures, with and without impairment of consciousness, and status epilepticus; Dementias and related diseases, including dementias of the Alzheimer's type (DAT), Alzheimer's disease, Pick's disease, vascular dementias, Lewy- body disease, dementias due to metabolic, toxic and deficiency diseases (including alcoholism, hypothyroidism, and vitamin B12 deficiency), AIDS-dementia complex, Creutzfeld- Jacob disease and atypical subacute spongiform encephalopathy; Parkinsonism and movement disorders, including Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, hepatolenticular degeneration, chorea (including Huntington's disease and hemiballismus), athetosis, dystonias (including spasmodic torticollis, occupational movement disorder, Gilles de la Tourette syndrome), tardive or drug induced dyskinesias, tremor and myoclonus; Motor neuron disease or amyotrophic lateral sclerosis (ALS); Other neurodegenerative and/or hereditary disorders of the nervous system, including spinocerebellar degenerations such as Friedrich's ataxia and other hereditary cerebellar ataxias, predominantly spinal muscular atrophies, hereditary neuropathies, and phakomatoses; Disorders of the peripheral nervous system, including trigeminal neuralgia, facial nerve disorders, disorders of the other cranial nerves, nerve root and plexus disorders, mononeuritis such as carpal tunnel syndrome and sciatica, hereditary and idiopathic peripheral neuropathies, inflammatory and toxic neuropathies; Multiple sclerosis and other demyelinating diseases of the nervous system; Infantile cerebral palsy (spastic), monoplegic, paraplegic or tetraplegic; Hemiplegia and hemiparesis, flaccid or spastic, and other paralytic syndromes; Cerebrovascular disorders, including subarachnoid hemorrhage, intracerebral hemorrhage, occlusion and stenosis of precerebral arteries, occlusion of cerebral arteries including thrombosis and embolism, brain ischemia, stroke, transient ischemic attacks, atherosclerosis, cerebrovascular dementias, aneurysms, cerebral deficits due to cardiac bypass surgery and grafting; Migraine, including classical migraine and variants such as cluster headache; Headache; Myoneural disorders including myasthenia gravis, acute muscle spasms, myopathies including muscular dystrophies, mytotonias and familial periodic paralysis; Disorders of the eye and visual pathways, including retinal disorders, and visual disturbances; Intracranial trauma/injury and their sequels; Trauma/injury to nerves and spinal cord and their sequels; Poisoning and toxic effects of nonmedicinal substances; Accidental poisoning by drugs, medicinal substances and biologicals acting on the central, peripheral and autonomic system; Neurological and psychiatric adverse effects of drugs, medicinal and biological substances; Disturbance of sphincter control and sexual function; Mental disorders usually diagnosed in infancy, childhood or adolescence, including: mental retardation, learning disorders, motor skill disorders, communication disorders, pervasive developmental disorders, attention deficit and disruptive behaviour disorders, feeding and eating disorders, TIC disorders, elimination disorders; Delirium and other cognitive disorders; Substance related disorders including: alcohol-related disorders, nicotine-related disorders, disorders related to cocaine, opioids, cannabis, hallucinogens and other drugs; Schizophrenia and other psychotic disorders; Mood disorders, including depressive disorders and bipolar disorders; Anxiety disorders, including panic disorders, phobias, obsessive-compulsive disorders, stress disorders, generalized anxiety disorders; Eating disorders, including anorexia and bulimia; Sleep disorders and sleep/wake disorders, including dyssomnias (e.g., insomnia, hypersomnia, idiopathic hypersomnolence, narcolepsy, hypersomnia associated with obstructive sleep apnea or narcolepsy, or breathing related sleep disorder), parasomnias, excessive daytime sleepiness (EDS), circadian rhythm sleep disorders (e.g., shift work sleep disorder, jet lag disorder, delayed sleep phase disorder, advanced phase sleep disorder, or non-24 hour sleep-wake syndrome), and excessive sleepiness associated with non-restorative sleep (NRS); Medication-induced movement disorders (including neuroleptic-induced parkinsonism and tardive dyskinesia); Endocrine and metabolic diseases including diabetes, disorders of the endocrine glands, hypoglycaemia; Acute and chronic pain; Nausea and vomiting; Irritable bowel syndrome; cancers, including gliomas, colorectal cancer, melanoma, prostate cancer; ; or autism spectrum disorders, including autism, Asperger syndrome, Fragile X syndrome, Rett syndrome, childhood disintegrative disorder, or pervasive developmental disorder not otherwise specified (PDD-NOS). Accordingly, the present invention relates to a compound of formula (I), as described and defined in the first, second or third aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition containing any of the aforementioned entities and optionally a pharmaceutically acceptable excipient, for use in the treatment and/or prophylaxis of any of the above-mentioned diseases, disorders or conditions. The invention also encompasses methods for the treatment and/or prophylaxis of any of the above-mentioned diseases, disorders or conditions, comprising administering an effective amount of a compound of formula (I), as defined in the first, second or third aspect, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition containing any of the aforementioned entities and optionally a pharmaceutically acceptable excipient, to a subject in need thereof (preferably a mammal, more preferably a human).
In particular, the conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling, to be treated and/or prevented by the compounds or the pharmaceutical compositions according to the invention, include: Dementias and related diseases, including dementias of the Alzheimer's type (DAT), Alzheimer's disease, Pick's disease, vascular dementias, Lewy-body disease, dementias due to metabolic, toxic and deficiency diseases (including alcoholism, hypothyroidism, and vitamin B12 deficiency), AIDS-dementia complex, Creutzfeld-Jacob disease and atypical subacute spongiform encephalopathy; Parkinsonism and movement disorders, including Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, hepatolenticular degeneration, chorea (including Huntington's disease and hemiballismus), athetosis, dystonias (including spasmodic torticollis, occupational movement disorder, Gilles de la Tourette syndrome), tardive or drug induced dyskinesias, tremor and myoclonus; Acute and chronic pain; Anxiety disorders, including panic disorders, phobias, obsessive-compulsive disorders, stress disorders and generalized anxiety disorders; Schizophrenia and other psychotic disorders; Mood disorders, including depressive disorders and bipolar disorders; Endocrine and metabolic diseases including diabetes, disorders of the endocrine glands and hypoglycaemia; or cancers, including gliomas, colorectal cancer, melanoma, prostate cancer.
The compounds and the pharmaceutical compositions according to the invention are envisaged to be used particularly in the treatment or prevention/prophylaxis of the following conditions/diseases/disorders: Dementias and related diseases, including dementias of the Alzheimer's type (DAT), Alzheimer's disease, Pick's disease, vascular dementias, Lewy-body disease, dementias due to metabolic, toxic and deficiency diseases (including alcoholism, hypothyroidism, and vitamin B12 deficiency), AIDS-dementia complex, Creutzfeld-Jacob disease and atypical subacute spongiform encephalopathy; Mood disorders, including depressive disorders and bipolar disorders; Endocrine and metabolic diseases including diabetes, disorders of the endocrine glands and hypoglycaemia; or cancers, including gliomas, colorectal cancer, melanoma, prostate cancer. Accordingly, the present invention relates to the compounds of formula (I), as defined in the first, second or third aspect, their pharmaceutically acceptable salts, solvates and prodrugs, as well as pharmaceutical compositions comprising any of the aforementioned entities and optionally a pharmaceutically acceptable excipient, for use in the treatment or prevention/prophylaxis of any of the above-mentioned conditions/diseases/disorders. In particular, the invention relates to a compound of formula (I) as defined in the first, second or third aspect, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising any of the aforementioned entities and optionally a pharmaceutically acceptable excipient, for use in the treatment or prevention/prophylaxis of Alzheimer's disease. In a preferred embodiment, the present invention thus provides a compound of formula (I) as defined in the first, second or third aspect, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising any of the aforementioned entities and optionally a pharmaceutically acceptable excipient, for use in the treatment or prophylaxis of a neurodegenerative disorder (particularly Alzheimer's disease).
The present invention furthermore provides a method for identifying an agent that binds to metabotropic glutamate receptor 2 (mGluR2), or in other words for determining the capability of one or more test agent(s) to bind to mGluR2, comprising the following steps: (a) contacting mGluR2 with a compound of the present invention (i.e., a compound of formula (I) as defined in the first, second or third aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof) which is labeled, preferably radio-labeled or fluorescence-labeled, under conditions that permit binding of the compound to mGluR2, thereby generating a bound, labeled compound; (b) detecting a signal that corresponds to the amount of the bound, labeled compound in the absence of test agent; (c) contacting the bound, labeled compound with a test agent; (d) detecting a signal that corresponds to the amount of the bound labeled compound in the presence of test agent; and (e) comparing the signal detected in step (d) to the signal detected in step (b) to determine whether the test agent binds to mGluR2. As will be understood, a substantially unchanged signal detected in step (d) in comparison with the signal detected in step (b) indicates that the test agent does not bind to the receptor, or binds to the receptor less strongly than the compound according to the invention. A decreased or increased signal detected in step (d) in comparison with the signal detected in step (b) indicates that the test agent binds to the receptor. Thus, agents that bind to mGluR2 can be identified among the test agents employed in this method. It will further be understood that it is preferred to remove unbound labeled compounds, e.g. in a washing step, before carrying out steps (b) and (d). The method may be carried out in any suitable in vitro environment, e.g., in an aqueous solution which may be provided, e.g., in a flask, a test tube, a Petri dish, or a microtiter plate.
The mGluR2 that is used in the above method may be a human form (Flor PJ, et al. Eur J Neurosci. 1995. 7(4):622-629), e.g., a protein of the accession number NP_000830.2, or a protein having at least 80% (preferably at least 90%, more preferably at least 95%, even more preferably at least 99%) amino acid identity to said protein of the accession number NP_000830.2, or a non-human form, including e.g. a mouse form or a homolog thereof found in a different species (e.g. in a different mammalian species), or a mutein of any of the aforementioned entities wherein the mutein retains the mGluR2 activity. Said mutein can preferably be obtained by substitution, insertion, addition and/or deletion of one or more (such as, e.g., 1 to 20, including 1 to 10 or 1 to 3) amino acid residues of said aforementioned entities. The mGluR2 to be used in the above method may also be a functional fragment of any of the aforementioned entities (including said muteins), i.e. a fragment which retains the mGluR2 activity of the respective aforementioned entity or, in other words, a fragment having essentially the same biological activity (i.e., at least about 60% activity, preferably at least about 70% activity, more preferably at least about 80% activity, even more preferably at least about 90% activity) as the respective aforementioned entity. A skilled person is readily in a position to determine whether mGluR2 activity is retained using techniques known in the art, e.g., knock-out and rescue experiments. Furthermore, the mGluR2 to be used in the above method may also be a compound comprising any one or more of the aforementioned entities (including, without limitation, a protein of the accession number NP_000830.2, a protein having at least 80% amino acid identity to said protein of the accession number NP_000830.2, or a functional fragment thereof), wherein the mGluR2 activity is retained. Preferably, the mGluR2 to be used in the above method is human mGluR2. The compounds of formula (I) according to the first and the second aspect of the invention will be described in more detail in the following:
Figure imgf000016_0001
(I)
A represents N or -CH. Preferably, A is N.
R1, R2 and R4 are each independently selected from R7, halogen, -CN, -OR7, -NR7R8, -COOR7, -SO3H, -B(OH)2, -CONR7R8, -COR7, -SR7,
SOR7, -SO2R7, -S02NR7R8, -NR7COR8, -NR7S02R8, -OCOR7,
NR7C(0)NR8R9, -NR7C(S)NR8R9, -NR7COOR8, aryl, or heteroaryl, wherein said aryl and said heteroaryl are each substituted with one or more groups (preferably with one, two or three groups; more preferably with one or two groups; even more preferably with one group) independently selected from R7, halogen, -CN, -OR7, NR7R8, -COOR7, -SO3H, -B(OH)2, -CONR7R8, -COR7, -SR7, -SOR7, -S02R7, -S02NR7R8, -NR7 COR8, -NR7S02R8, -OCOR7, -NR7C(0)NR8R9, -NR7C(S)NR8R9, or -NR7COOR8. Preferably, R1, R2 and R4 are each independently selected from R7, halogen, -CN, -OR7, -NR7R8, -COOR7, -S03H, -B(OH)2, -CONR7R8, -COR7, -SR7, - SOR7, -S02R7, -S02NR7R8, -NR7COR8,
NR7S02R8, -OCOR7, -NR7C(0)NR8R9, -NR7C(S)NR8R9, or -NR7COOR8. More preferably, R1, R2 and R4 are each independently selected from R7, halogen, -CN, -OR7, -NR7R8, -CONR7R8, - COR7, or -NR7COR8. Even more preferably, R1, R2 and R4 are each independently selected from hydrogen, halogen (e.g., -F, -CI or -Br), C1-C4 haloalkyl (e.g., -CF3), C1-C4 haloalkoxy (e.g., -OCF3), -CN, C1-C4 alkyl, C2-C4 alkenyl, cycloalkyi, heterocycloalkyl, aryl, heteroaryl, -OH, -0(d-C4 alkyl), -0-(d-C4 alkylene)-OH, -0-(C C4 alkylene)-0(Ci-C4 alkyl), -O-cycloalkyl, -0-(Ci-C4 alkylene)-cycloalkyl, -O-heterocycloalkyl, -0-(Ci-C4 alkylene)-heterocycloalkyl, -O-aryl, -0-(Ci-C4 alkylene)-aryl, -O-heteroaryl, -0-(Ci-C4 alkylene)-heteroaryl, -NH2, -NH(C C4 alkyl), -N(C C4 alkyl)(C C4 alkyl), -NH-cycloalkyl, -N(C C4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(Ci-C4 alkyl)-heterocycloalkyl, -NH-(Ci-C4 alkylene)-cycloalkyl, -N(C C4 alkyl)-(Ci-C4 alkylene)-cycloalkyl, -NH-(Ci-C4 alkylene)-heterocycloalkyl, -N(Ci-C4 alkyl)-(Ci-C4 alkylene)-heterocycloalkyl, -NH-aryl, -N(d- d alkyl)-aryl, -NH-heteroaryl, -N(C C4 alkyl)-heteroaryl, -NH-(C C4 alkylene)-aryl, -N(d-C4 alkyl)-(Ci-C4 alkylene)-aryl, -NH-(C C4 alkylene)-heteroaryl, -N(d-C4 alkyl)-(d-C4 alkylene)-heteroaryl, -CO-(d-C4 alkyl), -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-(d-C4 alkylene)-cycloalkyl, -CO-(Ci-C4 alkylene)-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, -CO-(Ci- C4 alkylene)-aryl, -CO-(C C4 alkylene)-heteroaryl, -CO-NH2, -CO-NH(C C4 alkyl), -CO-N(C d alkyl)(Ci-C4 alkyl), -CO-NH-cycloalkyl, -CO-N(Ci-C4 alkyl)-cycloalkyl, -CO-NH-(Ci-C4 alkylene)-cycloalkyl, -CO-N(C C4 alkyl)-(C C4 alkylene)-cycloalkyl, -CO- NH-heterocycloalkyl, -CO-N(d-C4 alkyl)-heterocycloalkyl, -CO-NH-(d-C4 alkylene)- heterocycloalkyl, -CO-N(d-C4 alkyl)-(C C4 alkylene)-heterocycloalkyl, -CO-NH-aryl, -CO- N(Ci-C4 alkyl)-aryl, -CO-NH-(C C4 alkylene)-aryl, -CO-N(C C4 alkyl)-(d-C4 alkylene)- aryl, -CO-NH-heteroaryl, -CO-N(C C4 alkyl)-heteroaryl, -CO-NH-(C C4 alkylene)- heteroaryl, -CO-N(C C4 alkyl)-(d-C4 alkylene)-heteroaryl, -NH-CHO, -N(C C4 alkyl)- CHO, -NH-CO(Ci-C4 alkyl), -N(C C4 alkyl)-CO(C C4 alkyl), -NH-CO-cycloalkyl, -N(d-C4 alkyl)-CO-cycloalkyl, -NH-CO-(d-C4 alkylene)-cycloalkyl, -N(C C4 alkyl)-CO-(C C4 alkylene)- cycloalkyl, -NH-CO-heterocycloalkyl, -N(d-C4 alkyl)-CO-heterocycloalkyl, -NH-CO-(d-C4 alkylene)-heterocycloalkyl, -N(d-C4 alkyl)-CO-(Ci-C4 alkylene)- heterocycloalkyl, -NH-CO-aryl, -N(C C4 alkyl)-CO-aryl, -NH-CO-(C C4 alkylene)-aryl, -N(C d alkyl)-CO-(Ci-C4 alkylene)-aryl, -NH-CO-heteroaryl, -N(C C4 alkyl)- CO-heteroaryl, -NH-CO-(C C4 alkylene)-heteroaryl, or -N(C C4 alkyl)-CO-(C C4 alkylene)- heteroaryl, wherein said cycloalkyi, said heterocycloalkyl, said aryl, said heteroaryl, the cycloalkyi moiety comprised in any of the aforementioned groups (i.e., the cycloalkyi moiety comprised in said -O-cycloalkyl, said -0-(CrC4 alkylene)-cycloalkyl, said -NH-cycloalkyl, said -N(Ci-C4 alkyl)-cycloalkyl, said -NH-(C C4 alkylene)-cycloalkyl, said -N(C C4 alkyl)-(Ci-C4 alkylene)-cycloalkyl, said -CO-cycloalkyl, said -CO-(Ci-C4 alkylene)-cycloalkyl, said -CO- NH-cycloalkyl, said -CO-N(Ci-C4 alkyl)-cycloalkyl, said -CO-NH-(C C4 alkylene)-cycloalkyl, said -CO-N(Ci-C4 alkyl)-(C C4 alkylene)-cycloalkyl, said -NH-CO-cycloalkyl, said -N(d-C4 alkyl)-CO-cycloalkyl, said -NH-CO-(C C4 alkylene)-cycloalkyl, or said -N(C C4 alkyl)-CO-(C C4 alkylene)-cycloalkyl), the heterocycloalkyl moiety comprised in any of the aforementioned groups (i.e., the heterocycloalkyl moiety comprised in said -O-heterocycloalkyl, said -0-(Ci-C4 alkylene)-heterocycloalkyl, said -NH-heterocycloalkyl, said -N(Ci-C4 alkyl)-heterocycloalkyl, said -NH-(Ci-C4 alkylene)-heterocycloalkyl, said -N(C C4 alkyl)-(Ci-C4 alkylene)-heterocycloalkyl, said -CO-heterocycloalkyl, said -CO-(Ci-C4 alkylene)-heterocycloalkyl, said -CO-NH-heterocycloalkyl, said -CO-N(Ci-C4 alkyl)-heterocycloalkyl, said -CO-NH-(CrC4 alkylene)-heterocycloalkyl, said -CO-N(Ci-C4 alkyl)-(Ci-C4 alkylene)-heterocycloalkyl, said -NH-CO-heterocycloalkyl, said -N(Ci-C4 alkyl)- CO-heterocycloalkyl, said -NH-CO-(CrC4 alkylene)-heterocycloalkyl, or said -N(Ci-C4 alkyl)- CO-(Ci-C4 alkylene)-heterocycloalkyl), the aryl moiety comprised in any of the aforementioned groups (i.e., the aryl moiety comprised in said -O-aryl, said -0-(Ci-C4 alkylene)-aryl, said -NH-aryl, said -N(C C4 alkyl)-aryl, said -NH-(C C4 alkylene)-aryl, said -N(Ci-C4 alkyl)-(C C4 alkylene)-aryl, said -CO-aryl, said -CO-(Ci-C4 alkylene)-aryl, said -CO-NH-aryl, said -CO- N(Ci-C4 alkyl)-aryl, said -CO-NH-(Ci-C4 alkylene)-aryl, said -CO-N(Ci-C4 alkyl)-(Ci-C4 alkylene)-aryl, said -NH-CO-aryl, said -N(C C4 alkyl)-CO-aryl, said -NH-CO-(C C4 alkylene)- aryl, or said -N(Ci-C4 alkyl)-CO-(CrC4 alkylene)-aryl), and the heteroaryl moiety comprised in any of the aforementioned groups (i.e., the heteroaryl moiety comprised in said -O-heteroaryl, said -0-(Ci-C4 alkylene)-heteroaryl, said -NH-heteroaryl, said -N(Ci-C4 alkyl)-heteroaryl, said -NH-(Ci-C4 alkylene)-heteroaryl, said -N(Ci-C4 alkyl)-(CrC4 alkylene)-heteroaryl, said -CO-heteroaryl, said -CO-(Ci-C4 alkylene)-heteroaryl, said -CO-NH-heteroaryl, said -CO- N(Ci-C4 alkyl)-heteroaryl, said -CO-NH-(C C4 alkylene)-heteroaryl, said -CO-N(Ci-C4 alkyl)-(Ci-C4 alkylene)-heteroaryl, said -NH-CO-heteroaryl, said -N(Ci-C4 alkyl)-CO-heteroaryl, said -NH-CO-(Ci-C4 alkylene)-heteroaryl, or said -N(Ci-C4 alkyl)-CO-(C C4 alkylene)- heteroaryl) are each optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from C1-C4 alkyl, halogen, -CF3, -CN, -OH, -0(Ci-C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(Ci-C4 alkyl)(C C4 alkyl). Even more preferably, R1, R2 and R4 are each independently selected from hydrogen, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, C1-C4 alkyl, C2-C4 alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -0(C C4 alkyl), -0-(d-C4 alkylene)-OH, -0-(C C4 alkylene)-0(Ci-C4 alkyl), -O-cycloalkyl, -0-(Ci-C4 alkylene)-cycloalkyl, -O-heterocycloalkyl, -0-(Ci-C4 alkylene)-heterocycloalkyl, -O-aryl, -0-(Ci-C4 alkylene)-aryl, -O-heteroaryl, -0-(Ci-C4 alkylene)-heteroaryl, -NH2, -NH(C C4 alkyl), -N(C C4 alkyl)(C C4 alkyl), -NH-cycloalkyl, -N(C C4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(Ci-C4 alkyl)-heterocycloalkyl, -NH-(Ci-C4 alkylene)-cycloalkyl, -N(C C4 alkyl)-(Ci-C4 alkylene)-cycloalkyl, -NH-(Ci-C4 alkylene)-heterocycloalkyl, -N(d-C4 alkyl)-(Ci-C4 alkylene)-heterocycloalkyl, -NH-aryl, -N(Ci- C4 alkyl)-aryl, -NH-heteroaryl, -N(C C4 alkyl)-heteroaryl, -NH-(C C4 alkylene)-aryl, -N(Ci-C4 alkyl)-(C C4 alkylene)-aryl, -NH-(C C4 alkylene)-heteroaryl, -N(Ci-C4 alkyl)-(Ci-C4 alkylene)-heteroaryl, -CO-(d-C4 alkyl), -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-(d-C4 alkylene)-cycloalkyl, -CO-(Ci-C4 alkylene)-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, -CO-(Ci- C4 alkylene)-aryl, -CO-(C C4 alkylene)-heteroaryl, -CO-NH2, -CO-NH(C C4 alkyl), -CO-N(C C4 alkyl)(Ci-C4 alkyl), -CO-NH-cycloalkyl, -CO-N(Ci-C4 alkyl)-cycloalkyl, -CO-NH-(Ci-C4 alkylene)-cycloalkyl, -CO-N(C C4 alkyl)-(C C4 alkylene)-cycloalkyl, -CO- NH-heterocycloalkyl, -CO-N(Ci-C4 alkyl)-heterocycloalkyl, -CO-NH-(Ci-C4 alkylene)- heterocycloalkyl, -CO-N(Ci-C4 alkyl)-(C C4 alkylene)-heterocycloalkyl, -CO-NH-aryl, -CO- N(Ci-C4 alkyl)-aryl, -CO-NH-(C C4 alkylene)-aryl, -CO-N(C C4 alkyl)-(Ci-C4 alkylene)- aryl, -CO-NH-heteroaryl, -CO-N(C C4 alkyl)-heteroaryl, -CO-NH-(C C4 alkylene)- heteroaryl, -CO-N(C C4 alkyl)-(Ci-C4 alkylene)-heteroaryl, -NH-CHO, -N(C C4 alkyl)- CHO, -NH-CO(Ci-C4 alkyl), -N(C C4 alkyl)-CO(C C4 alkyl), -NH-CO-cycloalkyl, -N(C C4 alkyl)-CO-cycloalkyl, -NH-CO-(d-C4 alkylene)-cycloalkyl, -N(C C4 alkyl)-CO-(d-d alkylene)- cycloalkyl, -NH-CO-heterocycloalkyl, -N(d-d alkyl)-CO-heterocycloalkyl, -NH-CO-(Ci-d alkylene)-heterocycloalkyl, -N(d-d alkyl)-CO-(Ci-d alkylene)- heterocycloalkyl, -NH-CO-aryl, -N(d-d alkyl)-CO-aryl, -NH-CO-(d-d alkylene)-aryl, -N(C d alkyl)-CO-(Ci-d alkylene)-aryl, -NH-CO-heteroaryl, -N(d-d alkyl)- CO-heteroaryl, -NH-CO-(d-d alkylene)-heteroaryl, or -N(d-d alkyl)-CO-(d-d alkylene)- heteroaryl, wherein said aryl, said heteroaryl, the aryl moiety comprised in any of the aforementioned groups, and the heteroaryl moiety comprised in any of the aforementioned groups are each optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from d-d alkyl, halogen, -CF3, -CN, -OH, -0(d-C4 alkyl), -NH2, -NH(d-d alkyl) or -N(d-d alkyl)(d-d alkyl). Even more preferably, R1, R2 and R4 are each independently selected from hydrogen, halogen, d-d haloalkyl, d-d haloalkoxy, -CN, d-d alkyl, d-d alkenyl, cycloalkyl, heterocycloalkyl, -OH, -0(d-C4 alkyl), -0-(d-d alkylene)-OH, -0-(d-d alkylene)-0(d-d alkyl), -O-cycloalkyl, -0-(d-d alkylene)-cycloalkyl, -O-heterocycloalkyl, -0-(Crd alkylene)-heterocycloalkyl, -NH2, -NH(Ci- d alkyl), -N(d-d alkyl)(d-d alkyl), -NH-cycloalkyl, -N(d-d alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(d-C4 alkyl)-heterocycloalkyl, -NH-(Ci-d alkylene)-cycloalkyl, -N(d-d alkyl)-(Ci-d alkylene)-cycloalkyl, -NH-(d-d alkylene)-heterocycloalkyl, -N(d-d alkyl)-(d-d alkylene)-heterocycloalkyl, -CO-NH2, -CO- NH(Ci-d alkyl), -CO-N(d-d alkyl)(d-d alkyl), -NH-CHO, -N(C C4 alkyl)-CHO, -NH-CO(C C4 alkyl), or -N(C C4 alkyl)-CO(C C4 alkyl). Even more preferably, R1, R2 and R4 are each independently selected from hydrogen, halogen, Ci-C4 haloalkyl, Ci-C4 haloalkoxy, Ci-C4 alkyl, -OH, -0(C C4 alkyl), -NH(C C4 alkyl), or -N(C C4 alkyl)(C C4 alkyl). Yet even more preferably, R1, R2 and R4 are each independently selected from hydrogen, halogen (e.g., -F or -CI), -CF3, methyl, -OCH3, or -NH(CH3).
It is particularly preferred that R1 and R4 are each hydrogen and R2 is selected from hydrogen, halogen (e.g., -F, -CI or -Br), d-C4 haloalkyl (e.g., -CF3), C C4 haloalkoxy (e.g., -OCF3), -CN, Ci-C4 alkyl, C2-C4 alkenyl, cycloalkyi, heterocycloalkyl, aryl, heteroaryl, -OH, -0(Ci-C4 alkyl), -0-(C C4 alkylene)-OH, -0-(C C4 alkylene)-0(C C4 alkyl), -O-cycloalkyl, -0-(C C4 alkylene)-cycloalkyl, -O-heterocycloalkyl, -0-(Ci-C4 alkylene)-heterocycloalkyl, -O-aryl, -0-(Ci- C4 alkylene)-aryl, -O-heteroaryl, -0-(C C4 alkylene)-heteroaryl, -NH2, -NH(C C4 alkyl), -N(C C4 alkyl)(Ci-C4 alkyl), -NH-cycloalkyl, -N(C C4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(C C4 alkyl)-heterocycloalkyl, -NH-(C C4 alkylene)-cycloalkyl, -N(C C4 alkyl)-(C C4 alkylene)-cycloalkyl, -NH-(C C4 alkylene)-heterocycloalkyl, -N(C C4 alkyl)-(Ci-C4 alkylene)-heterocycloalkyl, -NH-aryl, -N(Ci-C4 alkyl)-aryl, -NH-heteroaryl, -N(Ci-C4 alkyl)-heteroaryl, -NH-(C C4 alkylene)-aryl, -N(C C4 alkyl)-(C C4 alkylene)-aryl, -NH-(C C4 alkylene)-heteroaryl, -N(Ci-C4 alkyl)-(Ci-C4 alkylene)-heteroaryl, -CO-(Ci-C4 alkyl), -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-(C C4 alkylene)-cycloalkyl, -CO-(C C4 alkylene)-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, -CO-(C C4 alkylene)-aryl, -CO-(C C4 alkylene)-heteroaryl, -CO-NH2, -CO-NH(C C4 alkyl), -CO-N(C C4 alkyl)(C C4 alkyl), -CO- NH-cycloalkyl, -CO-N(C C4 alkyl)-cycloalkyl, -CO-NH-(C C4 alkylene)-cycloalkyl, -CO-N(C C4 alkyl)-(Ci-C4 alkylene)-cycloalkyl, -CO-NH-heterocycloalkyl, -CO-N(C C4 alkyl)-heterocycloalkyl, -CO-NH-(C C4 alkylene)-heterocycloalkyl, -CO-N(C C4 alkyl)-(C C4 alkylene)-heterocycloalkyl, -CO-NH-aryl, -CO-N(C C4 alkyl)-aryl, -CO-NH-(C C4 alkylene)- aryl, -CO-N(C C4 alkyl)-(C C4 alkylene)-aryl, -CO-NH-heteroaryl, -CO-N(C C4 alkyl)-heteroaryl, -CO-NH-(C C4 alkylene)-heteroaryl, -CO-N(C C4 alkyl)-(C C4 alkylene)- heteroaryl, -NH-CHO, -N(C C4 alkyl)-CHO, -NH-CO(C C4 alkyl), -N(C C4 alkyl)-CO(Ci-C4 alkyl), -NH-CO-cycloalkyl, -N(C C4 alkyl)-CO-cycloalkyl, -NH-CO-(C C4 alkylene)- cycloalkyi, -N(C C4 alkyl )-CO-(C C4 alkylene)-cycloalkyl, -NH-CO-heterocycloalkyl, -N(C C4 alkyl)-CO-heterocycloalkyl, -NH-CO-(C C4 alkylene)-heterocycloalkyl, -N(C C4 alkyl)-CO-(C C4 alkylene)-heterocycloalkyl, -NH-CO-aryl, -N(C C4 alkyl)-CO-aryl, -NH-CO-(C C4 alkylene)- aryl, -N(C C4 alkyl)-CO-(C C4 alkylene)-aryl, -NH-CO-heteroaryl, -N(C C4 alkyl)- CO-heteroaryl, -NH-CO-(C C4 alkylene)-heteroaryl, or -N(C C4 alkyl)-CO-(C C4 alkylene)- heteroaryl, wherein said cycloalkyi, said heterocycloalkyl, said aryl, said heteroaryl, the cycloalkyi moiety comprised in any of the aforementioned groups, the heterocycloalkyl moiety comprised in any of the aforementioned groups, the aryl moiety comprised in any of the aforementioned groups, and the heteroaryl moiety comprised in any of the aforementioned groups are each optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from C1-C4 alkyl, halogen, -CF3, -CN, -OH, -0(Ci-C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(C C4 alkyl)(C C4 alkyl). More preferably, R1 and R4 are each hydrogen and R2 is selected from hydrogen, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, C1-C4 alkyl, C2-C4 alkenyl, cycloalkyi, heterocycloalkyi, -OH, -0(Ci-C4 alkyl), -0-(C C4 alkylene)-OH, -0-(d-C4 alkylene)-0(C C4 alkyl), -O-cycloalkyl, -0-(d-C4 alkylene)-cycloalkyl, -O-heterocycloalkyl, -0-(Ci-C4 alkylene)-heterocycloalkyl, -NH2, -NH(Ci- C4 alkyl), -N(C C4 alkyl)(C C4 alkyl), -NH-cycloalkyl, -N(C C4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(Ci-C4 alkyl)-heterocycloalkyl, -NH-(Ci-C4 alkylene)-cycloalkyl, -N(C C4 alkyl)-(Ci-C4 alkylene)-cycloalkyl, -NH-(Ci-C4 alkylene)-heterocycloalkyl, -N(C C4 alkyl)-(C C4 alkylene)-heterocycloalkyl, -CO-NH2, -CO- NH(Ci-C4 alkyl), -CO-N(C C4 alkyl)(C C4 alkyl), -NH-CHO, -N(C C4 alkyl)-CHO, -NH-CO(C C4 alkyl), or -N(Ci-C4 alkyl)-CO(CrC4 alkyl). Even more preferably, R1 and R4 are each hydrogen and R2 is selected from hydrogen, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkyl, -OH, -0(C C4 alkyl), -NH(C C4 alkyl), or -N(C C4 alkyl)(C C4 alkyl). Yet even more preferably, R1 and R4 are each hydrogen and R2 is selected from hydrogen, -F, -CI, -CF3, methyl, -OCH3, or -NH(CH3). Still more preferably, R1 and R4 are each hydrogen and R2 is hydrogen or -F. Most preferably, R1, R2 and R4 are each hydrogen.
R3 is selected from hydrogen, halogen, -CN, -OR7, -NR7R8, -COOR7, -S03H, - B(OH)2, -CONR7R8, -COR7, -SR7, -SOR7, -S02R7, -S02NR7R8, -NR7COR8, - NR7S02R8, -OCOR7, -NR7C(0)NR8R9, -NR7C(S)NR8R9, -NR7COOR8, C C4 alkyl, C2-C4 alkenyl, cycloalkyi or heterocycloalkyi, wherein said C1-C4 alkyl and said C2-C4 alkenyl are each optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from halogen, -CF3, -CN, -OH, -0(C C4 alkyl), -NH2, -NH(Ci-C4 alkyl) or -N(Ci-C4 alkyl)(Ci-C4 alkyl), and further wherein said cycloalkyi and said heterocycloalkyi are each optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from: C1-C4 alkyl; halogen; -CF3; -CN; -OH; -0(Ci-C4 alkyl); C1-C4 alkyl substituted with one or more (e.g., one, two or three) -OH groups; -NH2; -NH(Ci-C4 alkyl); or -N(Ci-C4 alkyl)(C C4 alkyl).
Preferably, R3 is selected from hydrogen, halogen, -CN, -OR7, NR7R8, -COOR7, -CONR7R8, -COR7, -NR7COR8, C C4 alkyl, C2-C4 alkenyl, cycloalkyi or heterocycloalkyi, wherein said C1-C4 alkyl and said C2-C4 alkenyl are each optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from halogen, -CF3, -CN, -OH, -0(C C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(C C4 alkyl)(Ci-C4 alkyl), and further wherein said cycloalkyl and said heterocycloalkyl are each optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from: C C4 alkyl; halogen; -CF3; -CN; -OH; -0(Ci-C4 alkyl); C C4 alkyl substituted with one or more -OH groups; -NH2; -NH(C C4 alkyl); or -N(C C4 alkyl)(C C4 alkyl). More preferably, R3 is selected from hydrogen, halogen (e.g., -F, -CI or -Br), C C4 haloalkyl (e.g., -CF3), Ci-C4 haloalkoxy (e.g., -OCF3), -CN, C C4 alkyl, C2-C4 alkenyl, cycloalkyl, heterocycloalkyl, -OH, -0(C C4 alkyl), -O-cycloalkyl, -0-(C C4 alkylene)-cycloalkyl, -O-heterocycloalkyl, -0-(Ci-C4 alkylene)-heterocycloalkyl, -NH2, -NH(Ci- C4 alkyl), -N(C C4 alkyl)(C C4 alkyl), -NH-cycloalkyl, -N(C C4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(Ci-C4 alkyl)-heterocycloalkyl, -NH-(Ci-C4 alkylene)-cycloalkyl, -N(C C4 alkyl)-(Ci-C4 alkylene)-cycloalkyl, -NH-(Ci-C4 alkylene)-heterocycloalkyl, -N(Ci-C4 alkyl)-(Ci-C4 alkylene)-heterocycloalkyl, -CO-(Ci-C4 alkyl), -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-(d-C4 alkylene)-cycloalkyl, -CO-(C C4 alkylene)-heterocycloalkyl, -CO-NH2, -CO-NH(C C4 alkyl), -CO-N(C C4 alkyl)(C C4 alkyl), -CO-NH-cycloalkyl, -CO-N(C C4 alkyl)-cycloalkyl, -CO-NH-(C C4 alkylene)- cycloalkyl, -CO-N(C C4 alkyl)-(C C4 alkylene)-cycloalkyl, -CO-NH-heterocycloalkyl, -CO-N(C C4 alkyl)-heterocycloalkyl, -CO-NH-(C C4 alkylene)-heterocycloalkyl, -CO-N(C C4 alkyl)-(C C4 alkylene)-heterocycloalkyl, -NH-CO-cycloalkyl, -N(C C4 alkyl)-CO-cycloalkyl, -NH-CO-(C C4 alkylene)-cycloalkyl, -N(C C4 alkyl)-CO-(C C4 alkylene)- cycloalkyl, -NH-CO-heterocycloalkyl, -N(C C4 alkyl)-CO-heterocycloalkyl, -NH-CO-(C C4 alkylene)-heterocycloalkyl, -N(Ci-C4 alkyl)-CO-(Ci-C4 alkylene)-heterocycloalkyl, or -COOH, wherein said cycloalkyl, said heterocycloalkyl, the cycloalkyl moiety comprised in any of the aforementioned groups (i.e., the cycloalkyl moiety comprised in said -O-cycloalkyl, said -0-(Cr C4 alkylene)-cycloalkyl, said -NH-cycloalkyl, said -N(Ci-C4 alkyl)-cycloalkyl, said -NH-(Ci-C4 alkylene)-cycloalkyl, said -N(Ci-C4 alkyl)-(Ci-C4 alkylene)-cycloalkyl, said -CO-cycloalkyl, said -CO-(Ci-C4 alkylene)-cycloalkyl, said -CO-NH-cycloalkyl, said -CO-N(C C4 alkyl)-cycloalkyl, said -CO-NH-(C C4 alkylene)-cycloalkyl, said -CO-N(C C4 alkyl)-(C C4 alkylene)-cycloalkyl, said -NH-CO-cycloalkyl, said -N(Ci-C4 alkyl)-CO-cycloalkyl, said -NH-CO-(Ci-C4 alkylene)-cycloalkyl, or said -N(C C4 alkyl)-CO-(C C4 alkylene)- cycloalkyl), and the heterocycloalkyl moiety comprised in any of the aforementioned groups (i.e., the heterocycloalkyl moiety comprised in said -O-heterocycloalkyl, said -0-(Ci-C4 alkylene)-heterocycloalkyl, said -NH-heterocycloalkyl, said -N(Ci-C4 alkyl)-heterocycloalkyl, said -NH-(Ci-C4 alkylene)-heterocycloalkyl, said -N(C C4 alkyl)-(Ci-C4 alkylene)-heterocycloalkyl, said -CO-heterocycloalkyl, said -CO-(Ci-C4 alkylene)-heterocycloalkyl, said -CO-NH-heterocycloalkyl, said -CO-N(Ci-C4 alkyl)-heterocycloalkyl, said -CO-NH-(Ci-C4 alkylene)-heterocycloalkyl, said -CO-N(Ci-C4 alkyl)-(Ci-C4 alkylene)-heterocycloalkyl, said -NH-CO-heterocycloalkyl, said -N(Ci-C4 alkyl)- CO-heterocycloalkyl, said -NH-CO-(CrC4 alkylene)-heterocycloalkyl, or said -N(d-C4 alkyl)- CO-(Ci-C4 alkylene)-heterocycloalkyl) are each optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from: C1-C4 alkyl; halogen; -CF3; -CN; -OH; -0(C C4 alkyl); C1-C4 alkyl substituted with one or more -OH groups; -NH2; -NH(C C4 alkyl); or -N(C C4 alkyl)(C C4 alkyl). Even more preferably, R3 is selected from hydrogen, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, C1-C4 alkyl, cycloalkyl, heterocycloalkyi, -OH, -0(Ci-C4 alkyl), -O-cycloalkyl, -O-heterocycloalkyl, -NH2, -NH(C C4 alkyl), -N(C C4 alkyl)(Ci-C4 alkyl), -NH-cycloalkyl, -N(Ci-C4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(Ci-C4 alkyl)-heterocycloalkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-NH2, -CO-NH(Ci-C4 alkyl), -CO-N(C C4 alkyl)(C C4 alkyl), -CO-NH-cycloalkyl, -CO-N(C C4 alkyl)-cycloalkyl, -CO- NH-heterocycloalkyl, -CO-N(C C4 alkyl)-heterocycloalkyl, -NH-CO-cycloalkyl, -N(C C4 alkyl)- CO-cycloalkyl, -NH-CO-heterocycloalkyl, or -N(Ci-C4 alkyl)-CO-heterocycloalkyl, wherein said cycloalkyl, said heterocycloalkyi, the cycloalkyl moiety comprised in any of the aforementioned groups, and the heterocycloalkyi moiety comprised in any of the aforementioned groups are each optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from: C1-C4 alkyl; halogen; -CF3; -CN; -OH; -0(Ci-C4 alkyl); C1-C4 alkyl substituted with one or more -OH groups; -NH2; -NH(C C4 alkyl); or -N(C C4 alkyl)(Ci-C4 alkyl). Even more preferably, R3 is selected from hydrogen, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, C1-C4 alkyl, cycloalkyl, heterocycloalkyi, -OH, -0(d-C4 alkyl), -O-cycloalkyl, -O-heterocycloalkyl, -NH2, -NH(C C4 alkyl), -N(C C4 alkyl)(Ci-C4 alkyl), -NH-cycloalkyl, -N(Ci-C4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(Ci-C4 alkyl)-heterocycloalkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-NH2, -CO-NH(C C4 alkyl), or -CO-N(Ci-C4 alkyl)(Ci-C4 alkyl), wherein said cycloalkyl, said heterocycloalkyi, the cycloalkyl moiety comprised in any of the aforementioned groups, and the heterocycloalkyi moiety comprised in any of the aforementioned groups are each optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from: C1-C4 alkyl; halogen; -CF3; -CN; -OH; -0(C C4 alkyl); C1-C4 alkyl substituted with one or more -OH groups; -NH2; -NH(C C4 alkyl); or -N(C C4 alkyl)(C C4 alkyl). Even more preferably, R3 is selected from hydrogen, halogen (e.g., -F or -CI), Ci-C4 haloalkyl (e.g., -CF3), -CN, heterocycloalkyi (e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl), -0(Ci-C4 alkyl), -NH(C C4 alkyl), or -CO-N(C C4 alkyl)(Ci-C4 alkyl), wherein said heterocycloalkyi is optionally substituted with one or more groups (e.g., one or two groups) independently selected from: C C4 alkyl; halogen; -CF3; -CN; -OH; -0(C C4 alkyl); C C4 alkyl substituted with one or more -OH groups (e.g., -(CH2)1 -4-OH); -NH2; -NH(Ci-C4 alkyl); or -N(Ci-C4 alkyl)(Ci-C4 alkyl). Yet even more preferably, R3 is selected from hydrogen, -F, -CI, -CF3, -CN, 3-hydroxyazetidin-1-yl, 4-hydroxypiperidin-1 -yl, morpholin-4-yl, -OCH3, -NHCH3, -CO-N(CH3)2, or -CO-N(CH2CH3)2. Most preferably, R3 is hydrogen.
R5 is heteroaryl which is optionally substituted with one or more groups (e.g., one, two or three groups; preferably one or two groups; more preferably one group) independently selected from R7, halogen, -CN, -NR7R8, -CONR7R8, -COR7, -OR7, -SR7, -SOR7, S02R7, -S02NR7R8, -NR7COR8, -NR7S02R8, -OCOR7, or -COOR7.
Said heteroaryl is preferably a heteroaryl having 5 to 14 ring members and comprising one or more (preferably one, two, three or four) ring heteroatoms independently selected from O, S or N; more preferably, said heteroaryl is a heteroaryl having 5 or 6 ring members and comprising one or more (preferably one, two or three) ring heteroatoms independently selected from O, S or N (wherein the 5- to 14-membered heteroaryl and the 5- or 6-membered heteroaryl are optionally substituted, as defined for said heteroaryl). Even more preferably, said heteroaryl is pyridinyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, furanyl, thienyl, pyridazinyl, pyrimidinyl or pyrazinyl (wherein these specific groups are optionally substituted, as defined for said heteroaryl). Yet even more preferably, said heteroaryl is pyridinyl or pyrazolyl, yet even more preferably pyridinyl (such as, e.g., pyridin-4-yl, pyridin-3-yl or pyridin- 2-yl), and most preferably pyridin-4-yl (wherein the aforementioned specific heteroaryl groups are optionally substituted, as defined for said heteroaryl).
Said heteroaryl (including any of the above-mentioned specific heteroaryl groups) is preferably unsubstituted or substituted with one, two or three groups, more preferably it is substituted with one or two groups, and even more preferably it is substituted with one group. If said heteroaryl is pyridin-4-yl substituted with one group, it is preferred that this one substituent group is attached to the pyridin-4-yl group in position 2. If said heteroaryl is pyridin-4-yl substituted with two groups, it is preferred that these two substituent groups are attached to the pyridin-4-yl group in positions 2 and 6, respectively.
The optional substituent groups with which the heteroaryl as R5 (including any of the aforementioned specific heteroaryl groups) may be substituted are independently selected from R7, halogen, -CN, -NR7R8, -CONR7R8, -COR7, -OR7, -SR7, -SOR7, -S02R7, - S02NR7R8, -NR7COR8, -NR7S02R8, -OCOR7, or -COOR7. Preferably, these optional substituent groups are independently selected from R7, halogen, -CN, -NR7R8, -CONR7R8, -COR7, -OR7, or -NR7COR8, more preferably from R7, halogen, -CN, -NR7R8, -COR7, or -OR7. Even more preferably, these optional substituent groups are independently selected from C1-C4 alkyl, C2-C4 alkenyl, halogen (e.g., -F, -CI or -Br), C1-C4 haloalkyl (e.g., -CF3, -CHF2, or -CF2-CH3), C C4 haloalkoxy (e.g., -O-CH2-CF3, -O-CH2-CHF2, -O-CH2-CF2-CH3, -O-CH2-CF2-CF3, -0-CH(CF3)2, or -OCF3), -CN, cycloalkyi, heterocycloalkyl, aryl (e.g., phenyl), heteroaryl, -OH, -0(Ci-C4 alkyl), -O-cycloalkyl, -0-(Ci-C4 alkylene)-cycloalkyl, -O-heterocycloalkyl, -0-(Ci-C4 alkylene)-heterocycloalkyl, -N H2, -NH(C C4 alkyl), -N(C C4 alkyl)(Ci-C4 alkyl), -NH-cycloalkyl, -N(Ci-C4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(Ci-C4 alkyl)-heterocycloalkyl, -NH-(C C4 alkylene)-cycloalkyl, -N(C C4 alkyl)-(Ci-C4 alkylene)-cycloalkyl, -NH-(CrC4 alkylene)-heterocycloalkyl, -N(Ci-C4 alkyl)-(Ci-C4 alkylene)-heterocycloalkyl, -CO-(CrC4 alkyl), -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-(Ci-C4 alkylene)-cycloalkyl, or -CO-(Ci-C4 alkylene)-heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyi, said heterocycloalkyl, the cycloalkyi moiety comprised in any of the aforementioned groups (i.e., the cycloalkyi moiety comprised in said -O-cycloalkyl, the cycloalkyi moiety comprised in said -0-(CrC4 alkylene)-cycloalkyl, the cycloalkyi moiety comprised in said -NH-cycloalkyl, the cycloalkyi moiety comprised in said -N(d-C4 alkyl)-cycloalkyl, the cycloalkyi moiety comprised in said -NH-(Ci-C4 alkylene)-cycloalkyl, the cycloalkyi moiety comprised in said -N(Ci-C4 alkyl)-(Ci-C4 alkylene)-cycloalkyl, the cycloalkyi moiety comprised in said -CO-cycloalkyl, or the cycloalkyi moiety comprised in said -CO-(Ci-C4 alkylene)-cycloalkyl), and the heterocycloalkyl moiety comprised in any of the aforementioned groups (i.e., the heterocycloalkyl moiety comprised in said -O-heterocycloalkyl, the heterocycloalkyl moiety comprised in said -0-(CrC4 alkylene)-heterocycloalkyl, the heterocycloalkyl moiety comprised in said -NH-heterocycloalkyl, the heterocycloalkyl moiety comprised in said -N(Ci-C4 alkyl)-heterocycloalkyl, the heterocycloalkyl moiety comprised in said -NH-(Ci-C4 alkylene)-heterocycloalkyl, the heterocycloalkyl moiety comprised in said -N(Ci-C4 alkyl)-(Ci-C4 alkylene)-heterocycloalkyl, the heterocycloalkyl moiety comprised in said -CO-heterocycloalkyl, or the heterocycloalkyl moiety comprised in said -CO-(Ci-C4 alkylene)-heterocycloalkyl) are each optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from C1-C4 alkyl, halogen, -CF3, -CN, -OH, -0(C C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(Ci-C4 alkyl)(C C4 alkyl). Yet even more preferably, the optional substituent groups with which the heteroaryl as R5 may be substituted are independently selected from C1-C4 alkyl, C2-C4 alkenyl, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, cycloalkyi, heterocycloalkyl, -0(Ci-C4 alkyl), -O-cycloalkyl, or -O-heterocycloalkyl. Still more preferably, these optional substituent groups are independently selected from methyl, vinyl, propenyl (e.g., propen-2-yl), -F, -CI, -CF3, -0-CH2-CF3, -CN, cyclopropyl, or pyrrolidinyl (e.g., pyrrolidin-1 -yl). Accordingly, it is particularly preferred that R5 is heteroaryl having 5 or 6 ring members and comprising one or more (preferably one, two or three) ring heteroatoms independently selected from O, S or N, wherein said heteroaryl having 5 or 6 ring members is optionally substituted with one or more groups (preferably one or two groups; more preferably one group) independently selected from C1-C4 alkyl, C2-C4 alkenyl, halogen (e.g., -F, -CI or -Br), C1-C4 haloalkyl (e.g., -CF3, -CHF2, or -CF2-CH3), C C4 haloalkoxy (e.g., -O-CH2-CF3, -O-CH2-CHF2, -O-CH2-CF2-CH3, -O-CH2-CF2-CF3, -0-CH(CF3)2), or -OCF3), -CN, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -0(Ci-C4 alkyl), -O-cycloalkyl, -0-(Ci-C4 alkylene)-cycloalkyl, -O-heterocycloalkyl, -0-(Ci-C4 alkylene)-heterocycloalkyl, -N H2, -NH(C C4 alkyl), -N(C C4 alkyl)(Ci-C4 alkyl), -NH-cycloalkyl, -N(d-C4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(Ci-C4 alkyl)-heterocycloalkyl, -NH-(C C4 alkylene)-cycloalkyl, -N(C C4 alkyl)-(Ci-C4 alkylene)-cycloalkyl, -NH-(C C4 alkylene)-heterocycloalkyl, -N(C C4 alkyl)-(Ci-C4 alkylene)-heterocycloalkyl, -CO-(CrC4 alkyl), -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-(Ci-C4 alkylene)-cycloalkyl, or -CO-(Ci-C4 alkylene)-heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, the cycloalkyl moiety comprised in any of the aforementioned groups (i.e., the cycloalkyl moiety comprised in said -O-cycloalkyl, the cycloalkyl moiety comprised in said -0-(CrC4 alkylene)-cycloalkyl, the cycloalkyl moiety comprised in said -NH-cycloalkyl, the cycloalkyl moiety comprised in said -N(Ci-C4 alkyl)-cycloalkyl, the cycloalkyl moiety comprised in said -NH-(Ci-C4 alkylene)-cycloalkyl, the cycloalkyl moiety comprised in said -N(Ci-C4 alkyl)-(Ci-C4 alkylene)-cycloalkyl, the cycloalkyl moiety comprised in said -CO-cycloalkyl, or the cycloalkyl moiety comprised in said -CO-(Ci-C4 alkylene)-cycloalkyl), and the heterocycloalkyl moiety comprised in any of the aforementioned groups (i.e., the heterocycloalkyl moiety comprised in said -O-heterocycloalkyl, the heterocycloalkyl moiety comprised in said -0-(CrC4 alkylene)-heterocycloalkyl, the heterocycloalkyl moiety comprised in said -NH-heterocycloalkyl, the heterocycloalkyl moiety comprised in said -N(Ci-C4 alkyl)-heterocycloalkyl, the heterocycloalkyl moiety comprised in said -NH-(Ci-C4 alkylene)-heterocycloalkyl, the heterocycloalkyl moiety comprised in said -N(Ci-C4 alkyl)-(Ci-C4 alkylene)-heterocycloalkyl, the heterocycloalkyl moiety comprised in said -CO-heterocycloalkyl, or the heterocycloalkyl moiety comprised in said -CO-(Ci-C4 alkylene)-heterocycloalkyl) are each optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from C1-C4 alkyl, halogen, -CF3, -CN, -OH, -0(C C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(C C4 alkyl)(C C4 alkyl). More preferably, R5 is heteroaryl having 5 or 6 ring members and comprising one or more (preferably one, two or three) ring heteroatoms independently selected from O, S or N (e.g., pyridinyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, furanyl, thienyl, pyridazinyl, pyrimidinyl or pyrazinyl), wherein said heteroaryl having 5 or 6 ring members is optionally substituted with one or more substituent groups (preferably one or two substituent groups; more preferably one substituent group) independently selected from C1-C4 alkyl, C2-C4 alkenyl, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, cycloalkyl, heterocycloalkyl, -0(Ci-C4 alkyl), -O-cycloalkyl, or -O-heterocycloalkyl, wherein it is furthermore preferred that said substituent group(s) is/are selected independently from methyl, vinyl, propenyl (e.g., propen-2-yl), -F, -CI, -CF3, -0-CH2-CF3, -CN, cyclopropyl, or pyrrolidinyl (e.g., pyrrolidin-1 -yl). Even more preferably, R5 is pyridinyl (particularly pyridin-4-yl) which is optionally substituted with one or more groups (preferably one or two groups; more preferably one group) independently selected from C1-C4 alkyl, C2-C4 alkenyl, halogen (e.g., -F, -CI or -Br), C1-C4 haloalkyl (e.g., -CF3, -CHF2, or -CF2-CH3), C C4 haloalkoxy (e.g., -0-CH2-CF3, -0-CH2-CHF2, -0-CH2-CF2-CH3, -0-CH2-CF2-CF3, or -0-CH(CF3)2), -CN, cycloalkyi, heterocycloalkyi, aryl, heteroaryl, -OH, -0(Ci-C4 alkyl), -O-cycloalkyl, -0-(Ci-C4 alkylene)-cycloalkyl, -O-heterocycloalkyl, -0-(Ci-C4 alkylene)-heterocycloalkyl, -NH2, -NH(Ci- C4 alkyl), -N(C C4 alkyl)(C C4 alkyl), -NH-cycloalkyl, -N(C C4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(Ci-C4 alkyl)-heterocycloalkyl, -NH-(Ci-C4 alkylene)-cycloalkyl, -N(C C4 alkyl)-(Ci-C4 alkylene)-cycloalkyl, -NH-(Ci-C4 alkylene)-heterocycloalkyl, -N(d-C4 alkyl)-(CrC4 alkylene)-heterocycloalkyl, -CO-(Ci-C4 alkyl), -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-(C C4 alkylene)-cycloalkyl, or -CO-(d-C4 alkylene)-heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyi, said heterocycloalkyi, the cycloalkyi moiety comprised in any of the aforementioned groups (i.e., the cycloalkyi moiety comprised in said -O-cycloalkyl, the cycloalkyi moiety comprised in said -0-(Ci-C4 alkylene)-cycloalkyl, the cycloalkyi moiety comprised in said -NH-cycloalkyl, the cycloalkyi moiety comprised in said -N(Ci-C4 alkyl)-cycloalkyl, the cycloalkyi moiety comprised in said -NH-(Ci-C4 alkylene)-cycloalkyl, the cycloalkyi moiety comprised in said -N(Ci-C4 alkyl)-(Ci-C4 alkylene)-cycloalkyl, the cycloalkyi moiety comprised in said -CO-cycloalkyl, or the cycloalkyi moiety comprised in said -CO-(CrC4 alkylene)-cycloalkyl), and the heterocycloalkyi moiety comprised in any of the aforementioned groups (i.e., the heterocycloalkyi moiety comprised in said -O-heterocycloalkyl, the heterocycloalkyi moiety comprised in said -0-(Ci-C4 alkylene)-heterocycloalkyl, the heterocycloalkyi moiety comprised in said -NH-heterocycloalkyl, the heterocycloalkyi moiety comprised in said -N(Ci-C4 alkyl)-heterocycloalkyl, the heterocycloalkyi moiety comprised in said -NH-(Ci-C4 alkylene)-heterocycloalkyl, the heterocycloalkyi moiety comprised in said -N(Ci-C4 alkyl)-(Ci-C4 alkylene)-heterocycloalkyl, the heterocycloalkyi moiety comprised in said -CO-heterocycloalkyl, or the heterocycloalkyi moiety comprised in said -CO-(CrC4 alkylene)-heterocycloalkyl) are each optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from C1-C4 alkyl, halogen, -CF3, -CN, -OH, -0(C C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(C C4 alkyl)(Ci-C4 alkyl). Yet even more preferably, R5 is pyridinyl (particularly pyridin-4-yl) which is optionally substituted with one or more substituent groups (preferably one or two substituent groups; more preferably one substituent group) independently selected from C1-C4 alkyl, C2-C4 alkenyl, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, cycloalkyi, heterocycloalkyi, -0(Ci-C4 alkyi), -O-cycloalkyl, or -O-heterocycloalkyl, wherein it is furthermore preferred that said substituent group(s) is/are selected independently from methyl, vinyl, propenyl (e.g., propen-2-yl), -F, -CI, -CF3, -0-CH2-CF3, -CN, cyclopropyl, or pyrrolidinyl (e.g., pyrrolidin-1 -yl). Still more preferably, R5 is pyridin-4-yl which is substituted with one substituent group at position 2 of said pyridin-4-yl or with two substituent groups at position 2 and 6 of said pyridin- 4-yl, wherein said one or two substituent group(s) is/are selected independently from C1-C4 alkyi, C2-C4 alkenyl, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, cycloalkyl, heterocycloalkyl, -0(Ci-C4 alkyi), -O-cycloalkyl, or -O-heterocycloalkyl, and wherein it is furthermore preferred that said one or two substituent group(s) is/are selected independently from methyl, vinyl, propenyl (e.g., propen-2-yl), -F, -CI, -CF3, -0-CH2-CF3, -CN, cyclopropyl, or pyrrolidinyl (e.g., pyrrolidin-1 -yl). Most preferably, R5 is pyridin-4-yl which is substituted with one substituent group at position 2 of said pyridin-4-yl, wherein said substituent group is selected from C1-C4 alkyi, C2-C4 alkenyl, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, cycloalkyl, heterocycloalkyl, -0(Ci-C4 alkyi), -O-cycloalkyl, or -O-heterocycloalkyl, preferably said substituent group is selected from methyl, vinyl, propenyl (e.g., propen-2-yl), -F, -CI, -CF3, -0-CH2-CF3, -CN, cyclopropyl, or pyrrolidinyl (e.g., pyrrolidin-1 -yl), more preferably said substituent group is -CF3 or vinyl, and even more preferably said substituent group is -CF3. Accordingly, it is most preferred that R5 is 2-trifluoromethyl-pyridin-4- yi-
R6 is selected from C1-C4 alkyi, cycloalkyl (e.g., cyclopropyl), or heterocycloalkyl, wherein said C1-C4 alkyi is optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from cycloalkyl (e.g., cyclopropyl), halogen, -CF3, -CN, -OH or -0(C C4 alkyi), and further wherein, if R6 is cycloalkyl or heterocycloalkyl, then said cycloalkyl and said heterocycloalkyl are each optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from C1-C4 alkyi, cycloalkyl, halogen, -CF3, -CN, -OH or -0(C C4 alkyi).
Preferably, R6 is C1-C4 alkyi which is optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from cycloalkyl, halogen, -CF3, -CN, -OH or -0(C C4 alkyi). More preferably, R6 is C1-C4 alkyi which is optionally substituted with one or more fluoro atoms (such as, e.g., -(Ci-C3 alkylene)-CF3 or -(CrC3 alkylene)-CHF2). Even more preferably, R6 is C1-C4 alkyi, and yet even more preferably R6 is methyl (e.g., deuterium- enriched methyl, -CD3; or -C(1 H)3) or ethyl. Most preferably, R6 is methyl.
Each R7, R8 and R9 is independently selected from hydrogen, C1-C4 alkyi, C2-C4 alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, wherein said C1-C4 alkyl and said C2-C4 alkenyl are each optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from halogen, -CF3, -CN, cycloalkyi, cycloalkenyl, heterocycloalkyi, heterocycloalkenyl, aryl, heteroaryl, -OH, -0(Ci-C4 alkyl), - NH2, -NH(Ci-C4 alkyl) or -N(C C4 alkyl)(C C4 alkyl), and further wherein, if R7, R8 or R9 is cycloalkyi, cycloalkenyl, heterocycloalkyi, heterocycloalkenyl, aryl or heteroaryl, then said cycloalkyi, said cycloalkenyl, said heterocycloalkyi, said heterocycloalkenyl, said aryl and said heteroaryl are each optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from: C1-C4 alkyl; halogen; -CF3; -CN; -OH; -0(Ci-C4 alkyl); d- C4 alkyl substituted with one or more (e.g., one, two or three) -OH groups (such as, e.g., -(CH2)i-4-OH); -NH2; -NH(C C4 alkyl); or -N(C C4 alkyl)(C C4 alkyl).
The above detailed description of the compounds of formula (I) according to the first and the second aspect of the invention, including in particular the description and definition of the preferred meanings of the groups/variables A, R1, R2 and R4 to R9 also applies to the compounds of formula (I) according to the third aspect of the invention.
In accordance with the third aspect of the invention, the group R3 is selected from hydrogen, -F, -CI, -I, -CN, -OR7, -NR7R8, -COOR7, -SO3H, -B(OH)2, -CONR7R8, - COR7, -SR7, -SOR7, -S02R7, -S02NR7R8, -NR7COR8, -NR7S02R8, -OCOR7, - NR7C(0)NR8R9, -NR7C(S)NR8R9, -NR7COOR8, C C4 alkyl, C2-C4 alkenyl, cycloalkyi or heterocycloalkyi, wherein said C1-C4 alkyl and said C2-C4 alkenyl are each optionally substituted with one or more groups independently selected from halogen, -CF3, -CN, - OH, -0(Ci-C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(Ci-C4 alkyl)(C C4 alkyl), and further wherein said cycloalkyi and said heterocycloalkyi are each optionally substituted with one or more groups independently selected from: C1-C4 alkyl; halogen; -CF3; -CN; -OH; -0(Ci-C4 alkyl); d- C4 alkyl substituted with one or more -OH groups; -NH2; -NH(Ci-C4 alkyl); or -N(Ci-C4 alkyl)(Ci-C4 alkyl).
In this third aspect, R3 is preferably selected from hydrogen, -F, -CI, -I, -CN, -OR7, - NR7R8, -COOR7, -CONR7R8, -COR7, -NR7COR8, C C4 alkyl, C2-C4 alkenyl, cycloalkyi or heterocycloalkyi, wherein said C1-C4 alkyl and said C2-C4 alkenyl are each optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from halogen, -CF3, -CN, -OH, -0(C C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(C C4 alkyl)(Ci-C4 alkyl), and further wherein said cycloalkyi and said heterocycloalkyi are each optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from: C C4 alkyl; halogen; -CF3; -CN; -OH; -0(Ci-C4 alkyl); C C4 alkyl substituted with one or more -OH groups; -NH2; -NH(C C4 alkyl); or -N(C C4 alkyl)(C C4 alkyl). More preferably, R3 is selected from hydrogen, -F, -CI, -I, C1-C4 haloalkyl (e.g., -CF3), C1-C4 haloalkoxy (e.g., -OCF3), -CN, C1-C4 alkyl, C2-C4 alkenyl, cycloalkyl, heterocycloalkyi, -OH, -0(d-C4 alkyl), -O-cycloalkyl, -0-(CrC4 alkylene)-cycloalkyl, -O-heterocycloalkyl, -0-(Ci-C4 alkylene)-heterocycloalkyl, -N H2, -NH(C C4 alkyl), -N(C C4 alkyl)(Ci-C4 alkyl), -NH-cycloalkyl, -N(Ci-C4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(Ci-C4 alkyl)-heterocycloalkyl, -NH-(C C4 alkylene)-cycloalkyl, -N(C C4 alkyl)-(Ci-C4 alkylene)-cycloalkyl, -NH-(CrC4 alkylene)-heterocycloalkyl, -N(CrC4 alkyl)-(Ci-C4 alkylene)-heterocycloalkyl, -CO-(CrC4 alkyl), -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-(Ci-C4 alkylene)-cycloalkyl, -CO-(C C4 alkylene)-heterocycloalkyl, -CO-NH2, -CO-NH(Ci-C4 alkyl), -CO-N(C C4 alkyl)(C C4 alkyl), -CO-NH-cycloalkyl, -CO-N(C C4 alkyl)-cycloalkyl, -CO- NH-(Ci-C4 alkylene)-cycloalkyl, -CO-N(C C4 alkyl)-(C C4 alkylene)-cycloalkyl, -CO- NH-heterocycloalkyl, -CO-N(Ci-C4 alkyl)-heterocycloalkyl, -CO-N H-(Ci-C4 alkylene)- heterocycloalkyl, -CO-N(C C4 alkyl)-(C C4 alkylene)- heterocycloalkyl, -NH-CO-cycloalkyl, -N(Ci-C4 alkyl)-CO-cycloalkyl, -NH-CO-(C C4 alkylene)- cycloalkyl, -N(Ci-C4 alkyl )-CO-(d-C4 alkylene)-cycloalkyl, -NH-CO-heterocycloalkyl, -N(Ci-C4 alkyl)-CO-heterocycloalkyl, -NH-CO-(d-C4 alkylene)-heterocycloalkyl, -N(C C4 alkyl)-CO-(C C4 alkylene)-heterocycloalkyl, or -COOH, wherein said cycloalkyl, said heterocycloalkyi, the cycloalkyl moiety comprised in any of the aforementioned groups, and the heterocycloalkyi moiety comprised in any of the aforementioned groups are each optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from: C1-C4 alkyl; halogen; -CF3; -CN; -OH; -0(C C4 alkyl); C1-C4 alkyl substituted with one or more -OH groups; -NH2; -NH(C C4 alkyl); or -N(C C4 alkyl)(C C4 alkyl). Even more preferably, R3 is selected from hydrogen, -F, -CI, -I, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, C1-C4 alkyl, cycloalkyl, heterocycloalkyi, -OH, -0(Ci-C4 alkyl), -O-cycloalkyl, -O-heterocycloalkyl, -NH2, -NH(C C4 alkyl), -N(C C4 alkyl)(Ci-C4 alkyl), -NH-cycloalkyl, -N(Ci-C4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(Ci-C4 alkyl)-heterocycloalkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-NH2, -CO-NH(Ci-C4 alkyl), -CO-N(C C4 alkyl)(C C4 alkyl), -CO-NH-cycloalkyl, -CO-N(C C4 alkyl)-cycloalkyl, -CO- NH-heterocycloalkyl, -CO-N(C C4 alkyl)-heterocycloalkyl, -NH-CO-cycloalkyl, -N(C C4 alkyl)- CO-cycloalkyl, -NH-CO-heterocycloalkyl, or -N(Ci-C4 alkyl)-CO-heterocycloalkyl, wherein said cycloalkyl, said heterocycloalkyi, the cycloalkyl moiety comprised in any of the aforementioned groups, and the heterocycloalkyi moiety comprised in any of the aforementioned groups are each optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from: C1-C4 alkyl; halogen; -CF3; -CN; -OH; -0(CrC4 alkyl); C1-C4 alkyl substituted with one or more -OH groups; -NH2; -NH(C C4 alkyl); or -N(C C4 alkyl)(Ci-C4 alkyl). Even more preferably, R3 is selected from hydrogen, -F, -CI, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, C1-C4 alkyl, cycloalkyl, heterocycloalkyi, -OH, -0(Ci-C4 alkyi), -O-cycloalkyl, -O-heterocycloalkyl, -NH2, -NH(C C4 alkyi), -N(C C4 alkyl)(Ci-C4 alkyi), -NH-cycloalkyl, -N(C C4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(C C4 alkyl)-heterocycloalkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-NH2, -CO-NH(C C4 alkyi), or -CO-N(Ci-C4 alkyl)(Ci-C4 alkyi), wherein said cycloalkyi, said heterocycloalkyi, the cycloalkyi moiety comprised in any of the aforementioned groups, and the heterocycloalkyi moiety comprised in any of the aforementioned groups are each optionally substituted with one or more groups (e.g., one, two or three groups) independently selected from: C1-C4 alkyi; halogen; -CF3; -CN; -OH; -0(C C4 alkyi); C1-C4 alkyi substituted with one or more -OH groups; -NH2; -NH(C C4 alkyi); or -N(C C4 alkyl)(C C4 alkyi). Even more preferably, R3 is selected from hydrogen, -F, -CI, Ci-C4 haloalkyl (e.g., -CF3), -CN, heterocycloalkyi (e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl), -0(Ci-C4 alkyi), -NH(d-C4 alkyi), or -CO-N(Ci-C4 alkyl)(Ci-C4 alkyi), wherein said heterocycloalkyi is optionally substituted with one or more groups (e.g., one or two groups) independently selected from: C1-C4 alkyi; halogen; -CF3; -CN; -OH; -0(Ci-C4 alkyi); C1-C4 alkyi substituted with one or more -OH groups (e.g., -(CH2)i-4-OH); -NH2; -NH(C C4 alkyi); or -N(C C4 alkyl)(C C4 alkyi). Yet even more preferably, R3 is selected from hydrogen, -F, -CI, -CF3, -CN, 3-hydroxyazetidin-1-yl, 4-hydroxypiperidin-1-yl, morpholin-4-yl, -OCH3, -NHCH3, -CO-N(CH3)2, or -CO-N(CH2CH3)2. Most preferably, R3 is hydrogen. It is particularly preferred that the compound of formula (I) according to the first, second or third aspect of the invention is selected from:
2-(2-chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl 2-(2-methyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-ethyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-propyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-cyclopropyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-cyclobutyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-cyclopentyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-cyclohexyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl-2-(2-vinyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-isopropenyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-isopropyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-(4-methyl-5-oxo-4,5-dihydro-pyrazolo[1 ,5-a]quinazolin-2-yl)-pyridine-2-carbonitrile;
2-(2-fluoro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-methoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-ethoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-isopropoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 2-(2-cyclobutoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl-2-[2-(oxetan-3-yloxy)-pyridin-4-yl]-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-cyclopropylmethoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-[2-(2-methoxy-ethoxy)-pyridin-4-yl]-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl-2-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl-2-[2-(2,2-difluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-[2-(2,2-difluoro-propoxy)-pyridin-4-yl]-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl-2-[2-(2,2,3,3,3-pentafluoro-propoxy)-pyridin-4-yl]-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl-2-[2-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl(D3)-2-(2-tnfluoromethyl-pyridin-4-yl)-4l-l-pyrazolo[1 ,5-a]quinazoliri-5-one;
4-ethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-(2,2-difluoro-ethyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 4-(2-methoxy-ethyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl-2-(2-difluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-[2-(1 , 1-difluoro-ethyl)-pyridin-4-yl]-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-[2-(1 , 1-difluoro-ethyl)-pyridin-4-yl]-4-methyl(D3)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-chloro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-methoxy-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-trifluoromethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-on
7-fluoro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-bromo-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl-7-methylamino-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin
4-methyl-7-methyl(D3)amino-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5 one;
N-[4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5-a]quinazolin-7-yl]^ acetamide;
7-amino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-on
7-dimethylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazoli one;
7-ethylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 7-cyclobutylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
4-methyl-7-morpholin-4-yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 7-hydroxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 7-ethoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-(2-methoxy-ethoxy)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin
5-one;
4-methyl-7-(2-morpholin-4-yl-ethoxy)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
4-methyl-7-trifluoromethoxy-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
7- methanesulfonyl-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazoli one;
8-methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
8- fluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
8-chloro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl-8-trifluoromethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazo^ 8-bromo-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl-8-morpholin-4-yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin 4-methyl-8-pyrrolidin-1 -yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-o 4-methyl-8-methylamino-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazol^
8-(4-methoxy-piperidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
8-(4-hydroxy-piperidin-1 -yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
8-dimethylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazoli one;
4-methyl-8-(4-methyl-piperazin-1 -yl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
4-methyl-8-piperazin-1 -yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
8-(4-hydroxymethyl-piperidin-1 -yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazoin-5-one;
8-(3-hydroxy-azetidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
8-(3-hydroxymethyl-azetidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
8-(3-hydroxy-pyrrolidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
8-(4-hydroxy-4-methyl-piperidin-1 -yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H- pyrazolo[1 ,5-a]quinazolin-5-one;
4,8-dimethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 8-cyclopropyl-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-^ 8-cyclopentyl-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-on 4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5-a]quinazoline-8- carbonitrile;
4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5-a]quinazoline-8- carboxylic acid;
4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5-a]quinazoline-8- carboxylic acid amide;
4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5-a]quinazoline-8- carboxylic acid methylamide;
4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5-a]quinazoline-8- carboxylic acid dimethylamide;
4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5-a]quinazoline-8- carboxylic acid diethylamide;
4-methyl-8-(morpholine-4-carbonyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
4-methyl-8-(pyrrolidine-1-carbonyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
8- (2-hydroxy-ethoxy)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
4-methyl-6-trifluoromethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
6- fluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
9- methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 7,8-dimethoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 7,8-difluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
8-fluoro-7-methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
8-(4-hydroxy-piperidin-1 -yl)-7-methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H- pyrazolo[1 ,5-a]quinazolin-5-one;
8-dimethylamino-7-fluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
7- bromo-8-fluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
7- bromo-8-methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
8- methoxy-4-methyl-7-methylamino-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one; 7-chloro-2-(2-chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-chloro-2-(2-chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-chloro-2-(2-Fluoro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-chloro-4-methyl-2-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 2-(2-chloro-pyridin-4-yl)-7-methoxy-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-cyclopropyl-pyridin-4-yl)-7-methoxy-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-fluoro-pyridin-4-yl)-7-methoxy-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7- methoxy-4-methyl-2-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
4-methyl-2-(1 -methyl-1 H-pyrazol-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl-2-pyridin-4-yl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-chloro-6-methyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-cyclopropyl-6-methyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(3-fluoro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(3-chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl-2-(3-methyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
8- (3-Hydroxy-azetidine-1-carbonyl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
8-(3-Hydroxy-propoxy)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin^ 5-one;
2-(2-Cyclopropyl-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-Cyclopropyl-pyridin-4-yl)-8-(4-hydroxy-piperidin-1 -yl)-4-methyl-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
2-(2-Difluoromethyl-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-Difluoromethyl-pyridin-4-yl)-8-(4-hydroxy-piperidin-1-yl)-4-methyl-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
2-(2-Cyclobutyl-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-Chloro-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-Chloro-pyridin-4-yl)-8-(4-hydroxy-piperidin-1-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
7-Fluoro-8-(3-hydroxy-azetidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
7-Fluoro-4-methyl-8-(oxetan-3-yloxy)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
3-[7-Fluoro-4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5- a]quinazolin-8-ylamino]-propionitrile; 7-Fluoro-8-(2-hydroxymethyl-pyrrolidin-1-yl)-4-methyl-2-(2-trifluoromethyl^
pyrazolo[1 ,5-a]quinazolin-5-one;
7- Fluoro-8-(7-hydroxymethyl-1-aza-spiro[3.5]non-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridi yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
8-(3-Hydroxy-piperidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
8- (2,6-Dimethyl-morpholin-4-yl)-4-methyl-2-(2-trifluorom
a]quinazolin-5-one;
8-(2-Hydroxy-2-methyl-propylamino)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H
pyrazolo[1 ,5-a]quinazolin-5-one; and
pharmaceutically acceptable salts, solvates and prodrugs of any one of the aforementioned compounds.
In the following, where reference is made to the compounds of the general formula (I), this is intended to refer to the compounds of formula (I) according to the first, second and/or third aspect of the invention.
Compounds of the general formula (I) may exist in the form of different isomers, in particular stereoisomers (including geometric isomers (or cis-trans isomers), enantiomers and diastereomers) or tautomers. All such isomers of the compounds according to the invention are contemplated as being part of the present invention, either in admixture or in pure or substantially pure form. As for stereoisomers, the invention embraces mixtures (such as racemic forms) and the isolated optical isomers of the compounds according to the invention. The racemic forms can be resolved by physical methods, such as, e.g., fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography.
The scope of the invention also embraces compounds of the general formula (I), in which one or more atoms are replaced by a specific isotope of the corresponding atom. For example, the invention encompasses compounds of formula (I), in which one or more hydrogen atoms (or, e.g., all hydrogen atoms) are replaced by deuterium atoms (i.e., 2H; also referred to as "D"). Accordingly, the invention also embraces compounds of formula (I) which are enriched in deuterium. Naturally occurring hydrogen is an isotopic mixture comprising about 99.98 mol-% hydrogen-1 (1 H) and about 0.0156 mol-% deuterium (2H or D). The content of deuterium in one or more hydrogen positions in the compounds of formula (I) can be increased using deuteration techniques known in the art. For example, a compound of formula (I) or a reactant or precursor to be used in the synthesis of the compound of formula (I) can be subjected to an H/D exchange reaction using, e.g., heavy water (D20). Further suitable deuteration techniques are described in: Atzrodt J et al., Bioorg Med Chem, 20(18), 5658-5667, 2012; William JS et al., Journal of Labelled Compounds and Radiopharmaceuticals, 53(1 1 -12), 635-644, 2010; Modvig A et al., J Org Chem, 79, 5861 -5868, 2014. The content of deuterium can be determined, e.g., using mass spectrometry or NMR spectroscopy. Unless specifically indicated otherwise, it is preferred that the compound of formula (I) is not enriched in deuterium. Accordingly, the presence of naturally occurring hydrogen atoms or 1 H hydrogen atoms in the compounds of formula (I) is preferred. The present invention also embraces compounds of formula (I), in which one or more atoms are replaced by a positron-emitting isotope of the corresponding atom, such as, e.g., 18F, 11C, 13N, 150, 76Br, 77Br, 120l and/or 124l. Such compounds can be used as tracers or imaging probes in positron emission tomography (PET). The invention thus includes (i) compounds of formula (I), in which one or more fluorine atoms (or, e.g., all fluorine atoms) are replaced by 18F atoms, (ii) compounds of formula (I), in which one or more carbon atoms (or, e.g., all carbon atoms) are replaced by 11C atoms, (iii) compounds of formula (I), in which one or more nitrogen atoms (or, e.g., all nitrogen atoms) are replaced by 13N atoms, (iv) compounds of formula (I), in which one or more oxygen atoms (or, e.g., all oxygen atoms) are replaced by 150 atoms, (v) compounds of formula (I), in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by 76Br atoms, (vi) compounds of formula (I), in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by 77Br atoms, (vii) compounds of formula (I), in which one or more iodine atoms (or, e.g., all iodine atoms) are replaced by 120l atoms, and (viii) compounds of formula (I), in which one or more iodine atoms (or, e.g., all iodine atoms) are replaced by 124l atoms. In general, it is preferred that none of the atoms in the compounds of formula (I) are replaced by specific isotopes.
The scope of the invention embraces all pharmaceutically acceptable salt forms of the compounds of the general formula (I) which may be formed, e.g., by protonation of an atom carrying an electron lone pair which is susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of a carboxylic acid group with a physiologically acceptable cation as they are well known in the art. Exemplary base addition salts comprise, for example, alkali metal salts such as sodium or potassium salts; alkaline-earth metal salts such as calcium or magnesium salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, diethanol amine salts or ethylenediamine salts; aralkyl amine salts such as Ν,Ν-dibenzylethylenediamine salts, benetamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts or lysine salts. Exemplary acid addition salts comprise, for example, mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts, nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts or perchlorate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, undecanoate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, nicotinate, benzoate, salicylate or ascorbate salts; sulfonate salts such as methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, p- toluenesulfonate (tosylate), 2-naphthalenesulfonate, 3-phenylsulfonate, or camphorsulfonate salts; and acidic amino acid salts such as aspartate or glutamate salts.
Moreover, the scope of the invention embraces solid forms of the compounds of the general formula (I) in any solvated form, including e.g. solvates with water, for example hydrates, or with organic solvents such as, e.g., methanol, ethanol or acetonitrile, i.e. as a methanolate, ethanolate or acetonitrilate, respectively; or in the form of any polymorph.
Pharmaceutically acceptable prodrugs of compounds of the general formula (I) are derivatives which have chemically or metabolically cleavable groups and become, by solvolysis or under physiological conditions, the compounds of formula (I) which are pharmaceutically active in vivo. Prodrugs of compounds of formula (I) may be formed in a conventional manner with a functional group of the compounds such as with an amino, hydroxy or carboxy group. The prodrug derivative form often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgaard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to the person skilled in the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine. When a compound of the general formula (I) has a carboxyl group, an ester derivative prepared by reacting the carboxyl group with a suitable alcohol or an amide derivative prepared by reacting the carboxyl group with a suitable amine is exemplified as a prodrug. An especially preferred ester derivative as a prodrug is methylester, ethylester, n-propylester, isopropylester, n-butylester, isobutylester, tert-butylester, morpholinoethylester or Ν,Ν-diethylglycolamidoester. When a compound of formula (I) has a hydroxy group, an acyloxy derivative prepared by reacting the hydroxyl group with a suitable acylhalide or a suitable acid anhydride is exemplified as a prodrug. An especially preferred acyloxy derivative as a prodrug is -OC(=0)-CH3, -OC(=0)-C2H5, -OC(=0)-C3H7, -OC(=0)-(tert-butyl), -OC(=0)- C15H31 , -OC(=0)-CH2CH2COONa, -0(C=0)-CH(NH2)CH3 or -OC(=0)-CH2-N(CH3)2. When a compound of formula (I) has an amino group, an amide derivative prepared by reacting the amino group with a suitable acid halide or a suitable mixed anhydride is exemplified as a prodrug. An especially preferred amide derivative as a prodrug is -NHC(=0)-(CH2)2OCH3 or -NHC(=0)-CH(NH2)CH3.
The compounds of general formula (I) or pharmaceutically acceptable salts, solvates or prodrugs thereof, may be administered as compounds per se or may be formulated as medicaments. Within the scope of the present invention are pharmaceutical compositions comprising as an active ingredient one or more compounds of the general formula (I), or pharmaceutically acceptable salts, solvates or prodrugs thereof. The pharmaceutical compositions may optionally comprise one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, or antioxidants.
The pharmaceutical compositions may also comprise one or more solubility enhancers, such as, e.g., poly(ethylene glycol), including poly(ethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da, ethylene glycol, propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 80, macrogol-15-hydroxystearate, phospholipids, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, cyclodextrins, hydroxyethyl-3-cyclodextrin, hydroxypropyl-3-cyclodextrin, hydroxyethyl-γ- cyclodextrin, hydroxypropyl-Y-cyclodextrin, dihydroxypropyl-3-cyclodextrin, glucosyl-a- cyclodextrin, glucosyl-3-cyclodextrin, diglucosyl-3-cyclodextrin, maltosyl-a-cyclodextrin, maltosyl-3-cyclodextrin, maltosyl-y-cyclodextrin, maltotriosyl-3-cyclodextrin, maltotriosyl-γ- cyclodextrin, dimaltosyl-3-cyclodextrin, methyl-3-cyclodextrin, carboxyalkyl thioethers, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, vinyl acetate copolymers, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof. The pharmaceutical compositions can be formulated by techniques known to the person skilled in the art, such as the techniques published in Remington's Pharmaceutical Sciences, 20th Edition. The pharmaceutical compositions can be formulated as dosage forms for oral, parenteral, such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, rectal, nasal, topical, aerosol or vaginal administration. Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewing tablets and effervescent tablets. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions and powders and granules for reconstitution. Emulsions are a preferred dosage form for parenteral administration. Dosage forms for rectal and vaginal administration include suppositories and ovula. Dosage forms for nasal administration can be administered via inhalation and insufflation, for example by a metered inhaler. Dosage forms for topical administration include creams, gels, ointments, salves, patches and transdermal delivery systems.
The compounds of the general formula (I) or pharmaceutically acceptable salts, solvates or prodrugs thereof, or the above described pharmaceutical compositions, may be administered to a subject by any convenient route of administration, whether systemically/peripherally or at the site of desired action, including but not limited to one or more of: oral (e.g. as a tablet, capsule, or as an ingestible solution), topical (e.g., transdermal, intranasal, ocular, buccal, and sublingual), parenteral (e. g., using injection techniques or infusion techniques, and including, for example, by injection, e.g. subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, or intrasternal by, e.g., implant of a depot, for example, subcutaneously or intramuscularly), pulmonary (e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g. through mouth or nose), gastrointestinal, intrauterine, intraocular, subcutaneous, ophthalmic (including intravitreal or intracameral), rectal, and vaginal.
If said compounds or pharmaceutical compositions are administered parenterally, then examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecal^, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously administering the compounds pharmaceutical compositions, and/or by using infusion techniques. For parenteral administration, the compounds are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
Said compounds or pharmaceutical compositions can also be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications. The tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the agent may be combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof. Said compounds or pharmaceutical compositions may also be administered by sustained release systems. Suitable examples of sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules. Sustained-release matrices include, e.g., polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman, U. et al., Biopolymers 22:547-556 (1983)), poly(2-hydroxyethyl methacrylate) (R. Langer et al., J. Biomed. Mater. Res. 15:167- 277 (1981 ), and R. Langer, Chem. Tech. 12:98-105 (1982)), ethylene vinyl acetate (R. Langer et al., Id.) or poly-D-(-)-3-hydroxybutyric acid (EP133988). Sustained-release pharmaceutical compositions also include liposomally entrapped compounds. Liposomes containing a compound of the present invention can be prepared by methods known in the art, such as, e.g., the methods described in any one of: DE3218121 ; Epstein et al., Proc. Natl. Acad. Sci. (USA) 82:3688-3692 (1985); Hwang et al., Proc. Natl. Acad. Sci. (USA) 77:4030-4034 (1980); EP0052322; EP0036676; EP088046; EP0143949; EP0142641 ; Japanese Pat. Appl. 83- 1 18008; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP0102324. Alternatively, said compounds or pharmaceutical compositions can be administered in the form of a suppository or pessary, or may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compounds of the present invention may also be dermally or transdermal^ administered, for example, by the use of a skin patch. Said compounds or pharmaceutical compositions may also be administered by the pulmonary route, rectal routes, or the ocular route. For ophthalmic use, they can be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum. For topical application to the skin, said compounds or pharmaceutical compositions can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, 2-octyldodecanol, benzyl alcohol and water.
Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular individual subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual subject undergoing therapy.
A proposed, yet non-limiting dose of the compounds of the general formula (I) for administration to a human (of approximately 70 kg body weight) may be 0.05 to 2000 mg, preferably 0.1 mg to 1000 mg, of the active ingredient per unit dose. The unit dose may be administered, for example, 1 to 4 times per day. The unit dose may also be administered 1 to 7 times per week, e.g., with not more than one administration per day. The dose will depend on the route of administration. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient/subject as well as the severity of the condition to be treated. The precise dose and route of administration will ultimately be at the discretion of the attendant physician or veterinarian.
The subject or patient, such as the subject in need of treatment or prophylaxis, may be an animal (e.g., a non-human animal), a vertebrate animal, a mammal (e.g., a non-human mammal), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), a murine (e.g., a mouse), a canine (e.g., a dog), a feline (e.g., a cat), an equine (e.g., a horse), a primate, a simian (e.g., a monkey or ape), a monkey (e.g., a marmoset, a baboon), an ape (e.g., a gorilla, chimpanzee, orang-utan, gibbon), or a human. In the context of this invention, it is particularly envisaged that animals are to be treated which are economically, agronomically or scientifically important. Scientifically important organisms include, but are not limited to, mice, rats, and rabbits. Lower organisms such as, e.g., fruit flies like Drosophila melagonaster and nematodes like Caenorhabditis elegans may also be used in scientific approaches. Non-limiting examples of agronomically important animals are sheep, cattle and pigs, while, for example, cats and dogs may be considered as economically important animals. Preferably, the subject/patient is a mammal. More preferably, the subject/patient is a human or a non-human mammal (such as, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orang-utan, a gibbon, a sheep, cattle, or a pig). Most preferably, the subject/patient is a human.
The term "treatment" of a condition, disorder or disease as used herein is well known in the art. "Treatment" of a condition, disorder or disease implies that a disorder or disease is suspected or has been diagnosed in a patient/subject. A patient/subject suspected of suffering from a disorder or disease typically shows specific clinical and/or pathological symptoms which a skilled person can easily attribute to a specific pathological condition (i.e. diagnose a disorder or disease).
The treatment of a condition, disorder or disease may, for example, lead to a halt in the progression of the condition, disorder or disease (e.g. no deterioration of symptoms) or a delay in the progression of the disorder or disease (in case the halt in progression is of a transient nature only). Treatment may also lead to a partial response (e.g. amelioration of symptoms) or complete response (e.g. disappearance of symptoms) of the subject/patient suffering from the condition, disorder or disease. Amelioration of a condition, disorder or disease may, for example, lead to a halt in the progression of the disorder or disease or a delay in the progresssion of the disorder or disease. Such a partial or complete response may be followed by a relapse. It is to be understood that a subject/patient may experience a broad range of responses to a treatment (e.g. the exemplary responses as described herein above).
Treatment of a condition, disorder or disease may, inter alia, comprise curative treatment (preferably leading to a complete response and eventually to healing of the disorder or disease) and palliative treatment (including symptomatic relief).
Also the term "prophylaxis" or "prevention" of a condition, disorder or disease as used herein is well known in the art. For example, a patient/subject suspected of being prone to suffer from a condition, disorder or disease as defined herein may, in particular, benefit from a prophylaxis of the disorder or disease. Said subject/patient may have a susceptibility or predisposition for a condition, disorder or disease, including but not limited to hereditary predisposition. Such a predisposition can be determined by standard assays, using, for example, genetic markers or phenotypic indicators. It is to be understood that a condition, disorder or disease to be prevented in accordance with the present invention has not been diagnosed or cannot be diagnosed in said patient/subject (for example, said patient/subject does not show any clinical or pathological symptoms). Thus, the term "prophylaxis" comprises the use of compounds of the present invention before any clinical and/or pathological symptoms are diagnosed or determined or can be diagnosed or determined by the attending physician. The terms "prophylaxis" and "prevention" are used herein interchangeably.
In the method for identifying an agent that binds to group II metabotropic glutamate receptor (mGluR2) described herein above, the test agent may, for example, be selected from nucleic acids, DNA, RNA, PNA, oligonucleotides, aptamers (Gold, Ann. Rev. Biochem. 64 (1995), 763- 797)), aptazymes, RNAzymes, ribozymes (see e.g., EP-B1 0 291 533, EP-A1 0 321 201 , EP- B1 0 360 257), antisense DNA, antisense oligonucleotides, antisense RNA, siRNA, RNAi, shRNA, amino acids, peptides, polypeptides, proteins, glycoproteins, lipoproteins, nucleoproteins, antibodies (Harlow and Lane "Antibodies, A Laboratory Manual", CSH Press, Cold Spring Harbor, 1988), monocloncal antibodies, polyclonal antibodies, immunoglobulins, affibodies (Hansson, Immunotechnology 4 (1999), 237-252; Henning, Hum Gene Ther. 13 (2000), 1427-1439), immunoreactive fragments, immunoreactive derivatives, antigens, epitopes, haptens, cell-surface molecules, cofactors, ligands, small organic molecules, lectins or derivatives thereof, lectin fragments, trinectins (Phylos Inc., Lexington, Massachusetts, USA; Xu, Chem. Biol. 9 (2002), 933), anticalins (EP-B-1 1 017 814), hormones, peptide and protein hormones, non-peptide hormones, steroids, interleukins, interferons, cytokines, neurotransmitters, toxins, enzymes, polysaccharides, carbohydrates, lipids, lipopolysaccharides, vitamins, crown ethers, cyclodextrins, cryptands, calixarenes, aldehydes, thiols, amines, drugs, drugs of abuse, therapeutic agents, medicaments, pharmaceuticals, substrates, fragments, portions, components or products of microorganisms, metabolites of or antibodies to any of the above substances and the like. It is to be understood that the present invention specifically relates to each and every combination of features and embodiments described herein, including any combination of general and/or preferred features/embodiments. In particular, the invention specifically relates to each combination of meanings (including general and/or preferred meanings) for the various groups and variables comprised in the general formula (I).
As used herein, "alkyl" represents a straight or branched chain saturated acyclic hydrocarbon residue (i.e., a group consisting of carbon atoms and hydrogen atoms) which does not comprise any carbon-to-carbon double bonds or carbon-to-carbon triple bonds. As exemplary groups, methyl, ethyl, propyl and butyl are mentioned.
As used herein, "alkenyl" represents a straight or branched chain unsaturated acyclic hydrocarbon residue comprising one or more than one (such as two or three) carbon-to-carbon double bond(s) which does not comprise any carbon-to-carbon triple bonds.
As used herein, "alkylene" represents a straight or branched chain alkanediyl group which does not comprise any carbon-to-carbon double bonds or carbon-to-carbon triple bonds.
As used herein, "aryl" represents an aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic). "Aryl" may, for example, refer to phenyl or naphthyl. Unless defined otherwise, an "aryl" preferably has 6 to 10 ring members, and most preferably refers to phenyl.
As used herein, "heteroaryl" represents an aromatic ring group, including monocyclic aromatic rings as well as fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic), wherein said aromatic ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S, or N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized. "Heteroaryl" may, for example, refer to thienyl (thiophenyl), benzo[b]thienyl, naphtho[2,3- b]thienyl, thianthrenyl, furyl (furanyl), isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, pyrrolyl (including, without limitation, 2H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (pyridinyl; including, without limitation, 2-pyridyl, 3-pyridyl, and 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl (including, without limitation, 3H-indolyl), indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (including, without limitation, [1 , 10]phenanthrolinyl, [1 ,7]phenanthrolinyl, and [4,7]phenanthrolinyl), phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, oxazolyl, isoxazolyl, furazanyl, phenoxazinyl, pyrazolo[1 ,5-a]pyrimidinyl (including, without limitation, pyrazolo[1 ,5-a]pyrimidin-3-yl), 1 ,2- benzoisoxazol-3-yl, benzimidazolyl, 1 H-tetrazolyl, or 2H-tetrazolyl. Unless defined otherwise, a "heteroaryl" preferably refers to a 5 to 14 membered monocyclic ring or fused ring system comprising one or more (e.g., one, two, three or four) ring heteroatoms independently selected from O, S or N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized; and more preferably refers to a 5 or 6 membered monocyclic ring comprising one or more (e.g., one, two or three) ring heteroatoms independently selected from O, S or N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized. As used herein, "cycloalkyl" represents a saturated hydrocarbon ring, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings, such as ring systems composed of two or three fused rings). "Cycloalkyl" may, for example, refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Unless defined otherwise, a "cycloalkyl" preferably has 3 to 1 1 ring members, and more preferably has 3 to 7 ring members.
As used herein, "heterocycloalkyl" represents a saturated ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings, such as ring systems composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S, or N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized. "Heterocycloalkyl" may, for example, refer to oxetanyl, tetrahydrofuranyl, piperidinyl, piperazinyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, morpholinyl, pyrazolidinyl, tetrahydrothienyl, octahydroquinolinyl, octahydroisoquinolinyl, oxazolidinyl, isoxazolidinyl, azepanyl, diazepanyl, oxazepanyl or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl. Unless defined otherwise, a "heterocycloalkyl" preferably refers to a 3 to 1 1 membered saturated ring group, which is a monocyclic ring or a fused ring system, containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from O, S, or N.
As used herein, "cycloalkenyl" represents an unsaturated alicyclic (non-aromatic) hydrocarbon ring, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings, such as ring systems composed of two or three fused rings), wherein said hydrocarbon ring comprises at least one carbon-to-carbon double bond and does not comprise any carbon-to-carbon triple bond. Non-limiting examples of cycloalkenyl groups are cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cyclohexadienyl. Unless defined otherwise, a "cycloalkenyl" preferably has 3 to 1 1 ring members, and more preferably has 3 to 7 ring members. As used herein, "heterocycloalkenyl" represents an unsaturated alicyclic (non-aromatic) ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings, such as ring systems composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S, or N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and further wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms. "Heterocycloalkenyl" may, for example, refer to 1 ,2,3,6-tetrahydropyridinyl. Unless defined otherwise, a "heterocycloalkenyl" preferably refers to a 3 to 1 1 membered unsaturated alicyclic ring group, which is a monocyclic ring or a fused ring system, containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from O, S, or N, wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms.
As used herein, "halogen" represents fluoro, chloro, bromo, or iodo. As used herein, "haloalkyl" represents an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms. It will be understood that the maximum number of halogen atoms is limited by the number of available attachment sites and, thus, depends on the number of carbon atoms comprised in the alkyl moiety of the haloalkyl group. "Haloalkyl" may, for example, refer to -CF3, -CHF2, or -CF2-CH3.
As used herein, "haloalkoxy" represents an -O-alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms. It will be understood that the maximum number of halogen atoms is limited by the number of available attachment sites and, thus, depends on the number of carbon atoms comprised in the -O-alkyl moiety of the haloalkoxy group. "Haloalkoxy" may, for example, refer to -OCF3, -O-CH2-CF3, -O-CH2-CHF2, -O-CH2-CF2-CH3, -O-CH2-CF2-CF3, or -0-CH(CF3)2.
As used herein, the terms "optional", "optionally" and "may" denote that the indicated feature may be present but can also be absent. Whenever the term "optional", "optionally" or "may" is used, the present invention specifically relates to both possibilities, i.e., that the corresponding feature is present or, alternatively, that the corresponding feature is absent. For example, the expression "X is optionally substituted with Y" (or "X may be substituted with Y") means that X is either substituted with Y or is unsubstituted. Likewise, if a component of a composition is indicated to be "optional", the invention specifically relates to both possibilities, i.e., that the corresponding component is present (contained in the composition) or that the corresponding component is absent from the composition. Various groups are referred to as being "optionally substituted" in the context of this description. Generally, these groups may carry one or more than one, such as e.g. one, two, three or four substituents. It will be understood that the maximum number of substituents is limited by the number of attachment sites available on the substituted moiety. Unless defined otherwise in the specific context, these groups carry preferably not more than two substituents and may, in particular, carry only one substituent. Moreover, unless specifically defined otherwise, it is preferred that the optional substituents are absent.
For a person skilled in the field of synthetic chemistry, various ways for the preparation of the compounds of general formula (I) will be readily apparent. For example, the compounds of the invention can be prepared in accordance with or in analogy to the synthetic routes described in detail in the examples section. In particular, the compounds of formula (I) can be synthesized in accordance with the methods described in the following schemes (the substituent groups and variables shown in schemes 1 and 2 have the same meanings as the corresponding groups and variables in general formula (I)).
Intermediates E can be obtained in one step in the presence of the hydrazines D and the β-ketonitriles B under acidic conditions (Vasquez TE et al., Mol Divers, 7(2-4), 161-4, 2003). A way to generate hydrazines D is to convert the amino group of C into a diazonium salt in the presence of sodium nitrite under aqueous acidic conditions and to reduce it, e.g., with tin chloride (II). β-ketonitriles B can be generated from an activated acid A such as an acid chloride or an ester in the presence of the acetonitrile anion formed, e.g., from acetonitrile and butyl lithium (see scheme 1 ).
Figure imgf000048_0001
Scheme 1
Example G can be obtained from the pyrazolo[1 ,5-a]quinazolin-5-ones E in the presence of a base such as NaH, fBuOK or K2C03 and the electrophiles F where X1 is a halide or a pseudo halide (see scheme 2).
Figure imgf000049_0001
Scheme 2
Example G can be further modified by methods well known in the art. For instance, on an example G containing a halide or a pseudo halide a cross coupling reaction involving a metallic species such as boronic derivatives, tin derivatives or zinc derivatives (and a catalytic amount of a transition metal like palladium or nickel) can be used to introduce groups such as an aryl, a heteroaryl, an alkene or an alkyne. Also, on an example G containing a halide or a pseudo halide a nucleophile like an alcohol or an amine can be introduced. In some cases the nucleophilic displacement can be facilitated by a catalytic amount of a transition metal such palladium (David S. Surry and Stephen L. Buchwald, Chem Sci. 201 1 , 2(1 ), 27-50) or copper (Steven V. Ley and Andrew W. Thomas, Angew. Chem. Int. Ed., 2003, (42) 5400-5449; Yu Zhang et al., Organic letter, 2012, 14 (12), 3056-3059).
On an example G containing a hydroxyl group, an alkyl chain can be introduced with an electrophile such as a halo alkyl in the presence of a base such as NaH, tBuOK or K2C03. From an example G containing a carboxylic acid group, a nucleophile such as an amine can furnish an amide via activating agents (Christian A. G. N. Montalbetti and Virginie Falque, Tetrahedron, 61 , (2005) 10827-10852).
The compounds of formula (I) having a pyrroloquinazolinone scaffold (i.e., where A in formula (I) is CH) can be obtained in 2 steps, as shown in scheme 3 below. The dicyanide H is prepared according to procedures well known in the art. This compound reacts with 2-amino benzoic acid derivatives C to give the cyanide derivatives J. Then, the cyanide moiety can be removed under acidic conditions or other conditions such as basic hydrolysis followed by thermal decarboxylation.
Figure imgf000050_0001
Scheme 3
Like example G, example L can be obtained from the pyrroloquinazolinone K in the presence of a base such as NaH, fBuOK or K2C03 and the electrophiles F where X1 is a halide or a pseudo halide. Like example G, example L can be further modified by methods well known in the art.
The present invention particularly relates to the following items:
1. A compound of formula (I):
Figure imgf000050_0002
(I)
wherein:
A is N or -CH;
R1, R2 and R4 are each independently selected from R7, halogen, - CN, -OR7, -NR7R8, -COOR7, -S03H, -B(OH)2, -CONR7R8, - COR7, -SR7, -SOR7, -S02R7, -S02NR7R8, -NR7COR8, NR7S02R8, -OCOR7, -NR7C(0)NR8R9, -NR7C(S)NR8R9, -NR7COOR8, aryl, or heteroaryl, wherein said aryl and said heteroaryl are each substituted with one or more groups independently selected from R7, halogen, -CN, - OR7, -NR7R8, -COOR7, -S03H, -B(OH)2, -CONR7R8, -COR7, -SR7, - SOR7, -S02R7, -S02NR7R8, -NR7COR8, -NR7S02R8, -OCOR7, -NR7C(0)NR8R9, - NR7C(S)NR8R9, or -NR7COOR8;
R3 is selected from hydrogen, halogen, -CN, -OR7, NR7R8, -COOR7, -SO3H, -B(OH)2, -CONR7R8, -COR7, -SR7, - SOR7, -S02R7, -S02NR7R8, -NR7COR8, -NR7S02R8, -OCOR7, -NR7C(0)NR8R9, - NR7C(S)NR8R9, -NR7COOR8, C C4 alkyl, C2-C4 alkenyl, cycloalkyi or heterocycloalkyi, wherein said C1-C4 alkyl and said C2-C4 alkenyl are each optionally substituted with one or more groups independently selected from halogen, -CF3, -CN, -OH, -0(C C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(C C4 alkyl)(Ci-C4 alkyl), and further wherein said cycloalkyi and said heterocycloalkyi are each optionally substituted with one or more groups independently selected from: C C4 alkyl; halogen; -CF3; -CN; -OH; -0(C C4 alkyl); C C4 alkyl substituted with one or more -OH groups; -NH2; -NH(d-C4 alkyl); or -N(Ci-C4 alkyl)(Ci-C4 alkyl);
R5 is heteroaryl which is optionally substituted with one or more groups independently selected from R7, halogen, -CN, -NR7R8, -CONR7R8, -COR7, -OR7, -SR7, -SOR7, -S02R7, - S02NR7R8, -NR7COR8, -NR7S02R8, -OCOR7, or -COOR7;
R6 is selected from C1-C4 alkyl, cycloalkyi, or heterocycloalkyi, wherein said C1-C4 alkyl is optionally substituted with one or more groups independently selected from cycloalkyi, halogen, -CF3, -CN, -OH or -0(Ci-C4 alkyl), and further wherein, if R6 is cycloalkyi or heterocycloalkyi, then said cycloalkyi and said heterocycloalkyi are each optionally substituted with one or more groups independently selected from C1-C4 alkyl, cycloalkyi, halogen, -CF3, -CN, -OH or -0(C C4 alkyl); and each R7, R8 and R9 is independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, cycloalkyi, cycloalkenyl, heterocycloalkyi, heterocycloalkenyl, aryl or heteroaryl, wherein said C1-C4 alkyl and said C2-C4 alkenyl are each optionally substituted with one or more groups independently selected from halogen, -CF3, -CN, cycloalkyi, cycloalkenyl, heterocycloalkyi, heterocycloalkenyl, aryl, heteroaryl, -OH, -0(C C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(C C4 alkyl)(Ci-C4 alkyl), and further wherein, if R7, R8 or R9 is cycloalkyi, cycloalkenyl, heterocycloalkyi, heterocycloalkenyl, aryl or heteroaryl, then said cycloalkyi, said cycloalkenyl, said heterocycloalkyi, said heterocycloalkenyl, said aryl and said heteroaryl are each optionally substituted with one or more groups independently selected from: C1-C4 alkyl; halogen; -CF3; -CN; -OH; -0(Ci-C4 alkyl); C1-C4 alkyl substituted with one or more -OH groups; -NH2; -NH(d-C4 alkyl); or -N(C C4 alkyl)(C C4 alkyl); or a pharmaceutically acceptable salt, solvate or prodrug thereof for use as a medicament.
A compound of formula (I
Figure imgf000052_0001
wherein:
A is N or -CH;
R1, R2 and R4 are each independently selected from R7, halogen, - CN, -OR7, -NR7R8, -COOR7, -SO3H, -B(OH)2, -CONR7R8, - COR7, -SR7, -SOR7, -SO2R7, -S02NR7R8, -NR7COR8, NR7S02R8, -OCOR7, -NR7C(0)NR8R9, -NR7C(S)NR8R9, -NR7COOR8, aryl, or heteroaryl, wherein said aryl and said heteroaryl are each substituted with one or more groups independently selected from R7, halogen, -CN, - OR7, -NR7R8, -COOR7, -SO3H, -B(OH)2, -CONR7R8, -COR7, -SR7, - SOR7, -S02R7, -S02NR7R8, -NR7COR8, -NR7S02R8, -OCOR7, -NR7C(0)NR8R9, - NR7C(S)NR8R9, or -NR7COOR8;
R3 is selected from hydrogen, halogen, -CN, -OR7, NR7R8, -COOR7, -SO3H, -B(OH)2, -CONR7R8, -COR7, -SR7, - SOR7, -S02R7, -S02NR7R8, -NR7COR8, -NR7S02R8, -OCOR7, -NR7C(0)NR8R9, - NR7C(S)NR8R9, -NR7COOR8, C C4 alkyl, C2-C4 alkenyl, cycloalkyi or heterocycloalkyi, wherein said CrC4 alkyl and said C2-C4 alkenyl are each optionally substituted with one or more groups independently selected from halogen, -CF3, -CN, -OH, -0(C C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(C C4 alkyl)(Ci-C4 alkyl), and further wherein said cycloalkyi and said heterocycloalkyi are each optionally substituted with one or more groups independently selected from: C C4 alkyl; halogen; -CF3; -CN; -OH; -0(C C4 alkyl); C C4 alkyl substituted with one or more -OH groups; -NH2; -NH(d-C4 alkyl); or -N(Ci-C4 alkyl)(Ci-C4 alkyl);
R5 is heteroaryl which is optionally substituted with one or more groups independently selected from R7, halogen, -CN, -NR7R8, -CONR7R8, -COR7, -OR7, -SR7, -SOR7, -S02R7, - S02NR7R8, -NR7COR8, -NR7S02R8, -OCOR7, or -COOR7;
R6 is selected from C1-C4 alkyl, cycloalkyi, or heterocycloalkyi, wherein said C1-C4 alkyl is optionally substituted with one or more groups independently selected from cycloalkyi, halogen, -CF3, -CN, -OH or -0(Ci-C4 alkyl), and further wherein, if R6 is cycloalkyi or heterocycloalkyi, then said cycloalkyi and said heterocycloalkyi are each optionally substituted with one or more groups independently selected from C1-C4 alkyl, cycloalkyi, halogen, -CF3, -CN, -OH or -0(C C4 alkyl); and each R7, R8 and R9 is independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, cycloalkyi, cycloalkenyl, heterocycloalkyi, heterocycloalkenyl, aryl or heteroaryl, wherein said C1-C4 alkyl and said C2-C4 alkenyl are each optionally substituted with one or more groups independently selected from halogen, -CF3, -CN, cycloalkyi, cycloalkenyl, heterocycloalkyi, heterocycloalkenyl, aryl, heteroaryl, -OH, -0(C C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(C C4 alkyl)(Ci-C4 alkyl), and further wherein, if R7, R8 or R9 is cycloalkyi, cycloalkenyl, heterocycloalkyi, heterocycloalkenyl, aryl or heteroaryl, then said cycloalkyi, said cycloalkenyl, said heterocycloalkyi, said heterocycloalkenyl, said aryl and said heteroaryl are each optionally substituted with one or more groups independently selected from: C1-C4 alkyl; halogen; -CF3; -CN; -OH; -0(Ci-C4 alkyl); C1-C4 alkyl substituted with one or more -OH groups; -NH2; -NH(Ci-C4 alkyl); or -N(C C4 alkyl)(C C4 alkyl); or a pharmaceutically acceptable salt, solvate or prodrug thereof; with the proviso that the following compounds are excluded:
8-bromo-2-furan-2-yl-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
8-bromo-2-(2,6-dimethyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 8-bromo-4-methyl-2-(1-methyl-1 H-pyrazol-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 8-bromo-4-methyl-2-(1-ethyl-1 H-pyrazol-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 8-bromo-2-(2-methyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
8-bromo-4-methyl-2-pyridin-3-yl-4H-pyrazolo[1 ,5-a]quinazolin-5-one; and
8-bromo-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one.
A compound of formula (I
Figure imgf000054_0001
wherein:
A is N or -CH; R1, R2 and R4 are each independently selected from R7, halogen, -
CN, -OR7, -NR7R8, -COOR7, -S03H, -B(OH)2, -CONR7R8, - COR7, -SR7, -SOR7, -S02R7, -S02NR7R8, -NR7COR8, NR7S02R8, -OCOR7, -NR7C(0)NR8R9, -NR7C(S)NR8R9, -NR7COOR8, aryl, or heteroaryl, wherein said aryl and said heteroaryl are each substituted with one or more groups independently selected from R7, halogen, -CN, -
OR7, -NR7R8, -COOR7, -S03H, -B(OH)2, -CONR7R8, -COR7, -SR7, - SOR7, -S02R7, -S02NR7R8, -NR7COR8, -NR7S02R8, -OCOR7, -NR7C(0)NR8R9, - NR7C(S)NR8R9, or -NR7COOR8;
R3 is selected from hydrogen, -F, -CI, -I, -CN, -OR7, -NR7R8, -COOR7, - S03H, -B(OH)2, -CONR7R8, COR7, -SR7, -SOR7, -S02R7, -S02NR7R8, -NR7COR8, -NR7S02R8, -OCOR7, - NR7C(0)NR8R9, -NR7C(S)NR8R9, -NR7COOR8, C1-C4 alkyl, C2-C4 alkenyl, cycloalkyi or heterocycloalkyi, wherein said C1-C4 alkyl and said C2-C4 alkenyl are each optionally substituted with one or more groups independently selected from halogen, -CF3, -CN, -OH, -0(C C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(C C4 alkyl)(Ci-C4 alkyl), and further wherein said cycloalkyi and said heterocycloalkyi are each optionally substituted with one or more groups independently selected from: C1-C4 alkyl; halogen; -CF3; -CN; -OH; -0(Ci-C4 alkyl); C1-C4 alkyl substituted with one or more -OH groups; -NH2; -NH(d-C4 alkyl); or -N(C C4 alkyl)(C C4 alkyl);
R5 is heteroaryl which is optionally substituted with one or more groups independently selected from R7, halogen, -CN, -NR7R8, -CONR7R8, -COR7, -OR7, -SR7, -SOR7, -S02R7, - S02NR7R8, -NR7COR8, -NR7S02R8, -OCOR7, or -COOR7;
R6 is selected from C1-C4 alkyl, cycloalkyi, or heterocycloalkyi, wherein said C1-C4 alkyl is optionally substituted with one or more groups independently selected from cycloalkyi, halogen, -CF3, -CN, -OH or -0(Ci-C4 alkyl), and further wherein, if R6 is cycloalkyi or heterocycloalkyi, then said cycloalkyi and said heterocycloalkyi are each optionally substituted with one or more groups independently selected from C1-C4 alkyl, cycloalkyi, halogen, -CF3, -CN, -OH or -0(C C4 alkyl); and each R7, R8 and R9 is independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, cycloalkyi, cycloalkenyl, heterocycloalkyi, heterocycloalkenyl, aryl or heteroaryl, wherein said C1-C4 alkyl and said C2-C4 alkenyl are each optionally substituted with one or more groups independently selected from halogen, -CF3, -CN, cycloalkyi, cycloalkenyl, heterocycloalkyi, heterocycloalkenyl, aryl, heteroaryl, -OH, -0(C C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(C C4 alkyl)(Ci-C4 alkyl), and further wherein, if R7, R8 or R9 is cycloalkyi, cycloalkenyl, heterocycloalkyi, heterocycloalkenyl, aryl or heteroaryl, then said cycloalkyi, said cycloalkenyl, said heterocycloalkyi, said heterocycloalkenyl, said aryl and said heteroaryl are each optionally substituted with one or more groups independently selected from: C1-C4 alkyl; halogen; -CF3; -CN; -OH; -0(Ci-C4 alkyl); C1-C4 alkyl substituted with one or more -OH groups; -NH2; -NH(Ci-C4 alkyl); or -N(C C4 alkyl)(C C4 alkyl); or a pharmaceutically acceptable salt, solvate or prodrug thereof.
The compound for use according to item 1 or the compound of item 2, wherein R3 is selected from hydrogen, halogen, C1-C4 haloalkyl, Ci-C4 haloalkoxy, -CN, Ci-C4 alkyl, cycloalkyl, heterocycloalkyl, -OH, -0(Ci-C4 alkyl), -O-cycloalkyl, -O-heterocycloalkyl, -NH2, -NH(C C4 alkyl), -N(C C4 alkyl)(C C4 alkyl), -NH-cycloalkyl, -N(C C4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(C C4 alkyl)-heterocycloalkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-NH2, -CO-NH(Ci-C4 alkyl), -CO-N(Ci-C4 alkyl)(Ci-C4 alkyl), -CO-NH-cycloalkyl, -CO-N(Ci-C4 alkyl)-cycloalkyl, -CO-NH-heterocycloalkyl, -CO-N(Ci-C4 alkyl)-heterocycloalkyl, -NH-CO-cycloalkyl, -N(C C4 alkyl)-
CO-cycloalkyl, -NH-CO-heterocycloalkyl, or -N(Ci-C4 alkyl)-CO-heterocycloalkyl, wherein said cycloalkyl, said heterocycloalkyl, the cycloalkyl moiety comprised in any of the aforementioned groups, and the heterocycloalkyl moiety comprised in any of the aforementioned groups are each optionally substituted with one or more groups independently selected from: C C4 alkyl; halogen; -CF3; -CN; -OH; -0(Ci-C4 alkyl); d- C4 alkyl substituted with one or more -OH groups; -NH2; -NH(Ci-C4 alkyl); or -N(Ci-C4 alkyl)(Ci-C4 alkyl).
The compound for use according to item 1 or 4 or the compound of item 2 or 4, wherein R3 is selected from hydrogen, halogen, Ci-C4 haloalkyl, -CN, heterocycloalkyl, -0(Ci-C4 alkyl), -NH(C C4 alkyl), or -CO-N(C C4 alkyl)(C C4 alkyl), wherein said heterocycloalkyl is optionally substituted with one or more groups independently selected from: C C4 alkyl; halogen; -CF3; -CN; -OH; -0(C C4 alkyl); C C4 alkyl substituted with one or more -OH groups; -NH2; -NH(Ci-C4 alkyl); or -N(Ci-C4 alkyl)(Ci- C4 alkyl).
The compound of item 3, wherein R3 is selected from hydrogen, -F, -CI, -I, Ci-C4 haloalkyl, Ci-C4 haloalkoxy, -CN, C C4 alkyl, cycloalkyl, heterocycloalkyl, -OH, -0(Ci- C4 alkyl), -O-cycloalkyl, -O-heterocycloalkyl, -NH2, -NH(C C4 alkyl), -N(C C4 alkyl)(C C4 alkyl), -NH-cycloalkyl, -N(C C4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(C C4 alkyl)-heterocycloalkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-NH2, -CO-NH(C C4 alkyl), -CO-N(C C4 alkyl)(Ci-C4 alkyl), -CO-NH-cycloalkyl, -CO-N(C C4 alkyl)-cycloalkyl, -CO-NH-heterocycloalkyl, -CO-N(C C4 alkyl)-heterocycloalkyl, -NH-CO-cycloalkyl, -N(C C4 alkyl)-
CO-cycloalkyl, -NH-CO-heterocycloalkyl, or -N(Ci-C4 alkyl)-CO-heterocycloalkyl, wherein said cycloalkyl, said heterocycloalkyl, the cycloalkyl moiety comprised in any of the aforementioned groups, and the heterocycloalkyl moiety comprised in any of the aforementioned groups are each optionally substituted with one or more groups independently selected from: C1-C4 alkyl; halogen; -CF3; -CN; -OH; -0(Ci-C4 alkyl); d- C4 alkyl substituted with one or more -OH groups; -NH2; -NH(Ci-C4 alkyl); or -N(Ci-C4 alkyl)(Ci-C4 alkyl).
The compound of item 3 or 6, wherein R3 is selected from hydrogen, -F, -CI, C1-C4 haloalkyl, -CN, heterocycloalkyl, -0(d-C4 alkyl), -NH(C C4 alkyl), or -CO-N(Ci-C4 alkyl)(Ci-C4 alkyl), wherein said heterocycloalkyl is optionally substituted with one or more groups independently selected from: C1-C4 alkyl; halogen; -CF3; -CN; -OH; -0(Ci- C4 alkyl); C1-C4 alkyl substituted with one or more -OH groups; -NH2; -NH(Ci-C4 alkyl); or -N(Ci-C4 alkyl)(C C4 alkyl).
The compound for use according to any one of items 1 or 4 to 7 or the compound of any one of items 2 to 7, wherein R1, R2 and R4 are each independently selected from hydrogen, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, C1-C4 alkyl, C2-C4 alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -0(Ci-C4 alkyl), -0-(Ci-C4 alkylene)-OH, -0-(d-C4 alkylene)-0(C C4 alkyl), -O-cycloalkyl, -0-(d-C4 alkylene)-cycloalkyl, -O-heterocycloalkyl, -0-(Ci-C4 alkylene)-heterocycloalkyl, -O-aryl, -0-(Ci-C4 alkylene)-aryl, -O-heteroaryl, -0-(Ci-C4 alkylene)-heteroaryl, -NH2, -NH(C C4 alkyl), -N(C C4 alkyl)(d-C4 alkyl), -NH-cycloalkyl, -N(d-C4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(d-C4 alkyl)-heterocycloalkyl, -NH-(C C4 alkylene)-cycloalkyl, -N(d-C4 alkyl)-(d-C4 alkylene)-cycloalkyl, -NH-(d-C4 alkylene)-heterocycloalkyl, -N(d-C4 alkyl)-(d-C4 alkylene)-heterocycloalkyl, -NH-aryl, -N(d-C4 alkyl)-aryl, -NH-heteroaryl, -N(d-C4 alkyl)-heteroaryl, -NH-(C C4 alkylene)-aryl, -N(C C4 alkyl)-(d-C4 alkylene)-aryl, -NH-(C C4 alkylene)-heteroaryl, -N(C C4 alkyl)-(d-C4 alkylene)-heteroaryl, -CO-(C C4 alkyl), -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-(C C4 alkylene)-cycloalkyl, -CO-(Ci-C4 alkylene)-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, -CO-(Ci-C4 alkylene)-aryl, -CO-(d-C4 alkylene)-heteroaryl, -CO-NH2, -CO-NH(d-C4 alkyl), -CO- N(Ci-C4 alkyl)(Ci-C4 alkyl), -CO-NH-cycloalkyl, -CO-N(d-C4 alkyl)-cycloalkyl, -CO- NH-(Ci-C4 alkylene)-cycloalkyl, -CO-N(C C4 alkyl)-(d-C4 alkylene)-cycloalkyl, -CO- NH-heterocycloalkyl, -CO-N(C C4 alkyl)-heterocycloalkyl, -CO-NH-(C C4 alkylene)- heterocycloalkyl, -CO-N(d-C4 alkyl)-(d-C4 alkylene)-heterocycloalkyl, -CO- NH-aryl, -CO-N(C C4 alkyl)-aryl, -CO-NH-(C C4 alkylene)-aryl, -CO-N(C C4 alkyl)-(C C4 alkylene)-aryl, -CO-NH-heteroaryl, -CO-N(C C4 alkyl)-heteroaryl, -CO-NH-(Ci-C4 alkylene)-heteroaryl, -CO-N(C C4 alkyl)-(Ci-C4 alkylene)-heteroaryl, -NH-CHO, -N(C C4 alkyl)-CHO, -NH-CO(C C4 alkyl), -N(C C4 alkyl)-CO(Ci-C4 alkyl), -NH-CO-cycloalkyl, -N(C C4 alkyl)-CO-cycloalkyl, -NH-CO-(C C4 alkylene)- cycloalkyl, -N(Ci-C4 alkyl)-CO-(C C4 alkylene)- cycloalkyl, -NH-CO-heterocycloalkyl, -N(C C4 alkyl)-CO-heterocycloalkyl, -NH-CO-(C C4 alkylene)-heterocycloalkyl, -N(Ci-C4 alkyl)-CO-(C C4 alkylene)- heterocycloalkyl, -NH-CO-aryl, -N(C C4 alkyl)-CO-aryl, -NH-CO-(C C4 alkylene)- aryl, -N(C C4 alkyl)-CO-(C C4 alkylene)-aryl, -NH-CO-heteroaryl, -N(Ci-C4 alkyl)- CO-heteroaryl, -NH-CO-(d-C4 alkylene)-heteroaryl, or -N(C C4 alkyl)-CO-(Ci-C4 alkylene)-heteroaryl, wherein said aryl, said heteroaryl, the aryl moiety comprised in any of the aforementioned groups, and the heteroaryl moiety comprised in any of the aforementioned groups are each optionally substituted with one or more groups independently selected from Ci-C4 alkyl, halogen, -CF3, -CN, -OH, -0(Ci-C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(C C4 alkyl)(C C4 alkyl).
The compound for use according to any one of items 1 or 4 to 8 or the compound of any one of items 2 to 8, wherein R1, R2 and R4 are each independently selected from hydrogen, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, Ci-C4 alkyl, -OH, -0(Ci-C4 alkyl), -NH(C C4 alkyl), or -N(C C4 alkyl)(C C4 alkyl).
The compound for use according to any one of items 1 or 4 to 9 or the compound of any one of items 2 to 9, wherein R5 is heteroaryl having 5 or 6 ring members and comprising one or more ring heteroatoms independently selected from O, S or N, wherein said heteroaryl having 5 or 6 ring members is optionally substituted with one or more groups independently selected from C1-C4 alkyl, C2-C4 alkenyl, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, - OH, -0(Ci-C4 alkyl), -O-cycloalkyl, -0-(d-C4 alkylene)-cycloalkyl, -O-heterocycloalkyl, -0-(Ci-C4 alkylene)-heterocycloalkyl, -NH2, -NH(C C4 alkyl), -N(C C4 alkyl)(Ci-C4 alkyl), -NH-cycloalkyl, -N(C C4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(C C4 alkyl)-heterocycloalkyl, -NH-(C C4 alkylene)-cycloalkyl, -N(Ci-C4 alkyl)-(Ci-C4 alkylene)-cycloalkyl, -NH-(Ci-C4 alkylene)-heterocycloalkyl, -N(Ci-C4 alkyl)-(Ci-C4 alkylene)-heterocycloalkyl, -CO-(Ci-C4 alkyl), -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-(CrC4 alkylene)-cycloalkyl, or -CO-(Ci-C4 alkylene)-heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, the cycloalkyl moiety comprised in any of the aforementioned groups, and the heterocycloalkyl moiety comprised in any of the aforementioned groups are each optionally substituted with one or more groups independently selected from C1-C4 alkyl, halogen, -CF3, -CN, -OH, -0(Ci-C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(C C4 alkyl)(C C4 alkyl).
1 1 . The compound for use according to any one of items 1 or 4 to 10 or the compound of any one of items 2 to 10, wherein R5 is pyridinyl which is optionally substituted with one or more groups independently selected from C1-C4 alkyl, C2-C4 alkenyl, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -0(d-C4 alkyl), -O-cycloalkyl, -0-(d-C4 alkylene)-cycloalkyl, -O-heterocycloalkyl, -0-(Ci-C4 alkylene)-heterocycloalkyl, -NH2, -NH(C C4 alkyl), -N(C C4 alkyl)(Ci-C4 alkyl), -NH-cycloalkyl, -N(Ci-C4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(Ci-C4 alkyl)-heterocycloalkyl, -NH-(C C4 alkylene)-cycloalkyl, -N(Ci-C4 alkyl)-(Ci-C4 alkylene)-cycloalkyl, -NH-(Ci-C4 alkylene)-heterocycloalkyl, -N(Ci-C4 alkyl)-(Ci-C4 alkylene)-heterocycloalkyl, -CO-(Ci-C4 alkyl), -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-(CrC4 alkylene)-cycloalkyl, or -CO-(Ci-C4 alkylene)-heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, the cycloalkyl moiety comprised in any of the aforementioned groups, and the heterocycloalkyl moiety comprised in any of the aforementioned groups are each optionally substituted with one or more groups independently selected from C1-C4 alkyl, halogen, -CF3, -CN, -OH, -0(Ci-C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(C C4 alkyl)(C C4 alkyl). 12. The compound for use according to any one of items 1 or 4 to 1 1 or the compound of any one of items 2 to 1 1 , wherein R5 is pyridin-4-yl which is substituted with one substituent group at position 2 of said pyridin-4-yl or with two substituent groups at position 2 and 6 of said pyridin-4-yl, wherein said one or two substituent group(s) is/are selected independently from C1-C4 alkyl, C2-C4 alkenyl, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, cycloalkyl, heterocycloalkyl, -0(Ci-C4 alkyl), -O-cycloalkyl, or -O-heterocycloalkyl.
13. The compound for use according to any one of items 1 or 4 to 12 or the compound of any one of items 2 to 12, wherein R5 is pyridin-4-yl which is substituted with one substituent group at position 2 of said pyridin-4-yl, wherein said substituent group is selected from C1-C4 alkyl, C2-C4 alkenyl, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, cycloalkyl, heterocycloalkyl, -0(Ci-C4 alkyl), -O-cycloalkyl, or -O-heterocycloalkyl. The compound for use according to any one of items 1 or 4 to 13 or the compound of any one of items 2 to 13, wherein R5 is 2-trifluoromethyl-pyridin-4-yl. The compound for use according to any one of items 1 or 4 to 14 or the compound of any one of items 2 to 14, wherein R6 is CrC4 alkyl which is optionally substituted with one or more groups independently selected from cycloalkyl, halogen, -CF3, -CN, -OH or -0(Ci-C4 alkyl). The compound for use according to any one of items 1 or 4 to 15 or the compound of any one of items 2 to 15, wherein R6 is methyl. The compound for use according to any one of items 1 or 4 to 16 or the compound of any one of items 2 to 16, wherein A is N. The compound for use according to item 1 or the compound of item 2, wherein said compound is selected from:
2-(2-chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl 2-(2-methyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-ethyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-propyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-cyclopropyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-cyclobutyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-cyclopentyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-cyclohexyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl-2-(2-vinyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-isopropenyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-isopropyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-(4-methyl-5-oxo-4,5-dihydro-pyrazolo[1 ,5-a]quinazolin-2-yl)-pyridine-2-carbonitrile;
2-(2-fluoro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-methoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-ethoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-isopropoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-cyclobutoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl-2-[2-(oxetan-3-yloxy)-pyridin-4-yl]-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-cyclopropylmethoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 2-[2-(2-methoxy-ethoxy)-pyridin-4-yl]-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl-2-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl-2-[2-(2,2-difluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-[2-(2,2-difluoro-propoxy)-pyridin-4-yl]-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl-2-[2-(2,2,3,3,3-pentafluoro-propoxy)-pyridin-4-yl]-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
4-methyl-2-[2-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl(D3)-2-(2-tnfluoromethyl-pyridin-4-yl)-4l-l-pyrazolo[1 ,5-a]quinazoliri-5-one;
4-ethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-(2,2-difluoro-ethyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
4-(2-methoxy-ethyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
4-methyl-2-(2-difluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-[2-(1 , 1-difluoro-ethyl)-pyridin-4-yl]-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-[2-(1 , 1-difluoro-ethyl)-pyridin-4-yl]-4-methyl(D3)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-chloro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-methoxy-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-trifluoromethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-on
7-fluoro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-bromo-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4- methyl-7-methylamino-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin
5- one;
4-methyl-7-methyl(D3)amino-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
N-[4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5- a]quinazolin-7-yl]-acetamide;
7-amino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-dimethylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
7-ethylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
7-cyclobutylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one; 4-methyl-7-morpholin-4-yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
7-hydroxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
7-ethoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-(2-methoxy-ethoxy)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
4-methyl-7-(2-morpholin-4-yl-ethoxy)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
4-methyl-7-trifluoromethoxy-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
7- methanesulfonyl-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
8- methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
8-fluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 8-chloro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 4-methyl-8-trifluoromethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
8-bromo-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl-8-morpholin-4-yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
4- methyl-8-pyrrolidin-1-yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-
5- one;
4- methyl-8-methylamino-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin
5- one;
8-(4-methoxy-piperidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
8-(4-hydroxy-piperidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
8-dimethylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
4-methyl-8-(4-methyl-piperazin-1 -yl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
4- methyl-8-piperazin-1-yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-
5- one; 8-(4-hydroxymethyl-piperidin-1 -yl)-4-methyl-2-(2-trifl^
pyrazolo[1 ,5-a]quinazoin-5-one;
8-(3-hydroxy-azetidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
8-(3-hydroxymethyl-azetidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H- pyrazolo[1 ,5-a]quinazolin-5-one;
8-(3-hydroxy-pyrrolidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
8-(4-hydroxy-4-methyl-piperidin-1 -yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H- pyrazolo[1 ,5-a]quinazolin-5-one;
4,8-dimethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
8-cyclopropyl-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
8-cyclopentyl-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5-a]quinazoline- 8-carbonitrile;
4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5-a]quinazoline- 8-carboxylic acid;
4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5-a]quinazoline- 8-carboxylic acid amide;
4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5-a]quinazoline- 8-carboxylic acid methylamide;
4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5-a]quinazoline- 8-carboxylic acid dimethylamide;
4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5-a]quinazoline- 8-carboxylic acid diethylamide;
4-methyl-8-(morpholine-4-carbonyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
4-methyl-8-(pyrrolidine-1-carbonyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
8-(2-hydroxy-ethoxy)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
4-methyl-6-trifluoromethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
6-fluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 9-methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
7,8-dimethoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin- 5-one;
7,8-difluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
8-fluoro-7-methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
8-(4-hydroxy-piperidin-1-yl)-7-methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H- pyrazolo[1 ,5-a]quinazolin-5-one;
8-dimethylamino-7-fluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
7-bromo-8-fluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
7- bromo-8-methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
8- methoxy-4-methyl-7-methylamino-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
7-chloro-2-(2-chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-chloro-2-(2-chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-chloro-2-(2-Fluoro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-chloro-4-methyl-2-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
2-(2-chloro-pyridin-4-yl)-7-methoxy-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-cyclopropyl-pyridin-4-yl)-7-methoxy-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-fluoro-pyridin-4-yl)-7-methoxy-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7- methoxy-4-methyl-2-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
4-methyl-2-(1-methyl-1 H-pyrazol-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl-2-pyridin-4-yl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-chloro-6-methyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-cyclopropyl-6-methyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(3-fluoro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(3-chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl-2-(3-methyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
8- (3-Hydroxy-azetidine-1-carbonyl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H- pyrazolo[1 ,5-a]quinazolin-5-one; 8-(3-Hydroxy-propoxy)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
2-(2-Cyclopropyl-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 2-(2-Cyclopropyl-pyridin-4-yl)-8-(4-hydroxy-piperidin-1 -yl)-4-methyl-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
2-(2-Difluoromethyl-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 2-(2-Difluoromethyl-pyridin-4-yl)-8-(4-hydroxy-piperidin-1-yl)-4-methyl-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
2-(2-Cyclobutyl-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 2-(2-Chloro-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2- (2-Chloro-pyridin-4-yl)-8-(4-hydroxy-piperidin-1-yl)-4-methyl-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
7-Fluoro-8-(3-hydroxy-azetidin-1 -yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H- pyrazolo[1 ,5-a]quinazolin-5-one;
7-Fluoro-4-methyl-8-(oxetan-3-yloxy)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
3- [7-Fluoro-4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5- a]quinazolin-8-ylamino]-propionitrile;
7-Fluoro-8-(2-hydroxymethyl-pyrrolidin-1 -yl)-4-methyl-2-(2-trifluoromethyl-pyridi 4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7- Fluoro-8-(7-hydroxymethyl-1 -aza-spiro[3.5]non-1 -yl)-4-methyl-2-(2-trifluoromethyl- pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
8- (3-Hydroxy-piperidin-1 -yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo a]quinazolin-5-one;
8-(2,6-Dimethyl-morpholin-4-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-y ^
pyrazolo[1 ,5-a]quinazolin-5-one;
8-(2-Hydroxy-2-methyl-propylamino)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4 pyrazolo[1 ,5-a]quinazolin-5-one; and
pharmaceutically acceptable salts, solvates and prodrugs thereoof.
A pharmaceutical composition comprising a compound as defined in any one of items 1 to 18 or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable excipient.
20. A compound as defined in any one of items 1 to 18 or a pharmaceutically acceptable salt, solvate or prodrug thereof or the pharmaceutical composition of item 19 for use in the treatment and/or prophylaxis of conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling.
21 . Use of a compound as defined in any one of items 1 to 18 or a pharmaceutically acceptable salt, solvate or prodrug thereof for the preparation of a medicament for the treatment and/or prophylaxis of conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling. 22. A method of treating and/or preventing a condition associated with altered glutamatergic signalling and/or functions, and/or a condition which can be affected by alteration of glutamate level or signalling, the method comprising the administration of a compound as defined in any one of items 1 to 18 or a pharmaceutically acceptable salt, solvate or prodrug thereof or the pharmaceutical composition of item 19 to a subject in need of such treatment or prevention.
23. The compound for use according to item 20 or the pharmaceutical composition for use according to item 20 or the use of item 21 or the method of item 22, wherein the condition to be treated or prevented is selected from: epilepsy; dementias; parkinsonism and movement disorders; motor neuron disease or amyotrophic lateral sclerosis; neurodegenerative and/or hereditary disorders of the nervous system; disorders of the peripheral nervous system; multiple sclerosis and other demyelinating diseases of the nervous system; infantile cerebral palsy; paralytic syndromes including hemiplegia and hemiparesis; cerebrovascular disorders; migraine; headache; myoneural disorders; disorders of the eye and visual pathways; intracranial trauma/injury and their sequels; trauma/injury to nerves and spinal cord and their sequels; poisoning and toxic effects of nonmedicinal substances; accidental poisoning by drugs, medicinal substances and biologicals acting on the central, peripheral and autonomic system; neurological and psychiatric adverse effects of drugs, medicinal and biological substances; disturbance of sphincter control and sexual function; mental disorders; delirium and cognitive disorders; substance related disorders; schizophrenia and psychotic disorders; mood disorders; anxiety disorders; eating disorders; sleep disorders and sleep/wake disorders; medication-induced movement disorders; endocrine and metabolic diseases; acute and chronic pain; nausea and vomiting; irritable bowel syndrome; cancers; or autism spectrum disorders.
24. The compound for use according to item 20 or 23 or the pharmaceutical composition for use according to item 20 or 23 or the use of item 21 or 23 or the method of item 22 or 23, wherein the condition to be treated or prevented is selected from: dementias; parkinsonism and movement disorders; acute or chronic pain; anxiety disorders; schizophrenia; mood disorders; endocrine or metabolic diseases; or cancers. The compound for use according to item 24 or the pharmaceutical composition for use according to item 24 or the use of item 24 or the method of item 24, wherein said dementias are selected from: dementias of the Alzheimer's type (DAT); Alzheimer's disease; Pick's disease; vascular dementias; Lewy-body disease; dementias due to metabolic, toxic and deficiency diseases, including alcoholism, hypothyroidism, and vitamin B12 deficiency; AIDS-dementia complex; Creutzfeld-Jacob disease; or atypical subacute spongiform encephalopathy. The compound for use according to item 24 or the pharmaceutical composition for use according to item 24 or the use of item 24 or the method of item 24, wherein said parkinsonism and movement disorders are selected from: Parkinson's disease; multiple system atrophy; progressive supranuclear palsy; corticobasal degeneration; hepatolenticular degeneration; chorea, including Huntington's disease and hemiballismus; athetosis; dystonias, including spasmodic torticollis, occupational movement disorder, and Gilles de la Tourette syndrome; tardive or drug induced dyskinesias; tremor; or myoclonus. The compound for use according to item 24 or the pharmaceutical composition for use according to item 24 or the use of item 24 or the method of item 24, wherein said anxiety disorders are selected from: panic disorders, phobias, obsessive-compulsive disorders, stress disorders, or generalized anxiety disorders. The compound for use according to item 24 or the pharmaceutical composition for use according to item 24 or the use of item 24 or the method of item 24, wherein said mood disorders are selected from depressive disorders or bipolar disorders. The compound for use according to item 24 or the pharmaceutical composition for use according to item 24 or the use of item 24 or the method of item 24, wherein said endocrine or metabolic diseases are selected from diabetes, disorders of the endocrine glands, or hypoglycaemia.
The compound for use according to item 24 or the pharmaceutical composition for use according to item 24 or the use of item 24 or the method of item 24, wherein said cancers are selected from gliomas, colorectal cancer, melanoma, or prostate cancer.
31 . A compound as defined in any one of items 1 to 18 or a pharmaceutically acceptable salt, solvate or prodrug thereof or the pharmaceutical composition of item 19 for use in the treatment and/or prophylaxis of Alzheimer's disease.
32. Use of a compound as defined in any one of items 1 to 18 or a pharmaceutically acceptable salt, solvate or prodrug thereof for the preparation of a medicament for the treatment and/or prophylaxis of Alzheimer's disease.
33. A method of treating and/or preventing Alzheimer's disease, the method comprising the administration of a compound as defined in any one of items 1 to 18 or a pharmaceutically acceptable salt, solvate or prodrug thereof or the pharmaceutical composition of item 19 to a subject in need of such treatment or prevention.
34. The method of any one of items 22 to 30 or 33, wherein said subject is a human.
35. A method for identifying an agent that binds to metabotropic glutamate receptor 2 (mGluR2), comprising the following steps:
(a) contacting mGluR2 with the compound of any one of items 1 to 18, wherein said compound is radio-labeled or fluorescence-labeled, under conditions that permit binding of the compound to mGluR2, thereby generating bound, labeled compound;
(b) detecting a signal that corresponds to the amount of bound, labeled compound in the absence of test agent;
(c) contacting the bound, labeled compound with a test agent;
(d) detecting a signal that corresponds to the amount of bound labeled compound in the presence of test agent; and
(e) comparing the signal detected in step (d) to the signal detected in step (b) to determine whether the test agent binds to mGluR2.
In this specification, a number of documents including patent applications and scientific literature are cited. The disclosure of these documents, while not considered relevant for the patentability of this invention, is herewith incorporated by reference in its entirety. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.
The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention.
EXAMPLES
In this section, the term "compound" is used to refer to a synthesis intermediate while the term "example" refers to a compound of general formula (I) according to the present invention.
The compounds/examples described in this section are defined by their chemical formulae and their corresponding chemical names. In case of conflict between any chemical formula and the corresponding chemical name indicated herein, the present invention relates to both the compound/example defined by the chemical formula and the compound/example defined by the chemical name.
Experimental:
Experimental section.
All reagents were commercial grade and used without further purification. Commercially available anhydrous solvents were used for reactions conducted under inert atmosphere. Microwave experiments were performed with a Biotage initiator. The microwave modulates the power in order to reach the selected temperature as fast as possible. The time of each experiment is the time at the selected temperature.
Column chromatography were performed using a Biotage isolera 4® autopurification system, with the biotage® SNAP cartridge KP-SIL. Thin layer chromatography was carried out using pre-coated silica gel F-254plate.
Reaction were monitor and molecules were characterized using a waters aquity system couple with SQD2 platform or water HPLC system couple with Waters micromass platform. The HPLC system could be used also in preparative mode.
HPLC system:
The HPLC system was a Waters platform with a 2767 sample manager, a 2525 pump, a photodiode array detector (190-400 nM). The column used was a XSelect Ci8 3.5 μΜ (4.6 x 50 mm) in analytical mode and a XSelect d8 5 μΜ (30 x 100 mm) in preparative mode. The mobile phase in both cases consisted in an appropriate gradient of A and B. A was water with 0.05 % of TFA and B was MeOH with 0.05 % of TFA. Flow rate was 1 mL per min in analytical mode and 25 ml. min in preparative mode. All LCMS were performed at room temperature. HPLC is coupled with a Waters micromass platform. All mass spectra were full-scan experiments (mass range 100-800 amu). Mass spectra were obtained using electro spray ionization.
UPLC system:
The UPLC system was a Waters Aquity platform with a photodiode array detector (190-400 nM). The column used was a Acuity CSH d8 1.7 μΜ (2.1 x 30 mm) The mobile phase consisted in a gradient of A and B. A was water with 0.025 % of TFA and B was Acetonitrile with 0.025 % of TFA. Flow rate was 0.8 ml. per min. All analysis were performed at 55°C.
UPLC is coupled with a Waters SQD2 platform. All mass spectra were full-scan experiments (mass range 100-800 amu). Mass spectra were obtained using electro spray ionization.
1H NMR spectra were recorded on a Bruker AMX-400 spectrometer. Proton chemical shifts are listed relative to residual CDCI3 (7.24 ppm), DMSO (2.50 ppm) or D20 (4.78 ppm). Splitting patterns are designated as s (singlet), d (doublet), dd (double-doublet), t (triplet), tt (triplet- trplet), td (triplet-doublet), q (quartet), quint (quintuplet), sex (sextuplet), sept (septuplet), m (multiplet), b (broad), bs (broad singlet). Melting Points are measured on a Barnstead Electrothermal 9100 and are not corrected.
Most compounds and examples, when it is possible, are triturated in Et20 or pentane before drying. General procedure I: Formation of 4H-Pyrazolo[1 ,5-a]quinazolin-5-one E from hydrazine D and activated acid A via a keto-nitrile B not isolated (cf. Scheme 1 ).
Method (i): Under anhydrous condition, to a solution of acetonitrile (2.5 equiv.) in DME (c=0.6 mol.L"1) cooled at -78°C, BuLi (1 .6N in hexane - 2.5 equiv.) was added dropwise. The mixture was stirred for 1 hour at -78°C, then a solution of the acid derivative A (acid chloride or ester - 1.0 equiv.) in DME (cf=0.15 mol.L"1) was added dropwise. The reaction mixture was stirred at - 78°C for 1 hour and then was allowed to warm to room temperature and the next step was performed.
Acetic acid (same volume as DME) was added, DME was removed under reduced pressure and hydrazine D, HCI salt (1.0 equiv.) was introduced. The reaction mixture was heat under reflux for 2 hours. After cooling, the reaction mixture was concentrated and the residue was coevaporated twice with toluene before hydrolysis with saturated aqueous NaHC03 solution. The precipitate was collected, washed with water and dried under reduced pressure at 60°C with P205 for 18 hours. Sometimes, DME was switched by THF.
Method (ii): Under anhydrous condition, to a solution of acetonitrile (2.5 equiv.) in DME (c=0.8 mol.L"1) cooled at -78°C, BuLi (1 .6N in hexane - 2.5 equiv.) was added dropwise. The mixture was stirred for 1 hour at -78°C, then a solution of the acid derivative A (acid chloride or ester - 1.0 equiv.) in DME (cf=0.15 mol.L"1) was added dropwise. The reaction mixture was stirred at - 78°C for 1 hour and then was allowed to warm to room temperature and the next step was performed.
Acetic acid (10.0 equiv.) was added and hydrazine D, HCI salt (1 .0 equiv.) was introduced. The reaction mixture was warmed for 18 hours at 100°C. After cooling, the reaction mixture was concentrated and the residue was coevaporated twice with toluene before hydrolysis with saturated aqueous NaHC03 solution. The precipitate was collected, washed with water and dried under reduced pressure at 60°C with P205 for 18 hours.
Method (iii): Under anhydrous condition, to a solution of acetonitrile (2.5 equiv.) in THF (c=0.8 mol.L"1) cooled at -78°C, BuLi (1 .6N in hexane - 2.5 equiv.) was added dropwise. The mixture was stirred for 1 hour at -78°C, then a solution of the acid derivative A (acid chloride or ester - 1.0 equiv.) in THF (cf=0.15 mol.L"1) was added dropwise. The reaction mixture was stirred at - 78°C for 1 hour, then was allowed to warm to room temperature and hydrolysed with saturated aqueous NH4CI solution and extracted with DCM. The organic layer was washed with brine, dried over MgS04 or Na2S04 and concentrated. The ketonitrile B was used in the next step without further purification and was supposed quantitative.
To a solution of ketonitrile B (1 .0 equiv.) in acetic acid (c=0.15 mol.L"1) hydrazine D, HCI salt was added (1.0 equiv.). The reaction mixture was heated for 2 Hours at 120°C. After cooling, the reaction mixture was concentrated and the residue was coevaporated twice with toluene before hydrolysis with saturated aqueous NaHC03 solution. The precipitate was collected, washed with water and dried under reduced pressure at 60°C with P205 for 18 hours. Method (iv): Under anhydrous condition, to a solution of acetonitrile (2.5 equiv.) in THF (c=0.6 mol.L"1) cooled at -78°C, BuLi (1 .6N in hexane - 2.5 equiv.) was added dropwise. The mixture was stirred for 1 hour at -78°C, then a solution of the acid derivative A (acid chloride or ester - 1.0 equiv.) in THF (cf=0.15 mol.L"1) was added dropwise. The reaction mixture was stirred at - 78°C for 1 hour, and then acetic acid (same volume as THF) was added before the mixture was allowed to warm to room temperature.
THF was removed under reduced pressure and hydrazine D, HCI salt (1.0 equiv.) was introduced. The reaction mixture was heated for 2 hours at reflux. After cooling, the reaction mixture was hydrolysed with saturated aqueous NaHC03 solution. The precipitate was collected, washed with water and dried under reduced pressure at 60°C with P205 for 18 hours. Compound 1 : 2-(2-Chloro-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one.
Compound 1 was obtained according to general procedure l(i), starting from 2-Chloro- isonicotinic acid methyl ester in presence of 2-hydrazino-benzoic acid as a beige solid in 91 % yield.
1H-NMR (400 MHz, DMSO): 6.63 (s, 1 H, Ar); 7.52-7.56 (m, 1 H, Ar); 7.89-7.94 (m, 1 H, Ar); 7.98 (dd, J 5.1 Hz, J 1.5 Hz, 1 H, Ar); 8.06 (bs 1 H, Ar); 8.18 (d, J 8.0 Hz, J 1 .3 Hz, 1 H, Ar); 8.21 (d, J 7.8 Hz, 1 H, Ar); 8.50 (d, J 5.1 Hz, 1 H, Ar). Signal for NH is not observed.
M/Z (M[35CI]+H)+ = 297.1.
General procedure II: Formation of N-substituted 4H-Pyrazolo[1 ,5-a]quinazolin-5-one G from 4H-Pyrazolo[1 ,5-a]quinazolin-5-one E in presence of electrophile F (cf. Scheme 2).
Method (i): Under anhydrous condition, to a solution of quinazolin-5-one E (1.0 equiv.) in DMF (c=0.2 molL"1) cooled by an ice bath, NaH (60% in mineral oil, 1.7 equiv.) was added in 3 portions. The mixture was stirred for 15 minutes, then the electrophile F (2.5 equiv.) was added. The ice bath was removed, and the reaction was stirred at room temperature. When the reaction is completed, the mixture was hydrolysed with saturated aqueous NH4CI solution. The precipitate was collected, washed with water, Et20 and was dried under reduced pressure at 60°C with P205 for 18 hours. Method (ii): Under anhydrous condition, to a solution of quinazolin-5-one E (1 .0 equiv.) in DMF (c=0.2 molL"1) cooled by an ice bath, tBuOK (1 .7 equiv.) was added. The mixture was stirred for 5 minutes, then the electrophile F (2.5 equiv.) was added. The ice bath was removed, and the reaction was stirred at room temperature. When the reaction is completed, the mixture was hydrolysed with saturated aqueous NH4CI solution. The precipitate was collected, washed with water, dried under reduced pressure and purified if required.
Method (iii): Under anhydrous condition, to a solution of quinazolin-5-one E (1.0 equiv.) in DMA (c=0.2 molL"1) cooled by an ice bath, NaH (in mineral oil 60%, 1.7 equiv.) was added in 3 portions. The mixture was stirred for 10 minutes, then the electrophile F (2.5 equiv.) was added. The ice bath was removed, and the reaction was stirred at room temperature. When the reaction is completed, the mixture was hydrolysed. The precipitate was collected, washed with water, a minimum amount of EtOH, Et20 and was dried under reduced pressure at 60°C with P205 for 18 hours.
Example 1 : 2-(2-Chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one
Example 1 was obtained according to general procedure ll(i), starting from
compound 1 in presence of iodomethane. The reaction mixture was stirred
at room temperature for 120 min. Example 1 was obtained as a beige
solid in 70% yield.
1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, N-CH3); 7.08 (s, 1 H, Ar); 7.54-
Figure imgf000073_0001
7.58 (m, 1 H, Ar); 7.91 -7.96 (m, 2H, Ar); 8.02 (bs, 1 H, Ar); 8.19-8.27 (m,
2H, Ar); 8.52 (d, J 5.2 Hz, 1 H, Ar).
M/Z (M[35CI]+H)+ = 31 1.1.
General procedure III: Negeshi coupling: cross-coupling reaction of a halide and an organozinc derivative.
Under inert atmosphere, a mixture of halide, (1 .0 equiv.), organozinc derivative (1 .5 - 4.0 equiv.), PdCI2(dppf)2 (0.1 equiv.) and Cul (0.2 equiv.) in Dioxane (C=0.1 molL"1) was heated for 1 hour at 80°C. After cooling, the reaction mixture was hydrolysed and extracted with EtOAc or DCM. The organic layers were combined, washed with brine, dried over MgS04, concentrated and purified to afford the product.
In some cases, the HCI salt was prepared.
General procedure IV: Formation of HCI salt
Method (i): To a solution of the free base in DCM, HCI in Et20 (2N, 5 equiv.) was added. The resulting precipitate was collected, washed with Et20 and dried at 50°C under reduced pressure with P205.
Method (ii): To a solution or suspension of the free base in MeOH, HCI in MeOH (1.25N, 5 equiv.) was added. The mixture was vigorously stirred, then concentrated. The residue was taken in Et20. The resulting solid was collected, washed with Et20 and dried at 50°C under reduced pressure with P205. Method (iii): The free base was suspended in MeOH and HCI in MeOH (1.25N, 5 equiv.) was added. The suspension was vigorously stirred, and then the solid was collected, washed with Et20 and dried at 50°C under reduced pressure with P205. Example 2: 4-methyl 2-(2-methyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one.
Example 2 was obtained according to general procedure III starting from
example 1 in presence of dimethylzinc (in toluene 2M - 1.5 equiv.).
Purification by flash-chromatography (MeOH in DCM, 0 to 10%) afforded
example 2 as a beige solid in 58% yield.
1H-NMR (400 MHz, DMSO): 2.56 (s, 3H, CCH3); 3.57 (s, 3H, NCH3);
Figure imgf000074_0001
6.96 (s, 1 H, Ar); 7.53-7.57 (m, 1 H, Ar); 7.72-7.73 (m, 1 H, Ar); 7.82 (bs,
1 H, Ar); 7.91 -7.96 (m, 1 H, Ar); 8.19-8.22 (m, 2H, Ar); 8.55-8.56 (m, 1 H, Ar).
M/Z (M+H)+ = 291.2. Example 3: 2-(2-Ethyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one, HCI salt. Example 3 was obtained according to general procedure III starting from
example 1 in presence of diethylzinc (in toluene 1 M - 1 .5 equiv.).
Purification by flash-chromatography (EtOAc in cyclohexane, 40 to 70%)
and salt formation according to procedure IV(i) afforded example 3 as a
beige solid in 52% yield.
Figure imgf000074_0002
1H-NMR (400 MHz, DMSO): 1.40 (t, 3H, J 7.6 Hz, CCH2CH3); 3.08 (Q,
2H, J 7.6 Hz, CCH2CH3); 3.58 (s, 3H, NCH3); 7.25 (s, 1 H, Ar); 7.58-7.63 (m, 1 H, Ar); 7.95-7.99 (m, 1 H, Ar); 8.21-8.30 (m, 3H, Ar); 8.37 (bs, 1 H, Ar); 8.83 (d, J 6.1 Hz, 1 H, Ar). Signal for HCI is not observed.
M/Z (M+H)+ = 305.2.
MP: >250°C.
Example 4: 2-(2-propyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one, HCI salt. Example 4 was obtained according to general procedure III starting from example 1 in presence of propylzinc bromide (in THF 0.5M - 3.0 equiv.). Purification by flash- chromatography (MeOH in DCM, 0 to 10%) and salt formation
according to procedure IV(ii) afforded example 4 as a white solid in
37% yield.
1H-NMR (400 MHz, DMSO): 0.98 (t, 3H, J 7.5 Hz, CCH2CH2CH3);
1.85 (sex, 2H, J 7.5 Hz, CCH2CH2CH3); 3.03 (q, 2H, J 7.5 Hz,
CCH2CH2CH3); 3.58 (s, 3H, NCH3); 7.24 (s, 1 H, Ar); 7.59-7.63 (m,
Figure imgf000074_0003
1 H, Ar); 7.95-7.99 (m, 1 H, Ar); 8.22-8.28 (m, 3H, Ar); 8.36 (bs, 1 H, Ar); 8.84 (d, J 6.1 Hz, 1 H, Ar). Signal for HCI salt is not observed.
M/Z (M+H)+ = 319.2.
MP: >250°C.
Example 5: 2-( 2-Cyclopropyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1, 5-a]quinazolin-5-one, HCI salt.
Example 5 was obtained according to general procedure III starting from
example 1 in presence of cyclopropylzinc bromide (in THF 0.5M - 3.0
equiv.). Purification by flash-chromatography (EtOAct in cyclohexane, 50
to 80%) and salt formation according to procedure IV(i) afforded example
5 as a beige solid in 38% yield.
Figure imgf000075_0001
1H-NMR (400 MHz, DMSO): 1 .25-1.33 (m, 4H, 2CH2); 2.42-2.47 (m, 1 H, CCH); 3.57 (s, 3H,
NCH3); 7.22 (s, 1 H, Ar); 7.57-7.61 (m, 1 H, Ar); 7.93-7.99 (m, 2H, Ar); 8.10-8.1 1 (m, 1 H, Ar); 8.20-8.25 (m, 2H, Ar); 8.67 (d, J 5.9 Hz, 1 H, Ar). Signal for HCI salt is not observed.
M/Z (M+H)+ = 317.3.
MP: 248-251 °C.
Example 6: 2-(2-cyclobutyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one, HCI salt. Example 6 was obtained according to general procedure III starting
from example 1 in presence of cyclobutylzinc bromide (in THF 0.5M -
3.0 equiv.). Purification by flash-chromatography (MeOH in DCM, 0 to
5%) and salt formation according to procedure IV(iii) afforded
example 6 as a white solid in 8% yield.
Figure imgf000075_0002
1H-NMR (400 MHz, DMSO): 1 .90-1.99 (m, 1 H, CH); 2.07-2.19 (m,
1 H, CH); 2.43-2.48 (m, 4H, 2CH2); 3.59 (s, 3H, NCH3); 3.98 (quint, J 8.9 Hz, 1 H, CH); 7.30 (s,
1 H, Ar); 7.58-7.62 (m, 1 H, Ar); 7.95-7.99 (m, 1 H, Ar); ); 8.22-8.28 (m, 3H, Ar); 8.30 (bs, 1 H,
Ar); 8.79 (d, J 5.9 Hz, 1 H, Ar). Signal for HCI salt is not observed.
M/Z (M+H)+ = 331.0.
MP: 236-244°C.
Example 7: 2-(2-cyclopentyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one, HCI salt. Example 7 was obtained according to general procedure III starting
from example 1 in presence of cyclopentylzinc bromide (in THF
0.5M - 3.0 equiv.). Purification by flash-chromatography (MeOH in
DCM, 0 to 10%) and salt formation according to procedure IV(iii)
afforded example 7 as a white solid in 9% yield.
Figure imgf000076_0001
1H-NMR (400 MHz, DMSO): 1.73-1 .77 (m, 2H, 2CH); 1.86-192 (m, 4H, 4CH); 2.18-2.24 (m, 2H, 2CH); 3.44-3.53 (m, 1 H, CH); 3.58 (s, 3H, NCH3); 7.30 (s, 1 H, Ar); 7.58-7.62 (m, 1 H, Ar); 7.94-7.99 (m, 1 H, Ar); ); 8.23 (dd, J 8.0 Hz, J 1.3 Hz, 1 H, A); 8.25-8.27 (m, 2H, Ar); 8.32 (bs, 1 H, Ar); 8.80 (d, J 5.9 Hz, 1 H, Ar). Signal for HCI salt is not observed.
M/Z (M+H)+ = 345.2.
MP: >250°C.
Example 8: 2-(2-cyclohexyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one, HCI salt.
Example 8 was obtained according to general procedure III starting
from example 1 in presence of cyclohexylzinc bromide (in THF
0.5M - 3.0 equiv.). Purification by flash-chromatography (MeOH in
DCM, 0 to 10%) and salt formation according to procedure IV(ii)
afforded example 8 as a white solid in 25% yield.
Figure imgf000076_0002
1H-NMR (400 MHz, DMSO): 1 .27-1.48 (m, 3H, 3CH); 1.66-1 .79 (m, 3H, 3CH); 1.87-1 .90 (m, 2H, 2CH); 1.99-2.02 (m, 2H, 2CH); 3.03-3.10 (m, 1 H, CH); 3.59 (s, 3H, NCH3); 7.30 (s, 1 H, Ar); 7.59-7.62 (m, 1 H, Ar); 7.95-7.99 (m, 1 H, Ar); ); 8.23 (dd, J 8.0 Hz, J 1 .1 Hz, 1 H, A); 8.26-8.28 (m, 2H, Ar); 8.31 (bs, 1 H, Ar); 8.81 (d, J 5.9 Hz, 1 H, Ar). Signal for HCI salt is not observed. M/Z (M+H)+ = 359.3.
MP: >250°C.
Example 9: 4-Methyl-2-(2-vinyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one.
Under inert atmosphere, example 1 (1.0 equiv.), potassium
vinyltrifluoroborate (2.0 equiv.), PdOAc2 (0.1 equiv.), Ruphos (0.2
equiv.) and Cs2C03 (3.0 equiv.) in a mixture of dioxanne/water (90/10)
(C=0.1 molL"1) was submitted to microwave irradiation (130°C, 20 min,
P< 70W). To the uncompleted reaction, PdCI2(dppf)2 (0.1 equiv.) and
potassium vinyltrifluoroborate (2.0 equiv.), were added and the mixture
Figure imgf000076_0003
was submitted to microwave irradiation (130°C, 20 min, P< 70W) for a second time. After cooling, the reaction mixture was hydrolysed and then extracted with EtOAc. The organic layers were combined, washed with brine, dried over MgS04, concentrated and purified by flash-chromatography (EtOAc in cyclohexane, 0 to 50%). Example 9 was obtained as a brown solid in 63% yield.
1H-NMR (400 MHz, DMSO): 3.58 (s, 3H, NCH3); 5.56 (dd, J 10.8 Hz, J 1 .6 Hz, 1 H, CH); 6.36 (dd, J 17.4 Hz, J 1 .6 Hz, 1 H, CH); 6.92 (dd, J 17.4 Hz, J 10.8 Hz, 1 H, CH); 7.02 (s, 1 H, Ar); 7.53-7.57 (m, 1 H, Ar); 7.82 (dd, J 5.1 Hz, J 1.6 Hz, 1 H, Ar); 7.92-7.96 (m, 1 H, Ar); 8.04 (bs, 1 H, Ar); 8.21 -8.23 (m, 2H, Ar); 8.66 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 303.2.
General procedure V: Suzuki coupling: cross-coupling reaction of a halide and boronic acid derivatives.
Under inert atmosphere, a mixture of halide (1 .0 equiv.), boronic acid derivative (1 .5 - equiv.), PdCI2(dppf)2 (0.1 equiv.) and aqueous Na2C03 (1 .2 M - 3.0 equiv.) in DMF (C=0.15 molL"1) was heated for 3 hours at 100°C. After cooling, the reaction mixture was hydrolysed. The precipitate was collected, washed with water, Et20, dried under reduced presure and purified to afford the product.
Example 10: 2-(2-lsopropenyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one.
Example 10 was obtained according to general procedure V starting
from example 1 in presence of Isopropenylboronic acid pinacol ester.
Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded
example 10 as a beige solid in 68% yield.
1H-NMR (400 MHz, DMSO): 2.23 (s, 3H, CCH3); 3.58 (s, 3H, NCH3);
Figure imgf000077_0001
5.40 (m, 1 H, CH); 6.04 (m, 1 H, CH); 7.08 (s, 1 H, Ar); 7.53-7.57 (m, 1 H,
Ar); 7.84 (dd, J 5.1 Hz, J 1 .4 Hz, 1 H, Ar); 7.91-7.95 (m, 1 H, Ar); 8.13 (bs, 1 H, Ar); 8.20-8.24 (m, 2H, Ar); 8.67 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 317.2.
Example 1 1 : 2-(2-lsopropyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one, HCI salt.
To a solution of example 10 (1.0 equiv.) in MeOH (C=0.05 molL"1), Pd/C
(10 % w/w) was added. The reaction mixture was purged with hydrogen
and stirred for 48 hours at 60°C under 4 bars hydrogen pressure. Catalyst
was filtered off on celite and washed with MeOH. Filtrate was
Figure imgf000077_0002
concentrated and purified by flash-chromatography (MeOH in DCM, 0 to 5%). Salt formation according to procedure IV(iii) afforded example 1 1 as a white solid in 1 1 % yield. 1H-NMR (400 MHz, DMSO): 1 .44 (d, 6H, J 7.0 Hz, CH(CH3)2); 3.44 (sept, 1 H, J 7.0 Hz, CH(CH3)2); 3.58 (s, 3H, NCH3); 7.31 (s, 1 H, Ar); 7.58-7.62 (m, 1 H, Ar); 7.95-7.99 (m, 1 H, Ar); 8.23 (dd, J 8.0 Hz, J 1.4 Hz, 1 H, Ar); 8.25-8.30 (m, 2H, Ar); 8.36 (bs, 1 H, Ar); 8.82 (d, J 6.1 Hz, 1 H, Ar). Signal for HCI salt is not observed.
M/Z (M+H)+ = 319.0.
MP: >250°C.
General procedure VI: CN introduction starting from a halide or a pseudo halide. Under inert atmosphere, a mixture of halide, (1 .0 equiv.), zinc cyanide (1 .6 - equiv.) and Pd(PPh3)4 (0.1 equiv.) in DMF (C=0.2 molL"1) was submitted to microwave irradiation (130°C, 10 min, P< 70W). After cooling, the reaction mixture was hydrolysed with a saturated aqueous K2C03 solution. The precipitate was collected, washed with water, dried under reduced pressure and purified to afford the product.
Example 12: 4-(4-Methyl-5-oxo-4, 5-dihydro-pyrazolo[1,5-a]quinazolin-2-yl)-pyridine-2- carbonitrile.
Example 12 was obtained according to general procedure VI starting
from example 1 . Purification by flash-chromatography (MeOH in DCM, 0
to 10%) afforded example 12 as a white solid in 94% yield.
1H-NMR (400 MHz, DMSO): 3.59 (s, 3H, NCH3); 7.02 (s, 1 H, Ar); 7.55-
Figure imgf000078_0001
7.59 (m, 1 H, Ar); 7.92-7.96 (m, 1 H, Ar); 8.21-8.25 (m, 3H, Ar); 8.48 (bs, 1 H, Ar); 8.85 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 302.2.
MP: >250°C.
Compound 2: 2-(2-Fluoro-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one.
Compound 2 was obtained according to general procedure l(ii), starting from 2-fluoro- isonicotinic acid methyl ester in presence of 2-hydrazino-benzoic acid as a brown solid in 83% yield.
1H-NMR (400 MHz, DMSO): 6.64 (s, 1 H, Ar); 7.53-7.57 (m, 1 H, Ar); 7.71 (bs 1 H, Ar); 7.91 -7.96 (m, 2H, Ar); 8.16-8.21 (m, 2H, Ar); 8.33 (d, J 5.2 Hz, 1 H, Ar); 12.42 (bs, 1 H, NH).
M/Z (M+H)+ = 281.3. Example 13: 2-(2-Fluoro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one. Example 13 was obtained according to general procedure ll(i), starting
from compound 2 in presence of iodomethane. The reaction mixture was
stirred at room temperature for 120 min. Example 13 was obtained as a
brown solid in 78% yield.
1H-NMR (400 MHz, DMSO): 3.57 (s, 3H, NCH3); 7.08 (s, 1 H, Ar); 7.56-
Figure imgf000079_0001
7.60 (m, 1 H, Ar); 7.70 (bs 1 H, Ar); 7.92-7.97 (m, 2H, Ar); 8.22-8.24 (m, 2H, Ar); 8.37 (d, J 5.2
Hz, 1 H, Ar).
M/Z (M+H)+ = 295.2. Example 14: 2-( 2-Methoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1, 5-a]quinazolin-5-one.
To a solution of example 13 (1.0 equiv.) in MeOH (C=0.10 molL"1) sodium
methoxyde (2.0 equiv.) was introduced. The reaction mixture was
submitted twice to microwave irradiation (150°C, 5 min.). Sodium
methoxyde (2.0 equiv.) was added and the reaction mixture was submitted
to microwave irradiation (150°C, 5 min.). After cooling, the precipitate was
Figure imgf000079_0002
collected, washed with water and Et20 and was dried under reduced pressure to afford example 14 as a white solid in 66% yield.
1H-NMR (400 MHz, DMSO): 3.56 (s, 3H, NCH3); 3.92 (s, 3H, OCH3); 6.98 (s, 1 H, Ar); 7.34 (bs, 1 H, Ar); 7.53-7.57 (m, 2H, Ar); 7.91-7.95 (m, 1 H, Ar); 8.19-8.22 (m, 2H, Ar); 8.28 (d, J 5.3 Hz, 1 H, Ar).
M/Z (M+H)+ = 307.2.
MP: >250°C.
Example 15: 2-(2-ethoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one.
To a suspension of example 13 (1 .0 equiv.) in EtOH (C=0.10 molL"1)
sodium ethoxyde (5.0 equiv.) was introduced. The reaction mixture was
submitted twice to microwave irradiation (150°C, 15 min.). Sodium
ethoxyde (2.0 equiv.) was added four times and after each addition the
reaction mixture was submitted to microwave irradiation (150°C, 15
Figure imgf000079_0003
min.). After cooling, the precipitate was collected, washed with
saturated aqueous NH4CI solution, water and Et20 and was dried under reduced pressure to afford example 15 as a beige solid in 19% yield.
1H-NMR (400 MHz, DMSO): 1 .35 (t, 3H, J 7.0 Hz, OCH2CH3); 3.55 (s, 3H, NCH3); 4.36 (q, 2H, J 7.0 Hz, OCH2CH3); 6.98 (s, 1 H, Ar); 7.32 (bs, 1 H, Ar); 7.52-7.56 (m, 2H, Ar); 7.90-7.94 (m, 1 H, Ar); 8.18-8.21 (m, 2H, Ar); 8.25 (d, J 5.3 Hz, 1 H, Ar).
M/Z (M+H)+ = 321.0.
MP: 180-182°C. General procedure VII: Alcohol introduction via nucleophilic substition
Method (i): Under inert atmosphere, to a suspension of quinazolinone (1 .0 equiv.) in DMA (C=0.1 molL"1), alcohol (2.5 equiv.) and NaH (2.0 equiv.) were added. The reaction mixture was submitted to microwave irradiation (150°C, 5 min.). After cooling, the reaction mixture was hydrolysed. The resulting precipitate was collected, washed with water, dried under reduced pressure and purified to afford the product. Method (ii): Under inert atmosphere, to a suspension of quinazolinone (1 .0 equiv.) in DMA (C=0.1 molL"1), alcohol (2.5 equiv.) and NaH (2.0 equiv.) were added. The reaction mixture was heated for 3 hours at 100°C. After cooling, the reaction mixture was hydrolysed. The resulting precipitate was collected, washed with water, dried under reduced pressure and purified to afford the product.
Method (iii): Under inert atmosphere, to a solution of quinazolinone (1 .0 equiv.) and alcohol (10.0 equiv.) in THF (C = 0.2 molL"1), fBUOK (1.2 equiv.) was added. The reaction mixture was stirred for 17 hours at room temperature and then was hydrolysed. The resulting precipitate was collected, washed with water, dried under reduced pressure and purified to afford the product.
Example 16: 2-(2-lsopropoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one.
Example 16 was obtained according to general procedure Vll(i) starting
from example 13 in presence of isopropanol. Purification by flash- chromatography (MeOH in DCM, 0 to 5%) afforded example 16 as a
white solid in 13% yield.
1H-NMR (400 MHz, DMSO): 1.33 (d, 6H, J 6.2 Hz, OCH(CH3)2); 3.55
Figure imgf000080_0001
(s, 3H, NCH3); 5.30 (Sept, 1 H, J 6.2 Hz, OCH(CH3)2); 6.98 (s, 1 H, Ar);
7.28 (bs, 1 H, Ar); 7.49-7.56 (m, 2H, Ar); 7.90-7.94 (m, 1 H, Ar); 8.18-8.21 (m, 2H, Ar); 8.24 (d, J 5.2 Hz, 1 H, Ar).
M/Z (M+H)+ = 335.2.
MP: 173-176°C.
Example 17: 2-(2-Cyclobutoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one.
Example 17 was obtained according to general procedure Vll(i) starting from example 13 in presence of cyclobutanol. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 17 as a white solid in 24% yield.
Figure imgf000081_0001
MP: 218-222°C.
Example 18: 4-Methyl-2-[2-(oxetan-3-yloxy)-pyndin-4-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one. Example 18 was obtained according to general procedure Vll(i)
starting from example 13 in presence of 3-hydroxyoxetane.
Purification by flash-chromatography (MeOH in DCM, 0 to 5%)
afforded example 18 as a white solid in 20% yield.
1H-NMR (400 MHz, DMSO): 3.56 (s, 3H, NCH3); 4.61 (dd, J 7.0 Hz, J
5.7 Hz, 2H, OCH(CHaHb)20); 4.90-4.94 (m, 2H, OCH(CHaHb)20);
Figure imgf000081_0002
5.62 (quint, J 5.7 Hz, 1 H, OCH(CHaHb)20); 7.01 (s, 1 H, Ar); 7.43 (bs, 1 H, Ar); 7.53-7.60 (m,
2H, Ar); 7.91 -7.95 (m, 1 H, Ar); 8.19-8.22 (m, 3H, Ar).
M/Z (M+H)+ = 349.2.
MP: 219-223°C.
Example 19: 2-(2-Cyclopropylmethoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5- one.
Figure imgf000081_0003
2CH); 1 .23-1.31 (m, 1 H, CH); 3.55 (s, 3H, NCH3); 4.15 (d, J 7.1 Hz, 2H, OCH2); 6.99 (s, 1 H, Ar); 7.36 (bs, 1 H, Ar); 7.52-7.56 (m, 2H, Ar); 7.90-7.95 (m, 1 H, Ar); 8.18-8.21 (m, 2H, Ar); 8.23 (d, J 5.3 Hz, 1 H, Ar).
M/Z (M+H)+ = 347.0.
MP: 185-189°C.
Example 20: 2-[2-( 2-Methoxy-ethoxy)-pyridin-4-yl]-4-methyl-4H-pyrazolo[1, 5-a]quinazolin-5- one.
Example 20 was obtained according to general procedure Vll(i) starting from example 13 in presence of 2-methoxyethanol. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 20 as a white solid in 40% yield.
Figure imgf000082_0001
Example 21 : 4-Methyl-2-[2-(2, 2, 2-trifluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1 , 5-a]quinazolin-5- one.
Figure imgf000082_0002
2H, OCH2CF3); 7.05 (s, 1 H, Ar); 7.52-7.57 (m, 2H, Ar); 7.69 (d, J 5.3 Hz, 1 H, Ar); 7.91-7.95 (m, 1 H, Ar); 8.20-8.22 (m, 2H, Ar); 8.31 (d, J 5.3 Hz, 1 H, Ar).
M/Z (M+H)+ = 375.2
MP: 219-223°C. Example 22: 4-Methyl-2-[2-(2, 2-difluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1 , 5-a]quinazolin-5- one.
Figure imgf000082_0003
7.02 (s, 1 H, Ar); 7.45 (bs, 1 H, Ar); 7.52-7.57 (m, 1 H, Ar); 7.63 (dd, J 5.3 Hz, J 1.2 Hz, 1 H, Ar);
7.90-7.94 (m, 1 H, Ar); 8.19-8.21 (m, 2H, Ar); 8.28 (d, J 5.3 Hz, 1 H, Ar).
M/Z (M+H)+ = 357.1
MP: 209-213°C.
Example 23: 2-[2-(2, 2-Difluoro-propoxy)-pyridin-4-yl]-4-methyl-4H-pyrazolo[1 , 5-a]quinazolin-5-
Figure imgf000082_0004
(s, 3H, NCH3); 4.62 (t, J 13.1 Hz, 2H, OCH2CF2CH3); 7.03 (s, 1 H, Ar); 7.46 (bs, 1 H, Ar); 7.52- 7.57 (m, 1 H, Ar); 7.63 (dd, J 5.3 Hz, J 1 .3 Hz, 1 H, Ar); 7.90-7.94 (m, 1 H, Ar); 8.19-8.21 (m, 2H, Ar); 8.28 (d, J 5.3 Hz, 1 H, Ar).
M/Z (M+H)+ = 371.1
MP: 189-191 °C.
Example 24: 4-Methyl-2-[2-(2, 2, 3, 3, 3-pentafluoro-propoxy)-pyridin-4-yl]-4H-pyrazolo[1 ,5- a]quinazolin-5-one.
Example 24 was obtained according to general procedure Vll(ii)
starting from example 13 in presence of 2,2,3,3,-pentafluoropropanol.
In order to complete the reaction, 2,2,3,3,-pentafluoropropanol (2.5
equiv.) and NaH (2.0 equiv.) were introduced a second time, then the
Figure imgf000083_0001
mixture was warmed for 3 hours at 100°C. Trituration in Et20 afforded example 24 as a white solid in 55% yield.
1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, NCH3); 5.15 (t, J 13.8 Hz, 2H, OCH2CF2CF3); 7.07 (s, 1 H, Ar); 7.50 (bs, 1 H, Ar); 7.53-7.57 (m, 1 H, Ar); 7.70 (d, J 5.3 Hz, 1 H, Ar); 7.90-7.95 (m, 1 H, Ar); 8.20-8.22 (m, 2H, Ar); 8.32 (d, J 5.3 Hz, 1 H, Ar).
M/Z (M+H)+ = 425.1
MP: 150-155°C.
Example 25: 4-Methyl-2-[2-(2, 2, 2-trifluoro-1-trifluoromethyl-ethoxy)-pyridin-4-yl]-4H- pyrazolo[1,5-a]quinazolin-5-one
To a suspension of example 13 (1 .0 equiv.) in 1 ,1 , 1 ,3,3, 3-hexafluoro-2- propanol (C=0.07 molL"1), potassium tertbutoxyde (10.0 equiv.) was
introduced. The reaction mixture was submitted to microwave irradiation
(150°C, 60 min.). After cooling, the reaction mixture was hydrolysed with
Figure imgf000083_0002
saturated aqueous NH4CI solution and then extracted with DCM. The
organic layers were combined, washed with brine, dried over MgS04, concentrated and purified by flash-chromatography (MeOH in DCM, 0 to 5%). Example 25 was obtained as a white solid in 19% yield.
1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, NCH3); 7.10 (s, 1 H, Ar); 7.21 (sept, 1 H, J 6.5 Hz, CH(CF3)2); 7.54-7.58 (m, 1 H, Ar); 7.67 (bs, 1 H, Ar); 7.67 (dd, J 5.3 Hz, J 1.4 Hz, 1 H, Ar); 7.91 - 7.95 (m, 1 H, Ar); 8.20-8.23 (m, 2H, Ar); 8.38 (d, J 5.3 Hz, 1 H, Ar).
M/Z (M+H)+ = 443.2
MP: 188-194°C.
Compound 3: 2-(2-Trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one. Compound 3 was obtained according to general procedure l(iii), starting from 2-trifluoromethyl- isonicotinic acid ethyl ester in presence of 2-hydrazino-benzoic acid as a beige solid in 86% yield.
1H-NMR (400 MHz, DMSO): 6.76 (s, 1 H, Ar); 7.54-7.58 (m, 1 H, Ar); 7.91-7.96 (m, 1 H, Ar); 8.18 (dd, J 7.9 Hz, J 1.2 Hz, 1 H, Ar); 8.23-8.28 (m, 2H, Ar); 8.40 (bs, 1 H, Ar); 8.85 (d, J 5.0 Hz, 1 H, Ar); 12.39 (bs, 1 H, NH).
M/Z (M+H)+ = 331.2.
Example 26: 4-Methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H- pyrazolo[1, 5-a]quinazolin-5-one.
Example 26 was obtained according to general procedure ll(i), starting
from compound 3 in presence of iodomethane. The reaction mixture
was stirred at room temperature for 120 min. Example 26 was obtained
as a white solid in 86% yield.
Figure imgf000084_0001
1H-NMR (400 MHz, DMSO): 3.57 (s, 3H, NCH3); 7.18 (s, 1 H, Ar); 7.54-7.58 (m, 1 H, Ar); 7.91 -
7.96 (m, 1 H, Ar); 8.19-8.24 (m, 3H, Ar); 8.37 (bs, 1 H, Ar); 8.88 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 345.2.
MP: 232-244°C. Example 27: 4-Methyl(D3)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinaz
Example 27 was obtained according to general procedure ll(ii),
starting from compound 3 in presence of deuterated iodomethane
(CD3I). The reaction mixture was stirred at room temperature for 60
min. Trituration in Et20 afforded example 27 as a gray solid in 63%
yield.
1H-NMR (400 MHz, DMSO): 7.16 (s, 1 H, Ar); 7.53-7.58 (m, 1 H, Ar);
Figure imgf000084_0002
7.90-7.96 (m, 1 H, Ar); 8.18-8.23 (m, 3H, Ar); 8.36 (bs, 1 H, Ar); 8.88 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 348.1.
MP: 232-237°C.
Example 28: 4^thyl-2-(2-trifluoromethyl^yridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one. Example 28 was obtained according to general procedure ll(ii), starting
from compound 3 in presence of iodoethane. The reaction mixture was
stirred at room temperature for 30 min. Purification by preparative HPLC
afforded example 28 as a white solid in 18% yield.
1H-NMR (400 MHz, DMSO): 1.34 (t, 3H, J 7.1 Hz, NCH2CH3); 4.13 (q,
Figure imgf000084_0003
2H, J 7.1 Hz, NCH2CH3); 7.27 (s, 1 H, Ar); 7.55-7.59 (m, 1 H, Ar); 7.92-7.96 (m, 1 H, Ar); 8.20- 8.26 (m, 3H, Ar); 8.39 (bs, 1 H, Ar); 8.88 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 359.0.
MP: 214-220°C.
Example 29: 4-(2,2-Difluoro-ethyl)-2-(2-tn luoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one.
Example 29 was obtained according to general procedure ll(ii), starting
from compound 3 in presence of 1 , 1-difluoro-2-iodoethane. The reaction
mixture was stirred at room temperature overnight, then at 70°C for 2
hours. Purification by preparative HPLC afforded example 29 as a white
Figure imgf000085_0001
solid in 19% yield.
1H-NMR (400 MHz, DMSO): 4.55 (td, J 14.5 Hz, J 3.8 Hz, 2H, NCH2CHF2); 6.47 (tt, J 55.1 Hz, J 3.8 Hz, 1 H, NCH2CHF2); 7.35 (s, 1 H, Ar); 7.58-7.62 (m, 1 H, Ar); 7.96-8.00 (m, 1 H, Ar); 8.22- 8.28 (m, 3H, Ar); 8.36 (bs, 1 H, Ar); 8.90 (d, J 5.0 Hz, 1 H, Ar).
M/Z (M+H)+ = 395.4.
MP: 223-230°C.
Example 30: 4-(2-Methoxy-ethyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5- a]quinazolin-5-one.
Example 30 was obtained according to general procedure ll(ii), starting
from compound 3 in presence of 2-bromoethylmethyl ether. The reaction
mixture was stirred for 17 hours at room. Purification by preparative
HPLC afforded example 30 as a white solid in 30% yield.
Figure imgf000085_0002
1H-NMR (400 MHz, DMSO): 3.28 (s, 3H, OCH3); 3.74 (t, J 5.9 Hz, 2H,
OCH2CH2N); 4.29 (t, J 5.9 Hz, 2H, OCH2CH2N); 7.25 (s, 1 H, Ar); 7.56-7.60 (m, 1 H, Ar); 7.93- 7.97 (m, 1 H, Ar); 8.20-8.26 (m, 3H, Ar); 8.39 (bs, 1 H, Ar); 8.88 (d, J 5.0 Hz, 1 H, Ar).
M/Z (M+H)+ = 389.1.
MP: 165-174°C.
General procedure VIII: Formation of ester A via innate carbon-hydrogen functionalization.
Under inert atmosphere, a mixture of ethyl isocotinate (1 .0 equiv.) and sulfinate (2.0 equiv.) was suspended in a mixture of DCM:water (8:2 - C=0.14 mol.L"1). TFA (1.0 equiv.), then fertbutylhydroperoxide (3.0 equiv.) were added and the mixture was vigorously stirred. When the starting material is consumed, the mixture was hydrolysed with a saturated aqueous NaHC03 solution and extracted with DCM. The organic layer was washed with brine, dried over MgS04 or Na2S04 and concentrated. Compounds were used in the next steps without further purification. Compound 4: 2-Difluoromethyl-isonicotinic acid ethyl ester.
Compound 4 was obtained according to general procedure VIII using bis {[(difluoromethyl)sulfonyl]oxy}zinc (DFMS). The reaction mixture was stirred for 4 hours at room temperature. Compound 4 was isolated as a yellow oil in a quantitative yield. To facilitate the extraction step, EDTA (8% w/w) was added to the NaHC03 solution.
1H-NMR (400 MHz, DMSO): 1.35 (t, 3H, J 7.1 Hz, OCH2CH3); 4.39 (q, 2H, J 7.1 Hz, OCH2CH3); 7.09 (t, J 54.7 Hz, 1 H, CHF2); 8.02 (d, J 5.0 Hz, 1 H, Ar); 8.06 (s, 1 H, Ar); 8.92 (d, J 5.0 Hz, 1 H, Ar).
M/Z (M+H)+ = 202.0. Compound 5: 2-(2-difluoromethyl-pyridin-4-yl)-4H-pyrazolo[1, 5-a]quinazolin-5-one.
Compound 5 was obtained according to general procedure l(ii), starting from compound 4 in presence of 2-hydrazino-benzoic acid as a brown solid in 64% yield.
1H-NMR (400 MHz, DMSO): 6.68 (s, 1 H, Ar); 7.03 (t, J 54.8 Hz, 1 H, CHF2); 7.54-7.58 (m, 1 H, Ar); 7.92-7.96 (m, 1 H, Ar); 8.12-8.13 (m, 1 H, Ar); 8.18 (dd, J 8.0 Hz, J 1 .2 Hz, 1 H, Ar); 8.20- 8.24 (m, 2H, Ar); 8.77 (d, J 5.2 Hz, 1 H, Ar); 12.46 (bs, 1 H, NH).
M/Z (M+H)+ = 313.2.
Example 31 : 4-Methyl-2-(2-difluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazo
Example 31 was obtained according to general procedure ll(ii), starting
from compound 5 in presence of iodomethane. The reaction mixture was
stirred for 16 hours at room temperature. Purification by flash- chromatography (MeOH in DCM, 0 to 10%) afforded example 31 as a
white solid in 26% yield.
1H-NMR (400 MHz, DMSO): 3.57 (s, 3H, NCH3); 7.04 (t, J 55.0 Hz, 1 H,
Figure imgf000086_0001
CHF2); 7.12 (s, 1 H, Ar); 7.54-7.58 (m, 1 H, Ar); 7.91 -7.96 (m, 1 H, Ar); 8.10-8.12 (m, 1 H, Ar); 8.20-8.24 (m, 3H, Ar); 8.80 (d, J 5.0 Hz, 1 H, Ar).
M/Z (M+H)+ = 327.2.
MP: 192-196°C. Compound 6: 2-( 1, 1 -Difluoro-ethyl)-isonicotinic acid ethyl ester.
Compound 6 was obtained according to general procedure VIII using sodium 1 ,1 - difluoromethanesulfinate. The reaction mixture was stirred for 20 hours at room temperature. Compound 6 was isolated as a yellow oil in quantitative yield. To ensure a full conversion, sodium 1 , 1 -difluoromethanesulfinate (2.0 equiv.) and tertbutyl hydroperoxide (3.0 equiv.) were added a second time after 18 hours.
1H-NMR (400 MHz, DMSO): 1.35 (t, 3H, J 7.1 Hz, OCH2CH3); 2.03 (t, J 19.2 Hz, 1 H, CF2CH3); 4.39 (q, 2H, J 7.1 Hz, OCH2CH3); 7.99-8.01 (m, 1 H, Ar); 8.03-8.04 (m, 1 H, Ar); 8.90 (d, J 5.0 Hz, 1 H, Ar).
M/Z (M+H)+ = 216.4.
Compound 7: 2-[2-(1, 1-Difluoro-ethyl)-pyridin-4-yl]-4H-pyrazolo[1 , 5-a]quinazolin-5-one.
Compound 7 was obtained according to general procedure l(ii), starting from compound 6 in presence of 2-hydrazino-benzoic acid as a brown solid in 61 % yield.
1H-NMR (400 MHz, DMSO): 2.06 (t, J 19.1 Hz, 1 H, CF2CH3); 6.68 (s, 1 H, Ar); 7.54-7.58 (m, 1 H, Ar); 7.91 -7.96 (m, 1 H, Ar); 8.08-8.10 (m, 1 H, Ar); 8.18 (dd, J 8.0 Hz, J 1.3 Hz, 1 H, Ar); 8.23-8.24 (m, 2H, Ar); 8.75 (d, J 5.2 Hz, 1 H, Ar); 12.46 (bs, 1 H, NH).
M/Z (M+H)+ = 327.2.
Example 32: 2-[2-(1 , 1 -Difluoro-ethyl)-pyridin-4-yl]-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5- one.
Example 32 was obtained according to general procedure ll(i), starting
from compound 7 in presence of iodomethane. The reaction mixture
was stirred for 2 hours at room temperature. Example 32 was obtained
without further purification as a beige solid in 55% yield.
Figure imgf000087_0001
1H-NMR (400 MHz, DMSO): 2.07 (t, J 19.1 Hz, 1 H, CF2CH3); 3.57 (s,
3H, NCH3); 7.13 (s, 1 H, Ar); 7.54-7.58 (m, 1 H, Ar); 7.91 -7.95 (m, 1 H, Ar); 8.07-8.08 (m, 1 H, Ar); 8.20-8.24 (m, 3H, Ar); 8.78 (d, J 5.0 Hz, 1 H, Ar).
M/Z (M+H)+ = 341.2.
MP: 196-207°C.
Example 33: 2-[2-( 1 , 1 -Difluoro-e thy I) -pyridin-4-yl]-4-methyl( D3) -4H-pyrazolo[1 , 5-a ]quinazolin-5- one.
Example 33 was obtained according to general procedure ll(i), starting
from compound 7 in presence of iodomethane D3. The reaction mixture
was stirred for 2 hours at room temperature. Example 33 was obtained
without further purification as a beige solid in 52% yield.
Figure imgf000087_0002
1H-NMR (400 MHz, DMSO): 2.07 (t, J 19.1 Hz, 1 H, CF2CH3); 7.13 (s,
1 H, Ar); 7.54-7.58 (m, 1 H, Ar); 7.91 -7.95 (m, 1 H, Ar); 8.07-8.09 (m, 1 H, Ar); 8.20-8.24 (m, 3H, Ar); 8.78 (d, J 5.2 Hz, 1 H, Ar). M/Z (M+H)+ = 344.2.
MP: 198-205°C.
General procedure IX: Formation of hydrazine D from the corresponding amino derivative C (cf. Scheme 1).
To a suspension of amino acid A (1 .0 equiv.) in concentrated aqueous HCI solution (0.15 mol.L"1) cooled by an ice bath, a cold solution of NaN02 (1 .2 equiv.) in water (c=2.8 mol.L"1) was added dropwise. The reaction mixture turned yellow with a suspension. After 1 hour, under vigorous stirring, a cold solution of SnCI2 (3.1 equiv.) in concentrated aqueous HCI solution (c=2.8 mol.L"1) was added dropwise. A suspension was obtained. The reaction mixture was filtered off 2 hours later. The solid was washed with a minimum of a cold aqueous HCI solution (1 N) before being dried under reduced pressure at 80°C with P205 for 18 hours. Compound 8: 2-hydrazino-5-methyl -benzoic acid, HCI.
Compound 8 was obtained according to general procedure IX, starting from 2-amino-5-methyl- benzoic acid, as a beige solid in 90% yield.
1H-NMR (400 MHz, DMSO): 2.26 (s, 3H, CH3); 7.06 (d, J 8.5 Hz, 1 H, Ar); 7.41 (dd, J 8.5 Hz, 2.2 Hz, 1 H, Ar); 7.72 (d, J 2.2 Hz, 1 H, Ar); 8.93 (bs, 1 H, NH); 10.50 (bs, 3H, NH3).
M/Z (M+H)+ = 167.1.
Compound 9: 7-Methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5
Compound 9 was obtained according to general procedure l(iii), starting from 2-trifluoromethyl- isonicotinic acid ethyl ester in presence of hydrazine 8 as a brown solid in 30% yield.
1H-NMR (400 MHz, DMSO): 2.45 (s, 3H, CH3); 6.61 (s, 1 H, Ar); 7.66-7.68 (m, 1 H, Ar); 7.95
(bs, 1 H, Ar); 8.08-8.10 (m, 1 H, Ar); 8.22 (bs, 1 H, Ar); 8.35 (bs, 1 H, Ar); 8.82 (bs, 1 H, Ar).
Signal for NH is not observed.
M/Z (M+H)+ = 345.2. Example 34: 7-Methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one. Example 34 was obtained according to general procedure ll(i), starting
from compound 9 in presence of iodomethane. The reaction mixture
was stirred for 2 hours at room temperature. Example 34 was obtained
without further purification as a beige solid in 55% yield.
1H-NMR (400 MHz, DMSO): 3.59 (s, 3H, NCH3); 7.14 (s, 1 H, Ar); 7.73-
Figure imgf000088_0001
7.75 (m, 1 H, Ar); 7.99 (m, 1 H, Ar); 8.10-8.12 (m, 1 H, Ar); 8.21 -8.22 (m, 1 H, Ar); 8.35 (bs, 1 H, Ar); 8.86-8.87 (m, 1 H, Ar). Signal for CH3 is not observed. M/Z (M+H)+ = 359.1.
MP: 215-218°C.
Compound 10: 5-Chloro-2-hydrazino-benzoic acid, HCI.
Compound 10 was obtained according to general procedure IX, starting from 2-amino-5- chlorobenzoic acid, as a beige solid in 88% yield.
1H-NMR (400 MHz, DMSO): 7.07 (d, J 8.9 Hz, 1 H, Ar); 7.57 (dd, J 8.9 Hz, 2.5 Hz, 1 H, Ar); 7.75 (d, J 2.5 Hz, 1 H, Ar); 9.08 (bs, 1 H, NH); 10.73 (bs, 3H, NH3). Compound 1 1 : 7-Chloro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]qu
Compound 1 1 was obtained according to general procedure l(iii), starting from 2- trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 10 as a brown solid in 31 % yield.
1H-NMR (400 MHz, DMSO): 6.65 (s, 1 H, Ar); 7.88 (dd, J 8.8 Hz, J 2.4 Hz, 1 H, Ar); 8.07 (d, J 2.4 Hz, 1 H, Ar); 8.20 (d, J 8.8 Hz, 1 H, Ar); 8.23-8.24 (m, 1 H, Ar); 8.37 (bs, 1 H, Ar); 8.83 (d, J 4.9 Hz, 1 H, Ar). Signal for NH is not observed.
M/Z (M[35CI]+H)+ = 365.0.
Example 35: 7-Chloro-2-( 2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1, 5-a]quinazolin-5-one. Example 35 was obtained according to general procedure ll(i), starting
from compound 1 1 in presence of iodomethane. The reaction mixture
was stirred for 2 hours at room temperature. Example 35 was obtained
without further purification as a white solid in 68% yield.
1H-NMR (400 MHz, DMSO): 3.56 (s, 3H, NCH3); 7.20 (s, 1 H, Ar); 7.96
Figure imgf000089_0001
(dd, J 8.7 Hz, J 2.4 Hz, 1 H, Ar); 8.10 (d, J 2.4 Hz, 1 H, Ar); 8.22-8.24 (m, 2H, Ar); 8.36 (bs, 1 H,
Ar); 8.88 (d, J 5.0 Hz, 1 H, Ar).
M/Z (M[35CI]+H)+ = 379.4.
MP: 231 -236°C. Compound 12: 2-hydrazino-5-methoxy-benzoic acid, HCI.
Compound 12 was obtained according to general procedure IX, starting from 2-amino-5- methoxybenzoic acid, as a beige solid in quantitative yield.
1H-NMR (400 MHz, DMSO): 3.75 (s, 3H, OCH3); 7.15 (d, J 8.9 Hz, 1 H, Ar); 7.25 (dd, J 8.9 Hz, 2.8 Hz, 1 H, Ar); 7.42 (d, J 2.8 Hz, 1 H, Ar); 8.84 (bs, 1 H, NH); 10.17 (bs, 3H, NH3).
M/Z (M+H)+ = 183.1. Compound 13: 7-Methoxy-2-(2-trifluoromethyl^yridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5- one.
Compound 13 was obtained according to general procedure l(iii), starting from 2- trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 12 as a brown solid in 37% yield.
1H-NMR (400 MHz, DMSO): 3.86 (s, 3H, OCH3); 6.44 (s, 1 H, Ar); 7.33-7.35 (m, 1 H, Ar); 7.57 (bs, 1 H, Ar); 8.06-8.08 (m, 1 H, Ar); 8.16 (bs, 1 H, Ar); 8.30 (bs, 1 H, Ar); 8.77 (bs, 1 H, Ar). Signal for NH is not observed.
M/Z (M+H)+ = 361.0.
Example 36: 7-Methoxy-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5
Example 36 was obtained according to general procedure ll(i),
starting from compound 13 in presence of iodomethane. The reaction
mixture was stirred for 2 hours at room temperature. Example 36 was
obtained without further purification as a beige solid in 48% yield.
1H-NMR (400 MHz, DMSO): 3.59 (s, 3H, NCH3); 3.91 (s, 3H, OCH3);
Figure imgf000090_0001
7.20 (s, 1 H, Ar); 7.55 (dd, J 9.0 Hz, J 2.8 Hz, 1 H, Ar); 7.63 (d, J 2.8 Hz, 1 H, Ar); 8.21 (d, J 9.0 Hz, 1 H, Ar); 8.24-8.26 (m, 1 H, Ar); 8.38 (bs, 1 H, Ar); 8.88 (d, J 5.0 Hz, 1 H, Ar).
M/Z (M+H)+ = 375.1.
MP: 201 -205°C.
Compound 14: 2-hydrazino-5-trifluoromethyl-benzoic acid, HCI.
Compound 14 was obtained according to general procedure IX, starting from 2-amino-5- trifluoromethylbenzoic acid, as a beige solid in 64% yield.
1H-NMR (400 MHz, DMSO): 7.27 (d, J 8.9 Hz, 1 H, Ar); 7.89 (dd, J 8.9 Hz, 2.1 Hz, 1 H, Ar); 8.10 (d, J 2.1 Hz, 1 H, Ar); 9.38 (bs, 1 H, NH); 10.58 (bs, 3H, NH3).
M/Z (M+H)+ = 221.2.
Compound 15: 7-Trifluoromethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5- a]quinazolin-5-one.
Compound 15 was obtained according to general procedure l(iii), starting from 2- trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 14 as a brown solid in 40% yield.
1H-NMR (400 MHz, DMSO): 6.68 (s, 1 H, Ar); 8.17 (dd, J 8.6 Hz, J 1.5 Hz, 1 H, Ar); 8.26 (d, J 5.0 Hz, 1 H, Ar); 8.35-8.37 (m, 2H, Ar); 8.39 (bs, 1 H, Ar); 8.84 (d, J 5.0 Hz, 1 H, Ar). Signal for NH is not observed.
M/Z (M+H)+ = 399.1. Example 37: 7-Trifluoromethyl-2-(24rifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,^
Figure imgf000091_0001
1H-NMR (400 MHz, DMSO): 3.58 (s, 3H, NCH3); 7.25 (s, 1 H, Ar); 8.24-8.27 (m, 2H, Ar); 8.39- 8.41 (m, 3H, Ar); 8.88 (d, J 4.9 Hz, 1 H, Ar).
M/Z (M+H)+ = 413.2.
MP: 205-210°C.
Compound 16: 5-fluoro-2-hydrazino-5-trifluoromethyl-benzoic acid, HCI.
Compound 16 was obtained according to general procedure IX, starting from 2-amino-5- fluoromethylbenzoic acid, as a beige solid in 46% yield.
M/Z (M+H)+ = 171.8.
Compound 17: 7-fluoro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one. Compound 17 was obtained according to general procedure l(iv), starting from 2- trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 16 as a brown solid in 54% yield.
1H-NMR (400 MHz, DMSO): 6.78 (s, 1 H, Ar); 7.80-7.89 (m, 2H, Ar); 8.26-8.31 (m, 2H, Ar); 8.40 (bs, 1 H, Ar); 8.85 (d, J 4.9 Hz, 1 H, Ar); 12.64 (bs, 1 H, NH).
M/Z (M+H)+ = 349.0. Example 38: 7-fluoro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1, 5-a]quinazolin-5-one.
Example 38 was obtained according to general procedure ll(iii),
starting from compound 17 in presence of iodomethane. The reaction
mixture was stirred for 3 hours at room temperature. Example 38 was
obtained without further purification as a beige solid in 84% yield.
1H-NMR (400 MHz, DMSO): 3.57 (s, 3H, NCH3); 7.20 (s, 1 H, Ar); 7.82
Figure imgf000091_0002
(td, J 9.0 Hz, J 2.9 Hz, 1 H, Ar); 7.90 (dd, J 8.7 Hz, J 2.9 Hz, 1 H, Ar);
8.23-8.24 (m, 1 H, Ar); 8.28 (dd, J 9.0 Hz, J 4.6 Hz, 1 H, Ar); 8.37 (bs, 1 H, Ar); 8.88 (d, J 5.1 Hz,
1 H, Ar).
M/Z (M+H)+ = 363.0.
MP: > 250°C. Compound 18: 5-Bromo-2-hydrazino-benzoic acid, HCI.
Compound 18 was obtained according to general procedure IX, starting from 2-amino-5- bromo-benzoic acid, as a beige solid in a quantitative yield.
1H-NMR (400 MHz, DMSO): 7.10 (d, J 8.9 Hz, 1 H, Ar); 7.78 (dd, J 8.9 Hz, 2.5 Hz, 1 H, Ar); 7.97 (d, J 2.5 Hz, 1 H, Ar); 9.08 (bs, 1 H, NH); 10.64 (bs, 3H, NH3).
M/Z (M[79Br]-18+H)+ = 213.
Compound 19: 7-Bromo-2-( 2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1, 5-a]quinazolin-5-one. Compound 19 was obtained according to general procedure l(i), starting from 2-trifluoromethyl- isonicotinic acid ethyl ester in presence of hydrazine 8 as a brown solid in 24% yield.
1H-NMR (400 MHz, DMSO): 6.77 (s, 1 H, Ar); 8.08 (dd, J 8.7 Hz, J 2.3 Hz, 1 H, Ar); 8.16 (d, J 8.7 Hz, 1 H, Ar); 8.21 (d, J 2.3 Hz, 1 H, Ar); 8.24-8.26 (m, 1 H, Ar); 8.39 (bs, 1 H, Ar); 8.85 (d, J 5.1 Hz, 1 H, Ar); 12.62 (bs, 1 H, NH).
M/Z (M[79Br]+H)+ = 409.2.
Example 39: 7-Bromo-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one.
Example 39 was obtained according to general procedure ll(i),
starting from compound 19 in presence of iodomethane. The reaction
mixture was stirred for 2 hours at room temperature. Example 39 was
obtained without further purification as a brown solid in 85% yield.
1H-NMR (400 MHz, DMSO): 3.56 (s, 3H, N-CH3); 7.20 (s, 1 H, Ar);
Figure imgf000092_0001
8.09 (dd, J 8.8 Hz, J 2.3 Hz, 1 H, Ar); 8.17 (d, J 8.8 Hz, 1 H, Ar); 8.23-8.25 (m, 2H, Ar); 8.37 (bs,
1 H, Ar); 8.89 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M[79Br]+H)+ = 423.1 .
MP: 223-235°C.
General procedure X: Amine introduction via Buchwald, Ullmann or nucleophilic substition Method (i): Under inert atmosphere, a mixture of halide (1.0 equiv.), amine (2.4 equiv.), tBuOK (1 .6 equiv.; 2.4 more equivalent are added when the amine is an HCI salt) and BrettPhos precatalyst (0.1 equiv.) were suspended in DMA (C=0.1 molL"1). The mixture was warmed overnight at 80°C. After cooling, the reaction mixture was hydrolysed with saturated aqueous NH4CI solution. The solid was collected, washed with water, dried under reduced pressure and purified to afford the product. Method (ii): Under inert atmosphere, a mixture of halide (1 .0 equiv.), amine (2.4 equiv.), a solution of LiHMDS in THF (1 .0 N; 1.2 equiv.) and BrettPhos precatalyst (0.1 equiv.) were suspended in DME (C=0.1 molL"1) and stirred for 2 hours at room temperature. The reaction mixture was hydrolysed with a saturated aqueous NH4CI solution and then extracted with EtOAc. The organic layers were combined, washed with brine, dried over MgS04, concentrated and purified to afford the product.
Method (iii): Under inert atmosphere, in a seal tube, a mixture of halide (1.0 equiv.), amine (1 .2 equiv.), a solution of LiHMDS in THF (1.0 N; 2.4 equiv.) and BrettPhos precatalyst (0.1 equiv.) were suspended in DME (C=0.1 molL"1) and warmed for 2 hours at 60°C. The reaction mixture was hydrolysed with a saturated aqueous NH4CI solution. The solid was collected, washed with water, dried under reduced pressure and purified to afford the product.
Method (iv): Under inert atmosphere, in a seal tube, a mixture of halide (1.0 equiv.), amine (1 .5 equiv.), K3P04 (4.0 equiv.), Cul (0.1 equiv.) and DMPAO (0.2 equiv.) in DMSO (C=0.1 molL"1) was heated for 17 hours at 100°C. The reaction mixture was hydrolysed with a saturated aqueous NH4CI solution. The solid was collected, washed with water, dried under reduced pressure and purified to afford the product. Method (v): Under inert atmosphere, in a seal tube, a mixture of halide (1.0 equiv.), amine (1 .5 equiv.), tBuOK (3.0 equiv.) palladium acetate (0.1 equiv.) and BINAP (0.2 equiv.) were suspended in toluene (C=0.06 molL"1) and heated for 2 hours at 120°C. The reaction mixture was hydrolysed with a saturated aqueous NH4CI solution. The solid was collected, washed with water, dried under reduced pressure and purified to afford the product.
Method (vi): Under inert atmosphere, in a seal tube, a mixture of halide (1 .0 equiv.), amine (5.0 equiv.), K2C03 (5.0 equiv.) in DMA (C=0.1 molL"1) was heated for 1 hour at 90°C. The reaction mixture was hydrolysed with a saturated aqueous NH4CI solution. The solid was collected, washed with water, dried under reduced pressure and purified to afford the product.
Example 40: 4-Methyl-7-methylamino-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5- a]quinazolin-5-one.
Example 40 was obtained according to general procedure X(i) starting
from example 39 in presence of methylamine hydrochloride.
Purification by flash-chromatography (MeOH in DCM, 0 to 1 %)
afforded example 40 as a yellow solid in 34% yield.
Figure imgf000093_0001
1H-NMR (400 MHz, DMSO): 2.77 (d, J 5.0 Hz, 3H, NHCH3); 3.55 (s, 3H, NCH3); 6.30 (q, J 5.0
Hz, 1 H, NHCH3); 7.09 (s, 1 H, Ar); 7.14-7.17 (m, 2H, Ar); 8.00-8.02 (m, 1 H, Ar); 8.18-8.20 (m, 1 H, Ar); 8.32 (bs, 1 H, Ar); 8.84 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 373.7.
MP: >250°C.
Example 41 : 4-Methyl-7-methyl(D3)amino-2-(2 rifluoromethyl-pyridin-4-yl)-4H-pyrazolol1 ,5- a]quinazolin-5-one.
Example 41 was obtained according to general procedure X(i) starting
from example 39 in presence of methylamine(D3) hydrochloride.
Purification by flash-chromatography (MeOH in DCM, 0 to 5%)
afforded example 41 as a beige solid in 30% yield.
Figure imgf000094_0001
1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, NCH3); 6.26 (bs, 1 H, NH); 7.09 (s, 1 H, Ar); 7.14-7.17
(m, 2H, Ar); 7.99-8.02 (m, 1 H, Ar); 8.18-8.29 (m, 1 H, Ar); 8.32 (bs, 1 H, Ar); 8.84 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 377.0.
MP: >250°C.
Example 42: N-[4-Methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5- a]quinazolin-7-yl]-acetamide.
Under inert atmosphere, a mixture of bromide 39, (60.0 mg, 1 .0
equiv.), acetamide (8.8 mg, 1.05 equiv.), Cs2C03 (93.4 mg, 2.0
equiv.), Pd2dba3 (7.3 mg, 0.1 equiv.) and XantPhos (16.4 mg, 0.2
equiv.) were suspended in DMA (2.8 ml_, C=0.05 molL"1). The mixture
Figure imgf000094_0002
was heated for 2 hours at 1 10°C. After cooling, the reaction mixture
was hydrolysed with a saturated aqueous NH4CI solution. The solid was collected, washed with water, dried under reduced pressure and purified by flash-chromatography (MeOH in DCM, 0 to 3%) to afford example 42 as a beige solid in 63% yield.
1H-NMR (400 MHz, DMSO): 2.09 (s, 3H, COCH3); 3.56 (s, 3H, NCH3); 7.15 (s, 1 H, Ar); 8.09 (dd, J 9.0 Hz, J 2.4 Hz, 1 H, Ar); 8.16 (d, J 9.0 Hz, 1 H, Ar); 8.20-8.22 (m, 1 H, Ar); 8.35 (bs, 1 H, Ar); 8.47 (d, J 2.4 Hz, 1 H, Ar); 8.87 (d, J 5.1 Hz, 1 H, Ar); 10.32 (s, 1 H, NH).
M/Z (M+H)+ = 402.0.
MP: >250°C. Example 43: 7-Amino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin- 5-one. In a seal tube, a suspension of amide 42 (23.2 mg, 1.0 equiv.) in
HCI MeOH solution (1.25 N; 1.2 ml_, C=0.05 molL"1) was heated for
18 hours at 80°C. The reaction mixture was concentrated. The
resulting residue was suspended in Et20. Solid was collected,
washed with Et20 and dried under reduced pressure to afford
Figure imgf000095_0001
example 43 as a brown solid in 71 % yield.
1H-NMR (400 MHz, DMSO): 3.56 (s, 3H, NCH3); 7.15 (s, 1 H, Ar); 7.41 (dd, J 8.8 Hz, J 2.5 Hz, 1 H, Ar); 7.64 (d, J 2.5 Hz, 1 H, Ar); 8.10 (d, J 8.8 Hz, 1 H, Ar); 8.20-8.22 (m, 1 H, Ar); 8.35 (bs, 1 H, Ar); 8.86 (d, J 5.2 Hz, 1 H, Ar). Signal for NH2 is not observed.
M/Z (M+H)+ = 360.1.
MP: 245-250°C.
Example 44: 7-Dimethylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazob a]quinazolin-5-one.
Example 44 was obtained according to general procedure X(i)
starting from example 39 in presence of dimethylamine (2 N in
THF). After hydrolysis, example 44 was extracted with EtOAc.
Organic layers were washed with brine, dried over MgS04.
Figure imgf000095_0002
Purification by flash-chromatography (MeOH in DCM, 0 to 10%)
afforded example 44 as a yellow solid in 7% yield.
1H-NMR (400 MHz, DMSO): 3.04 (s, 6H, N(CH3)2); 3.60 (s, 3H, NCH3); 7.01 (s, 1 H, Ar); 7.36-
7.39 (m, 2H, Ar); 8.10 (d, J 8.6 Hz, 1 H, Ar); 8.17-8.19 (m, 1 H, Ar); 8.31 (bs, 1 H, Ar); 8.84 (d, J
5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 387.5.
MP: >250°C.
Example 45: 7-Ethylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one.
Example 45 was obtained according to general procedure X(i) starting
from example 39 in presence of ethylamine hydrochloride. Ethylamine
HCI (0.2 equiv.), tBuOK (0.2 equiv.) and BrettPhos precatalyst (0.1
iquiv.) were added and the reaction mixture was heated for two more
hours at 80°C. Purification by flash-chromatography (EtOAc in CyHex,
Figure imgf000095_0003
0 to 50%) afforded example 45 as a beige solid in 26% yield.
1H-NMR (400 MHz, DMSO): 1 .21 (t, J 7.1 Hz, 3H, NHCH2CH3); 3.09-3.15 (m, 2H, NHCH2CH3);
3.55 (s, 3H, NCH3); 6.21 (t, J 5.2 Hz, 1 H, NHCH2CH3); 7.09 (s, 1 H, Ar); 7.16-7.20 (m, 2H, Ar);
8.00 (d, J 8.7 Hz, 1 H, Ar); 8.18-8.19 (m, 1 H, Ar); 8.32 (bs, 1 H, Ar); 8.84 (d, J 5.0 Hz, 1 H, Ar). M/Z (M+H)+ = 388.0.
MP: 239-242°C.
Example 46: 7-Cyclobutylamino-4-methyl-2-(2-tn luoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one.
Example 46 was obtained according to general procedure X(i)
starting from example 39 in presence of cyclobutylamine.
Purification by preparative HPLC afforded example 46 as a beige
solid in 16% yield.
Figure imgf000096_0001
1H-NMR (400 MHz, DMSO): 1.73-1 .92 (m, 4H, CH2 + 2CHaHb); 2.35-2.40 (m, 2H, 2CHaHb); 3.55 (s, 3H, NCH3); 3.92 (sex, J 7.1 Hz, 1 H, NHCH(CH2)2); 6.55 (d, J 7.1 Hz, 1 H, NHCH(CH2)2); 7.10 (s, 1 H, Ar); 7.13 (dd, J 8.8 Hz, J 2.5 Hz, 1 H, Ar); 7.16 (d, J 2.5 Hz, 1 H, Ar); 8.00 (d, J 8.8 Hz, 1 H, Ar); 8.18-8.20 (m, 1 H, Ar); 8.33 (bs, 1 H, Ar); 8.84 (d, J 5.0 Hz, 1 H, Ar). M/Z (M+H)+ = 414.2.
MP: 220-225°C.
Example 47: 4-Methyl-7-morpholin-4-yl-2-(2-tn luoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one.
Example 47 was obtained according to general procedure X(ii)
starting from example 39 in presence of morpholine. Purification by
flash-chromatography (MeOH in DCM, 0 to 1 %) afforded example
47 as a grey solid in 21 % yield.
Figure imgf000096_0002
1H-NMR (400 MHz, DMSO): 3.22-3.25 (m, 4H, 2 CH2); 3.57 (s, 3H,
NCH3); 3.75-3.80 (m, 4H, 2 CH2); 7.14 (s, 1 H, Ar); 7.55 (d, J 2.8 Hz, 1 H, Ar); 7.62 (dd, J 9.1 Hz, J 2.8 Hz, 1 H, Ar); 8.1 1 (d, J 9.1 Hz, 1 H, Ar); 8.21-8.22 (m, 1 H, Ar); 8.35 (bs, 1 H, Ar); 8.86 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 430.3.
MP: 149-163°C. Example 48: 7-Hydroxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one.
Under inert atmosphere, in a seal tube, to a well degased mixture of
bromide 39 (100.0 mg, 1.0 equiv.), Pd2dba3 (12.2 mg, 0.1 equiv.) and
tBuXPhos (10.2 mg, 0.1 equiv.) in dioxane (0.5 ml_, C=0.5 molL"1), a
well degased solution of KOH (79.5 mg, 6.0 equiv.) in water (0.5 ml_,
Figure imgf000096_0003
C= 2.8 molL"1) was added dropwise and was heated for 16 hours at
100°C. After cooling, the reaction mixture was hydrolysed with a saturated aqueous NH4CI solution and then extracted with EtOAc. The organic Iayers were combined, washed with brine, dried over MgS04, concentrated and purified by flash-chromatography (MeOH in DCM, 0 to 5%) to afford example 48 as a white solid in 35% yield.
1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, NCH3); 7.13 (s, 1 H, Ar); 7.35 (dd, J 8.8 Hz, J 2.6 Hz, 1 H, Ar); 7.52 (d, J 2.6 Hz, 1 H, Ar); 8.09 (d, J 8.8 Hz, 1 H, Ar); 8.19-8.21 (m, 1 H, Ar); 8.34 (bs, 1 H, Ar); 8.86 (d, J 4.9 Hz, 1 H, Ar); 10.17 (s, 1 H, OH).
M/Z (M+H)+ = 361.5.
MP: >250°C. General procedure XI: Hydroxy group alkylation
Under inert atmosphere, to a suspension of hydroxyl quinazolinone (1 .0 equiv.) in DMF (C=0.1 molL"1), tBuOK (1.5 equiv.) was added. After 15 minutes, electrophile (1 .2 equiv.) was introduced and the reaction mixture was heated for 18 hours at 80°C. After cooling, the reaction mixture was hydrolysed. The resulting precipitate was collected, washed with water, dried under reduced pressure and purified to afford the product.
Example 49: 7-Ethoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pym^
Figure imgf000097_0001
chromatography (MeOH in DCM, 0 to 5%) afforded example 49 as a yellow solid in 27% yield. 1H-NMR (400 MHz, DMSO): 1.37 (t, J 7.0 Hz, 3H, OCH2CH3); 3.55 (s, 3H, NCH3); 4.13 (q, J 7.0 Hz, 2H, OCH2CH3); 7.1 1 (s, 1 H, Ar); 7.47 (dd, J 9.0 Hz, J 2.8 Hz, 1 H, Ar); 7.53 (d, J 2.8 Hz, 1 H, Ar); 8.1 1 (d, J 9.0 Hz, 1 H, Ar); 8.17-8.19 (m, 1 H, Ar); 8.31 (bs, 1 H, Ar); 8.85 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 389.1.
MP: 152-158°C.
Example 50: 7-(2-Methoxy-ethoxy)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5- a]quinazolin-5-one.
Example 50 was obtained according to general procedure XI
starting from example 48 in presence of 2-bromoethylmerthyl
ether. 2-bromoethylmerthyl ether (1.2 equiv.) and tBuOK (1 .5
equiv.) were added and the reaction mixture was heated for 48
Figure imgf000097_0002
hours at 80°C. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 50 as a white solid in 34% yield.
1H-NMR (400 MHz, DMSO): 3.34 (s, 3H, OCH3); 3.56 (s, 3H, NCH3); 3.70-3.72 (m, 2H, OCH2); 4.22-4.24 (m, 2H, OCH2); 7.14 (s, 1 H, Ar); 7.53 (dd, J 9.0 Hz, J 2.8 Hz, 1 H, Ar); 7.59 (d, J 2.8 Hz, 1 H, Ar); 8.15 (d, J 9.0 Hz, 1 H, Ar); 8.20-8.21 (m, 1 H, Ar); 8.34 (bs, 1 H, Ar); 8.86 (d, J 5.0 Hz, 1 H, Ar).
M/Z (M+H)+ = 419.2.
MP: 182-189°C.
Example 51 : 4-Methyl-7-(2-morpholin-4-yl-ethoxy)-2-(2-tn luoromethyl-pyridin-4-yl)-4H- pyrazolo[1,5-a]quinazolin-5-one, HCI salt.
Example 51 was obtained according to general procedure
Vll(i) starting from example 38 in presence of 4- hydroxyethylmorpholine. Salt formation according to
procedure IV(iii) afforded example 51 as a beige solid in
34% yield.
Figure imgf000098_0001
1H-NMR (400 MHz, DMSO): 3.25-3.29 (m, 4H, 2 NCH2); 3.50-3.54 (m, 2H, NCH2); 3.62 (s, 3H, NCH3); 3.88-3.90 (m, 4H, 2 OCH2); 4.54-4.56 (m, 2H, OCH2); 7.09 (s, 1 H, Ar); 7.62 (dd, J 8.9 Hz, J 2.5 Hz, 1 H, Ar); 7.77 (d, J 2.5 Hz, 1 H, Ar); 8.21 -8.22 (m, 1 H, Ar); 8.25 (d, J 8.9 Hz, 1 H, Ar); 8.35 (bs, 1 H, Ar); 8.87 (d, J 4.9 Hz, 1 H, Ar).
M/Z (M+H)+ = 474.1.
MP: > 250°C.
Compound 20: 2-Hydrazino-5-trifluoromethoxy-benzoic acid, HCI.
Compound 20 was obtained according to general procedure IX, starting from 2-Amino-5- trifluoromethoxylbenzoic acid, as a white solid in 59% yield.
1H-NMR (400 MHz, DMSO): 7.22 (d, J 9.1 Hz, 1 H, Ar); 7.66 (dd, J 9.1 Hz, 2.4 Hz, 1 H, Ar); 7.77 (d, J 2.4 Hz, 1 H, Ar); 9.12 (bs, 1 H, NH); 10.62 (bs, 3H, NH3).
Compound 21 : 7-Trifluoromethoxy-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one.
Compound 21 was obtained according to general procedure l(i), starting from 2-trifluoromethyl- isonicotinic acid ethyl ester in presence of hydrazine 20 as a brown solid in 61 % yield.
1H-NMR (400 MHz, DMSO): 6.82 (s, 1 H, Ar); 7.94-7.97 (m, 1 H, Ar); 8.02-8.03 (m, 1 H, Ar);
8.27-8.30 (m, 1 H, Ar); 8.35-8.37 (m, 1 H, Ar); 8.42 (bs, 1 H, Ar); 8.85-8.87 (m, 1 H, Ar); 12.69 (bs, 1 H, NH).
M/Z (M+H)+ = 415.2. Example 52: 4-Methyl-7-trifluoromethoxy-2-(2-trifluoromethyl-pyridin-4-yl)-4H^yrazolo a]quinazolin-5-one.
Example 52 was obtained according to general procedure ll(iii),
starting from compound 21 in presence of iodomethane. The
reaction mixture was stirred for 2 hours at room temperature.
Example 52 was obtained without further purification as a white
solid in 55% yield.
Figure imgf000099_0001
1H-NMR (400 MHz, DMSO): 3.57 (s, 3H, NCH3); 7.22 (s, 1 H, Ar); 7.95 (dd, J 9.0 Hz, 1 .7 Hz, 1 H, Ar); 8.05 (d, 1 .7 Hz, 1 H, Ar); 8.23-8.25 (m, 1 H, Ar); 8.34 (d, 9.0 Hz, 1 H, Ar); 8.38 (bs, 1 H, Ar); 8.89 (d, 4.9 Hz, 1 H, Ar).
M/Z (M+H)+ = 429.2.
MP: 240-245°C.
Compound 22: 2-Hydrazino-5-methanesulfonyl-benzoic acid, HCI.
Compound 22 was obtained according to general procedure IX, starting from 2-amino-5- methylsulfonylbenzoic acid, as a white solid in 51 % yield.
1H-NMR (400 MHz, DMSO): 3.19 (s, 3H, S02CH3); 7.26 (d, J 8.9 Hz, 1 H, Ar); 8.03 (dd, J 8.9 Hz, 2.3 Hz, 1 H, Ar); 8.32 (d, J 2.3 Hz, 1 H, Ar); 9.55 (bs, 1 H, NH); 10.62 (bs, 3H, NH3). Compound 23: 7-Methanesulfonyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one.
Compound 23 was obtained according to general procedure l(iv), starting from 2- trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 22 as a brown solid in 40% yield.
1H-NMR (400 MHz, DMSO): 3.35 (s, 3H, S02CH3); 6.85 (s, 1 H, Ar); 8.31 -8.32 (m, 1 H, Ar); 8.40-8.46 (m, 3H, Ar); 8.62 (bs, 1 H, Ar); 8.88 (d, 4.9 Hz, 1 H, Ar); 12.76 (bs, 1 H, NH).
M/Z (M+H)+ = 409.0.
Example 53: 7-Methanesulfonyl-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one.
Example 53 was obtained according to general procedure ll(iii),
starting from compound 23 in presence of iodomethane. The
reaction mixture was stirred for 3 hours at room temperature.
Example 53 was obtained without further purification as a white
Figure imgf000099_0002
solid in 54% yield.
1H-NMR (400 MHz, DMSO): 3.36 (s, 3H, S02CH3); 3.60 (s, 3H, NCH3); 7.28 (s, 1 H, Ar); 8.27- 8.28 (m, 1 H, Ar); 8.41 -8.46 (m, 3H, Ar); 8.65 (d, J 1 .6 Hz, 1 H, Ar); 8.92 (d, 5.1 Hz, 1 H, Ar). M/Z (M+H)+ = 423.1.
MP: > 250°C.
Compound 24: 2-Hydrazino-4-methoxy-benzoic acid, HCI.
Compound 24 was obtained according to general procedure IX, starting from 2-amino-4- methoxybenzoic acid, as a white solid in 96% yield.
1H-NMR (400 MHz, DMSO): 3.81 (s, 3H, OCH3); 6.50 (dd, J 8.8 Hz, 2.4 Hz, 1 H, Ar); 6.71 (d, J 2.4 Hz, 1 H, Ar); 7.82 (d, J 8.8 Hz, 1 H, Ar); 9.09 (bs, 1 H, NH); 10.03 (bs, 3H, NH3).
M/Z (M+H)+ = 183.1.
Compound 25: 8-Methoxy-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5- one.
Compound 25 was obtained according to general procedure l(iv), starting from 2- trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 24 as a pale brown solid in 76% yield.
1H-NMR (400 MHz, DMSO): 4.01 (s, 3H, OCH3); 6.75 (s, 1 H, Ar); 7.12 (dd, J 8.9 Hz, 2.4 Hz, 1 H, Ar); 7.65 (d, J 2.4 Hz, 1 H, Ar); 8.09 (d, J 8.9 Hz, 1 H, Ar); 8.28-8.30 (m, 1 H, Ar); 8.43 (bs, 1 H, Ar); 8.85 (d, J 5.1 Hz, 1 H, Ar); 12.34 (bs, 1 H, NH).
M/Z (M+H)+ = 361.1.
Example 54: 8-Methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5- a]quinazolin-5-one.
Example 54 was obtained according to general procedure ll(iii),
starting from compound 25 in presence of iodomethane. The
reaction mixture was stirred for 3 hours at room temperature.
Example 54 was obtained without further purification as a beige
solid in 68% yield.
Figure imgf000100_0001
1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, NCH3); 4.00 (s, 3H, OCH3); 7.12 (dd, J 8.8 Hz, J 2.5 Hz, 1 H, Ar); 7.17 (s, 1 H, Ar); 7.64 (d, J 2.5 Hz, 1 H, Ar); 8.12 (d, J 8.8 Hz, 1 H, Ar); 8.26-8.28 (m, 1 H, Ar); 8.40 (bs, 1 H, Ar); 8.89 (d, J 5.0 Hz, 1 H, Ar).
M/Z (M+H)+ = 375.1 .
MP: > 250°C.
Compound 26: 4-Fluoro-2-hydrazino-benzoic acid, HCI.
Compound 26 was obtained according to general procedure IX, starting from 2-amino-4- fluorobenzoic acid, as a white solid in 71 % yield. 1H-NMR (400 MHz, DMSO): 6.69-6.73 (m, 1 H, Ar); 6.93 (dd, J 1 1.9 Hz, J 2.5 Hz, 1 H, Ar); 7.93 (dd, J 8.9 Hz, J 6.8 Hz, 1 H, Ar); 9.14 (bs, 4H, NHNH3).
M/Z (M+H)+ = 171.2. Compound 27: 8-Fluoro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1, 5-a]quinazolin-5-one. Compound 27 was obtained according to general procedure l(iv), starting from 2- trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 26 as a pale brown solid in 53% yield.
1H-NMR (400 MHz, DMSO): 6.77 (s, 1 H, Ar); 7.40 (td, J 8.8 Hz, J 2.5 Hz, 1 H, Ar); 7.99 (dd, J 9.5 Hz, J 2.5 Hz, 1 H, Ar); 8.23 (dd, J 8.8 Hz, J 5.9 Hz, 1 H, Ar); 8.27-8.29 (m, 1 H, Ar); 8.43 (bs, 1 H, Ar); 8.86 (d, J 5.0 Hz, 1 H, Ar); 12.53 (bs, 1 H, NH).
M/Z (M+H)+ = 349.1.
Example 55: 8-Fluoro-4-methyl-2-(2-trifluoromethyl^yridin-4-yl)-4H^yrazolo[1,5-a]quinazolin- 5-one
Example 55 was obtained according to general procedure ll(iii),
starting from compound 27 in presence of iodomethane. The
reaction mixture was stirred for 3 hours at room temperature.
Example 55 was obtained without further purification as a beige
solid in 70% yield.
Figure imgf000101_0001
1H-NMR (400 MHz, DMSO): 3.56 (s, 3H, NCH3); 7.20 (s, 1 H, Ar); 7.41 (td, J 8.8 Hz, J 2.5 Hz,
1 H, Ar); 8.00 (dd, J 9.3 Hz, J 2.5 Hz, 1 H, Ar); 8.25-8.28 (m, 2H, Ar); 8.41 (bs, 1 H, Ar); 8.90 (d,
J 5.0 Hz, 1 H, Ar).
M/Z (M+H)+ = 363.1.
MP: > 250°C.
Compound 28: 4-Chloro-2-hydrazino-benzoic acid, HCI.
Compound 28 was obtained according to general procedure IX, starting from 2-amino-4- chlorobenzoic acid, as a white solid in 38% yield.
1H-NMR (400 MHz, DMSO): 7.00 (dd, J 8.6 Hz, 2.0 Hz, 1 H, Ar); 7.23 (d, J 2.0 Hz, 1 H, Ar); 7.88 (d, J 8.6 Hz, 1 H, Ar); 9.16 (bs, 1 H, NH); 10.74 (bs, 3H, NH3).
Compound 29: 8-Chloro-2-(2-trifluoromethyl^yridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one. Compound 29 was obtained according to general procedure l(iv), starting from 2- trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 28 as a pale brown solid in 57% yield.
1H-NMR (400 MHz, DMSO): 6.78 (s, 1 H, Ar); 7.60 (dd, J 8.5 Hz, 2.0 Hz, 1 H, Ar); 8.16 (d, J 8.5 Hz, 1 H, Ar); 8.25 (d, J 2.0 Hz, 1 H, Ar); 8.29-8.31 (m, 1 H, Ar); 8.44 (bs, 1 H, Ar); 8.86 (d, J 5.0 Hz, 1 H, Ar); 12.57 (bs, 1 H, NH).
M/Z (M[35CI]+H)+ = 365.0. Example 56: 8-Chloro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-p^
5-one
Figure imgf000102_0001
1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, NCH3); 7.19 (s, 1 H, Ar);
7.59 (dd, J 8.6 Hz, 2.0 Hz, 1 H, Ar); 8.18 (d, J 8.6 Hz, 1 H, Ar); 8.23 (d, J 2.0 Hz, 1 H, Ar); 8.25-
8.27 (m, 1 H, Ar); 8.40 (bs, 1 H, Ar); 8.89 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M[35CI]+H)+ = 379.1.
MP: 220-225°C.
Compound 30: 2-Hydrazino-4-trifluoromethyl-benzoic acid, HCI.
Compound 30 was obtained according to general procedure IX, starting from 2-amino-4- trifluoromethylbenzoic acid, as a beige solid in 62% yield.
1H-NMR (400 MHz, DMSO): 7.26 (d, J 8.7 Hz, 1 H, Ar); 7.92 (dd, J 8.7 Hz, 2.0 Hz, 1 H, Ar); 8.1 1 (d, J 2.0 Hz, 1 H, Ar); 9.42 (bs, 1 H, NH); 10.74 (bs, 3H, NH3).
M/Z (M+H)+ = 221.2.
Compound 31 : 8-Trifluoromethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5- a]quinazolin-5-one.
Compound 31 was obtained according to general procedure l(iii), starting from 2- trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 30 as a brown solid in 50% yield.
1H-NMR (400 MHz, DMSO): 6.68 (s, 1 H, Ar); 8.17 (dd, J 8.7 Hz, 1 .9 Hz, 1 H, Ar); 8.25-8.26 (m, 1 H, Ar); 8.34-8.39 (m, 3H, Ar); 8.84 (d, J 5.1 Hz, 1 H, Ar). Signal for NH is not observed.
M/Z (M+H)+ = 399.1. Example 57: 4-Methyl-8-trifluoromethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H^yra a]quinazolin-5-one
Example 57 was obtained according to general procedure ll(i),
starting from compound 31 in presence of iodomethane. The
reaction mixture was stirred for 2 hours at room temperature.
Example 57 was obtained without further purification as a brown
Figure imgf000103_0001
solid in 33% yield.
1H-NMR (400 MHz, DMSO): 3.57 (s, 3H, NCH3); 7.23 (s, 1 H, Ar); 8.24-8.26 (m, 2H, Ar); 8.37- 8.39 (m, 3H, Ar); 8.90 (d, J 4.9 Hz, 1 H, Ar).
M/Z (M+H)+ = 413.2.
Compound 32: 4-Bromo-2-hydrazino-benzoic acid, HCI.
Compound 32 was obtained according to general procedure I, starting from 2-amino-4-bromo- benzoic acid, as a white solid in a quantitative yield.
1H-NMR (400 MHz, DMSO): 7.14 (dd, J 8.5 Hz, 1 .9 Hz, 1 H, Ar); 7.37 (d, J 1.9 Hz, 1 H, Ar); 7.81 (d, J 8.5 Hz, 1 H, Ar); 9.15 (bs, 1 H, NH); 10.63 (bs, 3H, NH3).
M/Z (M[79Br]-18+H)+ = 213.
Compound 33: 8-Bromo-2-( 2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1, 5-a]quinazolin-5-one. Compound 33 was obtained according to general procedure l(i), starting from 2-trifluoromethyl- isonicotinic acid ethyl ester in presence of hydrazine 32 as a brown solid in 69% yield.
1H-NMR (400 MHz, DMSO): 6.60 (s, 1 H, Ar); 7.64 (dd, J 8.5 Hz, 1 .9 Hz, 1 H, Ar); 8.03 (d, J 8.5
Hz, 1 H, Ar); 8.23-8.25 (m, 1 H, Ar); 8.31 (d, 1 .9 Hz, 1 H, Ar); 8.38 (bs, 1 H, Ar); 8.82 (d, J 5.0 Hz,
1 H, Ar). Signal for NH is not observed.
M/Z (M[79Br]+H)+ = 409.0.
Example 58: 8-Bromo-4-methyl-2-(2-trifluoromethyl^yridin-4-yl)-4H^yrazolo[1,5-a]quinazolin-
Figure imgf000103_0002
58 was obtained without further purification as a beige solid in 84% \=N yield.
1H-NMR (400 MHz, DMSO): 3.53 (s, 3H, NCH3); 7.16 (s, 1 H, Ar); 7.71 (dd, J 8.5 Hz, 1 .9 Hz, 1 H, Ar); 8.07 (d, J 8.5 Hz, 1 H, Ar); 8.23-8.25 (m, 1 H, Ar); 8.34 (d, 1.9 Hz, 1 H, Ar); 8.34 (bs, 1 H, Ar); 8.87 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M[79Br]+H)+ = 423.2. Example 59: 4-Methyl-8-morpholin-4-yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one.
Example 59 was obtained according to general procedure X(v) starting from example 58 in presence of morpholine. Purification by flash-chromatography (MeOH in DCM, 0 to 2%) afforded example 59 as a beige solid in 44% yield.
Figure imgf000104_0001
M/Z (M+H)+ = 430.3.
MP: >250°C. Example 60: 4-Methyl-8-pyrrolidin-1-yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one.
Example 60 was obtained according to general procedure X(iii)
starting from example 58 in presence of pyrolidine. The reaction
was heated for 1 hour. Purification by flash-chromatography
(MeOH in DCM, 0 to 5%) afforded example 60 as a beige solid in
Figure imgf000104_0002
25% yield.
1H-NMR (400 MHz, CDCI3): 2.08-2.12 (m, 4H, 2 CH2); 3.48-3.52 (m, 4H, 2 CH2); 3.60 (s, 3H, NCH3); 6.28 (s, 1 H, Ar); 6.63 (dd, J 9.0 Hz, 2.4 Hz, 1 H, Ar); 7.14 (d, 2.4 Hz, 1 H, Ar); 7.95-7.97 (m, 1 H, Ar); 8.1 1 (d, J 9.0 Hz, 1 H, Ar); 8.22 (bs, 1 H, Ar); 8.77 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 414.2.
MP: >250°C.
4-Methyl-8-methylamino-2-(2-tn luoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-
Example 61 was obtained according to general procedure X(iii)
starting from example 58 in presence of methyl amine HCI. The
reaction was performed with 3.0 equiv of LiHMDS. The reaction
mixture was heated for 4 hours, then methylamine HCI (1.2
equiv.), LiHMDS (1 N in THF; 3.0 equiv.) and BrettPhos precatalyst
Figure imgf000104_0003
(0.1 equiv.) were added. The reaction mixture was further heated for one hour at 60°C. Purification by flash-chromatography (MeOH in DCM, 0 to 3%) afforded example 61 as a beige solid in 44% yield. 1 H-NMR (400 MHz, DMSO): 2.86 (d, J 4.9 Hz, 3H, NHCH3); 3.50 (s, 3H, NCH3); 6.72 (dd, J 8.8 Hz, 2.2 Hz, 1 H, Ar); 7.06 (s, 1 H, Ar); 7.08-7.12 (m, 2H, Ar + NHCH3); 7.87 (d, J 8.8 Hz, 1 H, Ar); 8.22-8.24 (m, 1 H, Ar); 8.35 (bs, 1 H, Ar); 8.87 (d, J 5.2 Hz, 1 H, Ar).
M/Z (M+H)+ = 374.0.
MP: >250°C.
Example 62: 8-(4-Methoxy-piperidin-1-yl)-4-methyl-2-(2-tn luoromethyl-pyridi pyrazolo[1, 5-a]quinazolin-5-one.
Example 62 was obtained according to general procedure
X(iii) starting from example 58 in presence of 4- methoxypiperidine HCI. The reaction was performed with 3.0
equiv of LiHMDS. The reaction mixture was heated for 2
Figure imgf000105_0001
hours, then 4-methoxypiperidine HCI (1 .2 equiv.), LiHM DS
(1 N in THF; 3.0 equiv.) and BrettPhos precatalyst (0.1 equiv.) were added. The reaction mixture was further heated for one hour at 60°C. Purification by flash-chromatography (MeOH in DCM, 0 to 3%) afforded example 62 as a beige solid in 48% yield.
1 H-NMR (400 MHz, DMSO): 1 .51 -1 .59 (m, 2H, 2 CHaHb); 1 .95-1 .99 (m, 2H, 2 CHaHb); 3.23- 3.30 (m, 5H, OCH3 + 2 NCHaHb); 3.45-3.51 (m, 4H, NCH3 +OCH); 3.45-3.51 (m, 2H, 2 NCHaHb); 7.08 (s, 1 H, Ar); 7.1 1 (dd, J 9.0 Hz, 2.4 Hz, 1 H, Ar); 7.45 (d, 2.4 Hz, 1 H, Ar); 7.93 (d, J 9.0 Hz, 1 H, Ar); 8.25-8.27 (m, 1 H, Ar); 8.37 (bs, 1 H, Ar); 8.86 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 458.2.
MP: >250°C.
Example 63: 8-(4^ydroxy-piperidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H- pyrazolo[1, 5-a]quinazolin-5-one.
Example 63 was obtained according to general procedure
X(iii) starting from example 58 in presence of 4- hydroxypiperidine. Purification by flash-chromatography
(MeOH in DCM, 0 to 5%) afforded example 63 as a beige
solid in 20% yield.
Figure imgf000105_0002
1 H-NMR (400 MHz, DMSO): 1 .43-1 .52 (m, 2H, 2 CHaHb); 1 .85-1 .89 (m, 2H, 2 CHaHb); 3.16- 3.24 (m, 2H, 2 NCHaHb); 3.51 (s, 3H, NCH3); 3.73-3.80 (m, 1 H, OCH); 3.82-3.87 (m, 2H, 2 NCHaHb); 4.77 (d, 4.2 Hz, 1 H, OH); 7.09 (s, 1 H, Ar); 7.1 1 (dd, J 9.1 Hz, 2.4 Hz, 1 H, Ar); 7.45 (d, 2.4 Hz, 1 H, Ar); 7.93 (d, J 9.1 Hz, 1 H, Ar); 8.26-8.28 (m, 1 H, Ar); 8.38 (bs, 1 H, Ar); 8.86 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 444.1 .
MP: 1 12-1 17°C. Example 64: 8-Dimethylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5^ a]quinazolin-5-one.
Example 64 was obtained according to general procedure X(iii) starting from example 58 in presence of dimethyl amine HCI. The reaction was performed with 3.0 equiv of LiHMDS. Purification by flash-chromatography (MeOH in DCM, 0 to 3%)
afforded example 64 as a beige solid in 43% yield.
1H-NMR (400 MHz, CDCI3): 3.18 (s, 6H, N(CH3)2); 3.60 (s, 3H,
NCH3); 6.28 (s, 1 H, Ar); 6.76 (dd, J 9.0 Hz, 2.5 Hz, 1 H, Ar); 7.29 (d,
2.5 Hz, 1 H, Ar); 7.96-7.98 (m, 1 H, Ar); 8.12 (d, J 9.0 Hz, 1 H, Ar);
8.22 (bs, 1 H, Ar); 8.77 (d, J 5.1 Hz, 1 H, Ar).
Figure imgf000106_0001
M/Z (M+H)+ = 388.0.
MP: >250°C. Example 65: 4-Methyl-8-(4-methyl-piperazin-1-yl)-2-(2-tn luoromethyl-pyridin-4-yl)-4H- pyrazolo[1,5-a]quinazolin-5-one, HCI salt.
Example 65 was obtained according to general procedure X(iii)
starting from example 58 in presence of N-methylpiperazine.
Purification by flash-chromatography (MeOH in DCM, 0 to 5%)
and salt formation according to procedure IV(ii) afforded example
Figure imgf000106_0002
65 as a brown solid in 35% yield.
1H-NMR (400 MHz, DMSO): 2.85 (s, 3H, NCH3); 3.13-3.24 (m, 2H, 2 NCHaHb); 3.36-3.42 (m,
2H, 2 NCHaHb); 3.54-3.58 (m, 5H, NCH3 + 2 NCHaHb); 4.23-4.26 (m, 2H, 2 NCHaHb); 7.15 (s,
1 H, Ar); 7.21 (dd, J 9.0 Hz, 2.4 Hz, 1 H, Ar); 7.78 (d, 2.4 Hz, 1 H, Ar); 8.03 (d, J 9.0 Hz, 1 H, Ar); 8.27-8.29 (m, 1 H, Ar); 8.41 (bs, 1 H, Ar); 8.89 (d, J 5.1 Hz, 1 H, Ar); 10.76 (bs, 1 H, NH).
M/Z (M+H)+ = 443.1.
MP: >250°C.
Example 66: 4-Methyl-8-piperazin-1-yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one, HCI salt.
Example 66 was obtained according to general procedure X(ii)
starting from example 58 in presence of piperazine (5.0 equiv.).
The reaction was performed with 3.0 equiv of LiHMDS and THF
was used as solvent. After hydrolysis, the resulting solid was
collected, washed with water, dried over MgS04 and purified by
Figure imgf000106_0003
flash-chromatography (MeOH in DCM, 0 to 20%). Salt formation
according to procedure IV(iii) afforded example 66 as a beige solid in 21 % yield. 1H-NMR (400 MHz, DMSO/D20): 3.25-3.29 (m, 4H, 2 NCH2); 3.46 (m, 3H, NCH3); 3.65-3.69 (m, 4H, 2 NCH2); 6.90 (s, 1 H, Ar); 7.12 (dd, J 9.0 Hz, 1.9 Hz, 1 H, Ar); 7.47 (d, 1 .9 Hz, 1 H, Ar); 7.96 (d, J 9.0 Hz, 1 H, Ar); 8.14-8.16 (m, 1 H, Ar); 8.29 (bs, 1 H, Ar); 8.88 (d, J 4.9 Hz, 1 H, Ar). M/Z (M+H)+ = 429.1.
MP: >250°C.
Example 67: 8-(4^ydroxymethyl-piperidin-1-yl)-4-methyl-2-(2-tn luoromethyl-pyridi pyrazolo[1, 5-a]quinazoin-5-one.
Example 67 was obtained according to general procedure X(iii)
starting from example 58 in presence of 4-piperidinemethanol.
The reaction mixture was heated for 2 hours, then 4- piperidinemethanol (1.2 equiv.), LiHMDS (1 N in THF; 2.4 equiv.)
Figure imgf000107_0001
and BrettPhos precatalyst (0.1 equiv.) were added. The reaction mixture was further heated for 17 hours at 60°C. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 67 as a beige solid in 28% yield.
1H-NMR (400 MHz, DMSO): 1.18-1 .28 (m, 2H, 2 CHaHb); 1.64-1 .72 (m, 1 H, CH); 1.78-1 .82 (m, 2H, 2 CHaHb); 2.93-3.00 (m, 2H, 2 NCHaHb); 3.27-3.31 (m, 2H, 2 NCHaHb); 3.50 (s, 3H, NCH3); 4.05-4.08 (m, 2H, CH2OH); 4.50-4.52 (m, 1 H, CH2OH); 7.07 (s, 1 H, Ar); 7.10 (dd, J 9.1 Hz, 2.4 Hz, 1 H, Ar); 7.42 (d, 2.4 Hz, 1 H, Ar); 7.92 (d, J 9.1 Hz, 1 H, Ar); 8.25-8.27 (m, 1 H, Ar); 8.36 (bs, 1 H, Ar); 8.86 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 458.2.
MP: 205-210°C.
Example 68: 8-(3-Hydroxy-azetidin-1-yl)-4-methyl-2-(2-tn luoromethyl-pyridin-4-yl)-4H- pyrazolo[1, 5-a]quinazolin-5-one.
Example 68 was obtained according to general procedure X(iv)
starting from example 58 in presence of 4-hydroxyazetidine.
Purification by flash-chromatography (MeOH in DCM, 0 to 5%)
afforded example 68 as a beige solid in 51 % yield.
Figure imgf000107_0002
1H-NMR (400 MHz, DMSO): 3.51 (s, 3H, NCH3); 3.81 (dd, J 8.7 Hz, 4.4 Hz, 2H, 2 NCHaHb); 4.29-4.33 (m, 2H, 2 NCHaHb); 4.63-4.70 (m, 1 H, CHOH); 5.82 (d, 6.2 Hz, 1 H, CHOH); 6.55 (dd, J 8.8 Hz, 2.3 Hz, 1 H, Ar); 6.91 (d, 2.3 Hz, 1 H, Ar); 7.10 (s, 1 H, Ar); 7.95 (d, J 8.8 Hz, 1 H, Ar); 8.25-8.26 (m, 1 H, Ar); 8.36 (bs, 1 H, Ar); 8.87 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 416.0.
MP: >250°C. Example 69: 8-(3-Hydroxymethyl-azetidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridi pyrazolo[1,5-a]quinazolin-5-one.
Example 69 was obtained according to general procedure X(iv)
starting from example 58 in presence of 4-azetidin-3-ylmethanol
HCI. Purification by flash-chromatography (MeOH in DCM, 0 to
5%) afforded example 69 as a beige solid in 38% yield.
Figure imgf000108_0001
1H-NMR (400 MHz, DMSO): 2.84-2.93 (m, 1 H, CH); 3.51 (s, 3H,
NCH3); 3.62 (t, J 5.4 Hz, 2H, 2 CHCH2OH); 3.82 (dd, J 8.1 Hz, J 5.4 Hz, 2H, 2 NCHaHb); 4.10 (t, J 8.1 Hz, 2H, 2 NCHaHb); 4.84 (t, 5.4 Hz, 1 H, CH2OH); 6.53 (dd, J 8.7 Hz, 2.2 Hz, 1 H, Ar); 6.89 (d, 2.2 Hz, 1 H, Ar); 7.08 (s, 1 H, Ar); 7.94 (d, J 8.7 Hz, 1 H, Ar); 8.24-8.25 (m, 1 H, Ar); 8.36 (bs, 1 H, Ar); 8.87 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 430.1.
MP: >250°C. Example 70: 8-(3-Hydroxy-pyrrolidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H- pyrazolo[1,5-a]quinazolin-5-one.
Example 70 was obtained according to general procedure X(iii)
starting from example 58 in presence of 3-pyrolidinol. The reaction
mixture was heated for 2 hours, then 3-pyrolidinol (1.2 equiv.),
LiHMDS (1 N in THF; 2.4 equiv.) and BrettPhos precatalyst (0.1
Figure imgf000108_0002
equiv.) were added. The reaction mixture was further heated for 17 hours at 60°C. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 70 as a beige solid in 47% yield.
1H-NMR (400 MHz, DMSO): 1.95-2.01 (m, 1 H, CHaHb); 2.06-2.15 (m, 1 H, CHaHb); 3.28-3.30 (m, 1 H, NCH); 3.50-3.54 (m, 5H, 2 NCH + NCH3); 3.58 (dd, J 10.7 Hz, 4.5 Hz, 1 H, NCHaHb);
4.47 (m, 1 H, CHOH); 5.07 (d, 3.7 Hz, 1 H, CHOH); 6.72 (dd, J 8.9 Hz, 2.3 Hz, 1 H, Ar); 7.04 (d,
2.3 Hz, 1 H, Ar); 7.07 (s, 1 H, Ar); 7.94 (d, J 8.9 Hz, 1 H, Ar); 8.24-8.26 (m, 1 H, Ar); 8.36 (bs, 1 H,
Ar); 8.86 (d, J 5.0 Hz, 1 H, Ar).
M/Z (M+H)+ = 430.2.
MP: >250°C.
Example 71 : 8-(4-Hydroxy-4-methyl-piperidin- 1 -yl)-4-methyl-2-( 2-trifluoromethyl-pyridin-4-yl)- 4H-pyrazolo[1,5-a]quinazolin-5-one.
Example 71 was obtained according to general procedure X(iv)
starting from example 58 in presence of 4-methylpiperidin-4-ol.
The reaction mixture was heated for 17 hours, then 4- methylpiperidin-4-ol (0.8 equiv.), K3P04 (2.0 equiv.), Cul (0.05
Figure imgf000108_0003
equiv.) and DMPAO (0.1 equiv.) were added. The reaction mixture was further heated for 24 hours at 100°C. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 71 as a beige solid in 22% yield.
1H-NMR (400 MHz, DMSO): 1.18 (s, 3H, CCH3); 1.53-1 .64 (m, 4H, 2 CH2); 3.37-3.43 (m, 2H, 2 NCHaHb); 3.51 (s, 3H, NCH3); 3.68-3.73 (m, 2H, 2 NCHaHb); 4.44 (s, 1 H, OH); 7.09 (s, 1 H, Ar); 7.1 1 (dd, J 9.1 Hz, 2.4 Hz, 1 H, Ar); 7.45 (d, 2.4 Hz, 1 H, Ar); 7.93 (d, J 9.1 Hz, 1 H, Ar); 8.26- 8.28 (m, 1 H, Ar); 8.38 (bs, 1 H, Ar); 8.86 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 458.2.
MP: >250°C.
Example 72: 4, 8-Dimethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1, 5-a]quinazolin-5-one. Example 72 was obtained according to general procedure III starting
from example 58 in presence of a solution of dimethylzinc in toluene
(2M - 4.0 equiv.). The reaction was performed without Cul and was
heated for 17 hours at 90°C. Purification by flash-chromatography
(MeOH in DCM, 0 to 5%) and trituration of the resulting solid by EtOH
Figure imgf000109_0001
and then Et20 afforded example 72 as an orange solid in 24% yield.
1H-NMR (400 MHz, DMSO): 2.54 (s, 3H, CH3); 3.55 (s, 3H, NCH3); 7.15 (s, 1 H, Ar); 7.36-7.39 (m, 1 H, Ar); 8.05 (bs, 1 H, Ar); 8.08 (d, J 8.2 Hz, 1 H, Ar); 8.23-8.25 (m, 1 H, Ar); 8.37 (bs, 1 H, Ar); 8.88 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 359.0.
MP: >250°C.
Example 73: 8-Cyclopropyl-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one.
Example 73 was obtained according to general procedure III starting
from example 58 in presence of a solution of cyclopropylzinc bromide
in THF (0.5N - 3.0 equiv.). Purification by flash-chromatography
(MeOH in DCM, 0 to 5%) afforded example 73 as a beige solid in 26%
Figure imgf000109_0002
yield.
1H-NMR (400 MHz, DMSO): 0.90-0.93 (m, 2H, 2CHaHb); 1.13-1 .18 (m, 2H, 2CHaHb); 2.20-2.27 (m, 1 H, CH); 3.55 (s, 3H, NCH3); 7.15 (s, 1 H, Ar); 7.22 (dd, J 8.3 Hz, J 1.6 Hz, 1 H, Ar); 7.93 (d, J 1.6 Hz, 1 H, Ar); 8.06 (d, J 8.3 Hz, 1 H, Ar); 8.25-8.27 (m, 1 H, Ar); 8.38 (bs, 1 H, Ar); 8.88 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 385.2.
MP: >250°C. Example 74: 8-Cyclopentyl-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5- a]quinazolin-5-one.
Example 74 was obtained according to general procedure III starting from example 58 in presence of a solution of cyclopentylzinc bromide in THF (0.5N - 2.2 equiv.). Purification by flash-chromatography (EtOAc in cyHex, 0 to 50%) afforded example
74 as a beige solid in 22% yield.
1H-NMR (400 MHz, DMSO at 80°C): 1 .67-1.77 (m, 4H, 2CH2); 1.84- 1.88 (m, 2H, 2CHaHb); 2.13-2.19 (m, 2H, 2CHaHb); 3.25-3.30 (m,
1 H, CH); 3.59 (s, 3H, NCH3); 7.06 (s, 1 H, Ar); 7.47 (dd, J 8.2 Hz, J
Figure imgf000110_0001
1.4 Hz, 1 H, Ar); 8.10 (d, J 1.4 Hz, 1 H, Ar); 8.14 (d, J 8.2 Hz, 1 H, Ar); 8.23-8.25 (m, 1 H, Ar); 8.35 (bs, 1 H, Ar); 8.87 (d, J 5.0 Hz, 1 H, Ar).
M/Z (M+H)+ = 413.4.
MP: 246-250°C. Example 75: 4-Methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5- a]quinazoline-8-carbonitrile.
Example 75 was obtained according to general procedure VI
starting from example 58. The reaction was heated for 17 hours at
100°C. Purification by flash-chromatography (MeOH in DCM, 0 to
2%) afforded example 75 as a beige solid in 22% yield.
Figure imgf000110_0002
1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, NCH3); 7.20 (s, 1 H, Ar);
7.93 (dd, J 8.1 Hz, 1 .4 Hz, 1 H, Ar); 8.23-8.25 (m, 1 H, Ar); 8.29 (d, J 8.1 Hz, 1 H, Ar); 8.40 (bs,
1 H, Ar); 8.65 (d, J 1 .4 Hz, 1 H, Ar); 8.89 (d, J 5.0 Hz, 1 H, Ar).
M/Z (M+H)+ = 370.2.
MP: >250°C.
Example 76: 4-Methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5- a]quinazoline-8-carboxylic acid.
To a solution of example 75 (287 mg, 1.0 equiv.) in DMSO (4ml_,
C=0.2 molL"1), a solution of aqueous NaOH (1 N, 4ml_, 5.1 equiv.)
was added and the mixture was heated for 17 hours at 90°C. After
cooling, the reaction mixture was hydrolyzed with an aqueous HCI
solution (1 N). The solid was collected, washed with water and
Figure imgf000110_0003
dried under reduced pressure at 50°C with P205. Trituration in Et20 afforded example 76 as a yellow solid in 69% yield.
1H-NMR (400 MHz, DMSO): 3.59 (s, 3H, NCH3); 7.24 (s, 1 H, Ar); 8.04 (dd, J 8.1 Hz, 1 .4 Hz, 1 H, Ar); 8.28-8.31 (m, 2H, Ar); 8.40 (bs, 1 H, Ar); 8.69 (d, J 1 .4 Hz, 1 H, Ar); 8.89 (d, J 5.0 Hz, 1 H, Ar). Signal for COOH is not observed.
M/Z (M+H)+ = 389.1.
MP: >250°C.
General procedure XII: Amide formation via acid activation
Method (i): Under inert atmosphere, to a solution of acid (1 .0 equiv.) in DMF (C=0.1 molL"1), BOP (1 .1 equiv.), diisopropylamine (1.1 equiv.), and amine (1.1 equiv.) were added. The resulting mixture was stirred for 1 hour at room temperature. The reaction mixture was hydrolysed with a saturated aqueous NH4CI solution. The solid was collected, washed with water, dried under reduced pressure and purified to afford the amide .
Example 77: 4-Methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1,5- a]quinazoline-8-carboxylic acid amide.
Example 77 was obtained according to general procedure Xll(i)
starting from example 58 with ammoniac as nucleophile (0.5 N in
Dioxane). The reaction mixture was stirred for 3 hours at room
temperature. Trituration in EtOH, DCM and then Et20 afforded
example 77 as a beige solid in 23% yield.
1H-NMR (400 MHz, DMSO): 3.58 (s, 3H, NCH3); 7.21 (s, 1 H, Ar); 7.77 (bs, 1 H, CONHaHb); 8.00 (dd, J 8.2 Hz, 1.2 Hz, 1 H, Ar); 8.25-8.29 (m, 2H, Ar); 8.40-8.42 (m, 2H, 1Ar + CONHaHb); 8.68 (d, J 1.2 Hz, 1 H, Ar); 8.89 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 388.0.
MP: >250°C.
Example 78: 4-Methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5- a]quinazoline-8-carboxylic acid methylamide.
Example 78 was obtained according to general procedure Xll(i)
starting from example 58 with methylamine HCI as nucleophile (2.2
equiv. of iPr2NEt was added instead of 1.1 equiv.). Trituration in
EtOH then Et20 afforded example 78 as a white solid in 33% yield.
1H-NMR (400 MHz, DMSO): 2.86 (d, J 4.6 Hz, 3H, CONHCH3);
Figure imgf000111_0002
3.57 (s, 3H, NCH3); 7.20 (s, 1 H, Ar); 7.94 (dd, J 8.3 Hz, 1 .6 Hz,
1 H, Ar); 8.24-8.26 (m, 2H, Ar); 8.39 (bs, 1 H, Ar); 8.60 (d, 1.6 Hz, 1 H, Ar); 8.88-8.90 (m, 2H, 1Ar + CONHCH3).
M/Z (M+H)+ = 402.5.
MP: >250°C. Example 79: 4-Methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5- a]quinazoline-8-carboxylic acid dimethylamide.
Example 79 was obtained according to general procedure Xll(i)
starting from example 58 with dimethylamine HCI as nucleophile
(3.0 equiv. of iPr2NEt was added instead of 1 .1 equiv.). The
reaction mixture was stirred for 17 hours at room temperature.
Trituration in EtOH then Et20 afforded example 79 as a beige
Figure imgf000112_0001
solid in 3% yield.
1H-NMR (400 MHz, DMSO): 2.94 (s, 3H, CON(CH3)(CH3)); 3.06 (s, 3H, CON(CH3)(CH3)); 3.58 (s, 3H, NCH3); 7.22 (s, 1 H, Ar); 7.54-7.55 (m, 1 H, Ar); 8.20-8.28 (m, 3H, Ar); 8.41 (bs, 1 H, Ar); 8.88-8.89 (m, 1 H, 1Ar).
M/Z (M+H)+ = 415.9. Example 80: 4-Methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5- a]quinazoline-8-carboxylic acid diethylamide.
Example 80 was obtained according to general procedure Xll(i)
starting from example 58 with diethylamine as nucleophile.
Purification by flash-chromatography (MeOH in DCM, 0 to 5%)
afforded example 80 as a white solid in 40% yield.
Figure imgf000112_0002
1H-NMR (400 MHz, DMSO): 1 .06-1.23 (m, 6H,
CON(CH2CH3)(CH2CH3)); 3.19-3.25 (m, 2H, CON(CH2CH3)(CH2CH3)); 3.48-3.54 (m, 2H,
CON(CH2CH3)(CH2CH3)); 3.58 (s, 3H, NCH3); 7.22 (s, 1 H, Ar); 7.50-7.53 (m, 1 H, Ar); 8.14 (bs,
1 H, Ar); 8.25 (d, J 8.2 Hz, 1 H, Ar); 8.27-8.28 (m, 1 H, Ar); 8.41 (bs, 1 H, Ar); 8.88 (d, J 4.9 Hz, 1 H, 1Ar).
M/Z (M+H)+ = 444.3.
MP: 240-245°C.
Example 81 : 4-Methyl-8-(morpholine-4-carbonyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H- pyrazolo[1, 5-a]quinazolin-5-one.
Example 81 was obtained according to general procedure Xll(i)
starting from example 58 with morpholine as nucleophile.
Trituration in DCM then Et20 afforded example 81 as a white
solid in 34% yield.
Figure imgf000112_0003
1H-NMR (400 MHz, DMSO): 3.52-3.58 (m, 4H, 2 CH2); 3.62 (s,
3H, NCH3); 3.64-3.69 (m, 4H, 2 CH2); 7.1 1 (s, 1 H, Ar); 7.55 (d, J 8.0 Hz, 1 H, Ar); 8.23-8.29 (m,
3H, Ar); 8.37 (bs, 1 H, Ar); 8.88 (d, J 4.7 Hz, 1 H, Ar). M/Z (M+H)+
MP: >250°C
Example 82: 4-Methyl-8-(pyrrolidine-1-carbonyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H- pyrazolo[1, 5-a]quinazolin-5-one.
Example 82 was obtained according to general procedure Xll(i)
starting from example 58 with pyrolidine as nucleophile.
Trituration in EtOH then Et20 afforded example 82 as a beige
solid in 56% yield.
Figure imgf000113_0001
1H-NMR (400 MHz, DMSO): 1.82-1 .96 (m, 4H, 2 CH2); 3.40 (t, J 6.4 Hz, 2H, 2NCHaHb); 3.54 (t, J 6.8 Hz, 2H, 2NCHaHb); 3.58 (s, 3H, NCH3); 7.21 (s, 1 H, Ar); 7.64 (dd, J 8.2 Hz, 1 .5 Hz, 1 H, Ar); 8.24 (d, 8.2 Hz, 1 H, Ar); 8.26-8.27 (m, 2H, Ar); 8.40 (bs, 1 H, Ar); 8.88 (d, J 5.1 Hz, 1 H, Ar). M/Z (M+H)+ = 442.0.
MP: >250°C.
Example 83: 8-(2^ydroxy-ethoxy)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5- a]quinazolin-5-one.
Example 83 was obtained according to general procedure
Vll(iii) starting from example 55 in presence of ethylene
glycol. The reaction mixture was heated for 3 hours at 60°C,
then fBuOK (1 .2 equiv.) were added and the mixture was
heated for additional 17 hours at 60°C. Trituration in DCM
Figure imgf000113_0002
and Et20 afforded example 83 as a beige solid in 47% yield.
1H-NMR (400 MHz, DMSO): 3.53 (s, 3H, NCH3); 3.79-3.82 (m, 2H, OCH2CH2OH); 4.23 (t, J 4.9 Hz, 2H, OCH2CH2OH); 4.97 (t, J 5.4 Hz, 1 H, OCH2CH2OH); 7.1 1 (dd, J 8.8 Hz, J 2.4 Hz, 1 H,
Ar); 7.13 (s, 1 H, Ar); 7.61 (d, J 2.4 Hz, 1 H, Ar); 8.09 (d, J 8.8 Hz, 1 H, Ar); 8.24-8.26 (m, 1 H,
Ar); 8.37 (bs, 1 H, Ar); 8.87 (d, J 5.0 Hz, 1 H, Ar).
M/Z (M+H)+ = 405.1.
MP: 128-134°C.
Compound 34: 2-Hydrazino-6-trifluoromethyl-benzoic acid, HCI.
Compound 34 was obtained according to general procedure IX, starting from 2-amino-6- trifluoromethylbenzoic acid, as a white solid in 35% yield.
1H-NMR (400 MHz, DMSO): 7.33-7.43 (m, 2H, Ar); 7.60-7.67 (m, 1 H, Ar); 8.06 (bs, 1 H, NH); 10.32 (bs, 3H, NH3).
M/Z (M-18+H)+ = 203.0. Compound 35: 6-Trifluoromethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5- a]quinazolin-5-one.
Compound 35 was obtained according to general procedure l(iii), starting from 2- trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 34 as a brown solid in 25% yield.
1H-NMR (400 MHz, DMSO): 6.34 (s, 1 H, Ar); 7.78 (d, J 7.4 Hz, 1 H, Ar); 7.82-7.86 (m, 1 H, Ar); 8.17-8.19 (m, 1 H, Ar); 8.32 (bs, 1 H, Ar); 8.50 (d, J 8.1 Hz, 1 H, Ar); 8.79 (d, J 5.1 Hz, 1 H, Ar). M/Z (M+H)+ = 399.1. Example 84: 4-Methyl-6-trifluoromethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ^ a]quinazolin-5-one
Example 84 was obtained according to general procedure ll(i), starting
from compound 35 in presence of iodomethane. The reaction mixture
was stirred for 2 hours at room temperature. Example 84 was
obtained without further purification as a grey solid in 19% yield.
1H-NMR (400 MHz, DMSO): 3.53 (s, 3H, NCH3); 7.20 (s, 1 H, Ar);
Figure imgf000114_0001
7.99-8.01 (m, 1 H, Ar); 8.06-8.1 1 (m, 1 H, Ar); 8.27-8.28 (m, 1 H, Ar); 8.41 (bs, 1 H, Ar); 8.66-8.68 (m, 1 H, Ar); 8.91 -8.92 (m, 1 H, Ar).
M/Z (M+H)+ = 413.1.
Compound 36: 6-Fluoro-2-hydrazino-benzoic acid, HCI.
Compound 36 was obtained according to general procedure IX, starting from 2-amino-6- fluoromethylbenzoic acid, as a beige solid in 48% yield.
1H-NMR (400 MHz, DMSO): 6.65 (dd, J 106 Hz, J 8.4 Hz, 1 H, Ar); 6.9 (d, J 8.5 Hz, 1 H, Ar); 7.51-7.57 (m, 1 H, Ar); 8.70 (bs, 1 H, NH); 10.28 (bs, 3H, NH3).
M/Z (M+H)+ = 171.8.
Compound 37: 6-Fluoro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one. Compound 37 was obtained according to general procedure l(iv), starting from 2- trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 36 as a pale brown solid in 53% yield.
1H-NMR (400 MHz, DMSO): 6.72 (s, 1 H, Ar); 7.32 (dd, J 1 1 .2 Hz, J 8.5 Hz, 1 H, Ar); 7.88-7.94 (m, 1 H, Ar); 8.08 (d, J 8.2 Hz, 1 H, Ar); 8.25-8.27 (m, 1 H, Ar); 8.40 (bs, 1 H, Ar); 8.85 (d, J 4.8 Hz, 1 H, Ar). Signal for NH is not observed.
M/Z (M+H)+ = 349.1. Example 85: 6-Fluoro-4-methyl-2-(2-trifluoromethyl^yridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin- 5-one
Example 85 was obtained according to general procedure ll(iii), starting from compound 37 in presence of iodomethane. The reaction mixture was stirred for 3 hours at room temperature.
Figure imgf000115_0001
M/Z (M+H)+ = 363.1.
MP: > 250°C.
Compound 38: 2-Hydrazino-3-methoxy-benzoic acid, HCI.
Compound 38 was obtained according to general procedure IX, starting from 2-amino-3- methoxylbenzoic acid, as a white solid in 19% yield.
1H-NMR (400 MHz, DMSO): 3.89 (s, 3H, OCH3); 7.18 (t, J 8.1 Hz, 1 H, Ar); 7.34 (dd, J 8.1 Hz, 1.3 Hz, 1 H, Ar); 7.55 (dd, J 8.1 Hz, J 1 .3 Hz, 1 H, Ar); 9.04 (bs, 1 H, NH); 9.75 (bs, 3H, NH3). Compound 39: 9-Methoxy-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1, 5-a]quinazolin-5- one.
Compound 39 was obtained according to general procedure l(iv), starting from 2- trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 38 as a brown solid in 24% yield.
1H-NMR (400 MHz, DMSO): 3.92 (s, 3H, OCH3); 6.32 (s, 1 H, Ar); 7.26 (t, J 7.8 Hz, 1 H, Ar); 7.33 (dd, J 7.8 Hz, J 1.5 Hz, 1 H, Ar); 7.74 (dd, J 7.8 Hz, J 1 .5 Hz, 1 H, Ar); 8.10-8.1 1 (m, 1 H, Ar); 8.24 (bs, 1 H, Ar); 8.71 (d, J 5.2 Hz, 1 H, Ar). Signal for NH is not observed.
M/Z (M+H)+ = 361.1. Example 86: 9-Methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one.
Example 86 was obtained according to general procedure ll(iii), starting
from compound 39 in presence of iodomethane. The reaction mixture
was stirred for 3 hours at room temperature. The solid was further
washed with DCM, DCM/MeOH, EtOH and Et20 to obtained example 86
as a white solid in 14% yield.
Figure imgf000115_0002
1H-NMR (400 MHz, DMSO): 3.61 (s, 3H, NCH3); 4.06 (s, 3H, OCH3); 7.07 (s, 1 H, Ar); 7.52 (t, J 8.0 Hz, 1 H, Ar); 7.64 (d, J 8.0 Hz, 1 H, Ar); 7.92 (d, J 8.0 Hz, 1 H, Ar); 8.22-8.24 (m, 1 H, Ar); 8.34 (bs, 1 H, Ar); 8.86 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 374.9.
MP: > 250°C.
Compound 40: 2-Hydrazino-4,5-dimethoxy-benzoic acid, HCI.
Compound 40 was obtained according to general procedure IX, starting from 2-amino-4,5- dimethoxybenzoic acid, as a beige solid in 92% yield.
1H-NMR (400 MHz, DMSO): 3.73 (s, 3H, OCH3); 3.85 (s, 3H, OCH3); 7.00 (s, 1 H, Ar); 7.36 (s, 1 H, Ar); 9.00 (bs, 1 H, NH); 10.24 (bs, 3H, NH3).
Compound 41 : 7, 8-Dimethoxy-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1, 5-a]quinazolin-5- one.
Compound 41 was obtained according to general procedure l(iv), starting from 2- trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 40 as a brown solid in 57% yield.
1H-NMR (400 MHz, DMSO): 3.90 (s, 3H, OCH3); 4.04 (s, 3H, OCH3); 6.74 (s, 1 H, Ar); 7.44 (s, 1 H, Ar); 7.68 (s, 1 H, Ar) 8.27-8.28 (m, 1 H, Ar); 8.41 (bs, 1 H, Ar); 8.84 (d, J 5.2 Hz, 1 H, Ar); 12.39 (bs, 1 H, NH).
Example 87: 7,8-Dimethoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5- a]quinazolin-5-one.
Example 87 was obtained according to general procedure ll(iii),
starting from compound 41 in presence of iodomethane. The
reaction mixture was stirred for 3 hours at room temperature.
Example 87 was obtained without further purification as a beige
Figure imgf000116_0001
solid in 63% yield.
1H-NMR (400 MHz, DMSO): 3.60 (s, 3H, NCH3); 3.92 (s, 3H, OCH3); 4.06 (s, 3H, OCH3); 7.05 (s, 1 H, Ar); 7.62 (s, 1 H, Ar); 7.72 (s, 1 H, Ar); 8.24-8.25 (m, 1 H, Ar); 8.36 (bs, 1 H, Ar); 8.86 (d, J 5.2 Hz, 1 H, Ar).
M/Z (M+H)+ = 405.0.
MP: > 250°C. Compound 42: 4,5-Difluoro-2-hydrazino-benzoic acid, HCI.
Compound 42 was obtained according to general procedure IX, starting from 2-amino-4,5- dimethoxybenzoic acid, as a beige solid in 67% yield. 1H-NMR (400 MHz, DMSO): 7.28 (dd, J 13.0 Hz, J 6.7 Hz, 1 H, Ar); 7.87 (dd, J 1 1 .2 Hz, J 9.6 Hz, 1 H, Ar); 9.12 (bs, 1 H, NH); 10.64 (bs, 3H, NH3).
Compound 43: 7, 8-Difluoro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1, 5-a]quinazolin-5- one.
Compound 43 was obtained according to general procedure l(iv), starting from 2- trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 42 as a brown solid in 48% yield.
1H-NMR (400 MHz, DMSO): 6.80 (s, 1 H, Ar); 8.15 (dd, J 10.2 Hz, J 8.2 Hz, 1 H, Ar); 8.26-8.31 (m, 2H, Ar); 8.44 (bs, 1 H, Ar); 8.86 (d, J 5.1 Hz, 1 H, Ar); 12.67 (bs, 1 H, NH).
M/Z (M+H)+ = 366.9.
Example 88: 7,8-Difluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one.
Example 88 was obtained according to general procedure ll(iii),
starting from compound 43 in presence of iodomethane. The reaction
mixture was stirred for 3 hours at room temperature. Example 88 was
obtained without further purification as a white solid in 13% yield.
1H-NMR (400 MHz, DMSO): 3.56 (s, 3H, NCH3); 7.20 (s, 1 H, Ar); 8.15
Figure imgf000117_0001
(dd, J 10.2 Hz, J 8.2 Hz, 1 H, Ar); 8.23-8.30 (m, 2H, Ar); 8.39 (bs, 1 H, Ar); 8.89 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 380.9.
MP: > 206-212°C. Compound 44: 4-Fluoro-2-hydrazino-5-methoxy-benzoic acid, HCI.
Compound 44 was obtained according to general procedure IX, starting from 2-amino-4-fluoro- 5-methoxybenzoic acid, as a white solid in 78% yield.
1H-NMR (400 MHz, DMSO): 3.82 (s, 3H, OCH3); 7.16 (d, J 13.5 Hz, 1 H, Ar); 7.58 (d, J 9.5 Hz, 1 H, Ar); 9.13 (bs, 1 H, NH); 10.55 (bs, 3H, NH3).
Compound 45: 8-Fluoro-7-methoxy-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5- a]quinazolin-5-one.
Compound 45 was obtained according to general procedure l(iv), starting from 2- trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 43 as a brown solid in 49% yield.
1H-NMR (400 MHz, DMSO): 3.98 (s, 3H, OCH3); 6.75 (s, 1 H, Ar); 7.76 (d, J 8.7 Hz, 1 H, Ar); 8.06 (d, J 1 1.2 Hz, 1 H, Ar); 8.24-8.26 (m, 1 H, Ar); 8.40 (bs, 1 H, Ar); 8.84 (d, J 5.1 Hz, 1 H, Ar); 12.55 (bs, 1 H, NH).
M/Z (M+H)+ = 379.0.
Example 89: 8-Fluoro-7-methoxy-4-methyl-2-(2-tn luoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one.
Example 89 was obtained according to general procedure ll(iii),
starting from compound 45 in presence of iodomethane. The
reaction mixture was stirred for 3 hours at room temperature.
Example 89 was obtained without further purification as a brown
solid in 79% yield.
Figure imgf000118_0001
1H-NMR (400 MHz, DMSO): 3.56 (s, 3H, NCH3); 3.98 (s, 3H, OCH3); 7.16 (s, 1 H, Ar); 7.76 (d, J 8.6 Hz, 1 H, Ar); 8.05 (d, J 1 1 .1 Hz, 1 H, Ar) 8.21-8.22 (m, 1 H, Ar); 8.37 (bs, 1 H, Ar); 8.87 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 393.0.
MP: 220-230°C.
90: 8-(4^ydroxy-piperidin-1-yl)-7-methoxy-4-methyl-2-(2-trifluoromethyl-pyridi
4H-pyrazolo[1,5-a]quinazolin-5-one.
Example 90 was obtained according to general procedure X(vi)
starting from example 89 in presence of 4-hydroxypiperidine.
Trituration in DCM afforded example 90 as a white solid in 80%
Figure imgf000118_0002
1H-NMR (400 MHz, DMSO): 1.54-1.62 (m, 2H, 2 CHaHb); 1 .89-1.93 (m, 2H, 2 CHaHb); 2.93- 2.99 (m, 2H, 2 NCHaHb); 3.54-3.56 (s, 5H, 2 NCHaHb + NCH3); 3.67-3.73 (m, 1 H, OCH); 3.92 (s, 3H, OCH3); 7.14 (s, 1 H, Ar); 7.50 (s, 1 H, Ar); 7.57 (s, 1 H, Ar) 8.25-8.26 (m, 1 H, Ar); 8.36 (bs, 1 H, Ar); 8.86 (d, J 5.0 Hz, 1 H, Ar). Signal for OH is not observed.
M/Z (M+H)+ = 474.1.
MP: >250°C. Compound 46: 8-Dimethylamino-7-fluoro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5- a]quinazolin-5-one.
Compound 46 was obtained according to general procedure X(vi) starting from compound 43 in presence of dimethylamine (2 N in THF). The reaction mixture was heated for 1 hour, then dimethylamine (2 N in THF, 1.6 equiv.) was added again. The reaction mixture was further heated for 17 Hrs at 90°C, then dimethylamine (2 N in THF, 1 .6 equiv.) was added a last time. The reaction mixture was further heated for 24 hours at 90°C. Compound 46 was isolate without further purification. M/Z (M+H)+ = 392.0.
Example 91 : 8-Dimethylamino-7-fluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H- pyrazolo[1,5-a]quinazolin-5-one.
Example 91 was obtained according to general procedure ll(iii), starting from compound 46 in presence of iodomethane. The reaction mixture was stirred for 3
hours at room temperature. Example 91 was obtained without
further purification as a white solid in 64% yield.
H-NMR (400 MHz, DMSO): 3.14 (s, 6H, N(CH3)2); 3.57 (s, 3H,
NCH3); 7.04 (s, 1 H, Ar); 7.48 (d, J 8.0 Hz, 1 H, Ar); 7.73 (d, J 14.3
Figure imgf000119_0001
Hz, 1 H, Ar); 8.23-8.25 (m, 1 H, Ar); 8.34 (bs, 1 H, Ar); 8.87 (d, J 5.2
Hz, 1 H, Ar).
M/Z (M+H)+ = 406.0.
MP: > 250°C.
Compound 47: 5-Bromo-4-fluoro-2-hydrazino-benzoic acid, HCI.
Compound 47 was obtained according to general procedure IX, starting from 2-amino-5- bromo-4-fluorobenzoic acid, as a white solid in 85% yield.
1H-NMR (400 MHz, DMSO): 7.15 (d, J 1 1 .5 Hz, 1 H, Ar); 8.08 (d, J 8.0 Hz, 1 H, Ar); 9.20 (bs, 1 H, NH); 10.58 (bs, 3H, NH3).
Compound 48: 7-Bromo-8-fluoro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one.
Compound 48 was obtained according to general procedure l(iv), starting from 2- trifluoromethyl-isonicotinic acid ethyl ester in presence of hydrazine 47 as a reddish solid in 52% yield.
M/Z (M[79Br]+H)+ = 427.0.
Example 92: 7-Bromo-8-fluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one.
Example 92 was obtained according to general procedure ll(iii),
starting from compound 48 in presence of iodomethane. The reaction
mixture was stirred for 3 hours at room temperature. Example 92 was
obtained without further purification as a brown solid in 97% yield.
Figure imgf000119_0002
1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, NCH3); 7.21 (s, 1 H, Ar); 8.16
(d, J 9.0 Hz, 1 H, Ar); 8.23-8.25 (m, 1 H, Ar); 8.38-8.40 m, 2H, Ar); 8.90 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M[79Br]+H)+ = 441 .0. MP: 230-235°C.
Example 93: 7-Bromo-8-mef/70xy-4-mef/7y/-2- 2-fr/7/uoromef/7y/-pyr/'d/'n-4-y/J-4H-pyrazo/o '7,5- a]quinazolin-5-one.
Example 93 was obtained according to general procedure Vll(iii)
starting from example 92 in presence of methanol. Trituration in
Et20 afforded example 93 as a beige solid in 78% yield.
1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, NCH3); 4.13 (s, 3H, OCH3);
7.20 (s, 1 H, Ar); 7.72 (s, 1 H, Ar); 8.26 (s, 1 H, Ar); 8.27-8.29 (m, 1 H,
Figure imgf000120_0001
Ar); 8.40 (bs, 1 H, Ar); 8.89 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M[79Br]+H)+ = 453.0.
MP: >250°C.
Example 94: 8-Mef/70xy-4-mef/7y/-7-mef/7y/am/'no-2-(2-fr/7/uoromef/7y/-pyr/'d/'n-4-y -4 - - pyrazolo[1, 5-a]quinazolin-5-one.
Example 94 was obtained according to general procedure X(iii)
starting from example 93 in presence of methylamine HCI. DMA
was used as solvent and the reaction was heated for 1 hour at
60°C. After hydrolysis with a saturated aqueous NH4CI solution,
example 95 was extracted with EtOAc. The organic layers were
Figure imgf000120_0002
combined, washed with brine and dried over MgS04. Purification
by preparative HPLC afforded example 94 as a yellow solid in 1 1 % yield.
1H-NMR (400 MHz, DMSO/D20): 2.80 (s, 3H, NHCH3); 3.55 (s, 3H, NCH3); 4.06 (s, 3H, OCH3);
5.66 (s, 3H, NHCH3); 7.00 (s, 1 H, Ar); 7.09 (s, 1 H, Ar); 7.54 (s, 1 H, Ar); 8.22-8.23 (m, 1 H, Ar); 8.35 (bs, 1 H, Ar); 8.85 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H+CH3CN)+ = 445.1 .
MP: >250°C.
Compound 49: 7-Chloro-2-(2-chloro-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one.
Compound 49 was obtained according to general procedure l(i), starting from 2-chloro- isonicotinic methyl ester in presence of hydrazine 10 as a brown solid in 51 % yield.
1H-NMR (400 MHz, DMSO): 6.68 (s, 1 H, Ar); 7.96-7.99 (m, 2H, Ar); 8.07 (bs, 1 H, Ar); 8.09 (d, J 2.3 Hz, 1 H, Ar); 8.22 (d, J 8.7 Hz, 1 H, Ar); 8.50 (d, J 5.2 Hz, 1 H, Ar); 12.55 (bs, 1 H, NH). M/Z (M[35CI]2+H)+ = 331.1 . Example 95: 7-Chloro-2-( 2-chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1, 5-a]quinazolin-5-one. Example 95 was obtained according to general procedure ll(iii), starting
from compound 49 in presence of iodomethane. The reaction mixture
was stirred for 2 hours at room temperature. DMF was used instead of
DMA. Example 95 was obtained without further purification as a beige
solid in 82% yield.
Figure imgf000121_0001
1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, NCH3); 7.1 1 (s, 1 H, Ar); 7.94-7.98 (m, 2H, Ar); 8.02 (bs, 1 H, Ar); 8.1 1 (d, J 2.3 Hz, 1 H, Ar); 8.21 (d, J 8.9 Hz, 1 H, Ar); 8.52 (d, J 5.1 Hz, 1 H, Ar). M/Z (M[35CI]2+H)+ = 345.1 .
MP: > 250°C.
Example 96: 7-Chloro-2-(2-chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one, HCI salt.
Example 96 was obtained according to general procedure III starting
from example 95 in presence of a solution of cyclopropylzinc
bromide in THF (0.5M - 3.0 equiv.). Purification by flash- chromatography (MeOH in DCM, 0 to 5%) and salt formation
Figure imgf000121_0002
according to procedure IV(i) afforded example 96 as a beige solid in
51 % yield.
1H-NMR (400 MHz, DMSO): 1 .17-1.23 (m, 4H, 2CH2); 2.28-2.35 (m, 1 H, CCH); 3.51 (s, 3H, NCH3); 7.15 (s, 1 H, Ar); 7.91 (bs, 1 H, Ar); 7.94 (dd, J 8.8 Hz, J 2.4 Hz, 1 H, Ar); 7.98-7.99 (m, 1 H, Ar); 8.08 (d, J 2.4 Hz, 1 H, Ar); 8.19 (d, J 8.8 Hz, 1 H, Ar); 8.60 (d, J 5.8 Hz, 1 H, Ar). Signal for HCI salt is not observed.
M/Z (M[35CI]2+H)+= 351 .4.
MP: 245-250°C.
Compound 50: 7-Chloro-2-(2-Fluoro-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one.
Compound 50 was obtained according to general procedure l(ii), starting from 2-fluoro- isonicotinic methyl ester in presence of hydrazine 10 as a brown solid in 54% yield.
1H-NMR (400 MHz, DMSO): 6.66 (s, 1 H, Ar); 7.71 (bs, 1 H, Ar); 7.92-7.93 (m, 1 H, Ar); 7.98 (dd, J 8.7 Hz, J 2.5 Hz, 1 H, Ar); 8.09 (d, J 2.5 Hz, 1 H, Ar); 8.20 (d, J 8.7 Hz, 1 H, Ar); 8.33 (d, J 5.2 Hz, 1 H, Ar); 12.59 (bs, 1 H, NH).
M/Z (M[35CI]+H)+ = 315.4. Example 97: 7-Chloro-2-(2-Fluoro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one. Example 97 was obtained according to general procedure ll(iii), starting
from compound 50 in presence of iodomethane. The reaction mixture
was stirred for 2 hours at room temperature. DMF was used instead of
DMA. Example 97 was obtained without further purification as a white
solid in 71 % yield.
Figure imgf000122_0001
1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, NCH3); 7.07 (s, 1 H, Ar); 7.66
(bs, 1 H, Ar); 7.88-7.90 (m, 1 H, Ar); 7.97 (dd, J 8.8 Hz, J 2.4 Hz, 1 H, Ar); 8.10 (d, J 2.4 Hz, 1 H, Ar); 8.19 (d, J 8.8 Hz, 1 H, Ar); 8.36 (d, J 5.2 Hz, 1 H, Ar).
M/Z (M[35CI]+H)+ = 329.2.
MP: > 250°C.
Example 98: 7-Chloro-4-methyl-2-[2-(2,2,2-tn luoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1 ,5- a]quinazolin-5-one.
Example 98 was obtained according to general procedure Vll(i)
starting from example 97 in presence of 2,2,2-trifluoroethanol.
The reaction was stirred for 5 hours at room temperature.
Trituration in Et20 afforded example 98 as a white solid in 87%
yield.
Figure imgf000122_0002
1H-NMR (400 MHz, DMSO): 3.54 (s, 3H, NCH3); 5.05 (q, J 9.1 Hz, 2H, OCH2CF3); 7.06 (s, 1 H, Ar); 7.50 (bs, 1 H, Ar); 7.66-7.67 (m, 1 H, Ar); 7.96 (dd, J 8.8 Hz, J 2.4 Hz, 1 H, Ar); 8.10 (d, J 2.4 Hz, 1 H, Ar); 8.19 (d, J 8.8 Hz, 1 H, Ar); 8.31 (d, J 5.3 Hz, 1 H, Ar).
M/Z (M[35CI]+H)+ = 409.4
MP: 180-190°C.
Compound 51 : 2-(2-Chloro-pyridin-4-yl)-7-methoxy-4H-pyrazolo[1 , 5-a ]quinazolin-5-one.
Compound 51 was obtained according to general procedure l(i), starting from 2-chloro- isonicotinic methyl ester in presence of hydrazine 12 as a brown solid in 54% yield.
1H-NMR (400 MHz, DMSO): 3.90 (s, 3H, OCH3); 6.65 (s, 1 H, Ar); 7.53 (d, J 9.0 Hz, J 2.9 Hz, 1 H, Ar); 7.60 (d, J 2.9 Hz, 1 H, Ar); 7.96 (d, J 5.2 Hz, J 1.4 Hz, 1 H, Ar); 8.04 (bs, 1 H, Ar); 8.16 (d, J 9.0 Hz, 1 H, Ar); 8.48 (d, J 5.2 Hz, 1 H, Ar); 12.45 (bs, 1 H, NH).
M/Z (M[35CI]+H)+ = 327.2. Example 99: 2-(2-Chloro-pyridin-4-yl)-7-methoxy-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one. Example 99 was obtained according to general procedure ll(iii),
starting from compound 51 in presence of iodomethane. The reaction
mixture was stirred for 2 hours at room temperature. DMF was used
instead of DMA. Example 99 was obtained without further purification
as a brown solid in 75% yield.
Figure imgf000123_0001
1H-NMR (400 MHz, DMSO): 3.56 (s, 3H, NCH3); 3.90 (s, 3H, OCH3);
7.05 (s, 1 H, Ar); 7.52 (d, J 9.0 Hz, J 2.9 Hz, 1 H, Ar); 7.60 (d, J 2.9 Hz, 1 H, Ar); 7.93 (d, J 5.2 Hz, J 1 .4 Hz, 1 H, Ar); 8.00 (bs, 1 H, Ar); 8.15 (d, J 9.0 Hz, 1 H, Ar); 8.51 (d, J 5.2 Hz, 1 H, Ar). M/Z (M[35CI]+H)+ = 341.2.
MP: > 250°C.
Example 100: 2-(2-Cyclopropyl-pyridin-4-yl)-7-methoxy-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin- 5-one, HCI salt.
Example 100 was obtained according to general procedure III
starting from example 99 in presence of a solution of
cyclopropylzinc bromide in THF (0.5M - 3.0 equiv.). Purification
by flash-chromatography (MeOH in DCM, 0 to 5%) and salt
formation according to procedure IV(i) afforded example 100 as
Figure imgf000123_0002
an orange solid in 39% yield.
1H-NMR (400 MHz, DMSO): 1.26-1.33 (m, 4H, 2CH2); 2.38-2.45 (m, 1 H, CCH); 3.57 (s, 3H, NCH3); 3.90 (s, 3H, OCH3); 7.19 (s, 1 H, Ar); 7.54 (dd, J 9.0 Hz, J 2.8 Hz, 1 H, Ar); 7.60 (d, J 2.8 Hz, 1 H, Ar); 7.96 (bs, H, Ar); 8.08-8.09 (m, 1 H, Ar); 8.17 (d, J 9.0 Hz, 1 H, Ar); 8.66 (d, J 5.9 Hz, 1 H, Ar). Signal for HCI salt is not observed.
M/Z (M+H)+ = 347.5.
MP: 230-240°C.
Compound 52: 2-(2-Fluoro-pyridin-4-yl)-7-methoxy-4H-pyrazolo[1 , 5-a ]quinazolin-5-one.
Compound 52 was obtained according to general procedure l(ii), starting from 2-chloro- isonicotinic methyl ester in presence of hydrazine 12 as a greenish solid in 40% yield.
M/Z (M+H)+ = 31 1.4. Example 101 : 2-(2-Fluoro-pyridin-4-yl)-7-methoxy-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5- one.
Figure imgf000124_0001
purification as a brown solid in 34% yield.
1H-NMR (400 MHz, DMSO): 3.57 (s, 3H, NCH3); 3.90 (s, 3H, OCH3); 7.04 (s, 1 H, Ar); 7.53- 7.55 (m, 1 H, Ar); 7.61 -7.66 (m, 2H, Ar); 7.89 (bs, 1 H, Ar); 814-8.16 (m, 1 H, Ar); 8.34-8.35 (m, 1 H, Ar).
M/Z (M+H)+ = 325.2.
MP: 235-245°C.
Example 102: 7-Methoxy-4-methyl-2-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1 ,5- a]quinazolin-5-one.
Example 102 was obtained according to general procedure Vll(i)
starting from example 101 in presence of 2,2,2-trifluoroethanol.
The reaction was stirred for 1 hour at 50°C. Trituration in EtOH
and cyclohexane afforded example 102 as a beige solid in 60%
yield.
Figure imgf000124_0002
1H-NMR (400 MHz, DMSO): 3.56 (s, 3H, NCH3); 3.90 (s, 3H, OCH3); 5.04-5.06 (m, 2H, OCH2CF3); 7.03 (s, 1 H, Ar); 7.50-7.54 (m, 2H, Ar); 7.61 -7.67 (m, 2H, Ar); 8.14-8.16 (m, 1 H, Ar); 8.30 (bs, 1 H, Ar).
M/Z (M+H)+ = 405.2
MP: 172-180°C.
Compound 53: 2-(1 -Methyl-1 H-pyrazol-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one.
Compound 53 was obtained according to general procedure l(i), starting 1 -Methyl-1 H- pyrazole-4-carboxylic acid methyl ester in presence of 2-hydrazino-benzoic acid as a brown solid in 55% yield.
1H-NMR (400 MHz, DMSO): 3.89 (s, 3H, NCH3); 6.10 (s, 1 H, Ar); 7.43-7.47 (m, 1 H, Ar); 7.84- 7.89 (m, 2H, Ar); 8.04-8.06 (m, 1 H, Ar); 8.1 1-8.14 (m, 1 H, Ar); 8.19 (bs, 1 H, Ar); 12.10 (bs, 1 H, NH).
M/Z (M+H)+ = 266.2.
Example 103: 4-Methyl-2-(1 -methyl-1 H-pyrazol-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one. Example 103 was obtained according to general procedure ll(i), starting
from compound 53 in presence of iodomethane. The reaction mixture
was stirred at room temperature for 2 Hrs. Example 103 was obtained
without further purification as a beige solid in 78% yield.
1H-NMR (400 MHz, DMSO): 3.53 (s, 3H, NCH3); 3.91 (s, 3H, NCH3); 6.48
Figure imgf000125_0001
(s, 1 H, Ar); 7.45-7.49 (m, 1 H, Ar); 7.86-7.90 (m, 2H, Ar); 8.05-8.08 (m,
1 H, Ar); 8.16-8.18 (m, 2H, Ar).
M/Z (M+H)+ = 280.2.
MP: 195-199°C.
Example 104: 4-Methyl-2-pyridin-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one, HCI salt.
To a solution of example 1 (50.0 mg, 1.0 equiv.) in MeOH (1 .6 ml_,
C=0.1 molL"1), Pd/C (10% w/w, 17 mg) was added. The reaction
mixture was sparged with hydrogen and hydrogen pressure was
maintained for 18 hours through balloon. The reaction mixture was
filtered off through a celite pad. The pad was washed with MeOH and
Figure imgf000125_0002
the filtrate was concentrated. Purification by flash-chromatography
(MeOH in DCM, 0 to 10%) and salt formation according to procedure IV(iii) afforded example 104 as a beige solid in 19% yield.
1H-NMR (400 MHz, DMSO): 3.59 (s, 3H, NCH3); 7.22 (s, 1 H, Ar); 7.59-7.63 (m, 1 H, Ar); 7.95- 7.99 (m, 1 H, Ar); 8.22-8.26 (m, 2H, Ar); 8.38-8.40 (m, 2H, Ar); 9.83 (d, J 6.3 Hz, 2H, Ar). Signal for HCI salt is not observed.
M/Z (M+H)+ = 277.2.
MP: >250°C.
Compound 54: 2-(2-Chloro-6-methyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one.
Compound 54 was obtained according to general procedure l(i), starting from 2-chloro-6- methylpyridine-4-carboxylic acid methyl ester in presence of 2-hydrazino-benzoic acid as a yellow solid in 87% yield.
1H-NMR (400 MHz, DMSO): 2.52 (s, 3H, CH3); 6.52 (s, 1 H, Ar); 7.47-7.51 (m, 1 H, Ar); 7.82- 7.88 (m, 3H, Ar); 8.13-8.18 (m, 2H, Ar). Signal for NH is not observed.
M/Z (M[35CI]+H)+ = 31 1.1. Example 105: 2-(2-Chloro-6-methyl^yridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one. Example 105 was obtained according to general procedure ll(i), starting
from compound 54 in presence of iodomethane. The reaction mixture
was stirred for 2 hours at room temperature. Example 105 was obtained
without further purification as a beige solid in 89% yield.
1H-NMR (400 MHz, DMSO): 2.53 (s, 3H, CH3); 3.54 (s, 3H, NCH3); 7.02
Figure imgf000126_0001
(s, 1 H, Ar); 7.53-7.57 (m, 1 H, Ar); 7.80-7.81 (m, 2H, Ar); 7.90-7.94 (m,
1 H, Ar); 8.18-8.20 (m, 2H, Ar).
M/Z (M[35CI]+H)+ = 325.2.
MP:236-242°C.
Example 106: 2-(2-Cyclopropyl-6-methyl^yridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5- one, HCI salt.
Example 106 was obtained according to general procedure III starting
from example 105 in presence of a solution of cyclopropylzinc bromide
in THF (0.5N - 3.0 equiv.). After hydrolysis, the solid was collected,
washed with water and MeOH. To the MeOH filtrate, aqueous HCI
solution (1 N) was added. The reslting precipitate was collected,
Figure imgf000126_0002
washed with water, Et20 and was dried under reduced pressure to
afford example 106 as a white solid in 26% yield.
1H-NMR (400 MHz, DMSO): 1 .26-1.36 (m, 4H, 2CH2); 2.53-2.55 (m, 1 H, CCH); 2.74 (s, 3H, CCH3); 3.56 (s, 3H, NCH3); 7.21 (s, 1 H, Ar); 7.57-7.61 (m, 1 H, Ar); 7.72 (bs, 1 H, Ar); 7.93-7.98 (m, 1 H, Ar); 8.6 (bs, 1 H, Ar); 8.19-8.24 (m, 2H, Ar). Signal for HCI salt is not observed.
M/Z (M+H)+ = 331.3.
MP: >250°C.
Compound 55: 2-(3-Fluoro-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one.
Compound 55 was obtained according to general procedure l(i), starting 3-fluoro-isonicotinic acid ethyl ester in presence of 2-hydrazino-benzoic acid as a brown solid in 33% yield. The reaction mixture was heated for 18 hours instead of 2 hours.
1H-NMR (400 MHz, DMSO): 6.40 (d, J 3.5 Hz, 1 H, Ar); 7.55-7.59 (m, 1 H, Ar); 7.92-7.97 (m, 1 H, Ar); 8.09 (dd, J 6.6 Hz, J 5.1 Hz, 1 H, Ar); 8.17-8.22 (m, 2H, Ar); 8.53-8.54 (m, 1 H, Ar); 8.71 (d, J 2.8 Hz, 1 H, Ar); 12.36 (bs, 1 H, NH).
M/Z (M+H)+ = 281.3.
Example 107: 2-(3-Fluoro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5-one. Example 107 was obtained according to general procedure ll(ii), starting
from compound 55 in presence of iodomethane. The reaction mixture was
stirred for 1 hour at room temperature. Example 107 was obtained without
further purification as a grey solid in 69% yield.
1H-NMR (400 MHz, DMSO): 3.51 (s, 3H, NCH3); 6.80 (d, J 3.0 Hz, 1 H, Ar);
Figure imgf000127_0001
7.56-7.50 (m, 1 H, Ar); 7.93-7.97 (m, 1 H, Ar); 8.08-8.1 1 (m, 1 H, Ar); 8.22- 8.24 (m, 2H, Ar); 8.55-8.57 (m, 1 H, Ar); 8.74 (d, J 2.8 Hz, 1 H, Ar).
M/Z (M+H)+ = 295.3.
MP: 244-247°C.
Compound 56: 2-(3-Chloro-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one.
Compound 56 was obtained according to general procedure l(i), starting 2-chloro-isonicotinic acid ethyl ester in presence of 2-hydrazino-benzoic acid as a brown solid in 71 % yield. The reaction mixture was heated for 18 hours instead of 2 hours.
1H-NMR (400 MHz, DMSO): 6.58 (s, 1 H, Ar); 7.55-7.59 (m, 1 H, Ar); 7.92-7.96 (m, 1 H, Ar); 8.02 (d, J 5.1 Hz, 1 H, Ar); 8.18-8.21 (m, 2H, Ar); 8.63 (d, J 5.1 Hz, 1 H, Ar); 8.78 (s, 1 H, Ar); 12.41 (bs, 1 H, NH).
M/Z (M[35CI]+H)+ = 297.2. Example 108: 2-(3-Chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1, 5-a]quinazolin-5-one.
Example 108 was obtained according to general procedure ll(ii), starting
from compound 56 in presence of iodomethane. The reaction mixture was
stirred for 1 hour at room temperature. Example 108 was obtained without
further purification as a grey solid in 57% yield.
1H-NMR (400 MHz, DMSO): 3.59 (s, 3H, NCH3); 6.93 (s, 1 H, Ar); 7.56-
Figure imgf000127_0002
7.60 (m, 1 H, Ar); 7.92-7.96 (m, 1 H, Ar); 7.99 (d, J 5.1 Hz, 1 H, Ar); 8.19-
8.24 (m, 2H, Ar); 8.64 (d, J 5.1 Hz, 1 H, Ar); 8.79 (s, 1 H, Ar).
M/Z (M[35CI]+H)+ = 31 1.1.
MP:230-236°C.
Example 109: 4-Methyl-2-(3-methyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one.
Example 109 was obtained according to general procedure III starting
from example 108 in presence of a solution of dimetylzinc in Toluene (2N
- 3.0 equiv.). After hydrolysis, the solid was collected. The solid was
dissolved in a DMSO/MeOH mixture. Smopex resin was added and the
suspension was stirred for 1 hour at room temperature. The resin was
Figure imgf000127_0003
filtered off, washed with DMSO and MeOH. Water was added to the filtrate. The resulting solid was collected, washed with water, EtOH, and Et20 and was dried under reduce pressure to afford example 109 as a beige solid in 27% yield.
1H-NMR (400 MHz, DMSO at 80°C): 2.64 (s, 3H, CCH3); 3.60 (s, 3H, NCH3); 6.70 (s, 1 H, Ar); 7.52-7.56 (m, 1 H, Ar); 7.71 (d, J 4.3 Hz, 1 H, Ar); 7.92-7.94 (m, 1 H, Ar); 8.18 (d, J 8.2 Hz, 1 H, Ar); 8.23 (d, J 8.0 Hz, J 1.0 Hz, 1 H, Ar); 8.52-8.61 (m, 2H, Ar).
M/Z (M+H)+ = 291.3.
MP: 145-150°C.
Example 1 10: 8-(3-Hydroxy-azetidine-1-carbonyl)-4-methyl-2-(2 rifluoromethyl-py
4H-pyrazolo[1,5-a]quinazolin-5-one.
Example 1 10 was obtained according to general procedure Xll(i),
starting from example 58 with 3-hydroxyazetidine hydrochloride
as nucleophile (diisopropylamine was added in excess in order to
Figure imgf000128_0001
release the free base). Purification by flash-chromatography
(MeOH in DCM, 0 to 5%) afforded example 1 10 as a white solid in 40% yield.
1H-NMR (400 MHz, DMSO): 3.57 (s, 3H, NCH3); 3.85-3.88 (m, 1 H, NCHaCHb); 4.09-4.12 (m,
1 H, NCHaCHb); 4.33-4.35 (m, 1 H, NCHaCHb); 4.50-4.56 (m, 2H, NCHaCHb + CH(OH)); 5.82
(bs, 1 H, OH); 7.21 (s, 1 H, Ar); 7.73 (dd, J 8.1 Hz, J 1.5 Hz, 1 H, Ar); 8.23 (d, J 8.1 Hz, 1 H, Ar);
8.29 (dd, J 5.1 Hz, J 1 .0 Hz, 1 H, Ar); 8.36 (d, J 1.4 Hz, 1 H, Ar); 8.39 (s, 1 H, Ar); 8.89 (d, J 5.1 Hz, 1 H Ar).
M/Z (M+H)+ = 444.1.
MP: >250°C.
Example 1 1 1 : 8-(3-Hydroxy-propoxy)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H- pyrazolo[1, 5-a]quinazolin-5-one.
Example 1 1 1 was obtained according to general procedure Vll(iii)
starting from example 55 in presence of 1 ,3-propanediol. The
reaction mixture was heated for 17 hours at 60°C. Purification by
flash-chromatography (MeOH in DCM, 0 to 5%) afforded example
1 1 1 as a white solid in 66% yield.
Figure imgf000128_0002
1H-NMR (400 MHz, DMSO): 1 .97 (quint, J 6.2 Hz, 2H, HOCH2CH2CH20); 3.55 (s, 3H, NCH3); 3.63 (q, J 5.4 Hz, 2H, HOCH2CH2CH20); 4.30 (t, J 6.3 Hz, 2H, HOCH2CH2CH20); 4.63 (t, J 5.1 Hz, 1 H, HOCH2); 7.14 (dd, J 8.8 Hz, J 2.4 Hz, 1 H, Ar); 7.17 (s, 1 H, Ar); 7.64 (d, J 2.3 Hz, 1 H, Ar); 8.12 (d, J 8.8 Hz, 1 H, Ar); 8.29 (dd, J 5.1 Hz, J 0.9 Hz, 1 H, Ar); 8.40 (s, 1 H, Ar); 8.90 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 419.1.
MP: 223-226°C. Compound 57: 2-(2-Cyclopropyl-pyridin-4-yl)-8-fluoro-4H-pyrazolo[1 ,5-a]quinazolin-5-one. Compound 57 was obtained according to general procedure l(i), starting 2-Cyclopropyl- isonicotinic acid methyl ester in presence compound 26 as a brown solid in 55% yield.
1 H-NMR (400 MHz, DMSO): 1.25-1 .27 (m, 4H, 2CH2); 2.36-2.42 (m, 1 H, CCH); 6.81 (s, 1 H, Ar); 7.42 (td, J 8.7 Hz, J 2.4 Hz, 1 H, Ar); 7.99 (dd, J 9.4 H, J 2.4 Hz, 1 H, Ar); 8.02 (bs, 1 H, Ar); 8.09-8.1 1 (m, 1 H, Ar); 8.24 (dd, J 8.7 Hz, J 5.8 Hz, 1 H, Ar); 8.64 (d, J 5.8 Hz, 1 H, Ar); 12.60 (bs, 1 H, NH).
M/Z (M+H)+ = 321.0.
Example 1 12: 2-(2-Cyclopropyl-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1,5-a]quinazolin-5- one.
Example 1 12 was obtained according to general procedure ll(iii),
starting from compound 57 in presence of iodomethane. The reaction
mixture was stirred at room temperature for 60 min. Example 1 12
was obtained as a beige solid in 70% yield.
Figure imgf000129_0001
1H-NMR (400 MHz, DMSO): 1 .01-1.04 (m, 4H, 2CH2); 2.18-2.23 (m,
1 H, CCH); 3.57 (s, 3H, NCH3); 7.00 (s, 1 H, Ar); 7.40 (td, J 8.7 Hz, J 2.3 Hz, 1 H, Ar); 7.70 (d, J 5.1 Hz, 1 H, Ar); 7.86 (bs, 1 H, Ar); 7.93 (dd, J 9.2 H, J 2.3 Hz, 1 H, Ar); 8.27 (dd, J 8.7 Hz, J 5.9 Hz, 1 H, Ar); 8.52 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 335.1.
MP: 230-235°C.
Example 1 13: 2-(2-Cyclopropyl-pyridin-4-yl)-8-(4-hydroxy-piperidin-1-yl)-4-methyl-4H- pyrazolo[1, 5-a]quinazolin-5-one.
Example 1 13 was obtained according to general procedure
X(vi) starting from example 1 12 in presence of 4- hydroxypiperidine. Example 1 13 was obtained as a beige solid
in 75% yield.
1H-NMR (400 MHz, DMSO): 0.99-1.01 (m, 4H, 2CH2), 1 .44-
Figure imgf000129_0002
1.52 (m, 2H, 2CHaHb); 1 .86-1.89 (m, 2H, 2CHaHb); 2.17-2.23
(m, 1 H, CCH); 3.19-3.25 (m, 2H, 2NCHaHb); 3.51 (s, 3H, NCH3); 3.74-3.79 (m, 1 H, CH(OH));
3.83-3.86 (m, 2H, 2NCHaHb); 4.77 (bs, 1 H, OH); 6.88 (s, 1 H, Ar); 7.16 (dd, J 9.1 Hz, J 2.2 Hz,
1 H, Ar); 7.45 (d, J 2.2 Hz, 1 H, Ar); 7.69-7.70 (m, 1 H, Ar); 7.85 (bs, 1 H, Ar); 7.95 (d, J 9.1 Hz, 1 H); 8.49 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 416.3.
MP: 221 -233°C. Compound 58: 2-(2-Difluoromethyl-pyridin-4-yl)-8-fluoro-4H-pyrazolo[1,5-a]quinazolin-5-one. Compound 58 was obtained according to general procedure l(ii), starting from compound 4 in presence compound 26. After 17 hours at 100°C with AcOH (10 equiv.) the reaction was not completed. DME was concentrated and AcOH (same volume as DME) was added. The reaction mixture was heated at 120°C for 3 hours. After cooling, the reaction mixture was concentrated and the residue was coevaporated twice with toluene before hydrolysis with saturated aqueous NaHC03 solution. The precipitate was collected, washed with water, EtOH and dried under reduced pressure at 60°C with P205 for 18 hours. Compound 58 was isolated as a brown solid in 45% yield.
1 H-NMR (400 MHz, DMSO): 6.68 (s, 1 H, Ar); 7.02 (t, J 54.9 Hz, 1 H, CHF2); 7.39 (td, J 8.7 Hz, J 2.5 Hz, 1 H, Ar); 7.95 (dd, J 9.4 H, J 2.5 Hz, 1 H, Ar); 8.13 (d, J 5.1 Hz, 1 H, Ar); 8.21-8.25 (m, 2H, Ar); 8.78 (d, J 5.1 Hz, 1 H, Ar); 12.49 (bs, 1 H, NH).
M/Z (M+H)+ = 331.1.
Example 1 14: 2-(2-Difluoromethyl-pyridin-4-yl) -8-fluoro-4-methyl-4H-pyrazolo[1 , 5-a ]quinazolin- 5-one.
Example 1 14 was obtained according to general procedure ll(iii),
starting from compound 58 in presence of iodomethane. The
reaction mixture was stirred at room temperature for 90 min.
Example 1 14 was obtained as a beige solid in 77% yield.
1H-NMR (400 MHz, DMSO): 3.55 (s, 3H, NCH3); 7.04 (t, J 54.9 Hz,
Figure imgf000130_0001
1 H, CHF2); 7.12 (s, 1 H, Ar); 7.40 (td, J 8.7 Hz, J 2.4 Hz, 1 H, Ar);
7.96 (dd, J 9.3 H, J 2.4 Hz, 1 H, Ar); 8.1 1 (d, J 4.8 Hz, 1 H, Ar); 8.23-8.27 (m, 2H, Ar); 8.81 (d, J 4.8 Hz, 1 H, Ar).
M/Z (M+H)+ = 345.0.
MP: 220-226°C.
Example 1 15: 2-(2-Difluoromethyl-pyridin-4-yl)-8-(4-hydroxy-piperidin-1-yl)-4-me pyrazolo[1, 5-a]quinazolin-5-one.
Example 1 15 was obtained according to general procedure
X(vi) starting from example 1 14 in presence of 4- hydroxypiperidine. Trituration in EtOH afforded example 1 15 as
a beige solid in 74% yield.
Figure imgf000130_0002
H-NMR (400 MHz, DMSO): 1.45-1 .52 (m, 2H, 2CHaHb); 1.87-
1.89 (m, 2H, 2CHaHb); 3.19-3.25 (m, 2H, 2NCHaHb), 3.52 (s, 3H, NCH3); 3.76-3.79 (m, 1 H, CH(OH)); 3.83-3.86 (m, 2H, 2NCHaHb); 4.78 (d, J 3.8 Hz, 1 H, OH); 6.90-7.17 (m, 3H, CHF2 + 2Ar); 7.45 (s, 1 H, Ar); 7.96 (d, J 9.0 Hz, 1 H, Ar); 8.14 (d, J 4.5 Hz, 1 H, Ar); 8.22 (bs, 1 H, Ar); 8.79 (d, J 4.5 Hz, 1 H, Ar).
M/Z (M+H)+ = 426.2.
MP: >250°C.
Compound 59: 2-Cyclobutyl-isonicotinic acid methyl ester.
Compound 59 was obtained according to general procedure III starting from 2-Chloro- isonicotinic acid methyl ester in presence of cyclobutylzinc bromide (in THF 0.5M - 3.0 equiv.). Purification by flash-chromatography (EtOAc in Cyclohexane, 0 to 80%) afforded compound 59 as yellow oil in 46% yield.
1H-NMR (400 MHz, DMSO): 1 .80-1.90 (m, 1 H, CH); 1.96-2.08 (m, 1 H, CH); 2.25-2.33 (m, 4H, 2CH2); 3.76 (quint, J 8.6 Hz, 1 H, CCH); 3.90 (s, 3H, OCH3); 7.63-7.65 (m, 2H, Ar); 8.73 (d, J 4.9 Hz, 1 H, Ar).
M/Z (M+H)+ = 192.1.
Compound 60: 2-(2-Cyclobutyl-pyridin-4-yl)-8-fluoro-4H-pyrazolo[1,5-a]quinazolin-5-one.
Compound 60 was obtained according to general procedure l(i), starting compound 59 in presence compound 26 as a brown solid in 37% yield.
1H-NMR (400 MHz, DMSO): 1 .88-1.94 (m, 1 H, CH); 2.00-2.16 (m, 1 H, CH); 2.28-2.45 (m, 4H, 2CH2); 3.86 (quint, J 8.7 Hz, 1 H, CCH); 6.76 (s, 1 H, Ar); 7.41 (td, J 8.6 Hz, J 2.3 Hz, 1 H, Ar); 7.98 (dd, J 9.4 H, J 2.3 Hz, 1 H, Ar); 8.05-8.12 (m, 2H, Ar); 8.24 (dd, J 8.6 Hz, J 5.9 Hz, 1 H, Ar); 8.70 (d, J 5.5 Hz, 1 H, Ar); 12.56 (bs, 1 H, NH).
M/Z (M+H)+ = 335.2. Example 1 16: 2-(2-Cyclobutyl-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1, 5-a]quinazolin-5- one.
Example 1 16 was obtained according to general procedure ll(iii),
starting from compound 60 in presence of iodomethane. The
reaction mixture was stirred at room temperature for 120 min.
Example 1 16 was obtained as a brown solid in 44% yield.
1H-NMR (400 MHz, DMSO): 1 .85-1.96 (m, 1 H, CH); 1.98-2.1 1 (m,
Figure imgf000131_0001
1 H, CH); 2.32-2.39 (m, 4H, 2CH2); 3.56 (s, 3H, NCH3); 3.74 (quint,
J 8.6 Hz, 1 H, CCH); 7.02 (s, 1 H, Ar); 7.39 (td, J 8.6 Hz, J 2.3 Hz, 1 H, Ar); 7.75-7.80 (m, 2H,
Ar); 7.93 (d, J 8.6 Hz, 1 H, Ar); 8.26 (dd, J 8.6 Hz, J 6.1 Hz, 1 H, Ar); 8.63 (d, J 4.7 Hz, 1 H, Ar). M/Z (M+H)+ = 349.0.
MP: 210-220°C. Compound 61 : 2-(2-Chloro-pyridin-4-yl)-8-fluoro-4H-pyrazolo[1,5-a]quinazolin-5-one.
Compound 61 was obtained according to general procedure l(i), starting from 2-chloro- isonicotinic methyl ester in presence of compound 26 as a brown solid in 44% yield.
1H-NMR (400 MHz, DMSO): 6.66 (s, 1 H, Ar); 7.39 (td, J 8.7 Hz, J 2.6 Hz, 1 H, Ar); 7.95 (dd, J 9.5 Hz, J 2.6 Hz, 1 H, Ar); 7.99 (dd, J 5.2 Hz, J 1 .4 Hz, 1 H, Ar); 8.09 (bs, 1 H, Ar); 8.22 (dd, J 8.7 Hz, J 5.8 Hz, 1 H, Ar); 8.50 (d, J 5.2 Hz, 1 H Ar); 12.40 (bs, 1 H, NH).
M/Z (M[35CI]+H)+ = 315.1.
Example 1 17: 2-( 2-Chloro-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1, 5-a]quinazolin-5-one. Example 1 17 was obtained according to general procedure ll(iii),
starting from compound 61 in presence of iodomethane. The reaction
mixture was stirred at room temperature for 60 min. Example 1 17 was
obtained as a beige solid in 71 % yield.
1H-NMR (400 MHz, DMSO): 3.54 (s, 3H, NCH3); 7.09 (s, 1 H, Ar);
Figure imgf000132_0001
7.38-7.42 (m, 1 H, Ar); 7.94-7.97 (m, 2H, Ar); 8.05 (s, 1 H, Ar); 8.24- 8.27 (m, 1 H, Ar); 8.54 (d, J 5.1 Hz, 1 H Ar).
M/Z (M[35CI]+H)+ = 329.1.
MP: >250°C. Example 1 18: 2-(2-Chloro-pyridin-4-yl)-8-(4-hydroxy-piperidin-1-yl)-4-methyl-4H-pyrazolo[1 ,5- a]quinazolin-5-one.
Example 1 18 was obtained according to general procedure X(vi)
starting from example 1 17 in presence of 4-hydroxypiperidine.
Trituration in EtOH afforded example 1 18 as a beige solid in
86% yield.
1H-NMR (400 MHz, DMSO): 1.48-1 .56 (m, 2H, 2CHaHb); 1 .91-
Figure imgf000132_0002
2.00 (m, 2H, 2CHaHb); 3.23-3.36 (m, 2H, 2NCHaHb); 3.55 (s, 3H, NCH3); 3.78-3.84 (m, 1 H, CH(OH)); 3.88-3.92 (m, 2H, 2NCHaHb); 4.81 (bs, 1 H, OH); 7.04 (s, 1 H, Ar); 7.17 (dd, J 9.1 Hz, J 2.3 Hz, 1 H, Ar); 7.50 (d, J 2.1 Hz, 1 H, Ar); 7.97-8.03 (m, 2H, Ar); 8.10 (s, 1 H, Ar); 8.56 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M[35CI]+H)+ = 410.1.
MP: >250°C. Example 1 19: 7-Fluoro-8-(3-hydroxy-azetidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridi 4H-pyrazolo[1,5-a]quinazolin-5-one.
Example 1 19 was obtained according to general procedure X(vi)
starting from example 88 in presence of 3-hydroxyazetidine.
Purification by flash-chromatography (MeOH in DCM, 0 to 7%)
afforded example 1 19 as a white solid in 56% yield.
Figure imgf000133_0001
1H-NMR (400 MHz, DMSO): 3.52 (s, 3H, NCH3); 385-3.98 (m, 2H, 2NCHaCHb); 4.44-4.47 (m, 2H, 2NCHaCHb); 4.63-4.68 (m, 1 H, CH(OH)); 5.83 (d, J 6.1 Hz, 1 H, OH); 7.01 (d, J 7.8 Hz, 1 H, Ar); 7.12 (s, 1 H, Ar); 7.63 (d, J 12.6 Hz, 1 H, Ar); 8 26 (d, J 4.8 Hz, 1 H, Ar); 8.37 (s, 1 H Ar); 8.89 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 434.2.
MP: >250°C.
Example 120: 7-Fluoro-4-methyl-8-(oxetan-3-yloxy)-2-(2-trifluoromethyl-pyridin-4-yl)-4H- pyrazolo[1, 5-a]quinazolin-5-one.
Example 120 was obtained according to general procedure
Vll(iii) starting from example 88 in presence of 3- hydroxyoxetane. The reaction mixture was stirred for 1 hour at
room temperature. Purification by flash-chromatography (MeOH
in DCM, 0 to 2%) afforded example 120 as a white solid in 35%
Figure imgf000133_0002
yield.
1H-NMR (400 MHz, DMSO): 3.61 (s, 3H, NCH3); 4.75-4.78 (m, 2H, 20CHaCHb); 5.13 (t, J 6.9 Hz, 2H, 20CHaCHb); 5.77-5.83 (m, 1 H, CH(O)); 7.25 (s, 1 H, Ar); 7.52 (d, J 7.1 Hz, 1 H, Ar); 8.03 (d, J 1 1.0 Hz, 1 H, Ar); 8.37 (d, J 5.1 Hz, 1 H, Ar); 8.46 (s, 1 H, Ar); 8.92 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 435.1.
MP: >250°C.
Example 121 : 3-[7-Fluoro-4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro- pyrazolo[1, 5-a]quinazolin-8-ylamino]-propionitrile.
Example 121 was obtained according to general procedure X(vi)
starting from example 88 in presence of 3-aminopropionitrile.
Example 121 was isolated as a beige solid in 64% yield.
1H-NMR (400 MHz, DMSO): 3.06 (t, J 6.4 Hz, 2H, NHCH2CH2CN);
3.62 (s, 3H, NCH3); 3.71 -3.76 (m, 2H, NHCH2CH2CN); 7.20 (s, 1 H,
Figure imgf000133_0003
Ar); 7.24-7.27 (m, 1 H, NH); 7.47 (d, J 7.3 Hz, 1 H, Ar); 7.81 (d, J 1 1 .7 Hz, 1 H, Ar); 8.35-8.36
(m, 1 H, Ar); 8.47 (s, 1 H, Ar); 8.80 (d, J 5.1 Hz, 1 H, Ar). M/Z (M+H)+ = 431.1.
MP: >250°C
Example 122: 7-Fluoro-8-(2-hydroxymethyl-pyrrolidin-1-yl)-4-methyl-2-(2-trifluoromethyl- pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one.
Example 122 was obtained according to general procedure X(vi)
starting from example 88 in presence of DL-prolinol. Example 122
was isolated as a brown solid in 64% yield.
1H-NMR (400 MHz, DMSO): 1 .91-1.92 (m, 4H, 2 CH2); 3.39-3.59
Figure imgf000134_0001
(m, 6H, NCH3+NCH2+NCH); 3.66 (bs, 1 H, HOCHaCHb); 4.22 (bs,
1 H, HOCHaCHb); 4.91 (bs, 1 H, OH); 7.1 1 (s, 1 H, Ar); 7.28 (d, J 7.7 Hz, 1 H, Ar); 7.67 (d, J 14.7 Hz, 1 H, Ar); 8.24-8.25 (m, 1 H, Ar); 8.35 (s, 1 H, Ar); 8.88 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 462.2.
MP: >250°C
Example 123: 7-Fluoro-8-(7-hydroxymethyl-1-aza-spiro[3.5]non-1-yl)-4-methyl-2-(2- trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one.
Example 123 was obtained according to general procedure X(vi)
starting from example 88 in presence of (1-Aza-spiro[3.5]non-7-yl)- methanol. Purification by TLC-preparative (MeOH in DCM, 4%)
afforded example 123 as a beige solid in 32% yield.
Figure imgf000134_0002
1H-NMR (400 MHz, DMSO): 0.98-1 .04 (m, 2H, 2CHaHb); 1 .34 (bs,
1 H, CH); 1.73-1 .75 (m, 2H, 2CHaHb); 1 .91-2.01 (m, 4H, 2CH2); 2.16-2.24 (m, 2H, CH2); 3.10
(t, J 5.6 Hz, 2H, NCH2); 3.51 (s, 3H, NCH3); 4.03-4.1 1 (m, 2H, HOCH2); 4.43 (t, J 5.3 Hz, 1 H, OH); 7.08-7.12 (m, 2H, Ar); 7.69 (d, J 13.3 Hz, 1 H, Ar); 8.24 (d, J 5.1 Hz, 1 H, Ar); 8.34 (s, 1 H,
Ar); 8.88 (d, J 5.2 Hz, 1 H, Ar).
M/Z (M+H)+ = 516.2.
MP: >250°C Example 124: 8-(3^ydroxy-pipendin-1-yl)-4-methyl-2-(2-tn luoromethyl-pyridin-4-yl)-4H pyrazolo[1,5-a]quinazolin-5-one.
Under inert atmosphere, in a seal tube, a mixture of example 58
(1 .0 equiv.), 3-hydroxypiperidine (1 .2 equiv.), a solution of
□ HMDS in THF (1.0 N; 3.0 equiv.) and RuPhos precatalyst (0.1
equiv.) were suspended in THF (C=0.1 molL"1) and warmed for 17
Figure imgf000134_0003
hours at 65°C. The reaction mixture was hydrolysed with a
saturated aqueous NH4CI solution. The solid was collected, washed with water, dried under reduced pressure. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 124 as a beige solid in 19% yield.
1H-NMR (400 MHz, DMSO): 1.41 -1 .58 (m, 2H, CH2); 1.81-1 .94 (m, 2H, CH2); 2.96-3.15 (m, 2H, NCHaHb +NCHaHc); 3.51 (s, 3H, NCH3); 3.59-3.66 (m, 1 H, NCHaCHb); 3.76-3.79 (m, 1 H, NCHaCHc); 3.84-3.88 (m, 1 H, CH(OH)); 4.96 (d, J 4.2 Hz, 1 H, OH); 7.07-7.10 (m, 2H, Ar); 7.43 (d, J 2.4 Hz, 1 H, Ar); 7.95 (d, J 9.0 Hz, 1 H, Ar); 8.28 (dd, J 5.1 Hz, J 1 .0 Hz, 1 H, Ar); 8.38 (s, 1 H, Ar); 8.87 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 444.1.
MP: >250°C
Example 125: 8-(2,6-Dimethyl-morpholin-4-yl)-4-methyl-2-(2-trifluoromethyl-pyrid
pyrazolo[1,5-a]quinazolin-5-one.
Under inert atmosphere, in a seal tube, a mixture of example 58
(1 .0 equiv.), 2,6-dimethylmorpholine (1.2 equiv.), a solution of
LiHMDS in THF (1 .0 N; 3.0 equiv.) and RuPhos precatalyst (0.1
equiv.) were suspended in THF (C=0.1 molL"1) and warmed for
3 days at 65°C. The reaction mixture was hydrolysed with a
Figure imgf000135_0001
saturated aqueous NH4CI solution. The solid was collected, washed with water, dried under reduced pressure. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 125 as a beige solid in 19% yield.
1H-NMR (400 MHz, DMSO): 1.22 (d, J 6.2 Hz, 6H, 2CH3); 2.53-2.56 (m, 2H, 2NCHaCHb); 3.51 (s, 3H, NCH3); 3.68-3.75 (m, 2H, 2NCHaCHb); 3.92-3.94 (m, 2H, 20CH); 7.10 (s, 1 H, Ar); 7.16 (dd, J 9.1 Hz, J 2.4 Hz, 1 H Ar); 7.46 (d, J 2.3 Hz, 1 H, Ar); 7.97 (d, J 9.0 Hz, 1 H, Ar); 8.27-8.28 (m, 1 H, Ar); 8.38 (s, 1 H, Ar); 8.88 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 458.1.
MP: >250°C
Example 126: 8-(2^ydroxy-2-methyl-propylamino)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)- 4H-pyrazolo[1,5-a]quinazolin-5-one.
Under inert atmosphere, in a seal tube, a mixture of example
58 (1.0 equiv.), 1-amino-2-methyl-2-propanol (1 .2 equiv.), a
solution of LiHMDS in THF (1.0 N; 3.0 equiv.) and BrettPhos
precatalyst (0.1 equiv.) were suspended in THF (C=0.1 molL"1)
and warmed for 17 hours at 65°C. The reaction mixture was
Figure imgf000135_0002
hydrolysed with a saturated aqueous NH4CI solution. The solid was collected, washed with water, dried under reduced pressure. Purification by flash-chromatography (MeOH in DCM, 0 to 5%) afforded example 126 as a white solid in 6% yield 1H-NMR (400 MHz, DMSO): 1 .21 (s, 6H, 2CH3); 3.16 (d, J 5.5 Hz, 2H, NCH2); 3.51 (s, 3H, NCH3); 4.58 (s, 1 H, OH); 6.87-6.88 (m, 2H, NH + Ar); 7.07 (s, 1 H, Ar); 7.29 (s, 1 H, Ar); 7.86 (d, J 8.8 Hz, 1 H, Ar); 8.24 (d, J 4.7 Hz, 1 H, Ar); 8.36 (s, 1 H, Ar); 8.88 (d, J 5.1 Hz, 1 H, Ar).
M/Z (M+H)+ = 432.0.
MP: >250°C
Example 127: Human mGluR2 and mGluR3 evaluation using Ca++ functional assay
Examples of the present invention were tested successively for their agonist and negative allosteric modulator activities on human mGluR2 (hmGluR2) and mGluR3 (hmGluR3) transiently over-expressed in HEK-293 cells. Compounds exert agonist activity if, by themselves in absence of glutamate, they are able to activate hmGluR2 or hmGluR3; and they exert negative allosteric modulator activity if they decrease the action of glutamate (which is employed at its EC8o concentration).
Cell Culture and Transfection
HEK-293 cells are maintained in Modified Eagle's Medium supplemented with 10% Foetal Calf Serum, 1 % Penicillin/Streptomycin and 1 % non-essential amino acids at 37°C/5% C02.
Cells are co-transfected by electroporation with four DNA plasmids encoding hmGluR2 or hmGluR3, a chimeric G protein allowing redirection of the activation signal to intracellular calcium pathway (Brabet I et al., Neuropharmacology 37(8), 1043-51 , 1998), and two glutamate transporters minimizing receptor desensitization by endogenous glutamate. After transfection, cells are cultured for 24 h at 37°C/5% C02.
Calcium Assay ICgg determination
Receptor activity is detected by changes in intracellular calcium measured using the fluorescent Ca2+ sensitive dye, Fluo4AM (Molecular Probes).
On the day of the assay, culture medium is aspirated and replaced during 3 hours by medium without serum supplemented with 1 % Glutamax, 1 % Penicillin/Streptomycin and 1 % nonessential amino acids. Then, cells are washed with freshly prepared buffer B (HBSS 1 X (PAA), Hepes 20 mM, MgS04-7H20 1 mM, Na2C03 3.3 mM, CaCI2-2H20 1.3 mM, 0.1 % BSA, Probenecid 2.5 mM) and loaded at 37°C in 5% C02 for 1.5 hours with buffer B containing 1 μΜ Fluo4AM, 0.1 mg/mL Pluronic Acid, 7 pg/mL Glutamate Pyruvate Transaminase and 2 mM sodium pyruvate. Afterwards cells are washed twice with buffer B. Then cells are detached using StemPro Accutase (Fischer Scientific), resuspended in buffer B and seeded in 384 well plate at a density of 30,000 cells per well. Addition of compounds and intracellular Ca2+ measurements (excitation 485 nm, emission 525 nm) are performed by the fluorescence microplate reader FLIPRTetra (Molecular Devices).
Agonist and negative allosteric modulator activities of compounds are consecutively evaluated on the same cell plate. Agonist activity is first tested during 10 minutes with the addition of compound alone on the cells. Then, cells are stimulated by an EC8o glutamate concentration and fluorescence is recorded for additional 3 minutes. EC8o glutamate concentration is the concentration giving 80% of the maximal glutamate response. Agonist or negative allosteric modulator activity(ies) are evaluated in comparison to basal signals evoked by buffer B or EC8o glutamate alone, respectively. For IC50 determination, a dose-response test is performed using 20 concentrations (ranging over 6 logs) of each compound. Dose-response curves are fitted using the sigmoidal dose- response (variable slope) analysis in GraphPad Prism program (Graph Pad Inc) and IC5o of negative allosteric modulator activity is calculated. Dose-response experiments are performed in duplicate, two times independently.
The compounds of the present invention were found to have no agonist activity on hmGluR2 and hmGluR3. On hmGluR2, the compounds of the present invention have preferably an IC50 of 5 μΜ or less, more preferably 1 μΜ or less and the ratio [IC5o hmGluR3] / [IC5o hmGluR2] is higher than 3, more preferably is higher than 5.
The following list represents selected examples of the compounds of the present invention showing hmGluR2 negative allosteric modulator activity with an ICso < 1 μΜ and a ratio [IC50 hmGluR3] / [IC50 hmGluR2] higher than 3:
- Examples: 1 , 2, 3, 4, 5, 6, 9, 10, 1 1 , 12, 14, 15, 16, 17, 19, 21 , 22, 23, 24, 25, 26, 27, 28, 31 , 32, 33, 34, 35, 36, 38, 39, 40, 41 , 44, 45, 48, 49, 55, 56, 58, 61 , 63, 64, 68, 70,
77, 78, 79, 80, 81 , 82, 85, 87, 88, 89, 90, 91 , 94, 95, 96, 98, 99, 100, 102, 105, 106, 108, 1 10, 1 13, 1 14, 1 15, 1 16, 1 17, 1 19, 120, 121 , 122, and 125.

Claims

A compound of formula (I):
Figure imgf000138_0001
(I)
n:
A is N or -CH;
R1, R2 and R4 are each independently selected from R7, halogen, - CN, -OR7, -NR7R8, -COOR7, -S03H, -B(OH)2, -CONR7R8, - COR7, -SR7, -SOR7, -S02R7, -S02NR7R8, -NR7COR8, NR7S02R8, -OCOR7, -NR7C(0)NR8R9, -NR7C(S)NR8R9, -NR7COOR8, aryl, or heteroaryl, wherein said aryl and said heteroaryl are each substituted with one or more groups independently selected from R7, halogen, -CN, - OR7, -NR7R8, -COOR7, -S03H, -B(OH)2, -CONR7R8, -COR7, -SR7, - SOR7, -S02R7, -S02NR7R8, -NR7COR8, -NR7S02R8, -OCOR7, -NR7C(0)NR8R9, - NR7C(S)NR8R9, or -NR7COOR8;
R3 is selected from hydrogen, halogen, -CN, -OR7, NR7R8, -COOR7, -SO3H, -B(OH)2, -CONR7R8, -COR7, -SR7, - SOR7, -S02R7, -S02NR7R8, -NR7COR8, -NR7S02R8, -OCOR7, -NR7C(0)NR8R9, - NR7C(S)NR8R9, -NR7COOR8, C C4 alkyl, C2-C4 alkenyl, cycloalkyi or heterocycloalkyi, wherein said C1-C4 alkyl and said C2-C4 alkenyl are each optionally substituted with one or more groups independently selected from halogen, -CF3, -CN, -OH, -0(C C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(C C4 alkyl)(Ci-C4 alkyl), and further wherein said cycloalkyi and said heterocycloalkyi are each optionally substituted with one or more groups independently selected from: C C4 alkyl; halogen; - CF3; -CN; -OH; -0(d-C4 alkyl); C C4 alkyl substituted with one or more -OH groups; -NH2; -NH(Ci-C4 alkyl); or -N(Ci-C4 alkyl)(Ci-C4 alkyl);
R5 is heteroaryl which is optionally substituted with one or more groups independently selected from R7, halogen, -CN, -NR7R8, -CONR7R8, -COR7, -OR7, -SR7, -SOR7, -S02R7, - S02NR7R8, -NR7COR8, -NR7S02R8, -OCOR7, or -COOR7;
R6 is selected from C1-C4 alkyl, cycloalkyl, or heterocycloalkyi, wherein said C1-C4 alkyl is optionally substituted with one or more groups independently selected from cycloalkyl, halogen, -CF3, -CN, -OH or -0(Ci-C4 alkyl), and further wherein, if R6 is cycloalkyl or heterocycloalkyi, then said cycloalkyl and said heterocycloalkyi are each optionally substituted with one or more groups independently selected from C1-C4 alkyl, cycloalkyl, halogen, -CF3, -CN, -OH or -0(C C4 alkyl); and each R7, R8 and R9 is independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyi, heterocycloalkenyl, aryl or heteroaryl, wherein said C1-C4 alkyl and said C2-C4 alkenyl are each optionally substituted with one or more groups independently selected from halogen, -CF3, -CN, cycloalkyl, cycloalkenyl, heterocycloalkyi, heterocycloalkenyl, aryl, heteroaryl, -OH, -0(C C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(C C4 alkyl)(Ci-C4 alkyl), and further wherein, if R7, R8 or R9 is cycloalkyl, cycloalkenyl, heterocycloalkyi, heterocycloalkenyl, aryl or heteroaryl, then said cycloalkyl, said cycloalkenyl, said heterocycloalkyi, said heterocycloalkenyl, said aryl and said heteroaryl are each optionally substituted with one or more groups independently selected from: C1-C4 alkyl; halogen; -CF3; -CN; -OH; -0(Ci-C4 alkyl); C1-C4 alkyl substituted with one or more -OH groups; -NH2; -NH(Ci-C4 alkyl); or -N(C C4 alkyl)(C C4 alkyl); armaceutically acceptable salt, solvate or prodrug thereof as a medicament. A compound of formula (I):
Figure imgf000140_0001
(I)
wherein:
A is N or -CH;
R1, R2 and R4 are each independently selected from R7, halogen, - CN, -OR7, -NR7R8, -COOR7, -S03H, -B(OH)2, -CONR7R8, - COR7, -SR7, -SOR7, -S02R7, -S02NR7R8, -NR7COR8, NR7S02R8, -OCOR7, -NR7C(0)NR8R9, -NR7C(S)NR8R9, -NR7COOR8, aryl, or heteroaryl, wherein said aryl and said heteroaryl are each substituted with one or more groups independently selected from R7, halogen, -CN, - OR7, -NR7R8, -COOR7, -S03H, -B(OH)2, -CONR7R8, -COR7, -SR7, - SOR7, -S02R7, -S02NR7R8, -NR7COR8, -NR7S02R8, -OCOR7, -NR7C(0)NR8R9, - NR7C(S)NR8R9, or -NR7COOR8; is selected from hydrogen, halogen, -CN, -OR7,
NR 7'nR8 -COOR7, -SO3H, -B(OH)2, -CONR7R8, -COR7, -SR7,
SOR7, -S02R7, -S02NR7R8, -NR7COR8, -NR7S02R8, -OCOR7, -NR7C(0)NR8R9, - NR7C(S)NR8R9, -NR7COOR8, C C4 alkyl, C2-C4 alkenyl, cycloalkyi or heterocycloalkyi, wherein said C1-C4 alkyl and said C2-C4 alkenyl are each optionally substituted with one or more groups independently selected from halogen, -CF3, -CN, -OH, -0(C C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(C C4 alkyl)(Ci-C4 alkyl), and further wherein said cycloalkyi and said heterocycloalkyi are each optionally substituted with one or more groups independently selected from: C C4 alkyl; halogen; -CF3; -CN; -OH; -0(C C4 alkyl); C C4 alkyl substituted with one or more -OH groups; -NH2; -NH(d-C4 alkyl); or -N(Ci-C4 alkyl)(Ci-C4 alkyl);
R5 is heteroaryl which is optionally substituted with one or more groups independently selected from R7, halogen, -CN, -NR7R8, -CONR7R8, -COR7, -OR7, -SR7, -SOR7, -S02R7, - S02NR7R8, -NR7COR8, -NR7S02R8, -OCOR7, or -COOR7;
R6 is selected from C1-C4 alkyl, cycloalkyl, or heterocycloalkyi, wherein said C1-C4 alkyl is optionally substituted with one or more groups independently selected from cycloalkyl, halogen, -CF3, -CN, -OH or -0(CrC4 alkyl), and further wherein, if R6 is cycloalkyl or heterocycloalkyi, then said cycloalkyl and said heterocycloalkyi are each optionally substituted with one or more groups independently selected from C1-C4 alkyl, cycloalkyl, halogen, -CF3, -CN, -OH or -0(C C4 alkyl); and each R7, R8 and R9 is independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyi, heterocycloalkenyl, aryl or heteroaryl, wherein said C1-C4 alkyl and said C2-C4 alkenyl are each optionally substituted with one or more groups independently selected from halogen, -CF3, -CN, cycloalkyl, cycloalkenyl, heterocycloalkyi, heterocycloalkenyl, aryl, heteroaryl, -OH, -0(C C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(C C4 alkyl)(Ci-C4 alkyl), and further wherein, if R7, R8 or R9 is cycloalkyl, cycloalkenyl, heterocycloalkyi, heterocycloalkenyl, aryl or heteroaryl, then said cycloalkyl, said cycloalkenyl, said heterocycloalkyi, said heterocycloalkenyl, said aryl and said heteroaryl are each optionally substituted with one or more groups independently selected from: C1-C4 alkyl; halogen; -CF3; -CN; -OH; -0(Ci-C4 alkyl); C1-C4 alkyl substituted with one or more -OH groups; -NH2; -NH(d-C4 alkyl); or -N(C C4 alkyl)(C C4 alkyl); or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein the term "heterocycloalkyi" refers to a saturated ring group which may be a monocyclic ring or a bridged ring, spiro ring and/or fused ring system, wherein said ring group contains one or more ring heteroatoms, wherein said ring heteroatoms are independently selected from O, S or N, and wherein one or more S ring atoms, if present, and/or one or more N ring atoms, if present, may be oxidized; with the proviso that the following compounds are excluded:
8-bromo-2-furan-2-yl-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
8-bromo-2-(2,6-dimethyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 8-bromo-4-methyl-2-(1-methyl-1 H- pyrazol-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
8-bromo-4-methyl-2-(1-ethyl-1 H-pyrazol-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
8-bromo-2-(2-methyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
8-bromo-4-methyl-2-pyridin-3-yl-4H-pyrazolo[1 ,5-a]quinazolin-5-one; and
8-bromo-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one.
The compound of claim 2, wherein R3 is selected from hydrogen, -F, -CI, -I, -CN, -OR7, -NR7R8, -COOR7, -SO3H, -B(OH)2, -CONR7R8,
COR7, -SR7, -SOR7, -SO2R7, -S02NR7R8, -NR7COR8, -NR7S02R8, -OCOR7, - NR7C(0)NR8R9, -NR7C(S)NR8R9, -NR7COOR8, C C4 alkyl, C2-C4 alkenyl, cycloalkyi or heterocycloalkyi, wherein said C C4 alkyl and said C2-C4 alkenyl are each optionally substituted with one or more groups independently selected from halogen, -CF3, -CN, - OH, -0(Ci-C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(C C4 alkyl)(C C4 alkyl), and further wherein said cycloalkyi and said heterocycloalkyi are each optionally substituted with one or more groups independently selected from: d-C4 alkyl; halogen; -CF3; -CN; -OH; -0(Ci-C4 alkyl); C C4 alkyl substituted with one or more -OH groups; -NH2; -NH(Ci-C4 alkyl); or -N(C C4 alkyl)(C C4 alkyl).
The compound of claim 2 or 3, wherein R3 is selected from hydrogen, -OR7, - NR7R8, -COOR7, -SO3H, -B(OH)2, -CONR7R8,
COR7, -SR7, -SOR7, -S02R7, -S02NR7R8, -NR7COR8, -NR7S02R8, -OCOR7, - NR7C(0)NR8R9, -NR7C(S)NR8R9, -NR7COOR8, C C4 alkyl, C2-C4 alkenyl, cycloalkyi or heterocycloalkyi, wherein said C C4 alkyl and said C2-C4 alkenyl are each optionally substituted with one or more groups independently selected from halogen, -CF3, -CN, - OH, -0(Ci-C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(C C4 alkyl)(C C4 alkyl), and further wherein said cycloalkyi and said heterocycloalkyi are each optionally substituted with one or more groups independently selected from: C C4 alkyl; halogen; -CF3; -CN; -OH; -0(Ci-C4 alkyl); C C4 alkyl substituted with one or more -OH groups; -NH2; -NH(Ci-C4 alkyl); or -N(C C4 alkyl)(C C4 alkyl).
The compound for use according to claim 1 or the compound of claim 2, wherein R3 is selected from hydrogen, halogen, C C4 haloalkyl, Ci-C4 haloalkoxy, -CN, Ci-C4 alkyl, cycloalkyi, heterocycloalkyi, -OH, -0(Ci-C4 alkyl), -O-cycloalkyl, -O-heterocycloalkyl, -NH2, -NH(C C4 alkyl), -N(C C4 alkyl)(C C4 alkyl), -NH-cycloalkyl, -N(C C4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(C C4 alkyl)-heterocycloalkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-NH2, -CO-NH(C C4 alkyl), -CO-N(C C4 alkyl)(C C4 alkyl), -CO-NH-cycloalkyl, -CO-N(C C4 alkyl)-cycloalkyl, -CO-NH-heterocycloalkyl, -CO-N(Ci-C4 alkyl)-heterocycloalkyl, -NH-CO-cycloalkyl, -N(Ci-C4 alkyl)-
CO-cycloalkyl, -NH-CO-heterocycloalkyl, or -N(Ci-C4 alkyl)-CO-heterocycloalkyl, wherein said cycloalkyl, said heterocycloalkyl, the cycloalkyl moiety comprised in any of the aforementioned groups, and the heterocycloalkyl moiety comprised in any of the aforementioned groups are each optionally substituted with one or more groups independently selected from: Ci-C4 alkyl; halogen; -CF3; -CN; -OH; -0(Ci-C4 alkyl); d- C4 alkyl substituted with one or more -OH groups; -NH2; -NH(Ci-C4 alkyl); or -N(Ci-C4 alkyl)(Ci-C4 alkyl).
The compound for use according to claim 1 or 5 or the compound of claim 2 or 5, wherein R3 is selected from hydrogen, halogen, Ci-C4 haloalkyl, -CN, heterocycloalkyl, -0(d-C4 alkyl), -NH(C C4 alkyl), or -CO-N(C C4 alkyl)(C C4 alkyl), wherein said heterocycloalkyl is optionally substituted with one or more groups independently selected from: Ci-C4 alkyl; halogen; -CF3; -CN; -OH; -0(Ci-C4 alkyl); d- C4 alkyl substituted with one or more -OH groups; -NH2; -NH(Ci-C4 alkyl); or -N(Ci-C4 alkyl)(Ci-C4 alkyl).
The compound for use according to any one of claims 1 , 5 or 6 or the compound of any one of claims 2 to 6, wherein R1, R2 and R4 are each independently selected from hydrogen, halogen, Ci-C4 haloalkyl, Ci-C4 haloalkoxy, -CN, Ci-C4 alkyl, C2-C4 alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -0(Ci-C4 alkyl), -0-(Ci-C4 alkylene)-OH, -0-(C C4 alkylene)-0(C C4 alkyl), -O-cycloalkyl, -0-(C C4 alkylene)-cycloalkyl, -O-heterocycloalkyl, -0-(Ci-C4 alkylene)-heterocycloalkyl, -O-aryl, -0-(Ci-C4 alkylene)-aryl, -O-heteroaryl, -0-(Ci-C4 alkylene)-heteroaryl, -NH2, -NH(C C4 alkyl), -N(C C4 alkyl)(C C4 alkyl), -NH-cycloalkyl, -N(C C4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(C C4 alkyl)-heterocycloalkyl, -NH-(C C4 alkylene)-cycloalkyl, -N(C C4 alkyl)-(C C4 alkylene)-cycloalkyl, -NH-(Ci-C alkylene)-heterocycloalkyl, -N(Ci-C alkyl)-(Ci-C alkylene)-heterocycloalkyl, -NH-aryl, -N(Ci-C alkyl)-aryl, -NH-heteroaryl, -N(Ci-C alkyl)-heteroaryl, -NH-(C C4 alkylene)-aryl, -N(C C4 alkyl)-(C C4 alkylene)-aryl, -NH-(C C4 alkylene)-heteroaryl, -N(C C4 alkyl)-(Ci-C4 alkylene)-heteroaryl, -CO-(C C4 alkyl), -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-(C C alkylene)-cycloalkyl, -CO-(Ci-C alkylene)-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, -CO-(Ci-C alkylene)-aryl, -CO-(C C4 alkylene)-heteroaryl, -CO-NH2, -CO-NH(C C4 alkyl), -CO- N(Ci-C4 alkyl)(Ci-C4 alkyl), -CO- NH-cycloalkyl, -CO-N(C C4 alkyl)-cycloalkyl, -CO-NH-(Ci-C4 alkylene)-cycloalkyl, -CO-N(C C4 alkyl)-(Ci-C4 alkylene)-cycloalkyl, -CO-NH-heterocycloalkyl, -CO-N(Ci-C4 alkyl)-heterocycloalkyl, -CO-NH-(Ci-C4 alkylene)-heterocycloalkyl, -CO-N(Ci-C4 alkyl)-(Ci-C4 alkylene)-heterocycloalkyl, -CO-NH-aryl, -CO-N(Ci-C4 alkyl)-aryl, -CO- NH-(Ci-C4 alkylene)-aryl, -CO-N(Ci-C4 alkyl)-(C C4 alkylene)-aryl, -CO- NH-heteroaryl, -CO-N(Ci-C4 alkyl)-heteroaryl, -CO-NH-(C C4 alkylene)- heteroaryl, -CO-N(C C4 alkyl)-(Ci-C4 alkylene)-heteroaryl, -NH-CHO, -N(C C4 alkyl)- CHO, -NH-CO(Ci-C4 alkyl), -N(C C4 alkyl)-CO(C C4 alkyl), -NH-CO-cycloalkyl, -N(C C4 alkyl)-CO-cycloalkyl, -NH-CO-(C C4 alkylene)-cycloalkyl, -N(C C4 alkyl)-CO-(Ci-C4 alkylene)-cycloalkyl, -NH-CO-heterocycloalkyl, -N(Ci-C4 alkyl)-
CO-heterocycloalkyl, -NH-CO-(C C4 alkylene)-heterocycloalkyl, -N(C C4 alkyl)- CO-(Ci-C4 alkylene)-heterocycloalkyl, -NH-CO-aryl, -N(C C4 alkyl)- CO-aryl, -NH-CO-(C C4 alkylene)-aryl, -N(C C4 alkyl)-CO-(C C4 alkylene)- aryl, -NH-CO-heteroaryl, -N(C C4 alkyl)-CO-heteroaryl, -NH-CO-(C C4 alkylene)- heteroaryl, or -N(Ci-C4 alkyl)-CO-(CrC4 alkylene)-heteroaryl, wherein said aryl, said heteroaryl, the aryl moiety comprised in any of the aforementioned groups, and the heteroaryl moiety comprised in any of the aforementioned groups are each optionally substituted with one or more groups independently selected from Ci-C4 alkyl, halogen, -CF3, -CN, -OH, -0(d-C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(C C4 alkyl)(C C4 alkyl).
The compound for use according to any one of claims 1 or 5 to 7 or the compound of any one of claims 2 to 7, wherein R1, R2 and R4 are each independently selected from hydrogen, halogen, Ci-C4 haloalkyl, C C4 haloalkoxy, C C4 alkyl, -OH, -0(Ci-C4 alkyl), -NH(C C4 alkyl), or -N(C C4 alkyl)(C C4 alkyl).
The compound for use according to any one of claims 1 or 5 to 8 or the compound of any one of claims 2 to 8, wherein R5 is heteroaryl having 5 or 6 ring members and comprising one or more ring heteroatoms independently selected from O, S or N, wherein said heteroaryl having 5 or 6 ring members is optionally substituted with one or more groups independently selected from C C4 alkyl, C2-C4 alkenyl, halogen, Ci-C4 haloalkyl, Ci-C4 haloalkoxy, -CN, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, - OH, -0(Ci-C4 alkyl), -O-cycloalkyl, -0-(C C4 alkylene)-cycloalkyl, -O-heterocycloalkyl, -0-(Ci-C4 alkylene)-heterocycloalkyl, -NH2, -NH(C C4 alkyl), -N(C C4 alkyl)(C C4 alkyl), -NH-cycloalkyl, -N(C C4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(C C4 alkyl)-heterocycloalkyl, -NH-(C C4 alkylene)-cycloalkyl, -N(C C4 alkyl)-(C C4 alkylene)-cycloalkyl, -NH-(Ci-C4 alkylene)-heterocycloalkyl, -N(Ci-C4 alkyl)-(Ci-C4 alkylene)-heterocycloalkyl, -CO-(Ci-C4 alkyl), -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-(Ci-C4 alkylene)-cycloalkyl, or -CO-(Ci-C4 alkylene)-heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, the cycloalkyl moiety comprised in any of the aforementioned groups, and the heterocycloalkyl moiety comprised in any of the aforementioned groups are each optionally substituted with one or more groups independently selected from C C4 alkyl, halogen, -CF3, -CN, -OH, -0(Ci-C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(C C4 alkyl)(C C4 alkyl).
0. The compound for use according to any one of claims 1 or 5 to 9 or the compound of any one of claims 2 to 9, wherein R5 is pyridinyl which is optionally substituted with one or more groups independently selected from C C4 alkyl, C2-C4 alkenyl, halogen, Ci-C4 haloalkyl, C C4 haloalkoxy, -CN, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -0(C C4 alkyl), -O-cycloalkyl, -0-(C C4 alkylene)-cycloalkyl, -O-heterocycloalkyl, -0-(Ci-C4 alkylene)-heterocycloalkyl, -NH2, -NH(C C4 alkyl), -N(C C4 alkyl)(C C4 alkyl), -NH-cycloalkyl, -N(C C4 alkyl)-cycloalkyl, -NH-heterocycloalkyl, -N(C C4 alkyl)-heterocycloalkyl, -NH-(C C4 alkylene)-cycloalkyl, -N(C C4 alkyl)-(C C4 alkylene)-cycloalkyl, -NH-(Ci-C4 alkylene)-heterocycloalkyl, -N(Ci-C4 alkyl)-(Ci-C4 alkylene)-heterocycloalkyl, -CO-(Ci-C4 alkyl), -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-(Ci-C4 alkylene)-cycloalkyl, or -CO-(Ci-C4 alkylene)-heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, the cycloalkyl moiety comprised in any of the aforementioned groups, and the heterocycloalkyl moiety comprised in any of the aforementioned groups are each optionally substituted with one or more groups independently selected from d-C4 alkyl, halogen, -CF3, -CN, -OH, -0(Ci-C4 alkyl), -NH2, -NH(C C4 alkyl) or -N(C C4 alkyl)(C C4 alkyl).
1 . The compound for use according to any one of claims 1 or 5 to 10 or the compound of any one of claims 2 to 10, wherein R5 is pyridin-4-yl which is substituted with one substituent group at position 2 of said pyridin-4-yl or with two substituent groups at position 2 and 6 of said pyridin-4-yl, wherein said one or two substituent group(s) is/are selected independently from C C4 alkyl, C2-C4 alkenyl, halogen, C C4 haloalkyl, Ci-C4 haloalkoxy, -CN, cycloalkyl, heterocycloalkyl, -0(Ci-C4 alkyl), -O-cycloalkyl, or -O-heterocycloalkyl. The compound for use according to any one of claims 1 or 5 to 1 1 or the compound of any one of claims 2 to 1 1 , wherein R5 is pyridin-4-yl which is substituted with one substituent group at position 2 of said pyridin-4-yl, wherein said substituent group is selected from C1-C4 alkyl, C2-C4 alkenyl, halogen, C C4 haloalkyl, Ci-C4 haloalkoxy, -CN, cycloalkyl, heterocycloalkyl, -0(Ci-C4 alkyl), -O-cycloalkyl, or -O-heterocycloalkyl.
The compound for use according to any one of claims 1 or 5 to 12 or the compound of any one of claims 2 to 12, wherein R5 is 2-trifluoromethyl-pyridin-4-yl.
The compound for use according to any one of claims 1 or 5 to 13 or the compound of any one of claims 2 to 13, wherein R6 is C C4 alkyl which is optionally substituted with one or more groups independently selected from cycloalkyl, halogen, -CF3, -CN, -OH or -0(Ci-C4 alkyl).
The compound for use according to any one of claims 1 or 5 to 14 or the compound of any one of claims 2 to 14, wherein R6 is methyl.
The compound for use according to any one of claims 1 or 5 to 15 or the compound of any one of claims 2 to 15, wherein A is N.
The compound for use according to claim 1 or the compound of claim 2, wherein said compound is selected from:
2-(2-chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl 2-(2-methyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-ethyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-propyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-cyclopropyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-cyclobutyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-cyclopentyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-cyclohexyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl-2-(2-vinyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-isopropenyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-isopropyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-(4-methyl-5-oxo-4,5-dihydro-pyrazolo[1 ,5-a]quinazolin-2-yl)-pyridine-2-carbonitrile;
2-(2-fluoro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 2-(2-methoxy-pyridin-4-yl)-4-methyl- 4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-ethoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-isopropoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-cyclobutoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl-2-[2-(oxetan-3-yloxy)-pyridin-4-yl]-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-cyclopropylmethoxy-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 2-[2-(2-methoxy-ethoxy)-pyridin-4-yl]-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 4-methyl-2-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 4-methyl-2-[2-(2,2-difluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 2-[2-(2,2-difluoro-propoxy)-pyridin-4-yl]-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl-2-[2-(2,2,3,3,3-pentafluoro-propoxy)-pyridin-4-yl]-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
4-methyl-2-[2-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl(D3)-2-(2-tnfluoromethyl-pyridin-4-yl)-4l-l-pyrazolo[1 ,5-a]quinazoliri-5-one; 4-ethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-(2,2-difluoro-ethyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
4-(2-methoxy-ethyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
4-methyl-2-(2-difluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-[2-(1 , 1-difluoro-ethyl)-pyridin-4-yl]-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-[2-(1 , 1-difluoro-ethyl)-pyridin-4-yl]-4-methyl(D3)-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 7-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-chloro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-methoxy-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-trifluoromethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-on
7-fluoro-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-bromo-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4- methyl-7-methylamino-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazoli
5- one;
4-methyl-7-methyl(D3)amino-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
N-[4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5- a]quinazolin-7-yl]-acetamide;
7-amino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 7-dimethylamino-4-methyl-2-(2- trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
7-ethylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
7-cyclobutylamino-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
4-methyl-7-morpholin-4-yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
7-hydroxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
7-ethoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-(2-methoxy-ethoxy)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
4-methyl-7-(2-morpholin-4-yl-ethoxy)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
4-methyl-7-trifluoromethoxy-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
7- methanesulfonyl-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
8- methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
8-fluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 8-chloro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 4-methyl-8-trifluoromethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
8-bromo-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl-8-morpholin-4-yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
4- methyl-8-pyrrolidin-1-yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-
5- one;
4- methyl-8-methylamino-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazoli
5- one;
8-(4-methoxy-piperidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
8-(4-hydroxy-piperidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one; 8-dimethylamino-4-methyl-2-(2- trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5 a]quinazolin-5-one;
4-methyl-8-(4-methyl-piperazin-1 -yl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
4- methyl-8-piperazin-1-yl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-
5- one;
8-(4-hydroxymethyl-piperidin-1 -yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H- pyrazolo[1 ,5-a]quinazoin-5-one;
8-(3-hydroxy-azetidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
8-(3-hydroxymethyl-azetidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H- pyrazolo[1 ,5-a]quinazolin-5-one;
8-(3-hydroxy-pyrrolidin-1-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
8-(4-hydroxy-4-methyl-piperidin-1 -yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H- pyrazolo[1 ,5-a]quinazolin-5-one;
4,8-dimethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
8-cyclopropyl-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
8-cyclopentyl-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5-a]quinazoline- 8-carbonitrile;
4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5-a]quinazoline- 8-carboxylic acid;
4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5-a]quinazoline- 8-carboxylic acid amide;
4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5-a]quinazoline- 8-carboxylic acid methylamide;
4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5-a]quinazoline- 8-carboxylic acid dimethylamide;
4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5-a]quinazoline- 8-carboxylic acid diethylamide;
4-methyl-8-(morpholine-4-carbonyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
4-methyl-8-(pyrrolidine-1-carbonyl)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one; 8- (2-hydroxy-ethoxy)-4-methyl-2-(2- trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
4- methyl-6-trifluoromethyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
6- fluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
9- methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
7,8-dimethoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-
5- one;
7,8-difluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5- one;
8-fluoro-7-methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
8-(4-hydroxy-piperidin-1-yl)-7-methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H- pyrazolo[1 ,5-a]quinazolin-5-one;
8-dimethylamino-7-fluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
7- bromo-8-fluoro-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
7- bromo-8-methoxy-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
8- methoxy-4-methyl-7-methylamino-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
7-chloro-2-(2-chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-chloro-2-(2-chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-chloro-2-(2-Fluoro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-chloro-4-methyl-2-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
2-(2-chloro-pyridin-4-yl)-7-methoxy-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-cyclopropyl-pyridin-4-yl)-7-methoxy-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-fluoro-pyridin-4-yl)-7-methoxy-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7-methoxy-4-methyl-2-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4-yl]-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
4-methyl-2-(1-methyl-1 H-pyrazol-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl-2-pyridin-4-yl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-chloro-6-methyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2-(2-cyclopropyl-6-methyl-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 2-(3-fluoro-pyridin-4-yl)-4-methyl-4H- pyrazolo[1 ,5-a]quinazolin-5-one;
2-(3-chloro-pyridin-4-yl)-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
4-methyl-2-(3-methyl-pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
8-(3-Hydroxy-azetidine-1-carbonyl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H- pyrazolo[1 ,5-a]quinazolin-5-one;
8-(3-Hydroxy-propoxy)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
2-(2-Cyclopropyl-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 2-(2-Cyclopropyl-pyridin-4-yl)-8-(4-hydroxy-piperidin-1 -yl)-4-methyl-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
2-(2-Difluoromethyl-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 2-(2-Difluoromethyl-pyridin-4-yl)-8-(4-hydroxy-piperidin-1-yl)-4-methyl-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
2-(2-Cyclobutyl-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one; 2-(2-Chloro-pyridin-4-yl)-8-fluoro-4-methyl-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
2- (2-Chloro-pyridin-4-yl)-8-(4-hydroxy-piperidin-1-yl)-4-methyl-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
7-Fluoro-8-(3-hydroxy-azetidin-1 -yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H- pyrazolo[1 ,5-a]quinazolin-5-one;
7-Fluoro-4-methyl-8-(oxetan-3-yloxy)-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1 ,5- a]quinazolin-5-one;
3- [7-Fluoro-4-methyl-5-oxo-2-(2-trifluoromethyl-pyridin-4-yl)-4,5-dihydro-pyrazolo[1 ,5- a]quinazolin-8-ylamino]-propionitrile;
7-Fluoro-8-(2-hydroxymethyl-pyrrolidin-1 -yl)-4-methyl-2-(2-trifluoromethyl-pyridin 4H-pyrazolo[1 ,5-a]quinazolin-5-one;
7- Fluoro-8-(7-hydroxymethyl-1 -aza-spiro[3.5]non-1 -yl)-4-methyl-2-(2-trifluoromethyl- pyridin-4-yl)-4H-pyrazolo[1 ,5-a]quinazolin-5-one;
8- (3-Hydroxy-piperidin-1 -yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo a]quinazolin-5-one;
8-(2,6-Dimethyl-morpholin-4-yl)-4-methyl-2-(2-trifluoromethyl-pyridin-4-y ^
pyrazolo[1 ,5-a]quinazolin-5-one;
8-(2-Hydroxy-2-methyl-propylamino)-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4 pyrazolo[1 ,5-a]quinazolin-5-one; and
pharmaceutically acceptable salts, solvates and prodrugs thereoof.
18. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 17 or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable excipient.
A compound as defined in any one of claims 1 to 17 or a pharmaceutically acceptable salt, solvate or prodrug thereof or the pharmaceutical composition of claim 18 for use in the treatment and/or prophylaxis of a condition associated with altered glutamatergic signalling and/or functions, and/or a condition which can be affected by alteration of glutamate level or signalling.
Use of a compound as defined in any one of claims 1 to 17 or a pharmaceutically acceptable salt, solvate or prodrug thereof for the preparation of a medicament for the treatment and/or prophylaxis of a condition associated with altered glutamatergic signalling and/or functions, and/or a condition which can be affected by alteration of glutamate level or signalling.
A method of treating and/or preventing a condition associated with altered glutamatergic signalling and/or functions, and/or a condition which can be affected by alteration of glutamate level or signalling, the method comprising the administration of a compound as defined in any one of claims 1 to 17 or a pharmaceutically acceptable salt, solvate or prodrug thereof or the pharmaceutical composition of claim 18 to a subject in need of such treatment or prevention.
The compound for use according to claim 19 or the pharmaceutical composition for use according to claim 19 or the use of claim 20 or the method of claim 21 , wherein the condition to be treated or prevented is selected from: epilepsy; dementias; parkinsonism and movement disorders; motor neuron disease or amyotrophic lateral sclerosis; neurodegenerative and/or hereditary disorders of the nervous system; disorders of the peripheral nervous system; multiple sclerosis and other demyelinating diseases of the nervous system; infantile cerebral palsy; paralytic syndromes including hemiplegia and hemiparesis; cerebrovascular disorders; migraine; headache; myoneural disorders; disorders of the eye and visual pathways; intracranial trauma/injury and their sequels; trauma/injury to nerves and spinal cord and their sequels; poisoning and toxic effects of nonmedicinal substances; accidental poisoning by drugs, medicinal substances and biologicals acting on the central, peripheral and autonomic system; neurological and psychiatric adverse effects of drugs, medicinal and biological substances; disturbance of sphincter control and sexual function; mental disorders; delirium and cognitive disorders; substance related disorders; schizophrenia and psychotic disorders; mood disorders; anxiety disorders; eating disorders; sleep disorders and sleep/wake disorders; medication-induced movement disorders; endocrine and metabolic diseases; acute and chronic pain; nausea and vomiting; irritable bowel syndrome; cancers; or autism spectrum disorders.
The compound for use according to claim 19 or 22 or the pharmaceutical composition for use according to claim 19 or 22 or the use of claim 20 or 22 or the method of claim 21 or 22, wherein the condition to be treated or prevented is selected from dementias, parkinsonism and movement disorders, acute or chronic pain, anxiety disorders, schizophrenia, mood disorders, endocrine or metabolic diseases, or cancers.
The compound for use according to claim 23 or the pharmaceutical composition for use according to claim 23 or the use of claim 23 or the method of claim 23, wherein said dementias are selected from: dementias of the Alzheimer's type (DAT); Alzheimer's disease; Pick's disease; vascular dementias; Lewy-body disease; dementias due to metabolic, toxic and deficiency diseases, including alcoholism, hypothyroidism, and vitamin B12 deficiency; AIDS-dementia complex; Creutzfeld-Jacob disease; or atypical subacute spongiform encephalopathy.
The compound for use according to claim 23 or the pharmaceutical composition for use according to claim 23 or the use of claim 23 or the method of claim 23, wherein said parkinsonism and movement disorders are selected from: Parkinson's disease; multiple system atrophy; progressive supranuclear palsy; corticobasal degeneration; hepatolenticular degeneration; chorea, including Huntington's disease and hemiballismus; athetosis; dystonias, including spasmodic torticollis, occupational movement disorder, and Gilles de la Tourette syndrome; tardive or drug induced dyskinesias; tremor; or myoclonus.
26. The compound for use according to claim 23 or the pharmaceutical composition for use according to claim 23 or the use of claim 23 or the method of claim 23, wherein said anxiety disorders are selected from: panic disorders, phobias, obsessive-compulsive disorders, stress disorders, or generalized anxiety disorders.
27. The compound for use according to claim 23 or the pharmaceutical composition for use according to claim 23 or the use of claim 23 or the method of claim 23, wherein said mood disorders are selected from depressive disorders or bipolar disorders.
28. The compound for use according to claim 23 or the pharmaceutical composition for use according to claim 23 or the use of claim 23 or the method of claim 23, wherein said endocrine or metabolic diseases are selected from diabetes, disorders of the endocrine glands, or hypoglycaemia. 29. The compound for use according to claim 23 or the pharmaceutical composition for use according to claim 23 or the use of claim 23 or the method of claim 23, wherein said cancers are selected from gliomas, colorectal cancer, melanoma, or prostate cancer.
30. A compound as defined in any one of claims 1 to 17 or a pharmaceutically acceptable salt, solvate or prodrug thereof or the pharmaceutical composition of claim 18 for use in the treatment and/or prophylaxis of Alzheimer's disease.
31 . Use of a compound as defined in any one of claims 1 to 17 or a pharmaceutically acceptable salt, solvate or prodrug thereof for the preparation of a medicament for the treatment and/or prophylaxis of Alzheimer's disease.
32. A method of treating and/or preventing Alzheimer's disease, the method comprising the administration of a compound as defined in any one of claims 1 to 17 or a pharmaceutically acceptable salt, solvate or prodrug thereof or the pharmaceutical composition of claim 18 to a subject in need of such treatment or prevention.
33. The method of any one of claims 21 to 29 or 32, wherein said subject is a human.
34. A method for identifying an agent that binds to metabotropic glutamate receptor 2 (mGluR2), comprising the following steps:
(a) contacting mGluR2 with the compound of any one of claims 1 to 17, wherein said compound is radio-labeled or fluorescence-labeled, under conditions that permit binding of the compound to mGluR2, thereby generating bound, labeled compound;
(b) detecting a signal that corresponds to the amount of bound, labeled compound in the absence of test agent;
(c) contacting the bound, labeled compound with a test agent;
(d) detecting a signal that corresponds to the amount of bound labeled compound in the presence of test agent; and
(e) comparing the signal detected in step (d) to the signal detected in step (b) to determine whether the test agent binds to mGluR2.
PCT/EP2015/072178 2014-09-26 2015-09-25 Substituted pyrazoloquinazolinones and pyrroloquinazolinones as allosteric modulators of group iimetabotropic glutamate receptors WO2016046404A1 (en)

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